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.