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Waite, J. H. ; Lichtenegger, H. C. ; Stucky, G. D. ; Hansma, P. Exploring molecular and mechanical gradients in structural bioscaffolds. Biochemistry 2004, 43 (24), 7653– 7662, DOI: 10.1021/bi049380h

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Exploring Molecular and Mechanical Gradients in Structural Bioscaffolds

Waite, J. Herbert; Lichtenegger, Helga C.; Stucky, Galen D.; Hansma, Paul

Biochemistry (2004), 43 (24), 7653-7662CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

Most organisms consist of a functionally adaptive assemblage of hard and soft tissues. Despite the obvious advantages of reinforcing soft protoplasm with a hard scaffold, such composites can lead to tremendous mech. stresses where the two meet. Although little is known about how nature relieves these stresses, it is generally agreed that fundamental insights about mol. adaptation at hard/soft interfaces could profoundly influence how the authors think about biomaterials. Based on two noncellular tissues, mussel byssus and polychaete jaws, recent studies suggest that one natural strategy to minimize interfacial stresses between adjoining stiff and soft tissue appears to be the creation of a "fuzzy" boundary, which avoids abrupt changes in mech. properties. Instead there is a gradual mech. change that accompanies the transcendence from stiff to soft and vice versa. In byssal threads, the biochem. medium for achieving such a gradual mech. change involves the elegant use of collagen-based self-assembling block copolymers. There are three distinct diblock copolymer types in which one block is always collagenous, whereas the other can be either elastin-like (soft), amorphous polyglycine (intermediate), or silk-like (stiff). Gradients of these are made by an incrementally titrated expression of the three proteins in secretory cells the titrn. phenotype of which is linked to their location. Thus, reflecting exactly the compn. of each thread, the distal cells secrete primarily the silk- and polyglycine-collagen diblocks, whereas the proximal cells secrete the elastin- and polyglycine-collagen diblocks. Those cells in between exhibit gradations of collagens with silk or elastin blocks. Spontaneous self-assembly appears to be by pH triggered metal binding by histidine (HIS)-rich sequences at both the amino and C-termini of the diblocks. In the polychaete jaws, HIS-rich sequences are expanded into a major block domain. Histidine predominates at over 20 mol % near the distal tip and diminishes to about 5 mol % near the proximal base. The abundance of histidine is directly correlated to transition metal content (Zn or Cu) as well as hardness detd. by nanoindentation. EXAFS analyses of the jaws indicate that transition metals such as Zn are directly bound to histidine ligands and may serve as crosslinkers.

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Mirzaali, M. J. ; Herranz de la Nava, A. ; Gunashekar, D. ; Nouri-Goushki, M. ; Doubrovski, E. ; Zadpoor, A. A. Fracture behavior of bio-inspired functionally graded soft–hard composites made by multi-material 3D printing: the case of colinear cracks. Materials 2019, 12 (17), 2735, DOI: 10.3390/ma12172735

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Fracture behavior of bio-inspired functionally graded soft-hard composites made by multi-material 3D printing: the case of colinear cracks

Mirzaali, Mohammad J.; Herranz de la Nava, Alba; Gunashekar, Deepthi; Nouri-Goushki, Mahdyieh; Doubrovski, Eugeni. L.; Zadpoor, Amir A.

Materials (2019), 12 (17), 2735CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)

The functional gradient is a concept often occurring in nature. This concept can be implemented in the design and fabrication of advanced materials with specific functionalities and properties. Functionally graded materials (FGMs) can effectively eliminate the interface problems in extremely hard-soft connections, and, thus, have numerous and diverse applications in high-tech industries, such as those in biomedical and aerospace fields. Here, using voxel-based multi-material additive manufg. (AM, = 3D printing) techniques, which works on the basis of material jetting, we studied the fracture behavior of functionally graded soft-hard composites with a pre-existing crack colinear with the gradient direction. We designed, additively manufd., and mech. tested the two main types of functionally graded composites, namely, composites with step-wise and continuous gradients. In addn., we changed the length of the transition zone between the hard and soft materials such that it covered 5%, 25%, 50%, or 100% of the width (W) of the specimens. The results showed that except for the fracture strain, the fracture properties of the graded specimens decreased as the length of the transition zone increased. Addnl., it was found that specimens with abrupt hard-soft transitions have significantly better fracture properties than those with continuous gradients. Among the composites with gradients, those with step-wise gradients showed a slightly better fracture resistance compared to those with continuous gradients. In contrast, FGMs with continuous gradients showed higher values of elastic stiffness and fracture energy, which makes each gradient function suitable for different loading scenarios. Moreover, regardless of the gradient function used in the design of the specimens, decreasing the length of the transition zone from 100%W to 5%W increased the fracture resistance of FGMs. We discuss the important underlying fracture mechanisms using data collected from digital image correlation (DIC), digital image microscopy, and SEM (SEM), which were used to analyze the fracture surface.

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Rao, R. T. ; Browe, D. P. ; Lowe, C. J. ; Freeman, J. W. An overview of recent patents on musculoskeletal interface tissue engineering. Connect. Tissue Res. 2016, 57 (1), 53– 67, DOI: 10.3109/03008207.2015.1089866

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An overview of recent patents on musculoskeletal interface tissue engineering

Rao, Rohit T.; Browe, Daniel P.; Lowe, Christopher J.; Freeman, Joseph W.

Connective Tissue Research (2016), 57 (1), 53-67CODEN: CVTRBC; ISSN:0300-8207. (Taylor & Francis Ltd.)

Interface tissue engineering involves the development of engineered grafts that promote integration between multiple tissue types. Musculoskeletal tissue interfaces are crit. to the safe and efficient transmission of mech. forces between multiple musculoskeletal tissues, e.g., between ligament and bone tissue. However, these interfaces often do not physiol. regenerate upon injury, resulting in impaired tissue function. Therefore, interface tissue engineering approaches are considered to be particularly relevant for the structural restoration of musculoskeletal tissues interfaces. In this article, we provide an overview of the various strategies used for engineering musculoskeletal tissue interfaces with a specific focus on the recent important patents that have been issued for inventions that were specifically designed for engineering musculoskeletal interfaces as well as those that show promise to be adapted for this purpose.

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Armitage, O. E. ; Oyen, M. L. Indentation across interfaces between stiff and compliant tissues. Acta Biomater. 2017, 56 , 36– 43, DOI: 10.1016/j.actbio.2016.12.036

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Indentation across interfaces between stiff and compliant tissues

Armitage, Oliver E.; Oyen, Michelle L.

Acta Biomaterialia (2017), 56 (), 36-43CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Bone-tendon, bone-ligament and bone-cartilage junctions are multi-tissue interfaces that connect materials that differ by two orders of magnitude in mech. properties, via gradual variations in mineral content and matrix compn. These sites mediate load transfer between highly dissimilar materials and are consequently a primary site of injury during orthopedic failure. Given the large incidence rate and the lack of suitable surgical solns. for their regeneration or repair, characterization of their natural structure and subsequent replication through tissue engineering is important. Here, we evaluate the ability and accuracy of instrumented indentation to characterize the mech. properties of both biol. tissues and engineered scaffolds with interfaces between materials that contain significant changes in mech. properties. In this study, finite element simulations and ref. samples are developed that characterize how accurately indentation measures the modulus of a material as it varies with distance across a continuous interface between dissimilar tissues with multiple orders of magnitude difference in properties. Finite element simulations accurately predicted discrepancies between the modulus function across an interface obsd. by indentation and the true modulus function of the material and hence allow us to understand the limits of instrumented indentation as a technique for quantifying gradual changes in material properties. It was found that in order to accurately investigate mech. property variations in tissues with significant modulus heterogeneity the indenter size should be less than 10 percent of the expected length scale of the modulus variations. The interfaces between stiff and compliant orthopedic tissues such as bone-tendon, bone-ligament and bone-cartilage are frequent sites of failure during both acute and chronic orthopedic injury and as such their replication via tissue engineering is of importance. The characterization and understanding of these tissue interfaces on a mech. basis is a key component of elucidating the structure-function relationships that allow them to function naturally and hence a core component of efforts to replicate them. This work uses finite element models and expts. to outline the ability of instrumented indentation to characterize the elastic modulus variations across tissue interfaces and provides guidelines for investigators seeking to use this method to understand any interface between dissimilar tissues.

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Rossetti, L. ; Kuntz, L. ; Kunold, E. ; Schock, J. ; Müller, K. ; Grabmayr, H. ; Stolberg-Stolberg, J. ; Pfeiffer, F. ; Sieber, S. ; Burgkart, R. The microstructure and micromechanics of the tendon–bone insertion. Nat. Mater. 2017, 16 (6), 664, DOI: 10.1038/nmat4863

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The microstructure and micromechanics of the tendon-bone insertion

Rossetti, L.; Kuntz, L. A.; Kunold, E.; Schock, J.; Mueller, K. W.; Grabmayr, H.; Stolberg-Stolberg, J.; Pfeiffer, F.; Sieber, S. A.; Burgkart, R.; Bausch, A. R.

Nature Materials (2017), 16 (6), 664-670CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

The exceptional mech. properties of the load-bearing connection of tendon to bone rely on an intricate interplay of its biomol. compn., microstructure and micromechanics. Here we identify that the Achilles tendon-bone insertion is characterized by an interface region of ∼500 μm with a distinct fiber organization and biomol. compn. Within this region, we identify a heterogeneous mech. response by micromech. testing coupled with multiscale confocal microscopy. This leads to localized strains that can be larger than the remotely applied strain. The subset of fibers that sustain the majority of loading in the interface area changes with the angle of force application. Proteomic anal. detects enrichment of 22 proteins in the interfacial region that are predominantly involved in cartilage and skeletal development as well as proteoglycan metab. The presented mechanisms mark a guideline for further biomimetic strategies to rationally design hard-soft interfaces.

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Armitage, O. E.; Oyen, M. L. Hard-soft tissue interface engineering. In Engineering Mineralized and Load Bearing Tissues; Springer: 2015; pp 187– 204.

Seidi, A. ; Ramalingam, M. ; Elloumi-Hannachi, I. ; Ostrovidov, S. ; Khademhosseini, A. Gradient biomaterials for soft-to-hard interface tissue engineering. Acta Biomater. 2011, 7 (4), 1441– 1451, DOI: 10.1016/j.actbio.2011.01.011

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Gradient biomaterials for soft-to-hard interface tissue engineering

Seidi, Azadeh; Ramalingam, Murugan; Elloumi-Hannachi, Imen; Ostrovidov, Serge; Khademhosseini, Ali

Acta Biomaterialia (2011), 7 (4), 1441-1451CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

A review. Interface tissue engineering (ITE) is a rapidly developing field that aims to fabricate biol. tissue alternates with the goal of repairing or regenerating the functions of diseased or damaged zones at the interface of different tissue types (also called "interface tissues"). Notable examples of the interface tissues in the human body include ligament-to-bone, tendon-to-bone and cartilage-to-bone. Engineering interface tissues is a complex process, which requires a combination of specialized biomaterials with spatially organized material compn., cell types and signaling mols. Therefore, the use of conventional biomaterials (monophasic or composites) for ITE has certain limitations to help stimulate the tissue integration or recreating the structural organization at the junction of different tissue types. The advancement of micro- and nanotechnologies enable us to develop systems with gradients in biomaterials properties that encourage the differentiation of multiple cell phenotypes and subsequent tissue development. In this review we discuss recent developments in the fabrication of gradient biomaterials for controlling cellular behavior such as migration, differentiation and heterotypic interactions. Moreover, we give an overview of potential uses of gradient biomaterials in engineering interface tissues such as soft tissues (e.g. cartilage) to hard tissues (e.g. bone), with illustrated exptl. examples. We also address fundamentals of interface tissue organization, various gradient biomaterials used in ITE, micro- and nanotechnologies employed for the fabrication of those gradients, and certain challenges that must be met in order for ITE to reach its full potential.

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Boys, A. J. ; McCorry, M. C. ; Rodeo, S. ; Bonassar, L. J. ; Estroff, L. A. Next generation tissue engineering of orthopedic soft tissue-to-bone interfaces. MRS Commun. 2017, 7 (3), 289– 308, DOI: 10.1557/mrc.2017.91

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Next generation tissue engineering of orthopedic soft tissue-to-bone interfaces

Boys, Alexander J.; McCorry, Mary Clare; Rodeo, Scott; Bonassar, Lawrence J.; Estroff, Lara A.

MRS Communications (2017), 7 (3), 289-308CODEN: MCROF8; ISSN:2159-6867. (Cambridge University Press)

Soft tissue-to-bone interfaces are complex structures that consist of gradients of extracellular matrix materials, cell phenotypes, and biochem. signals. These interfaces, called entheses for ligaments, tendons, and the meniscus, are crucial to joint function, transferring mech. loads and stabilizing orthopedic joints. When injuries occur to connected soft tissue, the enthesis must be re-established to restore function, but due to structural complexity, repair has proven challenging. Tissue engineering offers a promising soln. for regenerating these tissues. This prospective review discusses methodologies for tissue engineering the enthesis, outlined in three key design inputs: materials processing methods, cellular contributions, and biochem. factors.

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Galatz, L. M. ; Sandell, L. J. ; Rothermich, S. Y. ; Das, R. ; Mastny, A. ; Havlioglu, N. ; Silva, M. J. ; Thomopoulos, S. Characteristics of the rat supraspinatus tendon during tendon-to-bone healing after acute injury. J. Orthop. Res. 2006, 24 (3), 541– 550, DOI: 10.1002/jor.20067

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Characteristics of the rat supraspinatus tendon during tendon-to-bone healing after acute injury

Galatz, Leesa M.; Sandell, Linda J.; Rothermich, Stefan Y.; Das, Rosalina; Mastny, Ava; Havlioglu, Necat; Silva, Matthew J.; Thomopoulos, Stavros

Journal of Orthopaedic Research (2006), 24 (3), 541-550CODEN: JOREDR; ISSN:0736-0266. (John Wiley & Sons, Inc.)

Rotator cuff repair is known to have a high failure rate. Little is known about the natural healing process of the rotator cuff repair site, hence little can be done to improve the tendon's ability to heal. The purpose of this study was to investigate the collagen formation at the early repair site and to localize TGFβ-1 and 3 during early healing and compare their levels to cell proliferation and histol. changes. Bilateral supraspinatus tendons were transected and repaired in 60 rats. Specimens were harvested and evaluated at 0, 1, 3, 7, 10, 28, and 56 days. Histol. sections were evaluated for cell morphol. Immunohistochem. and in situ hybridization was performed to localize protein and mRNA for collagen types I and III and TGFβ-1 and 3. Proliferating cell nuclear antigen (PCNA) assay was performed to measure cell proliferation, and cells were counted to det. cell d. Biomech. properties were evaluated. Repair tissue demonstrated an initial inflammatory response with multinucleated cells present at 1 and 3 days, and lymphocytes and plasma cells presents at 7 and 10 days. Capillary proliferation began at 3 days and peaked at 10 days. Ultimate force increased significantly over the time period studied. Collagen I protein and mRNA significantly increased at 10 days, and reached a plateau by 28 and 56 days. Collagen III showed a similar trend, with an early increase, and remained high until 56 days. TGFβ-1 was localized to the forming scar tissue and showed a distinct peak at 10 days. TGFβ-3 was not seen at the healing insertion site. Cell proliferation and d. followed the same trend as TGFβ-1. A wound healing response does occur at the healing rotator cuff insertion site, however, the characteristics of the tendon after healing differ significantly from the uninjured tendon insertion site at the longest time-point studied. A distinctive collagen remodeling process occurred with an initial increase in the formation of collagen types I and III followed by a decrease toward baseline levels seen at time 0. Growth factor TGFβ-1 was localized to repair tissue and coincided with a peak in cell proliferation and cellularity. Repair sites remained unorganized histol. and biomechanically inferior in comparison to previously described uninjured insertion sites.

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Galatz, L. M. ; Ball, C. M. ; Teefey, S. A. ; Middleton, W. D. ; Yamaguchi, K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. JBJS 2004, 86 (2), 219– 224, DOI: 10.2106/00004623-200402000-00002

Chen, J. ; Xu, J. ; Wang, A. ; Zheng, M. Scaffolds for tendon and ligament repair: review of the efficacy of commercial products. Expert Rev. Med. Devices 2009, 6 (1), 61– 73, DOI: 10.1586/17434440.6.1.61

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Scaffolds for tendon and ligament repair: review of the efficacy of commercial products

Chen Jimin; Xu Jiake; Wang Allan; Zheng Minghao

Expert review of medical devices (2009), 6 (1), 61-73 ISSN:.

Driven by market demand, many biological and synthetic scaffolds have been developed during the last 15 years. Both positive and negative results have been reported in clinical applications for tendon and ligament repair. To obtain data for this review, multiple electronic databases were used (e.g., Pubmed and ScienceDirect), as well as the US FDA website and the reference lists from clinical trials, review articles and company reports, in order to identify studies relating to the use of these commercial scaffolds for tendon and ligament repair. The commercial names of each scaffold and the keywords 'tendon' and 'ligament' were used as the search terms. Initially, 378 articles were identified. Of these, 47 were clinical studies and the others were reviews, editorials, commentaries, animal studies or related to applications other than tendons and ligaments. The outcomes were reviewed in 47 reports (six on Restore, eight on Graftjacket, four on Zimmer, one on TissueMend, five on Gore-Tex, six on Lars, 18 on Leeds-Keio and one study used both Restore and Graftjacket). The advantages, disadvantages and future perspectives regarding the use of commercial scaffolds for tendon and ligament treatment are discussed. Both biological and synthetic scaffolds can cause adverse events such as noninfectious effusion and synovitis, which result in the failure of surgery. Future improvements should focus on both mechanical properties and biocompatibility. Nanoscaffold manufactured using electrospinning technology may provide great improvement in future practice.

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Bicho, D.; Pina, S.; Reis, R. L.; Oliveira, J. M. Commercial Products for Osteochondral Tissue Repair and Regeneration. In Osteochondral Tissue Engineering; Springer: 2018; pp 415– 428.

Li, X. ; Xie, J. ; Lipner, J. ; Yuan, X. ; Thomopoulos, S. ; Xia, Y. Nanofiber scaffolds with gradations in mineral content for mimicking the tendon-to-bone insertion site. Nano Lett. 2009, 9 (7), 2763– 2768, DOI: 10.1021/nl901582f

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Li, Xiaoran; Xie, Jingwei; Lipner, Justin; Yuan, Xiaoyan; Thomopoulos, Stavros; Xia, Younan

Nano Letters (2009), 9 (7), 2763-2768CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

We have demonstrated a simple and versatile method for generating a continuously graded, bonelike calcium phosphate coating on a nonwoven mat of electrospun nanofibers. A linear gradient in calcium phosphate content could be achieved across the surface of the nanofiber mat. The gradient had functional consequences with regard to stiffness and biol. activity. Specifically, the gradient in mineral content resulted in a gradient in the stiffness of the scaffold and further influenced the activity of mouse preosteoblast MC3T3 cells. This new class of nanofiber-based scaffolds can potentially be employed for repairing the tendon-to-bone insertion site via a tissue engineering approach.

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Levingstone, T. J. ; Thompson, E. ; Matsiko, A. ; Schepens, A. ; Gleeson, J. P. ; O'Brien, F. J. Multi-layered collagen-based scaffolds for osteochondral defect repair in rabbits. Acta Biomater. 2016, 32 , 149– 160, DOI: 10.1016/j.actbio.2015.12.034

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Levingstone, Tanya J.; Thompson, Emmet; Matsiko, Amos; Schepens, Alexander; Gleeson, John P.; O'Brien, Fergal J.

Acta Biomaterialia (2016), 32 (), 149-160CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Identification of a suitable treatment for osteochondral repair presents a major challenge due to existing limitations and an urgent clin. need remains for an off-the-shelf, low cost, one-step approach. A biomimetic approach, where the biomaterial itself encourages cellular infiltration from the underlying bone marrow and provides phys. and chem. cues to direct these cells to regenerate the damaged tissue, provides a potential soln. To meet this need, a multi-layer collagen-based osteochondral defect repair scaffold has been developed in our group. The objective of this study was to assess the in vivo response to this scaffold and det. its ability to direct regenerative responses in each layer in order to repair osteochondral tissue in a crit.-sized defect in a rabbit knee. Multi-layer scaffolds, consisting of a bone layer composed of type I collagen (bovine source) and hydroxyapatite (HA), an intermediate layer composed of type I and type II collagen and HA; and a superficial layer composed of type I and type II collagen (porcine source) and hyaluronic acid (HyA), were implanted into crit. size (3 × 5 mm) osteochondral defects created in the medial femoral condyle of the knee joint of New Zealand white rabbits and compared to an empty control group. Repair was assessed macroscopically, histol. and using micro-CT anal. at 12 wk post implantation. Anal. of repair tissue demonstrated an enhanced macroscopic appearance in the multi-layer scaffold group compared to the empty group. In addn., diffuse host cellular infiltration in the scaffold group resulted in tissue regeneration with a zonal organization, with repair of the subchondral bone, formation of an overlying cartilaginous layer and evidence of an intermediate tidemark. These results demonstrate the potential of this biomimetic multi-layered scaffold to support and guide the host reparative response in the treatment of osteochondral defects. Osteochondral defects, involving cartilage and the underlying subchondral bone, frequently occur in young active patients due to disease or injury. While some treatment options are available, success is limited and patients often eventually require joint replacement. To address this clin. need, a multi-layer collagen-based osteochondral defect repair scaffold designed to direct host-stem cell mediated tissue formation within each region, has been developed in our group. The present study investigates the in vivo response to this scaffold in a crit.-sized defect in a rabbit knee. Results shows the scaffolds ability to guide the host reparative response leading to tissue regeneration with a zonal organization, repair of the subchondral bone, formation of an overlying cartilaginous layer and evidence of an intermediate tidemark.

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Yan, L.-P. ; Silva-Correia, J. ; Oliveira, M. B. ; Vilela, C. ; Pereira, H. ; Sousa, R. A. ; Mano, J. F. ; Oliveira, A. L. ; Oliveira, J. M. ; Reis, R. L. Bilayered silk/silk-nanoCaP scaffolds for osteochondral tissue engineering: in vitro and in vivo assessment of biological performance. Acta Biomater. 2015, 12 , 227– 241, DOI: 10.1016/j.actbio.2014.10.021

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Bilayered silk/silk-nanoCaP scaffolds for osteochondral tissue engineering: In vitro and in vivo assessment of biological performance

Yan, Le-Ping; Silva-Correia, Joana; Oliveira, Mariana B.; Vilela, Carlos; Pereira, Helder; Sousa, Rui A.; Mano, Joao F.; Oliveira, Ana L.; Oliveira, Joaquim M.; Reis, Rui L.

Acta Biomaterialia (2015), 12 (), 227-241CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Novel porous bilayered scaffolds, fully integrating a silk fibroin (SF) layer and a silk-nano calcium phosphate (silk-nanoCaP) layer for osteochondral defect (OCD) regeneration, were developed. Homogeneous porosity distribution was achieved in the scaffolds, with calcium phosphate phase only retained in the silk-nanoCaP layer. The scaffold presented compressive moduli of 0.4 MPa in the wet state. Rabbit bone marrow mesenchymal stromal cells (RBMSCs) were cultured on the scaffolds, and good adhesion and proliferation were obsd. The silk-nanoCaP layer showed a higher alk. phosphatase level than the silk layer in osteogenic conditions. S.c. implantation in rabbits demonstrated weak inflammation. In a rabbit knee crit. size OCD model, the scaffolds firmly integrated into the host tissue. Histol. and immunohistochem. anal. showed that collagen II pos. cartilage and glycosaminoglycan regeneration presented in the silk layer, and de novo bone ingrowths and vessel formation were obsd. in the silk-nanoCaP layer. These bilayered scaffolds can therefore be promising candidates for OCD regeneration.

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Scaffaro, R. ; Lopresti, F. ; Maio, A. ; Sutera, F. ; Botta, L. Development of polymeric functionally graded scaffolds: A brief review. J. Appl. Biomater. Funct. Mater. 2017, 15 (2), 107– 121, DOI: 10.5301/jabfm.5000332

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Development of polymeric functonally graded scaffolds: a brief review

Scaffaro, Roberto; Loprest, Francesco; Maio, Andrea; Sutera, Fiorenza; Bota, Luigi

Journal of Applied Biomaterials & Functional Materials (2017), 15 (2), e107-e121CODEN: JABFBK; ISSN:2280-8000. (Wichtig Publishing)

A review. Over recent years, there has been a growing interest in multlayer scaffolds fabricaton approaches. In fact, func- tonally graded scaffolds (FGSs) provide biol. and mech. functons potentally similar to those of natve tssues. Based on the final applicaton of the scaffold, there are different propertes (phys., mech., bio- chem., etc.) which need to gradually change in space. Therefore, a no. of different technologies have been investgated, and ofen combined, to customize each region of the scaffolds as much as possible, aiming at achieving the best regeneratve performance. In general, FGSs can be categorized as bilayered or multlayered, depending on the no. of layers in the whole structure. In other cases, scaffolds are characterized by a contnuous gradient of 1 or more specific propertes that cannot be related to the presence of clearly distnguished layers. Since each traditonal approach presents peculiar advantages and disadvantages, FGSs are good candidates to overcome the limitatons of current treat- ment optons. In contrast to the reviews reported in the literature, which usually focus on the applicaton of FGS, this brief review provides an overview of the most common strategies adopted to prep. FGS.

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Xue, D. ; Zheng, Q. ; Zong, C. ; Li, Q. ; Li, H. ; Qian, S. ; Zhang, B. ; Yu, L. ; Pan, Z. Osteochondral repair using porous poly (lactide-co-glycolide)/nano-hydroxyapatite hybrid scaffolds with undifferentiated mesenchymal stem cells in a rat model. J. Biomed. Mater. Res., Part A 2010, 94 (1), 259– 270, DOI: 10.1002/jbm.a.32691

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Osteochondral repair using porous poly(lactide-co-glycolide)/nano-hydroxyapatite hybrid scaffolds with undifferentiated mesenchymal stem cells in a rat model

Xue, Deting; Zheng, Qiang; Zong, Chen; Li, Qun; Li, Hang; Qian, Shengjun; Zhang, Bo; Yu, Lina; Pan, Zhijun

Journal of Biomedical Materials Research, Part A (2010), 94A (1), 259-270CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)

In this study, a novel 3-dimensional poly(lactide-co-glycolide) (PLGA)/nano-hydroxyapatite (NHA) scaffold was fabricated by a thermally induced phase sepn. technique and its potential application in cartilage tissue-engineering was investigated. The PLGA scaffold was used as a control and mesenchymal stem cells (MSCs) were seeded in both scaffolds. After 12-days culture, SEM images and confocal laser scanning microscopy illustrated that MSCs attached more moderately and more cells distributed in PLGA/NHA scaffolds. MTT test and DNA assay showed that the viability and proliferation of MSCs in PLGA/NHA scaffolds were significantly superior to PLGA scaffolds during in vitro culture. Through in vivo study, the efficacy of this scaffold combining with MSCs for repairing articular osteochondral defects was evaluated in a rat model. Osteochondral defects in rats knees were left untreated, or treated with PLGA/NHA-MSCs composites or PLGA-MSCs composites. Twelve weeks after operation, histol. examn. revealed that the defects in the PLGA/NHA-MSCs treated group were filled with smooth and hyaline-like cartilage with abundant glycosaminoglycan and collagen type II deposition, but deficient in collagen type I at 12 wk after operation. To investigate the final fate of MSCs transplanted into the defect areas, the fluorescent dye CM-DiI was used to prelabel cells. At 12 wk after transplantation, the authors still obsd. the red fluorescence in the repair area. These findings suggest that the PLGA/NHA-MSCs composite may be potentially used for cartilage repair in clin. application. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.

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Reyes, R. ; Delgado, A. ; Sanchez, E. ; Fernandez, A. ; Hernandez, A. ; Evora, C. Repair of an osteochondral defect by sustained delivery of BMP-2 or TGFβ1 from a bilayered alginate–PLGA scaffold. J. Tissue Eng. Regener. Med. 2014, 8 (7), 521– 533, DOI: 10.1002/term.1549

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Repair of an osteochondral defect by sustained delivery of BMP-2 or TGFβ1 from a bilayered alginate-PLGA scaffold

Reyes, R.; Delgado, A.; Sanchez, E.; Fernandez, A.; Hernandez, A.; Evora, C.

Journal of Tissue Engineering and Regenerative Medicine (2014), 8 (7), 521-533CODEN: JTERAX; ISSN:1932-6254. (Wiley-Blackwell)

Regeneration of cartilage defects can be accelerated by localized delivery of appropriate growth factors (GFs) from scaffolds. In the present study we analyzed the in vitro and in vivo release rates and delivery efficacies of transforming growth factor-β1 (TGFβ1) and bone morphogenetic protein-2 (BMP-2) from a bilayered system, applied for osteochondral defect repair in a rabbit model. A bone-orientated, porous PLGA cylinder was overlaid with GF contg. PLGA microspheres, dispersed in an alginate matrix. Four microsphere formulations were incorporated: (a) blank ones; (b) microspheres contg. 50 ng TGFβ1; (c) microspheres contg. 2.5 μg BMP-2; and (d) microspheres contg. 5 μg BMP-2. Release kinetics and tissue distributions were detd. using iodinated (125I) GFs. Bioactivity of in vitro released BMP-2 and TGFβ1 was confirmed in cell-based assays. In vivo release profiles indicated good GF release control. 20% of BMP-2 and 15% of TGFβ1 were released during the first day. Virtually the total dose was delivered at the end of week 6. Significant histol. differences were obsd. between untreated and GF-treated specimens, there being esp. relevant short-term outcomes with 50 ng TGFβ1 and 5 μg BMP-2. Although the evaluation scores for the newly formed cartilage did not differ significantly, 5 μg BMP-2 gave rise to higher quality cartilage with improved surface regularity, tissue integration and increased collagen-type II and aggrecan immunoreactivity 2 wk post-implantation. Hence, the bilayered system controlled GF release rates and led to preserved cartilage integrity from 12 wk up to at least 24 wk. Copyright © 2012 John Wiley & Sons, Ltd.

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Jiang, J. ; Tang, A. ; Ateshian, G. A. ; Guo, X. E. ; Hung, C. T. ; Lu, H. H. Bioactive stratified polymer ceramic-hydrogel scaffold for integrative osteochondral repair. Ann. Biomed. Eng. 2010, 38 (6), 2183– 2196, DOI: 10.1007/s10439-010-0038-y

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Bioactive stratified polymer ceramic-hydrogel scaffold for integrative osteochondral repair

Jiang Jie; Tang Amy; Ateshian Gerard A; Guo X Edward; Hung Clark T; Lu Helen H

Annals of biomedical engineering (2010), 38 (6), 2183-96 ISSN:.

Due to the intrinsically poor repair potential of articular cartilage, injuries to this soft tissue do not heal and require clinical intervention. Tissue engineered osteochondral grafts offer a promising alternative for cartilage repair. The functionality and integration potential of these grafts can be further improved by the regeneration of a stable calcified cartilage interface. This study focuses on the design and optimization of a stratified osteochondral graft with biomimetic multi-tissue regions, including a pre-designed and pre-integrated interface region. Specifically, the scaffold based on agarose hydrogel and composite microspheres of polylactide-co-glycolide (PLGA) and 45S5 bioactive glass (BG) was fabricated and optimized for chondrocyte density and microsphere composition. It was observed that the stratified scaffold supported the region-specific co-culture of chondrocytes and osteoblasts which can lead to the production of three distinct yet continuous regions of cartilage, calcified cartilage and bone-like matrices. Moreover, higher cell density enhanced chondrogenesis and improved graft mechanical property over time. The PLGA-BG phase promoted chondrocyte mineralization potential and is required for the formation of a calcified interface and bone regions on the osteochondral graft. These results demonstrate the potential of the stratified scaffold for integrative cartilage repair and future studies will focus on scaffold optimization and in vivo evaluations.

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Calejo, I. ; Costa-Almeida, R. ; Reis, R. L. ; Gomes, M. E. A Physiology-Inspired Multifactorial Toolbox in Soft-to-Hard Musculoskeletal Interface Tissue Engineering. Trends Biotechnol. 2020, 38 , 83, DOI: 10.1016/j.tibtech.2019.06.003

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A Physiology-Inspired Multifactorial Toolbox in Soft-to-Hard Musculoskeletal Interface Tissue Engineering

Calejo, Isabel; Costa-Almeida, Raquel; Reis, Rui L.; Gomes, Manuela E.

Trends in Biotechnology (2020), 38 (1), 83-98CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)

Musculoskeletal diseases are increasing the prevalence of phys. disability worldwide. Within the body, musculoskeletal soft and hard tissues integrate through specific multitissue transitions, allowing for body movements. Owing to their unique compositional and structural gradients, injuries challenge the native interfaces and tissue regeneration is unlikely to occur. Tissue engineering strategies are emerging to emulate the physiol. environment of soft-to-hard tissue interfaces. Advances in biomaterial design enable control over biophys. parameters, but biomaterials alone are not sufficient to provide adequate support and guide transplanted cells. Therefore, biol., biophys., and biochem. tools can be integrated into a multifactorial toolbox, steering prospective advances toward engineering clin. relevant soft-to-hard tissue interfaces.

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Cross, L. M. ; Thakur, A. ; Jalili, N. A. ; Detamore, M. ; Gaharwar, A. K. Nanoengineered biomaterials for repair and regeneration of orthopedic tissue interfaces. Acta Biomater. 2016, 42 , 2– 17, DOI: 10.1016/j.actbio.2016.06.023

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Nanoengineered biomaterials for repair and regeneration of orthopedic tissue interfaces

Cross, Lauren M.; Thakur, Ashish; Jalili, Nima A.; Detamore, Michael; Gaharwar, Akhilesh K.

Acta Biomaterialia (2016), 42 (), 2-17CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Orthopedic interface tissue engineering aims to mimic the structure and function of soft-to-hard tissue junctions, particularly bone-ligament, bone-tendon, and bone-cartilage interfaces. A range of engineering approaches has been proposed to mimic the gradient architecture, phys. properties and chem. characteristics of interface tissues using conventional polymeric biomaterials. Recent developments in nanomaterials and nanofabrication technologies introduce a range of synthesis and fabrication tools to effectively engineer the structure and function of native tissue interfaces. In this review, we will focus on nanoengineered strategies used to replicate the structural and functional aspects of native biol. tissues for engineering bone-cartilage, bone-ligament, and bone-tendon interfaces. This review will also highlight some of the emerging applications and future potential of nanomaterials and fabrication technologies in engineering tissue interfaces. A major challenge in engineering interfaces is to control the phys. and structural characteristics of an artificial environment. The use of nanomaterials and nanoengineered strategies allow for greater control over the changes in structure and function at mol. and nanometer length scale. This review focuses on advanced nanomaterials and nanofabrication approaches developed to emulate bone-cartilage, bone-ligament, and bone-tendon interface regions. Some of the emerging nanoengineered biomaterials proposed to mimic tissue interfaces are also highlighted.

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Gao, F. ; Xu, Z. ; Liang, Q. ; Liu, B. ; Li, H. ; Wu, Y. ; Zhang, Y. ; Lin, Z. ; Wu, M. ; Ruan, C. Direct 3D printing of high strength biohybrid gradient hydrogel scaffolds for efficient repair of osteochondral defect. Adv. Funct. Mater. 2018, 28 (13), 1706644, DOI: 10.1002/adfm.201706644

Hu, X. ; Man, Y. ; Li, W. ; Li, L. ; Xu, J. ; Parungao, R. ; Wang, Y. ; Zheng, S. ; Nie, Y. ; Liu, T. 3D Bio-Printing of CS/Gel/HA/Gr Hybrid Osteochondral Scaffolds. Polymers 2019, 11 (10), 1601, DOI: 10.3390/polym11101601

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3D bio-printing of CS/Gel/HA/Gr hybrid osteochondral scaffolds

Hu, Xueyan; Man, Yuan; Li, Wenfang; Li, Liying; Xu, Jie; Parungao, Roxanne; Wang, Yiwei; Zheng, Shuangshuang; Nie, Yi; Liu, Tianqing; Song, Kedong

Polymers (Basel, Switzerland) (2019), 11 (10), 1601CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)

Cartilage is an important tissue contributing to the structure and function of support and protection in the human body. There are many challenges for tissue cartilage repair. However, 3D bio-printing of osteochondral scaffolds provides a promising soln. This study involved prepg. bio-inks with different proportions of chitosan (Cs), Gelatin (Gel), and Hyaluronic acid (HA). The rheol. properties of each bio-ink was used to identify the optimal bio-ink for printing. To improve the mech. properties of the bio-scaffold, Graphene (GR) with a mass ratio of 0.024, 0.06, and 0.1% was doped in the bio-ink. Bio-scaffolds were prepd. using 3D printing technol. The mech. strength, water absorption rate, porosity, and degrdn. rate of the bio-scaffolds were compared to select the most suitable scaffold to support the proliferation and differentiation of cells. P3 Bone mesenchymal stem cells (BMSCs) were inoculated onto the bio-scaffolds to study the biocompatibility of the scaffolds. The results of SEM showed that the Cs/Gel/HA scaffolds with a GR content of 0, 0.024, 0.06, and 0.1% had a good three-dimensional porous structure and interpenetrating pores, and a porosity of more than 80%. GR was evenly distributed on the scaffold as obsd. by energy spectrum analyzer and polarizing microscope. With increasing GR content, the mech. strength of the scaffold was enhanced, and pore walls became thicker and smoother. BMSCs were inoculated on the different scaffolds. The cells distributed and extended well on Cs/Gel/HA/GR scaffolds. Compared to traditional methods in tissue-engineering, this technique displays important advantages in simulating natural cartilage with the ability to finely control the mech. and chem. properties of the scaffold to support cell distribution and proliferation for tissue repair.

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Li, L. ; Li, J. ; Guo, J. ; Zhang, H. ; Zhang, X. ; Yin, C. ; Wang, L. ; Zhu, Y. ; Yao, Q. 3D molecularly functionalized cell-free biomimetic scaffolds for osteochondral regeneration. Adv. Funct. Mater. 2019, 29 (6), 1807356, DOI: 10.1002/adfm.201807356

Mirzaali, M. J. ; Cruz Saldívar, M. ; Herranz de la Nava, A. ; Gunashekar, D. ; Nouri-Goushki, M. ; Doubrovski, E. L. ; Zadpoor, A. A. Multi-material 3D printing of functionally graded hierarchical soft–hard composites. Adv. Eng. Mater. 2020, 22 (7), 1901142, DOI: 10.1002/adem.201901142

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Multi-Material 3D Printing of Functionally Graded Hierarchical Soft-Hard Composites

Mirzaali, Mohammad J.; Cruz Saldivar, Mauricio; Herranz de la Nava, Alba; Gunashekar, Deepthishre; Nouri-Goushki, Mahdiyeh; Doubrovski, Eugeni L.; Zadpoor, Amir Abbas

Advanced Engineering Materials (2020), 22 (7), 1901142CODEN: AENMFY; ISSN:1438-1656. (Wiley-VCH Verlag GmbH & Co. KGaA)

Hard biol. tissues (e.g., nacre and bone) have evolved for millions of years, enabling them to overcome the conflict between different mech. properties. The key to their success lies in the combination of limited material ingredients (i.e., hard and soft constituents) and mechanistic ingredients (e.g., functional gradients and building block hierarchical organization). However, the contribution of each material and mechanistic ingredient is still unknown, hindering the development of efficient synthetic composites. Quant. and systematic studies of hard-soft composites are required to unravel every factor's role in properties outcome. Herein, a voxel-by-voxel multi-material 3D printing technique is used to design and additively manuf. different groups of hard-soft composites. Several combinations of gradients, multilevel hierarchies, and brick-and-mortar arrangements are created. Single-edge notched fracture specimens are mech. tested and computationally simulated using extended finite element method (XFEM). It is found that functional gradients alone are not sufficient to improve fracture properties. However, up to twice the fracture energy of the hard face is obsd. when combining functional gradients with hierarchical designs, significantly increasing composite properties. Microscopic anal., digital image correlation, and strain distributions predicted with XFEM are used to discuss the mechanisms responsible for the obsd. behaviors.

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Putra, N. ; Mirzaali, M. ; Apachitei, I. ; Zhou, J. ; Zadpoor, A. Multi-material additive manufacturing technologies for Ti-, Mg-, and Fe-based biomaterials for bone substitution. Acta Biomater. 2020, 109 , 1– 20, DOI: 10.1016/j.actbio.2020.03.037

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Multi-material additive manufacturing technologies for Ti-, Mg-, and Fe-based biomaterials for bone substitution

Putra, N. E.; Mirzaali, M. J.; Apachitei, I.; Zhou, J.; Zadpoor, A. A.

