Hydrogel Microneedle Patches Loaded with Stem Cell Mitochondria-Enriched Microvesicles Boost the Chronic Wound Healing,ACS Nano

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Hydrogel Microneedle Patches Loaded with Stem Cell Mitochondria-Enriched Microvesicles Boost the Chronic Wound Healing
ACS Nano ( IF 15.8 ) Pub Date : 2024-09-05 , DOI: 10.1021/acsnano.4c06921
Wen-De Yao _{1,

2,

3} , Jun-Nian Zhou ₃ , Chao Tang ₃ , Ju-Lei Zhang _{2,

3} , Zhao-Yang Chen _{2,

3} , Yan Li _{2,

3} , Xiao-Jing Gong _{2,

3} , Ming-Yi Qu ₃ , Quan Zeng ₃ , Ya-Li Jia ₃ , Hai-Yang Wang ₃ , Tao Fan ₃ , Jing Ren ₂ , Ling-Li Guo ₂ , Jia-Fei Xi ₃ , Xue-Tao Pei ₃ , Yan Han _{1,

2} , Wen Yue ₃

Affiliation

Rescuing or compensating mitochondrial function represents a promising therapeutic avenue for radiation-induced chronic wounds. Adult stem cell efficacies are primarily dependent on the paracrine secretion of mitochondria-containing extracellular vesicles (EVs). However, effective therapeutic strategies addressing the quantity of mitochondria and mitochondria-delivery system are lacking. Thus, in this study, we aimed to design an effective hydrogel microneedle patch (MNP) loaded with stem cell-derived mitochondria-rich EVs to gradually release and deliver mitochondria into the wound tissues and boost wound healing. We, first, used metformin to enhance mitochondrial biogenesis and thereby increasing the secretion of mitochondria-containing EVs (termed “Met-EVs”) in adipose-derived stem cells. To verify the therapeutic effects of Met-EVs, we established an in vitro and an in vivo model of X-ray-induced mitochondrial dysfunction. The Met-EVs ameliorated the mitochondrial dysfunction by rescuing mitochondrial membrane potential, increasing adenosine 5′-triphosphate levels, and decreasing reactive oxygen species production by transferring active mitochondria. To sustain the release of EVs into damaged tissues, we constructed a Met-EVs@Decellularized Adipose Matrix (DAM)/Hyaluronic Acid Methacrylic Acid (HAMA)-MNP. Met-EVs@DAM/HAMA-MNP can load and gradually release Met-EVs and their contained mitochondria into wound tissues to alleviate mitochondrial dysfunction. Moreover, we found Met-EVs@DAM/HAMA-MNP can markedly promote macrophage polarization toward the M2 subtype with anti-inflammatory and regenerative functions, which can, in turn, enhance the healing process in mice with skin wounds combined radiation injuries. Collectively, we successfully fabricated a delivery system for EVs, Met-EVs@DAM/HAMA-MNP, to effectively deliver stem cell-derived mitochondria-rich EVs. The effectiveness of this system has been demonstrated, holding great potential for chronic wound treatments in clinic.

中文翻译：

水凝胶微针贴片载有富含干细胞线粒体的微泡，可促进慢性伤口愈合

挽救或补偿线粒体功能是治疗辐射引起的慢性伤口的一种有前途的治疗途径。成体干细胞的功效主要取决于含有线粒体的细胞外囊泡（EV）的旁分泌。然而，缺乏针对线粒体数量和线粒体递送系统的有效治疗策略。因此，在这项研究中，我们的目标是设计一种有效的水凝胶微针贴片（MNP），装载干细胞衍生的富含线粒体的EV，逐渐释放线粒体并将其输送到伤口组织中，促进伤口愈合。首先，我们使用二甲双胍增强线粒体生物合成，从而增加脂肪干细胞中含有线粒体的 EV（称为“Met-EV”）的分泌。为了验证 Met-EV 的治疗效果，我们建立了 X 射线诱导的线粒体功能障碍的体外和体内模型。 Met-EV 通过挽救线粒体膜电位、增加 5'-三磷酸腺苷水平以及通过转移活性线粒体来减少活性氧的产生来改善线粒体功能障碍。为了维持 EV 向受损组织的释放，我们构建了 Met-EVs@脱细胞脂肪基质 (DAM)/透明质酸甲基丙烯酸 (HAMA)-MNP。 Met-EVs@DAM/HAMA-MNP 可以加载并逐渐释放 Met-EVs 及其所含线粒体到伤口组织中，以缓解线粒体功能障碍。此外，我们发现Met-EVs@DAM/HAMA-MNP可以显着促进巨噬细胞向具有抗炎和再生功能的M2亚型极化，从而增强皮肤伤口合并放射损伤小鼠的愈合过程。总的来说，我们成功地制造了电动汽车的输送系统，Met-EVs@DAM/HAMA-MNP，以有效地输送干细胞衍生的富含线粒体的电动汽车。该系统的有效性已得到证实，在临床慢性伤口治疗方面具有巨大潜力。

更新日期：2024-09-05

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