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：
10696687
负责人：
Reza Shekarriz
金额：
$ 124.49万
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696687
关键词：
Acceleration Address Adult Advanced Development Advanced Glycosylation End Products Affect Aftercare Amputation Animal Model Animals Attention Behavior Biological Availability Blood Circulation Blood Vessels Chronic Clinical Clinical Research Development Devices Diabetes Mellitus Diabetic Foot Ulcer Dorsal Dose Effectiveness Endothelial Cells Endothelium Engineering Environment Evaluation Excision Excision biopsy Extracellular Matrix Family suidae Feasibility Studies Female Foot Ulcer Functional disorder Gangrene General Population Generations Goals Good Manufacturing Process Government Granulation Tissue Hepatotoxicity Histologic Human Hydrogen Sulfide Hyperglycemia Hypotension In Situ Infection Infusion procedures Ischemia Laboratories Lead Leukocytes Limb Salvage Limb structure Link Lower Extremity Malignant - descriptor Malignant neoplasm of lung Mediating Medical Device Metabolic Microvascular Dysfunction Miniature Swine Modality Modeling Molecular Morbidity - disease rate Mus New Mexico Nitric Oxide Operative Surgical Procedures Outcome Pain Pathway interactions Patients Performance Perfusion Peripheral arterial disease Persons Phase Physiology Population Production Public Health Publications Punch Biopsy Rattus Recurrence Reporting Research Research Personnel Resources Rest Risk Safety Signal Transduction Signaling Molecule Site Skin Small Business Innovation Research Grant Sprague-Dawley Rats Sterile coverings Study models Sulfides Surgical incisions Symptoms System Techniques Technology Testing Texas Therapeutic Therapy Evaluation Tissues Toxic effect Ulcer Universities VEGFA gene Validation Vascular Diseases Vascular Endothelial Growth Factors Vascular Endothelium Vascularization Visual aging population angiogenesis blood perfusion care burden chronic wound clinically relevant commercialization cost effectiveness diabetic diabetic patient diabetic rat diabetic wound healing effective therapy endothelial dysfunction healing hemodynamics improved inhibitor innovation limb amputation male manufacture meetings mortality multidisciplinary necrotic tissue novel novel therapeutics open wound patient population personalized care phase 1 study phase 2 study pre-clinical pressure product development prototype response safety testing sex success tool treatment duration validation studies wound wound care wound closure wound dressing 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. 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.

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。通过有针对性、精确地输送 HEALS™ 来实现个性化患者护理的一个重要机会是一个独特的机会。治疗系统，用于在治疗窗口内安全、受控地输送 H2S，并且仅输送至伤口部位在 SBIR 第一阶段可行性研究中，Exhalix 和新墨西哥大学团队开发并使用了这一点。实验室版本的 HEALS™，用于在斯普拉格进行缺血性皮瓣伤口愈合的初步动物研究结果表明，持续局部注射 H2S 可以显着改善血管生成、血管化、相比之下，通过注入 H2S 造成的 H2S 缺乏伤口。抑制剂 PAG 导致比基线愈合条件明显更高的组织坏死。根据拟议的 SBIR II 期更新研究，我们打算继续开发 HEALS™ 的先进原型。这些原型将在英国大学的健康和糖尿病大鼠中进行安全性和有效性测试。新墨西哥州以及德克萨斯农工大学的小型猪我们预计会取得成功。 II 期期间 HEALS ™的验证将导致 IIB 期临床研究和该技术的商业化。