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Design and optimization of a cold plasma application system for endoscopic treatment

par Thulliez, Max
Président du jury Reniers, François
Promoteur Delchambre, Alain
Co-Promoteur Devière, Jacques
Publication Non publié, 2022-07-08

Thèse de doctorat

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Résumé :

Endoscopic Mucosal Ablation (EMA) is a minimally invasive procedure which eradicates adiseased mucosa to enable regeneration to a healthy state. The procedure is used in clinical practiceto treat a precancerous condition of the esophagus called Barrett’s Esophagus (BE). Anotherpromising indication being studied is the treatment of the mucosa in the first part of the intestine(the duodenum) to improve conditions linked to insulin resistance, including Type 2 Diabetes Mellitus(T2DM) and Non-Alcoholic SteatoHepatitis (NASH). This work aims to propose an alternativetechnique for EMA, in order to improve the treatment of BE and propose a new treatment modalityfor T2DM and NASH. To this end, Cold Atmospheric Plasma (CAP) is considered. CAP is anionized gas containing reactive species which produces a biochemical effect on tissues at ambienttemperature. Over the past two decades plasma treatment has proliferated mainly for the propertiesof its Reactive Oxygen and Nitrogen Species (RONS) on cells. RONS induce an oxidative stressand trigger signaling cascades, resulting in a large range of effects from stimulation (proliferation,regeneration) to cell death, notably by apoptosis, a natural programmed cell death which can reduceinflammation and post-op burden. CAP being a reactive gaseous medium, its diffusion would offera homogeneous, fast, safe, versatile and convenient way of treating large portions of mucosa withminimal complications. In order to assess the potential of CAP EMA, this thesis presents thedesign and optimization of a cold plasma generation, transport and application system followedby an assessment of safety, feasibility and efficacy of the procedure. After establishing the clinical,functional, and safety requirements, a plasma generation and transport system is presented. Itincludes a helium carrier gas ignited by a nanosecond pulsed high voltage generator in a DielectricBarrier Discharge chamber. The latter contains a copper wire to maintain the plasma active inpost-discharge, whilst it is blown in a multilumen catheter. The multilumen transports separatelyan additional gas (O2) to boost CAP reactivity at the treatment site, where the exiting plasmaplume constitutes the treatment tool. A chemical and biological characterization of the system andits effect was then performed. The analysis of the plasma plume chemistry, fluid dynamics and effecton a KI-starch agarose hydrogel tissue model developed for this work was performed depending ongas flow, oxygen fraction, treatment duration and configuration Gas flow strongly relies on fluiddynamics. Oxygen fraction drastically affects plasma chemistry, favoring different reactions andproducing important treatment differences. Treatment duration linearly affects the treatment dose.Then, on primary cancer cell lines and mouse intestinal organoids, the induction of apoptosis wasconfirmed and the biological action of CAP thoroughly analyzed. Finally, an endoscopic system wasimplemented to allow in vivo procedures on a porcine model, which confirmed safety, feasibility andshowed the potential of CAP with the induction of apoptosis in the mucosa and a mini-ablation.CAP treatment remains however insufficient to produce a full EMA and further improvements areneeded before it can become a viable clinical practice.