Development of Biomimetic Regenerative Medicine Strategies
The structure-function and developmental biology results described above were used to guide regenerative medicine strategies for tendon-to-bone repair. Scaffolds were synthesized that mimicked the structure and mechanics of the healthy enthesis. Specifically, we developed aligned nanofiber scaffolds with spatial gradients in mineral (Figure 4).25,30 These structural and compositional gradients resulted in a functionally graded mechanical response, recreating the behavior of the natural enthesis. Furthermore, the gradient in mineral content led to spatially graded osteogenesis of mesenchymal stem cells.29 Additional enthesis features such as a variations in fiber orientation, a crimped fiber microstructure, and a cell phenotype gradient were also recreated in nanofiber scaffolds.28,31,32 These materials are currently being combined with mesenchymal stem cells and optimized for in vivo use.33,34
To apply developmental biology results to regenerative medicine, we developed a rotator cuff enthesis injury model that can be performed in neonatal and adult mice. Tendon-to-bone healing in the adult is scar mediated and often results in failure. In contrast, wound healing studies in skin 35-37 and tendon 38-40 show that tissues injured in utero or early postnatally heal via regenerative pathways rather than scar-mediated pathways. Using the enthesis injury model along with lineage tracing approaches, we are probing the necessity of the hedgehog-responsive cell lineage for enthesis regeneration, particularly related to mineralization. Understanding the necessity of enthesis cells from specific lineages for regeneration of a functional enthesis will allow us to put forward new strategies for enhanced tendon-to-bone repair.