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

项目总结/摘要 所提出的努力解决了对改善慢性伤口愈合结果的新型治疗工具的需求。最近 研究表明糖尿病足溃疡患者在治疗和愈合后1年内有40%的复发率， 近60%在3年内，65%在5年内，而5年死亡率仅超过肺癌。低 糖尿病人群中的肢体伤口通常是由内皮功能障碍引起的，内皮功能障碍是血液循环障碍的主要原因。 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 直到症状发展到足以引起严重肢体威胁性缺血（CLTI）、缺血性和 神经缺血性足部溃疡、伤口和截肢。此外，糖尿病伤口愈合的治疗策略是 由于缺乏有效性，无法应对与参与艾滋病毒/艾滋病的途径中断有关的挑战， 治愈反应伤口环境的变化包括高血糖相关的灌注不足、功能障碍 白细胞功能和晚期糖基化终末产物的积累以及ECM的破坏。硫化氢（H2S），a 最近发现的气体递质，已被证明可以促进内皮细胞中血管生成相关的行为 通过激活途径，包括一氧化氮信号传导和经典的HIF-1 α和VEGF-A介导的 血管生成级联反应。有显著证据表明内源性H2S缺乏与内皮功能障碍有关， 从而导致微血管紊乱和灌注不良。（外源性）H2S供体的全身给药已经被证实是有效的。 显示出显著提高缺血性伤口的愈合率。然而，系统性和广泛的治疗提供 H2S可导致意外后果，包括低血压、肝毒性和恶性血管生成。这留下 这是通过有针对性的精确输送H2S实现个性化患者护理的重要机会。HEALS™是一种独特的 用于在治疗窗内安全和受控地输送H2S并且仅输送到伤口部位的治疗系统， 这才是最重要的在SBIR第一阶段可行性研究中，Exhalix和新墨西哥州大学团队开发并使用了 HEALS™的实验室版本，用于在Sprague中进行缺血皮瓣伤口愈合的初步动物研究， 道利老鼠。结果表明，持续的H2S局部输注显著改善了血管生成、血管形成， 灌注和愈合效果优于正常愈合。相比之下，通过输注H2S产生的H2S缺乏伤口 抑制剂PAG导致组织坏死发生率显著高于基线愈合条件。期间 根据拟议的SBIR第二阶段更新研究，我们打算继续开发HEALS™的先进原型。 这些原型的安全性和有效性将在密歇根大学的健康和糖尿病大鼠中进行测试。 新墨西哥州，以及小型猪在得克萨斯州A&M大学。我们期待着成功的发展和 HEALS™在II期的验证将导致IIB期临床研究和该技术的商业化。

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. HEALS™ is a unique therapeutic system for safe and controlled delivery of H2S within a therapeutic window and only to the wound site where it matters most. In the SBIR Phase I feasibility study, Exhalix and the University of New Mexico team developed and used a laboratory version of HEALS™ to perform preliminary animal studies on healing of ischemic flap wounds in Sprague- Dawley rats. It was shown that sustained, local infusion of H2S dramatically improved angiogenesis, vascularization, perfusion, and healing effectiveness over normal healing. In contrast, H2S deficient wounds created by infusion of an H2S inhibitor, PAG, resulted in the development of markedly higher tissue necrosis over baseline healing conditions. During the proposed SBIR Phase II renewal studies, we intend to continue the development of advanced prototypes of HEALS™. These prototypes will be tested for safety and efficacy with healthy and diabetic rats of both sexes at the University of New Mexico, as well as miniature swine at Texas A&M University. We anticipate that successful development and validation of HEALS™ during Phase II will lead to Phase IIB clinical studies and commercialization of the technology.