Biomaterials for modulating cellular responses of endogenous tendon stem/progenitor cells: A promising avenue for tendon regeneration

Abstract Over the past decades, managing tendon disorders has remained a great clinical challenge. Due to the limited endogenous healing ability of tendons, current clinical approaches often result in unsatisfactory repair. Therapies based on mesenchymal stem cells (MSCs) are promising for treating various tendon disorders; however, recent clinical trials have shown that the therapeutic benefits of exogenous MSC transplantation are still unsatisfactory. Alternatively, harnessing endogenous tendon stem/progenitor cells (TSPCs) has emerged as a promising strategy to initiate tenogenesis and restore tendon homeostasis, which can overcome the limitations of exogenous MSCs transplantation, such as low utilization rate, uncontrollable cell fate, and high costs. Meanwhile, efforts in decoding heterogeneity of TSPCs, advances in material science, and regenerative medicine have enabled precise modulation of the TSPC niche and cellular responses through the tailored design of biomaterials. Biomaterials with tailored properties, such as hydrogels, scaffolds and decellularized tendon matrix, can provide physical or chemical cues that activate endogenous TSPCs for regeneration. Moreover, drug delivery systems mediated by biomaterials like nanoparticles, hydrogels, and microneedles can directly or indirectly promote tenogenic potential of TSPCs. This review provides an updated overview of the specific markers and functions associated with various TSPC subpopulations, highlighting their roles in tendon physiology and pathology. Additionally, we summarize current biomaterial‐based strategies for modulating cellular responses of endogenous TSPCs, including activating normal tenogenic potential, inhibiting pathological differentiation, senescence and apoptosis, and improving the TSPC niche. Lastly, we present future perspectives that emphasize the need for a more comprehensive understanding and targeted modulation of TSPCs and their microenvironment. In summary, this review provides key insights into the rational design of next‐generation biomaterials aimed at TSPC modulation with the ultimate goal of advancing clinical therapies for tendon disorders.