Development of wound care formulations for PVP/NO: A novel nitric oxide releasing platform with potent antimicrobial and anti-biofilm properties

这项SBIR研究工作的中心目标是推动一种新型生物材料的发展并将其商业化 用于伤口护理市场的基于氧化物(NO)的输送系统。此第一阶段提案将建立在iFyber的 这种生物材料作为一种有效的抗微生物和抗生物被膜平台的强有力的初步数据。具体来说， 通过过去的体外研究，iFyber已经表明该系统具有良好的抗菌和抗生物被膜能力。 体外和体外生物膜模型都证明了它的特性，在这些模型中，它的表现明显优于 市面上销售的革兰氏阳性/阴性细菌、酵母和霉菌的伤口护理敷料。结果 先导动物研究表明，该系统在活体内具有活性，但强调了配方 在进一步推进技术之前，将发展作为一个关键的重点领域。如果获得资金，iFyber的目标是利用这一点 第一阶段项目推进有效和创伤相关的局部配方，提供稳定和持久的 不--释放。这些配方将在计划于第二阶段进行的一系列动物研究中进一步推进。 一氧化氮释放技术提供了一种令人信服的替代标准抗菌治疗和 目前用于对抗伤口感染的抗生素。我们目前的数据集清楚地证明了 PVP/NO在解决微生物感染方面的临床效用，更重要的是，预防和 治疗困扰慢性皮肤伤口的微生物生物膜。这个第一阶段项目的一个重要里程碑 将通过开发基于PVP/NO的候选局部配方来扩展PVP/NO技术 这将作为一种针对微生物感染的非抗生素预防性治疗和一种治疗 对于慢性感染的伤口--伤口护理领域的两项未得到满足的需求。 第一阶段工作的完成将产生一个令人信服的数据集，其中概述了有效性并定义了 在局部应用方面对产品配方的最低要求。总之，这些研究将有助于 过渡到更广泛的第二阶段研究旨在支持以PVP/NO为基础的产品进入FDA的 监管流程。IFyber将讨论新开发的NO释放制剂的有效性 生物材料通过第一阶段的目标和任务概述如下： 目标1.通过筛选活动确定铅和意外情况下的专题配方 任务1.筛选基于PVP/NO的局部配方，以符合目标产品配置文件(TPP) 要求。过去的研发工作已经证明，如果不是这样，PVP/NO的释放是不会迅速的 防止同时暴露在氢/水中。在体内，这可能很难控制，在 需要持续释放。这可以通过控制PVP/NO在H/水中的暴露来实现 最近通过一种平衡的亲水性-亲脂性有机酸“BHLOA”方法显示 控制这些系统中的pH变化。在第一阶段，我们将在这些初步调查结果的基础上，进一步 推进BHLOA配方方法，以提供铅和支持PVP/NO配方 根据不释放和体外模型研究(任务2)的测试结果进行选择，然后 体内试验(任务3和4)。 任务2.验证抗生物被膜的效果，并选择铅和应急配方。这样做的目的是 任务1的任务是评估任务1中的候选配方在体外猪皮肤中的有效性 生物被膜模型以确定适用于伤口的抗微生物和抗生物被膜半固体敷料。A Main 这项任务的目标将是为实验动物研究(任务3和4)选择合适的配方。 目标2.通过临床前先导性研究指导PVP/NO原型开发 任务3.对选定的配方进行体内测试。通过以下方式确定的有希望的配方 任务1-2将在史蒂文·戴维斯教授的实验室进行的两项试验性活体研究中进行评估 在迈阿密大学。这些研究将确定生物被膜预防的有效性(研究1)和 减少现有的生物膜相关感染(研究2)，这些研究的结果将有助于 进一步向下选择用于未来第二阶段开发的PVP/NO配方。 任务4.确定PVP/NO的体内生物相容性基线。除了评估 预防感染和抗生物被膜的效果，候选PVP/NO制剂对非 还将根据伤口愈合过程评估感染伤口(研究3)；具体地说， 炎症反应、红斑、再上皮化、肉芽组织形成和初始分子 用于治疗和炎症过程的筛查。

The central goal of this SBIR research effort is to advance and commercialize a novel biomaterial with a nitric oxide (NO)-based delivery system for the wound care market. This Phase I proposal will build on iFyber’s strong preliminary data for this biomaterial as a potent antimicrobial and anti-biofilm platform. Specifically, through past in vitro studies, iFyber has shown this system to exhibit excellent antibacterial and anti-biofilm properties as evidenced by both in vitro and ex vivo biofilm models where it significantly outperforms commercially available wound care dressings for Gram positive/negative bacteria, yeast, and mold. Results form pilot animal studies have shown activity of this system, in vivo, but have highlighted formulation development as a key focus area prior to advancing the technology further. If funded, iFyber aims to use this Phase I project to advance effective and wound-relevant topical formulations that provide stable and sustained NO-release. These formulations will be further advanced in a full battery of animal studies planned for Phase II. Nitric oxide-releasing technologies offer a compelling alternative to standard antimicrobial treatments and antibiotics currently used to combat infection in wounds. Our current data set clearly demonstrate the potential clinical utility of PVP/NO in addressing microbial infection in general, and more importantly, prevention and treatment of microbial biofilms that plague chronic skin wounds. An important milestone for this Phase I