Developing biomarkers of healing and non-healing VLUs

项目摘要 该项目建议使用从废弃伤口敷料中捕获的伤口液分析来开发 这些生物标志物可以预测下肢静脉溃疡（VLU）的愈合结果并监测其愈合进展。 VLU代表了在慢性静脉曲张背景下发生在足跟区域的慢性溃疡的特定病例。 在所有慢性腿部溃疡中约占70%。考虑到人口老龄化， 令人担忧的画面出现了：病情较重的患者出现更多溃疡，治疗费用也越来越高。 尽管最近取得了进展，但超过50%的VLU患者无法通过标准护理治愈。的一个主要 改善结果的障碍是无法早期预测谁会和谁不会对标准做出反应， 照顾。因此，迫切需要预测愈合结果并区分愈合 无法治愈的超大型卢由于伤口内的动态分子变化，其微环境可以被破坏。 测试和监测，这提供了一个机会，以获得有关伤口状态的关键信息 生物学此外，反映伤口愈合状态的此类分子变化的定量将提供 重要的工具，可以指导治疗方法，直接影响临床结果。因此，两个预测 并且需要监测生物标志物以使治疗的前瞻性定制能够有效地：1）最大化生物标志物， 治疗结果，2）仅针对需要的患者进行更积极的治疗，3） 为每个VLU提供个性化的方法。在最初的发现阶段，我们将招募30名VLU患者（10名治疗者 和20名非治疗者），以确定一组蛋白质生物标志物，预测愈合结果（目标1）;那些可以 作为监测生物标志物（目标2）。我们将从废弃的伤口敷料中提取伤口液， 蛋白质，并将其与第4周的愈合结果相关联。我们有 生成的初步数据支持整体方法的可行性，并证实伤口敷料 （真实的分析或冷冻储存）可用于生物标记物定量。我们有 还确定了在伤口敷料的中心相对于周边的分子的空间上不同的定位， 从而产生分别反映伤口床和伤口边缘的生物学的特定轮廓。这个项目 将提供一个独特的机会，利用容易获得的废弃伤口敷料作为一个来源， 可用于生物标记物检测的伤口生物材料（渗出物）。它不仅将确定和验证特定的 一组生物标志物，可以预测愈合结果和/或监测愈合进展，但也将提供 简化的检测方法，可以很容易地实现。

Project Summary This project proposes to use wound fluid analyses captured from discarded wound dressings to develop biomarkers that can predict healing outcome and monitor healing progression of Venous Leg Ulcers (VLUs). VLUs represent a specific case of chronic ulcers occurring in the gaiter area in the setting of chronic venous insufficiency and account for about 70% of all chronic leg ulcers. Considering the aging of the population a concerning picture emerges: more ulcers occurring in sicker patients which are ever more expensive to treat. Despite recent advances, more than 50% of patients with VLUs fail to heal with standard care. One of the major obstacles to improving outcomes is the inability to predict early on who will and who will not respond to standard of care. Therefore, there is an urgent and unmet need to predict healing outcomes and to differentiate healing from non-healing VLUs. Due to dynamic molecular changes within the wound, its microenvironment can be tested and monitored, which offers an opportunity to obtain key information regarding the status of wound biology. Moreover, quantification of such molecular changes that reflect wound healing status would provide important tools that can guide treatment approach, directly impacting the clinical outcomes. Thus, both predictive and monitoring biomarkers are needed to enable prospective tailoring of therapies to efficiently: 1) maximize the treatment outcomes, 2) target more aggressive treatment to only those patients who need it and 3) develop personalized approaches to each VLU. In the initial discovery phase, we will enroll 30 VLU patients (10 healers and 20 non-healers) to identify a set of protein biomarkers that predict healing outcomes (Aim 1); those that can serve as monitoring biomarkers (Aim 2). We will extract wound fluid from discarded wound dressings and quantify proteins by using mass spectrometry (LC-MS/MS) and correlate them to healing outcomes at week 4. We have generated preliminary data that support feasibility of the overall approach and confirm that wound dressings (either analyzed in real time or stored frozen) of any type can be utilized for biomarker quantification. We have also identified spatially distinct localization of molecules at the center vs perimeter of the wound dressing, resulting in specific profiles that reflect the biology of the wound bed and wound edge respectively. This project will provide a unique opportunity to capitalize on easy access of discarded wound dressings as a source of wound biomaterial (exudate) that can serve for biomarker detection. It will not only identify and validate specific set of biomarkers that can predict healing outcome and/or monitor healing progression but will also provide streamlined method of detection that can be readily implemented.