Remodeling the Senescent Microenvironment for Promoting Osteoporotic Tendon-to-Bone Healing via Synergizing Senolytic Quercetin and Aligned Nanowire-Structured Hydrogels
Wei Song, Wencai Liu, Siyi Li, Yuhao Yu, Hui Xu, Tingwang Shi, Han‐Ping Yu, Yaohua He, Ying‐Jie Zhu, Weilin Yu
Abstract
Osteoporotic tendon-to-bone healing remains a major challenge, as cellular senescence disrupts tissue regeneration and impairs repair outcomes. Although the role of cellular senescence in rotator cuff repair is increasingly recognized, current strategies often overlook the complex pathological context, particularly the dual impacts of senescence on both bone marrow-derived mesenchymal stem cells (BMSCs) and tendon-derived stem cells (TDSCs). This gap hampers effective tendon-to-bone healing and integration, especially under osteoporotic conditions. Herein, a composite hydrogel system, quercetin-loaded aligned ultralong hydroxyapatite nanowire/gelatin-hyaluronic acid hydrogel (Que-AHNW/GH), has been developed to address these challenges. By integrating senolytic quercetin as a biological cue with highly aligned ultralong hydroxyapatite (HAP) nanowires as a topographical cue, the system remodels the senescent microenvironment, alleviating senescence in both BMSCs and TDSCs and promoting osteogenesis and tenogenesis. Que-AHNW/GH suppresses the PI3K/AKT pathway, enhances autophagy, and reduces senescence in both cell types. In vivo, Que-AHNW/GH improves bone tunnel regeneration, tendon repair, and tendon-to-bone integration in osteoporotic rats with rotator cuff injury. This system enhances biomechanical strength and gait performance and demonstrates excellent biosafety. These findings highlight the promising potential of Que-AHNW/GH as a multifunctional biomaterial for effectively promoting senescence-related tendon-to-bone healing, offering a promising solution for treating osteoporotic tendon-to-bone injuries.