Acta Biomaterialia (2020), 109 (), 1-20CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

The growing interest in multi-functional metallic biomaterials for bone substitutes challenges the current additive manufg. (AM, =3D printing) technologies. It is foreseeable that advances in multi-material AM for metallic biomaterials will not only allow for complex geometrical designs, but also improve their multi-functionalities by tuning the types or compns. of the underlying base materials, thereby presenting unprecedented opportunities for advanced orthopedic treatments. AM technologies are yet to be extensively explored for the fabrication of multi-functional metallic biomaterials, esp. for bone substitutes. The aim of this review is to present the viable options of the state-of-the-art multi-material AM for Ti-, Mg-, and Fe-based biomaterials to be used as bone substitutes. The review starts with a brief review of bone tissue engineering, the design requirements, and fabrication technologies for metallic biomaterials to highlight the advantages of using AM over conventional fabrication methods. Five AM technologies suitable for metal 3D printing are compared against the requirements for multi-material AM. Of these AM technologies, extrusion-based multi-material AM is shown to have the greatest potential to meet the requirements for the fabrication of multi-functional metallic biomaterials. Finally, recent progress in the fabrication of Ti-, Mg-, and Fe-based biomaterials including the utilization of multi-material AM technologies is reviewed so as to identify the knowledge gaps and propose the directions of further research for the development of multi-material AM technologies that are applicable for the fabrication of multi-functional metallic biomaterials. Addressing a crit. bone defect requires the assistance of multi-functional porous metallic bone substitutes. As one of the most advanced fabrication technol. in bone tissue engineering, additive manufg. is challenged for its viability in multi-material fabrication of metallic biomaterials. This article reviews how the current metal additive manufg. technologies have been and can be used for multi-material fabrication of Ti-, Mg-, and Fe-based bone substitutes. Progress on the Ti-, Mg-, and Fe-based biomaterials, including the utilization of multi-material additive manufg., are discussed to direct future research for advancing the multi-functional additively manufd. metallic bone biomaterials.

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Mirzaali, M. ; de la Nava, A. H. ; Gunashekar, D. ; Nouri-Goushki, M. ; Veeger, R. ; Grossman, Q. ; Angeloni, L. ; Ghatkesar, M. ; Fratila-Apachitei, L. ; Ruffoni, D. Mechanics of bioinspired functionally graded soft-hard composites made by multi-material 3D printing. Composite Structures 2020, 237 , 111867, DOI: 10.1016/j.compstruct.2020.111867

Mirzaali, M. J. ; Edens, M. E. ; de la Nava, A. H. ; Janbaz, S. ; Vena, P. ; Doubrovski, E. L. ; Zadpoor, A. A. Length-scale dependency of biomimetic hard-soft composites. Sci. Rep. 2018, 8 (1), 12052, DOI: 10.1038/s41598-018-30012-9

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Length-scale dependency of biomimetic hard-soft composites

Mirzaali M J; Edens M E; de la Nava A Herranz; Janbaz S; Zadpoor A A; Vena P; Doubrovski E L

Scientific reports (2018), 8 (1), 12052 ISSN:.

Biomimetic composites are usually made by combining hard and soft phases using, for example, multi-material additive manufacturing (AM). Like other fabrication methods, AM techniques are limited by the resolution of the device, hence, setting a minimum length scale. The effects of this length scale on the performance of hard-soft composites are not well understood. Here, we studied how this length scale affects the fracture toughness behavior of single-edge notched specimens made using random, semi-random, and ordered arrangements of the hard and soft phases with five different ratios of hard to soft phases. Increase in the length scale (40 to 960 μm) was found to cause a four-fold drop in the fracture toughness. The effects of the length scale were also modulated by the arrangement and volumetric ratio of both phases. A decreased size of the crack tip plastic zone, a crack path going through the soft phase, and highly strained areas far from the crack tip were the main mechanisms explaining the drop of the fracture toughness with the length scale.

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Gu, G. X.; Su, I.; Sharma, S.; Voros, J. L.; Qin, Z.; Buehler, M. J. Three-dimensional-printing of bio-inspired composites. J. Biomech. Eng. 2016, 138 (2), DOI: 10.1115/1.4032423 .

Nie, X. ; Chuah, Y. J. ; He, P. ; Wang, D.-A. Engineering a multiphasic, integrated graft with a biologically developed cartilage–bone interface for osteochondral defect repair. J. Mater. Chem. B 2019, 7 (42), 6515– 6525, DOI: 10.1039/C9TB00822E

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Engineering a multiphasic, integrated graft with a biologically developed cartilage-bone interface for osteochondral defect repair

Nie, Xiaolei; Chuah, Yon Jin; He, Pengfei; Wang, Dong-An

Journal of Materials Chemistry B: Materials for Biology and Medicine (2019), 7 (42), 6515-6525CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)

Tissue engineering is a promising approach to repair osteochondral defects, yet successful reconstruction of different layers in an integrated graft, esp. the interface remains challenging. The multiphasic, functionally integrated tissue engineering graft described herein mimics the entire osteochondral tissue in terms of structure and compn. at the cartilage, bone and cartilage-bone interface layer to repair osteochondral defects. In this manuscript, we report the fabrication of a multiphasic graft via bonding of a cartilaginous hydrogel and a sintered poly(lactic-co-glycolic acid) microsphere scaffold by an endogenous fibrotic cartilaginous extracellular matrix. We demonstrated that culturing chondrocytes within the alginate hydrogel conjugated to the poly(lactic-co-glycolic acid) scaffold allows for (i) gradient transition and integration from the cartilage layer to the subchondral bone layer as assessed by SEM, histol. and biochem., and (ii) superior tissue repair efficacy in a rabbit knee defect model. Industrialization of the graft remains an unsolved challenge as after decellularization the tissue repair efficacy of the graft decreased. Taken together, the multiphasic osteochondral graft repaired the osteochondral defects successfully and has the potential to be applied clin. as an implant in orthopaedic surgery.

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Calejo, I.; Costa-Almeida, R.; Reis, R. L.; Gomes, M. E. A Textile Platform Using Continuous Aligned and Textured Composite Microfibers to Engineer Tendon-to-Bone Interface Gradient Scaffolds. Adv. Healthcare Mater. 2019, 8 (15), 1900200 DOI: 10.1002/adhm.201900200 .

Tarafder, S. ; Brito, J. A. ; Minhas, S. ; Effiong, L. ; Thomopoulos, S. ; Lee, C. H. In situ tissue engineering of the tendon-to-bone interface by endogenous stem/progenitor cells. Biofabrication 2020, 12 (1), 015008, DOI: 10.1088/1758-5090/ab48ca

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In situ tissue engineering of the tendon-to-bone interface by endogenous stem/progenitor cells

Tarafder, Solaiman; Brito, John A.; Minhas, Sumeet; Effiong, Linda; Thomopoulos, Stavros; Lee, Chang H.

Biofabrication (2020), 12 (1), 015008CODEN: BIOFFN; ISSN:1758-5090. (IOP Publishing Ltd.)

The long-term success of surgical repair of rotator cuff tears is largely dependent on restoration of a functional tendon-to-bone interface. We implemented micro-precise spatiotemporal delivery of growth factors in three-dimensional printed scaffolds for integrative regeneration of a fibrocartilaginous tendon-to-bone interface. Sustained and spatially controlled release of tenogenic, chondrogenic and osteogenic growth factors was achieved using microsphere-based delivery carriers embedded in thin membrane-like scaffolds. In vitro, the scaffolds embedded with spatiotemporal delivery of growth factors successfully guided regional differentiation of mesenchymal progenitor cells, forming multiphase tissues with tendon-like, cartilage-like and bone-like regions. In vivo, when implanted at the interface between the supraspinatus tendon and the humeral head in a rat rotator cuff repair model, these scaffolds promoted recruitment of endogenous tendon progenitor cells followed by integrative healing of tendon and bone via re-formation of strong fibrocartilaginous interfaces. Our findings demonstrate the potential of in situ tissue engineering of tendon-to-bone interfaces by endogenous progenitor cells. The in situ tissue engineering approach shows translational potential for improving outcomes after rotator cuff repair.

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Liu, Z. ; Meyers, M. A. ; Zhang, Z. ; Ritchie, R. O. Functional gradients and heterogeneities in biological materials: Design principles, functions, and bioinspired applications. Prog. Mater. Sci. 2017, 88 , 467– 498, DOI: 10.1016/j.pmatsci.2017.04.013

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Functional gradients and heterogeneities in biological materials: Design principles, functions, and bioinspired applications

Liu, Zengqian; Meyers, Marc A.; Zhang, Zhefeng; Ritchie, Robert O.

Progress in Materials Science (2017), 88 (), 467-498CODEN: PRMSAQ; ISSN:0079-6425. (Elsevier Ltd.)

Living organisms have ingeniously evolved functional gradients and heterogeneities to create high-performance biol. materials from a fairly limited choice of elements and compds. during long-term evolution and selection. The translation of such design motifs into synthetic materials offers a spectrum of feasible pathways towards unprecedented properties and functionalities that are favorable for practical uses in a variety of engineering and medical fields. Here, we review the basic design forms and principles of naturally-occurring gradients in biol. materials and discuss the functions and benefits that they confer to organisms. These gradients are fundamentally assocd. with the variations in local chem. compns./constituents and structural characteristics involved in the arrangement, distribution, dimensions and orientations of the building units. The assocd. interfaces in biol. materials invariably demonstrate localized gradients and a variety of gradients are generally integrated over multiple length-scales within the same material. The bioinspired design and applications of synthetic functionally graded materials that mimic their natural paradigms are revisited and the emerging processing techniques needed to replicate the biol. gradients are described. It is expected that in the future bioinspired gradients and heterogeneities will play an increasingly important role in the development of high-performance materials for more challenging applications.

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Link, J. M. ; Salinas, E. Y. ; Hu, J. C. ; Athanasiou, K. A. The tribology of cartilage: Mechanisms, experimental techniques, and relevance to translational tissue engineering. Clin Biomech (Bristol, Avon) 2020, 79 , 104880, DOI: 10.1016/j.clinbiomech.2019.10.016

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The tribology of cartilage: Mechanisms, experimental techniques, and relevance to translational tissue engineering

Link Jarrett M; Salinas Evelia Y; Hu Jerry C; Athanasiou Kyriacos A

Clinical biomechanics (Bristol, Avon) (2020), 79 (), 104880 ISSN:.

Diarthrodial joints, found at the ends of long bones, function to dissipate load and allow for effortless articulation. Essential to these functions are cartilages, soft hydrated tissues such as hyaline articular cartilage and the knee meniscus, as well as lubricating synovial fluid. Maintaining adequate lubrication protects cartilages from wear, but a decrease in this function leads to tissue degeneration and pathologies such as osteoarthritis. To study cartilage physiology, articular cartilage researchers have employed tribology, the study of lubrication and wear between two opposing surfaces, to characterize both native and engineered tissues. The biochemical components of synovial fluid allow it to function as an effective lubricant that exhibits shear-thinning behavior. Although tribological properties are recognized to be essential to native tissue function and a critical characteristic for translational tissue engineering, tribology is vastly understudied when compared to other mechanical properties such as compressive moduli. Further, tribometer configurations and testing modalities vary greatly across laboratories. This review aims to define commonly examined tribological characteristics and discuss the structure-function relationships of biochemical constituents known to contribute to tribological properties in native tissue, address the variations in experimental set-ups by suggesting a move toward standard testing practices, and describe how tissue-engineered cartilages may be augmented to improve their tribological properties.

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Beck, E. C. ; Barragan, M. ; Tadros, M. H. ; Gehrke, S. H. ; Detamore, M. S. Approaching the compressive modulus of articular cartilage with a decellularized cartilage-based hydrogel. Acta Biomater. 2016, 38 , 94– 105, DOI: 10.1016/j.actbio.2016.04.019

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Approaching the compressive modulus of articular cartilage with a decellularized cartilage-based hydrogel

Beck, Emily C.; Barragan, Marilyn; Tadros, Madeleine H.; Gehrke, Stevin H.; Detamore, Michael S.

Acta Biomaterialia (2016), 38 (), 94-105CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

ECM-based materials are appealing for tissue engineering strategies because they may promote stem cell recruitment, cell infiltration, and cell differentiation without the need to supplement with addnl. biol. factors. Cartilage ECM has recently shown potential to be chondroinductive, particularly in a hydrogel-based system, which may be revolutionary in orthopedic medicine. However, hydrogels composed of natural materials are often mech. inferior to synthetic materials, which is a major limitation for load-bearing tissue applications. The objective was therefore to create an unprecedented hydrogel derived entirely from native cartilage ECM that was both mech. more similar to native cartilage tissue and capable of inducing chondrogenesis. Porcine cartilage was decellularized, solubilized, and then methacrylated and UV photocrosslinked to create methacrylated solubilized decellularized cartilage (MeSDCC) gels. Methacrylated gelatin (GelMA) was employed as a control for both biomechanics and bioactivity. Rat bone marrow-derived mesenchymal stem cells were encapsulated in these networks, which were cultured in vitro for 6 wk, where chondrogenic gene expression, the compressive modulus, swelling, and histol. were analyzed. One day after crosslinking, the elastic compressive modulus of the 20% MeSDCC gels was 1070 ± 150 kPa. Most notably, the stress strain profile of the 20% MeSDCC gels fell within the 95% confidence interval range of native porcine cartilage. Addnl., MeSDCC gels significantly upregulated chondrogenic genes compared to GelMA as early as day 1 and supported extensive matrix synthesis as obsd. histol. Given that these gels approached the mechanics of native cartilage tissue, supported matrix synthesis, and induced chondrogenic gene expression, MeSDCC hydrogels may be promising materials for cartilage tissue engineering applications. Future efforts will focus on improving fracture mechanics as well to benefit overall biomech. performance. Extracellular matrix (ECM)-based materials are appealing for tissue engineering strategies because they may promote stem cell recruitment, cell infiltration, and cell differentiation without the need to supplement with addnl. biol. factors. One such ECM-based material, cartilage ECM, has recently shown potential to be chondroinductive; however, hydrogels composed of natural materials are often mech. inferior to synthetic materials, which is a major limitation for load-bearing tissue applications. Therefore, this work is significant because we were the first to create hydrogels derived entirely from cartilage ECM that had mech. properties similar to that of native cartilage until hydrogel failure. Furthermore, these hydrogels had a compressive modulus of 1070 ± 150 kPa, they were chondroinductive, and they supported extensive matrix synthesis. In the current study, we have shown that these new hydrogels may prove to be a promising biomaterial for cartilage tissue engineering applications.

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Gardner-Morse, M. G. ; Tacy, N. J. ; Beynnon, B. D. ; Roemhildt, M. L. In situ microindentation for determining local subchondral bone compressive modulus. J. Biomech. Eng. 2010, 132 (9), 094502, DOI: 10.1115/1.4001872

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In situ microindentation for determining local subchondral bone compressive modulus

Gardner-Morse Mack G; Tacy Nelson J; Beynnon Bruce D; Roemhildt Maria L

Journal of biomechanical engineering (2010), 132 (9), 094502 ISSN:.

Alterations to joint tissues, including subchondral bone, occur with osteoarthritis. A microindentation technique was developed to determine the local compressive modulus of subchondral bone. This test, in conjunction with a cartilage indentation test at the same location, could evaluate changes of these material properties in both tissues. The accuracy of the technique was determined by applying it to materials of known moduli. The technique was then applied to rat tibial plateaus to characterize the local moduli of the subchondral bone. An established nanoindentation method was adopted to determine the modulus of subchondral bone following penetration of the overlying articular cartilage. Three cycles of repeated loadings were applied (2.452 N, 30 s hold). The slope of the load-displacement response during the unloading portion of the third cycle was used to measure the stiffness. Indentation tests were performed on two polyurethane foams and polymethyl-methacrylate for validation (n=15). Regression analysis was used to compare the moduli with reference values. Subchondral bone moduli of tibial plateaus from Sprague-Dawley rats (n=5) were measured for central and posterior locations of medial and lateral compartments. An analysis of variance was used to analyze the effects of compartment and test location. The measured moduli of the validation materials correlated with the reference values (R(2)=0.993, p=0.05). In rat tibial plateaus, the modulus of the posterior location was significantly greater than the center location (4.03+/-1.00 GPa and 3.35+/-1.16 GPa respectively, p=0.03). The medial compartment was not different from the lateral compartment. This method for measuring the subchondral bone in the same location as articular cartilage allows studies of the changes in these material properties with the onset and progression of osteoarthritis.

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Lyons, T. J. ; Stoddart, R. W. ; McClure, S. F. ; McClure, J. The tidemark of the chondro-osseous junction of the normal human knee joint. J. Mol. Histol. 2005, 36 (3), 207– 215, DOI: 10.1007/s10735-005-3283-x

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The tidemark of the chondro-osseous junction of the normal human knee joint

Lyons T J; Stoddart R W; McClure S F; McClure J

Journal of molecular histology (2005), 36 (3), 207-15 ISSN:1567-2379.

The chondro-osseous junction includes the junction between calcified and non-calcified cartilage matrices often referred to as the tidemark. A detailed knowledge of the structure, function and pathophysiology of the chondro-osseous junction is essential for an understanding both of the normal elongation of bones and of the pathogenesis of osteoarthrosis. In this study the molecular anatomy of the tidemark was studied using histochemical techniques, including lectin histochemistry, on blocks of normal cartilage from human knee joints. The tidemark stained with H and E, picro-sirius red, toluidine blue, safranin O and methyl green, but not with alcian blue in the presence of magnesium chloride at 0.05 M or above. It stained with only four lectins, those from Datura stramonium, Maclura pomifera, Erythrina crystagalli and Helix pomatia, out of the 19 used. Therefore, it is rich in collagen and contains hyaluronan, but appears to lack the glycosaminoglycans of 'conventional' proteoglycans and it expresses a very limited and distinctive lectin staining glycoprofile, which is probably attributable to specific glycoproteins. In addition, the tidemark had a distinct microanatomical trilaminate appearance. From all of these results it is clear that this part of the chondro-osseous junctional region is chemically more complex and distinctive than has previously been described.

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Bian, W. ; Lian, Q. ; Li, D. ; Wang, J. ; Zhang, W. ; Jin, Z. ; Qiu, Y. Morphological characteristics of cartilage-bone transitional structures in the human knee joint and CAD design of an osteochondral scaffold. BioMed. Eng. OnLine 2016, 15 (1), 82, DOI: 10.1186/s12938-016-0200-3

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Morphological characteristics of cartilage-bone transitional structures in the human knee joint and CAD design of an osteochondral scaffold

Bian Weiguo; Qiu Yusheng; Lian Qin; Li Dichen; Zhang Weijie; Wang Jin; Jin Zhongmin

Biomedical engineering online (2016), 15 (1), 82 ISSN:.

BACKGROUND: There is a lack of understanding of the morphological characteristics of the cartilage-bone interface. Materials that are currently being used in tissue engineering do not adequately support the regeneration of bone and cartilage tissues. The present study aimed to explore the morphological characteristics of cartilage-bone transitional structures in the human knee joint and to design a biomimetic osteochondral scaffold based on morphological data. METHODS: Histology, micro-computed tomography (micro-CT), and scanning electron microscopy (SEM) were used to investigate the microstructure of the cartilage-bone transitional structures. Morphological characteristics and their distribution were obtained and summarized into a biomimetic design. A three-dimensional model of a biomimetic osteochondral scaffold was CAD designed. A prototype of the resulting subchondral bone scaffold was constructed by stereolithography using resin. RESULTS: Micro-CT revealed that subchondral bone presented a gradually changing structure from the subchondral to spongy bone tissue. The subchondral bone plate was more compact with ~20 % porosity compared with ~60 % porosity for the spongy bone. Histology and SEM showed that cartilage was stabilized on the subchondral bone plate by conjunctions, imbedding, interlocking, and binding forces generated by collagen fibers. Some scattered defects allow blood vessel invasion and nutritional supply. CONCLUSIONS: The subchondral bone plate is not an intact plate between the cartilage and bone cavity, and some scattered defects exist that allow blood vessel invasion and nutritional supply. This characteristic was used to design an osteochondral scaffold. This could be used to construct an osteochondral complex that is similar to native bones.

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Imhof, H. ; Breitenseher, M. ; Kainberger, F. ; Rand, T. ; Trattnig, S. Importance of subchondral bone to articular cartilage in health and disease. Top Magn Reson Imaging 1999, 10 (3), 180– 92, DOI: 10.1097/00002142-199906000-00002

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Importance of subchondral bone to articular cartilage in health and disease

Imhof H; Breitenseher M; Kainberger F; Rand T; Trattnig S

Topics in magnetic resonance imaging : TMRI (1999), 10 (3), 180-92 ISSN:0899-3459.

The almost absolute barrier to diffusion of nutrients between articular cartilage and subchondral bone does not exist. These anatomic regions represent a functional unit. Repetitive overloading in degenerative disease leads primarily to lesions in the subchondral region (including vessels), which in turn impede flow of nutrition to articular cartilage. As a result, in degenerative joint disease the subchondral region shows reactive enhanced vascularization and heightened metabolism with insufficient repair. In aging, however, vascularization and metabolism are decreased; no repair takes place. In many cases, MRI allows visualization of these subchondral abnormalities. It also demonstrates the basic similarities of degenerative osteoarthritis, osteochondritis dissecans, and avascular necrosis. These different entities may have the same basic etiology but with different disease severity.

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Yang, P. J. ; Temenoff, J. S. Engineering orthopedic tissue interfaces. Tissue Eng., Part B 2009, 15 (2), 127– 141, DOI: 10.1089/ten.teb.2008.0371

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Engineering Orthopedic Tissue Interfaces

Yang, Peter J.; Temenoff, Johnna S.

Tissue Engineering, Part B: Reviews (2009), 15 (2), 127-141CODEN: TEPBAB; ISSN:1937-3368. (Mary Ann Liebert, Inc.)

A review. While a wide variety of approaches to engineering orthopedic tissues have been proposed, less attention has been paid to the interfaces, the specialized areas that connect two tissues of different biochem. and mech. properties. The interface tissue plays an important role in transitioning mech. load between disparate tissues. Thus, the relatively new field of interfacial tissue engineering presents new challenges-to not only consider the regeneration of individual orthopedic tissues, but also to design the biochem. and cellular compn. of the linking tissue. Approaches to interfacial tissue engineering may be distinguished based on if the goal is to recreate the interface itself, or generate an entire integrated tissue unit (such as an osteochondral plug). As background for future efforts in engineering orthopedic interfaces, a brief review of the biol. and mechanics of each interface (cartilage-bone, ligament-bone, meniscus-bone, and muscle-tendon) is presented, followed by an overview of the state-of-the-art in engineering each tissue, including advances and challenges specific to regenerating the interfaces.

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Di Luca, A. ; Van Blitterswijk, C. ; Moroni, L. The osteochondral interface as a gradient tissue: From development to the fabrication of gradient scaffolds for regenerative medicine. Birth Defects Res., Part C 2015, 105 (1), 34– 52, DOI: 10.1002/bdrc.21092

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The osteochondral interface as a gradient tissue: From development to the fabrication of gradient scaffolds for regenerative medicine

Di Luca, Andrea; Van Blitterswijk, Clemens; Moroni, Lorenzo

Birth Defects Research, Part C: Embryo Today--Reviews (2015), 105 (1), 34-52CODEN: BDRPDV; ISSN:1542-975X. (Wiley-Blackwell)

A review. The osteochondral (OC) interface is not only the interface between two tissues, but also the evolution of hard and stiff bone tissue to the softer and viscoelastic articular cartilage covering the joint surface. To generate a smooth transition between two tissues with such differences in many of their characteristics, several gradients are recognizable when moving from the bone side to the joint surface. It is, therefore, necessary to implement such gradients in the design of scaffolds to regenerate the OC interface, so to mimic the anatomical, biol., and physicochem. properties of bone and cartilage as closely as possible. In the past years, several scaffolds were developed for OC regeneration: biphasic, triphasic, and multilayered scaffolds were used to mimic the compartmental nature of this tissue. The structure of these scaffolds presented gradients in mech., physicochem., or biol. properties. The use of gradient scaffolds with already differentiated or progenitor cells has been recently proposed. Some of these approaches have also been translated in clin. trials, yet without the expected satisfactory results, thus suggesting that further efforts in the development of constructs, which can lead to a functional regeneration of the OC interface by presenting gradients more closely resembling its native environment, will be needed in the near future. The aim of this review is to analyze the gradients present in the OC interface from the early stage of embryonic life up to the adult organism, and give an overview of the studies, which involved gradient scaffolds for its regeneration.

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Chen, Q. ; Thouas, G. Metallic implant biomaterials. Mater. Sci. Eng., R 2015, 87 , 1– 57, DOI: 10.1016/j.mser.2014.10.001

Zhang, Y. ; Wang, F. ; Tan, H. ; Chen, G. ; Guo, L. ; Yang, L. Analysis of the mineral composition of the human calcified cartilage zone. Int. J. Med. Sci. 2012, 9 (5), 353– 360, DOI: 10.7150/ijms.4276

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Analysis of the mineral composition of the human calcified cartilage zone

Zhang, Ying; Wang, Fuyou; Tan, Hongbo; Chen, Guangxing; Guo, Lin; Yang, Liu

International Journal of Medical Sciences (2012), 9 (5), 353-360CODEN: IJMSGZ; ISSN:1449-1907. (Ivyspring International Publisher)

As the connecting tissue between the hyaline articular cartilage and the subchondral bone, calcified cartilage zone (CCZ) plays a great role in the force transmission and materials diffusion. However, the questions that remain to be resolved are its mineral compn. and organization. In this study, 40 healthy human knee specimens were harvested; first the CCZ was dissected and obsd. by Safranin O/fast green staining, then CCZ chem. characteristics were measured by using amino acid assay and X-ray diffraction. The percentage of dry wt. of type II collagen as an org. compd. of CCZ was 20.16% ± 0.96%, lower than that of the hyaline cartilage layer (61.39% ± 0.38%); the percentage of dry wt. of hydroxyapatite as an inorg. compd. was 65.09% ± 2.31%, less than that of subchondral bone (85.78% ± 3.42%). Our study provides the accurate data for the reconstruction of the CCZ in vitro and the elucidation of CCZ structure and function.

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Dijk, C. N. ; Mueller-Gerbl, M. The basic science of the subchondral bone. Knee Surgery, Sports Traumatology, Arthroscopy 2010, 18 (4), 419– 433, DOI: 10.1007/s00167-010-1054-z

Sophia Fox, A. J. ; Bedi, A. ; Rodeo, S. A. The basic science of articular cartilage: Structure, composition, and function. Sports Health 2009, 1 (6), 461– 468, DOI: 10.1177/1941738109350438

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The basic science of articular cartilage: structure, composition, and function

Sophia Fox Alice J; Bedi Asheesh; Rodeo Scott A

Sports health (2009), 1 (6), 461-8 ISSN:1941-7381.

There is no expanded citation for this reference.

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Gottardi, R. ; Hansen, U. ; Raiteri, R. ; Loparic, M. ; Düggelin, M. ; Mathys, D. ; Friederich, N. F. ; Bruckner, P. ; Stolz, M. Supramolecular Organization of Collagen Fibrils in Healthy and Osteoarthritic Human Knee and Hip Joint Cartilage. PLoS One 2016, 11 (10), e0163552, DOI: 10.1371/journal.pone.0163552

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Supramolecular organization of collagen fibrils in healthy and osteoarthritic human knee and hip joint cartilage

Gottardi, Riccardo; Hansen, Uwe; Raiteri, Roberto; Loparic, Marko; Duggelin, Marcel; Mathys, Daniel; Friederich, Niklaus F.; Bruckner, Peter; Stolz, Martin

PLoS One (2016), 11 (10), e0163552/1-e0163552/13CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Cartilage matrix is a composite of discrete, but interacting suprastructures, i.e. cartilage fibers with microfibrillar or network-like aggregates and penetrating extrafibrillar proteoglycan matrix. The biomech. function of the proteoglycan matrix and the collagen fibers are to absorb compressive and tensional loads, resp. Here, we are focusing on the suprastructural organization of collagen fibrils and the degrdn. process of their hierarchical organized fiber architecture studied at high resoln. at the authentic location within cartilage. We present electron micrographs of the collagenous cores of such fibers obtained by an improved protocol for SEM (SEM). Articular cartilages are permeated by small prototypic fibrils with a homogeneous diam. of 18 ± 5 nm that can align in their D-periodic pattern and merge into larger fibers by lateral assocn. Interestingly, these fibers have tissue-specific organizations in cartilage. They are twisted ropes in superficial regions of knee joints or assemble into parallel aligned cable-like structures in deeper regions of knee joint- or throughout hip joints articular cartilage. These novel observations contribute to an improved understanding of collagen fiber biogenesis, function, and homeostasis in hyaline cartilage.

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Singh, I. The architecture of cancellous bone. J. Anat. 1978, 127 (Pt 2), 305– 310

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The architecture of cancellous bone

Singh I

Journal of anatomy (1978), 127 (Pt 2), 305-10 ISSN:0021-8782.

The architecture of cancellous bone has been studied in macerated human bones. A number of distinct types of architecture can be recognized as follows: Type I consists of a very delicate meshwork of fine rods. Type II is made up of both rods and plates. Sub-type IIa is a meshwork similar to Type I, but a varying proportion of rad are replaced by delicate plates. Sub-type IIb shows the presence of thin but large fenestrated plates with a well marked orientation in preferred planes; these are interconnected by smaller plates and rods. Sub-type IIc is made up of relatively thick and extensive arranged for the most part parallel to one another, the plates being connected to each other by fine rods. Type III is made up entirely of plates. Delicate plates may form a meshwork in which a directional orientation may or may not be apparent (Sub-type IIIa). Elsewhere better defined, larger plates may enclose tubular spaces (Sub-type IIIb). In some areas (where cancellous bone is very dense) small relatively thick plates enclose irregular spaces; the appearance may closely resemble that of a honeycomb when the spaces are small, but elsewhere the spaces may show a definite directional orientation. The wall of the marrow cavity of long bones is seldom smooth. It is characterized by the presence of plates and rods in various configurations. A distinct marrow cavity is seen in the majority of clavicles examined.

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Mendler, M. ; Eich-Bender, S. G. ; Vaughan, L. ; Winterhalter, K. H. ; Bruckner, P. Cartilage contains mixed fibrils of collagen types II, IX, and XI. J. Cell Biol. 1989, 108 (1), 191– 7, DOI: 10.1083/jcb.108.1.191

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Cartilage contains mixed fibrils of collagen types II, IX, and XI

Mendler, Markus; Eich-Bender, Susanna G.; Vaughan, Lloyd; Winterhalter, Kaspar H.; Bruckner, Peter

Journal of Cell Biology (1989), 108 (1), 191-7CODEN: JCLBA3; ISSN:0021-9525.

The distribution of collagen XI in fibril fragments from 17-day chick embryo sternal cartilage was detd. by immunoelectron microscopy using specific polyclonal antibodies. The protein was distributed throughout the fibril fragments but was antigenically masked due to the tight packing of collagen mols. and could be identified only at sites where the fibril structure was partially disrupted. Collagens II and IX were also distributed uniformly along fibrils but, in contrast to collagen XI, were accessible to the antibodies in intact fibrils. Therefore, cartilage fibrils are heterotypically assembled from collagens II, IX, and XI. This implies that collagen XI is an integral component of the cartilage fibrillar network and homogeneously distributed throughout the tissue. This was confirmed by immunofluorescence.

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Hsueh, M. F. ; Khabut, A. ; Kjellström, S. ; Önnerfjord, P. ; Kraus, V. B. Elucidating the Molecular Composition of Cartilage by Proteomics. J. Proteome Res. 2016, 15 (2), 374– 88, DOI: 10.1021/acs.jproteome.5b00946

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Elucidating the Molecular Composition of Cartilage by Proteomics

Hsueh, Ming-Feng; Khabut, Areej; Kjellstrom, Sven; Onnerfjord, Patrik; Kraus, Virginia Byers

Journal of Proteome Research (2016), 15 (2), 374-388CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)

Articular cartilage consists of chondrocytes and two major components, a collagen-rich framework and highly abundant proteoglycans. Most prior studies defining the zonal distribution of cartilage have extd. proteins with guanidine-HCl. However, an unextd. collagen-rich residual is left after extn. In addn., the high abundance of anionic polysaccharide mols. extd. from cartilage adversely affects the chromatog. sepn. In this study, we established a method for removing chondrocytes from cartilage sections with minimal extracellular matrix protein loss. The addn. of surfactant to guanidine-HCl extn. buffer improved protein soly. Ultrafiltration removed interference from polysaccharides and salts. Almost four-times more collagen peptides were extd. by the in situ trypsin digestion method. However, as expected, proteoglycans were more abundant within the guanidine-HCl extn. These different methods were used to ext. cartilage sections from different cartilage layers (superficial, intermediate, and deep), joint types (knee and hip), and disease states (healthy and osteoarthritic), and the extns. were evaluated by quant. and qual. proteomic analyses. The results of this study led to the identifications of the potential biomarkers of osteoarthritis (OA), OA progression, and the joint specific biomarkers.

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Robinson, D. L. ; Kersh, M. E. ; Walsh, N. C. ; Ackland, D. C. ; de Steiger, R. N. ; Pandy, M. G. Mechanical properties of normal and osteoarthritic human articular cartilage. Journal of the Mechanical Behavior of Biomedical Materials 2016, 61 , 96– 109, DOI: 10.1016/j.jmbbm.2016.01.015

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Mechanical properties of normal and osteoarthritic human articular cartilage

Robinson, Dale L.; Kersh, Mariana E.; Walsh, Nicole C.; Ackland, David C.; de Steiger, Richard N.; Pandy, Marcus G.

Journal of the Mechanical Behavior of Biomedical Materials (2016), 61 (), 96-109CODEN: JMBBCP; ISSN:1878-0180. (Elsevier Ltd.)

Isotropic hyperelastic models have been used to det. the material properties of normal human cartilage, but there remains an incomplete understanding of how these properties may be altered by osteoarthritis. The aims of this study were to (1) measure the material consts. of normal and osteoarthritic human knee cartilage using isotropic hyperelastic models; (2) det. whether the material consts. correlate with histol. measures of structure and/or cartilage tissue damage; and (3) quantify the abilities of two common isotropic hyperelastic material models, the neo-Hookean and Yeoh models, to describe articular cartilage contact force, area, and pressure. Small osteochondral specimens of normal and osteoarthritic condition were retrieved from human cadaveric knees and from the knees of patients undergoing total knee arthroplasty and tested in unconfined compression at loading rates and large strains representative of wt.-bearing activity. Articular surface contact area and lateral deformation were measured concurrently and specimen-specific finite element models then were used to det. the hyperelastic material consts. Structural parameters were measured using histol. techniques while the severity of cartilage damage was quantified using the OARSI grading scale. The hyperelastic material consts. correlated significantly with OARSI grade, indicating that the mech. properties of cartilage for large strains change with tissue damage. The measurements of contact area described anisotropy of the tissue constituting the superficial zone. The Yeoh model described contact force and pressure more accurately than the neo-Hookean model, whereas both models under-predicted contact area and poorly described the anisotropy of cartilage within the superficial zone. These results identify the limits by which isotropic hyperelastic material models may be used to describe cartilage contact variables. This study provides novel data for the mech. properties of normal and osteoarthritic human articular cartilage and enhances our ability to model this tissue using simple isotropic hyperelastic materials.

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Hoemann, C. Molecular and Biochemical Assays of Cartilage Components. Methods in molecular medicine 2004, 101 , 127– 56, DOI: 10.1385/1-59259-821-8:127

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Molecular and biochemical assays of cartilage components

Hoemann, Caroline D.

Methods in Molecular Medicine (2004), 101 (Cartilage and Osteoarthritis, Volume 2), 127-156CODEN: MMMEFN ISSN:. (Humana Press Inc.)

A review. The procedure described below is useful for extg. proteins, nucleic acids, and glycosaminoglycans from 5-40 mg of cartilage or tissue-engineered cartilage samples. This extn. method will generate samples compatible with Western blot, RNase protection, di-Me methylene blue (DMB) assay for glycosaminoglycan, Hoechst DNA assay, and hydroxyproline assay. Most sol. matrix mols. can be extd. from pulverized samples using 4 M guanidine HCl, during a 30-min period of vortex agitation at 4°. Shorter agitation times can give inadequate solubilization. The guanidine HCl-insol. pellet must be re-extd. with guanidine thiocyanate buffer, to solubilize RNA addnl. The final insol. pellet can be rinsed with ethanol and digested with papain, to quantify collagen content as well as other insol. or crosslinked material. Samples between 1 and 5 mg may be directly digested with a small vol. of papain buffer for DMB, hydroxyproline, and Hoechst DNA assays.

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Wu, J. J. ; Woods, P. E. ; Eyre, D. R. Identification of cross-linking sites in bovine cartilage type IX collagen reveals an antiparallel type II-type IX molecular relationship and type IX to type IX bonding. J. Biol. Chem. 1992, 267 (32), 23007– 14, DOI: 10.1016/S0021-9258(18)50048-X

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Identification of cross-linking sites in bovine cartilage type IX collagen reveals an antiparallel type II-type IX molecular relationship and type IX to type IX bonding

Wu, Jiann Jiu; Woods, Patricia E.; Eyre, David R.

Journal of Biological Chemistry (1992), 267 (32), 23007-14CODEN: JBCHA3; ISSN:0021-9258.

Type IX collagen functions in covalent cross-linkage to type II collagen in cartilage (Eyre, D. R., et al., 1987). To understand this mol. relationship better, an anal. of all crosslinking sites labeled by [3H]borohydride was undertaken using the protein prepd. from fetal bovine cartilage. Sequence anal. of tryptic peptides contg. the 3H-labeled cross-links showed that each of the chains of type IX collagen, α1(IX), α2(IX), and α3(IX), contained a site of crosslinking at the amino terminus of the COL2 triple-helix to which the α1(II)N-telopeptide could bond. The α3(IX)COL2 domain alone also had an attachment site for the α1(II)C-telopeptide. The distance between the α1(II)N-telopeptide and α1(II)C-telopeptide interaction sites, 137 residues, is equal to the length of the hole zone (0.6D) in a type II collagen fibril. This implies an antiparallel type II to type IX crosslinking relationship. Peptide anal. also revealed an unknown amino acid sequence linked to the COL2 crosslinking domains in both the α1(IX) and α3(IX) chains. Using antibodies to this novel peptide, its origin in the collagen α3(IX)NC1 domain was established. In summary, the results confirm extensive covalent crosslinking between type IX and type II collagen mols. and reveal the existence of type IX-type IX bonding. These data provide a mol. basis for the proposed function of type IX collagen as a crit. contributor to the mech. stability and resistance to swelling of the collagen type II fibril framework of cartilage.

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Qu, D. ; Mosher, C. Z. ; Boushell, M. K. ; Lu, H. H. Engineering complex orthopaedic tissues via strategic biomimicry. Ann. Biomed. Eng. 2015, 43 (3), 697– 717, DOI: 10.1007/s10439-014-1190-6

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Engineering complex orthopaedic tissues via strategic biomimicry

Qu Dovina; Mosher Christopher Z; Boushell Margaret K; Lu Helen H

Annals of biomedical engineering (2015), 43 (3), 697-717 ISSN:.

The primary current challenge in regenerative engineering resides in the simultaneous formation of more than one type of tissue, as well as their functional assembly into complex tissues or organ systems. Tissue-tissue synchrony is especially important in the musculoskeletal system, wherein overall organ function is enabled by the seamless integration of bone with soft tissues such as ligament, tendon, or cartilage, as well as the integration of muscle with tendon. Therefore, in lieu of a traditional single-tissue system (e.g., bone, ligament), composite tissue scaffold designs for the regeneration of functional connective tissue units (e.g., bone-ligament-bone) are being actively investigated. Closely related is the effort to re-establish tissue-tissue interfaces, which is essential for joining these tissue building blocks and facilitating host integration. Much of the research at the forefront of the field has centered on bioinspired stratified or gradient scaffold designs which aim to recapitulate the structural and compositional inhomogeneity inherent across distinct tissue regions. As such, given the complexity of these musculoskeletal tissue units, the key question is how to identify the most relevant parameters for recapitulating the native structure-function relationships in the scaffold design. Therefore, the focus of this review, in addition to presenting the state-of-the-art in complex scaffold design, is to explore how strategic biomimicry can be applied in engineering tissue connectivity. The objective of strategic biomimicry is to avoid over-engineering by establishing what needs to be learned from nature and defining the essential matrix characteristics that must be reproduced in scaffold design. Application of this engineering strategy for the regeneration of the most common musculoskeletal tissue units (e.g., bone-ligament-bone, muscle-tendon-bone, cartilage-bone) will be discussed in this review. It is anticipated that these exciting efforts will enable integrative and functional repair of soft tissue injuries, and moreover, lay the foundation for the development of composite tissue systems and ultimately, total limb or joint regeneration.

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Ralphs, J. R. ; Benjamin, M. The joint capsule: structure, composition, ageing and disease. J. Anat. 1994, 184 (Pt 3), 503– 509

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The joint capsule: structure, composition, aging and disease

Ralphs, J. R.; Benjamin, M.

Journal of Anatomy (1994), 184 (3), 503-9CODEN: JOANAY; ISSN:0021-8782.

A review with many refs. The joint capsule is vital to the function of synovial joints. This article concs. on the specialized structures of the capsule--where capsular tissues attach to bone or form part of the articulation of the joint. It focuses on 2 joints: the rat knee and the proximal interphalangeal (PIP) joint of the human finger. Capsular involvement in joint pathol. is also discussed.

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Augat, P. ; Schorlemmer, S. The role of cortical bone and its microstructure in bone strength. Age Ageing 2006, 35 (Suppl 2), ii27– ii31, DOI: 10.1093/ageing/afl081

Lai, Y.-S. ; Chen, W.-C. ; Huang, C.-H. ; Cheng, C.-K. ; Chan, K.-K. ; Chang, T.-K. The Effect of Graft Strength on Knee Laxity and Graft In-Situ Forces after Posterior Cruciate Ligament Reconstruction. PLoS One 2015, 10 (5), e0127293, DOI: 10.1371/journal.pone.0127293

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The effect of graft strength on knee laxity and graft in-situ forces after posterior cruciate ligament reconstruction

Lai, Yu-Shu; Chen, Wen-Chuan; Huang, Chang-Hung; Cheng, Cheng-Kung; Chan, Kam-Kong; Chang, Ting-Kuo

PLoS One (2015), 10 (5), e0127293/1-e0127293/11CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Surgical reconstruction is generally recommended for posterior cruciate ligament (PCL) injuries; however, the use of grafts is still a controversial problem. In this study, a three-dimensional finite element model of the human tibiofemoral joint with articular cartilage layers, menisci, and four main ligaments was constructed to investigate the effects of graft strengths on knee kinematics and in-situ forces of PCL grafts. Nine different graft strengths with stiffness ranging from 0% (PCL rupture) to 200%, in increments of 25%, of an intact PCL's strength were used to simulate the PCL reconstruction. A 100 N posterior tibial drawer load was applied to the knee joint at full extension. Results revealed that the max. posterior translation of the PCL rupture model (0% stiffness) was 6.77 mm in the medial compartment, which resulted in tibial internal rotation of about 3.01°. After PCL reconstruction with any graft strength, the laxity of the medial tibial compartment was noticeably improved. Tibial translation and rotation were similar to the intact knee after PCL reconstruction with graft strengths ranging from 75% to 125% of an intact PCL. When the graft's strength surpassed 150%, the medial tibia moved forward and external tibial rotation greatly increased. The in-situ forces generated in the PCL grafts ranged from 13.15 N to 75.82 N, depending on the stiffness. In conclusion, the strength of PCL grafts have has a noticeable effect on anterior-posterior translation of the medial tibial compartment and its insitu force. Similar kinematic response may happen in the models when the PCL graft's strength lies between 75% and 125% of an intact PCL.

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Gibson, L. J. The mechanical behaviour of cancellous bone. J. Biomech. 1985, 18 (5), 317– 28, DOI: 10.1016/0021-9290(85)90287-8

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The mechanical behaviour of cancellous bone

Gibson L J

Journal of biomechanics (1985), 18 (5), 317-28 ISSN:0021-9290.

Cancellous bone has a cellular structure: it is made up of a connected network of rods and plates. Because of this, its mechanical behaviour is similar to that of other cellular materials such as polymeric foams. A recent study on the mechanisms of deformation in such materials has led to an understanding of how their mechanical properties depend on their relative density, cell wall properties and cell geometry. In this paper, the results of this previous study are applied to cancellous bone in an attempt to further understand its mechanical behaviour. The results of the analysis agree reasonably well with experimental data available in the literature.

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Paxton, J.; Baar, K.; Grover, L. Current progress in enthesis repair: strategies for interfacial tissue engineering. Orthopedic Muscul. Sys. 2013, 1, DOI: 10.4172/2161-0533.S1-003 .

Benjamin, M. ; Ralphs, J. R. Fibrocartilage in tendons and ligaments--an adaptation to compressive load. J. Anat. 1998, 193 (Pt 4), 481– 494, DOI: 10.1046/j.1469-7580.1998.19340481.x

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Fibrocartilage in tendons and ligaments--an adaptation to compressive load

Benjamin M; Ralphs J R

Journal of anatomy (1998), 193 ( Pt 4) (), 481-94 ISSN:0021-8782.

Where tendons and ligaments are subject to compression, they are frequently fibrocartilaginous. This occurs at 2 principal sites: where tendons (and sometimes ligaments) wrap around bony or fibrous pulleys, and in the region where they attach to bone, i.e. at their entheses. Wrap-around tendons are most characteristic of the limbs and are commonly wider at their point of bony contact so that the pressure is reduced. The most fibrocartilaginous tendons are heavily loaded and permanently bent around their pulleys. There is often pronounced interweaving of collagen fibres that prevents the tendons from splaying apart under compression. The fibrocartilage can be located within fascicles, or in endo- or epitenon (where it may protect blood vessels from compression or allow fascicles to slide). Fibrocartilage cells are commonly packed with intermediate filaments which could be involved in transducing mechanical load. The ECM often contains aggrecan which allows the tendon to imbibe water and withstand compression. Type II collagen may also be present, particularly in tendons that are heavily loaded. Fibrocartilage is a dynamic tissue that disappears when the tendons are rerouted surgically and can be maintained in vitro when discs of tendon are compressed. Finite element analyses provide a good correlation between its distribution and levels of compressive stress, but at some locations fibrocartilage is a sign of pathology. Enthesis fibrocartilage is most typical of tendons or ligaments that attach to the epiphyses of long bones where it may also be accompanied by sesamoid and periosteal fibrocartilages. It is characteristic of sites where the angle of attachment changes throughout the range of joint movement and it reduces wear and tear by dissipating stress concentration at the bony interface. There is a good correlation between the distribution of fibrocartilage within an enthesis and the levels of compressive stress. The complex interlocking between calcified fibrocartilage and bone contributes to the mechanical strength of the enthesis and cartilage-like molecules (e.g. aggrecan and type II collagen) in the ECM contribute to its ability to withstand compression. Pathological changes are common and are known as enthesopathies.

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Olvera, D. ; Sathy, B. N. ; Kelly, D. J. Spatial Presentation of Tissue-Specific Extracellular Matrix Components along Electrospun Scaffolds for Tissue Engineering the Bone–Ligament Interface. ACS Biomater. Sci. Eng. 2020, 6 (9), 5145– 5161, DOI: 10.1021/acsbiomaterials.0c00337

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Spatial Presentation of Tissue-Specific Extracellular Matrix Components along Electrospun Scaffolds for Tissue Engineering the Bone-Ligament Interface

Olvera, Dinorath; Sathy, Binulal N.; Kelly, Daniel J.

ACS Biomaterials Science & Engineering (2020), 6 (9), 5145-5161CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)

The bone-ligament interface transitions from a highly organized type I collagen rich matrix to a nonmineralized fibrocartilage region and finally to a mineralized fibrocartilage region that interfaces with the bone. Therefore, engineering the bone-ligament interface requires a biomaterial substrate capable of maintaining or directing the spatially defined differentiation of multiple cell phenotypes. To date the appropriate combination of biophys. and biochem. factors that can be used to engineer such a biomaterial substrate remain unknown. Here we show that microfiber scaffolds functionalized with tissue-specific extracellular matrix (ECM) components can direct the differentiation of MSCs toward the phenotypes seen at the bone-ligament interface. Ligament-ECM (L-ECM) promoted the expression of the ligament-marker gene tenomodulin (TNMD) and higher levels of type I and III collagen expression compared to functionalization with com. available type I collagen. Functionalization of microfiber scaffolds with cartilage-ECM (C-ECM) promoted chondrogenesis of MSCs, as evidenced by adoption of a round cell morphol. and increased SRY-box 9 (SOX9) expression in the absence of exogenous growth factors. Next, we fabricated a multiphasic scaffold by controlling the spatial presentation of L-ECM and C-ECM along the length of a single electrospun microfiber construct, with the distal region of the C-ECM coated fibers addnl. functionalized with an apatite layer (using simulated body fluid) to promote endochondral ossification. These ECM functionalized scaffolds promoted spatially defined differentiation of MSCs, with higher expression of TNMD obsd. in the region functionalized with L-ECM, and higher expression of type X collagen and osteopontin (markers of endochondral ossification) obsd. at the end of the scaffold functionalized with C-ECM and the apatite coating. Our results demonstrate the utility of tissue-specific ECM derived components as a cue for directing MSC differentiation when engineering complex multiphasic interfaces such as the bone-ligament enthesis.

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Kuntz, L. A. ; Rossetti, L. ; Kunold, E. ; Schmitt, A. ; von Eisenhart-Rothe, R. ; Bausch, A. R. ; Burgkart, R. H. Biomarkers for tissue engineering of the tendon-bone interface. PLoS One 2018, 13 (1), e0189668, DOI: 10.1371/journal.pone.0189668

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Biomarkers for tissue engineering of the tendon-bone interface

Kuntz, Lara A.; Rossetti, Leone; Kunold, Elena; Schmitt, Andreas; von Eisenhart-Rothe, Ruediger; Bausch, Andreas R.; Burgkart, Rainer H.

PLoS One (2018), 13 (1), e0189668/1-e0189668/24CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

The tendon-bone interface (enthesis) is a highly sophisticated biomaterial junction that allows stress transfer between mech. dissimilar materials. The enthesis encounters very high mech. demands and the regenerative capacity is very low resulting in high rupture recurrence rates after surgery. Tissue engineering offers the potential to recover the functional integrity of entheses. However, recent enthesis tissue engineering approaches have been limited by the lack of knowledge about the cells present at this interface. Here we investigated the cellular differentiation of enthesis cells and compared the cellular pattern of enthesis cells to tendon and cartilage cells in a next generation sequencing transcriptome study. We integrated the transcriptome data with proteome data of a previous study to identify biomarkers of enthesis cell differentiation. Transcriptomics detected 34468 transcripts in total in enthesis, tendon, and cartilage. Transcriptome comparisons revealed 3980 differentially regulated candidates for enthesis and tendon, 395 for enthesis and cartilage, and 946 for cartilage and tendon. An asym. distribution of enriched genes was obsd. in enthesis and cartilage transcriptome comparison suggesting that enthesis cells are more chondrocyte-like than tenocyte-like. Integrative anal. of transcriptome and proteome data identified ten enthesis biomarkers and six tendon biomarkers. The obsd. gene expression characteristics and differentiation markers shed light into the nature of the cells present at the enthesis. The presented markers will foster enthesis tissue engineering approaches by setting a bench-mark for differentiation of seeded cells towards a physiol. relevant phenotype.

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Petermann, H. ; Sander, M. Histological evidence for muscle insertion in extant amniote femora: implications for muscle reconstruction in fossils. J. Anat. 2013, 222 (4), 419– 436, DOI: 10.1111/joa.12028

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Histological evidence for muscle insertion in extant amniote femora: implications for muscle reconstruction in fossils

Petermann Holger; Sander Martin

Journal of anatomy (2013), 222 (4), 419-36 ISSN:.

Since the 19th century, identification of muscle attachment sites on bones has been important for muscle reconstructions, especially in fossil tetrapods, and therefore has been the subject of numerous biological and paleontological studies. At the microscopic level, in histological thin sections, the only features that can be used reliably for identifying tendon-bone or muscle-tendon-bone interactions are Sharpey's fibers. Muscles, however, do not only attach to the bone indirectly with tendons, but also directly. Previous studies failed to provide new indicators for muscle attachment, or to address the question of whether muscles with direct attachment can be identified histologically. However, histological identification of direct muscle attachments is important because these attachments do not leave visible marks (e.g. scars and rugosities) on the bone surface. We dissected the right hind limb and mapped the muscle attachment sites on the femur of one rabbit (Oryctolagus cuniculus), one Alligator mississippiensis, and one turkey (Meleagris cuniculus). We then extracted the femur and prepared four histological thin sections for the rabbit and the turkey and five histological thin sections for the alligator. Sharpey's fibers, vascular canal orientation, and a frayed periosteal margin can be indicators for indirect but also direct muscle attachment. Sharpey's fibers can be oriented to the cutting plane of the thin section at high angles, and two Sharpey's fibers orientations can occur in one area, possibly indicating a secondary force axis. However, only about 60% of mapped muscle attachment sites could be detected in thin sections, and frequently histological features suggestive of muscle attachment occurred outside mapped sites. While these insights should improve our ability to successfully identify and reconstruct muscles in extinct species, they also show the limitations of this approach.

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Aaron, J. Periosteal Sharpey's Fibres: a Novel Bone Matrix Regulatory System?. Front. Endocrinol. 2012, 3 , 98, DOI: 10.3389/fendo.2012.00098

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Periosteal Sharpey's fibers: a novel bone matrix regulatory system?

Aaron Jean E

Frontiers in endocrinology (2012), 3 (), 98 ISSN:.

Sharpey's "perforating" fibers (SF) are well known skeletally in tooth anchorage. Elsewhere they provide anchorage for the periosteum and are less well documented. Immunohistochemistry has transformed their potential significance by identifying their collagen type III (CIII) content and enabling their mapping in domains as permeating arrays of fibers (5-25 μ thick), protected from osteoclastic resorption by their poor mineralization. As periosteal extensions they are crucial in early skeletal development and central to intramembranous bone healing, providing unique microanatomical avenues for musculoskeletal exchange, their composition (e.g., collagen type VI, elastin, tenascin) combined with a multiaxial pattern of insertion suggesting a role more complex than attachment alone would justify. A proportion permeate the cortex to the endosteum (and beyond), fusing into a CIII-rich osteoid layer (<2 μ thick) encompassing all resting surfaces, and with which they apparently integrate into a PERIOSTEAL-SHARPEY FIBER-ENDOSTEUM (PSE) structural continuum. This intraosseous system behaves in favor of bone loss or gain depending upon extraneous stimuli (i.e., like Frost's hypothetical "mechanostat"). Thus, the birefringent fibers are sensitive to humoral factors (e.g., estrogen causes retraction, rat femur model), physical activity (e.g., running causes expansion, rat model), aging (e.g., causes fragmentation, pig mandible model), and pathology (e.g., atrophied in osteoporosis, hypertrophied in osteoarthritis, human proximal femur), and with encroaching mineral particles hardening the usually soft parts. In this way the unobtrusive periosteal SF network may regulate bone status, perhaps even contributing to predictable "hotspots" of trabecular disconnection, particularly at sites of tension prone to fatigue, and with the network deteriorating significantly before bone matrix loss.

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Lu, H. H. ; Thomopoulos, S. Functional attachment of soft tissues to bone: development, healing, and tissue engineering. Annu. Rev. Biomed. Eng. 2013, 15 , 201– 26, DOI: 10.1146/annurev-bioeng-071910-124656

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Functional attachment of soft tissues to bone: development, healing, and tissue engineering

Lu, Helen H.; Thomopoulos, Stavros

Annual Review of Biomedical Engineering (2013), 15 (), 201-226CODEN: ARBEF7; ISSN:1523-9829. (Annual Reviews)

Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in compn., structure, and mech. properties. These gradients minimize stress concns. and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solns. for their repair, interface regeneration remains a significant clin. challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the influence of mech. loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue-to-bone interface, and concludes with a summary of challenges and future directions.

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Apostolakos, J. ; Durant, T. J. ; Dwyer, C. R. ; Russell, R. P. ; Weinreb, J. H. ; Alaee, F. ; Beitzel, K. ; McCarthy, M. B. ; Cote, M. P. ; Mazzocca, A. D. The enthesis: a review of the tendon-to-bone insertion. Muscles, ligaments and tendons journal 2019, 4 (3), 333, DOI: 10.32098/mltj.03.2014.12

Ker, D. F. E. ; Wang, D. ; Behn, A. W. ; Wang, E. T. H. ; Zhang, X. ; Zhou, B. Y. ; Mercado-Pagán, Á. E. ; Kim, S. ; Kleimeyer, J. ; Gharaibeh, B. Functionally Graded, Bone-and Tendon-Like Polyurethane for Rotator Cuff Repair. Adv. Funct. Mater. 2018, 28 (20), 1707107, DOI: 10.1002/adfm.201707107

Benjamin, M. ; Kumai, T. ; Milz, S. ; Boszczyk, B. ; Boszczyk, A. A. ; Ralphs, J. The skeletal attachment of tendons─tendon 'entheses'. Comp. Biochem. Physiol., Part A: Mol. Integr. Physiol. 2002, 133 (4), 931– 945, DOI: 10.1016/S1095-6433(02)00138-1

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The skeletal attachment of tendons-tendon entheses'

Benjamin, M.; Kumai, T.; Milz, S.; Boszczyk, B. M.; Boszczyk, A. A.; Ralphs, J. R.

Comparative Biochemistry and Physiology, Part A: Molecular & Integrative Physiology (2002), 133A (4), 931-945CODEN: CBPAB5; ISSN:1095-6433. (Elsevier Science Inc.)

Tendon entheses can be classed as fibrous or fibrocartilaginous according to the tissue present at the skeletal attachment site. The former can be bony' or periosteal', depending on whether the tendon is directly attached to bone or indirectly to it via the periosteum. At fibrocartilaginous entheses, the uncalcified fibrocartilage dissipates collagen fiber bending and tendon narrowing away from the tidemark; calcified fibrocartilage anchors the tendon to the bone and creates a diffusion barrier between the two. Where there are addnl. fibrocartilaginous specialisations in the tendon and/or bone next to the enthesis, an enthesis organ' is created that reduces wear and tear. Little attention has been paid to bone at entheses, despite the obvious bearing this has on the mech. properties of the interface and the clin. importance of avulsion fractures. Disorders at entheses (enthesopathies) are common and occur in conditions such as diffuse idiopathic skeletal hyperostosis and the seroneg. spondyloarthropathies. They are also commonly seen as sporting injuries such as tennis elbow and jumper's knee.

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Milz, S. ; Rufai, A. ; Buettner, A. ; Putz, R. ; Ralphs, J. ; Benjamin, M. Three-dimensional reconstructions of the Achilles tendon insertion in man. J. Anat. 2002, 200 (2), 145– 152, DOI: 10.1046/j.0021-8782.2001.00016.x

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Three-dimensional reconstructions of the Achilles tendon insertion in man

Milz S; Rufai A; Buettner A; Putz R; Ralphs J R; Benjamin M

Journal of anatomy (2002), 200 (Pt 2), 145-52 ISSN:0021-8782.

The distribution of type II collagen in sagittal sections of the Achilles tendon has been used to reconstruct the three-dimensional (3D) shape and position of three fibrocartilages (sesamoid, periosteal and enthesis) associated with its insertion. The results showed that there is a close correspondence between the shape and position of the sesamoid and periosteal fibrocartilages--probably because of their functional interdependence. The former protects the tendon from compression during dorsiflexion of the foot, and the latter protects the superior tuberosity of the calcaneus. When the zone of calcified enthesis fibrocartilage and the subchondral bone are mapped in 3D, the reconstructions show that there is a complex pattern of interlocking between pieces of calcified fibrocartilage and bone at the insertion site. We suggest that this is of fundamental importance in anchoring the tendon to the bone, because the manner in which a tendon insertion develops makes it unlikely that many collagen fibres pass across the tissue boundary from tendon to bone. When force is transmitted to the bone from a loaded tendon, it is directed towards the plantar fascia by a series of highly orientated trabeculae that are clearly visible in 3D in thick resin sections.

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Gao, J. ; Messner, K. Quantitative comparison of soft tissue-bone interface at chondral ligament insertions in the rabbit knee joint. J. Anat. 1996, 188 , 367– 372

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Quantitative comparison of soft tissue-bone interface at chondral ligament insertions in the rabbit knee joint

Gao J; Messner K

Journal of anatomy (1996), 188 ( Pt 2) (), 367-73 ISSN:0021-8782.

At chondral ligament insertions the calcified fibrocartilage interdigitates deeply with the lamellar bone. The shape of this interface is formed under physiological loading conditions. For the purpose of morphological comparison between different ligament entheses in the rabbit knee, the number and frequency of interdigitations and thickness of calcified fibrocartilage were quantitated at the femoral insertion of the medial collateral ligament, both insertions of the cruciate ligaments, and the tibial insertion of the patellar ligament. Among the insertions, the femoral insertion of the medial collateral ligament showed the lowest frequency and depth of interdigitations at the soft tissue-bone interface, but had the thickest zone of calcified fibrocartilage. An inverse relationship was found at the insertion interface of the cruciate and patellar ligaments. The frequency and depth of interdigations at the bone-soft tissue interface at different chondral entheses seem to be related to the mechanical strength of the respective ligament; meanwhile it may be hypothesised that the thickness of the calcified fibrocartilage might be more related to the amount of motion which takes place at an insertion.

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Zhao, L. ; Thambyah, A. ; Broom, N. D. A multi-scale structural study of the porcine anterior cruciate ligament tibial enthesis. J. Anat. 2014, 224 (6), 624– 633, DOI: 10.1111/joa.12174

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A multi-scale structural study of the porcine anterior cruciate ligament tibial enthesis

Zhao Lei; Thambyah Ashvin; Broom Neil D

Journal of anatomy (2014), 224 (6), 624-33 ISSN:.

Like the human anterior cruciate ligament (ACL), the porcine ACL also has a double bundle structure and several biomechanical studies using this model have been carried out to show the differential effect of these two bundles on macro-level knee joint function. It is hypothesised that if the different bundles of the porcine ACL are mechanically distinct in function, then a multi-scale anatomical characterisation of their individual enthesis will also reveal significant differences in structure between the bundles. Twenty-two porcine knee joints were cleared of their musculature to expose the intact ACL following which ligament-bone samples were obtained. The samples were fixed in formalin followed by decalcification with formic acid. Thin sections containing the ligament insertion into the tibia were then obtained by cryosectioning and analysed using differential interference contrast (DIC) optical microscopy and scanning electron microscopy (SEM). At the micro-level, the anteromedial (AM) bundle insertion at the tibia displayed a significant deep-rooted interdigitation into bone, while for the posterolateral (PL) bundle the fibre insertions were less distributed and more focal. Three sub-types of enthesis were identified in the ACL and related to (i) bundle type, (ii) positional aspect within the insertion, and (iii) specific bundle function. At the nano-level the fibrils of the AM bundle were significantly larger than those in the PL bundle. The modes by which the AM and PL fibrils merged with the bone matrix fibrils were significantly different. A biomechanical interpretation of the data suggests that the porcine ACL enthesis is a specialized, functionally graded structural continuum, adapted at the micro-to-nano scales to serve joint function at the macro level.

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Chan, Y. L. ; Ngan, A. H. ; King, N. M. Nano-scale structure and mechanical properties of the human dentine-enamel junction. Journal of the mechanical behavior of biomedical materials 2011, 4 (5), 785– 95, DOI: 10.1016/j.jmbbm.2010.09.003

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Nano-scale structure and mechanical properties of the human dentine-enamel junction

Chan Y L; Ngan A H W; King N M

Journal of the mechanical behavior of biomedical materials (2011), 4 (5), 785-95 ISSN:.

Despite being an interface between two mechanically mismatched phases of the soft dentine and hard enamel, the dentine-enamel junction (DEJ) in a human tooth is in general capable of withstanding a long working life of repeated dynamic loading. The current poor understanding of the structure and properties of the DEJ has presented a major obstacle to designing better therapeutic protocols for complications concerning the DEJ. In this investigation, it was discovered that the DEJ is a thin, but gradual interface with characteristics transiting from those of dentine to those of enamel. The collagen fibres in dentine enter into the enamel side of the DEJ and terminate in a region in which the hydroxyapatite crystals begin to show enamel characteristics. Using focused ion beam machining, micro-beams were fabricated from regions within 50 μm of the DEJ and were subjected to bend tests. In spite of the similarity in the flexural strength of the DEJ and enamel, fractographs revealed cracks in the DEJ that propagated along structures with dentine characteristics. To the best of our knowledge, this is the first report on the testing of the mechanical properties of the DEJ.

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Thorp, H. ; Kim, K. ; Kondo, M. ; Maak, T. ; Grainger, D. W. ; Okano, T. Trends in Articular Cartilage Tissue Engineering: 3D Mesenchymal Stem Cell Sheets as Candidates for Engineered Hyaline-Like Cartilage. Cells 2021, 10 (3), 643, DOI: 10.3390/cells10030643

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Trends in articular cartilage tissue engineering: 3D mesenchymal stem cell sheets as candidates for engineered hyaline-like cartilage

Thorp, Hallie; Kim, Kyungsook; Kondo, Makoto; Maak, Travis; Grainger, David W.; Okano, Teruo

Cells (2021), 10 (3), 643CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)

Articular cartilage defects represent an inciting factor for future osteoarthritis (OA) and degenerative joint disease progression. Despite multiple clin. available therapies that succeed in providing short term pain redn. and restoration of limited mobility, current treatments do not reliably regenerate native hyaline cartilage or halt cartilage degeneration at these defect sites. Novel therapeutics aimed at addressing limitations of current clin. cartilage regeneration therapies increasingly focus on allogeneic cells, specifically mesenchymal stem cells (MSCs), as potent, banked, and available cell sources that express chondrogenic lineage commitment capabilities. Innovative tissue engineering approaches employing allogeneic MSCs aim to develop three-dimensional (3D), chondrogenically differentiated constructs for direct and immediate replacement of hyaline cartilage, improve local site tissue integration, and optimize treatment outcomes. Among emerging tissue engineering technologies, advancements in cell sheet tissue engineering offer promising capabilities for achieving both in vitro hyaline-like differentiation and effective transplantation, based on controlled 3D cellular interactions and retained cellular adhesion mols. This review focuses on 3D MSC-based tissue engineering approaches for fabricating "ready-to-use" hyaline-like cartilage constructs for future rapid in vivo regenerative cartilage therapies. We highlight current approaches and future directions regarding development of MSC-derived cartilage therapies, emphasizing cell sheet tissue engineering, with specific focus on regulating 3D cellular interactions for controlled chondrogenic differentiation and post-differentiation transplantation capabilities.

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Lynch, H. ; Johannessen, W. ; Wu, J. ; Jawa, A. ; Elliott, D. Effect of fiber orientation and strain rate on the nonlinear uniaxial tensile material Properties of Tendon. J. Biomech. Eng. 2003, 125 , 726– 31, DOI: 10.1115/1.1614819

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Effect of fiber orientation and strain rate on the nonlinear uniaxial tensile material properties of tendon

Lynch Heather Anne; Johannessen Wade; Wu Jeffrey P; Jawa Andrew; Elliott Dawn M

Journal of biomechanical engineering (2003), 125 (5), 726-31 ISSN:0148-0731.

Tendons are exposed to complex loading scenarios that can only be quantified by mathematical models, requiring a full knowledge of tendon mechanical properties. This study measured the anisotropic, nonlinear, elastic material properties of tendon. Previous studies have primarily used constant strain-rate tensile tests to determine elastic modulus in the fiber direction. Data for Poisson's ratio aligned with the fiber direction and all material properties transverse to the fiber direction are sparse. Additionally, it is not known whether quasi-static constant strain-rate tests represent equilibrium elastic tissue behavior. Incremental stress-relaxation and constant strain-rate tensile tests were performed on sheep flexor tendon samples aligned with the tendon fiber direction or transverse to the fiber direction to determine the anisotropic properties of toe-region modulus (E0), linear-region modulus (E), and Poisson's ratio (v). Among the modulus values calculated, only fiber-aligned linear-region modulus (E1) was found to be strain-rate dependent. The E1 calculated from the constant strain-rate tests were significantly greater than the value calculated from incremental stress-relaxation testing. Fiber-aligned toe-region modulus (E(1)0 = 10.5 +/- 4.7 MPa) and linear-region modulus (E1 = 34.0 +/- 15.5 MPa) were consistently 2 orders of magnitude greater than transverse moduli (E(2)0 = 0.055 +/- 0.044 MPa, E2 = 0.157 +/- 0.154 MPa). Poisson's ratio values were not found to be rate-dependent in either the fiber-aligned (v12 = 2.98 +/- 2.59, n = 24) or transverse (v21 = 0.488 +/- 0.653, n = 22) directions, and average Poisson's ratio values in the fiber-aligned direction were six times greater than in the transverse direction. The lack of strain-rate dependence of transverse properties demonstrates that slow constant strain-rate tests represent elastic properties in the transverse direction. However, the strain-rate dependence demonstrated by the fiber-aligned linear-region modulus suggests that incremental stress-relaxation tests are necessary to determine the equilibrium elastic properties of tendon, and may be more appropriate for determining the properties to be used in elastic mathematical models.

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Eckstein, F. ; Hudelmaier, M. ; Putz, R. The effects of exercise on human articular cartilage. J. Anat. 2006, 208 (4), 491– 512, DOI: 10.1111/j.1469-7580.2006.00546.x

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The effects of exercise on human articular cartilage

Eckstein F; Hudelmaier M; Putz R

Journal of anatomy (2006), 208 (4), 491-512 ISSN:0021-8782.

The effects of exercise on articular hyaline articular cartilage have traditionally been examined in animal models, but until recently little information has been available on human cartilage. Magnetic resonance imaging now permits cartilage morphology and composition to be analysed quantitatively in vivo. This review briefly describes the methodological background of quantitative cartilage imaging and summarizes work on short-term (deformational behaviour) and long-term (functional adaptation) effects of exercise on human articular cartilage. Current findings suggest that human cartilage deforms very little in vivo during physiological activities and recovers from deformation within 90 min after loading. Whereas cartilage deformation appears to become less with increasing age, sex and physical training status do not seem to affect in vivo deformational behaviour. There is now good evidence that cartilage undergoes some type of atrophy (thinning) under reduced loading conditions, such as with postoperative immobilization and paraplegia. However, increased loading (as encountered by elite athletes) does not appear to be associated with increased average cartilage thickness. Findings in twins, however, suggest a strong genetic contribution to cartilage morphology. Potential reasons for the inability of cartilage to adapt to mechanical stimuli include a lack of evolutionary pressure and a decoupling of mechanical competence and tissue mass.

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Desmond, K. W. ; Zacchia, N. A. ; Waite, J. H. ; Valentine, M. T. Dynamics of mussel plaque detachment. Soft Matter 2015, 11 (34), 6832– 9, DOI: 10.1039/C5SM01072A

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Dynamics of mussel plaque detachment

Desmond, Kenneth W.; Zacchia, Nicholas A.; Waite, J. Herbert; Valentine, Megan T.

Soft Matter (2015), 11 (34), 6832-6839CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)

Mussels are well known for their ability to generate and maintain strong, long-lasting adhesive bonds under hostile conditions. Many prior studies attribute their adhesive strength to the strong chem. interactions between the holdfast and substrate. While chem. interactions are certainly important, adhesive performance is also detd. by contact geometry, and understanding the coupling between chem. interactions and the plaque shape and mech. properties is essential in deploying bioinspired strategies when engineering improved adhesives. To investigate how the shape and mech. properties of the mussel's plaque contribute to its adhesive performance, we use a custom built load frame capable of fully characterizing the dynamics of the detachment. With this, we can pull on samples along any orientation, while at the same time measuring the resulting force and imaging the bulk deformations of the plaque as well as the holdfast-substrate interface where debonding occurs. We find that the force-induced yielding of the mussel plaque improves the bond strength by two orders of magnitude and that the holdfast shape improves bond strength by an addnl. order of magnitude as compared to other simple geometries. These results demonstrate that optimizing the contact geometry can play as important a role on adhesive performance as optimizing the chem. interactions as obsd. in other organisms and model systems.

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Lee, B. P. ; Messersmith, P. B. ; Israelachvili, J. N. ; Waite, J. H. Mussel-Inspired Adhesives and Coatings. Annu. Rev. Mater. Res. 2011, 41 (1), 99– 132, DOI: 10.1146/annurev-matsci-062910-100429

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Mussel-inspired adhesives and coatings

Lee, Bruce P.; Messersmith, P. B.; Israelachvili, J. N.; Waite, J. H.

Annual Review of Materials Research (2011), 41 (), 99-132CODEN: ARMRCU; ISSN:1531-7331. (Annual Reviews Inc.)

A review. Mussels attach to solid surfaces in the sea. Their adhesion must be rapid, strong, and tough, or else they will be dislodged and dashed to pieces by the next incoming wave. Given the dearth of synthetic adhesives for wet polar surfaces, much effort was directed to characterizing and mimicking essential features of the adhesive chem. practiced by mussels. Studies of these organisms have uncovered important adaptive strategies that help to circumvent the high dielec. and solvation properties of water that typically frustrate adhesion. In a chem. vein, the adhesive proteins of mussels are heavily decorated with Dopa, a catecholic functionality. Various synthetic polymers were functionalized with catechols to provide diverse adhesive, sealant, coating, and anchoring properties, particularly for crit. biomedical applications.

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Banea, M. D. ; da Silva, L. F. M. Adhesively bonded joints in composite materials: an overview. Proc. Inst. Mech. Eng., Part L 2009, 223 (1), 1– 18, DOI: 10.1243/14644207JMDA219

Ebnesajjad, S.; Landrock, A. H. Chapter 3 - Material Surface Preparation Techniques. In Adhesives Technology Handbook, 3rd ed.; Ebnesajjad, S., Landrock, A. H. , Eds.; William Andrew Publishing: Boston, 2015; pp 35– 66.

Bogy, D. B. Edge-Bonded Dissimilar Orthogonal Elastic Wedges Under Normal and Shear Loading. J. Appl. Mech. 1968, 35 (3), 460– 466, DOI: 10.1115/1.3601236

Liu, Y. X. ; Thomopoulos, S. ; Birman, V. ; Li, J. S. ; Genin, G. M. Bi-material attachment through a compliant interfacial system at the tendon-to-bone insertion site. Mech. Mater. 2012, 44 , 83– 92, DOI: 10.1016/j.mechmat.2011.08.005

Deymier, A. C. ; An, Y. ; Boyle, J. J. ; Schwartz, A. G. ; Birman, V. ; Genin, G. M. ; Thomopoulos, S. ; Barber, A. H. Micro-mechanical properties of the tendon-to-bone attachment. Acta Biomater. 2017, 56 , 25– 35, DOI: 10.1016/j.actbio.2017.01.037

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Micro-mechanical properties of the tendon-to-bone attachment

Deymier Alix C; Thomopoulos Stavros; An Yiran; Boyle John J; Schwartz Andrea G; Birman Victor; Genin Guy M; Barber Asa H

Acta biomaterialia (2017), 56 (), 25-35 ISSN:.

The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue that connects stiff bone to compliant tendon. The attachment site at the micrometer scale exhibits gradients in mineral content and collagen orientation, which likely act to minimize stress concentrations. The physiological micromechanics of the attachment thus define resultant performance, but difficulties in sample preparation and mechanical testing at this scale have restricted understanding of structure-mechanical function. Here, microscale beams from entheses of wild type mice and mice with mineral defects were prepared using cryo-focused ion beam milling and pulled to failure using a modified atomic force microscopy system. Micromechanical behavior of tendon-to-bone structures, including elastic modulus, strength, resilience, and toughness, were obtained. Results demonstrated considerably higher mechanical performance at the micrometer length scale compared to the millimeter tissue length scale, describing enthesis material properties without the influence of higher order structural effects such as defects. Micromechanical investigation revealed a decrease in strength in entheses with mineral defects. To further examine structure-mechanical function relationships, local deformation behavior along the tendon-to-bone attachment was determined using local image correlation. A high compliance zone near the mineralized gradient of the attachment was clearly identified and highlighted the lack of correlation between mineral distribution and strain on the low-mineral end of the attachment. This compliant region is proposed to act as an energy absorbing component, limiting catastrophic failure within the tendon-to-bone attachment through higher local deformation. This understanding of tendon-to-bone micromechanics demonstrates the critical role of micrometer scale features in the mechanics of the tissue. STATEMENT OF SIGNIFICANCE: The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue with features at a numerous scales that dissipate stress concentrations between compliant tendon and stiff bone. At the micrometer scale, the enthesis exhibits gradients in collagen and mineral composition and organization. However, the physiological mechanics of the enthesis at this scale remained unknown due to difficulty in preparing and testing micrometer scale samples. This study is the first to measure the tensile mechanical properties of the enthesis at the micrometer scale. Results demonstrated considerably enhanced mechanical performance at the micrometer length scale compared to the millimeter tissue length scale and identified a high-compliance zone near the mineralized gradient of the attachment. This understanding of tendon-to-bone micromechanics demonstrates the critical role of micrometer scale features in the mechanics of the tissue.

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Liu, Y. ; Birman, V. ; Chen, C. ; Thomopoulos, S. ; Genin, G. M. Mechanisms of bimaterial attachment at the interface of tendon to bone. J. Eng. Mater. Technol. 2011, 133 (1), 011006, DOI: 10.1115/1.4002641

Friese, N. ; Gierschner, M. B. ; Schadzek, P. ; Roger, Y. ; Hoffmann, A. Regeneration of Damaged Tendon-Bone Junctions (Entheses)─TAK1 as a Potential Node Factor. Int. J. Mol. Sci. 2020, 21 (15), 5177, DOI: 10.3390/ijms21155177

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Regeneration of damaged tendon-bone junctions (Entheses)-TAK1 as a potential node factor

Friese, Nina; Gierschner, Mattis Benno; Schadzek, Patrik; Roger, Yvonne; Hoffmann, Andrea

International Journal of Molecular Sciences (2020), 21 (15), 5177CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

Musculoskeletal dysfunctions are highly prevalent due to increasing life expectancy. Consequently, novel solns. to optimize treatment of patients are required. The current major research focus is to develop innovative concepts for single tissues. However, interest is also emerging to generate applications for tissue transitions where highly divergent properties need to work together, as in bone-cartilage or bone-tendon transitions. Finding medical solns. for dysfunctions of such tissue transitions presents an added challenge, both in research and in clinics. This review aims to provide an overview of the anatomical structure of healthy adult entheses and their development during embryogenesis. Subsequently, important scientific progress in restoration of damaged entheses is presented. With respect to enthesis dysfunction, the review further focuses on inflammation. Although mol., cellular and tissue mechanisms during inflammation are well understood, tissue regeneration in context of inflammation still presents an unmet clin. need and goes along with unresolved biol. questions. Furthermore, this review gives particular attention to the potential role of a signaling mediator protein, transforming growth factor beta-activated kinase-1 (TAK1), which is at the node of regenerative and inflammatory signaling and is one example for a less regarded aspect and potential important link between tissue regeneration and inflammation.

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Ho, S. P. ; Marshall, S. J. ; Ryder, M. I. ; Marshall, G. W. The tooth attachment mechanism defined by structure, chemical composition and mechanical properties of collagen fibers in the periodontium. Biomaterials 2007, 28 (35), 5238– 5245, DOI: 10.1016/j.biomaterials.2007.08.031

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The tooth attachment mechanism defined by structure, chemical composition and mechanical properties of collagen fibers in the periodontium

Ho, Sunita P.; Marshall, Sally J.; Ryder, Mark I.; Marshall, Grayson W.

Biomaterials (2007), 28 (35), 5238-5245CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

In this study, a comparison between structure, chem. compn. and mech. properties of collagen fibers at three regions within a human periodontium, has enabled us to define a novel tooth attachment mechanism. The three regions include, (1) the enthesis region: Insertion site of periodontal ligament (PDL) fibers (collagen fibers) into cementum at the root surface, (2) bulk cementum, and (3) the cementum-dentin junction (CDJ). Structurally, continuity in collagen fibers was obsd. from the enthesis, through bulk cementum and CDJ. At the CDJ the collagen fibers split into individual collagen fibrils and intermingled with the extracellular matrix of mantle dentin. Under wet conditions, the collagen fibers at the three regions exhibited significant swelling suggesting a compn. rich in polyanionic mols. such as glycosaminoglycans. Addnl., site-specific indentation illustrated a comparable elastic modulus between collagen fibers at the enthesis (1-3 GPa) and the CDJ (2-4 GPa). However, the elastic modulus of collagen fibers within bulk cementum was higher (4-7 GPa) suggesting presence of extrafibrillar mineral. It is known that the tooth forms a fibrous joint with the alveolar bone, which is termed a gomphosis. Although narrower in width than the PDL space, the hygroscopic CDJ can also be termed as a gomphosis; a fibrous joint between cementum and root dentin capable of accommodating functional loads similar to that between cementum and alveolar bone. From an engineering perspective, it is proposed that a tooth contains two fibrous joints that accommodate the masticatory cyclic loads. These joints are defined by the attachment of dissimilar materials via graded stiffness interfaces, such as: (1) alveolar bone attached to cementum with the PDL; and (2) cementum to root dentin with the CDJ. Thus, through variations in concns. of basic constituents, distinct regions with characteristic structures and graded properties allow for attachment and the load bearing characteristics of a tooth.

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Chung, J. Y. ; Chaudhury, M. K. Soft and Hard Adhesion. J. Adhes. 2005, 81 (10–11), 1119– 1145, DOI: 10.1080/00218460500310887

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Soft and hard adhesion

Chung, Jun Young; Chaudhury, Manoj K.

Journal of Adhesion (2005), 81 (10-11), 1119-1145CODEN: JADNAJ; ISSN:0021-8464. (Taylor & Francis, Inc.)

The force needed to pull a cylindrical stud from a soft elastomeric film depends on their elastic and geometric properties. For a rigid stud and a thick elastomeric film, the pull-off stress (σ) depends on the elastic modulus (E) of the film and the radius (a) of the stud as σ ∼ (E/a)1/2 (soft adhesion). However, when the film is very thin, the pull-off stress is significantly higher than the case with thick films, and its value depends on the elastic modulus and the thickness (h) of the film as σ ∼ (E/h)1/2 (hard adhesion). Here, we study the pull-off behavior of a soft cylindrical stud, one flat end of which is coated with a high modulus thin baseplate. As the flexural rigidity of this baseplate is varied, we observe the transition between the two types of adhesion. We present a simple phys. interpretation of the problem, which could be of value in understanding various bio fouling and adhesive situations.

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Zhang, Y. ; Yao, H. ; Ortiz, C. ; Xu, J. ; Dao, M. Bio-inspired interfacial strengthening strategy through geometrically interlocking designs. J. Mech Behav Biomed Mater. 2012, 15 , 70– 7, DOI: 10.1016/j.jmbbm.2012.07.006

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Bio-inspired interfacial strengthening strategy through geometrically interlocking designs

Zhang Yuming; Yao Haimin; Ortiz Christine; Xu Jinquan; Dao Ming

Journal of the mechanical behavior of biomedical materials (2012), 15 (), 70-7 ISSN:.

Many biological materials, such as nacre and bone, are hybrid materials composed of stiff brittle ceramics and compliant organic materials. These natural organic/inorganic composites exhibit much enhanced strength and toughness in comparison to their constituents and inspires enormous biomimetic endeavors aiming to synthesize materials with superior mechanical properties. However, most current synthetic composites have not exhibited their full potential of property enhancement compared to the natural prototypes they are mimicking. One of the key issues is the weak junctions between stiff and compliant phases, which need to be optimized according to the intended functions of the composite material. Motivated by the geometrically interlocking designs of natural biomaterials, here we propose an interfacial strengthening strategy by introducing geometrical interlockers on the interfaces between compliant and stiff phases. Finite element analysis (FEA) shows that the strength of the composite depends strongly on the geometrical features of interlockers including shape, size, and structural hierarchy. Even for the most unfavorable scenario when neither adhesion nor friction is present between stiff and compliant phases, the tensile strength of the composites with proper interlocker design can reach up to 70% of the ideal value. The findings in this paper would provide guidelines to the improvement of the mechanical properties of current biomimetic composites.

