MRL/MpJ tendon matrix-derived therapeutic promotes improved healing outcomes in scar-mediated canonical tendon healing

Abstract

Tendons are commonly injured connective soft tissues characterized by an ineffective healing response that results in scar formation and loss of functional and structural properties. Naturally occurring extracellular matrix (ECM) constructs have become a promising therapeutic for tendon injuries due to their capacity to harness a complex biological environment. However, in tendon, the ECM properties needed for improved healing remain unknown. Interestingly, we have determined that the improved tendon healing response of the scarless-healing MRL/MpJ is driven by intrinsic properties with therapeutic potential to modulate the proliferative and morphological behavior of cells derived from a canonically healing model in vitro. We hypothesize that a distinct composition of ECM deposited during the early healing response of the MRL/MpJ will harnesses the biological cues to stimulate improved structure and function in vivo of canonically healing B6 mice. Accordingly, MRL/MpJ and B6 patellar tendons were injured via midsubstance punch defects. Healing tendons were isolated after 3 or 7 days and encapsulated in PEG-4MAL hydrogels to develop ECM-derived therapeutic constructs. Constructs were then introduced into B6 mice as a treatment following full thickness midsubstance-punch injuries. Treatment with ECM-derived constructs from MRL/MpJ tendons after 7-days post-injury (M7) resulted in improved matrix alignment, tissue stiffness, decreased collagen III content and improved cell morphology in B6 tendons after 6 weeks post-injury. Furthermore, proteomic analysis showed that M7 contained a unique compositional profile rich in glycoproteins, thereby elucidating a valuable naturally-derived platform for the treatment of tendon injuries. Overall this work highlights promising targets for future therapeutic development and tissue engineering applications.