Ligament injuries cause joint instability and can lead to chronic joint disorders. The underlying cause of these functional deficits is the poor structural quality of the repaired matrix. Improvements to clinical outcomes require a mechanistic understanding ofthe physical mechanisms that instruct the restoration of matrix structure and function. The development and validation of mechanistic models would support the application and design of targeted interventions, such as soft-tissue mobilization, that apply mechanical stimuli directly to the remodeling matrix. The primary objective of this research proposal is to characterize physical mechanisms for matrix remodeling during ligament wound healing. The central hypothesis is that mechanical stimulation during wound healing can improve ligament repair by enhancing matrix composition and organization. To test this hypothesis, an experimental and computational methodology will be employed to measure and predict the structural and functional effect of mechanical stimulation on ligament reparative tissue. In Aims 1 and 2, a computational framework will be developed to predict matrix remodeling from mechanical stimulation using tissue-equivalent materials. In Aim 3, an in-vivo experiment will validate the predictive ability of this new model in a three-dimensional finite element simulation. Two potential projects stemming from this work include the design of soft tissue mobilization methods for use in human subjects (clinical trial); and the formulation of a new hypothesis on mechanotransduction mechanisms during repair. This may improve our ability to instruct signaling pathways during tissue repair, and help further our long-term goal of developing therapies for fast and full restoration of soft-tissue function after injury. As a Junior Investigator in the COBRE in Matrix Biology, I will work with my scientific mentor to complete the scientific aims and to develop a grant proposal for future R01 funding.

Successful completion ofthe proposed aims will improve our understanding ofthe importance of mechanical stimuli in the functional restoration of the extracellular matrix during ligament repair. We anticipate that results from this project will advance targeted treatment strategies for ligament injuries