Multidimensional biomimetic strategy integrating structural, functional and biological cues for enhanced tendon-to-bone interface regeneration

Failed tendon-bone interface (TBI) healing post-reconstruction is primarily attributed to persistent pathological microenvironments and insufficient fibrocartilage differentiation. However, effective tissue engineering strategies that concurrently regulate pathological microenvironments and promote fibrocartilage regeneration remain lacking. To address this, we developed a biomimetic strategy integrating fibrocartilage stem cells (FCSCs) with a novel dual-crosslinked BGBT hydrogel. This hydrogel, composed of bacterial cellulose, gelatin methacryloyl, borax, and tannic acid, mimics the native fibrocartilage extracellular matrix architecture, provides mechanical support, and regulates the microenvironment to promote fibrocartilage regeneration. <i>In vitro</i>, BGBT hydrogel significantly enhanced FCSCs proliferation and chondrogenic differentiation while modulating Sharpey fiber formation and inflammatory responses. <i>In vivo</i>, the BGBT@FCSC group exhibited superior new bone formation, biomechanical properties, and histological restoration of the tendon-bone interface compared to controls. RNA sequencing revealed that BGBT activated the PI3K pathway, driving FCSCs toward functional fibrocartilage lineages. This study presents a multifaceted biomimetic approach that integrates structural, functional, and biological cues to enhance TBI regeneration, offering a promising solution for clinical applications.