Invasive and non-invasive electrodes for successful drug and gene delivery in electroporation-based treatments

Abstract

Electroporation is an effective physical method for irreversible or reversible permeabilization of plasma membranes of biological cells and is typically used for tissue ablation or targeted drug/DNA delivery into living cells. In the context of cancer treatment, full recovery from an electroporation-based procedure is frequently dependent on the spatial distribution/homogeneity of the electric field in the tissue; therefore, the structure of electrodes/applicators plays an important role. This review focuses on the analysis of electrodes and in silico models used for electroporation in cancer treatment and gene therapy. We have reviewed various invasive and non-invasive electrodes; analyzed the spatial electric field distribution using finite element method analysis; evaluated parametric compatibility, and the pros and cons of application; and summarized options for improvement. Additionally, this review highlights the importance of tissue bioimpedance for accurate treatment planning using numerical modeling and the effects of pulse frequency on tissue conductivity and relative permittivity values.

Keywords: electrical tissue properties; electrodes; electroporation; spatial electric field distribution; tumors.

FIGURE 1

Most common keywords used in electroporation studies. Visualized using VOSviewer software, version 1.6.18 (Leiden University) (VOSviewer - Visualizing scientific landscapes, 2022). A filter of at least 30 minimum occurrences of the keywords has been used. Bigger circle size indicates higher rate of occurrence of a specific keyword.

FIGURE 2

Skin illustration: (A) healthy tissue; (B) cutaneous tumor (melanoma); (C) superficial or exophytic tumor; (D) deep-seated tumor.

FIGURE 3

Spatial electric field distribution of two-needle fixed-position electrodes (A–F) and non-parallelism issue with adjustable electrodes (G–I) with different lengths and gap size, using 500 V terminal voltage: (A) 5 mm gap between electrodes; (B) 10 mm gap between electrodes; (C) 15 mm gap between electrodes; (D) 20 mm length electrodes with 5 mm gap; (E) 20 mm length electrodes with 5 mm and 10 mm gap, top view; (F) 20 mm length electrodes with 10 mm gap, side view; (G) electrodes are rotated by 10° and 5°; (H) both electrodes are rotated by 8° and −8°; (I) both electrodes are rotated by −10° and 10°.

FIGURE 4

Array of adjustable needle electrodes for (A) corneous tumors and (B) deep-seated tumors.

FIGURE 5

Deployable expandable electrodes: (A) 5-needle electrode structure; (B) 4-needle electrode structure with 2 cm extension; (C) spatial electric field distribution of the 5-needle electrode when positioned at 0° angle; (D) spatial electric field distribution of the 4-needle electrode when positioned at 0° angle; (E) spatial electric field distribution of the 5-needle electrode when positioned at 10° angle; (F) spatial electric field distribution of the 4-needle electrode when positioned at 10° angle; (G) spatial electric field distribution of the 5-needle electrode when positioned at 20° angle; (H) spatial electric field distribution of the 4-needle electrode when positioned at 20° angle; (I) spatial electric field distribution of the 5-needle electrode when positioned at 30° angle; (J) spatial electric field distribution of the 4-needle electrode when positioned at 30° angle. *Simulation performed includes single diagonal and semi-diagonal terminal voltages (0°—120 V, 10°—1100 V, and 20° and 30°—1700 V).

FIGURE 6

Spatial electric field distribution generated by hexagonal and intradermal needle-type electrode arrays with 1500 V and 600 V terminal voltages, respectively, taking into account different depths of penetration. (A) Hexagonal electrodes, top view; (B) hexagonal 20-mm-length electrodes, side view; (C) hexagonal 30-mm-length electrodes, side view; (D) intradermal electrodes, top view; (E) intradermal 2-mm-length electrodes, side view; (F) intradermal 10-mm-length electrodes, side view.

FIGURE 7

Single-needle electrode model: (A) electrode structure; (B) spatial electric field distribution with 1300 V terminal voltage.

FIGURE 8

Curved electrodes using 1500 V terminal voltage. *Cp represents cut planes for electric field distribution analysis.

FIGURE 9

Microneedle array (A–F) and multi-needle roller (G–I) electrodes when 100 V voltage is applied: (A–D) microneedle array model; (E) spatial electric field distribution, top view; (F) spatial electric field distribution, side view; (G) multi-needle roller model; (H) spatial electric field distribution without conductive gel; (I) spatial electric field distribution with conductive gel channels.

FIGURE 10

Spatial electric field distribution of plate and round tweezer electrodes using 1000 V and 200 V terminal voltages, respectively. (A) Electroporation of a superficial tumor, when plates embrace the tumor sufficiently, side view; (B) electroporation of a superficial tumor, when plates embrace the tumor insufficiently, side view; (C) electroporation of the superficial tumor, top view; (D) electroporation of the skin, side view; (E) electroporation of melanoma or a small superficial tumor; (F) electroporation of the skin or melanoma, top view; (G) round tweezer electrode simulation model; (H) spatial electric field distribution, side view; (I) spatial electric field distribution, top view.

FIGURE 11

L-shaped (A–B) and 4-plate electrodes with (D–F) and without expansion (G–I) when 1300 V terminal voltage is used. (A) L-shaped electrode structure; (B) spatial electric field distribution, top view; (C) spatial electric field distribution, side view; (D) 4–plate electrode structure without plate expansion; (E) spatial electric field distribution without plate expansion, top view; (F) spatial electric field distribution without plate expansion, side view; (G) 4-plate electrode structure with plate expansion; (H) spatial electric field distribution with plate expansion by 8°, top view; (I) spatial electric field distribution without plate expansion by 8°, side view.

FIGURE 12

Micromachined pliable electroporation patch (ep-Patch) with rectanglular parallel gold electrodes, using 50 V terminal voltage. (A) Electrode structure; (B) spatial electric field distribution, top view; (C) spatial electric field distribution, side view.

FIGURE 13

Plate-and-fork-type electrodes using 500 V terminal voltage. (A) Commercially available electrodes; (B) electrode structure; (C) spatial electric field distribution, side view; (D) spatial electric field distribution, top view.