Tendons are integral components of the joint anatomy and play a key role in the load transfer between muscles and bones during locomotion. The healthy tendon environment is composed of a highly aligned extracellular matrix (ECM) structure with robust mechanical properties necessary to resist the high levels of loading experienced by these tissues on a regular basis. However, acute injuries due to trauma result in a number of detrimental changes to the tendon integrity, resulting in the excessive deposition of disorganize matrix, increased cellularity and cell rounding, and the loss of the tissue’s mechanical properties. Current clinical therapeutics to treat acute tendon injuries that result in tissue rupture, have focused on treatments involving surgical repair, immobilization and physical therapy. However, due to the inadequate natural healing response of tendons, these therapeutics have not been able to reduce the amount of scar tissue that is deposited at the injury site, or site of repair. Therefore, high incidences of re-injury continue to be a burden on patients even after a prolonged period of healing.

The lack of regenerative healing models that could inform the biological environment necessary to stimulate scarless healing in adult mammals has been a major hurdle towards the development of more effective tendon therapeutics. However, the discovery of the MRL/MpJ mouse, a promising model of adult mammalian regeneration, could help bridge this gap of knowledge. Still, while studies have identified a tissue specific scarless healing response within this model that extends to tendon injuries, much remains unknown about the driver of this regenerative healing response in the MRL/MpJ. Therefore, to further interrogate this matter, the overall goal of this thesis is to identify the driving force of improved healing in the MRL/MpJ and utilize this model as a tool to develop an innovative therapeutic system that stimulates improved healing of canonically healing tendons after acute injury.

To accomplish this goal, this thesis will be broken down into three major aims. In Aim 1 (Chapter 2), the MRL/MpJ was utilized as a naturally occurring model of adult mammalian regeneration to characterize the systemic and innate environment that lead to scarless healing. Subsequently, in Aim 2 (Chapter 3) an organ culture system was utilized to remove the systemic contributions from the tendon healing response, so that we could individually assess the innate, or tendon specific, contributions as drivers of scarless healing in this model. Finally, in Aim 3 (Chapter 4) our findings were translated into therapeutic development and an MRL/MpJ ECM derived therapeutic was used to evaluate in-vivo capability of MRL/MpJ derived constructs to treat canonical tendon injuries.

Together, this work provides a template for future therapeutic development, opening the door to identify the specific mechanisms necessary to push canonical tendon healing toward regeneration.