project will be to expand on the PVP/NO technology by developing candidate PVP/NO-based topical formulations that will serve as a non-antibiotic prophylactic treatment against microbial infection and as a treatment for chronically infected wounds – two unmet needs within the wound care field. Completion of Phase I efforts will result in a compelling data set that outlines the efficacy and defines the minimal requirements for product formulation in terms of topical application. Together, these studies will help in the transition to broader Phase II studies aimed to support entry of a PVP/NO-based product into the FDA's regulatory process. iFyber will address the efficacy of the newly developed formulations of the NO-releasing biomaterial through the Phase I aims and tasks outlined below: AIM 1. Identify lead and contingency topical formulations through a screening campaign Task 1. Screen PVP/NO-based topical formulations for adherence to target product profile (TPP) requirements. Past R&D efforts have established that NO release from the PVP/NO is rapid if not protected from simultaneous exposure to H+/water. This can be difficult to control, in vivo, where sustained release is desired. This can be done by controlling the exposure of PVP/NO to H+/water as we have recently shown through a balanced hydrophilicity-lipophilicity organic acid “BHLOA” approach to controlling pH change in these systems. In Phase I we will build on these preliminary findings by further advancing the BHLOA formulation approach to provide lead and back up PVP/NO formulations that will be selected based on test results from the NO-release and ex vivo model studies (Task 2) followed by pilot in vivo studies (Tasks 3 and 4). Task 2. Verify anti-biofilm efficacy and select lead and contingency formulations. The goal of this task is to evaluate the efficacy of the candidate formulations from Task 1 in an ex vivo porcine dermal model of biofilm to define suitable antimicrobial and anti-biofilm semi-solid dressings for wounds. A main goal in this task will be to down-select formulations for pilot animal studies (Tasks 3 and 4). AIM 2. Guide PVP/NO prototype development through pre-clinical pilot studies Task 3. Conduct in vivo testing on selected formulations. Promising formulations identified through Tasks 1-2 will be evaluated in two pilot in vivo studies conducted in the laboratory of Prof. Steven Davis at the University of Miami. These studies will establish efficacy in biofilm prevention (study 1) and reduction in an existing biofilm-associated infection (study 2), and results of these studies will help to further down-select PVP/NO formulations for future Phase II development. Task 4. Determine the baseline in vivo biocompatibility profile of PVP/NO. In addition to assessing infection prevention and anti-biofilm efficacy, the effects of the candidate PVP/NO formulations on non- infected wounds will also be assessed with respect to the wound healing process (study 3); specifically, inflammatory response, erythema, re-epithelialization, granulation tissue formation, and initial molecular screens for healing and inflammatory processes.