An Injectable BMP-2-Releasing Porous Hydrogel Regulating the Paracrine Effects of ADSCs Promotes Tendon-to-Bone Healing in Rotator Cuff Repair.

Rotator cuff tears often require surgical reconstruction; however, outcomes remain suboptimal, primarily because of the challenges in fully restoring the tendon-bone interface (TBI). The normal fibrocartilaginous transition zone is often replaced by fibrous scar tissue, thereby increasing the risk of retears. A porous hyaluronic acid methacrylate hydrogel is developed to encapsulate adipose-derived stem cells (ADSCs) and bone morphogenetic protein-2 (BMP-2). Gelatin microspheres served as porogens to create micropores within the hyaluronic acid methacrylate hydrogel (HMs), and hollow gelatin methacryloyl hydrogel microspheres are used to encapsulate BMP-2 (GMBs). In vitro experiments confirm substantial proliferation and homing of ADSCs within the porous hydrogel system. When the ADSCs-loaded composite hydrogel (HMs/MBs/ADSCs) is applied to a rat rotator cuff injury model, it effectively reconstructs the fibrocartilage transition zone and promotes TBI healing. Transcriptome sequencing is performed to elucidate the mechanisms underlying BMP-2-induced fibrocartilage reconstruction. Furthermore, integrated in vitro sequencing reveals that HMs/MBs/ADSCs modulated the tissue microenvironment to enhance tissue regeneration, primarily through BMP-2's regulation of the paracrine effects of ADSCs. This study explores the comprehensive pathway through which HMs/MBs/ADSCs enhance tissue regeneration, emphasizing the synergistic effects of BMP-2 and ADSCs, and offers novel insights into the mechanisms underlying TBI healing.