Tendon tears are common injuries that frequently re-tear after surgical repair due to an ineffective healing response. Current therapies are unable to restore structural and mechanical integrity. MRL/MpJ mice have been shown to heal without scar in several tissues, including tendon. While there are several hypotheses regarding the mechanisms that underlie the regenerative capacity of MRL/MpJ mice, prior findings from our group of improved structural and mechanical recovery of MRL/MpJ tendons after overuse injury (systemically noninflammatory), support a tissue-driven regeneration hypothesis. Findings were corroborated by preliminary work in organ culture, which indicated superior alignment in healing MRL/MpJ tendons in the absence of a systemic environment. In order to understand the scarless tendon healing response in MRL/MpJ and generate support for future study of the role of the local tendon environment as a driver of regenerative healing in MRL/MpJ, this thesis examines the MRL/MpJ healing response both in vivo and ex vivo. Acute injuries in patellar tendon and ear cartilage were examined with particular attention to the local tendon healing environment during the proliferative and remodeling stages of healing as well as the relationship between injuries in multiple tissues and their systemic inflammatory environment. Alterations in ECM composition and cell activity were found in MRL/MpJ tendons compared to C57BL/6, and the lack of correlations with the systemic environment and healing in ear cartilage supports the hypothesis of tissue-driven regeneration in MRL/MpJ.

Novel techniques for decellularization and recellularization of tendon are presented that have clinical applications for preparing enhanced tendon allografts and research applications for studying cell-ECM interactions. Furthermore, we demonstrate the development and validation of a mouse patellar tendon organ culture system. These novel techniques were used to interrogate the capacity of MRL/MpJ provisional extracellular matrix (ECM) from early stages of tendon healing to modulate cell activity and drive cells of different strains to remodel their extracellular environment. Our findings suggest the capacity of MRL/MpJ provisional ECM to modulate cell activity and highlight the importance of catabolism in MRL/MpJ tendons in order to achieve scarless healing.

Together, the work described in this thesis helps to further our understanding of the environment that leads to effective tendon healing and provides strong support for further study of the local tendon mechanisms that may drive scarless healing in MRL/MpJ mice. Several innovative research tools are presented, and their use in this work suggests interrogation of the role of the local environment in modulating cell activity in order to achieve scarless tendon healing.