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

• 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
• 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

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 在美国和全球范围内，不愈合伤口都是一个重要的临床问题。这些 伤口定义为12周以上仍未愈合的伤口， 并大大增加了他们对严重感染的易感性，如坏疽， 导致截肢。不愈合的伤口通常是其他慢性健康状况的副作用， 糖尿病足溃疡是家庭中最普遍的不愈合伤口形式之一 全球人口。预计在未来25年内，这些伤口的患病率将增加 因为糖尿病的发病率在全球范围内上升。这些伤口的有效愈合是复杂的 通过存在于不愈合伤口内的独特微环境，以及在糖尿病溃疡内， 特别地，创伤床中基质金属蛋白酶的上调防止了创伤床的稳健形成。 新的细胞外基质，限制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衰老“屏障”，其进一步抑制愈合。电流 糖尿病伤口的治疗包括活皮肤等同物、支架、富血小板血浆和高浓度的胶原蛋白。 剂量的生长因子;然而，这些疗法受到高成本、免疫学问题、缺乏 完全的生物化学和/或机械支持，用于完全的伤口修复，供应短缺， 制备方法和功效，以及脱靶并发症如肿瘤发生的风险。我们有 最近开发的SymHeal是一种合成的血小板模拟技术，能够与新生的 纤维蛋白在伤口床内形成微尺度的纤维蛋白-胶体支架，其可以诱导凝块收缩， 机械地激活成纤维细胞通过硬旋转迁移到伤口床中和伤口床内。我们最初的研究 证明SymHeal能够重现拟血小板凝块收缩， 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， SymHeal尚未在慢性伤口愈合模型中进行评估，这限制了目前的研究。 这一技术的转化潜力。该项目的长期目标是开发SymHeal， 在局部治疗不愈合的慢性伤口，特别是糖尿病溃疡， 这是伤口愈合领域内的重要临床需求，并有助于进一步临床转化 用于糖尿病患者的技术。本申请旨在评价SymHeal的有效性 单独和与负载的血小板衍生生长因子（PDGF）组合用于改善 成纤维细胞迁移和伤口愈合的糖尿病模型在体外和体内。我们的核心假设是 SymHeal将大大改善愈合和成纤维细胞迁移相对于未经治疗和临床 控制在这两个模型，并认为SymHeal加载PDGF将带来最大的改善 在体外和体内模型中以低于目前临床所需的剂量的伤口愈合中， 从而支持将该技术向前推进到大型动物中的进一步临床前开发 模型本项目的具体目的是：1）评价SymHeal在体外糖尿病模型中的疗效 伤口愈合和2）在糖尿病伤口愈合的体内模型中确定SymHeal功效。