Regenerative wound dressings for accelerating diabetic wound healing

项目摘要 仅在美国，糖尿病就影响着3400多万人。它是非创伤性下肢瘫痪的主要原因 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疗法 为了治疗糖尿病伤口，有效的治疗仍然是一个挑战，因为目前的疗法不能有效地解决糖尿病伤口的问题。 糖尿病伤口愈合缓慢的关键内在原因，即，慢性炎症、皮肤细胞功能异常（特别是 迁移）和延迟的血管生成。为了解决这些原因，控制TGFβ信号传导至关重要。TGFβ1/p38 该途径与伤口中的长期炎症和受损的细胞迁移直接相关。在此期间， TGFβ1/Smad 2/3通路是调节伤口愈合的关键细胞类型--肌成纤维细胞所必需的。因此，在本发明中， 抑制TGFβ1/p38通路而不影响TGFβ1/Smad 2/3通路将同时解决3个问题。 关键的内在原因，导致糖尿病伤口加速愈合。然而，这是任何人都无法做到的。 现有的方法。 在本项目中，我们建议创建一种新的伤口敷料来实现这一目标。它将由基于肽的 TGFβ受体II（TGFβRII）抑制剂ECG和活性氧（ROS）清除水凝胶。ECG将 从水凝胶中逐渐释放，持续抑制TGFβ1/p38通路，从而改善细胞迁移 减少组织炎症增强的内皮细胞迁移将导致加速的血管生成。的 水凝胶将上调糖尿病伤口中的ROS以进一步减少炎症。值得注意的是，ECG将 高糖对TGFβ1/Smad 2/3通路无影响。据我们所知， 现有的TGFβ受体抑制剂显示出抑制TGFβ1/p38途径的能力， 下调TGFβ1/Smad 2/3通路。 在我们的初步研究中，将单剂量伤口敷料应用于年轻糖尿病患者的切除伤口， 小鼠显著加速伤口闭合。伤口在第14天完全闭合。相比之下，伤口大小 对于水凝胶处理的伤口和未处理的伤口保持>53%。伤口敷料还降低了ROS含量， M1巨噬细胞密度和p-p38表达，并增加伤口中的血管密度。这些初步结果 证明ECG释放伤口敷料有望用于糖尿病伤口愈合。还有待检验的是， 伤口敷料可以促进糖尿病伤口在老化条件下的愈合，因为老化本身会损害细胞迁移， 血管生成 我们假设基于ECG和ROS清除水凝胶的伤口敷料将显著地 增强皮肤细胞迁移，刺激组织血管生成，并减少组织炎症，导致 加速年轻和老年条件下糖尿病伤口的愈合。目标1将检验假设， 最佳的伤口敷料将同时抑制ROS，增加皮肤细胞迁移，促进内皮管腔 形成，并减弱TGFβ和高糖条件下的炎性细胞因子分泌。目标#2将测试 假设开发的伤口敷料将加速年轻人和老年人的糖尿病伤口愈合 条件 该项目具有创新性，因为申报的伤口敷料将同时解决3个关键的内在问题 糖尿病伤口愈合的障碍，通过差异调节TGFβ信号传导，即，抑制TGFβ1/p38通路， 而不影响糖尿病创面愈合所必需的TGFβ1/Smad 2/3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.