Total Joint Resurfacing Previous attempts to repair articular cartilage have focused on the repair of focal defects. One of the main complications of focal defect repair is that integration of the repair tissue with the surrounding native cartilage is inconsistent and generally poor, which renders the repair site biomechanically unstable not clinically efficacious. In the case of severe osteoarthritis where the entire joint surface has deteriorated, the procedures for repair of focal cartilage defects are no longer applicable. For severe arthritis, total joint replacement is the final option which, although it has a generally good outcome, there are still long-term complications including, erosion of the articulating surface of the prostheses, and breaking or loosening of the prosthetic stem. These problems necessitate revision surgery which is progressively more difficult and complicated. To obviate this problem, we propose to design and test a tissue engineered cell-matrix composite for the total resurfacing of a joint or joint compartment, which is designed to eliminate cartilage-tocartilage integration problems and provide a cell-based option for totally resurfacing joints without totally replacing them. The primary challenges for tissue engineering the total cartilage resurfacing of a joint are to produce viable cartilage tissue of sufficient thickness and surface area to cover an entire joint, to produce cartilage that has appropriate mechanical properties to support the in vivo mechanical demands, and to ensure the integration of the construct with underlying bone. The goal of this proposal is to produce functional autologous cartilage constructs using tissue engineering principles wherein autologous cells, such as Mesenchymal Stem Cells (MSCs), auricular or articular chondrocytes are used to produce full-thickness replacement cartilage and that is then fused and allowed to integrate onto sub-chondral bone, thus totally replacing the deteriorated cartilage with autologous engineered cartilage. This approach is based on the hypothesis that the production of full-thickness cartilage implants obviates the intractable difficulty of lateral cartilage integration, and functional long-term repair will be accomplished by producing biomechanically sound autologous cartilage.
The specific aims of this proposal are: 1. To produce implantation-ready tissue engineered cartilage constructs: In a rabbit model, MSCs and culture-expanded chondrocytes will be used to produce full-thickness (300 um) cartilage constructs of sufficient area to cover an entire humeral condyle. Variables to be tested include the use of auricular or articular chondrocytes or MSCs;hyaluronan- or collagen-based scaffolds;and variations in culture conditions such as cell seeding density, medium flow rate, and the addition of growth factors such as TGF-p1, TGFpS, BMPs, and omega-3 fatty acids. 1. To test implantation-ready constructs in an ex vivo model for cartilage resurfacing: Implant materials synthesized to the proper thickness and surface area will be fixed onto explanted rabbit humeral condyles using four adhesive methods: a calcium phosphate paste, fibrin glue, a final using the zero-length cross-linker1-Ethyl-3-{3-dimethylaminopropyl} carbodiimide, and APTMS-MBA (aminopropyltrimethoxysilanemethylenebisacrylamide), a non-toxic polymer adhesive. These adhesive materials will be tested for their biomechanical properties in vitro, in organ culture, and after implantation into athymic mouse hosts for up to 6 weeks. Biomechanical properties to be tested include a map of surface stiffness, and measures under uniaxial tension and horizontal shear (to failure). MRI imaging, histological examination, and immunochemistry will be used to determine the consistency of cartilage thickness and integration into subchondral bone. 2. To test constructs in an in vivo model of cartilage resurfacing in rabbits: Autologous engineered cartilage constructs will be used to resurface entire humeral condyles in rabbits. The implants will be harvested and examined for biomechanical properties and histology at 4, 12, 24 and 48 weeks post-implantation. Through the use of the Cell, Bioreactor and Imaging Cores, the goals of this proposal will be more easily and efficiently accomplished. The Core components are very appropriate for this project as there is a high demand for cells (chondrocytes and MSCs), bioreactors are need to fabricate cartilage tissue, and imaging is needed for outcome analysis. If these studies are successful, the follow-up study would be to reproduce these results in a large animal pre-clinical model such as in sheep or goats. The long-term objective of this study is to provide an alternative treatment for severe arthritis of diarthrodial joints that is composed of living autologous tissue which, hopefully, will provide many years of functional use before the need for total joint replacement.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZAR1-CHW-J)
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Case Western Reserve University
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Whitney, G Adam; Kean, Thomas J; Fernandes, Russell J et al. (2018) Thyroxine Increases Collagen Type II Expression and Accumulation in Scaffold-Free Tissue-Engineered Articular Cartilage. Tissue Eng Part A 24:369-381
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