Diabetic ischemic wound treatment remains a critical clinical challenge. Neovascularization plays a significant role in wound healing during all stages of the tissue repair process. Strategies that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds, particularly diabetic wounds in highly ischemic conditions. We previously identified a cyclic peptide LXW7 that specifically binds to integrin αvβ3 on endothelial progenitor cells (EPCs) and endothelial cells (ECs), activates vascular endothelial growth factor (VEGF) receptors, and promotes EC growth and maturation. In this study, we designed and synthesized a multi-functional pro-angiogenic molecule by grafting LXW7 and collagen-binding peptides (SILY) to a dermatan sulfate (DS) glycosaminoglycan backbone, named LXW7-DS-SILY, and further employed this multi-functional molecule to functionalize collagen-based extracellular matrix (ECM) scaffolds. We confirmed that LXW7-DS-SILY modification significantly promoted EPC attachment and growth on the ECM scaffolds in vitro and supported EPC survival in vivo in the ischemic environment. When applied in an established Zucker Diabetic Fatty (ZDF) rat ischemic skin flap model, LXW7-DS-SILY-functionalized ECM scaffolds loaded with EPCs significantly improved wound healing, enhanced neovascularization and modulated collagen fibrillogenesis in the ischemic environment. Altogether, this study provides a promising novel treatment to accelerate diabetic ischemic wound healing, thereby reducing limb amputation and mortality of diabetic patients.

糖尿病缺血性伤口治疗仍然是一个关键的临床挑战。新血管形成在组织修复过程的各个阶段的伤口愈合中发挥着重要作用。增强血管生成和新血管形成以及改善缺血病理学的策略可以促进不良伤口的愈合，特别是高度缺血条件下的糖尿病伤口。我们之前发现了一种环肽LXW7，它与内皮祖细胞（EPC）和内皮细胞（EC）上的整合素αvβ3特异性结合，激活血管内皮生长因子（VEGF）受体，并促进EC生长和成熟。在本研究中，我们通过将LXW7和胶原结合肽（SILY）接枝到硫酸皮肤素（DS）糖胺聚糖主链上，设计并合成了一种多功能促血管生成分子，命名为LXW7-DS-SILY，并进一步利用了这种多功能促血管生成分子。功能分子使基于胶原蛋白的细胞外基质（ECM）支架功能化。我们证实，LXW7-DS-SILY 修饰显着促进体外ECM 支架上的 EPC 附着和生长，并支持 EPC在缺血环境中的体内存活。当应用于已建立的 Zucker 糖尿病脂肪 (ZDF) 大鼠缺血皮瓣模型时，装载 EPC 的 LXW7-DS-SILY 功能化 ECM 支架可显着改善缺血环境中的伤口愈合、增强新血管形成并调节胶原纤维生成。总而言之，这项研究提供了一种有前途的新疗法，可以加速糖尿病缺血性伤口愈合，从而减少糖尿病患者的截肢和死亡率。