Our group focuses on problems motivated by diseases of the musculoskeletal system including arthritis, connective tissue pathologies and, more generally, the molecular biology and biophysics of the extracellular matrix (ECM). As an example, it is well known that traumatic joint injury in humans causes cartilage degeneration and progression to post-traumatic osteoarthritis, but the mechanobiological mechanisms governing cellular transcription, translation, and post-translational responses to physical overload are not well understood. We use genomic and proteomic tools to identify key pathways associated with mechanical injury and the resulting cell-mediated proteolytic degradation of the ECM. Atomic force microscopy and related biophysical tools are used to image and probe the molecular structure of ECM proteoglycans and proteins synthesized by connective tissue cells in health and disease. Nanoindentation at the molecular, cellular and tissue levels aids in the discovery of molecular determinants underlying tissue pathology. Complementary projects focus on chondrogenesis of stem cells seeded within self-assembling peptide hydrogel scaffolds for repair of degraded or osteoarthritic cartilage. The molecular fine structure of stem cell-synthesized ECM molecules and the responses of these stem cells to physiological loading during and after differentiation are studied in vitro. Concurrent studies using small and large animal models are ongoing. Finally, there are currently no available disease-modifying drugs for osteoarthritis due, in part, to lack of appropriate delivery modalities. We are therefore studying the ability of electrostatic interactions linked to charged ECM molecules within target tissues to enable enhanced uptake, rapid penetration, and retention of potential therapeutics.