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

项目总结 无法愈合的伤口在美国和全球都是一个重要的临床问题。这些 伤口，定义为持续12周以上未愈合的伤口，会导致质量下降。 延长患者的生命，并大大增加他们对严重感染的敏感性，如可能发生的坏疽 导致截肢。无法愈合的伤口通常是其他慢性健康状况的副作用， 糖尿病足溃疡是国内最常见的无法愈合的伤口形式之一 和全球人口。预计在接下来的25年里，这些伤口的流行率将会增加。 随着世界范围内糖尿病发病率的上升。这些伤口的有效愈合是复杂的 由于无法愈合的伤口和糖尿病溃疡内存在的独特微环境 尤其是：伤口床中基质金属蛋白酶的上调可防止强健的 新的细胞外基质，限制成纤维细胞和角质形成细胞向创面床迁移的能力 并在伤口边缘形成一道老化的“屏障”，进一步抑制愈合。当前 糖尿病创面的治疗方法包括活的皮肤替代物、支架、富含血小板的血浆和高 剂量生长因子；然而，这些疗法受限于高昂的成本、免疫学方面的考虑、缺乏 全面的生物化学和/或机械支持，以完成伤口修复，供应短缺，变异性 制备方法和疗效，以及肿瘤形成等非靶标并发症的风险。我们有 最近开发的SymHeal，这是一种合成的、模拟血小板的技术，能够与新生 纤维蛋白在伤口床内形成微尺度纤维蛋白-胶体支架，可诱导血栓收缩和 通过趋化作用机械激活成纤维细胞迁移到伤口床内和伤口床内。我们的初步研究 证明SymHeal能够重现模拟血小板的血栓收缩并改善 皮肤伤口愈合的体外和体内小鼠模型的伤口愈合结果；然而， SymHeal尚未在慢性伤口愈合模型中进行评估，限制了当前的 这项技术的翻译潜力。该项目的长期目标是开发可供使用的SymHeal 在局部治疗无法愈合的慢性伤口，特别是糖尿病溃疡方面，以便更好地解决 伤口愈合领域的重要临床需求，并促进进一步的临床翻译 用于糖尿病患者的技术。本应用程序的目标是评估SymHeal的疗效 单用及与负载血小板衍生生长因子(PDGF)联合应用改善心力衰竭 体内和体外糖尿病模型中成纤维细胞的迁移和伤口愈合。我们的中心假设是 与未经治疗和临床治疗相比，SymHeal将极大地改善愈合和成纤维细胞迁移 两个模型中的控件，并且加载了PDGF的SymHeal将带来最大的改进 在体外和体内模型中以低于当前临床要求的剂量进行伤口愈合， 从而支持将这项技术向前推进到大型动物的进一步临床前开发 模特们。本项目的具体目标是：1)在糖尿病体外模型中评价赛美尔的疗效 2)在糖尿病伤口愈合的活体模型中确定SymHeal的疗效。

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.