Regenerative wound dressings for accelerating diabetic wound healing

加速糖尿病伤口愈合的再生伤口敷料

• 批准号: 10518977
• 负责人: Jianjun Guan
• 金额: $ 43.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10518977
• 关键词: Address; Affect; Affinity; Aging; Amputation; Attenuated; Binding; Biodistribution; Cell Survival; Cell physiology; Cell secretion; Cells; 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; Lead; Lower Extremity; 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; base; 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; macrophage; migration; monocyte; p38 Mitogen Activated Protein Kinase; preservation; programs; receptor; regenerative; wound; wound closure; wound dressing; wound healing; Address; Affect; Affinity; Aging; Amputation; Attenuated; Binding; Biodistribution; Cell Survival; Cell physiology; Cell secretion; Cells; 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; Lead; Lower Extremity; 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; base; 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; macrophage; migration; monocyte; p38 Mitogen Activated Protein Kinase; preservation; programs; receptor; regenerative; wound; wound closure; wound dressing; wound healing

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.

项目摘要 仅在美国，糖尿病就会影响超过3400万人。它是非创伤下肢的主要原因 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疗法 为了治疗糖尿病伤口，有效治疗仍然是一个挑战，因为当前的疗法无法有效解决 糖尿病伤口愈合缓慢的关键固有原因，即慢性炎症，皮肤细胞异常（部分地） 迁移）和延迟的血管生成。为了解决这些原因，控制TGFβ信号至关重要。 TGFβ1/p38 途径与长时间的感染直接相关，并在伤口中受损的细胞迁移受损。同时， 需要TGFβ1/SMAD2/3途径来调节伤口愈合的关键细胞类型，肌纤维细胞。像这样， 抑制TGFβ1/p38途径而不影响TGFβ1/SMAD2/3途径，将简单地解决3 关键的内在原因，导致加速糖尿病伤口愈合。但是，这无法通过任何 现有方法。 在这个项目中，我们建议创建一种新的伤口敷料来实现目标。它将由基于肽的 TGFβ受体II（TGFβRII）抑制剂ECG和活性氧（ROS） - 扫描水凝胶。心电图将 从水凝胶逐渐释放到连续抑制TGFβ1/p38途径，以改善细胞迁移 并减少组织注射。增强的内皮细胞迁移将导致加速血管生成。 水凝胶将在糖尿病伤口中清除ROS，以进一步减少炎症。值得注意的是，ECG会 在高葡萄糖条件下不影响TGFβ1/SMAD2/3途径。据我们所知，没有 现有的TGFβ受体抑制剂已显示出抑制TGFβ1/p38途径的能力 下调TGFβ1/SMAD2/3途径。 在我们的初步研究中，将单剂赢得敷料应用于年轻糖尿病的精美伤口 小鼠显着加速了伤口闭合。伤口在第14天完全关闭。相反，伤口大小 水凝胶处理和未处理的伤口保持> 53％。伤口敷料也减少了ROS含量， M1巨噬细胞密度和P-p38表达，并增加了伤口的血管密度。这些初步结果 证明释放ECG的伤口敷料有望用于糖尿病伤口愈合。尚未测试是否 伤口敷料可以在衰老状态下促进糖尿病伤口愈合，因为衰老本身会损害细胞迁移和 血管生成。 我们假设基于ECG和ROS扫除水凝胶的获胜敷料将显着 增强皮肤细胞迁移，刺激组织血管生成并减少组织注射，导致 在年轻和老年状况下加速了糖尿病伤口的愈合。 AIM＃1将检验以下假设 最佳伤口敷料将简单地清除ROS，增加皮肤细胞迁移，促进内皮管腔 在TGFβ和高葡萄糖条件下形成，并衰减炎症细胞因子分泌。 AIM＃2将测试 发达的伤口敷料将加速糖尿病伤口愈合的假设 状况。 该项目具有创新性 通过不同调节的TGFβ信号传导，即抑制TGFβ1/p38途径，糖尿病伤口可以治愈的障碍 虽然不影响糖尿病伤口愈合必不可少的TGFβ1/SMAD2/3途径。