Abstract：
Chronic wounds are often caused by diabetes and present a challenging clinical problem due to vascular problems leading to ischemia. This inhibits proper wound healing by delaying inflammatory responses and angiogenesis. To address this problem, we have developed injectable particle-loaded hydrogels which sequentially release Granulocyte-macrophage- colony-stimulating-factor (GM-CSF) and Vascular endothelial growth factor (VEGF) encapsulated in polycaprolactone-lecithin-geleol mono-diglyceride hybrid particles. GM-CSF promotes inflammation, while VEGF facilitates angiogenesis. The hybrid particles (200-1000 nm) designed within the scope of the study can encapsulate the model proteins Bovine Serum Albumin 65 ± 5 % and Lysozyme 77 ± 10 % and can release stably for 21 days. In vivo tests and histological findings revealed that in the hydrogels containing GM-CSF/VEGF-loaded hybrid particles, wound depth decreased, inflammation phase increased, and fibrotic scar tissue decreased, while mature granulation tissue was formed on day 10. These findings confirm that the hybrid particles first initiate the inflammation phase by delivering GM-CSF, followed by VEGF, increasing the number of vascularization and thus increasing the healing rate of wounds. We emphasize the importance of multi-component and sequential release in wound healing and propose a unifying therapeutic strategy to sequentially deliver ligands targeting wound healing stages, which is very important in the treatment of the diabetic wounds.
摘要：
慢性伤口通常由糖尿病引起,并且由于导致局部缺血的血管问题而呈现具有挑战性的临床问题。这通过延迟炎症反应和血管生成来抑制适当的伤口愈合。为了解决这个问题,我们开发了可注射的颗粒载水凝胶,该凝胶可依次释放包封在聚己内酯-卵磷脂-geleol甘油单酯杂化颗粒中的粒细胞-巨噬细胞-集落刺激因子(GM-CSF)和血管内皮生长因子(VEGF).GM-CSF促进炎症,而VEGF促进血管生成。在研究范围内设计的杂化颗粒(200-1000nm)可以包封模型蛋白牛血清白蛋白65±5%和溶菌酶77±10%,并且可以稳定释放21天。体内试验和组织学发现表明，在含有GM-CSF/VEGF的混合颗粒的水凝胶中，伤口深度减少，炎症阶段增加，纤维化瘢痕组织减少，而成熟的肉芽组织在第10天形成。这些发现证实了混合颗粒首先通过递送GM-CSF开始炎症阶段，其次是VEGF,增加血管形成的数量，从而提高伤口的愈合率。我们强调多组分和顺序释放在伤口愈合中的重要性，并提出了一种统一的治疗策略，以顺序递送靶向伤口愈合阶段的配体。这在糖尿病伤口的治疗中非常重要。
