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The rotator cuff and Achilles tendons along with the anterior cruciate ligament (ACL) are frequently injured with limited healing capacity. At the soft-hard tissue interface, enthesis is prone to get damaged and its regeneration in osteochondral defects is essential for complete healing. The current clinical techniques used in suturing procedures to reattach tendons to bones need much improvement for the generation of the native interface tissue, that is, enthesis, for patients to regain their full functions. Recently, inspired by the composite native tissue, much effort has been made to fabricate composite scaffolds for enthesis tissue regeneration. This review first focuses on the studies that used composite scaffolds for the regeneration of enthesis. Then, the use of polysaccharides for osteochondral tissue engineering is reviewed and their potential for enthesis regeneration is presented based on their supporting effects on osteogenesis and chondrogenesis. Gellan gum (GG) is selected and reviewed as a promising polysaccharide due to its unique osteogenic and chondrogenic activities that help avoid the inherent weakness of dissimilar materials in composite scaffolds. In addition, original preliminary results showed that GG supports collagen type I production and upregulation of osteogenic marker genes.Impact StatementEnthesis regeneration is essential for complete and functional healing of tendon and ligament tissues. Current suturing techniques to reattach the tendon/ligament to bones have high failure rates. This review highlights the studies on biomimetic scaffolds aimed to regenerate enthesis. In addition, the potential of using polysaccharides to regenerate enthesis is discussed based on their ability to regenerate osteochondral tissues. Gellan gum is presented as a promising biopolymer that can be modified to simultaneously support bone and cartilage regeneration by providing structural continuity for the scaffold.

Regenerative Rehabilitation represents a multifaceted approach that merges mechanobiology with therapeutic intervention to harness the body's intrinsic tissue repair and regeneration capacity. This review delves into the intricate interplay between mechanical loading and cellular responses in the context of musculoskeletal tissue healing. It emphasizes the importance of understanding the phases involved in translating mechanical forces into biochemical responses at the cellular level. The review paper also covers the mechanosensitivity of macrophages, fibroblasts, and mesenchymal stem cells, which play a crucial role during regenerative rehabilitation since these cells exhibit unique mechanoresponsiveness during different stages of the tissue healing process. Understanding how mechanical loading amplitude and frequency applied during regenerative rehabilitation influences macrophage polarization, fibroblast-to-myofibroblast transition (FMT), and mesenchymal stem cell differentiation is crucial for developing effective therapies for musculoskeletal tissues. In conclusion, this review underscores the significance of mechanome-guided strategies in regenerative rehabilitation. By exploring the mechanosensitivity of different cell types and their responses to mechanical loading, this field offers promising avenues for accelerating tissue healing and functional recovery, ultimately enhancing the quality of life for individuals with musculoskeletal injuries and degenerative diseases.