SDF-1α/BMP-12 loaded biphasic sustained-release SIS hydrogel/SA microspheres composite for tendon regeneration

Due to the inherent limited regenerative capacity of tendons, rendering countermeasures for tendon injury remains challenging. The pathophysiology of tendon healing is complex and contains three sequential phases including inflammation, proliferation and remodeling. Aiming at the treatment of different stages of tendon injury, in our work, an injectable small intestinal submucosa hydrogel/sodium alginate microspheres (SIS/SA) composite co-encapsulating stromal cell derived factor-1α (SDF-1α) and bone morphogenetic protein-12 (BMP-12) was developed for effective tendon regeneration. BMP-12 was initially embedded into SA microspheres by microfluid method, and then, microspheres were subsequently encapsulated into the SDF-1α loaded SIS hydrogel. The two bioactive molecules were released in a biphasic and controlled manner to facilitate cell recruitment in the early stage and tendon differentiation in the long-time stage, respectively. Meanwhile, with the degradation of hydrogel/microspheres composite, the regeneration process was accelerated through multiple pathways encompassing immune regulation, angiogenesis, and extracellular matrix (ECM) synthesis. The findings of this study present a compelling translational strategy with significant clinical potential for advancing tendon regeneration therapies.