Integrating Disease Mechanisms and Design Strategies in Gradient Biomaterials for Soft-Hard Tissue Interfaces.

Engineered soft-hard tissue interfaces such as the tendon-bone, cartilage-bone, bone-ligament, and periodontal complexes are essential for load transfer and functional integration. However, injuries or degeneration at these sites is highly prevalent and remains a significant clinical challenge. Current repair strategies struggle to replicate native structure, compositional, and bioactivity gradients. Moreover, there is a lack of insight into their actual advantages over nongradient designs, and their ability to induce native-like interface regeneration remains unclear. Research across different interfaces is often fragmented, hindering the extraction of generalizable design principles. This review integrates disease mechanisms with material innovations to provide a critical synthesis of recent progress in gradient biomaterials for soft-hard tissue interfaces. This study compares gradient with nongradient strategies, identifies commonalities and differences across multiple interfaces, and discusses whether gradient designs truly promote native-like regeneration. Furthermore, this study highlights emerging fabrication technologies and translational challenges. By linking mechanistic insights with material strategies, this review aims to outline universal design principles and future directions for the development of clinically effective gradient biomaterials in complex interface regeneration.