Pro-chondrogenic and immunomodulatory melatonin-loaded electrospun membranes for tendon-to-bone healing

Reconstructing the native structure of the tendon-to-bone insertion site (enthesis) in rotator cuff repair has always been a great challenge for orthopedic surgeons. Difficulty arises mainly due to the limited enthesis regenerative capability and severe inflammatory cell infiltration, which result in fibrovascular scar formation instead of native cartilage-like enthesis. Therefore, tissue engineering scaffolds with pro-chondrogenic and immunomodulatory capabilities may offer a new strategy for native enthesis regeneration. In this study, melatonin-loaded aligned polycaprolactone (PCL) electrospun fibrous membranes were fabricated. The sustained release of melatonin from this membrane significantly promoted the chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) in a long-term chondroid pellet model. After the membranes were implanted in a rat acute rotator cuff tear model, melatonin-loaded PCL membranes inhibited macrophage infiltration in the tendon-to-bone interface at the early healing phase, increasing chondroid zone formation, promoting collagen maturation, decreasing fibrovascular tissue formation and eventually improving the biomechanical strength of the regenerated enthesis. Taken together, melatonin-loaded PCL membranes possess great clinical application potential for tendon-to-bone healing.