univerza v ljubljani

damijan miklavcic

Damijan Miklavcic is a tenured professor at the Faculty of Electrical Engineering, University of Ljubljana. He is the world-leading expert in the field of electroporation. In the past 30 years, he contributed to a better understanding of electroporation on membrane, cell, and tissue level. He has been involved in basic research demonstrating on preclinical level improved efficacy of selected cancer drugs by electroporation, developing electrodes and devices, and providing numerical modelling towards treatment planning. He was involved in the development of irreversible electroporation for cardiac ablation, which holds great promise and lends itself as a game changer in cardiac electrophysiology. He is also developing DNA delivery to cells by electroporation for cell and gene-based therapies. According to Google scholar, his works received 33.273 citations, h-index 100.


Electroporation: from the laboratory technique to a technological platform – the complexity and interdisciplinary approach

When a cell is exposed to an electric field of sufficient amplitude its membrane becomes permeable for molecules that otherwise are deprived of transmembrane transport mechanisms. If electric pulse parameters are selected in a way to increase membrane permeability only transiently, the membrane reseals, and the cell survives. Initially, electroporation was introduced as a laboratory technique for bacteria transformation. It has later been demonstrated that electroporation of membrane can be achieved in all types of cells (including mammalian) and that they can be transfected by electroporation both in vitro and in vivo/in situ. This has recently been shown to be of use also in CAR-T cell-based treatments as well as for DNA-based vaccination.

The electroporation has grown from laboratory technique to a technological platform that is being used in food technology, biotechnology, and biomedicine. In tumor treatment it is used as electrochemotherapy or as an ablation method based on irreversible electroporation. Some chemotherapeutic drugs which have intracellular target but lack efficient transport across the membrane (e.g. bleomycin, cisplatin) can greatly benefit from membrane permeabilization (electroporation). Bleomycin cytotoxicity has been demonstrated to be increased 1.000-10.000 times, whereas for cisplatin this potentiation in vitro was 10-100 times. This potentiation of drug cytotoxicity was effectively translated from in vitro to in vivo preclinical trials and finally introduced into clinical practice as electrochemotherapy. The metastases of different origin have responded locally to electrochemotherapy with an overall complete response rate of 59.4% and objective response rate of 84.1%. Since 2006, electrochemotherapy has been introduced into more than 220 clinical centers in Europe with 3000 patients being treated in 2022 and is paving its way into standard clinical use. Electrochemotherapy however still awaits widespread adoption around the world.
Electroporation can also result in cell death through non-thermal mechanisms. This has been recognized as an efficient ablation method which kills the cells, but spares tissue scaffold and as such allows involvement of immune response and saving critical structures. Recent clinical trials in treating deep seated tumors by interventional radiologists by means of needle electrodes proved feasibility of irreversible electroporation being a treatment modality with promising prospects and as a valuable new tool in the armamentarium of oncologists.

As a nonthermal ablation irreversible electroporation was also developed and recently clinically tested in intracardiac ablation where it goes by the name of Pulsed Field Ablation (PFA). Cardiac ablation by irreversible electroporation, has been recognized as an effective nonthermal ablation modality benefiting from localized ablation of arrhythmogenic tissue while sparing surrounding critical structures as esophagus and phrenic nerve. The response of cells and tissue to high voltage electric pulses is, however, complex and requires further studies and thorough understanding. Electric pulses not only cause cell death, but also reversible electroporation, which renders cells (cardiomyocytes and nerves) transiently stunned. Electric pulses also affect tissue perfusion and can cause coronary spasms. Intracardiac delivery of high voltage electric pulses (in the order of 1000 V with currents 10 A) is challenging and may give rise to bubble formation in the left heart.
Based on the available evidence, the efficacy of PFA is comparable to established thermal ablation techniques in terms of treatment outcome but of unparalleled safety. The excellent safety profile of PFA is believed to be a result of its unique tissue selectivity, i.e., cardiac tissue being more sensitive to PFA than other tissues. Potentially, PFA represents a safe and effective solution for treatment of atrial fibrillation and is already being actively investigated for treating other arrhythmias. However, the exact mechanisms of PFA are not well understood. In addition, available PFA systems differ in their proprietary pulse waveforms, which are however thought to be an important variable of treatment success. To fully realize the potential of PFA, a thorough understanding of the molecular and cellular mechanisms of electroporation and their application in clinical practice is required. Also missing are intraprocedural indexes that will guide cardiac electrophysiologists to achieve durable transmural lesions.

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