A method for defining tissue injury criteria reveals ligament deformation thresholds are multimodal

Soft tissue injuries (such as ligament, tendon, and meniscus tears) are the result of extracellular matrix damage from excessive tissue stretching. Deformation thresholds for soft tissues, however, remain largely unknown due to a lack of methods that can measure and compare the spatially heterogeneous damage and deformation that occurs in these materials. Here, we propose a method for defining tissue injury criteria: multimodal strain limits for biological tissues analogous to yield criteria that exist for crystalline materials. Specifically, we developed a method for defining injury criteria for mechanically-driven fibrillar collagen denaturation in soft tissues, using regional multimodal deformation and damage data. We established this new method using the murine medial collateral ligament (MCL) as our model tissue. Our findings revealed that multiple modes of deformation contribute to collagen denaturation in the murine MCL, contrary to the common assumption that collagen damage is driven by strain in the fiber direction alone. Remarkably, our results indicated that hydrostatic strain, or volumetric expansion, may be the best predictor of mechanically-driven collagen denaturation in ligament tissue, suggesting crosslink-mediated stress transfer plays a role in molecular damage accumulation. This work demonstrates that collagen denaturation can be driven by multiple modes of deformation and provides a method for defining deformation thresholds, or injury criteria, from spatially heterogeneous data.