Highly bio-adapted hydrogels for tendon-bone interface regeneration: Natural healing inspiration, design strategies,...

Against the dual backdrop of a global push to promote physical activity and the progressive degeneration of the musculoskeletal system due to aging, a significant imbalance has emerged between life expectancy and quality of life. Tendon-bone interface (TBI) injuries markedly impair physical function and overall well-being. The anatomical gradient structure of the TBI, along with the spatiotemporal complexity of its cellular composition and distribution, poses substantial challenges to postoperative healing. This review examines the vulnerability of the TBI under physiological conditions, the spatial gradient distribution of various functional cell types, and the concentration gradients of cytokines. We further introduce the reparative processes that occur following TBI injury and highlight key strategies for interface regeneration. In recent years, advances in tissue engineering have endowed hydrogels with unique biological properties and potential to mimic the gradient architecture of native TBI tissue, making them promising candidates for TBI repair and thereby improving clinical outcomes. We categorize current hydrogel-based strategies for enhancing TBI healing into four main types: improving hydrogel physicochemical properties, mimicking native anatomical structures, replicating dynamic gradients of cells and cytokines, and responding adaptively to the healing microenvironment. Lastly, we discuss the selection of functional cells and the mechanisms through which bioactive factors contribute to TBI regeneration. In summary, this review provides insights into the design of highly bio-adapted hydrogels tailored to the gradient structure and biological property of the TBI and offers guidance for future research on hydrogel-based therapeutic strategies.