A collagen wound dressing augmented with a proteoglycan mimic to enhance chronic

描述(由申请人提供)：本提案涉及PHS 2012-02年度NIH、CDC、FDA和ACF针对小型企业创新研究资助申请的综合征集(家长SBIR[R43/R44])。慢性伤口每年影响美国650万人，占所有发达国家人口的1%-2%，仅在美国每年的治疗费用就高达250亿美元。不断增加的老年人口，加上糖尿病和肥胖率的上升，预计将推动慢性伤口市场的增长。慢性创面具有高水平的炎症活动，特别是基质金属蛋白酶(MMPs)，导致慢性创面细胞外基质的高周转。由于血管减少，慢性创面也经常处于缺血状态。在慢性创面环境中，基质金属蛋白酶活性增加，血管减少，细胞外基质产生不稳定，都会导致皮肤持续降解和随后的溃疡。提供一种外源性组织工程支架，例如基于胶原的ECM，已经在治疗不可愈合的伤口方面取得了一些临床成功，因为它们能够提供一种底物，可以结合并增加常驻生长因子的活性。然而，现有的产品可能会在慢性伤口的腐蚀性环境中过早降解，并且往往无法实现必要的细胞渗透、血管生成和上皮化以促进伤口愈合。Glytrix有 开发了一种名为DS-sily的合成蛋白多糖。该分子受到天然蛋白多糖核心蛋白的启发，由硫酸皮肤素(DS)骨架和附着的胶原结合多肽(SIly)组成。这种蛋白多糖模拟物已被证明：1)结合并保护胶原支架免受基质金属蛋白酶降解；2)促进内皮细胞和角质形成细胞的增殖；3)减少肉芽组织和可见的瘢痕形成，并增加大鼠伤口创伤后的抗张强度。这些特点导致了一种假设，即用ds-sily增强胶原支架会导致支架在慢性伤口环境中降解得更慢，并通过增强常驻生长因子来增加伤口的血管和上皮化，从而产生更有效的效果。 与单纯的胶原蛋白支架相比，慢性伤口的愈合。由于它们的生物学活性不同，两个不同分子量的DS-sily分子将与胶原蛋白敷料一起在延迟愈合的大鼠模型中进行检测。伤口愈合标记物将包括上皮化、炎症、组织重塑和基质降解和沉积。成功完成这一第一阶段的SBIR将产生一个单一的DS-sily分子，通过按照FDA的要求测试分子的生物兼容性，该分子将在开发中向前推进。GMP合成、生物兼容性测试和一项小型临床安全性研究将成为第二阶段奖项的里程碑。

DESCRIPTION (provided by applicant): This proposal addresses PHS 2012-02 Omnibus Solicitation of the NIH, CDC, FDA and ACF for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44]). Chronic wounds affect 6.5 million people in the US each year, and 1-2% of the population in all developed countries, with treatment costs in the US alone reaching $25 billion annually. The increasing elderly population, in addition to the rising rates of diabetes and obesity, is expected to drive growth in the chronic wound market. Chronic wounds have a high level of inflammatory activity, specifically matrix metalloproteinases (MMPs) that leads to high turnover of the extracellular matrix in a chronic wound. Chronic wounds also are often in an ischemic state, due to decreased vascularity. The increased MMP activity, decreased vascularity, and unstable ECM production in a chronic wound environment all lead to continued skin degradation and subsequent ulceration. Providing an exogenous tissue engineered scaffold, such as a collagen based ECM, has shown some clinical success in treating nonhealing wounds due to their ability to provide a substrate that can bind and increase the activity of resident growth factors. However, existing products can be prematurely degraded in the caustic environment of the chronic wound, and often do not achieve the necessary cellular infiltration, angiogenesis, and epithelialization to facilitate wound healing. Glytrix has developed a synthetic proteoglycan called DS-SILY. The molecule, inspired by the native proteoglycan decorin, is composed of a dermatan sulfate (DS) backbone with attached collagen binding peptides (SILY). This proteoglycan mimic has been shown to: 1) bind to and protect collagen scaffolds from MMP degradation; 2) promote the proliferation of both endothelial cells and keratinocytes; and 3) decrease granulation tissue and visible scarring and increase tensile strength after incisional wounding in a rat model. These characteristics have led to the hypothesis that augmentation of a collagen scaffold with DS-SILY will lead to slower degradation of the scaffold in the chronic wound environment, and will increase vascularity and epithelialization of the wound by potentiating resident growth factors, resulting in more effective healing of chronic wounds as compared to a collagen scaffold alone. Due to their different biological activities, two DS-SILY molecules with varying molecular weights will be examined in combination with a collagen dressing in a rat model of delayed healing. Wound healing markers will include epithelializaton, inflammation, tissue remodeling, and matrix degradation and deposition. Successful completion of this Phase I SBIR will result in a single DS-SILY molecule that will move forward in development by testing biocompatibility of the molecule as required by the FDA. GMP synthesis, biocompatibility testing, and a small clinical safety study will be the milestones for a Phase II award.