Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taiwan.
Department of Materials Science and Engineering, National Tsing Hua University, Hsinchu, Taiwan.
Biomaterials. 2025 Mar;314:122848. doi: 10.1016/j.biomaterials.2024.122848. Epub 2024 Sep 24.
Chronic wound healing often encounters challenges characterized by prolonged inflammation and impaired angiogenesis. While the immune response plays a pivotal role in orchestrating the intricate process of wound healing, excessive inflammation can hinder tissue repair. In this study, a bilayer alginate hydrogel system encapsulating polyelectrolyte complex nanoparticles (PCNs) loaded with anti-inflammatory cytokines and angiogenic growth factors is developed to address the challenges of chronic wound healing. The alginate hydrogel is designed using two distinct crosslinking methods to achieve differential degradation, thereby enabling precise spatial and temporal controlled release of PCNs. Initially, interleukin-10 (IL-10) is released to mitigate inflammation, while unsaturated PCNs bind and remove accumulated pro-inflammatory cytokines at the wound site. Subsequently, angiogenic growth factors, including vascular endothelial growth factor and platelet-derived growth factor, are released to promote vascularization and vessel maturation. Our results demonstrate that the bilayer hydrogel exhibits distinct degradation kinetics between the two layers, facilitating the staged release of multiple signaling molecules. In vitro experiments reveal that IL-10 can activate the Jak1/STAT3 pathway, thereby suppressing pro-inflammatory cytokines and chemokines while down-regulating inflammation-related genes. In vivo studies demonstrate that application of the hydrogel in chronic wounds using diabetic murine model promotes healing by positively modulating multiple integral reparative mechanisms. These include reducing inflammation, promoting macrophage polarization towards a pro-regenerative phenotype, enhancing keratinocyte migration, stimulating angiogenesis, and expediting wound closure. In conclusion, our hydrogel system effectively mitigates inflammatory responses and provides essential physiological cues by inducing a synergistic angiogenic effect, thus offering a promising approach for the treatment of chronic wounds.
慢性伤口愈合常常面临各种挑战，其特征表现为炎症持续时间长和血管生成受损。尽管免疫反应在协调伤口愈合这一复杂过程中起着关键作用，但过度的炎症反应会阻碍组织修复。在这项研究中，开发了一种双层海藻酸钠水凝胶系统，该系统包埋了载有抗炎细胞因子和血管生成生长因子的聚电解质复合物纳米颗粒（PCNs），以应对慢性伤口愈合的挑战。海藻酸钠水凝胶采用两种不同的交联方法设计，以实现差异化降解，从而能够精确地控制 PCNs 的时空释放。最初，白细胞介素-10（IL-10）被释放以减轻炎症，而不饱和的 PCNs 在伤口部位结合并去除积累的促炎细胞因子。随后，血管生成生长因子，包括血管内皮生长因子和血小板衍生生长因子，被释放以促进血管生成和血管成熟。我们的研究结果表明，双层水凝胶在两层之间表现出不同的降解动力学，有利于多种信号分子的阶段性释放。体外实验表明，IL-10 可以激活 Jak1/STAT3 通路，从而抑制促炎细胞因子和趋化因子，同时下调与炎症相关的基因。体内研究表明，在糖尿病小鼠模型的慢性伤口中应用水凝胶可以通过积极调节多种完整修复机制来促进愈合。这些机制包括减轻炎症、促进巨噬细胞向促再生表型极化、增强角质形成细胞迁移、刺激血管生成和加速伤口闭合。总之，我们的水凝胶系统通过诱导协同的血管生成效应，有效地减轻炎症反应并提供必要的生理线索，为慢性伤口的治疗提供了一种有前途的方法。
