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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要拟议的工作解决了对改善慢性伤口愈合结果的新型治疗工具的需求。研究表明，糖尿病足溃疡患者在治疗治愈后1年内复发率高达40%， 3年内接近60%，5年内接近65%，而5年死亡率仅次于肺癌。糖尿病人群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。外周动脉疾病（PAD）和微血管疾病等循环问题很常见。直到症状发展到足以导致严重肢体威胁性缺血（CLTI）、缺血和此外，糖尿病伤口愈合的治疗策略是神经缺血性足部溃疡、伤口和截肢。由于缺乏有效解决与破坏相关途径相关的挑战而受到阻碍伤口环境的变化包括高血糖相关的灌注不足、功能障碍。白细胞功能以及晚期糖基化终末产物和破坏的 ECM 的积累。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以及经典的 HIF-1α 和 VEGF-A 介导的有重要证据表明内源性 H2S 缺乏与内皮功能障碍有关。因此，（外源性）H2S 供体的微血管紊乱和灌注不良。研究表明，它可以显着提高缺血性伤口的愈合率，但是，全身和广泛的治疗递送。 H2S 可导致意想不到的后果，包括低血压、肝毒性和恶性血管生成。在拟议的 SBIR 中，这是通过有针对性、精确的 H2S 输送来实现个性化患者护理的重要机会。第一阶段研究，我们打算展示一种独特的治疗系统，可以透皮检测内源性水平 H2S，同时输送局部维持 H2S 水平在治疗窗口内所需的外源量。 Exhalix 和新墨西哥大学医学院的合作，我们将展示可行性以及这种治疗方法在小范围内改善缺血性伤口愈合优于基线条件的优点我们预计拟议的可行性研究将持续 12 个月并成功实现我们的目标。将导致第二阶段的工作，以开发原型并在大型动物上进行演示。