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Han, L. ; Wang, L. ; Song, J. ; Boyce, M. C. ; Ortiz, C. Direct quantification of the mechanical anisotropy and fracture of an individual exoskeleton layer via uniaxial compression of micropillars. Nano Lett. 2011, 11 (9), 3868– 74, DOI: 10.1021/nl201968u

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Direct Quantification of the Mechanical Anisotropy and Fracture of an Individual Exoskeleton Layer via Uniaxial Compression of Micropillars

Han, Lin; Wang, Lifeng; Song, Juha; Boyce, Mary C.; Ortiz, Christine

Nano Letters (2011), 11 (9), 3868-3874CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

A common feature of the outer layer of protective biol. exoskeletons is structural anisotropy. We directly quantify the mech. anisotropy and fracture of an individual material layer of a hydroxyapatite (HAP)-based nanocomposite exoskeleton, the outmost ganoine of Polypterus senegalus scale. Uniaxial compression was conducted on cylindrical micropillars of ganoine fabricated via focused ion beam at different orientations relative to the hydroxyapatite rod long axis (θ = 0°, 45°, 90°). Engineering stress vs. strain curves revealed significant elastic and plastic anisotropy, off-axial strain hardening, and noncatastrophic crack propagation within ganoine. Off-axial compression (θ = 45°) showed the lowest elastic modulus, E (36.2 GPa), and yield stress, σY (0.81 GPa), while compression at θ = 0° showed the highest E (51.8 GPa) and σY (1.08 GPa). A 3-dimensional elastic-plastic composite nanostructural finite element model revealed this anisotropy was correlated to the alignment of the HAP rods and could facilitate energy dissipation and damage localization, thus preventing catastrophic failure upon penetration attacks.

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Wang, R. Z. ; Suo, Z. ; Evans, A. G. ; Yao, N. ; Aksay, I. A. Deformation mechanisms in nacre. J. Mater. Res. 2001, 16 (9), 2485– 2493, DOI: 10.1557/JMR.2001.0340

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Deformation mechanisms in nacre

Wang, R. Z.; Suo, Z.; Evans, A. G.; Yao, N.; Aksay, I. A.

Journal of Materials Research (2001), 16 (9), 2485-2493CODEN: JMREEE; ISSN:0884-2914. (Materials Research Society)

Nacre (mother-of-pearl) from mollusk shells is a biol. formed lamellar ceramic. The inelastic deformation of this material has been exptl. examd., with a focus on understanding the underlying mechanisms. Slip along the lamellae tablet interface has been ascertained by testing in compression with the boundaries oriented at 45° to the loading axis. The steady-state shear resistance, τss, has been detd. and inelastic strain shown to be as high as 8%. The inelastic deformation was realized by massive interlamellae shearing. Testing in tension parallel to the tablets indicates inelastic strain of ∼1%, occurring at a steady-state stress, σss ≈ 110 MPa. The strain was assocd. with the formation of multiple dilatation bands at the intertablet boundaries accompanied by interlamellae sliding. Nano-asperities on the aragonite tablets and their interposing topol. provide the resistance to interfacial sliding and establish the level of the stress needed to attain the inelastic strain. Detailed mechanisms and their significance for the design of robust ceramics are discussed.

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Launey, M. E. ; Munch, E. ; Alsem, D. H. ; Barth, H. B. ; Saiz, E. ; Tomsia, A. P. ; Ritchie, R. O. Designing highly toughened hybrid composites through nature-inspired hierarchical complexity. Acta Mater. 2009, 57 (10), 2919– 2932, DOI: 10.1016/j.actamat.2009.03.003

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Designing highly toughened hybrid composites through nature-inspired hierarchical complexity

Launey, M. E.; Munch, E.; Alsem, D. H.; Barth, H. B.; Saiz, E.; Tomsia, A. P.; Ritchie, R. O.

Acta Materialia (2009), 57 (10), 2919-2932CODEN: ACMAFD; ISSN:1359-6454. (Elsevier Ltd.)

The notion of replicating the unique fracture resistance of natural composites in synthetic materials has generated much interest but has yielded few real technol. advances. With ice-templated structures, the concept of hierarchical design can be applied to conventional compds. such as alumina and poly(Me methacrylate) (PMMA) to make bulk hybrid composites that display exceptional toughness that can be nearly 300 times higher in energy terms than either of their constituents. These toughnesses far surpass what can be expected from a simple rule of mixts. For an 80% Al2O3-PMMA composite, a fracture toughness >30 MPa-m1/2 was achieved at a tensile strength of ∼200 MPa. Indeed, in terms of specific strength and toughness, these properties for alumina-based ceramics are at best comparable to those of aluminum alloys. The approach is flexible and can be readily translated to multiple material combinations.

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Eugene Stanley, H. Fractal landscapes in physics and biology. Phys. A 1992, 186 (1), 1– 32, DOI: 10.1016/0378-4371(92)90362-T

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De Blasio, F. V. The role of suture complexity in diminishing strain and stress in ammonoid phragmocones. Lethaia 2008, 41 (1), 15– 24, DOI: 10.1111/j.1502-3931.2007.00037.x

Li, Y. ; Ortiz, C. ; Boyce, M. C. Bioinspired, mechanical, deterministic fractal model for hierarchical suture joints. Phys. Rev. E 2012, 85 (3 Pt 1), 031901, DOI: 10.1103/PhysRevE.85.031901

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Li, Yaning; Ortiz, Christine; Boyce, Mary C.

Physical Review E: Statistical, Nonlinear, and Soft Matter Physics (2012), 85 (3-1), 031901/1-031901/14CODEN: PRESCM; ISSN:1539-3755. (American Physical Society)

Many biol. systems possess hierarchical and fractal-like interfaces and joint structures that bear and transmit loads, absorb energy, and accommodate growth, respiration, and/or locomotion. In this paper, an elastic deterministic fractal composite mech. model was formulated to quant. investigate the role of structural hierarchy on the stiffness, strength, and failure of suture joints. From this model, it was revealed that the no. of hierarchies (N) can be used to tailor and to amplify mech. properties nonlinearly and with high sensitivity over a wide range of values (orders of magnitude) for a given vol. and wt. Addnl., increasing hierarchy was found to result in mech. interlocking of higher-order teeth, which creates addnl. load resistance capability, thereby preventing catastrophic failure in major teeth and providing flaw tolerance. Hence, this paper shows that the diversity of hierarchical and fractal-like interfaces and joints found in nature have definitive functional consequences and is an effective geometric-structural strategy to achieve different properties with limited material options in nature when other structural geometries and parameters are biol. challenging or inaccessible. This paper also indicates the use of hierarchy as a design strategy to increase design space and provides predictive capabilities to guide the mech. design of synthetic flaw-tolerant bioinspired interfaces and joints.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpslSltrw%253D&md5=416d14a0c47e6b713d5ca2c972eba108

Li, Y. ; Ortiz, C. ; Boyce, M. C. Stiffness and strength of suture joints in nature. Phys. Rev. E 2011, 84 (6 Pt 1), 062904, DOI: 10.1103/PhysRevE.84.062904

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Li, Yaning; Ortiz, Christine; Boyce, Mary C.

Physical Review E: Statistical, Nonlinear, and Soft Matter Physics (2011), 84 (6-1), 062904/1-062904/5CODEN: PRESCM; ISSN:1539-3755. (American Physical Society)

Suture joints are remarkable mech. structures found throughout nature composed of compliant interlocking seams connecting stiffer components. This study investigates the underlying mechanisms and the role of geometry governing the unique mech. behavior of suture joints. Anal. and numerical composite models are formulated for two suture geometries characterized by a single repeating wavelength (e.g., triangular and rectangular). Stiffness, strength, and local stress distributions are predicted to assess variations in deformation and failure mechanisms. A unique homogeneous stress field is obsd. throughout both the skeletal and interfacial components of the triangular geometry, thus providing advantages in load transmission, wt., stiffness, strength, energy absorption, and fatigue over the rectangular geometry. The results obtained have relevance to biomimetic design and optimization, suture growth and fusion, and evolutionary phenotype diversity.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFGgtQ%253D%253D&md5=f35cbbb255c988978fdeff7bf7bb8f90

Lin, E. ; Li, Y. ; Ortiz, C. ; Boyce, M. C. 3D printed, bio-inspired prototypes and analytical models for structured suture interfaces with geometrically-tuned deformation and failure behavior. J. Mech. Phys. Solids 2014, 73 , 166– 182, DOI: 10.1016/j.jmps.2014.08.011

Li, Y. ; Ortiz, C. ; Boyce, M. C. A generalized mechanical model for suture interfaces of arbitrary geometry. J. Mech. Phys. Solids 2013, 61 (4), 1144– 1167, DOI: 10.1016/j.jmps.2012.10.004

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Hosseini Maryam S; Cordisco Fernando A; Zavattieri Pablo D

Journal of the mechanical behavior of biomedical materials (2019), 96 (), 244-260 ISSN:.

Geometrically patterned interfaces seem to be a common motif in Nature. In particular, geometry plays an important role in increasing the strength, toughness and damage tolerance among different species. Here, we investigate the role of the shape of the opening crack behind the crack tip as the crack propagates along the interface. In particular, we studied the shape of the interface behind the crack tip for different amplitude-to-wavelength aspect ratios with two analytical models and compared with finite element simulations through the J-integral. Additionally, we explore the role of material length scale by investigating the relationship between the geometrical characteristic lengths and the emerging material length scale using a finite element-based cohesive zone model. The results suggest that geometrical toughening is influenced by a size effect, but it is bounded between two extreme conditions.

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Ahankari, S. S.; Kar, K. K. Functionally Graded Composites: Processing and Applications. In Composite Materials; Springer: Berlin, Heidelberg, 2017; pp 119– 168.

Mahamood, R. M. ; Member, E. T. A. ; Shukla, D. M. ; Pityana, S. Functionally graded material: An overview. World Congress on Engineering 2012, 3 , 2– 6

100

Pompe, W. ; Worch, H. ; Epple, M. ; Friess, W. ; Gelinsky, M. ; Greil, P. ; Hempel, U. ; Scharnweber, D. ; Schulte, K. Functionally graded materials for biomedical applications. Mater. Sci. Eng., A 2003, 362 (1), 40, DOI: 10.1016/S0921-5093(03)00580-X

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Functionally graded materials for biomedical applications

Pompe, W.; Worch, H.; Epple, M.; Friess, W.; Gelinsky, M.; Greil, P.; Hempel, U.; Scharnweber, D.; Schulte, K.

Materials Science & Engineering, A: Structural Materials: Properties, Microstructure and Processing (2003), A362 (1-2), 40-60CODEN: MSAPE3; ISSN:0921-5093. (Elsevier Science B.V.)

A review. Functional gradation is one characteristic feature of living tissue. Bio-inspired materials open new approaches for manufg. implants for bone replacement. Different routes for new implant materials are presented using the principle of functional gradation. An artificial biomaterial for knee joint replacement has been developed by building a graded structure consisting of ultra-high mol. wt. polyethylene (UHMWPE) fiber reinforced high-d. polyethylene combined with a surface of UHMWPE. The ingrowth behavior of titanium implants into hard tissue can be improved by depositing a graded biopolymer coating of fibronectin, collagen types I and III with a gradation, derived from the mechanisms occurring during healing in vivo. Functionally graded porous hydroxyapatite (HAP) ceramics can be produced using alternative routes, e.g. sintering of laminated structures of HAP tapes filled with polymer spheres or combining biodegradable polyesters such as polylactide, polylactide-co-glycolide and polyglycolide, with carbonated nanocryst. hydroxyapatite. HAP-collagen I scaffolds are an appropriate material for in vitro growth of bone. The scaffold has to be functionally graded in order to create an optimized mech. behavior as well as the intended improvement of the cell ingrowth.

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101

Rousseau, M. Nacre, a Natural Biomaterial. In Biomaterials Applications for Nanomedicine; Pignatello, R. , Ed.; InTech: 2011; pp 281– 298.

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Fratzl, P. ; Gupta, H. S. ; Fischer, F. D. ; Kolednik, O. Hindered Crack Propagation in Materials with Periodically Varying Young's Modulus─Lessons from Biological Materials. Adv. Mater. 2007, 19 (18), 2657– 2661, DOI: 10.1002/adma.200602394

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Hindered crack propagation in materials with periodically varying young's modulus-lessons from biological materials

Fratzl, Peter; Gupta, Himadri S.; Fischer, Franz Dieter; Kolednik, Otmar

Advanced Materials (Weinheim, Germany) (2007), 19 (18), 2657-2661CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

Many biol. materials, such as glass sponges, nacre or bone have a lamellar structure. While it is well known that weak interfaces between lamellae may deflect cracks and, thus, increase the toughness, we analyze the influence of periodic variations in Young's modulus. Even without weak interfaces, a ratio of 5 between max. and min. modulus can be sufficient to stop a crack in the vicinity of the stiffness min.

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Bouville, F. ; Stevenson, A. J. ; Deville, S. ; Maire, E. ; Meille, S. ; Van De Moortele, B. Strong, tough and stiff bioinspired ceramics from brittle constituents. Nat. Mater. 2014, 13 (5), 508– 514, DOI: 10.1038/nmat3915

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Strong, tough and stiff bioinspired ceramics from brittle constituents

Bouville, Florian; Maire, Eric; Meille, Sylvain; Van de Moortele, Bertrand; Stevenson, Adam J.; Deville, Sylvain

Nature Materials (2014), 13 (5), 508-514CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

High strength and high toughness are usually mutually exclusive in engineering materials. In ceramics, improving toughness usually relies on the introduction of a metallic or polymeric ductile phase, but this decreases the material's strength and stiffness as well as its high-temp. stability. Although natural materials that are both strong and tough rely on a combination of mechanisms operating at different length scales, the relevant structures have been extremely difficult to replicate. Here, we report a bioinspired approach based on widespread ceramic processing techniques for the fabrication of bulk ceramics without a ductile phase and with a unique combination of high strength (470 MPa), high toughness (22 MPa m1/2), and high stiffness (290 GPa). Because only mineral constituents are needed, these ceramics retain their mech. properties at high temps. (600°). Our bioinspired, material-independent approach should find uses in the design and processing of materials for structural, transportation and energy-related applications.

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Mahmoud, D. ; Mohamed, A. E. Lattice Structures and Functionally Graded Materials Applications in Additive Manufacturing of Orthopedic Implants: A Review. J. Manuf. Mater. Process. 2017, 1 (2), 13, DOI: 10.3390/jmmp1020013

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Lattice structures and functionally graded materials applications in additive manufacturing of orthopedic implants: a review

Mahmoud, Dalia; Elbestawi, Mohamed A.

Journal of Manufacturing and Materials Processing (2017), 1 (2), 13CODEN: JMMPBJ; ISSN:2504-4494. (MDPI AG)

A major advantage of additive manufg. (AM) technologies is the ability to print customized products, which makes these technologies well suited for the orthopedic implants industry. Another advantage is the design freedom provided by AM technologies to enhance the performance of orthopedic implants. This paper presents a state-of-the-art overview of the use of AM technologies to produce orthopedic implants from lattice structures and functionally graded materials. It discusses how both techniques can improve the implants' performance significantly, from a mech. and biol. point of view. The characterization of lattice structures and the most recent finite element anal. models are explored. Addnl., recent case studies that use functionally graded materials in biomedical implants are surveyed. Finally, this paper reviews the challenges faced by these two applications and suggests future research directions required to improve their use in orthopedic implants.

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Huiskes, R. ; Weinans, H. ; Van Rietbergen, B. The relationship between stress shielding and bone resorption around total hip stems and the effects of flexible materials. Clin. Orthop. Relat. Res. 1992, 124– 134, DOI: 10.1097/00003086-199201000-00014

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The relationship between stress shielding and bone resorption around total hip stems and the effects of flexible materials

Huiskes R; Weinans H; van Rietbergen B

Clinical orthopaedics and related research (1992), (274), 124-34 ISSN:0009-921X.

Bone resorption around hip stems is a disturbing phenomenon, although its clinical significance and its eventual effects on replacement longevity are as yet uncertain. The relationship between implant flexibility and the extent of bone loss, frequently established in clinical patient series and animal experiments, does suggest that the changes in bone morphology are an effect of stress shielding and a subsequent adaptive remodeling process. This relationship was investigated using strain-adaptive bone-remodeling theory in combination with finite element models to simulate the bone remodeling process. The effects of stem material flexibility, bone flexibility, and bone reactivity on the process and its eventual outcome were studied. Stem flexibility was also related to proximal implant/bone interface stresses. The results sustain the hypothesis that the resorptive processes are an effect of bone adaptation to stress shielding. The effects of stem flexibility are confirmed by the simulation analysis. It was also established that individual differences in bone reactivity and mechanical bone quality (density and stiffness) may account for the individual variations found in patients and animal experiments. Flexible stems reduce stress shielding and bone resorption. However, they increase proximal interface stresses. Hence, the cure against bone resorption they represent may develop into increased loosening rates because of interface debonding and micromotion. The methods presented in this paper can be used to establish optimal stem-design characteristics or check the adequacy of designs in preclinical testing procedures.

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Saini, M. ; Singh, Y. ; Arora, P. ; Arora, V. ; Jain, K. Implant biomaterials: A comprehensive review. World J. Clin Cases 2015, 3 (1), 52– 7, DOI: 10.12998/wjcc.v3.i1.52

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Implant biomaterials: A comprehensive review

Saini Monika; Singh Yashpal; Arora Pooja; Arora Vipin; Jain Krati

World journal of clinical cases (2015), 3 (1), 52-7 ISSN:2307-8960.

Appropriate selection of the implant biomaterial is a key factor for long term success of implants. The biologic environment does not accept completely any material so to optimize biologic performance, implants should be selected to reduce the negative biologic response while maintaining adequate function. Every clinician should always gain a thorough knowledge about the different biomaterials used for the dental implants. This article makes an effort to summarize various dental bio-materials which were used in the past and as well as the latest material used now.

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Ishikawa, K.; Matsuya, S.; Miyamoto, Y.; Kawate, K. 9.05 - Bioceramics. In Comprehensive Structural Integrity; Milne, I., Ritchie, R. O., Karihaloo, B. , Eds.; Pergamon: Oxford, 2003; pp 169– 214.

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Jones, J. R. ; Lin, S. ; Yue, S. ; Lee, P. D. ; Hanna, J. V. ; Smith, M. E. ; Newport, R. J. Bioactive glass scaffolds for bone regeneration and their hierarchical characterisation. Proc. Inst. Mech. Eng., Part H 2010, 224 (12), 1373– 87, DOI: 10.1243/09544119JEIM836

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Bioactive glass scaffolds for bone regeneration and their hierarchical characterisation

Jones J R; Lin S; Yue S; Lee P D; Hanna J V; Smith M E; Newport R J

Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine (2010), 224 (12), 1373-87 ISSN:0954-4119.

Scaffolds are needed that can act as temporary templates for bone regeneration and actively stimulate vascularized bone growth so that bone grafting is no longer necessary. To achieve this, the scaffold must have a suitable interconnected pore network and be made of an osteogenic material. Bioactive glass is an ideal material because it rapidly bonds to bone and degrades over time, releasing soluble silica and calcium ions that are thought to stimulate osteoprogenitor cells. Melt-derived bioactive glasses, such as the original Bioglass composition, are available commercially, but porous scaffolds have been difficult to produce because Bioglass and similar compositions crystallize on sintering. Sol-gel foam scaffolds have been developed that avoid this problem. They have a hierarchical pore structure comprising interconnected macropores, with interconnect diameters in excess of the 100 microm that is thought to be needed for vascularized bone ingrowth, and an inherent nanoporosity of interconnected mesopores (2-50 nm) which is beneficial for the attachment of osteoprogenitor cells. They also have a compressive strength in the range of cancellous bone. This paper describes the optimized sol-gel foaming process and illustrates the importance of optimizing the hierarchical structure from the atomic through nano, to the macro scale with respect to biological response.

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Mesquita, P. ; Branco, R. ; Afonso, A. ; Vasconcelos, M. ; Cavalheiro, J. Mineralised Membranes for Bone Regeneration. Key Eng. Mater. 2003, 254–256 , 1091– 1094, DOI: 10.4028/www.scientific.net/KEM.254-256.1091

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Liu, X. ; Rahaman, M. N. ; Fu, Q. Bone regeneration in strong porous bioactive glass (13–93) scaffolds with an oriented microstructure implanted in rat calvarial defects. Acta Biomater. 2013, 9 (1), 4889– 98, DOI: 10.1016/j.actbio.2012.08.029

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Bone regeneration in strong porous bioactive glass (13-93) scaffolds with an oriented microstructure implanted in rat calvarial defects

Liu, Xin; Rahaman, Mohamed N.; Fu, Qiang

Acta Biomaterialia (2013), 9 (1), 4889-4898CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

There is a need for synthetic bone graft substitutes to repair large bone defects resulting from trauma, malignancy and congenital diseases. Bioactive glass has attractive properties as a scaffold material but factors that influence its ability to regenerate bone in vivo are not well understood. In the present work, the ability of strong porous scaffolds of 13-93 bioactive glass with an oriented microstructure to regenerate bone was evaluated in vivo using a rat calvarial defect model. Scaffolds with an oriented microstructure of columnar pores (porosity = 50%; pore diam. = 50-150 μm) showed mostly osteoconductive bone regeneration, and new bone formation, normalized to the available pore area (vol.) of the scaffolds, increased from 37% at 12 wk to 55% at 24 wk. Scaffolds of the same glass with a trabecular microstructure (porosity = 80%; pore width = 100-500 μm), used as the pos. control, showed bone regeneration in the pores of 25% and 46% at 12 and 24 wk, resp. The brittle mech. response of the as-fabricated scaffolds changed markedly to an elastoplastic response in vivo at both implantation times. Thus, both groups of 13-93 bioactive glass scaffolds could potentially be used to repair large bone defects, but scaffolds with the oriented microstructure could also be considered for the repair of loaded bone.

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Von Euw, S. ; Wang, Y. ; Laurent, G. ; Drouet, C. ; Babonneau, F. ; Nassif, N. ; Azais, T. Bone mineral: new insights into its chemical composition. Sci. Rep. 2019, 9 (1), 8456, DOI: 10.1038/s41598-019-44620-6

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Bone mineral: new insights into its chemical composition

Von Euw Stanislas; Wang Yan; Laurent Guillaume; Babonneau Florence; Nassif Nadine; Azais Thierry; Von Euw Stanislas; Drouet Christophe

Scientific reports (2019), 9 (1), 8456 ISSN:.

Some compositional and structural features of mature bone mineral particles remain unclear. They have been described as calcium-deficient and hydroxyl-deficient carbonated hydroxyapatite particles in which a fraction of the PO4(3-) lattice sites are occupied by HPO4(2-) ions. The time has come to revise this description since it has now been proven that the surface of mature bone mineral particles is not in the form of hydroxyapatite but rather in the form of hydrated amorphous calcium phosphate. Using a combination of dedicated solid-state nuclear magnetic resonance techniques, the hydrogen-bearing species present in bone mineral and especially the HPO4(2-) ions were closely scrutinized. We show that these HPO4(2-) ions are concentrated at the surface of bone mineral particles in the so-called amorphous surface layer whose thickness was estimated here to be about 0.8 nm for a 4-nm thick particle. We also show that their molar proportion is much higher than previously estimated since they stand for about half of the overall amount of inorganic phosphate ions that compose bone mineral. As such, the mineral-mineral and mineral-biomolecule interfaces in bone tissue must be driven by metastable hydrated amorphous environments rich in HPO4(2-) ions rather than by stable crystalline environments of hydroxyapatite structure.

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Sunho, O. ; Namsik, O. ; Mark, A. ; Joo, L. O. Bioceramics for Tissue Engineering Applications – A Review. Am. J. Biochem. Biotechnol. 2006, 2 , 49– 56, DOI: 10.3844/ajbbsp.2006.49.56

113

Milazzo, M. ; Contessi Negrini, N. ; Scialla, S. ; Marelli, B. ; Farè, S. ; Danti, S. ; Buehler, M. J. Additive Manufacturing Approaches for Hydroxyapatite-Reinforced Composites. Adv. Funct. Mater. 2019, 29 (35), 1903055, DOI: 10.1002/adfm.201903055

114

Balani, K.; Verma, V.; Agarwal, A.; Narayan, R. Biosurfaces: a Materials Science and Engineering Perspective; John Wiley & Sons: 2015.

115

Ding, C. ; Qiao, Z. ; Jiang, W. ; Li, H. ; Wei, J. ; Zhou, G. ; Dai, K. Regeneration of a goat femoral head using a tissue-specific, biphasic scaffold fabricated with CAD/CAM technology. Biomaterials 2013, 34 (28), 6706– 16, DOI: 10.1016/j.biomaterials.2013.05.038

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Regeneration of a goat femoral head using a tissue-specific, biphasic scaffold fabricated with CAD/CAM technology

Ding, Chunming; Qiao, Zhiguang; Jiang, Wenbo; Li, Haowei; Wei, Jianhe; Zhou, Guangdong; Dai, Kerong

Biomaterials (2013), 34 (28), 6706-6716CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Tissue engineering is considered as a promising approach for the regeneration of biol. joint theor. and thus provides a potential treatment option for advanced osteoarthritis. However, no significant progresses so far have been made in regenerating biol. joint. In this study, a biphasic scaffold, which was consisted of polylactic acid-coated polyglycolic acid (PGA/PLA) scaffold and poly-ε-caprolactone/hydroxyapatite (PCL/HA) scaffold, was designed and used for regeneration of goat femoral head. The content of PLA and HA was optimized to a proper ratio, thus the scaffolds could achieve appropriate stiffness which was more conducive to articular cartilage and bone regeneration resp. Furthermore, computer-aided design and manufg. (CAD/CAM) technol. was employed to fabricate the biphasic scaffolds into the desired shape and structure. The biphasic scaffolds with fine cell biocompatibility matched perfectly. Chondrocytes and bone marrow stromal cells (BMSCs) were seeded into the scaffolds for cartilage and bone regeneration resp. After 10 wk of implantation in nude mice s.c., the cell-scaffold constructs successfully regenerated goat femoral heads. The regenerated femoral heads presented a precise appearance in shape and size similar to that of native goat femoral heads with a smooth, continuous, avascular, and homogeneous cartilage layer on the surface and stiff bone-like tissue in the microchannels of PCL/HA scaffold. Addnl., histol. examn. of the regenerated cartilage and bone showed typical histol. structures and biophys. properties similar to that of native ones with specific matrix deposition and a well-integrated osteochondral interface. The strategy established in the study provides a promising approach for regenerating a biol. joint which could be used to reconstruct the impaired joint.

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Castro, N. J. ; O'Brien, C. M. ; Zhang, L. G. Biomimetic biphasic 3-D nanocomposite scaffold for osteochondral regeneration. AIChE J. 2014, 60 (2), 432– 442, DOI: 10.1002/aic.14296

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Biomimetic biphasic 3-D nanocomposite scaffold for osteochondral regeneration

Castro, Nathan J.; O'Brien, Christopher M.; Zhang, Lijie Grace

AIChE Journal (2014), 60 (2), 432-442CODEN: AICEAC; ISSN:0001-1541. (John Wiley & Sons, Inc.)

Scaffold-based interfacial tissue engineering aims to not only provide the structural and mech. framework for cellular growth and tissue regeneration, but also direct cell behavior. Due to the disparity in compn. of the osteochondral (cartilage and bone) interface, this work has developed a novel biomimetic biphasic nanocomposite scaffold integrating two biocompatible polymers contg. tissue-specific growth factor-encapsulated core-shell nanospheres. Specifically, a poly(caprolactone) (PCL)-based bone layer was successfully integrated with a poly(ethylene glycol) (PEG) hydrogel cartilage layer. In addn., a novel nanosphere fabrication technique for efficient growth factor encapsulation and sustained delivery via a wet coaxial electrospray technique was developed. Human bone marrow mesenchymal stem cell (hMSC) adhesion, osteogenic, and chondrogenic differentiation were evaluated. Our in vitro results showed significantly improved hMSC adhesion and differentiation in bone and cartilage layers, resp. Studies have demonstrated promising results with novel biphasic nanocomposite scaffold for osteochondral tissue regeneration, thus, warranting further studies. © 2013 American Institute of Chem. Engineers AIChE J, 2013.

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Erisken, C. ; Kalyon, D. M. ; Wang, H. Functionally graded electrospun polycaprolactone and b-tricalcium phosphate nanocomposites for tissue engineering applications. Biomaterials 2008, 29 (30), 4065– 4073, DOI: 10.1016/j.biomaterials.2008.06.022

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Functionally graded electrospun polycaprolactone and β-tricalcium phosphate nanocomposites for tissue engineering applications

Erisken, Cevat; Kalyon, Dilhan M.; Wang, Hongjun

Biomaterials (2008), 29 (30), 4065-4073CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Fabricating functionally graded scaffolds from biodegradable polymers to enable the mimicking of native tissue is an important challenge. Here we demonstrate the fabrication and utilization of functionally graded non-woven meshes of polycaprolactone incorporated with tricalcium phosphate nanoparticles using a new hybrid twin-screw extrusion/electrospinning (TSEE) process, which allows the time-dependent feeding of various solid and liq. ingredients and their melting, dispersion, deaeration and pressurization together with electrospinning within the confines of a single process. Using this hybrid method, the concn. of tricalcium phosphate nanoparticles could be tailored to vary in a targeted/controlled manner between the two surfaces of the scaffold mesh. The graded scaffolds were seeded and cultured with mouse preosteoblast cells (MC3T3-E1). Within 4 wk, the tissue constructs revealed the formation of continuous gradations in extracellular matrix with various markers including collagen synthesis and mineralization, akin to the type of variations obsd. in the typical bone-cartilage interface in terms of the distributions of concn. of Ca particles and of mech. properties assocd. with this. The demonstrated hybrid method should allow much better control of the distributions of various ingredients, including the concns. of drugs/growth factors, as well as the porosity, mech. property, wettability, biodegrdn. rate distributions in tissue engineering scaffolds, aiming to mimic the elegant complex distributions found in native tissue.

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Barbeck, M. ; Serra, T. ; Booms, P. ; Stojanovic, S. ; Najman, S. ; Engel, E. ; Sader, R. ; Kirkpatrick, C. J. ; Navarro, M. ; Ghanaati, S. Analysis of the in vitro degradation and the in vivo tissue response to bi-layered 3D-printed scaffolds combining PLA and biphasic PLA/bioglass components - Guidance of the inflammatory response as basis for osteochondral regeneration. Bioactive materials 2017, 2 (4), 208– 223, DOI: 10.1016/j.bioactmat.2017.06.001

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118

Analysis of the in vitro degradation and the in vivo tissue response to bi-layered 3D-printed scaffolds combining PLA and biphasic PLA/bioglass components - Guidance of the inflammatory response as basis for osteochondral regeneration

Barbeck Mike; Serra Tiziano; Engel Elisabeth; Navarro Melba; Booms Patrick; Sader Robert; Kirkpatrick Charles James; Ghanaati Shahram; Stojanovic Sanja; Najman Stevo; Engel Elisabeth; Engel Elisabeth

Bioactive materials (2017), 2 (4), 208-223 ISSN:.

The aim of the present study was the in vitro and in vivo analysis of a bi-layered 3D-printed scaffold combining a PLA layer and a biphasic PLA/bioglass G5 layer for regeneration of osteochondral defects in vivo Focus of the in vitro analysis was on the (molecular) weight loss and the morphological and mechanical variations after immersion in SBF. The in vivo study focused on analysis of the tissue reactions and differences in the implant bed vascularization using an established subcutaneous implantation model in CD-1 mice and established histological and histomorphometrical methods. Both scaffold parts kept their structural integrity, while changes in morphology were observed, especially for the PLA/G5 scaffold. Mechanical properties decreased with progressive degradation, while the PLA/G5 scaffolds presented higher compressive modulus than PLA scaffolds. The tissue reaction to PLA included low numbers of BMGCs and minimal vascularization of its implant beds, while the addition of G5 lead to higher numbers of BMGCs and a higher implant bed vascularization. Analysis revealed that the use of a bi-layered scaffold shows the ability to observe distinct in vivo response despite the physical proximity of PLA and PLA/G5 layers. Altogether, the results showed that the addition of G5 enables to reduce scaffold weight loss and to increase mechanical strength. Furthermore, the addition of G5 lead to a higher vascularization of the implant bed required as basis for bone tissue regeneration mediated by higher numbers of BMGCs, while within the PLA parts a significantly lower vascularization was found optimally for chondral regeneration. Thus, this data show that the analyzed bi-layered scaffold may serve as an ideal basis for the regeneration of osteochondral tissue defects. Additionally, the results show that it might be able to reduce the number of experimental animals required as it may be possible to analyze the tissue response to more than one implant in one experimental animal.

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Hajiali, F. ; Tajbakhsh, S. ; Shojaei, A. Fabrication and Properties of Polycaprolactone Composites Containing Calcium Phosphate-Based Ceramics and Bioactive Glasses in Bone Tissue Engineering: A Review. Polym. Rev. 2018, 58 (1), 164– 207, DOI: 10.1080/15583724.2017.1332640

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119

Fabrication and Properties of Polycaprolactone Composites Containing Calcium Phosphate-Based Ceramics and Bioactive Glasses in Bone Tissue Engineering: A Review

Hajiali, Faezeh; Tajbakhsh, Saeid; Shojaei, Akbar

Polymer Reviews (Philadelphia, PA, United States) (2018), 58 (1), 164-207CODEN: PRPPCY; ISSN:1558-3716. (Taylor & Francis, Inc.)

A review. Polycaprolactone (PCL) is a bioresorbable and biocompatible polymer that has been widely used in long-term implants and controlled drug release applications. However, when it comes to tissue engineering, PCL suffers from some shortcomings such as slow degrdn. rate, poor mech. properties, and low cell adhesion. The incorporation of calcium phosphate-based ceramics and bioactive glasses into PCL has yielded a class of hybrid biomaterials with remarkably improved mech. properties, controllable degrdn. rates, and enhanced bioactivity that are suitable for bone tissue engineering. This review presents a comprehensive study on recent advances in the fabrication and properties of PCL-based composite scaffolds contg. calcium phosphate-based ceramics and bioglasses in terms of porosity, degrdn. rate, mech. properties, in vitro and in vivo biocompatibility and bioactivity for bone regeneration applications. The fabrication routes range from traditional methods such as solvent casting and particulate leaching to novel approaches including solid free-form techniques.

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Shalumon, K. T. ; Sheu, C. ; Fong, Y. T. ; Liao, H.-T. ; Chen, J.-P. Microsphere-Based Hierarchically Juxtapositioned Biphasic Scaffolds Prepared from Poly(Lactic-co-Glycolic Acid) and Nanohydroxyapatite for Osteochondral Tissue Engineering. Polymers 2016, 8 (12), 429, DOI: 10.3390/polym8120429

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120

Microsphere-based hierarchically juxtapositioned biphasic scaffolds prepared frompoly(lactic-co-glycolic acid) and nanohydroxyapatite for osteochondral tissue engineering

Shalumon, K. T.; Sheu, Chialin; Fong, Yi Teng; Liao, Han-Tsung; Chen, Jyh-Ping

Polymers (Basel, Switzerland) (2016), 8 (12), 429/1-429/30CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)

This study aims to prep. biphasic osteochondral scaffolds based on seamless joining of sintered polymer and polymer/ceramic microspheres for co-culture of chondrocytes and bone marrow stem cells (BMSCs). Poly(lactide-co-glycolide) (PLGA) microspheres and 10% nanohydroxyapatite (nHAP)-incorporated PLGA (PGA/nHAP) microspheres were prepd. through the oil-in-water pptn. method. Virgin (V) and composite (C) scaffolds were prepd. from 250-500μm PLGA and PLGA/nHAP microspheres, resp., while osteochondral (OC) scaffolds were fabricated through the combination of V and C scaffolds. Physico-chem. properties of scaffolds were characterized through microscopic-spectroscopic evaluations. The effect of nHAP in scaffolds was investigated through thermogravimetric anal. and mech. testing, while surface hydrophobicity was tested through contact angle measurements. Rabbit chondrocytes and BMSCs were used for cell culture, and cell morphol. and proliferation were detd. from SEM and DNA assays. Alizarin red and Alcian blue stains were used to identify the in vitro bone and cartilage tissue-specific regeneration, while cetylpyridinium chloride was used to quant. est. calcium in mineralized bone. For co-culture in OC scaffolds, BMSCs were first seeded in the bone part of the scaffold and cultured in osteogenic medium, followed by seeding chondrocytes in the cartilage part, and cultured in chondrocyte medium. High cell viability was confirmed from the Live/Dead assays. Actin cytoskeleton organization obtained by DAPI-phalloidin staining revealed proper organization of chondrocytes and BMSCs in OC scaffolds. Immunofluorescent staining of bone (type I collagen and osteocalcin (OCN)) and cartilage marker proteins (type II collagen (COL II)) confirmed cellular behavior of osteoblasts and chondrocytes in vitro. Using an ectopic osteochondral defect model by s.c. implantation of co-cultured OC scaffolds in nude mice confirmed cell proliferation and tissue development from gross view and SEM observation. IF staining of OCN and COL II in the bone and cartilage parts of OC scaffolds and tissue-specific histol. anal. exhibited a time-dependent tissue re-modeling and confirmed the potential application of the biphasic scaffold in osteochondral tissue engineering.

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Schaefer, D. ; Martin, I. ; Shastri, P. ; Padera, R. F. ; Langer, R. ; Freed, L. E. ; Vunjak-Novakovic, G. In vitro generation of osteochondral composites. Biomaterials 2000, 21 (24), 2599– 2606, DOI: 10.1016/S0142-9612(00)00127-7

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121

In vitro generation of osteochondral composites

Schaefer, D.; Martin, I.; Shastri, P.; Padera, R. F.; Langer, R.; Freed, L. E.; Vunjak-Novakovic, G.

Biomaterials (2000), 21 (24), 2599-2606CODEN: BIMADU; ISSN:0142-9612. (Elsevier Science Ltd.)

Osteochondral repair involves the regeneration of articular cartilage and underlying bone, and the development of a well-defined tissue-to-tissue interface. We investigated tissue engineering of three-dimensional cartilage/bone composites based on biodegradable polymer scaffolds, chondrogenic and osteogenic cells. Cartilage constructs were created by cultivating primary bovine calf articular chondrocytes on polyglycolic acid meshes; bone-like constructs were created by cultivating expanded bovine calf periosteal cells on foams made of a blend of poly-lactic-co-glycolic acid and polyethylene glycol. Pairs of constructs were sutured together after 1 or 4 wk of isolated culture, and the resulting composites were cultured for an addnl. 4 wk. All composites were structurally stable and consisted of well-defined cartilaginous and bone-like tissues. The fraction of glycosaminoglycan in the cartilaginous regions increased with time, both in isolated and composite cultures. In contrast, the mineralization in bone-like regions increased during isolated culture, but remained approx. const. during the subsequent composite culture. The integration at the cartilage/bone interface was generally better for composites consisting of immature (1-wk) than mature (4-wk) constructs. This study demonstrates that osteochondral tissue composites for potential use in osteochondral repair can be engineered in vitro by culturing mammalian chondrocytes and periosteal cells on appropriate polymer scaffolds.

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Astete, C. ; Sabliov, C. Synthesis and characterization of PLGA nanoparticles. J. Biomater. Sci., Polym. Ed. 2006, 17 (3), 247– 289, DOI: 10.1163/156856206775997322

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122

Synthesis and characterization of PLGA nanoparticles

Astete, Carlos E.; Sabliov, Cristina M.

Journal of Biomaterials Science, Polymer Edition (2006), 17 (3), 247-289CODEN: JBSEEA; ISSN:0920-5063. (VSP)

A review. Poly(lactide-co-glycolide) (PLGA) nanoparticles of different phys. characteristics (size, size distribution, morphol., zeta potential) can be synthesized by controlling the parameters specific to the synthesis method employed. The aim of this review is to clearly, quant. and comprehensively describe the top-down synthesis techniques available for PLGA nanoparticle formation, as well as the techniques commonly used for nanoparticle characterization. Many examples are discussed in detail to provide the reader with an extensive knowledge base on the important parameters specific to the synthesis method described and ways in which these parameters can be manipulated to control the nanoparticle phys. characteristics.

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Tahriri, M. ; Moztarzadeh, F. Preparation, characterization, and in vitro biological evaluation of PLGA/nano-fluorohydroxyapatite (FHA) microsphere-sintered scaffolds for biomedical applications. Appl. Biochem. Biotechnol. 2014, 172 (5), 2465– 79, DOI: 10.1007/s12010-013-0696-y

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123

Preparation, characterization, and in vitro biological evaluation of PLGA/nano-fluorohydroxyapatite (FHA) microsphere-sintered scaffolds for biomedical applications

Tahriri, Mohammadreza; Moztarzadeh, Fathollah

Applied Biochemistry and Biotechnology (2014), 172 (5), 2465-2479CODEN: ABIBDL; ISSN:0273-2289. (Springer)

In this research, the novel three-dimensional (3D) porous scaffolds made of poly(lactic-co-glycolic acid) (PLGA)/nano-fluorohydroxyapatite (FHA) composite microspheres was prepd. and characterize for potential bone repair applications. We employed a microsphere sintering method to produce 3D PLGA/nano-FHA scaffolds composite microspheres. The mech. properties, pore size, and porosity of the composite scaffolds were controlled by varying parameters, such as sintering temp., sintering time, and PLGA/nano-FHA ratio. The exptl. results showed that the PLGA/nano-FHA (4:1) scaffold sintered at 90 °C for 2 h demonstrated the highest mech. properties and an appropriate pore structure for bone tissue engineering applications. Furthermore, MTT assay and alk. phosphatase activity (ALP activity) results ascertained that a general trend of increasing in cell viability was seen for PLGA/nano-FHA (4:1) scaffold sintered at 90 °C for 2 h by time with compared to control group. Eventually, obtained exptl. results demonstrated PLGA/nano-FHA microsphere-sintered scaffold deserve attention utilizing for bone tissue engineering.

