HEALS™: An Active Hydrogen Sulfide Delivery Technique for Accelerated, Effective Wound Healing

项目摘要/摘要 拟议的努力满足了对改善慢性伤口愈合结果的新治疗工具的需求。近期 研究表明，糖尿病足溃疡患者在治疗和愈合后1年内复发率为40%， 近60%的人在3年内死亡，65%的人在5年内死亡，而5年的死亡率仅次于肺癌。更低的位置 糖尿病人群的肢体创伤通常是由内皮功能障碍引起的，内皮功能障碍是导致血液的主要原因 循环问题，如外周动脉疾病(PAD)和微血管疾病。内皮功能障碍通常是 错过，直到症状发展到足以导致严重的肢体威胁缺血(CLTI)、缺血和 神经缺血型足部溃疡、伤口和截肢。此外，糖尿病创面愈合的治疗策略包括 受阻于它们在应对与中断参与的路径相关的挑战方面缺乏有效性 治疗反应。伤口环境的变化包括高血糖相关的血流灌注不足、功能障碍。 白细胞功能受损，晚期糖基化终末产物积聚，细胞外基质紊乱。硫化氢(H2S)，a 最近发现的气体递质，已被证明促进血管内皮细胞的血管生成相关行为 通过激活包括一氧化氮信号和典型的缺氧诱导因子-1和血管内皮生长因子-A介导的通路 血管生成级联反应。有显著证据表明，内源性硫化氢缺乏与内皮功能障碍和 结果是微血管紊乱和血流灌注不良。对(外源性)硫化氢捐赠者的系统性管理 能显著提高缺血创面的愈合率。然而，系统和广泛的治疗性交付 硫化氢可能导致意想不到的后果，包括低血压、肝毒性和恶性血管生成。这片树叶 通过有针对性、精准的硫化氢输送，为患者提供个性化护理的重要机会。在拟议的SBIR中 第一阶段的研究，我们打算展示一种独特的治疗系统，经皮检测内源性的水平 同时提供局部维持治疗窗口内硫化氢水平所需的外源量。在这 Exhalix和新墨西哥大学医学院的合作努力，我们将展示其可行性 这种治疗方法的优点是在小鼠的基础上改善了缺血性伤口的愈合 动物模型。我们预期拟议的可行性研究将持续12个月，并成功实现我们的目标。 将导致第二阶段的努力，开发原型并在更大的动物上进行演示。

Project Summary/Abstract The proposed effort addresses the need for novel therapeutic tools that improve chronic wound healing outcome. Recent studies show that patients with diabetic foot ulcers have a 40% recurrence rate within 1 year after treatment and healing, nearly 60% within 3 years, and 65% within 5 years, while the 5-year mortality rate is exceeded only by lung cancer. Lower limb wounds in the diabetic population are generally caused by endothelial dysfunction, the leading cause of blood circulation issues such as peripheral artery disease (PAD) and microvascular disorder. Endothelial dysfunction is often missed until the symptoms become advanced enough to cause critical limb threatening ischemia (CLTI), ischemic and neuro-ischemic foot ulcers, wounds, and amputations. In addition, therapeutic strategies for diabetic wound healing are stymied by their lack of effectiveness in addressing the challenges associated with disruption of pathways involved in the healing response. The changes in the wound environment include hyperglycemia-related perfusion deficiency, dysfunction of leukocyte function and accumulation of advanced glycation-end products and disrupted ECM. Hydrogen sulfide (H2S), a recently discovered gasotransmitter, has been shown to promote angiogenesis-related behavior in endothelial cells through activation of pathways that include nitric oxide signaling and the canonical HIF-1 and VEGF-A-mediated angiogenesis cascade. There is significant evidence linking deficiency in endogenous H2S to endothelial dysfunction and consequently microvascular disorder and poor perfusion. Systemic administration of (exogenous) H2S donors have been shown to markedly improve healing rate in ischemic wounds. However, systemic and widespread therapeutic delivery of H2S can lead to unintended consequences including hypotension, hepatotoxicity, and malignant angiogenesis. This leaves a significant opportunity for individualizing patient care through targeted, precision delivery of H2S. In the proposed SBIR Phase I study, we intend to demonstrate a unique therapeutic system that transdermally detects endogenous levels of H2S while delivering an exogenous amount needed to locally maintain the H2S levels within a therapeutic window. In this collaborative effort between Exhalix and the University of New Mexico School of Medicine, we will show the feasibility and merits of this therapeutic approach for ischemic wound healing improvements over baseline conditions on small animal models. We anticipate that the proposed feasibility study will last 12 months and success in reaching our objectives will lead to a Phase II effort for development of prototypes and demonstration on larger animals.