Cocktail Cell‐Reprogrammed Hydrogel Microspheres Achieving Scarless Hair Follicle Regeneration

The scar repair inevitably causes damage of skin function and loss of skin appendages such as hair follicles (HF). It is of great challenge in wound repair that how to intervene in scar formation while simultaneously remodeling HF niche and inducing in situ HF regeneration. Here, chemical reprogramming techniques are used to identify a clinically chemical cocktail (Tideglusib and Tamibarotene) that can drive fibroblasts toward dermal papilla cell (DPC) fate. Considering the advantage of biomaterials in tissue repair and their regulation in cell behavior that may contributes to cellular reprogramming, the artificial HF seeding (AHFS) hydrogel microspheres, inspired by the natural processes of “seeding and harvest”, are constructed via using a combination of liposome nanoparticle drug delivery system, photoresponsive hydrogel shell, positively charged polyamide modification, microfluidic and photocrosslinking techniques. The identified chemical cocktail is as the core nucleus of AHFS. In vitro and in vivo studies show that AHFS can regulate fibroblast fate, induce fibroblast‐to‐DPC reprogramming by activating the PI3K/AKT pathway, finally promoting wound healing and in situ HF regeneration while inhibiting scar formation in a two‐pronged translational approach. In conclusion, AHFS provides a new and effective strategy for functional repair of skin wounds. Inspired by the natural process “seeding, germination, maturation, and harvest”, fibroblast fate‐regulating seed microspheres that can reset dermal fibroblast fate, inhibit scar signaling, activate DPC program and induce in situ hair follicle regeneration are developed by high‐throughput mechanism‐driven phenotype compound screening techniques, liposome nanoparticle drug delivery system, surface positive charge modification, microfluidic, and UV photopolymerization technology.