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Dwivedi, R. ; Kumar, S. ; Pandey, R. ; Mahajan, A. ; Nandana, D. ; Katti, D. S. ; Mehrotra, D. Polycaprolactone as biomaterial for bone scaffolds: Review of literature. Journal of Oral Biology and Craniofacial Research 2020, 10 (1), 381– 388, DOI: 10.1016/j.jobcr.2019.10.003

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124

Polycaprolactone as biomaterial for bone scaffolds: Review of literature

Dwivedi Ruby; Nandana Deepti; Mehrotra Divya; Kumar Sumit; Pandey Rahul; Mahajan Aman; Katti Dhirendra S

Journal of oral biology and craniofacial research (2020), 10 (1), 381-388 ISSN:2212-4268.

Bone tissue engineering using polymer based scaffolds have been studied a lot in last decades. Considering the qualities of all the polymers desired to be used as scaffolds, Polycaprolactone (PCL) polyester apart from being biocompatible and biodegradable qualifies to an appreciable level due its easy availability, cost efficacy and suitability for modification. Its adjustable physio-chemical state, biological properties and mechanical strength renders it to withstand physical, chemical and mechanical, insults without significant loss of its properties. This review aims to critically analyse the efficacy of PCL as a biomaterial for bone scaffolds.

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Wong, B. L. ; Sah, R. L. Mechanical asymmetry during articulation of tibial and femoral cartilages: local and overall compressive and shear deformation and properties. J. Biomech. 2010, 43 (9), 1689– 1695, DOI: 10.1016/j.jbiomech.2010.02.035

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125

Mechanical asymmetry during articulation of tibial and femoral cartilages: local and overall compressive and shear deformation and properties

Wong Benjamin L; Sah Robert L

Journal of biomechanics (2010), 43 (9), 1689-95 ISSN:.

During knee movement, femoral cartilage articulates against cartilage from the tibial plateau, and the resulting mechanical behavior is yet to be fully characterized. The objectives of this study were to determine (1) the overall and depth-varying axial and shear strains and (2) the associated moduli, of femoral and tibial cartilages during the compression and shearing of apposing tibial and femoral samples. Osteochondral blocks from human femoral condyles (FCs) characterized as normal and donor-matched lateral tibial plateau (TP) were apposed, compressed 13%, and subjected to relative lateral motion. When surfaces began to slide, axial (-E(zz)) and shear (E(xz)) strains and compressive (E) and shear (G) moduli, overall and as a function of depth, were determined for femoral and tibial cartilages. Tibial -E(zz) was approximately 2-fold greater than FC -E(zz) near the surface (0.38 versus 0.22) and overall (0.16 versus 0.07). Near the surface, E(xz) of TP was 8-fold higher than that of FC (0.41 versus 0.05), while overall E(xz) was 4-fold higher (0.09 versus 0.02). For TP and FC, -E(zz) and E(xz) were greatest near the surface and decreased monotonically with depth. E for FC was 1.7-fold greater than TP, both near the surface (0.40 versus 0.24MPa) and overall (0.76 versus 0.47MPa). Similarly, G was 7-fold greater for FC (0.22MPa) than TP near the surface (0.03MPa) and 3-fold higher for FC (0.38MPa) than TP (0.13MPa) overall. These results indicate that tibial cartilage deforms and strains more axially and in shear than the apposing femoral cartilage during tibial-femoral articulation, reflecting their respective moduli.

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Abdullah, S. Usage of synthetic tendons in tendon reconstruction. BMC Proc. 2015, 9 (Suppl 3), A68– A68, DOI: 10.1186/1753-6561-9-S3-A68

127

Senatov, F. S. ; Kopylov, A. N. ; Anisimova, N. Y. ; Kiselevsky, M. V. ; Maksimkin, A. V. UHMWPE-based nanocomposite as a material for damaged cartilage replacement. Mater. Sci. Eng., C 2015, 48 , 566– 571, DOI: 10.1016/j.msec.2014.12.050

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UHMWPE-based nanocomposite as a material for damaged cartilage replacement

Senatov, F. S.; Kopylov, A. N.; Anisimova, N. Yu.; Kiselevsky, M. V.; Maksimkin, A. V.

Materials Science & Engineering, C: Materials for Biological Applications (2015), 48 (), 566-571CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)

In the present work dispersion-strengthened nanocomposites based on ultra-high mol. wt. polyethylene (UHMWPE) after mech. activation were studied. Mech. activation was performed for hardening of the boundaries between the polymer particles, reducing the fusion defects and increasing of wear-resistance. Three types of samples were prepd.: UHMWPE, UHMWPE/Al2O3 nanocomposite and UHMWPE/Al2O3 nanocomposite after mech. activation. UHMWPE/Al2O3 nanocomposites prepd. with mech. activation show the best mech. properties in compression and higher wear-resistance. UHMWPE/Al2O3 nanocomposites prepd. with mech. activation were chosen for in vivo study by orthotopical transplantation in rats. Animals' activity has been being monitored for 60 days after surgery. No signs of inflammation, cellular infiltration, destruction of material or bone-cartilage defect were found. Implanted sample has not changed its position of implantation, there were no any shifts. Obtained data shows that UHMWPE-based nanocomposite is a promising material for creating bioimplants for cartilage defect replacement.

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Wagner, E. R. ; Parry, J. ; Dadsetan, M. ; Bravo, D. ; Riester, S. M. ; van Wijnen, A. J. ; Yaszemski, M. J. ; Kakar, S. Chondrocyte Attachment, Proliferation, and Differentiation on Three-Dimensional Polycaprolactone Fumarate Scaffolds. Tissue Eng., Part A 2017, 23 (13–14), 622– 629, DOI: 10.1089/ten.tea.2016.0341

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128

Chondrocyte Attachment, Proliferation, and Differentiation on Three-Dimensional Polycaprolactone Fumarate Scaffolds

Wagner, Eric R.; Parry, Joshua; Dadsetan, Mahrokh; Bravo, Dalibel; Riester, Scott M.; van Wijnen, Andre J.; Yaszemski, Michael J.; Kakar, Sanjeev

Tissue Engineering, Part A (2017), 23 (13-14), 622-629CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

Current treatment options for cartilage injuries are limited. The goals of this study are to create a biodegradable polymer scaffold with the capabilities of sustaining chondrocyte growth and proliferation, enable cell-to-cell communication and tissue regeneration through large pores, and assess the biol. augmentation of the scaffold capabilities using platelet lysate (PL). We synthesized biodegradable polycaprolactone fumarate (PCLF) scaffolds to allow cell-cell communication through large interconnected pores. Molds were printed using a three-dimensional printer and scaffolds synthesized through UV crosslinking. Culture medium included alpha modified Eagle media with either 10% fetal bovine serum (FBS) or 5% PL, a mixt. of platelet release products, after being seeded onto scaffolds through a dynamic bioreactor. Assays included cellular proliferation (MTS), toxicity and viability (live/dead immunostaining), differentiation (glycosaminoglycan [GAG], alk. phosphatase [ALP], and total collagen), and immunostaining for chondrogenic markers collagen II and Sox 9 (with collagen I as a neg. control). Immunostaining at 2 and 4 wk for the expression of chondrogenic markers Collagen II and Sox 9 was increased when compared with control human fibroblasts. These results show that the PCLF polymer scaffold enables chondrocytes to attach, proliferate, and retain their chondrogenic phenotypes, demonstrating potential in chondrocyte engineering and cartilage regeneration.

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Medvedeva, E. V.; Grebenik, E. A.; Gornostaeva, S. N.; Telpuhov, V. I.; Lychagin, A. V.; Timashev, P. S.; Chagin, A. S. Repair of Damaged Articular Cartilage: Current Approaches and Future Directions. Int. J. Mol. Sci. 2018, 19 (8), 2366 DOI: 10.3390/ijms19082366 .

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129

Repair of damaged articular cartilage: current approaches and future directions

Medvedeva, Ekaterina V.; Grebenik, Ekaterina A.; Gornostaeva, Svetlana N.; Telpuhov, Vladimir I.; Lychagin, Aleksey V.; Timashev, Peter S.; Chagin, Andrei S.

International Journal of Molecular Sciences (2018), 19 (8), 2366/1-2366/23CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

A review. Articular hyaline cartilage is extensively hydrated, but it is neither innervated nor vascularized, and its low cell d. allows only extremely limited self-renewal. Most clin. and research efforts currently focus on the restoration of cartilage damaged in connection with osteoarthritis or trauma. Here, we discuss current clin. approaches for repairing cartilage, as well as research approaches which are currently developing, and those under translation into clin. practice. We also describe potential future directions in this area, including tissue engineering based on scaffolding and/or stem cells as well as a combination of gene and cell therapy. Particular focus is placed on cell-based approaches and the potential of recently characterized chondro-progenitors; progress with induced pluripotent stem cells is also discussed. In this context, we also consider the ability of different types of stem cell to restore hyaline cartilage and the importance of mimicking the environment in vivo during cell expansion and differentiation into mature chondrocytes.

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Frenkel, S. R. ; Bradica, G. ; Brekke, J. H. ; Goldman, S. M. ; Ieska, K. ; Issack, P. ; Bong, M. R. ; Tian, H. ; Gokhale, J. ; Coutts, R. D. ; Kronengold, R. T. Regeneration of articular cartilage--evaluation of osteochondral defect repair in the rabbit using multiphasic implants. Osteoarthritis Cartilage 2005, 13 (9), 798– 807, DOI: 10.1016/j.joca.2005.04.018

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130

Regeneration of articular cartilage--evaluation of osteochondral defect repair in the rabbit using multiphasic implants

Frenkel S R; Bradica G; Brekke J H; Goldman S M; Ieska K; Issack P; Bong M R; Tian H; Gokhale J; Coutts R D; Kronengold R T

Osteoarthritis and cartilage (2005), 13 (9), 798-807 ISSN:1063-4584.

OBJECTIVE: To investigate whether two different multiphasic implants could initiate and sustain repair of osteochondral defects in rabbits. The implants address the malleable properties of cartilage while also addressing the rigid characteristics of subchondral bone. DESIGN: The bone region of both devices consisted of D, D-L, L-polylactic acid invested with hyaluronan (HY). The cartilage region of the first device was a polyelectrolytic complex (PEC) hydrogel of HY and chitosan. In the second device the cartilage region consisted of type I collagen scaffold. Eighteen rabbits were implanted bilaterally with a device, or underwent defect creation with no implant. At 24 weeks, regenerated tissues were evaluated grossly, histologically and via immunostaining for type II collagen. RESULTS: PEC devices induced a significantly better repair than untreated shams. Collagen devices resulted in a quality of repair close to that of the PEC group, although its mean repair score (19.0+/-4.2) did not differ significantly from that of the PEC group (20.4+/-3.7) or the shams (16.5+/-6.3). The percentage of hyaline-appearing cartilage in the repair was highest with collagen implants, while the degree of bonding of repair to the host, structural integrity of the neocartilage, and reconstitution of the subchondral bone was greatest with PEC devices. Cartilage in both device-treated sites stained positive for type II collagen and GAG. CONCLUSIONS: Both implants are capable of maintaining hyaline-appearing tissue at 24 weeks. The physicochemical region between the cartilage and bone compartments makes these devices well suited for delivery of different growth factors or drugs in each compartment, or different doses of the same factor. It also renders these devices excellent vehicles for chondrocyte or stem cell transplantation.

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Diduch, D. R. ; Jordan, L. C. ; Mierisch, C. M. ; Balian, G. Marrow stromal cells embedded in alginate for repair of osteochondral defects. Arthroscopy 2000, 16 (6), 571– 7, DOI: 10.1053/jars.2000.4827

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131

Marrow stromal cells embedded in alginate for repair of osteochondral defects

Diduch D R; Jordan L C; Mierisch C M; Balian G

Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association (2000), 16 (6), 571-7 ISSN:.

Articular cartilage defects of sufficient size ultimately degenerate with time, leading to arthritic changes. Numerous strategies have been used to address full-thickness cartilage defects, yet none thus far has been successful in restoring the articular surface to its preinjury state. We compared the effects of agarose, alginate, and type I collagen gels on the expression of cartilage-specific markers from rabbit marrow stromal cells and then assessed the in vivo effects of cells seeded in alginate beads on the repair of full-thickness osteochondral defects in the rabbit model. Marrow aspirates from rabbits were cultured and the stromal population selected. Marrow stromal cells were then placed in either 1.2% w/v alginate, type I collagen gels (3 mg/mL), or 0.5% agarose suspension culture. After 2, 5, 10, and 20 days in culture, the RNA was extracted and analyzed by reverse transcription polymerase chain reaction for the cartilage-specific markers aggrecan and type II collagen. The strongest increase in aggrecan and type II collagen gene expression was found in the agarose suspension followed by alginate; type I collagen gels induced the lowest levels. Alginate beads were chondrogenic and maintained their size and consistency over time in culture, whereas the cell-seeded collagen gels invariably contracted. Full-thickness defects measuring 3 x 6 mm x 3 mm deep were then created in the medial femoral condyles of rabbit knees and filled with alginate beads, alginate beads seeded with stromal cells, or left empty. Alginate beads containing stromal cells remained within the defects and progressively filled the defects with regenerate tissue. Histologic analysis showed viable, phenotypically chondrogenic cells in the defects. The matrix stained positive with safranin O, indicating proteoglycan synthesis, and bonding between the regenerate and host tissue was excellent. We have shown quantitative differences in the chondrogenic effects of the biomaterials tested. Alginate induces the chondrogenic phenotype in marrow stromal cells in vitro, and possesses the necessary physical characteristics and handling properties to support cells and serve as a carrier to fill full-thickness osteochondral defects in vivo.

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Mohan, N. ; Gupta, V. ; Sridharan, B. ; Sutherland, A. ; Detamore, M. S. The potential of encapsulating ″raw materials″ in 3D osteochondral gradient scaffolds. Biotechnol. Bioeng. 2014, 111 (4), 829– 841, DOI: 10.1002/bit.25145

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132

The potential of encapsulating "raw materials" in 3D osteochondral gradient scaffolds

Mohan, Neethu; Gupta, Vineet; Sridharan, BanuPriya; Sutherland, Amanda; Detamore, Michael S.

Biotechnology and Bioengineering (2014), 111 (4), 829-841CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)

Scaffolds with continuous gradients in material compn. and bioactive signals enable a smooth transition of properties at the interface. Components like chondroitin sulfate (CS) and bioactive glass (BG) in 3D scaffolds may serve as "raw materials" for synthesis of new extracellular matrix (ECM), and may have the potential to completely or partially replace expensive growth factors. We hypothesized that scaffolds with gradients of ECM components would enable superior performance of engineered constructs. Raw material encapsulation altered the appearance, structure, porosity, and degrdn. of the scaffolds. They allowed the scaffolds to better retain their 3D structure during culture and provided a buffering effect to the cells in culture. Following seeding of rat mesenchymal stem cells, there were several instances where glycosaminoglycan (GAG), collagen, or calcium contents were higher with the scaffolds contg. raw materials (CS or BG) than with those contg. transforming growth factor (TGF)-β3 or bone morphogenetic protein (BMP)-2. It was also noteworthy that a combination of both CS and TGF-β3 increased the secretion of collagen type II. Moreover, cells seeded in scaffolds contg. opposing gradients of CS/TGF-β3 and BG/BMP-2 produced clear regional variations in the secretion of tissue-specific ECM. The study demonstrated raw materials have the potential to create a favorable microenvironment for cells; they can significantly enhance the synthesis of certain extracellular matrix (ECM) components when compared to expensive growth factors; either alone or in combination with growth factors they can enhance the secretion of tissue specific matrix proteins. Raw materials are promising candidates that can be used to either replace or be used in combination with growth factors. Success with raw materials in lieu of growth factors could have profound implications in terms of lower cost and faster regulatory approval for more rapid translation of regenerative medicine products to the clinic.

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Gao, J. ; Dennis, J. E. ; Solchaga, L. A. ; Goldberg, V. M. ; Caplan, A. I. Repair of osteochondral defect with tissue-engineered two-phase composite material of injectable calcium phosphate and hyaluronan sponge. Tissue Eng. 2002, 8 (5), 827– 37, DOI: 10.1089/10763270260424187

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133

Repair of osteochondral defect with tissue-engineered two-phase composite material of injectable calcium phosphate and hyaluronan sponge

Gao, Jizong; Dennis, James E.; Solchaga, Luis A.; Goldberg, Victor M.; Caplan, Arnold I.

Tissue Engineering (2002), 8 (5), 827-837CODEN: TIENFP; ISSN:1076-3279. (Mary Ann Liebert, Inc.)

Articular cartilage has limited capacity for repair. In the present study, tissue-engineered two-phase composite material was used for the repair of osteochondral defects in young adult rabbit knee. This composite material is composed of an injectable calcium phosphate (ICP) and a hyaluronan (HA) derivate of either ACP or HYAFF 11 sponge. The osteochondral defect, 3 mm in diam. and 3 mm deep, was created in the wt.-bearing region of the medial femoral condyle. The bone portion of the defect was first filled with ICP to a level approx. 1 mm below the articular surface. HA sponge (3 mm in diam. and 1-1.2 mm thick), with or without loading of autologous bone marrow-derived progenitor cells (MPCs), was then inserted into the defect on top of the ICP as it hardened. Animals were allowed free cage activity postoperatively, and killed 4 or 12 wk (for the HYAFF 11 sponge group) after the surgery. At 4 wk, histol. examn. showed that the defect was filled up to 90-100% of its depth. Whitish repair tissue on the top appeared to be integrated with the surrounding articular cartilage. Four distinct zones of repair tissue were identified: a superficial layer, a chondroid tissue layer, an interface between HA sponge and ICP, and the ICP material. Evidence of extensive osteoclastic and osteoblastic activities was obsd. in the bone tissue surrounding the defect edge and in ICP material. By 12 wk, the zonal features of the repair tissue became more distinct; chondrocytes were arranged in a columnar array, and a calcified layer of cartilage was formed beneath the chondroid tissue in some specimens. The healing tissue of the HA sponge material loaded with MPCs had higher cellular d. and better integration with the surrounding cartilage than HA sponge material not loaded with MPCs. This study suggests that using a two-phase composite graft may hold potential for the repair of osteochondral defects by providing mech. support that mimicks subchondral bone, while also providing a chondrogenic scaffold for the top cartilage repair.

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Li, J. ; Mareddy, S. ; Tan, D. M. ; Crawford, R. ; Long, X. ; Miao, X. ; Xiao, Y. A minimal common osteochondrocytic differentiation medium for the osteogenic and chondrogenic differentiation of bone marrow stromal cells in the construction of osteochondral graft. Tissue Eng., Part A 2009, 15 (9), 2481– 90, DOI: 10.1089/ten.tea.2008.0463

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A Minimal Common Osteochondrocytic Differentiation Medium for the Osteogenic and Chondrogenic Differentiation of Bone Marrow Stromal Cells in the Construction of Osteochondral Graft

Li, Jian; Mareddy, Shobha; Tan, Dawn Meifang; Crawford, Ross; Long, Xing; Miao, Xigeng; Xiao, Yin

Tissue Engineering, Part A (2009), 15 (9), 2481-2490CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

To regenerate the complex tissue such as bone-cartilage construct using tissue engineering approach, controllable differentiation of bone marrow stromal cells (BMSCs) into chondrogenic and osteogenic lineages is crucially important. This study proposes to test a min. common osteochondrocytic differentiation medium (MCDM) formulated by including common sol. supplements (dexamethasone and ascorbic acid) used to induce chondrogenic and osteogenic differentiation. The MCDM coupled with supplemented growth factors was tested for its ability to differentiate BMSCs into osteogenic and chondrogenic lineages in both two-dimensional and three-dimensional culture systems. When transforming growth factor β3 was added to MCDM, BMSCs differentiated to chondrocyte-like cells, evidenced by the expression of glycosaminoglycans and type II collagen, whereas osteogenic differentiation was induced by supplementing osteogenic protein-1, resulting in detectable expression of osteopontin and osteocalcin. These chondrogenic and osteogenic differentiation markers were significantly enhanced in the three-dimensional cultures compared to the two-dimensional monolayer cultures. The results achieved in this study lay a foundation for future development of osteochondral graft, which could be engineered from bilayered scaffold with spatially loaded growth factors to control BMSC differentiation.

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Cao, Z. ; Hou, S. ; Sun, D. ; Wang, X. ; Tang, J. Osteochondral regeneration by a bilayered construct in a cell-free or cell-based approach. Biotechnol. Lett. 2012, 34 (6), 1151– 7, DOI: 10.1007/s10529-012-0884-9

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135

Osteochondral regeneration by a bilayered construct in a cell-free or cell-based approach

Cao, Zheng; Hou, Shuxun; Sun, Daming; Wang, Xiaoning; Tang, Junjun

Biotechnology Letters (2012), 34 (6), 1151-1157CODEN: BILED3; ISSN:0141-5492. (Springer)

A bilayered construct with or without adipose-derived stem cells (ASCs) was applied to repair full-thickness defects in the patellar groove of 18 rabbits. Non-treated and treated defects were divided into 3 groups: a control group (n = 12), a cell-free group (n = 12) and a cell-based group (n = 12). Histol. appearance and grading were evaluated at 8 and 12 wk. At 12 wk, osteochondral-like tissues completely filled in the defects and integrated with host tissues in the cell-based group. The semi-quant. score of the cell-based group (4.2 ± 1.2), which is a total score ranging from 0 (best) to 20 (worst), was significantly better than that of the other 2 groups (cell-free: 13.8 ± 2.5; control: 10.3 ± 2.4). This finding indicated that the bilayered constructs combined with ASCs could be an effective way to enhance osteochondral regeneration.

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Guo, X. ; Park, H. ; Liu, G. ; Liu, W. ; Cao, Y. ; Tabata, Y. ; Kasper, F. K. ; Mikos, A. G. In vitro generation of an osteochondral construct using injectable hydrogel composites encapsulating rabbit marrow mesenchymal stem cells. Biomaterials 2009, 30 (14), 2741– 52, DOI: 10.1016/j.biomaterials.2009.01.048

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136

In vitro generation of an osteochondral construct using injectable hydrogel composites encapsulating rabbit marrow mesenchymal stem cells

Guo, Xuan; Park, Hansoo; Liu, Guangpeng; Liu, Wei; Cao, Yilin; Tabata, Yasuhiko; Kasper, F. Kurtis; Mikos, Antonios G.

Biomaterials (2009), 30 (14), 2741-2752CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Injectable, biodegradable hydrogel composites of crosslinked oligo(poly(ethylene glycol) fumarate) (OPF) and gelatin microparticles (MPs) were utilized to fabricate a bilayered osteochondral construct consisting of a chondrogenic layer and an osteogenic layer, and to investigate the differentiation of rabbit marrow mesenchymal stem cells (MSCs) encapsulated in both layers in vitro. The results showed that MSCs in the chondrogenic layer were able to undergo chondrogenic differentiation, esp. in the presence of TGF-β1-loaded MPs. In the osteogenic layer, cells maintained their osteoblastic phenotype. Although calcium deposition in the osteogenic layer was limited, cells in the osteogenic layer significantly enhanced chondrogenic differentiation of MSCs in the chondrogenic layer. The greatest effect was obsd. when MSCs were encapsulated with TGF-β1-loaded MPs and cultured with osteogenic cells in the bilayered constructs. Overall, this study demonstrates the fabrication of bilayered hydrogel composites that mimic the structure and function of osteochondral tissue, along with the application of these composites as cell and growth factor carriers.

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Cunniffe, G. M. ; Díaz-Payno, P. J. ; Sheehy, E. J. ; Critchley, S. E. ; Almeida, H. V. ; Pitacco, P. ; Carroll, S. F. ; Mahon, O. R. ; Dunne, A. ; Levingstone, T. J. ; Moran, C. J. ; Brady, R. T. ; O'Brien, F. J. ; Brama, P. A. J. ; Kelly, D. J. Tissue-specific extracellular matrix scaffolds for the regeneration of spatially complex musculoskeletal tissues. Biomaterials 2019, 188 , 63– 73, DOI: 10.1016/j.biomaterials.2018.09.044

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137

Tissue-specific extracellular matrix scaffolds for the regeneration of spatially complex musculoskeletal tissues

Cunniffe, Grainne M.; Diaz-Payno, Pedro J.; Sheehy, Eamon J.; Critchley, Susan E.; Almeida, Henrique V.; Pitacco, Pierluca; Carroll, Simon F.; Mahon, Olwyn R.; Dunne, Aisling; Levingstone, Tanya J.; Moran, Conor J.; Brady, Robert T.; O'Brien, Fergal J.; Brama, Pieter A. J.; Kelly, Daniel J.

Biomaterials (2019), 188 (), 63-73CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Biol. scaffolds generated from tissue-derived extracellular matrix (ECM) are commonly used clin. for soft tissue regeneration. Such biomaterials can enhance tissue-specific differentiation of adult stem cells, suggesting that structuring different ECMs into multi-layered scaffolds can form the basis of new strategies for regenerating damaged interfacial tissues such as the osteochondral unit. In this study, mass spectrometry is used to demonstrate that growth plate (GP) and articular cartilage (AC) ECMs contain a unique array of regulatory proteins that may be particularly suited to bone and cartilage repair resp. Applying a novel iterative freeze-drying method, porous bi-phasic scaffolds composed of GP ECM overlaid by AC ECM are fabricated, which are capable of spatially directing stem cell differentiation in vitro, promoting the development of graded tissues transitioning from calcified cartilage to hyaline-like cartilage. Evaluating repair 12-mo post-implantation into critically-sized caprine osteochondral defects reveals that these scaffolds promote regeneration in a manner distinct to com. control-scaffolds. The GP layer supports endochondral bone formation, while the AC layer stimulates the formation of an overlying layer of hyaline cartilage with a collagen fiber architecture better recapitulating the native tissue. These findings support the use of a bi-layered, tissue-specific ECM derived scaffolds for regenerating spatially complex musculoskeletal tissues.

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Dua, R. ; Centeno, J. ; Ramaswamy, S. Augmentation of engineered cartilage to bone integration using hydroxyapatite. J. Biomed. Mater. Res., Part B 2014, 102 (5), 922– 932, DOI: 10.1002/jbm.b.33073

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138

Augmentation of engineered cartilage to bone integration using hydroxyapatite

Dua, Rupak; Centeno, Jerry; Ramaswamy, Sharan

Journal of Biomedical Materials Research, Part B: Applied Biomaterials (2014), 102B (5), 922-932CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)

Articular cartilage injuries occur frequently in the knee joint. Photopolymerizable cartilage tissue engineering approaches appear promising; however, fundamentally, forming a stable interface between the subchondral bone and tissue engineered cartilage components remains a major challenge. We investigated the utility of hydroxyapatite (HA) nanoparticles to promote controlled bone-growth across the bone-cartilage interface in an in vitro engineered tissue model system using bone marrow-derived stem cells. Samples incorporated with HA demonstrated significantly higher interfacial shear strength (at the junction between engineered cartilage and engineered bone) compared with the constructs without HA (p < 0.05), after 28 days of culture. Interestingly, this increased interfacial shear strength due to the presence of HA was obsd. as early as 7 days and appeared to have sustained itself for an addnl. three weeks without interacting with strength increases attributable to subsequent secretion of engineered tissue matrix. Histol. evidence showed that there was ∼7.5% bone in-growth into the cartilage region from the bone side. The mechanism of enhanced engineered cartilage to bone integration with HA incorporation appeared to be facilitated by the deposition of calcium phosphate in the transition zone. These findings indicate that controlled bone in-growth using HA incorporation permits more stable anchorage of the injectable hydrogel-based engineered cartilage construct via augmented integration between bone and cartilage. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 922-932, 2014.

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Burla, F. ; Tauber, J. ; Dussi, S. ; van Der Gucht, J. ; Koenderink, G. H. Stress management in composite biopolymer networks. Nat. Phys. 2019, 15 (6), 549– 553, DOI: 10.1038/s41567-019-0443-6

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139

Stress management in composite biopolymer networks

Burla, Federica; Tauber, Justin; Dussi, Simone; van der Gucht, Jasper; Koenderink, Gijsje H.

Nature Physics (2019), 15 (6), 549-553CODEN: NPAHAX; ISSN:1745-2473. (Nature Research)

Living tissues show an extraordinary adaptiveness to strain, which is crucial for their proper biol. functioning1,2. The phys. origin of this mech. behavior has been widely investigated using reconstituted networks of collagen fibers, the principal load-bearing component of tissues3-5. However, collagen fibers in tissues are embedded in a soft hydrated polysaccharide matrix, which generates substantial internal stresses, and the effect of this on tissue mechanics is unknown6-8. Here, by combining mech. measurements and computer simulations, we show that networks composed of collagen fibers and a hyaluronan matrix exhibit synergistic mechanics characterized by an enhanced stiffness and delayed strain stiffening. We demonstrate that the polysaccharide matrix has a dual effect on the composite response involving both internal stress and elastic reinforcement. Our findings elucidate how tissues can tune their strain-sensitivity over a wide range and provide a novel design principle for synthetic materials with programmable mech. properties.

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Baldino, L.; Maffulli, N.; Reverchon, E. 14 - Bone–tendon interface. In Regenerative Engineering of Musculoskeletal Tissues and Interfaces; Nukavarapu, S. P., Freeman, J. W., Laurencin, C. T. , Eds.; Woodhead Publishing: 2015; pp 345– 361.

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Amini, A. R. ; Laurencin, C. T. ; Nukavarapu, S. P. Bone tissue engineering: recent advances and challenges. Critical reviews in biomedical engineering 2012, 40 (5), 363– 408, DOI: 10.1615/CritRevBiomedEng.v40.i5.10

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141

Bone tissue engineering: recent advances and challenges

Amini Ami R; Laurencin Cato T; Nukavarapu Syam P

Critical reviews in biomedical engineering (2012), 40 (5), 363-408 ISSN:0278-940X.

The worldwide incidence of bone disorders and conditions has trended steeply upward and is expected to double by 2020, especially in populations where aging is coupled with increased obesity and poor physical activity. Engineered bone tissue has been viewed as a potential alternative to the conventional use of bone grafts, due to their limitless supply and no disease transmission. However, bone tissue engineering practices have not proceeded to clinical practice due to several limitations or challenges. Bone tissue engineering aims to induce new functional bone regeneration via the synergistic combination of biomaterials, cells, and factor therapy. In this review, we discuss the fundamentals of bone tissue engineering, highlighting the current state of this field. Further, we review the recent advances of biomaterial and cell-based research, as well as approaches used to enhance bone regeneration. Specifically, we discuss widely investigated biomaterial scaffolds, micro- and nano-structural properties of these scaffolds, and the incorporation of biomimetic properties and/or growth factors. In addition, we examine various cellular approaches, including the use of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs), and platelet-rich plasma (PRP), and their clinical application strengths and limitations. We conclude by overviewing the challenges that face the bone tissue engineering field, such as the lack of sufficient vascularization at the defect site, and the research aimed at functional bone tissue engineering. These challenges will drive future research in the field.

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Beldjilali-Labro, M.; Garcia Garcia, A.; Farhat, F.; Bedoui, F.; Grosset, J. F.; Dufresne, M.; Legallais, C. , Biomaterials in Tendon and Skeletal Muscle Tissue Engineering: Current Trends and Challenges. Materials 2018, 11 (7), 1116 DOI: 10.3390/ma11071116 .

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142

Biomaterials in tendon and skeletal muscle tissue engineering: current trends and challenges

Beldjilali-Labro, Megane; Garcia, Alejandro Garcia; Farhat, Firas; Bedoui, Fahmi; Grosset, Jean-Francois; Dufresne, Murielle; Legallais, Cecile

Materials (2018), 11 (7), 1116/1-1116/49CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)

Tissue engineering is a promising approach to repair tendon and muscle when natural healing fails. Biohybrid constructs obtained after cells' seeding and culture in dedicated scaffolds have indeed been considered as relevant tools for mimicking native tissue, leading to a better integration in vivo. They can also be employed to perform advanced in vitro studies to model the cell differentiation or regeneration processes. In this review, we report and analyze the different solns. proposed in literature, for the reconstruction of tendon, muscle, and the myotendinous junction. They classically rely on the three pillars of tissue engineering, i.e., cells, biomaterials and environment (both chem. and phys. stimuli). We have chosen to present biomimetic or bioinspired strategies based on understanding of the native tissue structure/functions/properties of the tissue of interest. For each tissue, we sorted the relevant publications according to an increasing degree of complexity in the materials' shape or manuf. We present their biol. and mech. performances, obsd. in vitro and in vivo when available. Although there is no consensus for a gold std. technique to reconstruct these musculo-skeletal tissues, the reader can find different ways to progress in the field and to understand the recent history in the choice of materials, from collagen to polymer-based matrixes.

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Laurent, C. d. ; Liu, X. ; De Isla, N. ; Wang, X. ; Rahouadj, R. Defining a scaffold for ligament tissue engineering: What has been done, and what still needs to be done. Journal of Cellular Immunotherapy 2018, 4 (1), 4– 9, DOI: 10.1016/j.jocit.2018.09.002

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Qazi, T. H. ; Mooney, D. J. ; Pumberger, M. ; Geißler, S. ; Duda, G. N. Biomaterials based strategies for skeletal muscle tissue engineering: Existing technologies and future trends. Biomaterials 2015, 53 , 502– 521, DOI: 10.1016/j.biomaterials.2015.02.110

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Biomaterials based strategies for skeletal muscle tissue engineering: Existing technologies and future trends

Qazi, Taimoor H.; Mooney, David J.; Pumberger, Matthias; Geissler, Sven; Duda, Georg N.

Biomaterials (2015), 53 (), 502-521CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

A review. Skeletal muscles have a robust capacity to regenerate, but under compromised conditions, such as severe trauma, the loss of muscle functionality is inevitable. Research carried out in the field of skeletal muscle tissue engineering has elucidated multiple intrinsic mechanisms of skeletal muscle repair, and has thus sought to identify various types of cells and bioactive factors which play an important role during regeneration. In order to maximize the potential therapeutic effects of cells and growth factors, several biomaterial based strategies have been developed and successfully implemented in animal muscle injury models. A suitable biomaterial can be utilized as a template to guide tissue reorganization, as a matrix that provides optimum micro-environmental conditions to cells, as a delivery vehicle to carry bioactive factors which can be released in a controlled manner, and as local niches to orchestrate in situ tissue regeneration. A myriad of biomaterials, varying in geometrical structure, phys. form, chem. properties, and biofunctionality have been investigated for skeletal muscle tissue engineering applications. In the current review, we present a detailed summary of studies where the use of biomaterials favorably influenced muscle repair. Biomaterials in the form of porous three-dimensional scaffolds, hydrogels, fibrous meshes, and patterned substrates with defined topogs., have each displayed unique benefits, and are discussed herein. Addnl., several biomaterial based approaches aimed specifically at stimulating vascularization, innervation, and inducing contractility in regenerating muscle tissues are also discussed. Finally, we outline promising future trends in the field of muscle regeneration involving a deeper understanding of the endogenous healing cascades and utilization of this knowledge for the development of multifunctional, hybrid, biomaterials which support and enable muscle regeneration under compromised conditions.

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Casanellas, I. ; García-Lizarribar, A. ; Lagunas, A. ; Samitier, J. Producing 3D Biomimetic Nanomaterials for Musculoskeletal System Regeneration. Front. Bioeng. Biotechnol. 2018, 6 , 128, DOI: 10.3389/fbioe.2018.00128

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145

Producing 3D Biomimetic Nanomaterials for Musculoskeletal System Regeneration

Casanellas Ignasi; Garcia-Lizarribar Andrea; Lagunas Anna; Samitier Josep; Casanellas Ignasi; Garcia-Lizarribar Andrea; Samitier Josep; Lagunas Anna; Samitier Josep

Frontiers in bioengineering and biotechnology (2018), 6 (), 128 ISSN:2296-4185.

The human musculoskeletal system is comprised mainly of connective tissues such as cartilage, tendon, ligaments, skeletal muscle, and skeletal bone. These tissues support the structure of the body, hold and protect the organs, and are responsible of movement. Since it is subjected to continuous strain, the musculoskeletal system is prone to injury by excessive loading forces or aging, whereas currently available treatments are usually invasive and not always effective. Most of the musculoskeletal injuries require surgical intervention facing a limited post-surgery tissue regeneration, especially for widespread lesions. Therefore, many tissue engineering approaches have been developed tackling musculoskeletal tissue regeneration. Materials are designed to meet the chemical and mechanical requirements of the native tissue three-dimensional (3D) environment, thus facilitating implant integration while providing a good reabsorption rate. With biological systems operating at the nanoscale, nanoengineered materials have been developed to support and promote regeneration at the interprotein communication level. Such materials call for a great precision and architectural control in the production process fostering the development of new fabrication techniques. In this mini review, we would like to summarize the most recent advances in 3D nanoengineered biomaterials for musculoskeletal tissue regeneration, with especial emphasis on the different techniques used to produce them.

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Thomopoulos, S.; Birman, V.; Genin, G. M. Structural interfaces and attachments in biology; Springer, Science & Business Media: New York, NY, 2013.

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Loh, G. H. ; Pei, E. ; Harrison, D. ; Monzón, M. D. An overview of functionally graded additive manufacturing. Additive Manufacturing 2018, 23 , 34– 44, DOI: 10.1016/j.addma.2018.06.023

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147

An overview of functionally graded additive manufacturing

Loh, Giselle Hsiang; Pei, Eujin; Harrison, David; Monzon, Mario D.

Additive Manufacturing (2018), 23 (), 34-44CODEN: AMDAD2; ISSN:2214-7810. (Elsevier B.V.)

A review. Functionally Graded Additive Manufg. (FGAM) is a layer-by-layer fabrication process that involves gradationally varying the material organization within a component to achieve an intended function. FGAM establishes a radical shift from contour modeling to performance modeling by having the performance-driven functionality built directly into the material. FGAM can strategically control the d. and porosity of the compn. or can combine distinct materials to produce a seamless monolithic structure. This paper presents a state-of-art conceptual understanding of FGAM, covering an overview of current techniques that can enable the prodn. of FGAM parts as well as identify current technol. limitations and challenges. The possible strategies for overcoming those barriers are presented and recommendations on future design opportunities are discussed.

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Sun, M. ; Chi, G. ; Li, P. ; Lv, S. ; Xu, J. ; Xu, Z. ; Xia, Y. ; Tan, Y. ; Xu, J. ; Li, L. ; Li, Y. Effects of Matrix Stiffness on the Morphology, Adhesion, Proliferation and Osteogenic Differentiation of Mesenchymal Stem Cells. Int. J. Med. Sci. 2018, 15 (3), 257– 268, DOI: 10.7150/ijms.21620

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148

Effects of matrix stiffness on the morphology, adhesion, proliferation and osteogenic differentiation of mesenchymal stem cells

Sun, Meiyu; Chi, Guangfan; Li, Pengdong; Lv, Shuang; Xu, Juanjuan; Xu, Ziran; Xia, Yuhan; Tan, Ye; Xu, Jiayi; Li, Lisha; Li, Yulin

International Journal of Medical Sciences (2018), 15 (3), 257-268CODEN: IJMSGZ; ISSN:1449-1907. (Ivyspring International Publisher)

BMMSCs have drawn great interest in tissue engineering and regenerative medicine attributable to their multi-lineage differentiation capacity. Increasing evidence has shown that the mech. stiffness of extracellular matrix is a crit. determinant for stem cell behaviors. However, it remains unknown how matrix stiffness influences MSCs commitment with changes in cell morphol., adhesion, proliferation, self-renewal and differentiation. We employed fibronectin coated polyacrylamide hydrogels with variable stiffnesses ranging from 13 to 68 kPa to modulate the mech. environment of BMMSCs and found that the morphol. and adhesion of BMMSCs were highly dependent on mech. stiffness. Cells became more spread and more adhesive on substrates of higher stiffness. Similarly, the proliferation of BMMSCs increased as stiffness increased. Sox2 expression was lower during 4h to 1 wk on the 13-16 kPa and 62-68 kPa, in contrast, it was higher during 4h to 1 wk on the 48-53 kPa. Oct4 expression on 13-16 kPa was higher than 48-53 kPa at 4h, and it has no significant differences at other time point among three different stiffness groups. On 62-68 kPa, BMMSCs were able to be induced toward osteogenic phenotype and generated a markedly high level of RUNX2, ALP, and Osteopontin. The cells exhibited a polygonal morphol. and larger spreading area. These results suggest that matrix stiffness modulates commitment of BMMSCs. Our findings may eventually aid in the development of novel, effective biomaterials for the applications in tissue engineering.

