Gradient hydrogel with bioactive glass for tendon-bone interface regeneration: Enhancing biomechanical strength and synchronized tissue regeneration.

The interface between tendon and bone is characterized by a gradient multi-tissue structure in a small-sized, localized region, and the tendon insertion cannot fully regenerate following repair for its rupture. Therefore, tendon-bone healing remains a significant challenge in the field of sports medicine. This study aims to design and fabricate a bioactive hydrogel with a continuous ion concentration gradient, using bioactive glass (BG), modified alginate (AlgMA), and gelatin. Under the condition of the sustained release of bioactive ions and gradient-induced signals, bone marrow mesenchymal stem cells (BMSCs) can be successfully differentiated into chondrocytes and osteoblasts, which aids in promoting tendon-bone interface regeneration. In vivo experimental results demonstrated that the hydrogel with a BG gradient exhibited superior formation of gradient mineralized fibrocartilage compared to other groups, with the highest fibrocartilage proportion (35.65 %), which was 1.36-fold and 4.4-fold higher than that of the uniform hydrogel group and the control group, respectively. The implantation of the gradient hydrogel facilitated the synchronized regeneration of tendon, fibrocartilage, and bone at the tendon-bone interface, thereby enhancing the biomechanical strength of the enthesis. These findings suggest that using this biomimetic BG-gradient hydrogel scaffold could be a powerful tool supporting the repair of tendon insertion avulsion. STATEMENT OF SIGNIFICANCE: The gradient structure at the tendon-bone interface is notoriously challenging to heal following injury. To address this challenge, this study proposes an innovative solution that involves the combination of BG with photocrosslinked alginate/gelatin hydrogels. This combination aims to construct a continuous ionic concentration gradient hydrogel that effectively mimics the natural hydroxyapatite gradient present at the tendon-bone interface. Simultaneous multi-tissue regeneration was achieved by directing the differentiation of BMSCs into osteoblasts in high BG regions and chondrocytes in low BG regions, as demonstrated by in vivo experiments. This study not only presents a scalable and reproducible fabrication strategy but also introduces a new paradigm for functional hard-soft tissue interfaces, with potential applications in ligament-bone and cartilage-bone repair.