Repair and regeneration of osteochondral defects in mouse articular joints

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1133883WeiIn a high percentage of patients, damages to the articular cartilage surface and the underlying subchondral bone can easily progress to joint degeneration, especially osteoarthritis which is the main cause of chronic disability in US. Extensive efforts have been made in osteochondral defect treatment, but there is still no widely accepted method which produces consistent satisfactory results. The regenerated cartilage is inferior to the original cartilage morphologically, biochemically, and biomechanically. Instead of forming articular cartilage, fibrocartilage is normally generated, which lacks of the long-term stability and cannot withstand prolonged stress to the joint. Thus, there is a need for a new approach that outperforms currently used methods. In this study, we propose to develop a graded scaffold with structure and mechanical properties mimicking those of natural cartilage, load the scaffold with articular-specific chondroprogenitor cells identified by GFP reporters, and then implant the cell-loaded scaffold into a novel transgenic mouse cartilage model to test for osteochondral repair and regeneration. It is expected that an optimum cell-scaffold construct will be determined which effectively regenerates osteochondral cartilage with excellent functionality and long-term stability.Intellectual merits: The novelty of the current proposal includes: (1) the development of a graded scaffold with structure, orientation, composition and mechanical properties mimicking those of natural cartilage and subchondral bone; (2) the development of an in-depth understanding of chondrocytes differentiation pathways and establishment of their lineage interrelationships; (3) the identification of articular-specific chondroprogenitor cells using a series of cartilage GFP reporters; (4) the development of an informative transgenic murine cartilage model to assess osteochondral repair and its integration with host tissues at a relatively low cost.Broader impact: The proposed project has a broader impact on various scientific disciplines. The results of the proposed research will contribute to our understanding of the cell-scaffold interactions, chondrocyte differentiation pathways, and host/donor cell contribution to the articular cartilage restoration for the first time. The information gained here will be an essential ingredient in developing and interpreting tissue engineering strategies to determine the optimal scaffold design and source of progenitors, and whether a repair process is initiated from the host or donor. Distinguishing the completeness of the repair in terms of the composition of cells that fill the repair region will be another measure of success of a repair strategy. The proposed research will be transformative to the tissue engineering field as it directly addresses the existing problems of the osteochondral cartilage repair and its approach may provide an effect solution to these problems.This project will result in the training of a graduate student and a number of undergraduate students in areas of tissue engineering, while exposing them to a multidisciplinary working environment. Efforts will be made to recruit female and minority students by integrating our research activities with existing recruiting efforts at the Department, the School and the University levels as well as participating in activities organized by various professional societies dedicated to underrepresented minorities. In addition, we will perform K-12 outreach to get high school students, especially female and underrepresented minorities, excited about engineering research. The results obtained from the project will be disseminated broadly via publishing in scientific journals, presenting in conferences and publicizing to general public via a website. We will make sure that all data will be kept for at least three years after conclusion of the award or three years after public release, whichever is later. We will also make our transgenic mice available to the tissue engineering community so that more researchers can use them to optimize their repair strategies.