Cartilage Integration: in Vitro to In Vivo Translation

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DESCRIPTION (provided by applicant): A common challenge in tissue engineering is the development of treatments that satisfy the biomechanical requirements of the interfaces between implants and host tissues. In treatments of an articular cartilage defect with a tissue implant, the implant needs to form an adherent and integrated interface with the adjacent host cartilage, but often fails to do so. Conversely, the implant needs to form an articular surface in apposition with host tissue that is a lubricated, low-friction interface, but often fails to do so and instead undergo fibrillation. Nature has achieved integrated and lubricated interfaces thru specific biological processes and molecules. Thus, a biomimetic approach may be useful in achieving the desired interfaces. Our overall hypothesis is that tailoring cartilaginous implants and host tissues to enhance site- specific integration or, alternatively, lubrication can create key localized features that facilitate successful treatment of cartilage defects. The development of human clinical therapies typically involves translation of in vitro investigations through intermediate in vivo studies in animal models. In vitro studies of ours and others have shown that integration of cartilaginous tissue with native cartilage can be accelerated by treatments to stimulate cell- based formation of a collagen network across the interface, whereas lubrication characteristics typical of the articular surface can be achieved by surface localization of cells secreting a lubricant molecule called lubricin (Lub) or Superficial Zone Protein (SZP). To test the utility of these concepts in tissue implants, we established methods, applicable to both in vitro and in vivo studies, (a) for determining the efficacy of integrative cartilage repair, (b) for tracking implanted cells, and (c) for localizing Lub/SZP-secreting cells. Here, we propose to use these methods to address the following translational hypotheses: (1) at the interface region between implant and host cartilage, sufficient cells secreting type II collagen into a receptive matrix facilitates collagen network deposition and successful integration. (2) At the articular surface region of the implant, sufficient cells producing Lub/SZP facilitates maintenance of smooth articulation. Relevance to Public Health. The proposed work will advance research toward clinical treatment of cartilage defects, that otherwise progress to osteoarthritis. If the hypotheses are shown to be correct, the results will (a) extend the concept that the targeted modification of tissue surfaces can be useful for integration or, alternatively, lubrication, (b) delineate the role of implanted versus host cells, and (c) demonstrate how in vitro models of articular defect repair can be translated in vivo.