Decellularized Scaffolds for Ligament/Tendon Regeneration: Challenges, Opportunities and Future Directions

Decellularized scaffolds have gained significant attention in tissue engineering, particularly for tendon and ligament regeneration, due to their ability to retain native extracellular matrix (ECM) architecture and biochemical cues. These decellularized scaffolds offer a biocompatible and bioactive framework that closely mimics the native tissue niche, promoting cellular infiltration, proliferation, and differentiation. Unlike synthetic materials, decellularized tissues can better support functional healing while minimizing immune responses. Tendon and ligament injuries pose a unique challenge due to the dense collagenous structure, limited vascularization, and poor intrinsic healing capacity of these tissues. While autografts and allografts are commonly used, limitations such as donor site morbidity, limited availability, and risk of immune rejection pose treats. Decellularized scaffolds offer a compelling solution by providing mechanical support while promoting natural tissue regeneration. Yet, developing these scaffolds remains challenging, as differences in tissue size, ECM composition, and porosity make it difficult to apply a universal decellularization approach. The major decellularization hurdle is to remove cellular components effectively without compromising the scaffold’s structural integrity or biological activity. In addition, achieving immune tolerance and enhancing vascular growth are essential for proper integration and long-lasting performance of the graft. This review highlights the latest advancements in decellularized scaffolds for tendon and ligament repair, discussing the various physical, chemical, and enzymatic methods used for decellularization. It also examines current limitations and strategies being explored to overcome them, such as combining scaffolds with growth factors, stem cells, or pro-angiogenic agents. Beyond musculoskeletal repair, the potential of decellularized scaffolds is expanding into broader applications in tissue and organ engineering. Future research should focus on standardizing decellularization protocols, improving vascular integration, and translating laboratory success into clinically viable products that can enhance patient outcomes in regenerative medicine.