Mechanistic view of skin electroporation – models and dosimetry for successful applications: an expert review

ABSTRACT

Introduction

Skin electroporation is a promising treatment for transdermal drug delivery, gene electrotransfer, skin rejuvenation, electrochemotherapy, and wound disinfection. Although a considerable amount of in vitro and in vivo studies exists, the translation to clinics is not as fast as one would hope. We hypothesize the reason lies in the inadequate dosimetry, i.e. electrode configurations, pulse parameters, and pulse generators used. We suggest adequate dosimetry can be determined by mathematical modeling which would allow comparison of protocols and facilitate translation into clinics.

Areas covered

We introduce the mechanisms and applications of skin electroporation, present existing mathematical models and compare the influence of different model parameters. We review electrodes and pulse generators, prototypes, as well as commercially available models.

Expert opinion

The reasons for slow translation of skin electroporation treatments into clinics lie in uncontrolled and inadequate dosimetry, poor reporting rendering comparisons between studies difficult, and significant differences in animal and human skin morphology often dismissed in reports. Mathematical models enable comparison of studies, however, when the parameters of the pulses and electrode configuration are not adequately reported, as is often the case, comparisons are difficult, if not impossible. For each skin electroporation treatment, systematic studies determining optimal parameters should be performed and treatment parameters standardized.

KEYWORDS:

• Computer models
• dosimetry
• electrodes
• gene electrotransfer
• mathematical models
• mesotherapy
• pulse generator
• pulse generators
• skin electroporation
• skin rejuvenation
• transdermal drug delivery
• wound disinfection

Article highlights

• Mathematical models of skin electroporation facilitate our understanding of the phenomena, help to reveal relevant parameters for treatment efficacy, decrease the number of in vitro and in vivo experiments needed and enable predictions about the treatment efficacy.

• One of the reasons for slow translation of skin electroporation into clinics are non-standard pulse parameters, non-standard electrode configurations, generators not complying with their technical specifications or lacking technical specifications, poor or missing reporting on the delivered waveforms, electric field distribution, not performing the current–voltage measurements and significantly different skin structure of animals and humans.

• We suggest guidelines for reporting the dosimetry to be followed. The use of high-quality electroporation equipment, with reliable and traceable operation, together with controlled dosimetry and predictive modeling raises the quality of studies and enables faster development of the field and eventual translation into clinics.

• We propose that the pulse parameters and electrode configurations for skin electroporation should be determined and standardized with the use of mathematical models, taking into account the electric field distribution, electrical, thermal, and chemical damage, drug/plasmid distribution and other parameters, deemed relevant for the treatment.

• When designing new clinical as well as esthetic (for the use in cosmetics) pulse generators, these should comply with existing standards. In Europe, they have to comply with a Medical Device Regulation MDR 2017/745, and in the USA, the device should be approved by the FDA (Food and Drug Administration). Also, new standards specific to electroporation devices should be developed.

This box summarizes the key points contained in the article.

Acknowledgments

The authors would like to thank dr. B. Kos and H. Cindrič for their help with numerical model and dr. M. Reberšek for his help with hardware review.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was partly supported by the Slovenian Research Agency (ARRS) [research core funding No. P2-0249] and partly by the Republic of Slovenia and the European Regional Development Fund within the scope of the Smartgene.si project.