Yu Bingyang, Zhang Chao, Zhu Dongzhen, Su Yanlin, Guo Xu, Tian Feng, Li Jianjun, Li Zhao, Song Wei, Kong Yi, Du Jinpeng, Zhang Mengde, Huang Yuyan, Liang Liting, Liu Qinghua, Tan Yaxin, Kong Yue, Wang Yuzhen, Hou Linhao, Huang Sha
Department of Biomaterial, College of Life Sciences, Mudanjiang Medical University, Mudanjiang 157011, China.
Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, P. R. China.
ACS Appl Mater Interfaces. 2025 Jul 16;17(28):40143-40156. doi: 10.1021/acsami.5c07357. Epub 2025 Jul 2.
Severe skin injuries often lead to dysfunctional healing marked by fibrosis and loss of vascular, neural, and appendage structures. While mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) offer regenerative potential, their therapeutic efficacy is limited by poor delivery efficiency. Here, we present a bioengineered strategy combining ultrasound stimulation with a gelatin methacryloyl (GelMA) hydrogel-EV delivery platform to address these challenges. Ultrasound serves as a mechanobiological primer, enhancing MSC-EVs internalization via calcium-dependent cytoskeletal remodeling, thereby amplifying pro-regenerative pathways such as angiogenesis (such as VEGF), matrix modulation (such as TGF-β/Smad), and neural repair (such as NGF). In vitro, ultrasound (420 kHz, 5 V) synergized with MSC-EVs (60 μg/mL) significantly boosted fibroblast viability, migration, and secretory functions. In a murine full-thickness wound model, the ultrasound-activated GelMA-EV system accelerated re-epithelialization (90% closure by Day 14), induced robust neovascularization and neurogenesis, and facilitated unprecedented hair follicle regeneration. Mechanistic studies revealed ultrasound-driven calcium in-flow and actin depolymerization as key mediators of enhanced MSC-EVs uptake. This synergistic integration of physical and biochemical cues establishes a transformative paradigm for functional skin regeneration, bridging a critical gap in regenerative therapeutics.
严重的皮肤损伤往往会导致功能失调的愈合，其特征为纤维化以及血管、神经和附属结构的丧失。虽然间充质干细胞衍生的细胞外囊泡（MSC-EVs）具有再生潜力，但其治疗效果受到递送效率低下的限制。在此，我们提出一种生物工程策略，将超声刺激与甲基丙烯酰化明胶（GelMA）水凝胶-EV递送平台相结合，以应对这些挑战。超声作为一种机械生物学引发剂，通过钙依赖性细胞骨架重塑增强MSC-EVs的内化，从而放大促再生途径，如血管生成（如VEGF）、基质调节（如TGF-β/Smad）和神经修复（如NGF）。在体外，超声（420 kHz，5 V）与MSC-EVs（60 μg/mL）协同作用显著提高了成纤维细胞的活力、迁移和分泌功能。在小鼠全层伤口模型中，超声激活的GelMA-EV系统加速了上皮再形成（第14天闭合90%），诱导了强大的新生血管形成和神经发生，并促进了前所未有的毛囊再生。机制研究表明，超声驱动的钙内流和肌动蛋白解聚是增强MSC-EVs摄取的关键介质。这种物理和生化线索的协同整合为功能性皮肤再生建立了一种变革性模式，弥合了再生治疗中的一个关键差距。
