Construction of Large‐Scale Bioengineered Hair Germs and In Vivo Transplantation

Hair follicle (HF) regeneration technology holds promise for treating hair loss, but creating a biomimetic structure that mimics the natural follicle microenvironment remains challenging. Here a novel bioengineered hair germ (BHG) is developed using thermodynamically incompatible mucopolysaccharides to enhance HF regeneration efficiency. Mucopolysaccharide-based hydrogels are synthesized by grafting amino and diethylamino groups (dihydroxyphenylalanine-grafted hyaluronic acid (HME) hydrogels) for rapid gelation and strong wetting adhesion. Dual-layered microspheres are fabricated using a co-flow microfluidic system, with HME as the outer shell and gelatin methacrylate (GelMA) as the core, achieving thermodynamic incompatibility. The Wnt3a protein is encapsulated for sustained release. RNA sequencing, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and functional validation are used to study the molecular mechanisms of HF regeneration. Results show that HME hydrogels exhibit excellent adhesion, shear-thinning behavior, and biocompatibility. The microspheres release Wnt3a for up to 9 days, with high-throughput sequencing revealing upregulation of HF regeneration genes like Ctnnb1 and Lef1, and activation of the Wnt signaling pathway, while hypoxia-related genes such as Hif-1ɑ are downregulated. Pathway enrichment analyses confirm the enrichment of HF regeneration pathways. In conclusion, the HME-based BHG microspheres effectively promote in vivo HF regeneration, offering a promising solution for hair loss treatment and regeneration.