? Articular cartilage lines the surfaces of joints and functions to transmit the forces associated with joint loading. Limited by its poor healing capacity, there exists a growing demand for cell-based strategies for repair. Given the mechanical role of the native tissue, the successful replacement of articular cartilage using engineered constructs will require grown tissue possessing functional mechanical properties. In this study, we propose the combination of chondrocytes or mesenchymal stem cells (which can undergo chondrogenic differentiation) in a hydrogel environment (agarose and self-assembling peptide hydrogels), and focus on the development of compressive and tensile properties of these constructs. Tensile properties in mature cartilage are anisotropic, particularly in the superficial zone, and emerge during adolescence as maturation occurs with joint loading. Borrowing from this developmental concept, we suggest a novel bioreactor system designed to recapitulate the sliding contact that occurs between two contacting articular cartilage layers. Using this bioreactor, chondrocyte biosynthesis and chondrogenic differentiation of MSCs will be valuated as a function of pre-incubation period and duration and intermittency of sliding. It is hypothesized that the patterns of gene expression and differentiation will be dictated by the relation of the position in the gel to the applied contact, with enhancements occurring beneath and along the line of contact, particularly in the superficial layer. Subsequent long-term studies will utilize these optimized loading protocols to direct the increase the compressive and tensile (in the direction of sliding) mechanical properties of MSC- and chondrocyte-laden hydrogel constructs. Furthermore, it is hypothesized that these constructs will exhibit enhanced collagen content as well as a parallel collagen fiber orientation in the direction of sliding contact. This application examines the ability of chondrocyte- and MSC-laden hydrogels to achieve cartilage-like tensile properties, and to instill anisotropy in these constructs via culture in a novel sliding contact bioreactor system. These studies will provide insight into the mechanisms of cartilage differentiation and maturation. If realized, the specific aims of this proposal will further our efforts to produce clinically relevant chondrocyteand MSC-laden functional cartilage replacements that exhibit the complex material properties and anisotropies that define the native tissue and are necessary for its mature function. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
1R03AR053668-01A1
Application #
7194052
Study Section
Special Emphasis Panel (ZAR1-EHB-M (O1))
Program Officer
Wang, Fei
Project Start
2007-02-02
Project End
2010-01-31
Budget Start
2007-02-02
Budget End
2008-01-31
Support Year
1
Fiscal Year
2007
Total Cost
$78,646
Indirect Cost
Name
University of Pennsylvania
Department
Orthopedics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Huang, Alice H; Farrell, Megan J; Mauck, Robert L (2010) Mechanics and mechanobiology of mesenchymal stem cell-based engineered cartilage. J Biomech 43:128-36
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Erickson, Isaac E; Huang, Alice H; Chung, Cindy et al. (2009) Differential maturation and structure-function relationships in mesenchymal stem cell- and chondrocyte-seeded hydrogels. Tissue Eng Part A 15:1041-52
Erickson, I E; Huang, A H; Sengupta, S et al. (2009) Macromer density influences mesenchymal stem cell chondrogenesis and maturation in photocrosslinked hyaluronic acid hydrogels. Osteoarthritis Cartilage 17:1639-48
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Huang, Alice H; Motlekar, Nuzhat A; Stein, Ashley et al. (2008) High-throughput screening for modulators of mesenchymal stem cell chondrogenesis. Ann Biomed Eng 36:1909-21
Kelly, Terri-Ann N; Fisher, Matthew B; Oswald, Elizabeth S et al. (2008) Low-serum media and dynamic deformational loading in tissue engineering of articular cartilage. Ann Biomed Eng 36:769-79

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