Regenerative wound dressings for accelerating diabetic wound healing

加速糖尿病伤口愈合的再生伤口敷料

基本信息

批准号：
10684878
负责人：
Jianjun Guan
金额：
$ 46.54万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-16 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684878
关键词：
Acceleration Address Affect Affinity Aging Amputation Attenuated Binding Biodistribution Cell Survival Cell physiology Cell secretion Chronic Clinical Collagen Complications of Diabetes Mellitus Development Diabetes Mellitus Diabetic mouse Dose Endothelial Cells Endothelium Excision Fibroblasts Generations Glucose Goals Hydrogels Impairment In Vitro Inflammation Inflammatory Injectable Lower Extremity Macrophage Myofibroblast Pathway interactions Peptides Persons Principal Investigator Reactive Oxygen Species Research Signal Transduction Skin Skin Abnormalities Splint Device Sterile coverings Tensile Strength Testing Tissues Topical application Toxic effect Transforming Growth Factor beta aged angiogenesis biomaterial compatibility cell motility cell type chronic wound cytokine density diabetic ulcer diabetic wound healing effective therapy healing improved in vivo inhibitor innovation keratinocyte limb amputation migration monocyte p38 Mitogen Activated Protein Kinase preservation programs receptor regenerative wound wound closure wound dressing wound healing

项目摘要

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.

项目概要仅在美国，糖尿病就影响了超过 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，同时已经探索了各种治疗方法。对于治疗糖尿病伤口，有效的治疗仍然是一个挑战，因为目前的疗法无法有效解决这一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（特别是为了解决这些原因，控制 TGFβ1/p38 信号至关重要。同时，该途径与长期炎症和伤口细胞迁移受损直接相关。 TGFβ1/Smad2/3 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。抑制 TGFβ1/p38 通路而不影响 TGFβ1/Smad2/3 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，我们建议创建一种新的伤口敷料来实现这一目标，它将由基于肽的物质组成。 TGFβ 受体 II (TGFβRII) 抑制剂 ECG 和活性氧 (ROS) 清除水凝胶 ECG 将。逐渐从水凝胶中释放，持续抑制TGFβ1/p38通路，从而改善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加速。水凝胶将清除糖尿病伤口中上调的活性氧，进一步减少炎症，值得注意的是，心电图会。据我们所知，在高葡萄糖条件下不影响 TGFβ1/Smad2/3 通路。现有的 TGFβ 受体抑制剂已显示出抑制 TGFβ1/p38 通路的能力，且无需下调 TGFβ1/Smad2/3 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的伤口愈合速度显着加快，第 14 天伤口完全闭合。相反，伤口尺寸变小。经水凝胶处理和未经处理的伤口仍保持 >53%。伤口敷料还降低了 ROS 含量。 M1巨噬细胞密度和p-p38表达，以及伤口中血管密度的增加这些初步结果。表明心电图释放伤口敷料有望促进糖尿病伤口愈合，但尚待测试。伤口敷料可以促进老年情况下的糖尿病伤口愈合，因为衰老本身会损害细胞迁移和血管生成。我们追求基于心电图和ROS清除水凝胶的伤口敷料将显着增强皮肤细胞迁移，刺激组织血管生成，减少组织炎症，从而目标#1 将检验以下假设：在年轻和年长的情况下加速糖尿病伤口的愈合。最佳的伤口敷料将同时清除ROS，增加皮肤细胞迁移，促进内皮腔目标 #2 将测试 TGFβ 和高葡萄糖条件下的炎症细胞因子的形成，并减弱炎症细胞因子的分泌。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状况。该项目具有创新性，因为所提出的伤口敷料将同时解决 3 个关键的内在问题通过差异调节 TGFβ 信号传导（即抑制 TGFβ1/p38 通路）来消除糖尿病伤口愈合的障碍，同时不影响糖尿病伤口愈合所必需的 TGFβ1/Smad2/3 通路。