Periodic Reporting for period 1 - IgnitePLASMA (A minimally Invasive surgical platform aGainst paNcreatIc and biliary Tract cancErs using cold atmospheric PLASMA)
Reporting period: 2024-04-01 to 2025-03-31
Pancreatic (PC) and biliary tract (BTC) cancer are rare gastrointestinal adenocarcinomas with an increasing incidence particularly among the elderly and women, and a poor prognosis poses major clinical challenges and public health burden. Cold atmospheric pressure plasma (CAP) has shown potential regressing various cancer types in the lab setting. Owing to their low gas temperature, CAP is a unique source of high concentrations of reactive radicals, electrons, ions, UV etc., which may induce various effects in living tissue. CAP has shown selectivity in where cancer cells are treated with minimal effect to healthy ones. This renders plasma suitable to treat carcinomas in very sensitive areas or organs where an unmet need to minimise damage/side-effects exists. CAP can be delivered through dielectric tubes of variable length, makes it ideal for minimally invasive and precise laparoscopic and endoscopic cancer operations. Despite the great promise and potential of this concept, there is no single laparoscopic or endoscopic medical platform in the market today based on CAP to treat carcinomas. This project proposes a novel solution using cutting edge plasma technology, modelling, and a system-level approach. The in-silico will combine plasma fluid with solid tumour simulation so the diffusion and effect of the plasma reactive species, electric field on the carcinoma can be determined. Furthermore, it will take input from pre-surgery diagnostics (MRI, ultrasound, etc.) for model initialisation and primary plasma operational window determination. During surgery, diagnostics will feed a Bayesian optimisation model for personalised automatic adaptation so that the desired dose of CAP therapeutic agents is delivered to the patient. The technology will be demonstrated through in-vivo experiments, thus, lay the foundation for clinical trials and market introduction for the care of PC/BTCs.
In the first twelve (12) months of the project there has been significant scientific and technological progress towards realizing the long term vision of bringing cold atmospheric pressure plasma to to the patient for the treatment of pancreatic and biliary cancer. Specifically:
Work Package 1 (WP1). CAP (Cold Atmospheric Pressure plasma) sources design, implementation. The first operating version of the plasma platform for the biological experiments (in SU) has been developed. Specifically, the hardware (i.e. mechanical, electrical, electronics, and optical components) and the software (multiple-microprocessor programming, graphic user interface / touchscreens, and closed loop schedule) of the plasma platform (both for the sinusoidal and pulsed versions) has been designed, while the sinusoidal version has been fully implemented and it is ready for testing. It is standalone and it can be adapted to meet the needs of diverse end-users in plasma biomedicine (for either basic research or/and industrial applications). It features close loop operation where the source can lock into one parameter (such as voltage, current, power, etc.) and keep it stable irrespective of the operating environment.
Work Package 2 (WP2).Therapeutic effect of CAP on preclinical cancer models. Using both ex vivo human liver slices and primary human epithelial cells, we demonstrated that CAP induces dose-dependent cytotoxicity, with greater sensitivity observed in tumor cells than in healthy hepatocytes and biliary epithelial cells. Notably, mesenchymal-like biliary cancer cells (HuCCT1) were more sensitive than epithelial-like ones (EGI-1), suggesting phenotype-dependent selectivity. Direct CAP exposure triggered DNA damage and apoptosis, while plasma-activated medium (PAM) had no cytotoxic effect on healthy cells, underscoring the role of non-chemical plasma components. In vivo/Ex vivo experiments on mice models showed that CAP significantly delayed tumor growth without visible skin damage or hazardous heating. However, reactive species (RONS) did not penetrate the skin barrier, highlighting its protective role. Efforts to establish real-time treatment monitoring identified temperature and surrogate markers as potential avenues.
Work Package 3: Plasma and cancer/host tissue in-silico models and digital interface. Developed two in silico models of coupled gas flow and plasma dynamics, a plasma-chemistry reduction mode, and an agent-based model for cancer cell dynamics. On the first leg of the modelling efforts, we have considerable progress where we are at the stage of the final validation tests of a 3D fluid dynamics / cold atmospheric plasma simulator that encompasses modelling the formation and propagation of streamer discharges while assuming a simplistic model of plasma chemistry. In parallel we have been developing a 2D-axisymmetric version of the above that accounts for a detailed description of the plasma chemistry. To bridge the two modelling approaches (the coarse-grained plasma chemistry but 3D geometry model versus the detailed plasma chemistry but 2D geometry model), and lead towards accelerating the computational efficiency of our in silico platform, we have built a Python-based plasma-chemistry reduction library, and we are at the stage of completing the validation and performance tests of our library. Finally, we develop an agent-based model to simulate the dynamics of (cancerous and host) cell, model the cell—cell and cell—matrix interactions, while also we are building ODE solvers to simulate intracellular processes as well as the effect of plasma reactive species on cell viability and cytotoxicity.
Work Package 1 (WP1). CAP (Cold Atmospheric Pressure plasma) sources design, implementation. The first operating version of the plasma platform for the biological experiments (in SU) has been developed. Specifically, the hardware (i.e. mechanical, electrical, electronics, and optical components) and the software (multiple-microprocessor programming, graphic user interface / touchscreens, and closed loop schedule) of the plasma platform (both for the sinusoidal and pulsed versions) has been designed, while the sinusoidal version has been fully implemented and it is ready for testing. It is standalone and it can be adapted to meet the needs of diverse end-users in plasma biomedicine (for either basic research or/and industrial applications). It features close loop operation where the source can lock into one parameter (such as voltage, current, power, etc.) and keep it stable irrespective of the operating environment.
Work Package 2 (WP2).Therapeutic effect of CAP on preclinical cancer models. Using both ex vivo human liver slices and primary human epithelial cells, we demonstrated that CAP induces dose-dependent cytotoxicity, with greater sensitivity observed in tumor cells than in healthy hepatocytes and biliary epithelial cells. Notably, mesenchymal-like biliary cancer cells (HuCCT1) were more sensitive than epithelial-like ones (EGI-1), suggesting phenotype-dependent selectivity. Direct CAP exposure triggered DNA damage and apoptosis, while plasma-activated medium (PAM) had no cytotoxic effect on healthy cells, underscoring the role of non-chemical plasma components. In vivo/Ex vivo experiments on mice models showed that CAP significantly delayed tumor growth without visible skin damage or hazardous heating. However, reactive species (RONS) did not penetrate the skin barrier, highlighting its protective role. Efforts to establish real-time treatment monitoring identified temperature and surrogate markers as potential avenues.
Work Package 3: Plasma and cancer/host tissue in-silico models and digital interface. Developed two in silico models of coupled gas flow and plasma dynamics, a plasma-chemistry reduction mode, and an agent-based model for cancer cell dynamics. On the first leg of the modelling efforts, we have considerable progress where we are at the stage of the final validation tests of a 3D fluid dynamics / cold atmospheric plasma simulator that encompasses modelling the formation and propagation of streamer discharges while assuming a simplistic model of plasma chemistry. In parallel we have been developing a 2D-axisymmetric version of the above that accounts for a detailed description of the plasma chemistry. To bridge the two modelling approaches (the coarse-grained plasma chemistry but 3D geometry model versus the detailed plasma chemistry but 2D geometry model), and lead towards accelerating the computational efficiency of our in silico platform, we have built a Python-based plasma-chemistry reduction library, and we are at the stage of completing the validation and performance tests of our library. Finally, we develop an agent-based model to simulate the dynamics of (cancerous and host) cell, model the cell—cell and cell—matrix interactions, while also we are building ODE solvers to simulate intracellular processes as well as the effect of plasma reactive species on cell viability and cytotoxicity.
It is expected that the successful completion of the project and especially the implementation of the long-term vision (of being able to provide effective therapy for pancreatic and biliary tract cancer) will have significant impact in the life of the patients and their families, in the economy (producing licensing, patents possible startups, hiring early-stage researchers etc.). Within the first year of the project, we can see the foundations for this impact in the following categories:
Citizens: Admittedly there is minimal impact on citizens in the first year of the project. However, the long-term vision of the project will have the highest impact on the citizens by providing therapy for cancers with very poor prognosis.
Economy: This project has brought employment opportunities for researchers and engineers in Cyprus, Greece and France. Currently, three are plans for filing for IP protection and taking steps for commercialization.
Early-Stage Players: An early-stage researcher (ESR) member from UCY, started working in the project from June 2024 having an important contribution in the development of the numerical models was awarded the prestigious MSCA fellowship supervised by Prof. Vasileios Vavourakis under the MSCA COFUND 2020 ONISILOS program hosted by UCY. This represents a major achievement for his career and is a testament of the quality of the work he developed at IgnitePLASMA. Furthermore, young PhDs (one from UCY, one from SU and one from UP), undergraduate (one from UP), and Masters (one from UP) students have been actively involved in the project. This provides them an excellent opportunity to learn (and be exposed to) plasma physics, biology, medical applications and the management and forming of international consortia.
Citizens: Admittedly there is minimal impact on citizens in the first year of the project. However, the long-term vision of the project will have the highest impact on the citizens by providing therapy for cancers with very poor prognosis.
Economy: This project has brought employment opportunities for researchers and engineers in Cyprus, Greece and France. Currently, three are plans for filing for IP protection and taking steps for commercialization.
Early-Stage Players: An early-stage researcher (ESR) member from UCY, started working in the project from June 2024 having an important contribution in the development of the numerical models was awarded the prestigious MSCA fellowship supervised by Prof. Vasileios Vavourakis under the MSCA COFUND 2020 ONISILOS program hosted by UCY. This represents a major achievement for his career and is a testament of the quality of the work he developed at IgnitePLASMA. Furthermore, young PhDs (one from UCY, one from SU and one from UP), undergraduate (one from UP), and Masters (one from UP) students have been actively involved in the project. This provides them an excellent opportunity to learn (and be exposed to) plasma physics, biology, medical applications and the management and forming of international consortia.