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

HEALS™：一种活性硫化氢输送技术，可加速、有效伤口愈合

• 批准号: 10323467
• 负责人: Reza Shekarriz
• 金额: $ 30万
• 依托单位: EXHALIX, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2022-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323467
• 关键词: ANGPT1 gene; Address; Advanced Glycosylation End Products; Affect; Aftercare; Amputation; Animal Model; Animals; Antiinflammatory Effect; Apoptosis; Applications Grants; Behavior; Blood; Blood Circulation; Blood Vessels; Blood flow; Bypass; Cardiovascular Physiology; Cell Death; Cell Therapy; Chronic; Clinical; Collaborations; Coma; Competence; Coughing; Cytoprotection; Data; Dermal; Detection; Development; Device or Instrument Development; Diabetes Mellitus; Diabetic Foot Ulcer; Diagnosis; Disease; Doctor of Philosophy; Dorsal; Effectiveness; Endothelial Cells; Endothelium; Environment; Evaluation; Extracellular Matrix; Family suidae; Feasibility Studies; Foot Ulcer; Functional disorder; Gangrene; Gases; General Population; Glycine; Government; Granulation Tissue; Hemorrhage; Hepatotoxicity; Histology; Human; Hydrogen Sulfide; Hyperglycemia; Hypotension; Infection; Investigation; Ischemia; Laboratories; Lead; Leukocytes; Limb Salvage; Limb structure; Link; Lower Extremity; Lung; Lyase; Malignant - descriptor; Malignant neoplasm of lung; Measurement; Measures; Mediating; Microfluidics; Microvascular Dysfunction; Modality; Molecular Analysis; Monitor; Morbidity - disease rate; Neoplasm Metastasis; New Mexico; Nitric Oxide; Operative Surgical Procedures; Outcome; Pain; Paralysed; Pathway interactions; Patients; Perfusion; Peripheral arterial disease; Phase; Physiological; Population; Public Health; Rattus; Recurrence; Reporting; Research; Research Personnel; Resources; Rest; Risk; Running; Seizures; Shortness of Breath; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; Sprague-Dawley Rats; Sulfides; Surgical Flaps; Surgical wound; Symptoms; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Thinness; Tissues; Toxic effect; Translating; Ulcer; Universities; VEGFA gene; Validation; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascularization; Vasodilation; aging population; angiogenesis; care burden; chronic wound; commercialization; diabetic; diabetic wound healing; effectiveness evaluation; endothelial dysfunction; endothelial stem cell; gene therapy; healing; hemodynamics; human subject; hypoxia inducible factor 1; improved; inhibitor/antagonist; innovation; interest; limb amputation; medical schools; meetings; mortality; neurotoxicity; non-healing wounds; novel; novel therapeutics; personalized care; phase 1 study; phase 2 study; pre-clinical; professor; prototype; real time monitoring; response; restoration; sensor; skin ulcer; skin wound; success; technology development; tissue repair; tool; tumor growth; wearable device; wound; wound care; wound closure; wound environment; wound healing; wound treatment

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.

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，全身性和广泛的治疗递送 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。在拟议的SBIR中， I期研究，我们打算证明一个独特的治疗系统，透皮检测内源性水平的 H2S，同时递送将H2S水平局部维持在治疗窗内所需的外源量。在这 Exhalix和新墨西哥州大学医学院之间的合作努力，我们将展示其可行性 以及这种治疗方法相对于基线条件改善缺血性伤口愈合的优点， 动物模型我们预期拟议的可行性研究将持续12个月，并能成功达到我们的目标 将导致第二阶段的努力，为发展原型和示范较大的动物。