Total Joint ResurfacingPrevious attempts to repair articular cartilage have focused on the repair of focal defects. One of themain complications of focal defect repair is that integration of the repair tissue with the surrounding nativecartilage is inconsistent and generally poor, which renders the repair site biomechanically unstable notclinically efficacious. In the case of severe osteoarthritis where the entire joint surface has deteriorated, theprocedures for repair of focal cartilage defects are no longer applicable. For severe arthritis, total jointreplacement is the final option which, although it has a generally good outcome, there are still long-termcomplications including, erosion of the articulating surface of the prostheses, and breaking or loosening ofthe prosthetic stem. These problems necessitate revision surgery which is progressively more difficult andcomplicated. To obviate this problem, we propose to design and test a tissue engineered cell-matrixcomposite for the total resurfacing of a joint or joint compartment, which is designed to eliminate cartilage-tocartilageintegration problems and provide a cell-based option for totally resurfacing joints without totallyreplacing them.The primary challenges for tissue engineering the total cartilage resurfacing of a joint are to produceviable cartilage tissue of sufficient thickness and surface area to cover an entire joint, to produce cartilagethat has appropriate mechanical properties to support the in vivo mechanical demands, and to ensure theintegration of the construct with underlying bone. The goal of this proposal is to produce functionalautologous cartilage constructs using tissue engineering principles wherein autologous cells, such asMesenchymal Stem Cells (MSCs), auricular or articular chondrocytes are used to produce full-thicknessreplacement cartilage and that is then fused and allowed to integrate onto sub-chondral bone, thus totallyreplacing the deteriorated cartilage with autologous engineered cartilage.This approach is based on the hypothesis that the production of full-thickness cartilage implantsobviates the intractable difficulty of lateral cartilage integration, and functional long-term repair will beaccomplished 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, MSCsand culture-expanded chondrocytes will be used to produce full-thickness (300 um) cartilage constructs ofsufficient area to cover an entire humeral condyle. Variables to be tested include the use of auricular orarticular chondrocytes or MSCs; hyaluronan- or collagen-based scaffolds; and variations in culture conditionssuch 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: Implantmaterials synthesized to the proper thickness and surface area will be fixed onto explanted rabbit humeralcondyles using four adhesive methods: a calcium phosphate paste, fibrin glue, a final using the zero-lengthcross-linker1-Ethyl-3-{3-dimethylaminopropyl} carbodiimide, and APTMS-MBA (aminopropyltrimethoxysilanemethylenebisacrylamide),a non-toxic polymer adhesive. These adhesive materials will be tested for theirbiomechanical properties in vitro, in organ culture, and after implantation into athymic mouse hosts for up to6 weeks. Biomechanical properties to be tested include a map of surface stiffness, and measures underuniaxial tension and horizontal shear (to failure). MRI imaging, histological examination, andimmunochemistry will be used to determine the consistency of cartilage thickness and integration intosubchondral bone.2. To test constructs in an in vivo model of cartilage resurfacing in rabbits: Autologousengineered cartilage constructs will be used to resurface entire humeral condyles in rabbits. The implantswill 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 moreeasily and efficiently accomplished. The Core components are very appropriate for this project as there is ahigh demand for cells (chondrocytes and MSCs), bioreactors are need to fabricate cartilage tissue, andimaging is needed for outcome analysis.If these studies are successful, the follow-up study would be to reproduce these results in a largeanimal pre-clinical model such as in sheep or goats. The long-term objective of this study is to provide analternative treatment for severe arthritis of diarthrodial joints that is composed of living autologous tissuewhich, hopefully, will provide many years of functional use before the need for total joint replacement.
Showing the most recent 10 out of 32 publications
