THERAPEUTIC UTILITY OF THE MRL/MPJ REGENERATIVE MOUSE IN CLINICALLY-RELEVANT TENDON INJURIES
Due to their critical role in joint stability and locomotion, injuries to the tendon cause pain, disability, and diminished quality of life. Tendon injuries are usually progressive, in which incurred damage does not repair, leading to chronic tendinopathy which can then progress to rupture. Existing therapies range from physical therapy, corticosteroids, and biologics to surgical repair in late-stages of disease, but all existing methods fail to effectively repair underlying damage, leading to further progression of injury. Thus, there is an unmet clinical need for effective therapeutics to halt the progression of tendinopathy. The MRL/MpJ regenerative mouse strain (MRL) has demonstrated enhanced recovery of structure and function in a variety of tissue injuries, including a tendon punch excision. However, this exaggerated injury fails to recapitulate the progressive nature of clinical tendinopathy. Accordingly, the enhanced healing capacity of the MRL in clinically relevant, progressive stages of tendinopathy is unknown. To elucidate the utility of the MRL to recapitulate various tendon injuries, Chapter 2 investigates the MRL as a model of enhanced healing following surgical repair of the supraspinatus tendon in late-stage tendon disease. Our findings indicate that the MRL restore enhanced structure, composition, and function following rotator cuff repair through a temporal balance of collagens. This study establishes a platform to interrogate specific mechanisms that may underlie effective healing following surgical repair. Subsequently, because current surgical repair procedures experience high rates of re-tear, Chapter 3 investigates the efficacy of the MRL in earlier stages of tendinopathy following chronic overuse, which is associated with a markedly disparate biological cascade than previously investigated acute injuries. We demonstrate that the MRL is capable of recovering composition, structure, and function in these disparate injuries, highlighting its broad utility to harness as a therapeutic. Finally, our previously developed MRL cell- and matrix-derived components were evaluated as a therapeutic in early onset tendinopathy in Chapter 4. Taken together, this work identifies a platform for future investigation of mechanisms associated with enhanced healing in various stages of tendinopathy. Furthermore, the ability of MRL-derived therapeutics to attenuate early onset tendinopathy motivates further investigation of these disease-modifying biologics to halt the progression of tendinopathy.
extracellular matrix; mechanobiology; orthopedics; regeneration; rotator cuff; tendon
van der Meulen, Marjolein; Hayashi, Kei
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis