SymHeal: A novel therapy for treating non-healing diabetic ulcers

SymHeal：一种治疗不愈合糖尿病溃疡的新疗法

基本信息

批准号：
10602837
负责人：
Seema Nandi
金额：
$ 22.95万
依托单位：
SELSYM BIOTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602837
关键词：
3-Dimensional Address Affect Affinity Age Amputation Animal Model Apligraf Area Becaplermin Binding Biochemical Blood Platelets Cell Surface Receptors Cells Chronic Clinical Clot retraction Coagulation Process Collagen Colloids Coupled Deposition Diabetes Mellitus Diabetic Foot Ulcer Diabetic mouse Dose Electrons Evaluation Extracellular Matrix FDA approved Fibrin Fibroblasts Gangrene Goals Growth Factor Health Health Care Costs Healthcare Healthcare Industry Histology Image Immunoglobulin Fragments Immunohistochemistry Immunologics In Vitro Incidence Infection Injury Lead Matrix Metalloproteinases Mechanical Stimulation Mechanics Mediating Methods Microscopy Mission Modeling Morphology Outcome PECAM1 gene Pain Patient Care Patients Persons Phase Plasma Platelet-Derived Growth Factor Polymers Population Predisposition Preparation Prevalence Process Public Health Quality of life Recurrence Risk Rodent Model Scanning Site Skin Skin Substitutes Skin wound healing Technology Therapeutic Thick Time Tissues Topical application United States United States National Institutes of Health Up-Regulation Wound models cell motility chronic ulcer chronic wound clinical translation cost cryogenics diabetic diabetic patient diabetic ulcer diabetic wound healing effective therapy efficacy evaluation efficacy study experience fibrin receptor healing improved in vitro Model in vivo in vivo Model innovation keratinocyte migration mimetics mouse model non-healing wounds novel novel therapeutics particle preclinical development prevent response scaffold senescence side effect skin wound translational potential tumorigenesis wound wound bed wound closure wound healing

项目摘要

PROJECT SUMMARY Non-healing wounds are a significant clinical problem both in the United States and globally. These wounds, defined as wounds that remain unhealed for upwards of 12 weeks, result in diminished quality of life for patients and greatly increase their susceptibility to serious infections such as gangrene that may lead to amputations. Non-healing wounds often arise as a side effect of other chronic health conditions, with diabetic foot ulcers being one of the most prevalent forms of non-healing wounds in the domestic and global population. The prevalence of these wounds is projected to increase over the next 25 years as incidence rates of diabetes mellitus rise worldwide. Effective healing of these wounds is complicated by the unique microenvironment present within non-healing wounds, and within diabetic ulcers in particular; upregulation of matrix metalloproteinases in the wound bed prevent the robust formation of new extracellular matrix, limiting the ability of fibroblasts and keratinocytes to migrate into the wound bed and resulting in a senescent “barrier” of cells around the wound edge that further inhibits healing. Current treatments for diabetic wounds include living skin equivalents, scaffolds, platelet-rich plasma, and high dose growth factors; however, these therapies are limited by high cost, immunologic concerns, lack of full biochemical and/or mechanical support for complete wound repair, supply shortages, variability in preparation methods and efficacy, and risk of off-target complications such as tumorigenesis. We have recently developed SymHeal, a synthetic, platelet-mimetic technology capable of interfacing with nascent fibrin within the wound bed to form micro-scale fibrin-colloid scaffolds that can induce clot contraction and mechanically activate fibroblast migration into and within the wound bed via durotaxis. Our initial studies demonstrate that SymHeal is capable of recapitulating platelet-mimetic clot contraction and improving wound healing outcomes in both in vitro and in vivo murine models of dermal wound healing; however, SymHeal has not yet been evaluated in a model of chronic wound healing, limiting the current translational potential of this technology. The long-term goal of this project is to develop SymHeal for use in topical treatment of non-healing chronic wounds, particularly diabetic ulcers, in order to better address a significant clinical need within the wound healing field and facilitate further clinical translation of this technology for use in diabetic patients. The objective in this application is to evaluate SymHeal efficacy alone and in combination with loaded platelet-derived growth factor (PDGF) for the improvement of fibroblast migration and wound healing in diabetic models in vitro and in vivo. Our central hypothesis is that SymHeal will greatly improve healing and fibroblast migration relative to untreated and clinical controls in both models, and that SymHeal loaded with PDGF will bring about the greatest improvement in wound healing in both the in vitro and in vivo model at lower dosing than is currently required clinically, thereby supporting moving this technology forward into further preclinical development in large animal models. The specific aims of this project are 1) Evaluate SymHeal efficacy in an in vitro model of diabetic wound healing and 2) Determine SymHeal efficacy in an in vivo model of diabetic wound healing.

项目摘要在美国和全球，非愈合的伤口都是一个重大的临床问题。这些伤口定义为伤口持续12周以上，导致质量降低患者的生命，并大大增加了他们对严重感染（例如坏疽）的敏感性导致截肢。非愈合伤口通常是其他慢性健康状况的副作用，糖尿病足溃疡是国内最普遍的非愈合伤口形式之一和全球人口。预计这些伤口的患病率将在未来25年内增加随着糖尿病的发病率在全球范围内上升。这些伤口的有效愈合很复杂通过非污染伤口中存在的独特微环境以及在糖尿病性溃疡内特别的;伤口床中基质金属蛋白酶的上调，以防止形成可靠的新的细胞外基质，限制了成纤维细胞和角质形成细胞迁移到伤口床的能力并导致伤口边缘周围的细胞的感觉“屏障”，从而进一步抑制愈合。当前的糖尿病伤口的治疗包括生命皮肤等效物，脚手架，富含血小板的血浆和高剂量生长因子；但是，这些疗法受到高成本，免疫问题的限制，缺乏完整的生化和/或机械支持，以进行完全伤口修复，供应短缺，可变性制备方法和效率，以及脱靶并发症（例如肿瘤发生）的风险。我们有最近开发了Symheal，这是一种合成，血小板模拟技术，能够与新生接口伤口床内的纤维蛋白形成微型纤维蛋白 - 胶体胶囊脚手架，可引起凝块收缩和机械地通过Durotaxis机械激活成纤维细胞迁移到伤口床内和内部。我们的最初研究证明Symheal能够概括血小板模拟的凝块合同并改善皮肤伤口愈合的体外和体内鼠模型中的伤口愈合结果;然而，在慢性伤口愈合模型中尚未评估Symheal，限制了电流这项技术的翻译潜力。该项目的长期目标是开发Symheal供使用在局部治疗非治疗的慢性伤口，尤其是糖尿病性溃疡，以便更好地解决伤口愈合场内的临床需求很大，并促进了这一点的进一步临床翻译用于糖尿病患者的技术。本应用程序的目的是评估同伴效率单独并与负载的血小板衍生生长因子（PDGF）结合起来改善在体外和体内，糖尿病模型中成纤维细胞迁移和伤口愈合。我们的中心假设是相对于未经治疗和临床这两个模型中的控件，以及带有PDGF的同志将带来最大的改进在较低剂量的体外和体内模型中的伤口愈合中，都比目前在临床上所要求的从而支持将这项技术推向大型动物的进一步临床前发展型号。该项目的具体目的是1）评估糖尿病体外模型中的同伴效率伤口愈合和2）确定糖尿病伤口愈合的体内模型中的共光效率。