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149

Mullen, C. A. ; Vaughan, T. J. ; Billiar, K. L. ; McNamara, L. M. The effect of substrate stiffness, thickness, and cross-linking density on osteogenic cell behavior. Biophys. J. 2015, 108 (7), 1604– 1612, DOI: 10.1016/j.bpj.2015.02.022

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149

The Effect of Substrate Stiffness, Thickness, and Cross-Linking Density on Osteogenic Cell Behavior

Mullen, Conleth A.; Vaughan, Ted J.; Billiar, Kristen L.; McNamara, Laoise M.

Biophysical Journal (2015), 108 (7), 1604-1612CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)

Osteogenic cells respond to mech. changes in their environment by altering their spread area, morphol., and gene expression profile. In particular, the bulk modulus of the substrate, as well as its microstructure and thickness, can substantially alter the local stiffness experienced by the cell. Although bone tissue regeneration strategies involve culture of bone cells on various biomaterial scaffolds, which are often cross-linked to enhance their phys. integrity, it is difficult to ascertain and compare the local stiffness experienced by cells cultured on different biomaterials. In this study, we seek to characterize the local stiffness at the cellular level for MC3T3-E1 cells plated on biomaterial substrates of varying modulus, thickness, and crosslinking concn. Cells were cultured on flat and wedge-shaped gels made from polyacrylamide or cross-linked collagen. The crosslinking d. of the collagen gels was varied to investigate the effect of fiber crosslinking in conjunction with substrate thickness. Cell spread area was used as a measure of osteogenic differentiation. Finite element simulations were used to examine the effects of fiber crosslinking and substrate thickness on the resistance of the gel to cellular forces, corresponding to the equiv. shear stiffness for the gel structure in the region directly surrounding the cell. The results of this study show that MC3T3 cells cultured on a soft fibrous substrate attain the same spread cell area as those cultured on a much higher modulus, but nonfibrous substrate. Finite element simulations predict that a dramatic increase in the equiv. shear stiffness of fibrous collagen gels occurs as crosslinking d. is increased, with equiv. stiffness also increasing as gel thickness is decreased. These results provide an insight into the response of osteogenic cells to individual substrate parameters and have the potential to inform future bone tissue regeneration strategies that can optimize the equiv. stiffness experienced by a cell.

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150

Ehrbar, M. ; Sala, A. ; Lienemann, P. ; Ranga, A. ; Mosiewicz, K. ; Bittermann, A. ; Rizzi, S. C. ; Weber, F. E. ; Lutolf, M. P. Elucidating the role of matrix stiffness in 3D cell migration and remodeling. Biophys. J. 2011, 100 (2), 284– 93, DOI: 10.1016/j.bpj.2010.11.082

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150

Elucidating the Role of Matrix Stiffness in 3D Cell Migration and Remodeling

Ehrbar, M.; Sala, A.; Lienemann, P.; Ranga, A.; Mosiewicz, K.; Bittermann, A.; Rizzi, S. C.; Weber, F. E.; Lutolf, M. P.

Biophysical Journal (2011), 100 (2), 284-293CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)

Reductionist in vitro model systems which mimic specific extracellular matrix functions in a highly controlled manner, termed artificial extracellular matrixes (aECM), have increasingly been used to elucidate the role of cell-ECM interactions in regulating cell fate. To better understand the interplay of biophys. and biochem. effectors in controlling three-dimensional cell migration, a poly(ethylene glycol)-based aECM platform was used in this study to explore the influence of matrix crosslinking d., represented here by stiffness, on cell migration in vitro and in vivo. In vitro, the migration behavior of single preosteoblastic cells within hydrogels of varying stiffness and susceptibilities to degrdn. by matrix metalloproteases was assessed by time-lapse microscopy. Migration behavior was seen to be strongly dependent on matrix stiffness, with two regimes identified: a nonproteolytic migration mode dominating at relatively low matrix stiffness and proteolytic migration at higher stiffness. Subsequent in vivo expts. revealed a similar stiffness dependence of matrix remodeling, albeit less sensitive to the matrix metalloprotease sensitivity. Therefore, our aECM model system is well suited to unveil the role of biophys. and biochem. determinants of physiol. relevant cell migration phenomena.

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151

Charrier, E. E. ; Pogoda, K. ; Wells, R. G. ; Janmey, P. A. Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation. Nat. Commun. 2018, 9 (1), 449, DOI: 10.1038/s41467-018-02906-9

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151

Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation

Charrier Elisabeth E; Pogoda Katarzyna; Janmey Paul A; Charrier Elisabeth E; Wells Rebecca G; Pogoda Katarzyna

Nature communications (2018), 9 (1), 449 ISSN:.

The mechanical properties of extracellular matrices can control the function of cells. Studies of cellular responses to biomimetic soft materials have been largely restricted to hydrogels and elastomers that have stiffness values independent of time and extent of deformation, so the substrate stiffness can be unambiguously related to its effect on cells. Real tissues, however, often have loss moduli that are 10 to 20% of their elastic moduli and behave as viscoelastic solids. The response of cells to a time-dependent viscous loss is largely uncharacterized because appropriate viscoelastic materials are lacking for quantitative studies. Here we report the synthesis of soft viscoelastic solids in which the elastic and viscous moduli can be independently tuned to produce gels with viscoelastic properties that closely resemble those of soft tissues. Systematic alteration of the hydrogel viscosity demonstrates the time dependence of cellular mechanosensing and the influence of viscous dissipation on cell phenotype.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvlvFGjtg%253D%253D&md5=c92d3a8be1222d3486be9de834b30996

152

Olivares-Navarrete, R. ; Lee, E. M. ; Smith, K. ; Hyzy, S. L. ; Doroudi, M. ; Williams, J. K. ; Gall, K. ; Boyan, B. D. ; Schwartz, Z. Substrate Stiffness Controls Osteoblastic and Chondrocytic Differentiation of Mesenchymal Stem Cells without Exogenous Stimuli. PLoS One 2017, 12 (1), e0170312, DOI: 10.1371/journal.pone.0170312

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152

Substrate stiffness controls osteoblastic and chondrocytic differentiation of mesenchymal stem cells without exogenous stimuli

Olivares-Navarrete, Rene; Lee, Erin M.; Smith, Kathryn; Hyzy, Sharon L.; Doroudi, Maryam; Williams, Joseph K.; Gall, Ken; Boyan, Barbara D.; Schwartz, Zvi

PLoS One (2017), 12 (1), e0170312/1-e0170312/18CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Stem cell fate has been linked to the mech. properties of their underlying substrate, affecting mechanoreceptors and ultimately leading to downstream biol. response. Studies have used polymers to mimic the stiffness of extracellular matrix as well as of individual tissues and shown mesenchymal stem cells (MSCs) could be directed along specific line-ages. In this study, we examd. the role of stiffness in MSC differentiation to two closely related cell phenotypes: osteoblast and chondrocyte. We prepd. four Me acrylate/methyl methacrylate (MA/MMA) polymer surfaces with elastic moduli ranging from 0.1 MPa to 310 MPa by altering monomer concn. MSCs were cultured in media without exogenous growth factors and their biol. responses were compared to committed chondrocytes and osteoblasts. Both chondrogenic and osteogenic markers were elevated when MSCs were grown on substrates with stiffness <10 MPa. Like chondrocytes, MSCs on lower stiffness substrates showed elevated expression of ACAN, SOX9, and COL2 and proteoglycan content; COMP was elevated in MSCs but reduced in chondrocytes. Substrate stiffness altered levels of RUNX2 mRNA, alk. phosphatase specific activity, osteocalcin, and osteoprotegerin in osteoblasts, decreasing levels on the least stiff substrate. Expression of integrin subunits α1, α2, α5, αv, β1, and β3 changed in a stiffness- and cell type-dependent manner. Silencing of integrin subunit beta 1 (ITGB1) in MSCs abolished both osteoblastic and chondrogenic differentiation in response to substrate stiffness. Our results suggest that substrate stiffness is an important mediator of osteoblastic and chondrogenic differentiation, and integrin β1 plays a pivotal role in this process.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnslSiu74%253D&md5=a94bd2f749f25ad0cc196f1affc2d3ef

153

Obbink-Huizer, C. ; Oomens, C. W. ; Loerakker, S. ; Foolen, J. ; Bouten, C. V. ; Baaijens, F. P. Computational model predicts cell orientation in response to a range of mechanical stimuli. Biomech. Model. Mechanobiol. 2014, 13 (1), 227– 36, DOI: 10.1007/s10237-013-0501-4

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153

Computational model predicts cell orientation in response to a range of mechanical stimuli

Obbink-Huizer Christine; Oomens Cees W J; Loerakker Sandra; Foolen Jasper; Bouten Carlijn V C; Baaijens Frank P T

Biomechanics and modeling in mechanobiology (2014), 13 (1), 227-36 ISSN:.

To build anisotropic, mechanically functioning tissue, it is essential to understand how cells orient in response to mechanical stimuli. Therefore, a computational model was developed which predicts cell orientation, based on the actin stress fiber distribution inside the cell. In the model, the stress fiber distribution evolves dynamically according to the following: (1) Stress fibers contain polymerized actin. The total amount of depolymerized plus polymerized actin is constant. (2) Stress fibers apply tension to their environment. This active tension is maximal when strain rate and absolute strain are zero and reduces with increasing shortening rate and absolute strain. (3) A high active fiber stress in a direction leads to a large amount of fibers in this direction. (4) The cell is attached to a substrate; all fiber stresses are homogenized into a total cell stress, which is in equilibrium with substrate stress. This model predicts that on a substrate of anisotropic stiffness, fibers align in the stiffest direction. Under cyclic strain when the cellular environment is so stiff that no compaction occurs (1 MPa), the model predicts strain avoidance, which is more pronounced with increasing strain frequency or amplitude. Under cyclic strain when the cellular environment is so soft that cells can compact it (10 kPa), the model predicts a preference for the cyclically strained compared to the compacting direction. These model predictions all agree with experimental evidence. For the first time, a computational model predicts cell orientation in response to this range of mechanical stimuli using a single set of parameters.

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154

Chen, K. ; Vigliotti, A. ; Bacca, M. ; McMeeking, R. M. ; Deshpande, V. S. ; Holmes, J. W. Role of boundary conditions in determining cell alignment in response to stretch. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (5), 986, DOI: 10.1073/pnas.1715059115

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154

Role of boundary conditions in determining cell alignment in response to stretch

Chen, Kellen; Vigliotti, Andrea; Bacca, Mattia; McMeeking, Robert M.; Deshpande, Vikram S.; Holmes, Jeffrey W.

Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (5), 986-991CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

The ability of cells to orient in response to mech. stimuli is essential to embryonic development, cell migration, mechanotransduction, and other crit. physiol. functions in a range of organs. Endothelial cells, fibroblasts, mesenchymal stem cells, and osteoblasts all orient perpendicular to an applied cyclic stretch when plated on stretchable elastic substrates, suggesting a common underlying mechanism. However, many of these same cells orient parallel to stretch in vivo and in 3D culture, and a compelling explanation for the different orientation responses in 2D and 3D has remained elusive. Here, we conducted a series of expts. designed specifically to test the hypothesis that differences in strains transverse to the primary loading direction give rise to the different alignment patterns obsd. in 2D and 3D cyclic stretch expts. ("strain avoidance"). We found that, in static or low-frequency stretch conditions, cell alignment in fibroblast-populated collagen gels correlated with the presence or absence of a restraining boundary condition rather than with compaction strains. Cyclic stretch could induce perpendicular alignment in 3D culture but only at frequencies an order of magnitude greater than reported to induce perpendicular alignment in 2D. We modified a published model of stress fiber dynamics and were able to reproduce our exptl. findings across all conditions tested as well as published data from 2D cyclic stretch expts. These exptl. and model results suggest an explanation for the apparently contradictory alignment responses of cells subjected to cyclic stretch on 2D membranes and in 3D gels.

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155

Bischofs, I. ; Schwarz, U. Cell organization in soft media due to active mechanosensing. Proc. Natl. Acad. Sci. U. S. A. 2003, 100 , 9274– 9, DOI: 10.1073/pnas.1233544100

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155

Cell organization in soft media due to active mechanosensing

Bischofs, I. B.; Schwarz, U. S.

Proceedings of the National Academy of Sciences of the United States of America (2003), 100 (16), 9274-9279CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

Adhering cells actively probe the mech. properties of their environment and use the resulting information to position and orient themselves. We show that a large body of exptl. observations can be consistently explained from one unifying principle, namely that cells strengthen contacts and cytoskeleton in the direction of large effective stiffness. Using linear elasticity theory to model the extracellular environment, we calc. optimal cell organization for several situations of interest and find excellent agreement with expts. for fibroblasts, both on elastic substrates and in collagen gels: cells orient in the direction of external tensile strain; they orient parallel and normal to free and clamped surfaces, resp.; and they interact elastically to form strings. Our method can be applied for rational design of tissue equiv. Moreover, our results indicate that the concept of contact guidance has to be reevaluated. We also suggest that cell-matrix contacts are up-regulated by large effective stiffness in the environment because, in this way, build-up of force is more efficient.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmtlykt78%253D&md5=cfc84f629cc562da610dd707382a7fd0

156

Bell, E. ; Ivarsson, B. ; Merrill, C. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc. Natl. Acad. Sci. U. S. A. 1979, 76 (3), 1274– 1278, DOI: 10.1073/pnas.76.3.1274

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156

Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro

Bell, Eugene; Ivarsson, Bengt; Merrill, Charlotte

Proceedings of the National Academy of Sciences of the United States of America (1979), 76 (3), 1274-8CODEN: PNASA6; ISSN:0027-8424.

Fibroblasts were able to condense a hydrated collagen lattice to a tissue-like structure 1/28th the area of the starting gel in 24 h. The rate of the process could be regulated by varying the protein content of the lattice, the cell no., or the concn. of an inhibitor, such as Colcemid. Fibroblasts of high population doubling level propagated in vitro, which had left the cell cycle, carried out the contraction at least as efficiently as cycling cells. The potential uses of the system as an immunol. tolerated tissue for wound healing and as a model for studying fibroblast function are discussed.

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157

Harris, A. K. ; Stopak, D. ; Wild, P. Fibroblast traction as a mechanism for collagen morphogenesis. Nature 1981, 290 (5803), 249– 51, DOI: 10.1038/290249a0

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157

Fibroblast traction as a mechanism for collagen morphogenesis

Harris A K; Stopak D; Wild P

Nature (1981), 290 (5803), 249-51 ISSN:0028-0836.

To make visible the traction forces exerted by individuals cells, we have previously developed a method of culturing them on thin distortable sheets of silicone rubber. We have now used this method to compare the forces exerted by various differentiated cell types and have examined the effects of cellular traction on re-precipitated collagen-matrices. We find that the strength of cellular traction differs greatly between cell types and this traction is paradoxically weakest in the most mobile and invasive cells (leukocytes and nerve growth cones). Untransformed fibroblasts exert forces very much larger than those actually needed for locomotion. This strong traction distorts collagen gels dramatically, creating patterns similar to tendons and organ capsules. We propose that this morphogenetic rearrangement of extracellular matrices is the primary function of fibroblast traction and explains its excessive strength.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M7kvVyntA%253D%253D&md5=4f9f4ac45d7c21a1ca3f1b88864f1fc1

158

Petroll, W. M. ; Cavanagh, H. D. ; Jester, J. V. Dynamic three-dimensional visualization of collagen matrix remodeling and cytoskeletal organization in living corneal fibroblasts. Scanning 2004, 26 (1), 1– 10, DOI: 10.1002/sca.4950260102

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158

Dynamic three-dimensional visualization of collagen matrix remodeling and cytoskeletal organization in living corneal fibroblasts

Petroll W Matthew; Cavanagh H Dwight; Jester James V

Scanning (2004), 26 (1), 1-10 ISSN:0161-0457.

The remodeling of extracellular matrices by cells plays a defining role in developmental morphogenesis and wound healing, as well as in tissue engineering. Three-dimensional (3-D) type I collagen matrices have been used extensively as an in vitro model for studying cell-induced matrix reorganization at the macroscopic level. However, few studies have directly assessed the dynamic process of 3-D matrix remodeling at the cellular and subcellular level. We recently developed an experimental model for investigating cell-matrix mechanical interactions by plating green fluorescen protein (GFP)-zyxin transfected cells inside fibrillar collagen matrices and performing high-magnification time-lapse differential interference microscopy (DIC) and wide-field fluorescent imaging. In this study, we extend this experimental model by performing four-dimensional (4-D) reflected light and fluorescent confocal imaging (using either visible light or multiphoton excitation) of living corneal fibroblasts transfected to express GFP-zyxin or GFP-alpha-actinin, 18 h after plating inside 3-D collagen matrices. Reflected light confocal imaging allowed detailed visualization of the cells and the fibrillar collagen surrounding them. By overlaying maximum intensity projections of reflected light and GFP-zyxin or GFP-alpha-actinin images and generating stereo pair reconstructions, 3-D interactions between focal adhesions and collagen fibrils in living cells could be visualized directly. Focal adhesions were generally oriented parallel to the direction of collagen fibril alignment in front of the cell. Killing the cells induced relaxation of transient cell-induced tension on the matrix; however, significant permanent remodeling always remained. Time-lapse 3-D imaging demonstrated an active response to the Rho-kinase inhibitor Y-27632, as indicated by cell elongation, extracellular matrix relaxation, and extension of pseudopodial processes. It is interesting that, at higher cell densities, groups of collagen fibrils were compacted and aligned into straps between neighboring cells. Overall, the continued development and application of this new approach should provide important insights into the basic underlying biochemical and biomechanical regulatory mechanisms controlling matrix remodeling by corneal fibroblasts.

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159

Ploetz, C. ; Zycband, E. ; Birk, D. Collagen fibril assembly and deposition in the developing dermis: Segmental deposition in extracellular compartments. J. Struct. Biol. 1991, 106 , 73– 81, DOI: 10.1016/1047-8477(91)90064-4

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159

Collagen fibril assembly and deposition in the developing dermis: segmental deposition in extracellular compartments

Ploetz C; Zycband E I; Birk D E

Journal of structural biology (1991), 106 (1), 73-81 ISSN:1047-8477.

The hierarchy of extracytoplasmic compartmentalization and fibrillar organization as well as the assembly and deposition of collagen fibrils was characterized in the 15-day chick embryo dermis using transmission electron microscopy. At least two levels of extracellular compartmentalization are recognizable at this stage of dermal development. The first compartment consists of a series of narrow channels containing single or small groups (less than 5) of collagen fibrils. These channels course deep within the cell and are open to the extracellular space. The second extracellular compartment consists of fibrils grouped as small bundles in close association with the cell surface and is most often defined by a single fibroblast. A third level of fibril organization and compartmentalization is sometimes apparent at this stage of dermal development consisting of laterally associated bundles, more characteristic of the mature dermis. This compartment is associated with the fibroblast surface, but is less well defined than the fibril channels or bundle-forming compartments. Dermal collagen fibrils within bundles are discontinuous. Numerous fibrils ends are identified from serial sections and the ends gradually taper. These data indicate that the dermal fibroblast compartmentalizes the extracellular space and deposits collagen fibril segments during dermal morphogenesis. A model for the genesis of the extracellular compartments and their role in collagen fibrillogenesis and development of regularly arranged connective tissues, tendon, and cornea has been proposed. Dermal development conforms to this model and we suggest that extracytoplasmic compartmentalization of the steps in matrix assembly and segmental deposition of collagen fibrils are important mechanisms in the development of a wide variety of connective tissues.

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160

Yannas, I. V. Similarities and differences between induced organ regeneration in adults and early foetal regeneration. J. R. Soc., Interface 2005, 2 (5), 403– 417, DOI: 10.1098/rsif.2005.0062

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160

Similarities and differences between induced organ regeneration in adults and early foetal regeneration

Yannas Ioannis V

Journal of the Royal Society, Interface (2005), 2 (5), 403-17 ISSN:1742-5689.

At least three organs (skin, peripheral nerves and the conjunctiva) have been induced to regenerate partially in adults following application of porous, degradable scaffolds with highly specific structure (templates). Templates blocked contraction and scar formation by inducing a reduction in the density of contractile fibroblasts (probably myofibroblasts) and by preventing these cells to organize themselves appropriately in the wound. In contrast, during early foetal healing, myofibroblasts were absent and wounds did not close by contraction but rather by spontaneous regeneration. The adult regenerative process has so far led to imperfect recovery of the physiological anatomy of skin (skin appendages were missing), while early foetal healing has led to apparently complete restoration. Furthermore, the mechanism of the adult regenerative process involves thwarting of myofibroblast function while, during early foetal healing, differentiation of myofibroblasts has not yet occurred. The data suggest that induced organ regeneration in the adult is the result of partial reversion to early foetal healing. If so, the adult may conceal a foetal response that may be subject to activation following application of highly active scaffolds or of other substances or cells.

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Luo, L. ; Chu, J. ; Eswaramoorthy, R. ; Mulhall, K. ; Kelly, D. Engineering Tissues That Mimic the Zonal Nature of Articular Cartilage Using Decellularized Cartilage Explants Seeded with Adult Stem Cells. ACS Biomater. Sci. Eng. 2017, 3 (9), 1933– 1943, DOI: 10.1021/acsbiomaterials.6b00020

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161

Engineering Tissues That Mimic the Zonal Nature of Articular Cartilage Using Decellularized Cartilage Explants Seeded with Adult Stem Cells

Luo, Lu; Chu, Johnnie Y. J.; Eswaramoorthy, Rajalakshmanan; Mulhall, Kevin J.; Kelly, Daniel J.

ACS Biomaterials Science & Engineering (2017), 3 (9), 1933-1943CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)

Articular cartilage (AC) possesses uniquely complex mech. properties; for example its stiffness increases with depth through the tissue and it softens when compressed. These properties are integral to the function of AC and can be attributed to the tissue's collagen network and how it interacts with neg. charged proteoglycans. In this study, scaffolds contg. arrays of channels were produced from decellularized AC explants derived from skeletally immature and mature pigs. These scaffolds were then repopulated with human infrapatellar fat pad derived stem cells (FPSCs). After 4 wk in culture, FPSCs filled channels within the decellularized explants with a matrix rich in proteoglycans and collagen. Cellular and neo-matrix alignment within these scaffolds appeared to be influenced by the underlying collagen architecture of the decellularized cartilage. Repopulating scaffolds derived from decellularized skeletally mature cartilage with FPSCs led to the development of engineered cartilage with depth-dependent mech. properties mimicking aspects of native tissue. Furthermore, these constructs displayed the characteristic strain softening behavior of AC. These findings highlight the importance of the collagen network to engineering mech. functional cartilage grafts.

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162

Petersen, A. ; Princ, A. ; Korus, G. ; Ellinghaus, A. ; Leemhuis, H. ; Herrera, A. ; Klaumünzer, A. ; Schreivogel, S. ; Woloszyk, A. ; Schmidt-Bleek, K. ; Geissler, S. ; Heschel, I. ; Duda, G. N. A biomaterial with a channel-like pore architecture induces endochondral healing of bone defects. Nat. Commun. 2018, 9 (1), 4430, DOI: 10.1038/s41467-018-06504-7

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162

A biomaterial with a channel-like pore architecture induces endochondral healing of bone defects

Petersen A; Princ A; Korus G; Ellinghaus A; Herrera A; Klaumunzer A; Schreivogel S; Woloszyk A; Schmidt-Bleek K; Geissler S; Duda G N; Petersen A; Schmidt-Bleek K; Geissler S; Duda G N; Leemhuis H; Heschel I; Herrera A; Schreivogel S; Duda G N; Woloszyk A

Nature communications (2018), 9 (1), 4430 ISSN:.

Biomaterials developed to treat bone defects have classically focused on bone healing via direct, intramembranous ossification. In contrast, most bones in our body develop from a cartilage template via a second pathway called endochondral ossification. The unsolved clinical challenge to regenerate large bone defects has brought endochondral ossification into discussion as an alternative approach for bone healing. However, a biomaterial strategy for the regeneration of large bone defects via endochondral ossification is missing. Here we report on a biomaterial with a channel-like pore architecture to control cell recruitment and tissue patterning in the early phase of healing. In consequence of extracellular matrix alignment, CD146+ progenitor cell accumulation and restrained vascularization, a highly organized endochondral ossification process is induced in rats. Our findings demonstrate that a pure biomaterial approach has the potential to recapitulate a developmental bone growth process for bone healing. This might motivate future strategies for biomaterial-based tissue regeneration.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvjtlGisQ%253D%253D&md5=080b636c97759aca97f085522da6f548

163

Olvera, D. ; Sathy, B. N. ; Carroll, S. F. ; Kelly, D. J. Modulating microfibrillar alignment and growth factor stimulation to regulate mesenchymal stem cell differentiation. Acta Biomater. 2017, 64 , 148– 160, DOI: 10.1016/j.actbio.2017.10.010

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163

Modulating microfibrillar alignment and growth factor stimulation to regulate mesenchymal stem cell differentiation

Olvera, Dinorath; Sathy, Binulal N.; Carroll, Simon F.; Kelly, Daniel J.

Acta Biomaterialia (2017), 64 (), 148-160CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

The ideal tissue engineering (TE) strategy for ligament regeneration should recapitulate the bone-calcified cartilage -fibrocartilage-soft tissue interface. Aligned electrospun-fibers have been shown to guide the deposition of a highly organized extracellular matrix (ECM) necessary for ligament TE. However, recapitulating the different tissues obsd. in the bone-ligament interface using such constructs remains a challenge. This study aimed to explore how fiber alignment and growth factor stimulation interact to regulate the chondrogenic and ligamentous differentiation of mesenchymal stem cells (MSCs). To this end aligned and randomly-aligned electrospun microfibrillar scaffolds were seeded with bone marrow derived MSCs and stimulated with transforming growth factor β3 (TGFβ3) or connective tissue growth factor (CTGF), either individually or sequentially. Without growth factor stimulation, MSCs on aligned-microfibers showed higher levels of tenomodulin (TNMD) and aggrecan gene expression compared to MSCs on randomly-oriented fibers. MSCs on aligned-microfibers stimulated with TGFβ3 formed cellular aggregates and underwent robust chondrogenesis, evidenced by increased type II collagen expression and sulfated glycosaminoglycans (sGAG) synthesis compared to MSCs on randomly-oriented scaffolds. Bone morphogenetic protein 2 (BMP2) and type I collagen gene expression were higher on randomly-oriented scaffolds stimulated with TGFβ3, suggesting this substrate was more supportive of an endochondral phenotype. In the presence of CTGF, MSCs underwent ligamentous differentiation, with increased TNMD expression on aligned compared to randomly aligned scaffolds. Upon sequential growth factor stimulation, MSCs expressed types I and II collagen and deposited higher overall levels of collagen compared to scaffolds stimulated with either growth factor in isolation. These findings demonstrate that modulating the alignment of microfibrillar scaffolds can be used to promote either an endochondral, chondrogenic, fibrochondrogenic or ligamentous MSC phenotype upon presentation of appropriate biochem. cues. Polymeric electrospun fibers can be tuned to match the fibrillar size and anisotropy of collagen fibers in ligaments, and can be mech. competent. Therefore, their use is attractive when attempting to tissue engineer the bone-ligament interface. A central challenge in this field is recapitulating the cellular phenotypes obsd. across the bone-ligament interface. Here we demonstrated that it is possible to direct MSCs seeded onto aligned electrospun fibers towards either a ligamentogenic, chondrogenic or fibrochondrogenic phenotype upon presentation of appropriate biochem. cues. This opens the possibility of using aligned microfibrillar scaffolds that are spatially functionalized with specific growth factors to direct MSC differentiation for engineering the bone-ligament interface.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Oiu73K&md5=7300ee453b0b25e71162680efe7790cb

164

Pauly, H. ; Nelson Sathy, B. ; Olvera, D. ; McCarthy, H. ; Kelly, D. ; Popat, K. ; Dunne, N. ; Donahue, T. Hierarchically Structured Electrospun Scaffolds with Chemically Conjugated Growth Factor for Ligament Tissue Engineering. Tissue Engineering Part A Aug 2017, 23 (15–16), 823– 836

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164

Hierarchically Structured Electrospun Scaffolds with Chemically Conjugated Growth Factor for Ligament Tissue Engineering

Pauly, Hannah M.; Sathy, Binulal N.; Olvera, Dinorath; McCarthy, Helen O.; Kelly, Daniel J.; Popat, Ketul C.; Dunne, Nicholas J.; Haut Donahue, Tammy Lynn

Tissue Engineering, Part A (2017), 23 (15-16), 823-836CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

The anterior cruciate ligament (ACL) of the knee is vital for proper joint function and is commonly ruptured during sports injuries or car accidents. Due to a lack of intrinsic healing capacity and drawbacks with allografts and autografts, there is a need for a tissue-engineered ACL replacement. Our group has previously used aligned sheets of electrospun polycaprolactone nanofibers to develop solid cylindrical bundles of longitudinally aligned nanofibers. We have shown that these nanofiber bundles support cell proliferation and elongation and the hierarchical structure and material properties are similar to the native human ACL. It is possible to combine multiple nanofiber bundles to create a scaffold that attempts to mimic the macroscale structure of the ACL. The goal of this work was to develop a hierarchical bioactive scaffold for ligament tissue engineering using connective tissue growth factor (CTGF)-conjugated nanofiber bundles and evaluate the behavior of mesenchymal stem cells (MSCs) on these scaffolds in vitro and in vivo. CTGF was immobilized onto the surface of individual nanofiber bundles or scaffolds consisting of multiple nanofiber bundles. The conjugation efficiency and the release of conjugated CTGF were assessed using XPS, assays, and immunofluorescence staining. Scaffolds were seeded with MSCs and maintained in vitro for 7 days (individual nanofiber bundles), in vitro for 21 days (scaled-up scaffolds of 20 nanofiber bundles), or in vivo for 6 wk (small scaffolds of 4 nanofiber bundles), and ligament-specific tissue formation was assessed in comparison to non-CTGF-conjugated control scaffolds. Results showed that CTGF conjugation encouraged cell proliferation and ligament-specific tissue formation in vitro and in vivo. The results suggest that hierarchical electrospun nanofiber bundles conjugated with CTGF are a scalable and bioactive scaffold for ACL tissue engineering.

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Rowland, C. R. ; Colucci, L. A. ; Guilak, F. Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds. Biomaterials 2016, 91 , 57– 72, DOI: 10.1016/j.biomaterials.2016.03.012

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165

Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds

Rowland, Christopher R.; Colucci, Lina A.; Guilak, Farshid

Biomaterials (2016), 91 (), 57-72CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

The native extracellular matrix of cartilage contains entrapped growth factors as well as tissue-specific epitopes for cell-matrix interactions, which make it a potentially attractive biomaterial for cartilage tissue engineering. A limitation to this approach is that the native cartilage extracellular matrix possesses a pore size of only a few nanometers, which inhibits cellular infiltration. Efforts to increase the pore size of cartilage-derived matrix (CDM) scaffolds dramatically attenuate their mech. properties, which makes them susceptible to cell-mediated contraction. In previous studies, we have demonstrated that collagen crosslinking techniques are capable of preventing cell-mediated contraction in CDM disks. In the current study, we investigated the effects of CDM concn. and pore architecture on the ability of CDM scaffolds to resist cell-mediated contraction. Increasing CDM concn. significantly increased scaffold mech. properties, which played an important role in preventing contraction, and only the highest CDM concn. (11% wt./wt.) was able to retain the original scaffold dimensions. However, the increase in CDM concn. led to a concomitant decrease in porosity and pore size. Generating a temp. gradient during the freezing process resulted in unidirectional freezing, which aligned the formation of ice crystals during the freezing process and in turn produced aligned pores in CDM scaffolds. These aligned pores increased the pore size of CDM scaffolds at all CDM concns., and greatly facilitated infiltration by mesenchymal stem cells (MSCs). These methods were used to fabricate of anatomically-relevant CDM hemispheres. CDM hemispheres with aligned pores supported uniform MSC infiltration and matrix deposition. Furthermore, these CDM hemispheres retained their original architecture and did not contract, warp, curl, or splay throughout the entire 28-day culture period. These findings demonstrate that given the appropriate fabrication parameters, CDM scaffolds are capable of maintaining complex structures that support MSC chondrogenesis.

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Zhang, T. ; Zhang, H. ; Zhang, L. ; Jia, S. ; Liu, J. ; Xiong, Z. ; Sun, W. Biomimetic design and fabrication of multilayered osteochondral scaffolds by low-temperature deposition manufacturing and thermal-induced phase-separation techniques. Biofabrication 2017, 9 , 025021, DOI: 10.1088/1758-5090/aa7078

[Crossref], [PubMed], [CAS], Google Scholar

166

Biomimetic design and fabrication of multilayered osteochondral scaffolds by low-temperature deposition manufacturing and thermal-induced phase-separation techniques

Zhang, Ting; Zhang, Hefeng; Zhang, Laquan; Jia, Shuaijun; Liu, Jian; Xiong, Zhuo; Sun, Wei

Biofabrication (2017), 9 (2), 025021/1-025021/14CODEN: BIOFFN; ISSN:1758-5090. (IOP Publishing Ltd.)

Integrative osteochondral repair is a useful strategy for cartilage-defect repair. To mimic the microenvironment, it is necessary that scaffolds effectively mimic the extracellular matrix of natural cartilage and subchondral bone. In this study, biomimetic osteochondral scaffolds contg. an oriented cartilage layer, a compact layer, and a three-dimensional (3D)-printed core-sheath structured-bone layer were developed. The oriented cartilage layer was designed to mimic the structural and material characteristics of native cartilage tissue and was fabricated with cartilage matrix-chitosan materials, using thermal-induced phase-sepn. technol. The 3D-printed core-sheath structured-bone layer was fabricated with poly(L-lactide-co-glycolide)/β-tricalcium phosphate-collagen materials by low-temp. deposition technol., using a specially designed core-sheath nozzle, and was designed to mimic the mech. characteristics of subchondral bone and improve scaffold hydrophilicity. Our results indicated that the scaffolds exhibited good biocompatibility, and 24 wk after implantation, the femoral condyle surface was relatively flat and consisted of a large quantity of hyaloid cartilage. Furthermore, histol. staining revealed regenerated trabecular bone formed in the subchondral bone-defect area. These results provided a new method to fabricate biomimetic osteochondral scaffolds and demonstrated their effectiveness for future clin. applications in cartilage-defect repair.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlWks73N&md5=1cfff7586e78c5bbcbf6d7b3655d7611

167

Domingues, R. M. ; Chiera, S. ; Gershovich, P. ; Motta, A. ; Reis, R. L. ; Gomes, M. E. Enhancing the Biomechanical Performance of Anisotropic Nanofibrous Scaffolds in Tendon Tissue Engineering: Reinforcement with Cellulose Nanocrystals. Adv. Healthcare Mater. 2016, 5 (11), 1364– 75, DOI: 10.1002/adhm.201501048

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167

Enhancing the Biomechanical Performance of Anisotropic Nanofibrous Scaffolds in Tendon Tissue Engineering: Reinforcement with Cellulose Nanocrystals

Domingues, Rui M. A.; Chiera, Silvia; Gershovich, Pavel; Motta, Antonella; Reis, Rui L.; Gomes, Manuela E.

Advanced Healthcare Materials (2016), 5 (11), 1364-1375CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)

Anisotropically aligned electrospun nanofibrous scaffolds based on natural/synthetic polymer blends have been established as a reasonable compromise between biol. and biomech. performance for tendon tissue engineering (TE) strategies. However, the limited tensile properties of these biomaterials restrict their application in this field due to the load-bearing nature of tendon/ligament tissues. Herein, the use of cellulose nanocrystals (CNCs) as reinforcing nanofillers in aligned electrospun scaffolds based on a natural/synthetic polymer blend matrix, poly-ε-caprolactone/chitosan (PCL/CHT) is reported. The incorporation of small amts. of CNCs (up to 3 wt%) into tendon mimetic nanofiber bundles has a remarkable biomaterial-toughing effect (85% ± 5%, p < 0.0002) and raises the scaffolds mech. properties to tendon/ligament relevant range (σ = 39.3 ± 1.9 MPa and E = 540.5 ± 83.7 MPa, p < 0.0001). Aligned PCL/CHT/CNC nanocomposite fibrous scaffolds meet not only the mech. requirements for tendon TE applications but also provide tendon mimetic extracellular matrix (ECM) topog. cues, a key feature for maintaining tendon cell's morphol. and behavior. The strategy proposed here may be extended to other anisotropic aligned nanofibrous scaffolds based on natural/synthetic polymer blends and enable the full exploitation of the advantages provided by their tendon mimetic fibrous structures in tendon TE.

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168

[Crossref], [PubMed], [CAS], Google Scholar

168

Hierarchically Structured Electrospun Scaffolds with Chemically Conjugated Growth Factor for Ligament Tissue Engineering

Pauly, Hannah M.; Sathy, Binulal N.; Olvera, Dinorath; McCarthy, Helen O.; Kelly, Daniel J.; Popat, Ketul C.; Dunne, Nicholas J.; Haut Donahue, Tammy Lynn

Tissue Engineering, Part A (2017), 23 (15-16), 823-836CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlemt7zN&md5=2bf3e62b11f579a6244a196e39c9e625

169

Jia, S. ; Zhang, T. ; Xiong, Z. ; Pan, W. ; Liu, J. ; Sun, W. In Vivo Evaluation of a Novel Oriented Scaffold-BMSC Construct for Enhancing Full-Thickness Articular Cartilage Repair in a Rabbit Model. PLoS One 2015, 10 (12), e0145667, DOI: 10.1371/journal.pone.0145667

170

Ibrahim, N. S. ; Krishnamurithy, G. ; Rao Balaji Raghavendran, H. ; Puvaneswary, S. ; Wuey Min, N. ; Kamarul, T. Novel HA-PVA/NOCC bilayered scaffold for osteochondral tissue-engineering applications - Fabrication, characterization, in vitro and in vivo biocompatibility study. Mater. Lett. 2013, 113 , 25– 29, DOI: 10.1016/j.matlet.2013.09.026

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170

Novel hydroxyapatite/N,O-carboxymethylated chitosan bilayered scaffold for osteochondral tissue-engineering applications - Fabrication, characterization, in vitro and in vivo biocompatibility study

Ibrahim, Nurul Syuhada; Krishnamurithy, Genasan; Rao Balaji Raghavendran, Hanumantha; Puvaneswary, Subramaniam; Wuey Min, Ng; Kamarul, Tunku

Materials Letters (2013), 113 (), 25-29CODEN: MLETDJ; ISSN:0167-577X. (Elsevier B.V.)

This study aimed to examine the bilayered scaffold contg. hydroxyapatite (HA) and N, O-carboxymethylated chitosan (PVA/NOCC) seeded with mesenchymal stem cells in vitro to det. its potential use as a scaffold in tissue engineering. SEM anal. revealed that pores in this scaffold were interconnected with parallel grooves and ridges. EDS indicated that the level of calcium was relatively higher in HA. FTIR confirmed the presence of functional groups corresponding to alkyl halide, alkyne, hydroxyl group, and alkane groups, while XRD results revealed that the phase content of HA and hydrogel comprised org. substance. Significantly higher levels of differentiation markers, namely, alk. phosphatase and glycosaminoglycans, were detected in the scaffold cultures. Furthermore, histol. and blood profile demonstrated biocompatibility of this bilayered scaffold in a rat model. In conclusion, our results demonstrate that bilayered scaffold may be a promising construct for osteochondral defects.

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171

[Crossref], [PubMed], [CAS], Google Scholar

171

Hierarchically Structured Electrospun Scaffolds with Chemically Conjugated Growth Factor for Ligament Tissue Engineering

Pauly, Hannah M.; Sathy, Binulal N.; Olvera, Dinorath; McCarthy, Helen O.; Kelly, Daniel J.; Popat, Ketul C.; Dunne, Nicholas J.; Haut Donahue, Tammy Lynn

Tissue Engineering, Part A (2017), 23 (15-16), 823-836CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlemt7zN&md5=2bf3e62b11f579a6244a196e39c9e625

172

Galperin, A. ; Oldinski, R. A. ; Florczyk, S. J. ; Bryers, J. D. ; Zhang, M. ; Ratner, B. D. Integrated Bi-Layered Scaffold for Osteochondral Tissue Engineering. Adv. Healthcare Mater. 2013, 2 (6), 872– 883, DOI: 10.1002/adhm.201200345

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172

Integrated Bi-Layered Scaffold for Osteochondral Tissue Engineering

Galperin, Anna; Oldinski, Rachael A.; Florczyk, Stephen J.; Bryers, James D.; Zhang, Miqin; Ratner, Buddy D.

