Arthroscopic Raman Monitoring of Cartilage Content for PTOA Diagnosis and Chondroregenerative Treatment Response PTOA is a common, incapacitating, chronic condition among individuals who sustain traumatic joint injuries. Currently, even after “successful” surgical reconstruction of the trauma-induced pathoanatomy, supplemented with chondroregenerative interventions, cartilage degeneration continues to progress. Therapies to improve PTOA clinical outcomes are being developed, including chondroprotective disease modifying drugs that mitigate or reverse degeneration of cartilage lesions and chondroregenerative tissue engineering platforms that better recapitulate the composition and structure of healthy hyaline cartilage. However, the ability to assess the efficacy of PTOA treatments that preserve and/or regenerate cartilage is burdened by a lack of standardized diagnostic biomarkers that can objectively evaluate the efficacy of PTOA treatments. For clinical diagnostics, arthroscopic- based macroscopic cartilage grading systems (Outerbridge, ICRS) and MRI portrayals of cartilage composition are, at best, only moderately correlated with quantitative assessments of cartilage composition and material properties relevant to the mechanical integrity and functional performance of the regenerate tissue. Raman spectroscopy is an inelastic light scattering technique that reflects individual molecular vibrational bonds, corresponding to specific biochemical building blocks of key cartilage constituents: GAG, collagen, and water. We propose developing a comprehensive Raman platform for monitoring cartilage compositional biomarkers over the hierarchy of model systems employed for cartilage treatment research, including: 1) a clinical Raman- based arthroscopic probe that achieves real-time analysis of cartilage in in vivo animal studies and patient clinical trials, and 2) a tissue-culture compatible Raman-spectroscopy-interfaced plate reader for the rapid, non- destructive, repeated-measure analysis of live cartilage explants ex vivo. We hypothesize that derived Raman biomarkers can predict the composition, morphology, and material properties of cartilage in response to chondroprotective and/or chondroregenerative treatments more accurately than MRI and arthroscopic-based macroscopic cartilage grading systems (Outerbridge, ICRS). We examine this hypothesis over the hierarchy of PTOA therapy-development model systems including in vitro systems—Ovine cartilage explants subjected to injury and treatment with chondroprotective drugs, engineered cartilage grafts subjected to physiologic + supra- physiologic loading inflammatory cytokines, and human cartilage explants from autopsy and arthroplasty donors—and an in vivo system-- an ovine stifle joint subjected to PTOA injury, surgical repair, and drug treatments. Through objective assessments of the efficacy of emerging cartilage therapies over the hierarchy of R+D model systems—ex vivo, in vivo, clinical—Raman spect...