Regenerative wound dressings for accelerating diabetic wound healing

项目摘要 仅在美国，糖尿病患者就超过3400万人。它是非创伤性下肢的主要原因 截肢，主要是由于慢性糖尿病伤口的发展。虽然已经探索了各种治疗方法 要治疗糖尿病伤口，有效的治疗仍然是一个挑战，因为目前的治疗方法不能有效地解决 糖尿病伤口愈合缓慢的主要内在原因，即慢性炎症、皮肤细胞功能异常(特别是 迁移)，以及延迟血管生成。为了解决这些原因，控制转化生长因子β信号是至关重要的。转化生长因子β1/p38 该途径与创面长期炎症和细胞迁移受损直接相关。同时， 转化生长因子β1/SMAD2/3途径是调控创伤愈合的关键细胞类型--肌成纤维细胞所必需的。因此， 在不影响转化生长因子β1/Smad2/3途径的情况下抑制转化生长因子β1/p38通路将同时解决3 导致糖尿病伤口加速愈合的关键内在原因。然而，这是任何人都无法实现的。 现有的方法。 在这个项目中，我们建议创造一种新的创面敷料来实现这一目标。它将由一种基于多肽的 转化生长因子β受体II(转化生长因子βRII)抑制剂心电和一种清除活性氧(ROS)水凝胶。心电图会 逐渐从水凝胶中释放出来，持续抑制转化生长因子β1/p38通路，从而促进细胞迁移 并减少组织炎症。内皮细胞迁移的增强将导致血管生成的加速。这个 水凝胶将清除糖尿病伤口中上调的ROS，进一步减轻炎症。值得注意的是，心电图将 不影响高糖条件下转化生长因子β1/Smad2/3信号转导通路。据我们所知，没有一个 现有的转化生长因子β受体抑制剂已显示出抑制转化生长因子β1/p38途径的能力，而不需要 下调转化生长因子β1/Smad2/3信号通路。 在我们的初步研究中，在年轻糖尿病患者的切除创面中应用单剂创面敷料 小鼠的伤口愈合速度显著加快。伤口在第14天完全闭合。相比之下，伤口的大小 对于水凝胶处理的和未处理的伤口，仍有53%。创面敷料也降低了ROS含量， 创面M_1巨噬细胞密度和p-p38表达增加，血管密度增加。这些初步结果 说明缓释心电创面敷料在糖尿病创面愈合中具有良好的应用前景。目前还没有测试是否会 创面敷料可以在衰老条件下促进糖尿病伤口的愈合，因为衰老本身会损害细胞迁移和修复。 血管生成。 我们推测，基于心电和清除ROS的水凝胶的创面敷料将显著 促进皮肤细胞迁移，刺激组织血管生成，减少组织炎症，导致 在年轻和老年条件下加速糖尿病伤口的愈合。目标1将检验假设 最佳的创面敷料将同时清除ROS，增加皮肤细胞迁移，促进内皮腔 在转化生长因子β和高糖条件下形成并抑制炎性细胞因子的分泌。AIM#2将测试 研发的创面敷料将促进青年和老年人糖尿病创面愈合的假说 条件。 这个项目是创新的，因为建议的伤口敷料将同时解决三个关键的内在 糖尿病创面愈合的障碍，通过差异调节转化生长因子β信号，即抑制转化生长因子β1/p38通路， 而不影响糖尿病创面愈合所必需的转化生长因子β1/Smad2/3通路。

Project Summary Diabetes affects more than 34 million people in the US alone. It is the leading cause of non-traumatic lower limb amputation, largely due to the development of chronic diabetic wounds. While various therapies have been explored to treat diabetic wounds, effective treatment remains a challenge as current therapies cannot efficiently address the key intrinsic causes of slow diabetic wound healing, i.e., chronic inflammation, abnormal skin cell functions (particularly migration), and delayed angiogenesis. To address these causes, it is crucial to control TGFβ signaling. TGFβ1/p38 pathway is directly associated with prolonged inflammation, and impaired cell migration in wounds. Meanwhile, TGFβ1/Smad2/3 pathway is required to regulate a critical cell type for wound healing, myofibroblasts. As such, inhibiting TGFβ1/p38 pathway without affecting TGFβ1/Smad2/3 pathway will simultaneously address the 3 key intrinsic causes, leading to accelerated diabetic wound healing. However, this cannot be achieved by any existing approaches. In this project, we propose to create a new wound dressing to achieve the goal. It will consist of a peptide-based TGFβ receptor II (TGFβRII) inhibitor ECG, and a reactive oxygen species (ROS)-scavenging hydrogel. The ECG will be gradually released from the hydrogel to continuously inhibit TGFβ1/p38 pathway so as to improve cell migration and decrease tissue inflammation. The enhanced endothelial cell migration will lead to accelerated angiogenesis. The hydrogel will scavenge upregulated ROS in the diabetic wounds to further decrease inflammation. Notably, ECG will not affect TGFβ1/Smad2/3 pathway under high glucose condition. To the best of our knowledge, none of the existing TGFβ receptor inhibitors have shown capability of inhibiting TGFβ1/p38 pathway without downregulating TGFβ1/Smad2/3 pathway. In our preliminary study, application of a single dose of wound dressing into excisional wounds in young diabetic mice significantly accelerated wound closure. The wounds completely closed at day 14. In contrast, the wound size remained >53% for the hydrogel-treated, and untreated wounds. The wound dressing also decreased ROS content, M1 macrophage density and p-p38 expression, and increased vessel density in the wounds. These preliminary results demonstrate that ECG-releasing wound dressing is promising for diabetic wound healing. It is yet to test whether the wound dressing can promote diabetic wound healing under aged condition, as aging itself impairs cell migration and angiogenesis. We hypothesize that the wound dressing based on ECG and ROS-scavenging hydrogel will significantly enhance skin cell migration, stimulate tissue angiogenesis, and decrease tissue inflammation, leading to accelerated healing of diabetic wounds under young and aged conditions. Aim #1 will test the hypothesis that optimal wound dressings will simultaneously scavenge ROS, increase skin cell migration, promote endothelial lumen formation, and attenuate inflammatory cytokine secretion under TGFβ and high glucose conditions. Aim #2 will test the hypothesis that the developed wound dressings will accelerate diabetic wound healing under young and aged conditions. This project is innovative because the proposed wound dressings will simultaneously address the 3 key intrinsic hurdles for diabetic wounds to heal, by differentially regulating TGFβ signaling, i.e., inhibiting TGFβ1/p38 pathway, while not affecting TGFβ1/Smad2/3 pathway that is essential for diabetic wound healing.