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.

项目摘要/摘要拟议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。最近的研究表明，糖尿病足溃疡患者在治疗和愈合后的1年内复发率为40％，在3年内将近60％，在5年内65％，而5年死亡率仅超过肺癌。降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，这是血液的主要原因循环问题，例如周围动脉疾病（PAD）和微血管疾病。内皮功能障碍通常是错过，直到症状变得足够前进以引起肢体威胁性缺血（CLTI），缺血性和神经 - 缺血性足部溃疡，伤口和截肢。此外，糖尿病伤口愈合的理论策略是由于缺乏有效性在解决与涉及的途径相关的挑战时所困扰的康复反应。伤口环境的变化包括高血糖相关的灌注缺乏症，功能障碍白细胞功能和晚期糖基末端产物的积累和ECM的破坏。硫化氢（H2S），A 最近发现的固定剂已被证明可以促进内皮细胞中与血管生成相关的行为通过激活包括一氧化氮信号传导和规范HIF-1和VEGF-A介导的途径血管生成级联。有大量的证据表明内源性H2s缺乏与内皮功能障碍和因此，微血管疾病和灌注不良。（外源）H2S供体的系统性给药显示可显着提高缺血性伤口的愈合率。但是，全身和宽度的治疗性交付 H2S会导致意外后果，包括低血压，肝毒性和恶性血管生成。这离开了通过针对性的，精确的H2递送，将患者护理个性化的重要机会。在拟议的sbir中第一阶段研究，我们打算展示一个独特的治疗系统，该系统翻译得很 H2在提供外源性的同时，在治疗窗口内局部维持H2S水平。在这个 exhalix和新墨西哥大学医学院之间的合作努力，我们将展示可行性这种治疗方法的优点是缺血性伤口愈合的改善，以改善小基线条件动物模型。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II期为开发原型和大型动物的示范的努力。