Advanced Healthcare Materials (2013), 2 (6), 872-883CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)

Osteochondral tissue engineering poses the challenge of combining both cartilage and bone tissue engineering fundamentals. In this study, a sphere-templating technique was applied to fabricate an integrated bi-layered scaffold based on degradable poly(hydroxyethyl methacrylate) hydrogels. One layer of the integrated scaffold was designed with a single defined, monodispersed pore size of 38 μm and pore surfaces coated with hydroxyapatite particles to promote regrowth of subchondral bone while the second layer had 200 μm pores with surfaces decorated with hyaluronan for articular cartilage regeneration. Mech. properties of the construct as well as cytocompatibility of the scaffold and its degrdn. products were elucidated. To examine the potential of the biphasic scaffold for regeneration of osteochondral tissue the designated cartilage and bone layers of the integrated bi-layered scaffold were seeded with chondrocytes differentiated from human mesenchymal stem cells and primary human mesenchymal stem cells, resp. Both types of cells were co-cultured within the scaffold in std. medium without sol. growth/differentiation factors over 4 wk. The ability of the integrated bi-layered scaffold to support simultaneous matrix deposition and adequate cell growth of two distinct cell lineages in each layer during 4 wk of co-culture in vitro in the absence of sol. growth factors was demonstrated.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptlCgsrc%253D&md5=8efdca285cf5a2dd806e42ed0210f9a8

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Ding, X. ; Zhu, M. ; Xu, B. ; Zhang, J. ; Zhao, Y. ; Ji, S. ; Wang, L. ; Li, X. ; Kong, D. ; Ma, X. ; Yang, Q. Integrated trilayered silk fibroin scaffold for osteochondral differentiation of adipose-derived stem cells. ACS Appl. Mater. Interfaces 2014, 6 (19), 16696– 705, DOI: 10.1021/am5036708

[ACS Full Text ], [CAS], Google Scholar

173

Integrated Trilayered Silk Fibroin Scaffold for Osteochondral Differentiation of Adipose-Derived Stem Cells

Ding, Xiaoming; Zhu, Meifeng; Xu, Baoshan; Zhang, Jiamin; Zhao, Yanhong; Ji, Shenglu; Wang, Lina; Wang, Lianyong; Li, Xiulan; Kong, Deling; Ma, Xinlong; Yang, Qiang

ACS Applied Materials & Interfaces (2014), 6 (19), 16696-16705CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

Repairing osteochondral defects (OCD) remains a formidable challenge due to the high complexity of native osteochondral tissue and the limited self-repair capability of cartilage. Osteochondral tissue engineering is a promising strategy for the treatment of OCD. In this study, we fabricated a novel integrated trilayered scaffold using silk fibroin and hydroxyapatite by combining paraffin-sphere leaching with a modified temp. gradient-guided thermal-induced phase sepn. (TIPS) technique. This biomimetic scaffold is characterized by three layers: a chondral layer with a longitudinally oriented microtubular structure, a bony layer with a 3D porous structure and an intermediate layer with a dense structure. Live/dead and CCK-8 tests indicated that this scaffold possesses good biocompatibility for supporting the growth, proliferation, and infiltration of adipose-derived stem cells (ADSCs). Histol. and immunohistochem. stainings and real-time polymerase chain reaction (RT-PCR) confirmed that the ADSCs could be induced to differentiate toward chondrocytes or osteoblasts in vitro at chondral and bony layers in the presence of chondrogenic- or osteogenic-induced culture medium, resp. Moreover, the intermediate layer could play an isolating role for preventing the cells within the chondral and bony layers from mixing with each other. In conclusion, the trilayered and integrated osteochondral scaffolds can effectively support cartilage and bone tissue generation in vitro and are potentially applicable for OC tissue engineering in vivo.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFamsLnM&md5=53603a8c8cf356ece5cc89d47cdcfb69

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Zhou, T. ; Wu, J. ; Liu, J. ; Luo, Y. ; Wan, Y. Fabrication and characterization of layered chitosan/silk fibroin/nano-hydroxyapatite scaffolds with designed composition and mechanical properties. Biomedical materials (Bristol, England) 2015, 10 (4), 045013, DOI: 10.1088/1748-6041/10/4/045013

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174

Fabrication and characterization of layered chitosan/silk fibroin/nano-hydroxyapatite scaffolds with designed composition and mechanical properties

Zhou Ting; Wu Jingjing; Liu Jiaoyan; Luo Ying; Wan Ying

Biomedical materials (Bristol, England) (2015), 10 (4), 045013 ISSN:.

Chitosan/nano-hydroxyapatite (HA) composites were first prepared and then used together with chitosan and silk fibroin (SF) to produce a type of four-layer porous scaffold that is potentially applicable for articular cartilage repair. The bottom layer of the scaffold was built with the chitosan/HA composite and the other three layers of the scaffold were fabricated using chitosan/SF composites in which the content of the chitosan and SF was altered in a mutually reversed trend. The so-produced chitosan/SF/HA scaffolds were further crosslinked using tripolyphosphate to achieve enhanced mechanical properties. Interconnected porous microstructures throughout the scaffolds were constructed using a temperature gradient processing technique, and the resultant scaffolds were endowed with graded pore-sizes and porosities as well as porous interface zones between contiguous layers without visual clefts. The compressive modulus and stress at 10% strain of the scaffolds in wet state showed a gradient-changed trend which partially mimics the compressive mechanical properties of an articular cartilage matrix. Cell culture on some chitosan/SF/HA scaffolds for a period of time of up to 14 d showed that the scaffolds were able to well support the growth and infiltration of cells, suggesting that the presently developed chitosan/SF/HA scaffolds have promising potential for articular cartilage repair.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252FpsVOltA%253D%253D&md5=acd28a598be8e409024e6dbb2f953dba

175

Granito, R. N. ; Muniz Renno, A. C. ; Yamamura, H. ; de Almeida, M. C. ; Menin Ruiz, P. L. ; Ribeiro, D. A. Hydroxyapatite from Fish for Bone Tissue Engineering: A Promising Approach. Int. J. Mol. Cell. Med. 2018, 7 (2), 80– 90, DOI: 10.22088/IJMCM.BUMS.7.2.80

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175

Hydroxyapatite from fish for bone tissue engineering: a promising approach

Granito, Renata Neves; Renno, Ana Claudia Muniz; Yamamura, Hirochi; de Almeida, Matheus Cruz; Ruiz, Pedro Luiz Menin; Ribeiro, Daniel Araki

International Journal of Molecular and Cellular Medicine (2018), 7 (2), 80-90CODEN: IJMCJO; ISSN:2251-9645. (Babol University of Medical Sciences, Cellular and Molecular Biology Research Center)

Natural or synthetic hydroxyapatite (HA) has been frequently used as implant materials for orthopaedic and dental applications, showing excellent bioactivity, adequate mech. rigidity and structure, osteocond. and angiogenic properties, no toxicity, and absence of inflammatory or antigenic reactions. HA can be easily synthesized or extd. from natural sources, such as bovine bone. However, the manufg. costs to obtain HA are high, restricting the therapy. Herein, much effort has been paid for obtaning alternative natural sources for HA. The potential of HA extd. from skeleton of animals has been investigated. The aim of this review is to exploit the potential of HA derived from fish to fulfill biol. activities for bone tissue engineering. In particular, HA from fish is easy to be manufd. regarding the majority of protocols that are based on the calcination method. Furthermore, the compn. and structure of HA from fish were evaluated; the biomaterial showed good biocompatibility as a result of non-cytotoxicity and handling properties, demonstrating advantages in comparison with synthetic ones. Interestingly, another huge benefit brought by HA from bone fish is its pos. effect for environment since this technique considerably reduces waste. Certainly, the process of transforming fish into HA is an environmentally friendly process and stands as a good chance for reducing costs of treatment in bone repair or replacement with little impact into the environment.

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Zhou, H. ; Lee, J. Nanoscale hydroxyapatite particles for bone tissue engineering. Acta Biomater. 2011, 7 (7), 2769– 81, DOI: 10.1016/j.actbio.2011.03.019

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176

Nanoscale hydroxyapatite particles for bone tissue engineering

Zhou, Hongjian; Lee, Jaebeom

Acta Biomaterialia (2011), 7 (7), 2769-2781CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

A review. Hydroxyapatite (HAp) exhibits excellent biocompatibility with soft tissues such as skin, muscle and gums, making it an ideal candidate for orthopedic and dental implants or components of implants. Synthetic HAp has been widely used in repair of hard tissues, and common uses include bone repair, bone augmentation, as well as coating of implants or acting as fillers in bone or teeth. However, the low mech. strength of normal HAp ceramics generally restricts its use to low load-bearing applications. Recent advancements in nanoscience and nanotechnol. have reignited investigation of nanoscale HAp formation in order to clearly define the small-scale properties of HAp. It has been suggested that nano-HAp may be an ideal biomaterial due to its good biocompatibility and bone integration ability. HAp biomedical material development has benefited significantly from advancements in nanotechnol. This feature article looks a fresh at nano-HAp particles, highlighting the importance of size, crystal morphol. control, and composites with other inorg. particles for biomedical material development.

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Khanarian, N. T. ; Haney, N. M. ; Burga, R. A. ; Lu, H. H. A functional agarose-hydroxyapatite scaffold for osteochondral interface regeneration. Biomaterials 2012, 33 (21), 5247– 5258, DOI: 10.1016/j.biomaterials.2012.03.076

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177

A functional agarose-hydroxyapatite scaffold for osteochondral interface regeneration

Khanarian, Nora T.; Haney, Nora M.; Burga, Rachel A.; Lu, Helen H.

Biomaterials (2012), 33 (21), 5247-5258CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Regeneration of the osteochondral interface is crit. for integrative and functional cartilage repair. This study focuses on the design and optimization of a hydrogel-ceramic composite scaffold of agarose and hydroxyapatite (HA) for calcified cartilage formation. The first study objective was to compare the effects of HA on non-hypertrophic and hypertrophic chondrocytes cultured in the composite scaffold. Specifically, cell growth, biosynthesis, hypertrophy, and scaffold mech. properties were evaluated. Next, the ceramic phase of the scaffold was optimized in terms of particle size (200 nm vs. 25 μm) and dose (0-6 wt./vol.%). It was obsd. that while deep zone chondrocyte (DZC) biosynthesis and hypertrophy remained unaffected, hypertrophic chondrocytes measured higher matrix deposition and mineralization potential with the addn. of HA. Most importantly, higher matrix content translated into significant increases in both compressive and shear mech. properties. While cell hypertrophy was independent of ceramic size, matrix deposition was higher only with the addn. of micron-sized ceramic particles. In addn., the highest matrix content, mech. properties and mineralization potential were found in scaffolds with 3% micro-HA, which approximates both the mineral aggregate size and content of the native interface. These results demonstrate that the biomimetic hydrogel-ceramic composite is optimal for calcified cartilage formation and is a promising design strategy for osteochondral interface regeneration.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlvFaisbc%253D&md5=d16bcec2604407aabfafa14d9d31b467

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Chen, J. ; Chen, H. ; Li, P. ; Diao, H. ; Zhu, S. ; Dong, L. ; Wang, R. ; Guo, T. ; Zhao, J. ; Zhang, J. Simultaneous regeneration of articular cartilage and subchondral bone in vivo using MSCs induced by a spatially controlled gene delivery system in bilayered integrated scaffolds. Biomaterials 2011, 32 (21), 4793– 805, DOI: 10.1016/j.biomaterials.2011.03.041

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178

Simultaneous regeneration of articular cartilage and subchondral bone in vivo using MSCs induced by a spatially controlled gene delivery system in bilayered integrated scaffolds

Chen, Jiangning; Chen, Huan; Li, Pei; Diao, Huajia; Zhu, Shiyu; Dong, Lei; Wang, Rui; Guo, Ting; Zhao, Jianning; Zhang, Junfeng

Biomaterials (2011), 32 (21), 4793-4805CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Engineering complex tissues is important but difficult to achieve in tissue regeneration. Osteochondral tissue engineering for the repair of osteochondral defect, involving simultaneous regeneration of bone and cartilage, has attracted considerable attention and also serves as an optimal model system for developing effective strategies aimed at regenerating complex tissues. In the present study, we formulated a bilayered gene-activated osteochondral scaffold consisting of plasmid TGF-β1-activated chitosan-gelatin scaffold for chondrogenic layer and plasmid BMP-2-activated hydroxyapatite/chitosan-gelatin scaffold for osteogenic layer. Mesenchymal stem cells seeded in each layer of the bilayered gene- activated osteochondral scaffold showed significant cell proliferation, high expression of TGF-β1 protein and BMP-2 protein resp. The results showed that spatially controlled and localized gene delivery system in the bilayered integrated scaffolds could induce the mesenchymal stem cells in different layers to differentiate into chondrocytes and osteoblasts in vitro, resp., and simultaneously support the articular cartilage and subchondral bone regeneration in the rabbit knee ostochondral defect model. This study gives the evidence that multi-tissue regeneration through the combination of biomimetic and multi-phasic scaffold design, spatially controlled and localized gene delivery system and multi-lineage differentiation of a single stem cell population represents a promising strategy for facilitating the development of complex tissue or organ systems.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmtVWlsbo%253D&md5=4204a2bf7dc4ff97807328e60df8e737

179

Gao, F. ; Xu, Z. ; Liang, Q. ; Li, H. ; Peng, L. ; Wu, M. ; Zhao, X. ; Cui, X. ; Ruan, C. ; Liu, W. Osteochondral Regeneration with 3D-Printed Biodegradable High-Strength Supramolecular Polymer Reinforced-Gelatin Hydrogel Scaffolds. Advanced Science 2019, 6 , 1900867, DOI: 10.1002/advs.201900867

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179

Osteochondral Regeneration with 3D-Printed Biodegradable High-Strength Supramolecular Polymer Reinforced-Gelatin Hydrogel Scaffolds

Gao Fei; Xu Ziyang; Li Haofei; Liu Wenguang; Liang Qingfei; Peng Liuqi; Wu Mingming; Zhao Xiaoli; Cui Xu; Ruan Changshun

Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2019), 6 (15), 1900867 ISSN:2198-3844.

Biomacromolecules with poor mechanical properties cannot satisfy the stringent requirement for load-bearing as bioscaffolds. Herein, a biodegradable high-strength supramolecular polymer strengthened hydrogel composed of cleavable poly(N-acryloyl 2-glycine) (PACG) and methacrylated gelatin (GelMA) (PACG-GelMA) is successfully constructed by photo-initiated polymerization. Introducing hydrogen bond-strengthened PACG contributes to a significant increase in the mechanical strengths of gelatin hydrogel with a high tensile strength (up to 1.1 MPa), outstanding compressive strength (up to 12.4 MPa), large Young's modulus (up to 320 kPa), and high compression modulus (up to 837 kPa). In turn, the GelMA chemical crosslinking could stabilize the temporary PACG network, showing tunable biodegradability by adjusting ACG/GelMA ratios. Further, a biohybrid gradient scaffold consisting of top layer of PACG-GelMA hydrogel-Mn(2+) and bottom layer of PACG-GelMA hydrogel-bioactive glass is fabricated for repair of osteochondral defects by a 3D printing technique. In vitro biological experiments demonstrate that the biohybrid gradient hydrogel scaffold not only supports cell attachment and spreading but also enhances gene expression of chondrogenic-related and osteogenic-related differentiation of human bone marrow stem cells. Around 12 weeks after in vivo implantation, the biohybrid gradient hydrogel scaffold significantly facilitates concurrent regeneration of cartilage and subchondral bone in a rat model.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mvntlyluw%253D%253D&md5=23d4f3d8094e54756b27f9fd562923b3

180

Canadas, R. l. F. ; Ren, T. ; Marques, A. P. ; Oliveira, J. M. ; Reis, R. L. ; Demirci, U. Biochemical Gradients to Generate 3D Heterotypic-Like Tissues with Isotropic and Anisotropic Architectures. Adv. Funct. Mater. 2018, 28 (48), 1804148, DOI: 10.1002/adfm.201804148

181

Gelse, K. ; Pöschl, E. ; Aigner, T. Collagens─structure, function, and biosynthesis. Adv. Drug Delivery Rev. 2003, 55 (12), 1531– 1546, DOI: 10.1016/j.addr.2003.08.002

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181

Collagens - structure, function, and biosynthesis

Gelse, K.; Poschl, E.; Aigner, T.

Advanced Drug Delivery Reviews (2003), 55 (12), 1531-1546CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)

A review. The extracellular matrix represents a complex alloy of variable members of diverse protein families defining structural integrity and various physiol. functions. The most abundant family is the collagens with >20 different collagen types identified so far. Collagens are centrally involved in the formation of fibrillar and microfibrillar networks of the extracellular matrix, basement membranes as well as other structures of the extracellular matrix. This review focuses on the distribution and function of various collagen types in different tissues. It introduces their basic structural subunits and points out major steps in the biosynthesis and supramol. processing of fibrillar collagens as prototypical members of this protein family. A final outlook indicates the importance of different collagen types not only for the understanding of collagen-related diseases, but also as a basis for the therapeutic use of members of this protein family.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXptVGrsL8%253D&md5=61ae07ac85a28983d6c6605f14c0f8c2

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Liu, C. ; Han, Z. ; Czernuszka, J. T. Gradient collagen/nanohydroxyapatite composite scaffold: Development and characterization. Acta Biomater. 2009, 5 (2), 661– 669, DOI: 10.1016/j.actbio.2008.09.022

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182

Gradient collagen/nanohydroxyapatite composite scaffold: development and characterization

Liu, Chaozong; Han, Zhiwu; Czernuszka, J. T.

Acta Biomaterialia (2009), 5 (2), 661-669CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

This paper reports an in situ diffusion method for the fabrication of compositionally graded collagen/nanohydroxyapatite (HA) composite scaffold. The method is diffusion based and causes the pptn. of nano-HA crystallites in situ. A collagen matrix acts as a template through which calcium ions (Ca2+) and phosphate ions (PO43-) diffuse and ppt. a non-stoichiometric HA. It was obsd. that needle-like prismatic nano-HA crystallites (about 2 × 2 × 20 nm) pptd. in the interior of the collagen template onto the collagen fibrils. Chem. and microstructural anal. revealed a gradient of the Ca to P ratio across the width of the scaffold template, resulting in the formation of a Ca-rich side and a Ca-depleted side of scaffold. The Ca-rich side featured low porosity and agglomerates of the nano-HA crystallites, while the Ca-depleted side featured higher porosity and nano-HA crystallites integrated with collagen fibrils to form a porous network structure.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXisV2rsbo%253D&md5=623bdf70eb3d9ecd50adadce80ddeeb8

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Daly, A. C. ; Critchley, S. E. ; Rencsok, E. M. ; Kelly, D. J. A comparison of different bioinks for 3D bioprinting of fibrocartilage and hyaline cartilage. Biofabrication 2016, 8 (4), 045002, DOI: 10.1088/1758-5090/8/4/045002

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183

A comparison of different bioinks for 3D bioprinting of fibrocartilage and hyaline cartilage

Daly, Andrew C.; Critchley, Susan E.; Rencsok, Emily M.; Kelly, Daniel J.

Biofabrication (2016), 8 (4), 045002/1-045002/10CODEN: BIOFFN; ISSN:1758-5090. (IOP Publishing Ltd.)

Cartilage is a dense connective tissue with limited self-repair capabilities. Mesenchymal stem cell (MSC) laden hydrogels are commonly used for fibrocartilage and articular cartilage tissue engineering, however they typically lack the mech. integrity for implantation into high load bearing environments. This has led to increased interested in 3D bioprinting of cell laden hydrogel bioinks reinforced with stiffer polymer fibers. The objective of this study was to compare a range of commonly used hydrogel bioinks (agarose, alginate, GelMA and BioINK) for their printing properties and capacity to support the development of either hyaline cartilage or fibrocartilage in vitro. Each hydrogel was seeded with MSCs, cultured for 28 days in the presence of TGF-β3 and then analyzed for markers indicative of differentiation towards either a fibrocartilaginous or hyaline cartilage-like phenotype. Alginate and agarose hydrogels best supported the development of hyaline-like cartilage, as evident by the development of a tissue staining predominantly for type II collagen. In contrast, GelMA and BioIN (a PEGMAbased hydrogel) supported the development of a more fibrocartilage-like tissue, as evident by the development of a tissue contg. both type I and type II collagen. GelMA demonstrated superior printability, generating structures with greater fidelity, followed by the alginate and agarose bioinks. High levels of MSC viability were obsd. in all bioinks post-printing (∼80%). Finally we demonstrate that it is possible to engineer mech. reinforced hydrogels with high cell viability by co-depositing a hydrogel bioink with polycaprolactone filaments, generating composites with bulk compressive moduli comparable to articular cartilage. This study demonstrates the importance of the choice of bioink when bioprinting different cartilaginous tissues for musculoskeletal applications.

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184

Chocholata, P. ; Kulda, V. ; Babuska, V. Fabrication of Scaffolds for Bone-Tissue Regeneration. Materials 2019, 12 (4), 568, DOI: 10.3390/ma12040568

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184

Fabrication of scaffolds for bone-tissue regeneration

Chocholata, Petra; Kulda, Vlastimil; Babuska, Vaclav

Materials (2019), 12 (4), 568CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)

The present article describes the state of the art in the rapidly developing field of bone tissue engineering, where many disciplines, such as material science, mech. engineering, clin. medicine and genetics, are interconnected. The main objective is to restore and improve the function of bone tissue by scaffolds, providing a suitable environment for tissue regeneration and repair. Strategies and materials used in oral regenerative therapies correspond to techniques generally used in bone tissue engineering. Researchers are focusing on developing and improving new materials to imitate the native biol. neighborhood as authentically as possible. The most promising is a combination of cells and matrixes (scaffolds) that can be fabricated from different kinds of materials. This review summarizes currently available materials and manufg. technologies of scaffolds for bone-tissue regeneration.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1GisrnP&md5=1225b06e52190725f177dc3d75b301d5

185

Shah, R. B. ; Schwendeman, S. P. A biomimetic approach to active self-microencapsulation of proteins in PLGA. J. Controlled Release 2014, 196 , 60– 70, DOI: 10.1016/j.jconrel.2014.08.029

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185

A biomimetic approach to active self-microencapsulation of proteins in PLGA

Shah, Ronak B.; Schwendeman, Steven P.

Journal of Controlled Release (2014), 196 (), 60-70CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

A biomimetic approach to org. solvent-free microencapsulation of proteins based on the self-healing capacity of poly (DL)-lactic-co-glycolic acid (PLGA) microspheres contg. glycosaminoglycan-like biopolymers (BPs), was examd. To screen BPs, aq. solns. of BP [high mol. wt. dextran sulfate (HDS), low mol. wt. dextran sulfate (LDS), chondroitin sulfate (CS), heparin (HP), hyaluronic acid (HA), chitosan (CH)] and model protein lysozyme (LYZ) were combined in different molar and mass ratios, at 37 °C and pH 7. The BP-PLGA microspheres (20-63 μm) were prepd. by a double water-oil-water emulsion method with a range of BP content, and trehalose and MgCO3 to control microclimate pH and to create percolating pores for protein. Biomimetic active self-encapsulation (ASE) of proteins [LYZ, vascular endothelial growth factor165 (VEGF) and fibroblast growth factor (FgF-20)] was accomplished by incubating blank BP-PLGA microspheres in low concn. protein solns. at ∼ 24 °C, for 48 h. Pore closure was induced at 42.5 °C under mild agitation for 42 h. Formulation parameters of BP-PLGA microspheres and loading conditions were studied to optimize protein loading and subsequent release. LDS and HP were found to bind > 95% LYZ at BP:LYZ > 0.125 wt./wt., whereas HDS and CS bound > 80% LYZ at BP:LYZ of 0.25-1 and < 0.33, resp. HA-PLGA microspheres were found to be not ideal for obtaining high protein loading (> 2% wt./wt. of LYZ). Sulfated BP-PLGA microspheres were capable of loading LYZ (∼ 2-7% wt./wt.), VEGF (∼ 4% wt./wt.), and FgF-20 (∼ 2% wt./wt.) with high efficiency. Protein loading was found to be dependent on the loading soln. concn., with higher protein loading obtained at higher loading soln. concn. within the range investigated. Loading also increased with content of sulfated BP in microspheres. Release kinetics of proteins was evaluated in-vitro with complete release media replacement. Rate and extent of release were found to depend upon vol. of release (with non-sink conditions obsd. < 5 mL release vol. for ∼ 18 mg loaded BP-PLGA microspheres), ionic strength of release media and loading soln. concn. HDS-PLGA formulations were identified as having ideal loading and release characteristics. These optimal microspheres released ∼ 73-80% of the encapsulated LYZ over 60 days, with > 90% of protein being enzymically active. Nearly 72% of immunoreactive VEGF was similarly released over 42 days, without significant losses in heparin binding affinity in the release medium.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFCnsbrI&md5=d53cce696caf131da3ebcdb602076959

186

Ma, X. ; Qu, X. ; Zhu, W. ; Li, Y.-S. ; Yuan, S. ; Zhang, H. ; Liu, J. ; Wang, P. ; Lai, C. S. E. ; Zanella, F. ; Feng, G.-S. ; Sheikh, F. ; Chien, S. ; Chen, S. Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (8), 2206– 2211, DOI: 10.1073/pnas.1524510113

[Crossref], [PubMed], [CAS], Google Scholar

186

Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

Ma, Xuanyi; Qu, Xin; Zhu, Wei; Li, Yi-Shuan; Yuan, Suli; Zhang, Hong; Liu, Justin; Wang, Pengrui; Edwin Lai, Cheuk Sun; Zanella, Fabian; Feng, Gen-Sheng; Sheikh, Farah; Chien, Shu; Chen, Shaochen

Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (8), 2206-2211CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiol. relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphol. organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P 450 induction. The application of bioprinting technol. in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xit12rsL4%253D&md5=c41568838ddf0c85e1dc55348ec40a8f

187

Dimaraki, A.; Díaz-Payno, P. J.; Minneboo, M.; Nouri-Goushki, M.; Hosseini, M.; Kops, N.; Narcisi, R.; Mirzaali, M. J.; Osch, G. J. V. M. v.; Fratila-Apachitei, L. E.; Zadpoor, A. A. Bioprinting of a Zonal-Specific Cell Density Scaffold: A Biomimetic Approach for Cartilage Tissue Engineering. Appl. Sci. 2021, 11 (17), 7821 DOI: 10.3390/app11177821 .

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187

Bioprinting of a Zonal-Specific Cell Density Scaffold: A Biomimetic Approach for Cartilage Tissue Engineering

Dimaraki, Angeliki; Diaz-Payno, Pedro J.; Minneboo, Michelle; Nouri-Goushki, Mahdiyeh; Hosseini, Maryam; Kops, Nicole; Narcisi, Roberto; Mirzaali, Mohammad J.; van Osch, Gerjo J. V. M.; Fratila-Apachitei, Lidy E.; Zadpoor, Amir A.

Applied Sciences (2021), 11 (17), 7821CODEN: ASPCC7; ISSN:2076-3417. (MDPI AG)

The treatment of articular cartilage defects remains a significant clin. challenge. This is partially due to current tissue engineering strategies failing to recapitulate native organization. Articular cartilage is a graded tissue with three layers exhibiting different cell densities: the superficial zone having the highest d. and the deep zone having the lowest d. However, the introduction of cell gradients for cartilage tissue engineering, which could promote a more biomimetic environment, has not been widely explored. Here, we aimed to bioprint a scaffold with different zonal cell densities to mimic the organization of articular cartilage. The scaffold was bioprinted using an alginate-based bioink contg. human articular chondrocytes. The scaffold design included three cell densities, one per zone: 20 x 106 (superficial), 10 x 106 (middle), and 5 x 106 (deep) cells/mL. The scaffold was cultured in a chondrogenic medium for 25 days and analyzed by live/dead assay and histol. The live/dead anal. showed the ability to generate a zonal cell d. with high viability. Histol. anal. revealed a smooth transition between the zones in terms of cell distribution and a higher sulfated glycosaminoglycan deposition in the highest cell d. zone. These findings pave the way toward bioprinting complex zonal cartilage scaffolds as single units, thereby advancing the translation of cartilage tissue engineering into clin. practice.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXit1Gru7%252FM&md5=ba6876ec56dfacda4fd7a667f0ec00a2

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Nowicki, M. A. ; Castro, N. J. ; Plesniak, M. W. ; Zhang, L. G. 3D printing of novel osteochondral scaffolds with graded microstructure. Nanotechnology 2016, 27 (41), 414001, DOI: 10.1088/0957-4484/27/41/414001

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188

3D printing of novel osteochondral scaffolds with graded microstructure

Nowicki, Margaret A.; Castro, Nathan J.; Plesniak, Michael W.; Zhang, Lijie Grace

Nanotechnology (2016), 27 (41), 414001/1-414001/10CODEN: NNOTER; ISSN:1361-6528. (IOP Publishing Ltd.)

Osteochondral tissue has a complex graded structure where biol., physiol., and mech. properties vary significantly over the full thickness spanning from the subchondral bone region beneath the joint surface to the hyaline cartilage region at the joint surface. This presents a significant challenge for tissue-engineered structures addressing osteochondral defects. Fused deposition modeling (FDM) 3D bioprinters present a unique soln. to this problem. The objective of this study is to use FDM-based 3D bioprinting and nanocryst. hydroxyapatite for improved bone marrow human mesenchymal stem cell (hMSC) adhesion, growth, and osteochondral differentiation. FDM printing parameters can be tuned through computer aided design and computer numerical control software to manipulate scaffold geometries in ways that are beneficial to mech. performance without hindering cellular behavior. Addnl., the ability to fine-tune 3D printed scaffolds increases further through our investment casting procedure which facilitates the inclusion of nanoparticles with biochem. factors to further elicit desired hMSC differentiation. For this study, FDM was used to print investment-casting molds innovatively designed with varied pore distribution over the full thickness of the scaffold. The mech. and biol. impacts of the varied pore distributions were compared and evaluated to det. the benefits of this phys. manipulation. The results indicate that both mech. properties and cell performance improve in the graded pore structures when compared to homogeneously distributed porous and non-porous structures. Differentiation results indicated successful osteogenic and chondrogenic manipulation in engineered scaffolds.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvF2jsL%252FF&md5=adac1c6f52fbce0dcfa2853a0ad4814a

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Critchley, S. ; Sheehy, E. J. ; Cunniffe, G. ; Diaz-Payno, P. ; Carroll, S. F. ; Jeon, O. ; Alsberg, E. ; Brama, P. A. J. ; Kelly, D. J. 3D printing of fibre-reinforced cartilaginous templates for the regeneration of osteochondral defects. Acta Biomater. 2020, 113 , 130– 143, DOI: 10.1016/j.actbio.2020.05.040

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189

3D printing fibre-reinforced cartilaginous templates regeneration osteochondral defects

Critchley, Susan; Sheehy, Eamon J.; Cunniffe, Grainne; Diaz-Payno, Pedro; Carroll, Simon F.; Jeon, Oju; Alsberg, Eben; Brama, Pieter A. J.; Kelly, Daniel J.

Acta Biomaterialia (2020), 113 (), 130-143CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Successful osteochondral defect repair requires regenerating the subchondral bone while simultaneously promoting the development of an overlying layer of articular cartilage that is resistant to vascularization and endochondral ossification. During skeletal development articular cartilage also functions as a surface growth plate, which postnatally is replaced by a more spatially complex bone-cartilage interface. Motivated by this developmental process, the hypothesis of this study is that bi-phasic, fiber-reinforced cartilaginous templates can regenerate both the articular cartilage and subchondral bone within osteochondral defects created in caprine joints. To engineer mech. competent implants, we first compared a range of 3D printed fiber networks (PCL, PLA and PLGA) for their capacity to mech. reinforce alginate hydrogels while simultaneously supporting mesenchymal stem cell (MSC) chondrogenesis in vitro. These mech. reinforced, MSC-laden alginate hydrogels were then used to engineer the endochondral bone forming phase of bi-phasic osteochondral constructs, with the overlying chondral phase consisting of cartilage tissue engineered using a co-culture of infrapatellar fat pad derived stem/stromal cells (FPSCs) and chondrocytes. Following chondrogenic priming and s.c. implantation in nude mice, these bi-phasic cartilaginous constructs were found to support the development of vascularised endochondral bone overlaid by phenotypically stable cartilage. These fiber-reinforced, bi-phasic cartilaginous templates were then evaluated in clin. relevant, large animal (caprine) model of osteochondral defect repair. Although the quality of repair was variable from animal-to-animal, in general more hyaline-like cartilage repair was obsd. after 6 mo in animals treated with bi-phasic constructs compared to animals treated with com. control scaffolds. This variability in the quality of repair points to the need for further improvements in the design of 3D bioprinted implants for joint regeneration. Successful osteochondral defect repair requires regenerating the subchondral bone while simultaneously promoting the development of an overlying layer of articular cartilage. In this study, we hypothesised that bi-phasic, fiber-reinforced cartilaginous templates could be leveraged to regenerate both the articular cartilage and subchondral bone within osteochondral defects. To this end we used 3D printed fiber networks to mech. reinforce engineered transient cartilage, which also contained an overlying layer of phenotypically stable cartilage engineered using a co-culture of chondrocytes and stem cells. When chondrogenically primed and implanted into caprine osteochondral defects, these fiber-reinforced bi-phasic cartilaginous grafts were shown to spatially direct tissue development during joint repair. Such developmentally inspired tissue engineering strategies, enabled by advances in biofabrication and 3D printing, could form the basis of new classes of regenerative implants in orthopaedic medicine.3D printing of fiber-reinforced cartilaginous templates for regeneration of osteochondral defects.

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Paxton, J. Z. ; Grover, L. M. ; Baar, K. Engineering an in vitro model of a functional ligament from bone to bone. Tissue Eng., Part A 2010, 16 (11), 3515– 25, DOI: 10.1089/ten.tea.2010.0039

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190

Engineering an In Vitro Model of a Functional Ligament from Bone to Bone

Paxton, Jennifer Z.; Grover, Liam M.; Baar, Keith

Tissue Engineering, Part A (2010), 16 (11), 3515-3525CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

For musculoskeletal tissues that transmit loads during movement, the interfaces between tissues are essential to minimizing injury. Therefore, the reprodn. of functional interfaces within engineered musculoskeletal tissues is crit. to the successful transfer of the technol. to the clinic. The goal of this work was to rapidly engineer ligament equiv. in vitro that contained both the soft tissue sinew and a hard tissue bone mimetic. This goal was achieved using cast brushite (CaHPO4·2H2O) anchors to mimic bone and a fibrin gel embedded with fibroblasts to create the sinew. The constructs formed within 7 days. Fourteen days after seeding, the interface between the brushite and sinew could withstand a stress of 9.51 ± 1.7 kPa before failure and the sinew reached a Young's modulus value of 0.16 ± 0.03 MPa. Treatment with ascorbic acid and proline increased the collagen content of the sinew (from 1.34% ± 0.2% to 8.34% ± 0.37%), strength of the interface (29.24 ± 6 kPa), and modulus of the sinew (2.69 ± 0.25 MPa). Adding transforming growth factor-β resulted in a further increase in collagen (11.25% ± 0.39%), interface strength (42 ± 8 kPa), and sinew modulus (5.46 ± 0.68 MPa). Both scanning electron and Raman microscopy suggested that the interface between the brushite and sinew mimics the in vivo tidemark at the enthesis. This work describes a major step toward the development of tissue-engineered ligaments for the repair of ligament ruptures in humans.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlKhs7%252FO&md5=d076f0da0c4a5a81a2b69557a4dcfb92

191

Font Tellado, S. ; Bonani, W. ; Balmayor, E. R. ; Foehr, P. ; Motta, A. ; Migliaresi, C. ; van Griensven, M. Fabrication and Characterization of Biphasic Silk Fibroin Scaffolds for Tendon/Ligament-to-Bone Tissue Engineering. Tissue Eng., Part A 2017, 23 (15–16), 859– 872, DOI: 10.1089/ten.tea.2016.0460

[Crossref], [PubMed], [CAS], Google Scholar

191

Fabrication and Characterization of Biphasic Silk Fibroin Scaffolds for Tendon/Ligament-to-Bone Tissue Engineering

Font Tellado, Sonia; Bonani, Walter; Balmayor, Elizabeth R.; Foehr, Peter; Motta, Antonella; Migliaresi, Claudio; van Griensven, Martijn

Tissue Engineering, Part A (2017), 23 (15-16), 859-872CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

Tissue engineering is an attractive strategy for tendon/ligament-to-bone interface repair. The structure and extracellular matrix compn. of the interface are complex and allow for a gradual mech. stress transfer between tendons/ligaments and bone. Thus, scaffolds mimicking the structural features of the native interface may be able to better support functional tissue regeneration. In this study, we fabricated biphasic silk fibroin scaffolds designed to mimic the gradient in collagen mol. alignment present at the interface. The scaffolds had two different pore alignments: anisotropic at the tendon/ligament side and isotropic at the bone side. Total porosity ranged from 50% to 80% and the majority of pores (80-90%) were <100-300μm. Young's modulus varied from 689 to 1322 kPa depending on the type of construct. In addn., human adipose-derived mesenchymal stem cells were cultured on the scaffolds to evaluate the effect of pore morphol. on cell proliferation and gene expression. Biphasic scaffolds supported cell attachment and influenced cytoskeleton organization depending on pore alignment. In addn., the gene expression of tendon/ligament, enthesis, and cartilage markers significantly changed depending on pore alignment in each region of the scaffolds. In conclusion, the biphasic scaffolds fabricated in this study show promising features for tendon/ligament-to-bone tissue engineering.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlemt7zM&md5=31e8579b099271f638ef2f0f61336b04

192

Liu, H. ; Yang, L. ; Zhang, E. ; Cai, D. ; Zhu, S. ; Bunpetch, V. ; Cai, Y. ; Hu, Y. ; Chen, X. ; Ouyang, H. ; Zhang, R. ; Ran, J. ; Dai, X. ; Heng, B. C. Biomimetic tendon extracellular matrix composite gradient scaffold enhances ligament-to-bone junction reconstruction. Acta Biomater. 2017, 56 , 129– 140, DOI: 10.1016/j.actbio.2017.05.027

[Crossref], [PubMed], [CAS], Google Scholar

192

Biomimetic tendon extracellular matrix composite gradient scaffold enhances ligament-to-bone junction reconstruction

Liu, Huanhuan; Yang, Long; Zhang, Erchen; Zhang, Rui; Cai, Dandan; Zhu, Shouan; Ran, Jisheng; Bunpetch, Varitsara; Cai, Youzhi; Heng, Boon Chin; Hu, Yejun; Dai, Xuesong; Chen, Xiao; Ouyang, Hongwei

Acta Biomaterialia (2017), 56 (), 129-140CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Management of ligament/tendon-to-bone-junction healing remains a formidable challenge in the field of orthopedic medicine to date, due to deficient vascularity and multi-tissue transitional structure of the junction. Numerous strategies have been employed to improve ligament-bone junction healing, including delivery of stem cells, bioactive factors, and synthetic materials, but these methods are often inadequate at recapitulating the complex structure-function relationships at native tissue interfaces. Here, we developed an easily-fabricated and effective biomimetic composite to promote the regeneration of ligament-bone junction by phys. modifying the tendon extracellular matrix (ECM) into a Random-Aligned-Random composite using ultrasound treatment. The differentiation potential of rabbit bone marrow stromal cells on the modified ECM were examd. in vitro. The results demonstrated that the modified ECM enhanced expression of chondrogenesis and osteogenesis-assocd. epigenetic genes (Jmjd1c, Kdm6b), transcription factor genes (Sox9, Runx2) and extracellular matrix genes (Col2a1, Ocn), resulting in higher osteoinductivity than the untreated tendon ECM in vitro. In the rabbit anterior cruciate ligament (ACL) reconstruction model in vivo, micro-computed tomog. (Micro-CT) and histol. anal. showed that the modified Random-Aligned-Random composite scaffold enhanced bone and fibrocartilage formation at the interface, more efficaciously than the unmodified tendon ECM. Therefore, these results demonstrated that the biomimetic Random-Aligned-Random composite could be a promising scaffold for ligament/tendon-bone junction repair. The native transitional region consists of several distinct yet contiguous tissue regions, composed of soft tissue, non-calcified fibrocartilage, calcified fibrocartilage, and bone. A stratified graft whose phases are interconnected with each other is essential for supporting the formation of functionally continuous multi-tissue regions. Various techniques have been attempted to improve adherence of the ligament/tendon graft to bone, including utilization of stem cells, growth factors and biomaterials, but these methods are often inadequate at recapitulating the complex structure-function relationships at native tissue interfaces. Here, we developed an easily-fabricated and effective biomimetic composite to promote the regeneration of ligament-bone junction by phys. modifying the tendon extracellular matrix (ECM) into a Random-Aligned-Random composite using ultrasound treatment. The modified ECM enhanced expression of chondrogenesis and osteogenesis-assocd. epigenetic genes expression in vitro. In the rabbit anterior crucial ligament reconstruction model in vivo, results showed that the modified Random-Aligned-Random composite enhances the bone and fibrocartilage formation in the interface, proving to be more efficient than the unmodified tendon ECM. Therefore, these results demonstrated that the biomimetic Random-Aligned-Random composite could be a promising scaffold for ligament/tendon-bone junction repair.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpvVKhtbY%253D&md5=fa3471748837842d261060c39bcbf4c7

193

Sant, S. ; Coutinho, D. F. ; Gaharwar, A. K. ; Neves, N. M. ; Reis, R. L. ; Gomes, M. E. ; Khademhosseini, A. Self-Assembled Hydrogel Fiber Bundles from Oppositely Charged Polyelectrolytes Mimic Micro-/Nanoscale Hierarchy of Collagen. Adv. Funct. Mater. 2017, 27 (36), 1606273, DOI: 10.1002/adfm.201606273

194

Spalazzi, J. P. ; Dagher, E. ; Doty, S. B. ; Guo, X. E. ; Rodeo, S. A. ; Lu, H. H. In vivo evaluation of a multiphased scaffold designed for orthopaedic interface tissue engineering and soft tissue-to-bone integration. J. Biomed. Mater. Res., Part A 2008, 86A (1), 1– 12, DOI: 10.1002/jbm.a.32073

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194

In vivo evaluation of a multiphase scaffold designed for orthopedic interface tissue engineering and soft tissue-to-bone integration

Spalazzi, Jeffrey P.; Dagher, Elias; Doty, Stephen B.; Guo, X. Edward; Rodeo, Scott A.; Lu, Helen H.

