三维重建功能性皮肤治疗重大皮肤损伤的关键技术与临床研究

皮肤是人体最大的器官，重大皮肤损伤严重危害人类健康，但目前缺乏有效治疗方法。支架材料复合干细胞实现原位再生皮肤类器官产品是重大皮肤损伤理想的治疗手段，而现有产品存在干细胞存活率低、临床疗效欠佳等问题。本项目研究目标：通过三维重建功能性皮肤，实现重大损伤皮肤组织的结构性再生和功能性修复。项目开展了支架材料复合干细胞促进大鼠皮肤缺损创面愈合的实验研究，建立了大动物全层创面缺损模型，探索了无瘢痕愈合机制，进行了皮肤创面高质量愈合研究，实施了汗腺、毛发等附属器再生相关研究。通过课题的实施，形成以下成果:（1）获得1种干细胞友好性生物载体材料；（2）制备即用型人工皮肤并申报国家三类医疗器械；（3）基于干细胞结合生物载体材料的原位皮肤再生技术，构建重大皮肤缺损无疤痕高效愈合体系，成功再生毛发、汗腺等附属器官，实现皮肤结构性修复与功能性再生;（4）基于生物载体材料-外泌体复合体实现皮肤损伤高效愈合，形成皮肤创面无细胞替代治疗新方案；（6）国际上首次构建了小鼠汗腺的单细胞RNA+ATAC组学数据库，绘制了皮肤汗腺发育图谱，发现汗腺发育调控关键转录因子，构建高分化汗腺类器官并成功移植体内实现汗腺原位再生；（7）阐明干细胞无疤痕愈合机制；（8）实现超声调控组织干细胞的创面高效愈合；（8）提出超声促进毛发再生新理论；（9）核心产品抢救2万多例皮肤缺损患者，该成果具有重要的临床应用意义。

Skin is the largest organ of the human body. Severe skin injuries severely endanger human health, yet effective treatment options remain scarce currently. The in situ regenerated skin organoid product prepared by combining scaffold materials and stem cells is an ideal therapeutic approach for severe skin injuries, while existing products suffer from issues such as low survival rate of transplanted stem cells and unsatisfactory clinical outcomes. The research objectives of this project are: to achieve structural regeneration and functional repair of severely injured skin tissues through three-dimensional (3D) reconstruction of functional skin. The project conducted experimental studies on scaffold materials combined with stem cells to promote wound healing in rat skin defects; established full-thickness skin wound defect models in large animals; explored the mechanism of scar-free healing; carried out studies on high-quality healing of skin wounds; and implemented research related to the regeneration of skin appendages such as sweat glands and hair follicles. Through the implementation of this project, the following achievements have been obtained:
(1) One stem cell-friendly bio-carrier material was developed;
(2) A ready-to-use artificial skin was prepared, and a national Class III medical device application was submitted;
(3) Based on the in situ skin regeneration technology combining stem cells and bio-carrier materials, an efficient scar-free healing system for severe skin defects was constructed. Skin appendages such as hair follicles and sweat glands were successfully regenerated, achieving structural repair and functional regeneration of skin;
(4) Efficient healing of skin injuries was achieved using bio-carrier material-exosome complexes, and a novel cell-free alternative therapeutic regimen for skin wounds was established;
(6) For the first time internationally, a single-cell RNA and ATAC omics database of mouse sweat glands was constructed, a developmental atlas of skin sweat glands was mapped, key transcription factors regulating sweat gland development were discovered, and highly differentiated sweat gland organoids were constructed and successfully transplanted in vivo to achieve in situ regeneration of sweat glands;
(7) The mechanism of scar-free healing mediated by stem cells was elucidated;
(8) Efficient wound healing was realized by ultrasound-mediated regulation of tissue stem cells;
(8) A novel theory of ultrasound-promoting hair regeneration was proposed;
(9) The core products have saved more than 20,000 patients with skin defects, and this achievement has important clinical application significance.