PDF(Pubmed)
Abstract：
Failed skin wound healing, through delayed wound healing or wound dehiscence, is a global public health issue that imposes significant burdens on individuals and society. Although the application of growth factor is an effective method to improve the pace and quality of wound healing, the clinically approved factors are limited. Parathyroid hormone (PTH) demonstrates promising results in wound healing by promoting collagen deposition and cell migration, but its application is limited by potentially inhibitory effects when administered continuously and locally. Through partially replacing and repeating the amino acid domains of PTH(1-34), we previously designed a novel PTH analog, PTH(3-34)(29-34) or MY-1, and found that it avoided the inhibitory effects of PTH while retaining its positive functions. To evaluate its role in wound healing, MY-1 was encapsulated in liposomes and incorporated into the methacryloyl gelatin (GelMA) hydrogel, through which an injectable nanocomposite hydrogel (GelMA-MY@Lipo, or GML) was developed. In vitro studies revealed that the GML had similar properties in terms of the appearance, microstructure, functional groups, swelling, and degradation capacities as the GelMA hydrogel. In vitro drug release testing showed a relatively more sustainable release of MY-1, which was still detectable in vivo 9 days post-application. When the GML was topically applied to the wound areas of rat models, wound closure as well as tensile strength were improved. Further studies showed that the effects of GML on wound repair and tensile strength were closely related to the promotion of fibroblast migration to the wound area through the controlled release of MY-1. Mechanically, MY-1 enhanced fibroblast migration by activating PI3K/AKT signaling and its downstream molecule, Rac1, by which it increased fibroblast aggregation in the early stage and resulting in denser collagen deposition at a later time. Overall, these findings demonstrated that the nanocomposite hydrogel system promoted skin wound healing and increased tensile strength, thus offering new potential in the treatment of wound healing.
摘要：
皮肤伤口愈合失败，通过延迟伤口愈合或伤口开裂，是一个全球性的公共卫生问题，给个人和社会带来了巨大的负担。虽然应用生长因子是提高伤口愈合速度和质量的有效方法,临床批准的因素是有限的。甲状旁腺激素（PTH）通过促进胶原蛋白沉积和细胞迁移在伤口愈合中显示出有希望的结果，但是当连续和局部给药时，其应用受到潜在抑制作用的限制。通过部分替换和重复PTH（1-34）的氨基酸结构域，我们之前设计了一个新的PTH类似物，PTH（3-34）（29-34）或MY-1，并发现它避免了PTH的抑制作用，同时保留了其积极功能。评估其在伤口愈合中的作用，将MY-1封装在脂质体中并掺入甲基丙烯酰明胶（GelMA）水凝胶中，可注射纳米复合水凝胶(GelMA-MY@Lipo，或GML)被开发。体外研究表明，GML在外观方面具有相似的特性，微观结构，功能组，肿胀,和降解能力作为GelMA水凝胶。体外药物释放测试显示MY-1的相对更可持续的释放,其在施用后9天仍可在体内检测到。当GML局部应用于大鼠模型的伤口区域时，伤口闭合以及拉伸强度得到改善。进一步研究表明,GML对创面修复和抗张强度的影响与通过MY-1控释促进成纤维细胞向创面区域迁移密切相关。机械上,MY-1通过激活PI3K/AKT信号及其下游分子增强成纤维细胞迁移,Rac1，通过它在早期增加成纤维细胞的聚集，并在以后的时间导致更致密的胶原蛋白沉积。总的来说,这些发现表明，纳米复合水凝胶系统促进皮肤伤口愈合和增加拉伸强度，从而为伤口愈合的治疗提供了新的潜力。
