Topical Drug Delivery System as an Anti-Inflammatory and Pro-Angiogenic Therapy for Diabetic Wound Healing

总结 糖尿病患者中受损的伤口愈合代表了主要的临床问题，导致长时间的伤口愈合。 住院和重大医疗支出。这是极端的经济负担，代表着 仅在美国每年就有780亿美元。三分之二的非创伤性截肢手术之前都有糖尿病 每20秒就有一条下肢因糖尿病伤口而失去。糖尿病伤口愈合不良 是多因素的，但中心致病特征是慢性炎症。这些可怕的易感染的溃疡 使用当前的技术难以治疗，并且代表了市场上显著未满足的需求。 目前通常用于这些病症的治疗包括标准绷带或碱性水凝胶 其具有许多缺点，包括它们引起炎症反应，需要被去除， 经常改变，并且不能持续释放药物。GelSana Therapeutics，Inc.处理这一 需要其专有的伤口愈合水凝胶，帮助伤口愈合显着更快， 当今敷料的缺点水凝胶是基于聚合物，排斥蛋白质吸附和防止 异物反应。此外，这类材料已被证明是抗炎的。研究中 GelSana用伤口愈合能力受损的糖尿病小鼠证明， 将愈合时间缩短到盐水治疗糖尿病伤口时间的2/3，与 健康的老鼠这表明，该材料单独可以纠正糖尿病对伤口愈合的损害。 GelSana材料也已经显示出优于市售可得的水凝胶中使用的另一种类型的水凝胶。 在这些糖尿病小鼠伤口愈合所需的时间内，此外，负载有聚乙烯醇的水凝胶可用于制备水凝胶。 消炎药能将愈合时间缩短一半在这个项目中，GelSana专有 两性离子水凝胶将用作上级伤口敷料材料 通过减少炎症来愈合损伤，其中将从这些敷料持续递送IL-10， 证明了进一步解决糖尿病伤口环境中的慢性炎症， 血管化，从而使糖尿病溃疡愈合的速度等于或快于非血管化的糖尿病溃疡。 糖尿病（健康）盐水治疗的伤口。该第一阶段项目将证明GelSana两性离子 具有和不具有IL-10的水凝胶通过（1）体外表征药物释放和生物活性和（2）评估 在体内鼠糖尿病溃疡模型中的功效。这将通过以下目标实现：目标1：量化 IL-10从两性离子水凝胶中的释放速率和生物活性。目标2：量化 药物的持续释放对药物装置产品改善创伤愈合的能力的影响， 小鼠模型。这项工作将导致一类新的抗炎促再生水凝胶伤口 具有持续释放的新型治疗剂的敷料，所述新型治疗剂对抗氧化应激和炎症， 促进糖尿病伤口中的血管生成以治疗性地减少炎症，减少愈合时间，以及 提高组织修复质量。

SUMMARY Impaired wound healing in diabetic patients represents a major clinical problem, resulting in prolonged hospitalizations and significant healthcare expenditures. The financial burden of this is extreme, representing $78 billion annually in the U.S. alone. Two-thirds of all non-traumatic amputations are preceded by a diabetic wound, and every 20 seconds a lower limb is lost to a diabetic wound. The impaired healing of diabetic wounds is multifactorial, but a central pathogenic feature is chronic inflammation. These terrible, infection-prone ulcers are difficult to treat using current technologies and represent a significant under-met need in the marketplace. Current treatments commonly employed for these conditions involve standard bandages or basic hydrogels which have many drawbacks, including that they cause inflammatory response, need to be removed and changed often, and are not capable of sustained drug release. GelSana Therapeutics, Inc. is addressing this need with its proprietary wound healing hydrogels that help heal wounds significantly faster and without the downsides of today’s dressings. The hydrogels are based on polymers that repel protein adsorption and prevent the foreign body response. Further, this class of materials have been shown to be anti-inflammatory. In studies with diabetic mice with impaired wound healing abilities, GelSana has demonstrated that the hydrogels alone cut the healing time down to 2/3 of the time of saline-treated diabetic wounds, matching the healing time of healthy mice. This indicates that the material alone can correct the diabetic impairment to wound healing. GelSana materials have also been shown to outperform another type of hydrogel used in commercially available products in the time of healing required for these diabetic murine wounds. Furthermore, hydrogels laden with an anti-inflammatory drug cut the healing time down by a staggering one-half. In this project, GelSana proprietary zwitterionic hydrogels will serve as superior wound dressing materials to aid in correcting the diabetic wound healing impairment by reducing inflammation, where sustained delivery of IL-10 from these dressings will be demonstrated to further resolve chronic inflammation in the diabetic wound environment and improve vascularization, thus allowing the diabetic ulcer to heal at a rate equivalent to or faster than that found in non- diabetic (healthy) saline-treated wounds. This Phase I project will demonstrate feasibility for GelSana zwitterionic hydrogels with and without IL-10 by (1) characterizing drug release and bioactivity in vitro and (2) assessing efficacy in an in vivo murine diabetic ulcer model. This will be accomplished with these Aims: Aim 1: To quantify the release rate and bioactivity of IL-10 from zwitterionic hydrogels. Aim 2: To quantify the impact of sustained release of the drug on the ability of the drug-device product to improve wound healing in a murine model. This work will result in a new class of anti-inflammatory pro-regenerative hydrogel wound dressings with sustained release of novel therapeutics that combat oxidative stress and inflammation and promote angiogenesis in diabetic wounds to therapeutically decrease inflammation, decrease healing time, and increase tissue repair quality.