Biomechanics of the Primitive Matrix in Embryonic Cartilage and Meniscus

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This grant will support research on the development of cartilage and meniscus. Knee joint pain affects approximately 25 percent of adults, resulting in limited mobility and impaired life quality. Knee pain is often caused by the degeneration of two joint tissues, articular cartilage and meniscus. This degradation can be the result of disease and/or injury. Articular cartilage covers the ends of bones. Mechanically speaking, articular cartilage provides compressive load bearing and energy dissipation in the knee. The meniscus, another knee structure, increases join stability. Despite decades of efforts, there has been limited success in the regeneration of cartilage and meniscus. One major obstacle is that we do not understand how the two tissues are formed during embryonic development. This work will combine novel nanotechnology, microdissection and gene expression tools, to project will study the development of these two tissues from gestation to newborn ages in mouse knees. Outcomes will provide new insights about the initial molecular events that give rise to these two tissues. This will establish a new engineering benchmarks that can be used in regenerative medicine efforts to restore cartilage and meniscus biomechanical functions. Education and outreach activities will be integrated with the research goal to give trainees a better understanding of biomechanics. These activities will include senior design projects, science workshops, museum exhibitions and YouTube crash courses.Articular cartilage and meniscus have distinct extracellular matrices (ECMs). Cartilage ECM is mainly composed of type II collagen fibrils and proteoglycans, while meniscus ECM is dominated by circumferential type I collagen fibers. Preliminary data show that at the embryonic stage, the primitive matrices of both tissues show ubiquitous presence of type VI collagen and perlecan, the biomarkers of pericellular matrix (PCM). This work will thus test the hypothesis that the embryonic primitive matrix resembles the PCM of mature tissues, and elucidate the roles of this PCM-like primitive matrix in cell mechanobiology and matrix development. This work will 1) identify the critical time point, at which the primitive matrix separates into the PCM and bulk of ECM, 2) elucidate the biomechanical evolvement of the primitive matrix via atomic force microscopy (AFM)-based nanomechanical tests, and 3) determine the contribution of sulfated glycosaminoglycans (sGAGs) in the primitive matrix biomechanics and cell mechanotransduction. Studying cartilage and meniscus together, this work will identify the common and differentiated molecular events that contribute to the formation of the two tissues. In conclusion, this project will generate new knowledge on the molecular, structural and mechanical events during the initial formation of cartilage and meniscus, providing a new basis for guiding tissue regeneration and disease intervention.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.