Biomechanical Simulations of Progressing Osteoarthritis to Advance Understanding and Therapies

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The objective of this project is to understand the influence of intra-tissue stress distributions on the progression of osteoarthritis (OA) in human cartilage by leveraging new mechanical and imaging experiments, novel simulations of evolving virtual human cartilage in vivo, and multiple images of the knee from the NIH-funded Osteoarthritis Initiative (OAI) database. OA is a disease of the synovial joint, with degeneration and loss of articular cartilage as one hallmark change. Mechanical stresses play a key role in the destructive evolution of the disease. Both overloading (e.g. trauma) and reduced loading (e.g. immobilization) of cartilage induce molecular and microstructural changes that lead to mechanical softening, fibrillation, and erosion. Crucially, there is currently no direct method to correlate spatially resolved intra-tissue stresses with progression of OA in individual patients. Events with the Connecticut Science Center's Women in Science Initiative will spark STEM interest in female middle school students. High school, undergraduate and graduate students will perform new experiments and establish simulations.The primary hypothesis is that intra-tissue stresses (e.g. maximum shear stresses) will more strongly correlate with structurally defined OA progression measured by changes in both the network of collagen fibers (organization and density) and gross tissue volume, than with corresponding strains. Objective 1 establishes chemo-biomechanical constitutive relations for evolving OA ex vivo by measuring the large-shear stress-strain response of OA human cartilage; imaging the corresponding cell viability, composition, and microstructure; establishing functions describing the turnover of structurally significant cartilage constituents; and incorporating these within a custom simulation framework. Objective 2 establishes and validates simulations of evolving virtual human cartilage in vivo by establishing patient-specific models using the OAI data; training simulations to produce measured time-course outcomes; performing sensitivity and statistical analyses; and performing validation studies using additional OAI patients. The studies will link physical activity, and the resulting mechanical stimuli, to progression of OA and loss of cartilage function.