Tendon and ligament injuries account for 20-30% of all musculoskeletal disorders, which are the leading cause of disability in the United States. Such injuries are the end result of a degenerative process involving altered cell behavior. To address this issue, our research investigates the interplay between tendon multiscale mechanics and mechanobiology in the context of tissue remodeling (e.g., degeneration, repair, and development). The ultimate goals of this work are to identify the causes of tendon pathology, discover novel therapeutic options, and direct the design of biomaterials that can recapitulate the behavior of native tissue. Furthermore, our research will produce fundamental knowledge regarding the feedback loop between local tissue mechanics and cellular mechanobiology, which is an important contributor to numerous diseases outside orthopaedics, including tissue fibrosis and cancer. This multidisciplinary work involves the use of multiscale mechanical testing, computational modeling, cell and tissue culture, and biomaterial fabrication.
Role of Altered Mechanics in Tendon Degeneration
A primary cause of tendon degeneration is overuse (i.e., fatigue loading), which produces repeated microscale damage of the load-bearing collagen fibrils. In addition to direct mechanical damage, tendon degeneration is characterized by the accumulation of atypical tissue components (e.g., cartilaginous, fat, and calcium deposits), which further weakens the tissue and drives the progression of degeneration. Why resident tenocytes produce these atypical matrix deposits rather than repair the native tissue structure is unknown. We hypothesize that fatigue damage induces changes in the local tissue mechanical microenvironment (e.g., strains, stiffness, topography), which alters the biophysical stimuli presented to tenocytes and leads to their adoption of abnormal (i.e., non-tenogenic) phenotypes. However, it is unclear whether the changes in tendon microscale mechanics caused by fatigue damage are responsible for the altered cellular activity observed with tendon degeneration. Therefore, the objectives of this project are to identify the in situ changes in tendon microscale mechanics caused by fatigue damage and to determine whether the altered mechanical microenvironment modifies tenocyte behavior leading to tendon degeneration.
Establishment of Hierarchical Structure and Function during Tendon Development
While biomaterials are needed to help repair or replace degenerate tendons, current tissue engineering approaches fail to replicate the native hierarchical structure, which is responsible for the tissue’s load-bearing capacity and toughness. Specifically, the fractal assembly of collagen molecules into fibrils, fibrils into fascicles, and fascicles into tendon produces a stiff material that is strongly resistant to local defects. However, it is unclear how tendon hierarchical structure and multiscale behavior is established during development. Additionally, it is unknown how the evolving mechanical microenvironment affects cellular activity driving tendon development. A better understanding of these processes will provide key insight into designing engineered tissues that can replicate tendon function and improve tendon repair. The objectives of this project are to investigate how tendon hierarchical mechanics are established during development and determine the role that cellular mechanotransduction plays in this process.