DEVELOPMENT OF A GENERAL LETHAL CRITERION FOR IRREVERSIBLE ELECTROPORATION

Irreversible electroporation (IRE) is a non-thermal and promising technique for tumor ablation that generates an ablation zone producing permanent nanopores in the membrane of cells, thus leading to cell death. The ablation zone is determined with a designed treatment plan, including a selection of electric pulse scheme (or protocol) and an optimization for the configuration of electrodes surrounding tumor. The goal of treatment plan is to generate an ablation zone which can completely encompass the tumor while minimizing the damage to surrounding healthy tissue. The determination of ablation zone requires a criterion that can judge whether tumor tissue is dead or lethal after IRE ablation. Currently, the cell lethality criterion is represented by the electric field strength, i.e., a threshold called lethal electric field threshold (LET), under the electric field, above which cells are considered dead. In clinic, LET is experimentally determined first based on a tissue phantom of a type of cells (e.g., liver cancer cell) with a specific pulse protocol, and this LET was used to determine the ablation zone until which can exactly cover the tumor zone by adjusting the pulse strength and electrode configuration. There are several limitations with the current way that LET is determined. First, the tissue phantom can not represent real tissue in a sufficient accuracy. Second, the current LETs are highly context-dependent and not transferable between different cell types or pulse parameters. Third, individual differences among patients cannot be considered; more specifically, in clinical settings, the LET obtained from a disease (e.g., liver cancer) phantom is used as a representative across all liver cancer patients. To overcome the limitations of the current way of determining LET, this dissertation presents a body of work to develop a new methodology to determine LET. The proposed methodology is based on several ideas. The first idea is that individual patient cells in cluster are examined for their viability and LET is determined upon the condition that all cells in cluster are dead. The second idea is to establish a cellular lethal criterion which may be universally applicable across various types of cells. The study of this dissertation has developed (a) a testbed to facilitate the understanding and determination of LET for different types of cells and different pulse protocols, (b) an image-based method to automatically examine the morphology of cells, and (c) a simulation system for understanding the evolution of electro-pores. The finding of the study includes that (1) the lethality of a cell generated by electroporation is connected to the pore area ratio (PAR), which is defined as the ratio of pore areas to the cell surface area; (2) the cellular lethal criterion is constructed by three attributes, X: the percentage of cell membrane with pores; Y: the threshold of PAR with PAR greater than Y; Z: the duration of time for the state of PAR greater than Y; (3) by the study of a variety of cell lines and a variety of pulse protocols, the commonality with the cellular lethal criterion is surprisingly reached, i.e., X=33%, Y=0.0001, Z=309 microseconds; (4) the cellular lethal criterion has been verified to determine individualized LETs across different types of cells and pulse protocols comparing to the experimentation on monolayer cell phantoms with good alignments. As such, the cellular critical condition developed in this dissertation is also called General Lethal Criterion (GLC). This GLC can be used to determined LETs for different pulse protocols and cell/tissue types as a universal standard. Scientifically, this study discovers the knowledge about the lethality of cells under electrorotation, namely PAR and its spatiotemporal distribution, specifically constructing the GLC with three attributes suitable to different types of cells and different pulse protocols. This discovery has a profound contribution to the field of life science and medicine. Clinically, the outcome of this study has paved a way to significantly improve the quality of treatment of IRE ablation by considering individual differences in cancer tumors. There are a couple of future works. First, the accuracy of the GLC with three attributes needs to be further improved and their underlying biophysical and biochemical reason needs to be explored. Second, the clinical application of the GLC needs to be studied.

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biomedical Engineering

Grantor

University of Saskatchewan

Year dc:date.issued

2025

Author dc:creator

• Ding, Lujia

Advisors dc:contributor.advisor

• Zhang, Chris
• Moser, Michael

Committee members dc:contributor.committeemember

• Lin, Yen-Han
• Chen, Li
• Wilson, Lee
• Badea, Ildiko
• Davalos, Rafael

• General lethal criterion
• Irreversible electroporation

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10388/17064

OAI identifier oai:identifier

oai:harvest.usask.ca:10388/17064