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Tools and methods for in vivo electroporation

Final Report Summary - TAMIVIVE (Tools and methods for in vivo electroporation)

The general objective of the TAMIVIVE project was to develop tools and methods for electroporation and, in particular, for clinical treatments based on electroporation. Being a project funded by a Marie Curie International Reintegration Grant (IRG), an underlying objective of the project was to facilitate the integration of the beneficiary researcher, Dr. Antoni Ivorra, into the European research arena for electroporation as an independent researcher.
Electroporation, or electropermeabilization, is the phenomenon in which cell membrane permeability to ions and molecules is increased after exposing the cell to high electric fields, either in the form of short DC pulses or in the form of short AC bursts. During the last decades, use of the electroporation phenomenon has become a routine technique in microbiology laboratories for in vitro gene transfection. Recent discoveries showing that electroporation can also enhance in vivo gene transfection, enhance in vivo uptake of chemotherapeutic agents for cancer treatment and ablate tissues in a non-thermal mode have promoted the use of electroporation for clinical treatments and, particularly, for cancer treatment.
Depending on the number of pulses, their magnitude, their duration and other factors, permeabilization induced by electroporation will be temporary and will not compromise viability of the cell (i.e. "reversible electroporation") or will be permanent, or too intense, so that cell homeostasis will be severely disrupted and the cell will end up dying by necrotic or apoptotic processes (i.e. "irreversible electroporation", IRE). Reversible electroporation is the basis for “electrogenetherapy”, which consists in facilitating gene delivery to cells in tissue by electric pulses for therapeutic purposes, and it is also the basis for “electrochemotherapy”, which consists in facilitating the penetration of anticancer drugs into malignant cells in tissue. Irreversible electroporation is the basis for a novel non-thermal tissue ablation method which is sometimes labeled as Non-Thermal Irreversible Electroporation (NTIRE) and which is employed for destroying solid tumors.
The project has produced wide-ranging results in the field of electroporation. For instance, it has shown that pancreatic tumors in mice can be safely ablated using irreversible electroporation (Cancer Letters 2012 317(1):16-23) and it has demonstrated a new industrial method for liquid media pasteurization based on applying radiofrequency electric fields which also cause irreversible electroporation (Innovative Food Science & Emerging Technologies 2014 22:116-123).
A specific objective of the project was to develop tools and methods for managing the electric field distribution in tissue electroporation treatments since such distribution determines the treatment extent and effectiveness. In relation to that it must be pointed out the development of minimally invasive electrodes for clinical electroporation and a mechanism for deploying them (pending for publication and patent application). Also in relation with field management it must be noted a long term ongoing collaboration with a team of clinicians for simultaneously treating multiple liver tumor nodules by means of irreversible electroporation. The technique proposed for such liver treatment is based modulating the electrical conductivity of tissues by means of ionic fluids.
Equally significant, if not more so, are the developments in the broad field of clinical bioelectricity that spun out from the electroporation focus of the project. In this sense it is worth noting the invention of an electrochemical method for preventing needle tract tumor seeding when biopsies are taken (Ann Biomed Eng. 2011 39(7):2080-9, WO/2012/080394) which in turn spun out the development of a method for preventing infections when prostate biopsies are taken (WO/2014/064304) which is a major clinical problem with market implications and now is being explored by Dr. Ivorra and colleagues for industrial development and commercialization. Also in the same sense it is worth noting the development of a heterodox method for performing functional electrical stimulation by means of implantable micro-stimulators. This method has the potential to reduce the diameter of the implants to one-tenth the diameter of current micro-stimulators and, more importantly, to allow that most of the implants’ volume consists of flexible materials (PLoS One. 2011 6(8):e23456, Biosystems & Biorobotics 2014 7: 447-455). Among other clinical applications, these micro-stimulators could be the basis for solutions to patients suffering paralysis due to spinal cord injury or other neurological disorders
Scholarly, in quantitative terms, the project has yielded six peer-reviewed journal publications and two patents, among other results.
The project has also been successful regarding the underlying objective of the project, that is, to facilitate the integration of the beneficiary researcher into the European electroporation research arena as an independent researcher. First it must be pointed out that the grant has been pivotal for establishing his own independent lab ( now composed by 3 PhD students, the beneficiary researcher and a variable number of MSc and undergrad students. Now the beneficiary researcher has a broad network of collaborators in the electroporation field and participates, as founding member and member of the management team, in the COST Action “European network for development of electroporation-based technologies and treatments” (EP4Bio2Med). In addition, this grant has also facilitated securing two national grants and it could result in securing an ERC Consolidator grant in the future as the beneficiary researcher successfully went through the first stage in the evaluation process with a project proposal based on the micro-stimulators technology that spun out of the TAMIVIVE project.