Decellularized Biomaterials for Tendon-to-Bone Healing: Advances and Translational Challenges.

Abstract

Repair of the tendon-to-bone interface remains a major clinical challenge owing to its complex hierarchical architecture and limited intrinsic regenerative capacity. Decellularized biomaterials have emerged as promising scaffolds for tendon and ligament repair due to their native extracellular matrix composition, structural similarity, and biological activity. This review summarizes recent advances in the application of decellularized biomaterials for tendon-to-bone interface healing, covering both preclinical investigations and clinical trials of scaffolds derived from diverse sources, including porcine small intestinal submucosa, dermal matrix, tendon, amniotic membrane, pericardium, and Wharton's jelly. Particular emphasis is placed on current design strategies aimed at improving regenerative performance, including biomimetic architectural design, three-dimensional bioprinting for gradient interface engineering, regulation of the immune microenvironment, integration of stem cells or their derivatives, and sequential delivery of bioactive components. Despite encouraging preclinical outcomes, clinical translation remains limited and inconsistent. Major barriers include residual immunogenicity, batch-to-batch variations in bioactivity, an incomplete understanding of the mechanisms governing interface regeneration, and the scarcity of high-quality clinical evidence. Future research should therefore focus on optimizing decellularization protocols, refining scaffold architecture and functional modification strategies, integrating stem cells or stem cell-derived therapeutics, and conducting rigorous translational and clinical studies to bridge the gap between experimental success and clinical application. STATEMENT OF SIGNIFICANCE: Tendon-to-bone interface (TBI) healing remains a major challenge in regenerative medicine because the native enthesis has a complex graded architecture that is difficult to restore after injury. Decellularized biomaterials are promising for TBI repair because they retain native extracellular matrix components, structural biomimicry, and intrinsic bioactivity. This review provides a critical synthesis of recent advances in decellularized biomaterials for TBI healing, covering tissue sources and preclinical and clinical evidence. It also highlights emerging functionalization strategies, including biomimetic design, three-dimensional bioprinting, immune modulation, stem cell integration, and spatiotemporally controlled bioactive delivery. By addressing both regenerative potential and translational barriers, this review offers a timely framework for designing decellularized scaffolds for clinically effective tendon-to-bone regeneration.