Development of a closed-loop control system for plasma medicine

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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.