Strong living scaffolds for load-bearing musculoskeletal tissue regeneration

Load-bearing musculoskeletal tissues, including bone, cartilage, tendon, ligament, and skeletal muscle, possess highly specialized biological and biomechanical properties that enable weight support, movement, and protection of vital organs. However, intrinsic limitations in self-healing and exposure to complex physiological forces render them particularly vulnerable to injury and degeneration, resulting in musculoskeletal disorders with significant global impact. Current clinical solutions, ranging from bioinert metallic or polymeric implants to bioinductive, biodegradable scaffolds, provide temporary mechanical stabilization or promote tissue remodeling, yet often fail to achieve simultaneous mechanical robustness and biological functionality. To overcome these limitations, regenerative scaffolds incorporating living cells have emerged as a new paradigm. Nevertheless, conventional cell-laden hydrogels suffer from inadequate load-bearing capacity, whereas polymer scaffolds, although mechanically robust, lack the biological microenvironment to support functional regeneration. Recent research has therefore focused on developing strong living scaffolds that integrate toughness and cytocompatibility through two main approaches: mechanical reinforcement of cell-laden hydrogels and design of polymer-hydrogel hybrid scaffolds. This review summarizes the biology and biomechanics of load-bearing musculoskeletal tissues, evaluates clinically established bioinert and bioinductive implants, and highlights advanced approaches for engineering strong living scaffolds that combine robust mechanical strength with biological activity. Finally, we discuss future challenges and opportunities toward the clinical translation of next generation regenerative biomaterials for musculoskeletal tissue repair.