Development of a closed-loop control system for plasma medicine

项目摘要 血浆医学是一个有前途的、相对较新的领域，其包括发现和开发 冷等离子体的生物医学应用（a.k.a.非热、非平衡或大气等离子体）。冷 通过使用强电磁场在大气压下对气体进行电离来产生多种形式的等离子体。 压力和环境温度。当冷等离子体应用于活细胞或组织时， 从细胞代谢和功能的细微变化到程序性或坏死性细胞死亡，依赖于 血浆性质（或血浆量）。在涉及血浆的治疗策略中，所递送的剂量是血浆的浓度。 成功治疗的重要决定因素。次优的血浆剂量可能是无效的，而血浆 超过达到所需结果所需的剂量可能会引起不良副作用。但没有 存在有效血浆剂量的实时测量。等离子体的测定和控制输送 目前，剂量依赖于评估血浆的二级或三级效应的结果的经验性措施， 暴露后数小时至数天。迫切需要调节冷等离子体输送， 与生物学和临床相关的主要血浆效应物（标志物）的同时测量 定义血浆剂量所需的结局（终点）。这项资助的目的是开发端点 基于等离子体的治疗的检测策略，使用等离子体促进的伤口修复作为终点， 氧化还原电位（ORP）作为主要的可检测标志物。我们的假设是 之间的绝对氧化还原电位和细胞反应，使我们能够开发一种基于氧化还原电位传感器的方法， 监测等离子体剂量并将该信息输入闭环控制系统。拟议的研究是 创新，因为它将使用ORP检测作为传感器控制的闭环反馈控制的基础 将根据终点结果来调节血浆输送的系统。合作研究 和开发工作将结合联合收割机在体内伤口愈合模型（罗格斯大学）、体外 上皮伤口修复模型和血浆生物学（德雷克塞尔大学），具有设备工程方面的专业知识 和等离子体化学（北卡罗来纳州州立大学）。拟议的研究是围绕以下框架 具体目标：（1）建立CAP剂量范围、可测量的生物学参数和 使用伤口愈合的体内和体外模型的伤口愈合结果;（2）将传感器输出与 体外划痕试验中的细胞反应;（3）开发用于调节血浆的闭环控制系统 递送;和（4）在体外和体内挑战和优化控制器。我们专注于端点检测， 用于伤口愈合的反馈控制将促进用于这种特定治疗用途的开发努力， 等离子体，但也将提供一个坚实的基础，应用端点检测到其他翻译应用 冷等离子体，包括治疗皮肤病，癌症，以及病毒和细菌感染 病原体

Project Summary Plasma medicine is a promising, relatively new field that encompasses the discovery and development of biomedical applications for cold plasma (a.k.a. non-thermal, non-equilibrium, or atmospheric plasma). Cold plasma is generated in several forms by using a strong electromagnetic field to ionize gas at atmospheric pressure and ambient temperature. When cold plasma is applied to living cells or tissues, the effects can range from subtle changes in cellular metabolism and function to programmed or necrotic cell death, dependent on plasma properties (or amount of plasma). In therapeutic strategies involving plasma, the dose delivered is an important determinant of a successful treatment. A sub-optimal plasma dose may be ineffective, while a plasma dose in excess of that required to achieve the desired outcome may cause adverse side effects. However, no real-time measure of an effective plasma dose exists. The determination and controlled delivery of a plasma dose, at present, relies on empirical measures of outcome that assess secondary or tertiary effects of plasma hours to days after the exposure. There is a critical need for regulation of cold plasma delivery that uses concurrent measurement of primary plasma effectors (markers) that correlate with biological and clinical outcomes (endpoints) necessary to define plasma dose. The objective of this grant is to develop endpoint detection strategies for plasma-based therapies, using plasma-facilitated wound repair as the endpoint and oxidation-reduction potential (ORP) as the primary detectable marker. The hypothesis is that there is a link between the absolute ORP and cellular responses, allowing us to develop an ORP sensor-based method that monitors the plasma dose and feeds this information in a closed-loop control system. The proposed research is innovative because it will use ORP detection as the basis for a sensor-controlled, closed-loop feedback control system that will regulate plasma delivery as determined by the endpoint outcome. Collaborative investigational and development efforts will combine experience in models of in vivo wound healing (Rutgers University), in vitro models of epithelial wound repair, and plasma biology (Drexel University) with expertise in device engineering and plasma chemistry (North Carolina State University). The proposed research is framed around the following specific aims: (1) Establish correlations between CAP dose ranges, measurable biological parameters and wound healing outcomes using in vivo and in vitro models of wound healing; (2) correlate sensor outputs with cellular responses in the in vitro scratch assay; (3) develop a closed-loop control system for regulated plasma delivery; and (4) challenge and optimize the controller in vitro and in vivo. Our focus on endpoint detection and feedback control for wound healing will facilitate developmental efforts for this particular therapeutic use of plasma, but will also provide a solid foundation for applying endpoint detection to other translational applications of cold plasma, including therapies for dermatological conditions, cancer, and infections by viral and bacterial pathogens.