Regeneration of the gradient structure at the tendon-bone interface: Biomimetic design strategies of biomaterials and...

Tendon-bone interface (TBI) injuries cause excessive deposition of fibrous scar tissue, leading to irreversible destruction of the complex gradient hierarchy and markedly deteriorating mechanical-functional properties, presenting a persistent repair dilemma in clinical practice. Tissue engineering offers a promising strategy for the regeneration of functional interface tissue, with its core principle being the achievement of effective tissue healing through biomimicry of the gradient structure in the TBI rather than mere anatomical reconnection. Given the heterogeneity of the interface, biomaterials are often designed with stratified structures to replicate the characteristic variations across different regions. These materials, by mimicking the gradient structures of natural tissue, can guide directional cell migration and differentiation, thereby promoting the regeneration of gradient interface tissue. Additionally, they can serve as delivery vehicles for stem cells and bioactive molecules, both of which have been demonstrated as key players in tissue repair. This review summarizes the applications of biomaterials in interface tissue regeneration. First, it introduces the structural and functional aspects of interface tissue and its developmental maturation process. Next, it discusses current therapeutic approaches for TBI healing and highlights the unique advantages of biomaterials in this field. Emphasis is placed on biomimetic strategies for constructing interfacial gradients through material-based approaches, including mechanical gradients, cellular gradients, extracellular matrix (ECM) gradients, structural gradients, and electrical field gradients. Finally, the current challenges and future research directions in the application of biomaterials for interface tissue regeneration are outlined.