Acta Biomaterialia ( IF 9.4 ) Pub Date : 2023-10-11 , DOI: 10.1016/j.actbio.2023.10.011 Seohui Lee 1 , Sang Min Lee 1 , Sang Hyun Lee 1 , Woong-Ku Choi 1 , Sung-Jun Park 2 , Do Yeon Kim 1 , Sae Woong Oh 1 , Jieun Oh 1 , Jae Youl Cho 1 , Jongsung Lee 1 , Pham Ngoc Chien 3 , Sun Young Nam 3 , Chan Yeong Heo 4 , Yoon-Sik Lee 2 , Eun-A Kwak 5 , Woo-Jae Chung 6
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A versatile hydrogel was developed for enhancing bioactive wound healing by introducing the amphiphilic GHK peptide (GHK-C16) into a photo-crosslinkable tyramine-modified hyaluronic acid (HA-Ty). GHK-C16 self-assembled into GHK nanofibers (GHK NF) in HA-Ty solution, which underwent in situ gelation after the wound area was filled with precursor solution. Blue light irradiation (460–490 nm), with riboflavin phosphate as a photoinitiator, was used to trigger crosslinking, which enhanced the stability of the highly degradable hyaluronic acid and enabled sustained release of the nanostructured GHK derivatives. The hydrogels provided a microenvironment that promoted the proliferation of dermal fibroblasts and the activation of cytokines, leading to reduced inflammation and increased collagen expression during wound healing. The complexation of Cu2+ into GHK nanofibers resulted in superior wound healing capabilities compared with non-lipidated GHK peptide with a comparable level of growth factor (EGF). Additionally, nanostructured Cu-GHK improved angiogenesis through vascular endothelial growth factor (VEGF) activation, which exerted a synergistic therapeutic effect. Furthermore, in vivo wound healing experiments revealed that the Cu-GHK NF/HA-Ty hydrogel accelerated wound healing through densely packed remodeled collagen in the dermis and promoting the growth of denser fibroblasts. HA-Ty hydrogels incorporating GHK NF also possessed improved mechanical properties and a faster wound healing rate, making them suitable for advanced bioactive wound healing applications.
Statement of significance
By combining photo-crosslinkable tyramine-modified hyaluronic acid with self-assembled Cu-GHK-C16 peptide nanofibers (Cu-GHK NF), the Cu-GHK NF/HA-Ty hydrogel offers remarkable advantages over conventional non-structured Cu-GHK for wound healing. It enhances cell proliferation, migration, and collagen remodeling—critical factors in tissue regeneration. The incorporation of GHK nanofibers complexed with copper ions imparts potent anti-inflammatory effects, promoting cytokine activation and angiogenesis during wound healing. The Cu-GHK NF/hydrogel's unique properties, including in situ photo-crosslinking, ensure high customization and potency in tissue regeneration, providing a cost-effective alternative to growth factors. In vivo experiments further validate its efficacy, demonstrating significant wound closure, collagen remodeling, and increased fibroblast density. Overall, the Cu-GHK NF/HA-Ty hydrogel represents an advanced therapeutic option for wound healing applications.
中文翻译：
嵌入 GHK 肽纳米纤维的原位光交联透明质酸水凝胶，用于生物活性伤口愈合
通过将两亲性 GHK 肽 (GHK-C16) 引入可光交联的酪胺修饰透明质酸 (HA-Ty) 中，开发了一种多功能水凝胶，用于增强生物活性伤口愈合。 GHK-C16在HA-Ty溶液中自组装成GHK纳米纤维（GHK NF），在伤口区域充满前体溶液后发生原位凝胶化。采用蓝光照射（460-490 nm），以磷酸核黄素作为光引发剂，引发交联，从而增强了高度可降解的透明质酸的稳定性，并使纳米结构的 GHK 衍生物持续释放。水凝胶提供了促进真皮成纤维细胞增殖和细胞因子激活的微环境，从而在伤口愈合过程中减少炎症并增加胶原蛋白表达。与具有相当水平的生长因子 (EGF) 的非脂化 GHK 肽相比，Cu 2+络合到 GHK 纳米纤维中产生了优异的伤口愈合能力。此外，纳米结构的Cu-GHK通过激活血管内皮生长因子（VEGF）改善血管生成，从而发挥协同治疗作用。此外，体内伤口愈合实验表明，Cu-GHK NF/HA-Ty 水凝胶通过真皮中密集的重塑胶原蛋白加速伤口愈合，并促进更致密的成纤维细胞的生长。含有 GHK NF 的 HA-Ty 水凝胶还具有改进的机械性能和更快的伤口愈合速度，使其适合先进的生物活性伤口愈合应用。
重要性声明
通过将可光交联的酪胺修饰透明质酸与自组装的 Cu-GHK-C16 肽纳米纤维（Cu-GHK NF）相结合，Cu-GHK NF/HA-Ty 水凝胶比传统的非结构化 Cu-GHK 具有显着的优势。伤口愈合。它增强细胞增殖、迁移和胶原蛋白重塑——组织再生的关键因素。与铜离子复合的 GHK 纳米纤维的加入具有强大的抗炎作用，在伤口愈合过程中促进细胞因子激活和血管生成。 Cu-GHK NF/水凝胶的独特特性（包括原位光交联）确保了组织再生的高度定制和效力，为生长因子提供了一种经济高效的替代品。体内实验进一步验证了其功效，证明了显着的伤口闭合、胶原重塑和成纤维细胞密度增加。总体而言，Cu-GHK NF/HA-Ty 水凝胶代表了伤口愈合应用的先进治疗选择。
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