Journal of Biomedical Materials Research, Part A (2008), 86A (1), 1-12CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)

Achieving functional graft integration with subchondral bone poses a significant challenge for orthopedic soft tissue repair and reconstruction. Soft tissues such as the anterior cruciate ligament (ACL) integrate with bone through a fibrocartilage interface, which minimizes stress concns. and mediates load transfer between soft and hard tissues. The authors propose that biol. fixation can be achieved by regenerating this fibrocartilage interface on biol. or synthetic ACL grafts. This study focuses on the in vivo evaluation of a stratified scaffold predesigned to mimic the multitissue transition found at the ACL-to-bone interface. Specifically, the scaffold consists of three distinct yet continuous phases: Phase A for ligament formation, Phase B for the interface, and Phase C for the bone region. Interface-relevant cell types, specifically fibroblasts, chondrocytes, and osteoblasts, will be tri-cultured on this scaffold, and the formation of cell type- and phase-specific matrix heterogeneity as well as fibrocartilage formation will be evaluated over 8 wk in a s.c. athymic rat model. Acellular scaffolds as well as scaffolds cocultured with fibroblasts and osteoblasts will serve as controls. It was found that the triphasic scaffold supported multilineage cellular interactions as well as tissue infiltration and abundant matrix prodn. in vivo. In addn., controlled phase-specific matrix heterogeneity was induced on the scaffold, with distinct mineral and fibrocartilage-like tissue regions formed in the tri-cultured group. Cell seeding had a pos. effect on both host infiltration and matrix elaboration, which also translated into increased mech. properties in the seeded groups compared to the acellular controls. In summary, the biomimetic and multiphasic design coupled with spatial control of cell distribution enables multitissue regeneration on the stratified scaffold, and demonstrates the potential for regenerating the interface between soft tissue grafts and bone.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntFaktb8%253D&md5=9f9f7985436b02d945f2eff09b4eb760

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Mosher, C. Z. ; Spalazzi, J. P. ; Lu, H. H. Stratified scaffold design for engineering composite tissues. Methods (Amsterdam, Neth.) 2015, 84 , 99– 102, DOI: 10.1016/j.ymeth.2015.03.029

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195

Stratified scaffold design for engineering composite tissues

Mosher, Christopher Z.; Spalazzi, Jeffrey P.; Lu, Helen H.

Methods (Amsterdam, Netherlands) (2015), 84 (), 99-102CODEN: MTHDE9; ISSN:1046-2023. (Elsevier B.V.)

A significant challenge to orthopaedic soft tissue repair is the biol. fixation of autologous or allogeneic grafts with bone, whereby the lack of functional integration between such grafts and host bone has limited the clin. success of anterior cruciate ligament (ACL) and other common soft tissue-based reconstructive grafts. The inability of current surgical reconstruction to restore the native fibrocartilaginous insertion between the ACL and the femur or tibia, which minimizes stress concn. and facilitates load transfer between the soft and hard tissues, compromises the long-term clin. functionality of these grafts. To enable integration, a stratified scaffold design that mimics the multiple tissue regions of the ACL interface (ligament-fibrocartilage-bone) represents a promising strategy for composite tissue formation. Moreover, distinct cellular organization and phase-specific matrix heterogeneity achieved through co- or tri-culture within the scaffold system can promote biomimetic multi-tissue regeneration. Here, we describe the methods for fabricating a tri-phasic scaffold intended for ligament-bone integration, as well as the tri-culture of fibroblasts, chondrocytes, and osteoblasts on the stratified scaffold for the formation of structurally contiguous and compositionally distinct regions of ligament, fibrocartilage and bone. The primary advantage of the tri-phasic scaffold is the recapitulation of the multi-tissue organization across the native interface through the layered design. Moreover, in addn. to ease of fabrication, each scaffold phase is similar in polymer compn. and therefore can be joined together by sintering, enabling the seamless integration of each region and avoiding delamination between scaffold layers.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvFWlsbo%253D&md5=9c738deeb16366a243b4ddf55f283420

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Liu, W. ; Lipner, J. ; Xie, J. ; Manning, C. N. ; Thomopoulos, S. ; Xia, Y. Nanofiber scaffolds with gradients in mineral content for spatial control of osteogenesis. ACS Appl. Mater. Interfaces 2014, 6 (4), 2842– 9, DOI: 10.1021/am405418g

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196

Nanofiber Scaffolds with Gradients in Mineral Content for Spatial Control of Osteogenesis

Liu, Wenying; Lipner, Justin; Xie, Jingwei; Manning, Cionne N.; Thomopoulos, Stavros; Xia, Younan

ACS Applied Materials & Interfaces (2014), 6 (4), 2842-2849CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

Reattachment of tendon to bone has been a challenge in orthopedic surgery. The disparate mech. properties of the two tissues make it difficult to achieve direct surgical repair of the tendon-to-bone insertion. Healing after surgical repair typically does not regenerate the natural attachment, a complex tissue that connects tendon and bone across a gradient in both mineral content and cell phenotypes. To facilitate the regeneration of the attachment, our groups have developed a nanofiber-based scaffold with a graded mineral coating to mimic the mineral compn. of the native tendon-to-bone insertion. In the present work, we evaluated the ability of this scaffold to induce graded osteogenesis of adipose-derived mesenchymal stem cells (ASCs). Results from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferating cell nuclear antigen staining indicated that cell proliferation was neg. correlated with the mineral content. In contrast, alk. phosphatase staining, an indicator of osteogenesis, was pos. correlated with the mineral content. Likewise, runt-related transcription factor 2 (an early marker of osteoblast differentiation) and osteocalcin (a late marker of osteoblast differentiation) immunostaining were both pos. correlated with the mineral content. These results indicate that a gradient in mineral content on the surface of a nanofiber scaffold is capable of inducing graded differentiation of ASCs into osteoblasts for enthesis repair.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpt1ykuw%253D%253D&md5=523471b80e949c5cd07d9ce5ddd7e75d

197

Nowlin, J. ; Bismi, M. A. ; Delpech, B. ; Dumas, P. ; Zhou, Y. ; Tan, G. Z. Engineering the hard–soft tissue interface with random-to-aligned nanofiber scaffolds. Nanobiomedicine 2018, DOI: 10.1177/1849543518803538

198

Ramalingam, M. ; Young, M. F. ; Thomas, V. ; Sun, L. ; Chow, L. C. ; Tison, C. K. ; Chatterjee, K. ; Miles, W. C. ; Simon, C. G., Jr. Nanofiber scaffold gradients for interfacial tissue engineering. J. Biomater. Appl. 2013, 27 (6), 695– 705, DOI: 10.1177/0885328211423783

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198

Nanofiber scaffold gradients for interfacial tissue engineering

Ramalingam Murugan; Young Marian F; Thomas Vinoy; Sun Limin; Chow Laurence C; Tison Christopher K; Chatterjee Kaushik; Miles William C; Simon Carl G Jr

Journal of biomaterials applications (2013), 27 (6), 695-705 ISSN:.

We have designed a 2-spinnerette device that can directly electrospin nanofiber scaffolds containing a gradient in composition that can be used to engineer interfacial tissues such as ligament and tendon. Two types of nanofibers are simultaneously electrospun in an overlapping pattern to create a nonwoven mat of nanofibers containing a composition gradient. The approach is an advance over previous methods due to its versatility - gradients can be formed from any materials that can be electrospun. A dye was used to characterize the 2-spinnerette approach and applicability to tissue engineering was demonstrated by fabricating nanofibers with gradients in amorphous calcium phosphate nanoparticles (nACP). Adhesion and proliferation of osteogenic cells (MC3T3-E1 murine pre-osteoblasts) on gradients was enhanced on the regions of the gradients that contained higher nACP content yielding a graded osteoblast response. Since increases in soluble calcium and phosphate ions stimulate osteoblast function, we measured their release and observed significant release from nanofibers containing nACP. The nanofiber-nACP gradients fabricated herein can be applied to generate tissues with osteoblast gradients such as ligaments or tendons. In conclusion, these results introduce a versatile approach for fabricating nanofiber gradients that can have application for engineering graded tissues.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38vhsVelsw%253D%253D&md5=2e973bf043b8ce189251d4c957cc7cc6

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Kolluru, P. V. ; Lipner, J. ; Liu, W. ; Xia, Y. ; Thomopoulos, S. ; Genin, G. M. ; Chasiotis, I. Strong and tough mineralized PLGA nanofibers for tendon-to-bone scaffolds. Acta Biomater. 2013, 9 (12), 9442– 9450, DOI: 10.1016/j.actbio.2013.07.042

[Crossref], [PubMed], [CAS], Google Scholar

199

Strong and tough mineralized PLGA nanofibers for tendon-to-bone scaffolds

Kolluru, Pavan V.; Lipner, Justin; Liu, Wenying; Xia, Younan; Thomopoulos, Stavros; Genin, Guy M.; Chasiotis, Ioannis

Acta Biomaterialia (2013), 9 (12), 9442-9450CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Engineering complex tissues such as the tendon-to-bone insertion sites require a strong and tough biomimetic material system that incorporates both mineralized and unmineralized tissues with different strengths and stiffnesses. However, increasing strength without degrading toughness is a fundamental challenge in materials science. Here, we demonstrate a promising nanofibrous polymer-hydroxyapatite system, in which, a continuous fibrous network must function as a scaffold for both mineralized and unmineralized tissues. It is shown that the high toughness of this material system could be maintained without compromising on the strength with the addn. of hydroxyapatite mineral. Individual electrospun poly (lactide-co-glycolide) (PLGA) nanofibers demonstrated outstanding strain-hardening behavior and ductility when stretched uniaxially, even in the presence of surface mineralization. This highly desirable hardening behavior which results in simultaneous nanofiber strengthening and toughening was shown to depend on the initial cross-sectional morphol. of the PLGA nanofibers. For pristine PLGA nanofibers, it was shown that ellipsoidal cross-sections provide the largest increase in fiber strength by almost 200% compared to bulk PLGA. This exceptional strength accompanied by 100% elongation was shown to be retained for thin and strongly bonded conformal mineral coatings, which were preserved on the nanofiber surface even for such very large extensions.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVSktrbM&md5=3daf6a3e3ea71a248e70f9124148e467

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Lipner, J. ; Boyle, J. ; Thomopoulos, S. ; Liu, Y. ; Genin, G. M. ; Liu, W. ; Xia, Y. The mechanics of PLGA nanofiber scaffolds with biomimetic gradients in mineral for tendon-to-bone repair. Journal of the Mechanical Behavior of Biomedical Materials 2014, 40 (1), 59– 68, DOI: 10.1016/j.jmbbm.2014.08.002

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200

The mechanics of PLGA nanofiber scaffolds with biomimetic gradients in mineral for tendon-to-bone repair

Lipner, J.; Liu, W.; Liu, Y.; Boyle, J.; Genin, G. M.; Xia, Y.; Thomopoulos, S.

Journal of the Mechanical Behavior of Biomedical Materials (2014), 40 (), 59-68CODEN: JMBBCP; ISSN:1878-0180. (Elsevier Ltd.)

Attachment of dissimilar materials is prone to failure due to stress concns. that can arise their interface. A compositionally or structurally graded transition can dissipate these stress concns. and thereby toughen an attachment. The interface between compliant tendon and stiff bone utilizes a monotonic change in hydroxylapatite mineral ("mineral") content to produce a gradient in mech. properties and mitigate stress concns. Previous efforts to mimic the natural tendon-to-bone attachment have included electrospun nanofibrous polymer scaffolds with gradients in mineral. Mineralization of the nanofiber scaffolds has typically been achieved using simulated body fluid (SBF). Depending on the specific formulation of SBF, mineral morphologies ranged from densely packed small crystals to platelike crystal florets. Although this mineralization of scaffolds produced increases in modulus, the peak modulus achieved remained significantly below that of bone. Missing from these prior empirical approaches was insight into the effect of mineral morphol. on scaffold mechanics and on the potential for the approach to ultimately achieve moduli approaching that of bone. Here, we applied two mineralization methods to generate scaffolds with spatial gradations in mineral content, and developed methods to quantify the stiffening effects and evaluate them in the context of theor. bounds. We asked whether either of the mineralization methods we developed holds potential to achieve adequate stiffening of the scaffold, and tested the hypothesis that the smoother, denser mineral coating could attain more potent stiffening effects. Testing this hypothesis required development of and comparison to homogenization bounds, and development of techniques to est. mineral vol. fractions and spatial gradations in modulus. For both mineralization strategies, energy dispersive X-ray anal. demonstrated the formation of linear gradients in mineral concn. along the length of the scaffolds, and Raman spectroscopic anal. revealed that the mineral produced was hydroxylapatite. Mech. testing showed that the stiffness gradient using the new method was significantly steeper. By analyzing the scaffolds using micromech. modeling techniques and extrapolating from our exptl. results, we present evidence that the new mineralization protocol has the potential to achieve levels of stiffness adequate to contribute to enhanced repair of tendon-to-bone attachments.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSqt7jO&md5=41150828aea6d232929c04fdf0e5b577

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Kim, B. S. ; Kim, E. J. ; Choi, J. S. ; Jeong, J. H. ; Jo, C. H. ; Cho, Y. W. Human collagen-based multilayer scaffolds for tendon-to-bone interface tissue engineering. J. Biomed. Mater. Res., Part A 2014, 102 (11), 4044– 54, DOI: 10.1002/jbm.a.35057

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201

Human collagen-based multilayer scaffolds for tendon-to-bone interface tissue engineering

Kim Beob Soo; Kim Eun Ji; Choi Ji Suk; Jeong Ji Hoon; Jo Chris Hyunchul; Cho Yong Woo

Journal of biomedical materials research. Part A (2014), 102 (11), 4044-54 ISSN:.

The natural tendon-to-bone region has a gradient in structure and composition, which is translated into a spatial variation of chemical, physical, and biological properties. This unique transitional tissue between bone and tendon is not normally recreated during natural bone-to-tendon healing. In this study, we have developed a human collagen-based multilayer scaffold mimicking the tendon-to-bone region. The scaffold consists of four different layers with the following composition gradient: (a) a tendon layer composed of collagen; (b) an uncalcified fibrocartilage layer composed of collagen and chondroitin sulfate; (c) a calcified fibrocartilage layer composed of collagen and less apatite; (d) a bone layer composed of collagen and apatite. The chemical, physical, and mechanical properties of the scaffold were characterized by a scanning electron microscope, porosimeter, universal tensile machine, Fourier transform infrared spectrometer, energy dispersive X-ray analysis apparatus, and thermogravimetric analysis apparatus. The multilayer scaffold provided a gradual transition of the physical, chemical, and mechanical environment and supported the adhesion and proliferation of human fibroblasts, chondrocytes, and osteoblasts toward each corresponding matrix. Overall, our results suggest the feasibility of a human collagen-based multilayer scaffold for regeneration of hard-to-soft interface tissues.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3ltlyhtQ%253D%253D&md5=96451145b50ec700adac9291bec2545a

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Paxton, J. Z. ; Donnelly, K. ; Keatch, R. P. ; Baar, K. Engineering the bone-ligament interface using polyethylene glycol diacrylate incorporated with hydroxyapatite. Tissue Eng., Part A 2009, 15 (6), 1201– 9, DOI: 10.1089/ten.tea.2008.0105

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202

Engineering the Bone-Ligament Interface Using Polyethylene Glycol Diacrylate Incorporated with Hydroxyapatite

Paxton, Jennifer Z.; Donnelly, Kenneth; Keatch, Robert P.; Baar, Keith

Tissue Engineering, Part A (2009), 15 (6), 1201-1209CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

Ligaments and tendons have previously been tissue engineered. However, without the bone attachment, implantation of a tissue-engineered ligament would require it to be sutured to the remnant of the injured native tissue. Due to slow repair and remodeling, this would result in a chronically weak tissue that may never return to preinjury function. In contrast, orthopedic autograft reconstruction of the ligament often uses a bone-to-bone technique for optimal repair. Since bone-to-bone repairs heal better than other methods, implantation of an artificial ligament should also occur from bone-to-bone. The aim of this study was to investigate the use of a poly(ethylene glycol) diacrylate (PEGDA) hydrogel incorporated with hydroxyapatite (HA) and the cell-adhesion peptide RGD (Arg-Gly-Asp) as a material for creating an in vitro tissue interface to engineer intact ligaments (i.e., bone-ligament-bone). Incorporation of HA into PEG hydrogels reduced the swelling ratio but increased mech. strength and stiffness of the hydrogels. Further, HA addn. increased the capacity for cell growth and interface formation. RGD incorporation increased the swelling ratio but decreased mech. strength and stiffness of the material. Optimum levels of cell attachment were met using a combination of both HA and RGD, but this material had no better mech. properties than PEG alone. Although adherence of the hydrogels contg. HA was achieved, failure occurs at about 4 days with 5% HA. Increasing the proportion of HA improved interface formation; however, with high levels of HA, the PEG HA composite became brittle. This data suggests that HA, by itself or with other materials, might be well suited for engineering the ligament-bone interface.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtlWmurs%253D&md5=4497acc57f48c955f889c144b4474d40

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Li, H. ; Fan, J. ; Sun, L. ; Liu, X. ; Cheng, P. ; Fan, H. Functional regeneration of ligament-bone interface using a triphasic silk-based graft. Biomaterials 2016, 106 , 180– 192, DOI: 10.1016/j.biomaterials.2016.08.012

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203

Functional regeneration of ligament-bone interface using a triphasic silk-based graft

Li, Hongguo; Fan, Jiabing; Sun, Liguo; Liu, Xincheng; Cheng, Pengzhen; Fan, Hongbin

Biomaterials (2016), 106 (), 180-192CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

The biodegradable silk-based scaffold with unique mech. property and biocompatibility represents a favorable ligamentous graft for tissue-engineering anterior cruciate ligament (ACL) reconstruction. However, the low efficiency of ligament-bone interface restoration barriers the isotropic silk graft to common ACL therapeutics. To enhance the regeneration of the silk-mediated interface, we developed a specialized stratification approach implementing a sequential modification on isotropic silk to constitute a triphasic silk-based graft in which three regions resp. referring to ligament, cartilage and bone layers of interface were divided, followed by resp. biomaterial coating. Furthermore, three types of cells including bone marrow mesenchymal stem cells (BMSCs), chondrocytes and osteoblasts were resp. seeded on the ligament, cartilage and bone region of the triphasic silk graft, and the cell/scaffold complex was rolled up as a multilayered graft mimicking the stratified structure of native ligament-bone interface. In vitro, the trilineage cells loaded on the triphasic silk scaffold revealed a high proliferative capacity as well as enhanced differentiation ability into their corresponding cell lineage. 24 Wk postoperatively after the construct was implanted to repair the ACL defect in rabbit model, the silk-based ligamentous graft exhibited the enhancement of osseointegration detected by a robust pullout force and formation of three-layered structure along with conspicuously corresponding matrix deposition via micro-CT and histol. anal. These findings potentially broaden the application of silk-based ligamentous graft for ACL reconstruction and further large animal study.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlaiu7zI&md5=040dd25677c88947e933b58eb141e820

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Samavedi, S. ; Olsen Horton, C. ; Guelcher, S. A. ; Goldstein, A. S. ; Whittington, A. R. Fabrication of a model continuously graded co-electrospun mesh for regeneration of the ligament-bone interface. Acta Biomater. 2011, 7 (12), 4131– 4138, DOI: 10.1016/j.actbio.2011.07.008

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204

Fabrication of a model continuously graded co-electrospun mesh for regeneration of the ligament-bone interface

Samavedi, Satyavrata; Olsen Horton, C.; Guelcher, Scott A.; Goldstein, Aaron S.; Whittington, Abby R.

Acta Biomaterialia (2011), 7 (12), 4131-4138CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

Current scaffolds for the regeneration of anterior cruciate ligament injuries are unable to capture intricate mech. and chem. gradients present in the natural ligament-bone interface. As a result, stress concns. can develop at the scaffold-bone interface, leading to poor osseointegration. Hence, scaffolds that possess appropriate mechano-chem. gradients would help establish normal loading properties at the interface, while promoting scaffold integration with bone. With the long-term goal of investigating regeneration of the ligament-bone interface, this feasibility study aimed to fabricate a continuously graded mesh. Specifically, graded meshes were fabricated by co-electrospinning nanohydroxyapatite/polycaprolactone (nHAP-PCL) and poly(ester urethane) urea elastomer solns. from offset spinnerets. Next, mineral crystallites were selectively deposited on the nHAP-PCL fibers by treatment with a 5× simulated body fluid (5× SBF). X-ray diffraction and energy-dispersive spectroscopy indicated calcium-deficient hydroxyapatite-like mineral crystallites with an av. Ca/P ratio of 1.48. Tensile testing demonstrated the presence of a mech. gradient, which became more pronounced upon treatment with 5× SBF. Finally, biocompatibility of the graded meshes was verified using an MC3T3-E1 osteoprogenitor cell line. The study demonstrates that graded meshes, for potential application in interfacial tissue engineering, can be fabricated by co-electrospinning.

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Samavedi, S. ; Guelcher, S. A. ; Goldstein, A. S. ; Whittington, A. R. Response of bone marrow stromal cells to graded co-electrospun scaffolds and its implications for engineering the ligament-bone interface. Biomaterials 2012, 33 (31), 7727– 7735, DOI: 10.1016/j.biomaterials.2012.07.008

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205

Response of bone marrow stromal cells to graded co-electrospun scaffolds and its implications for engineering the ligament-bone interface

Samavedi, Satyavrata; Guelcher, Scott A.; Goldstein, Aaron S.; Whittington, Abby R.

Biomaterials (2012), 33 (31), 7727-7735CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

Biomaterial scaffolds with gradients in architecture, mech. and chem. properties have the potential to improve the osseointegration of ligament grafts by recapitulating phenotypic gradients that exist at the natural ligament-bone (L-B) interface. Towards the larger goal of regenerating the L-B interface, this in vitro study was performed to investigate the potential of two scaffolds with mineral gradients in promoting a spatial gradient of osteoblastic differentiation. Specifically, the first graded scaffold was fabricated by co-electrospinning two polymer solns. (one doped with nano-hydroxyapatite particles) from offset spinnerets, while the second was created by immersing the first scaffold in a 5 × simulated body fluid. Rat bone marrow stromal cells, cultured in the presence of osteogenic supplements, were found to be metabolically active on all regions of both scaffolds after 1 and 7 days of culture. Gene expression of bone morphogenic protein-2 and osteopontin was elevated on mineral-contg. regions as compared to regions without mineral, while the expression of alk. phosphatase mRNA revealed the opposite trend. Finally, the presence of osteopontin and bone sialoprotein confirmed osteoblastic phenotypic maturation by day 28. This study indicates that co-electrospun scaffolds with gradients in mineral content can guide the formation of phenotypic gradients and may thus promote the regeneration of the L-B interface.

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Spalazzi, J. P. ; Doty, S. B. ; Moffat, K. L. ; Levine, W. N. ; Lu, H. H. Development of controlled matrix heterogeneity on a triphasic scaffold for orthopedic interface tissue engineering. Tissue Eng. 2006, 12 (12), 3497– 508, DOI: 10.1089/ten.2006.12.3497

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206

Development of controlled matrix heterogeneity on a triphasic scaffold for orthopedic interface tissue engineering

Spalazzi, Jeffrey P.; Doty, Stephen B.; Moffat, Kristen L.; Levine, William N.; Lu, Helen H.

Tissue Engineering (2006), 12 (12), 3497-3508CODEN: TIENFP; ISSN:1076-3279. (Mary Ann Liebert, Inc.)

Biol. fixation of orthopedic soft tissue grafts to bone poses a significant clin. challenge. The clin. success of soft tissue-based grafts for anterior cruciate ligament (ACL) reconstruction is limited by the lack of functional graft integration with subchondral bone. Soft tissues such as the ACL connect to subchondral bone via a complex interface whereby three distinct tissue regions (ligament, fibrocartilage, and bone) work in concert to facilitate load transfer from soft to hard tissue while minimizing stress concn. at the interface. Although a fibrovascular tissue forms at the graft-to-bone interface following surgery, this tissue is nonphysiol. and represents a weak link between the graft and bone. We propose that the re-establishment of the native multi-tissue interface is essential for biol. graft fixation. In vivo observations and our in vitro monolayer co-culture results suggest that osteoblast-fibroblast interaction is important for interface regeneration. This study focuses on the design of a triphasic scaffold system mimicking the multi-tissue organization of the native ACL-to-bone interface and the evaluation of osteoblast-fibroblast interactions during three-dimensional co-culture on the triphasic scaffold. We found that the triphasic scaffold supported cell proliferation, migration and phenotypic matrix prodn. while maintaining distinct cellular regions and phase-specific extracellular matrix deposition over time. This triphasic scaffold is designed to guide the eventual reestablishment of an anatomically oriented and mech. functional fibrocartilage interfacial region directly on biol. and synthetic soft tissue grafts. The results of this study demonstrate the feasibility of multi-tissue regeneration on a single scaffold, and the potential of interface tissue engineering to enable the biol. fixation of soft tissue grafts to bone.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVChu7s%253D&md5=614e8039aeeb0381794ebf803c683987

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Lu, H. H. ; Spalazzi, J. P. Biomimetic stratified scaffold design for ligament-to-bone interface tissue engineering. Comb. Chem. High Throughput Screening 2009, 12 (6), 589– 97, DOI: 10.2174/138620709788681925

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207

Biomimetic stratified scaffold design for ligament-to-bone interface tissue engineering

Lu, Helen H.; Spalazzi, Jeffrey P.

Combinatorial Chemistry & High Throughput Screening (2009), 12 (6), 589-597CODEN: CCHSFU; ISSN:1386-2073. (Bentham Science Publishers Ltd.)

A review. The emphasis in the field of orthopedic tissue engineering is on imparting biomimetic functionality to tissue engineered bone or soft tissue grafts and enabling their translation to the clinic. A significant challenge in achieving extended graft functionality is engineering the biol. fixation of these grafts with each other as well as with the host environment. Biol. fixation will require re-establishment of the structure-function relationship inherent at the native soft tissue-to-bone interface on these tissue engineered grafts. To this end, strategic biomimicry must be incorporated into advanced scaffold design. To facilitate integration between distinct tissue types (e.g., bone with soft tissues such as cartilage, ligament, or tendon), a stratified or multi-phasic scaffold with distinct yet continuous tissue regions is required to pre-engineer the interface between bone and soft tissues. Using the ACL-to-bone interface as a model system, this review outlines the strategies for stratified scaffold design for interface tissue engineering, focusing on identifying the relevant design parameters derived from an understanding of the structure-function relationship inherent at the soft-to-hard tissue interface. The design approach centers on first addressing the challenge of soft tissue-to-bone integration ex vivo, and then subsequently focusing on the relatively less difficult task of bone-to-bone integration in vivo. In addn., the authors will review stratified scaffold design aimed at exercising spatial control over heterotypic cellular interactions, which are crit. for facilitating the formation and maintenance of distinct yet continuous multi-tissue regions. Finally, potential challenges and future directions in this emerging area of advanced scaffold design will be discussed.

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Harris, E. ; Liu, Y. ; Cunniffe, G. ; Morrissey, D. ; Carroll, S. ; Mulhall, K. ; Kelly, D. J. Biofabrication of soft tissue templates for engineering the bone-ligament interface. Biotechnol. Bioeng. 2017, 114 (10), 2400– 2411, DOI: 10.1002/bit.26362

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208

Biofabrication of soft tissue templates for engineering the bone-ligament interface

Harris, Ella; Liu, Yurong; Cunniffe, Grainne; Morrissey, David; Carroll, Simon; Mulhall, Kevin; Kelly, Daniel J.

Biotechnology and Bioengineering (2017), 114 (10), 2400-2411CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)

Regenerating damaged tissue interfaces remains a significant clin. challenge, requiring recapitulation of the structure, compn., and function of the native enthesis. In the ligament-to-bone interface, this region transitions from ligament to fibrocartilage, to calcified cartilage and then to bone. This gradation in tissue types facilitates the transfer of load between soft and hard structures while minimizing stress concns. at the interface. Previous attempts to engineer the ligament-bone interface have utilized various scaffold materials with an array of various cell types and/or biol. cues. The primary goal of this study was to engineer a multiphased construct mimicking the ligament-bone interface by driving differentiation of a single population of mesenchymal stem cells (MSCs), seeded within blended fibrin-alginate hydrogels, down an endochondral, fibrocartilaginous, or ligamentous pathway through spatial presentation of growth factors along the length of the construct within a custom-developed, dual-chamber culture system. Furthermore, there was also evidence of spatially defined progression toward an endochondral phenotype when chondrogenically primed MSCs within this construct were addnl. exposed to hypertrophic cues. The study demonstrates the feasibility of engineering spatially complex soft tissues within a single MSC laden hydrogel through the defined presentation of biochem. cues. Biotechnol. Bioeng. 2017;9999: 1-12. 2017 Wiley Periodicals, Inc.

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Moffat, K. L. ; Kwei, A. S. P. ; Spalazzi, J. P. ; Doty, S. B. ; Levine, W. N. ; Lu, H. H. Novel nanofiber-based scaffold for rotator cuff repair and augmentation. Tissue Eng., Part A 2009, 15 (1), 115– 126, DOI: 10.1089/ten.tea.2008.0014

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209

Novel Nanofiber-Based Scaffold for Rotator Cuff Repair and Augmentation

Moffat, Kristen L.; Kwei, Anne S.-P.; Spalazzi, Jeffrey P.; Doty, Stephen B.; Levine, William N.; Lu, Helen H.

Tissue Engineering, Part A (2009), 15 (1), 115-126CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)

The debilitating effects of rotator cuff tears and the high incidence of failure assocd. with current grafts underscore the clin. demand for functional solns. for tendon repair and augmentation. To address this challenge, we have designed a poly(lactide-co-glycolide) (PLGA) nanofiber-based scaffold for rotator cuff tendon tissue engineering. In addn. to scaffold design and characterization, the objective of this study was to evaluate the attachment, alignment, gene expression, and matrix elaboration of human rotator cuff fibroblasts on aligned and unaligned PLGA nanofiber scaffolds. Addnl., the effects of in vitro culture on scaffold mech. properties were detd. over time. It has been hypothesized that nanofiber organization regulates cellular response and scaffold properties. It was obsd. that rotator cuff fibroblasts cultured on the aligned scaffolds attached along the nanofiber long axis, whereas the cells on the unaligned scaffold were polygonal and randomly oriented. Moreover, distinct integrin expression profiles on these two substrates were obsd. Quant. anal. revealed that cell alignment, distribution, and matrix deposition conformed to nanofiber organization and that the obsd. differences were maintained over time. Mech. properties of the aligned nanofiber scaffolds were significantly higher than those of the unaligned, and although the scaffolds degraded in vitro, physiol. relevant mech. properties were maintained. These observations demonstrate the potential of the PLGA nanofiber-based scaffold system for functional rotator cuff repair. Moreover, nanofiber organization has a profound effect on cellular response and matrix properties, and it is a crit. parameter for scaffold design.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1elsA%253D%253D&md5=4170126d027f54572d8da11e1303ba2a

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Xie, J. ; Li, X. ; Lipner, J. ; Manning, C. N. ; Schwartz, A. G. ; Thomopoulos, S. ; Xia, Y. ″Aligned-to-random″ nanofiber scaffolds for mimicking the structure of the tendon-to-bone insertion site. Nanoscale 2010, 2 (6), 923– 6, DOI: 10.1039/c0nr00192a

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210

"Aligned-to-random" nanofiber scaffolds for mimicking the structure of the tendon-to-bone insertion site

Xie, Jingwei; Li, Xiaoran; Lipner, Justin; Manning, Cionne N.; Schwartz, Annie G.; Thomopoulos, Stavros; Xia, Younan

Nanoscale (2010), 2 (6), 923-926CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

The authors have demonstrated the fabrication of "aligned-to-random" electrospun nanofiber scaffolds that mimic the structural organization of collagen fibers at the tendon-to-bone insertion site. Tendon fibroblasts cultured on such a scaffold exhibited highly organized and haphazardly oriented morphologies, resp., on the aligned and random portions.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlKru7nE&md5=c1ec34c8dfd5341ea94920967eaedf8b

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Xie, J. ; Ma, B. ; Michael, P. L. ; Shuler, F. D. Fabrication of nanofiber scaffolds with gradations in fiber organization and their potential applications. Macromol. Biosci. 2012, 12 (10), 1336– 1341, DOI: 10.1002/mabi.201200115

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211

Fabrication of Nanofiber Scaffolds With Gradations in Fiber Organization and Their Potential Applications

Xie, Jingwei; Ma, Bing; Michael, Praveesuda Lorwattanapongsa; Shuler, Franklin D.

Macromolecular Bioscience (2012), 12 (10), 1336-1341CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)

A new and simple method for fabrication of nanofiber scaffolds with gradations in fiber organization is reported. The nanofiber organization, achieved by deposition of random fibers on the uniaxially aligned nanofiber mat in a gradient manner, directed morphol. changes of applied adipose-derived stem cells. These morphol. changes and resultant biochem. changes can help mimic the structural orientation of complex biomech. structures like the collagen fiber structure at the tendon-to-bone insertion site. In addn., chem. gradients can be established through nanoencapsulation in this novel scaffold allowing for enhanced biomedical applications.

https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWmsLnN&md5=9de16f3935207347933c032de38e09c8

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Samavedi, S. ; Vaidya, P. ; Gaddam, P. ; Whittington, A. R. ; Goldstein, A. S. Electrospun meshes possessing region-wise differences in fiber orientation, diameter, chemistry and mechanical properties for engineering bone-ligament-bone tissues. Biotechnol. Bioeng. 2014, 111 (12), 2549– 2559, DOI: 10.1002/bit.25299

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212

Electrospun meshes possessing region-wise differences in fiber orientation, diameter, chemistry and mechanical properties for engineering bone-ligament-bone tissues

Samavedi, Satyavrata; Vaidya, Prasad; Gaddam, Prudhvidhar; Whittington, Abby R.; Goldstein, Aaron S.

Biotechnology and Bioengineering (2014), 111 (12), 2549-2559CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)

Although bone-patellar tendon-bone (B-PT-B) autografts are the gold std. for repair of anterior cruciate ligament ruptures, they suffer from drawbacks such as donor site morbidity and limited supply. Engineered tissues modeled after B-PT-B autografts are promising alternatives because they have the potential to regenerate connective tissue and facilitate osseointegration. Towards the long-term goal of regenerating ligaments and their bony insertions, the objective of this study was to construct 2D meshes and 3D cylindrical composite scaffolds - possessing simultaneous region-wise differences in fiber orientation, diam., chem. and mech. properties - by electrospinning two different polymers from off-set spinnerets. Using a dual drum collector, 2D meshes consisting of an aligned polycaprolactone (PCL) fiber region, randomly oriented poly(lactide-co-glycolide) (PLGA) fiber region and a transition region (comprised of both PCL and PLGA fibers) were prepd., and region-wise differences were confirmed by microscopy and tensile testing. Bone marrow stromal cells (BMSCs) cultured on these meshes exhibited random orientations and low aspect ratios on the random PLGA regions, and high aspect ratios and alignment on the aligned PCL regions. Next, meshes contg. an aligned PCL region flanked by two transition regions and two randomly oriented PLGA regions were prepd. and processed into 3D cylindrical composite scaffolds using an interpenetrating photo-crosslinkable polyethylene glycol diacrylate hydrogel to recapitulate the shape of B-PT-B autografts. Tensile testing indicated that cylindrical composites were mech. robust, and eventually failed due to stress concn. in the aligned PCL region. In summary, this study demonstrates a process to fabricate electrospun meshes possessing region-wise differences in properties that can elicit region-dependent cell responses, and be readily processed into scaffolds with the shape of B-PT-B autografts. Biotechnol.Bioeng. 2014;111: 2549-2559. © 2014 Wiley Periodicals, Inc.

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Criscenti, G. ; Longoni, A. ; Di Luca, A. ; De Maria, C. ; van Blitterswijk, C. A. ; Vozzi, G. ; Moroni, L. Triphasic scaffolds for the regeneration of the bone-ligament interface. Biofabrication 2016, 8 (1), 015009, DOI: 10.1088/1758-5090/8/1/015009

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213

Triphasic scaffolds for the regeneration of the bone-ligament interface

Criscenti, G.; Longoni, A.; Di Luca, A.; De Maria, C.; van Blitterswijk, C. A.; Vozzi, G.; Moroni, L.

Biofabrication (2016), 8 (1), 015009/1-015009/13CODEN: BIOFFN; ISSN:1758-5090. (IOP Publishing Ltd.)

A triphasic scaffold (TPS) for the regeneration of the bone-ligament interface was fabricated combining a 3D fiber deposited polycaprolactone structure and a polylactic co-glycolic acid electrospun. The scaffold presented a gradient of phys. and mech. properties which elicited different biol. responses from human mesenchymal stem cells. Biol. test were performed on the whole TPS and on scaffolds comprised of each single part of the TPS, considered as the controls. The TPS showed an increase of the metabolic activity with culturing time that seemed to be an av. of the controls at each time point. The importance of differentiation media for bone and ligament regeneration was further investigated. Metabolic activity anal. on the different areas of the TPS showed a similar trend after 7 days in both differentiation media. Total alk. phosphatase (ALP) activity anal. showed a statistically higher activity of the TPS in mineralization medium compared to the controls. A different glycosaminoglycans amt. between the TPS and its controls was detected, displaying a similar trend with respect to ALP activity. Results clearly indicated that the integration of electrospinning and additive manufg. represents a promising approach for the fabrication of scaffolds for the regeneration of tissue interfaces, such as the bone-to-ligament one, because it allows mimicking the structural environment combining different biomaterials at different scales.

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Sun Han Chang, R. A. ; Shanley, J. F. ; Kersh, M. E. ; Harley, B. A. C. Tough and tunable scaffold-hydrogel composite biomaterial for soft-to-hard musculoskeletal tissue interfaces. Sci. Adv. 2020, 6 (34), eabb6763, DOI: 10.1126/sciadv.abb6763

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Bhardwaj, N. ; Kundu, S. C. Electrospinning: A fascinating fiber fabrication technique. Biotechnol. Adv. 2010, 28 (3), 325– 347, DOI: 10.1016/j.biotechadv.2010.01.004

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215

Electrospinning: A fascinating fiber fabrication technique

Bhardwaj, Nandana; Kundu, Subhas C.

Biotechnology Advances (2010), 28 (3), 325-347CODEN: BIADDD; ISSN:0734-9750. (Elsevier)

A review. With the emergence of nanotechnol., researchers become more interested in studying the unique properties of nanoscale materials. Electrospinning, an electrostatic fiber fabrication technique has evinced more interest and attention in recent years due to its versatility and potential for applications in diverse fields. The notable applications include in tissue engineering, biosensors, filtration, wound dressings, drug delivery, and enzyme immobilization. The nanoscale fibers are generated by the application of strong elec. field on polymer soln. or melt. The non-wovens nanofibrous mats produced by this technique mimics extracellular matrix components much closely as compared to the conventional techniques. The sub-micron range spun fibers produced by this process, offer various advantages like high surface area to vol. ratio, tunable porosity and the ability to manipulate nanofiber compn. in order to get desired properties and function. Over the years, more than 200 polymers have been electropun for various applications and the no. is still increasing gradually with time. With these in perspectives, we aim to present in this review, an overview of the electrospinning technique with its promising advantages and potential applications. We have discussed the electrospinning theory, spinnable polymers, parameters (soln. and processing), which significantly affect the fiber morphol., solvent properties and melt electrospinning (alternative to soln. electrospinning). Finally, we have focused on varied applications of electrospun fibers in different fields and concluded with the future prospects of this efficient technol.

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Yang, G. Z. ; Li, H. P. ; Yang, J. H. ; Wan, J. ; Yu, D. G. Influence of Working Temperature on The Formation of Electrospun Polymer Nanofibers. Nanoscale Res. Lett. 2017, 12 , 15, DOI: 10.1186/s11671-016-1824-8

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Abel, S. B. ; Liverani, L. ; Boccaccini, A. R. ; Abraham, G. A. Effect of benign solvents composition on poly(ε-caprolactone) electrospun fiber properties. Mater. Lett. 2019, 245 , 86– 89, DOI: 10.1016/j.matlet.2019.02.107

218

Puppi, D. ; Chiellini, F. Wet-spinning of biomedical polymers: from single-fibre production to additive manufacturing of three-dimensional scaffolds. Polym. Int. 2017, 66 (12), 1690– 1696, DOI: 10.1002/pi.5332

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Wet-spinning of biomedical polymers: from single-fibre production to additive manufacturing of three-dimensional scaffolds

Puppi, Dario; Chiellini, Federica

Polymer International (2017), 66 (12), 1690-1696CODEN: PLYIEI; ISSN:0959-8103. (John Wiley & Sons Ltd.)

Wet-spinning of polymeric materials has been widely investigated for various biomedical applications, such as extracorporeal blood treatment, controlled drug release and tissue engineering. This review is aimed at summarizing and assessing current advances in wet-spinning of biomedical polymers to manuf. single fibers and three-dimensional scaffolds, as well as their functionalization through loading with bioactive agents. The theor. principles and the main technol. aspects of fiber prodn. by wet-spinning on either a lab. or an industrial scale are outlined. The non-solvent-induced phase inversion detg. polymer coagulation during the wet-spinning process is discussed by highlighting its influence on the resulting fiber morphol. and how it can be exploited to induce a nano/microporosity in the solidified polymeric matrix. The versatility of wet-spinning in material selection, bioactive agent loading and fiber morphol. tuning is underlined through an overview of significant literature reporting on the processing of various naturally derived and synthetic polymers. A special focus is given to cutting-edge advancements in the application of additive manufg. principles to wet-spinning for enhanced control and reproducibility of three-dimensional polymeric scaffold morphol. at different scale levels (i.e. macrostructural to micro/nanostructural features). © 2017 Society of Chem. Industry.

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Rider, P. ; Kačarević, Z. e. P. ; Alkildani, S. ; Retnasingh, S. ; Barbeck, M. Bioprinting of tissue engineering scaffolds. J. Tissue Eng. 2018, DOI: 10.1177/2041731418802090