Acta Biomaterialia ( IF 9.4 ) Pub Date : 2022-10-27 , DOI: 10.1016/j.actbio.2022.10.038 Weidong Zhu 1 , Yunqing Dong 1 , Pengcheng Xu 2 , Qiao Pan 1 , Keyao Jia 1 , Panshi Jin 1 , Mou Zhou 3 , Yubing Xu 3 , Rui Guo 4 , Biao Cheng 1
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Diabetic wounds are difficult to heal because of persistent inflammation and limited angiogenesis. Resveratrol (RES) is an anti-inflammatory and antioxidant agent. Platelet-derived extracellular vesicles (PDEVs) are rich in growth factors and cytokines, which promote proliferation and angiogenesis. However, single drug treatment has limited efficacy and delivery efficiency. Bioengineering can improve the limited effect of single drugs by combining drugs and materials to obtain complementary or cooperative bioengineered drugs. In this study, gelatin methacrylate (GelMA) and silk fibroin glycidyl methacrylate (SFMA) were used to synthesize GelMA/SFMA composite hydrogels with suitable mechanical properties, swelling ratio and biodegradability. The composite hydrogel was used as a wound dressing for sustained drug release. RES was loaded into mesoporous silica nanoparticles (MSNs) to synthesize MSN-RES to enhance the release dynamic, and MSN-RES and PDEVs were combined with the composite hydrogels to form GelMA/SFMA/MSN-RES/PDEVs hydrogels. The GelMA/SFMA/MSN-RES/PDEVs had low cytotoxicity and good biocompatibility, inhibited macrophage iNOS expression, and promoted the tube formation by human umbilical vein endothelial cells (HUVECs) in vitro. In a diabetic mouse wound model, the GelMA/SFMA/MSN-RES/PDEVs hydrogels decreased the expression of pro-inflammatory factors TNF-α and iNOS, increased the expression of anti-inflammatory factors TGF-β1 and Arg-1, promoted angiogenesis, and accelerated wound healing. Interestingly, the GelMA/SFMA/MSN-RES/PDEVs hydrogels promoted the expression of extracellular purinergic signaling pathway-related CD73 and adenosine 2A receptor (A2A-R). Therefore, the GelMA/SFMA/MSN-RES/PDEVs hydrogels could be used as wound dressings to regulate the inflammation and angiogenesis of diabetic wounds and accelerate wound healing.
Statement of significance
Drugs often fail to function because of a continuous oxidative stress microenvironment and inflammation. Here, a GelMA/SFMA hydrogel, with enhanced mechanical properties and liquid absorption ability, is proposed for sustained release of drugs. In addition to carrying platelet-derived extracellular vesicles (PDEVs) with pro-angiogenic effects, the hydrogels were also loaded with nanoparticle-encapsulated resveratrol with anti-inflammatory activities, aiming to reduce inflammation and oxidative stress in the wound microenvironment, such that the wound could receive proliferative repair signals to achieve sequential treatment and heal quickly. We also experimentally predicted that the regulatory mechanism of the GelMA/SFMA/MSN-RES/PDEVs in wound healing might be related to the extracellular purinergic signaling pathway.
中文翻译：
含有载有白藜芦醇的纳米颗粒和血小板衍生的细胞外囊泡的复合水凝胶可促进糖尿病小鼠的伤口愈合
由于持续的炎症和有限的血管生成，糖尿病伤口很难愈合。白藜芦醇 (RES) 是一种抗炎剂和抗氧化剂。血小板衍生的细胞外囊泡 (PDEV) 富含生长因子和细胞因子，可促进增殖和血管生成。然而，单一药物治疗的疗效和递送效率有限。生物工程可以通过药物与材料的结合，获得互补或协同的生物工程药物，提高单一药物的有限作用。本研究使用甲基丙烯酸明胶 (GelMA) 和丝素蛋白甲基丙烯酸缩水甘油酯 (SFMA) 合成具有合适机械性能、溶胀比和生物降解性的 GelMA/SFMA 复合水凝胶。复合水凝胶用作伤口敷料以持续释放药物。将 RES 负载到介孔二氧化硅纳米粒子 (MSN) 中以合成 MSN-RES 以增强释放动力学，并将 MSN-RES 和 PDEV 与复合水凝胶结合形成 GelMA/SFMA/MSN-RES/PDEV 水凝胶。GelMA/SFMA/MSN-RES/PDEVs 具有低细胞毒性和良好的生物相容性，抑制巨噬细胞 iNOS 表达，促进人脐静脉内皮细胞 (HUVECs) 的管形成体外。在糖尿病小鼠伤口模型中，GelMA/SFMA/MSN-RES/PDEVs 水凝胶降低促炎因子 TNF-α 和 iNOS 的表达，增加抗炎因子 TGF-β1 和 Arg-1 的表达，促进血管生成, 并加速伤口愈合。有趣的是，GelMA/SFMA/MSN-RES/PDEVs 水凝胶促进了细胞外嘌呤能信号通路相关的 CD73 和腺苷 2A 受体 (A2A-R) 的表达。因此，GelMA/SFMA/MSN-RES/PDEVs 水凝胶可用作伤口敷料，以调节糖尿病伤口的炎症和血管生成，加速伤口愈合。
重要性声明
由于持续的氧化应激微环境和炎症，药物通常无法发挥作用。在这里，提出了一种具有增强的机械性能和液体吸收能力的 GelMA/SFMA 水凝胶用于药物的缓释。除了携带具有促血管生成作用的血小板衍生细胞外囊泡（PDEV）外，水凝胶还装载了具有抗炎活性的纳米颗粒包裹的白藜芦醇，旨在减少伤口微环境中的炎症和氧化应激，从而使伤口可接收增殖修复信号，实现序贯治疗，快速愈合。我们还通过实验预测，GelMA/SFMA/MSN-RES/PDEVs 在伤口愈合中的调控机制可能与细胞外嘌呤能信号通路有关。
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