The Enhancement of Tumor Ablation Effect by the Combination of High-Frequency and Low-Voltage Bipolar Electroporation Pulses.

The H-FIRE (high-frequency irreversible electroporation) protocol employs high-frequency bipolar pulses (HFBPs) with a width of ∼1 µs for tumor ablation with slight muscle contraction. However, H-FIRE pulses need a higher electric field to generate a sufficient ablation effect, which may cause undesirable thermal damage. OBJECTIVE: Recently, combining short high-voltage IRE monopolar pulses with long low-voltage IRE monopolar pulses was shown to enlarge the ablation region. This finding indicates that combining HFBPs with low-voltage bipolar pulses (LVBPs), which are called composited bipolar pulses (CBPs), may enhance the ablation effect. METHODS: This study designed a pulse generator by modifying a full-bridge inverter. The cell suspension and 3D tumor mimic experiments (U251 cells) were performed to examine the enhancement of the ablation effect. RESULTS: The generator outputs HFBPs with 0-±2.5 kV and LVBPs with 0-±0.3 kV in one period. The pulse parameters are adjustable by programming on a human-computer interface. The cell suspension experiments showed that CBPs could enhance cytotoxicity, as compared to HFBPs with no cell-killing effect. Even at lower electric energy, the cell viability by CBPs was significantly lower than that of the HFBPs protocol. The ablation experiments on the 3D tumor mimic showed that the CBPs could create a larger connected ablation area. In contrast, the HFBPs protocol with a similar dose generated a nonconnected ablation area. CONCLUSION: Results indicate that the CBPs protocol can enhance the ablation effect of HFBPs protocol. SIGNIFICANCE: This proposed generator that uses the CBPs principle may be a useful tool for tumor ablation.

The Enlargement of Ablation Area by Electrolytic Irreversible Electroporation (E-IRE) Using Pulsed Field with Bias DC Field.

Irreversible electroporation (IRE) by high-strength electric pulses is a biomedical technique that has been effectively used for minimally invasive tumor therapy while maintaining the functionality of adjacent important tissues, such as blood vessels and nerves. In general, pulse delivery using needle electrodes can create a reversible electroporation region beyond both the ablation area and the vicinity of the needle electrodes, limiting enlargement of the ablation area. Electrochemical therapy (EChT) can also be used to ablate a tumor near electrodes by electrolysis using a direct field with a constant current or voltage (DC field). Recently, reversible electroporated cells have been shown to be susceptible to electrolysis at relatively low doses. Reversible electroporation can also be combined with electrolysis for tissue ablation. Therefore, the objective of this study is to use electrolysis to remove the reversible electroporation area and thereby enlarge the ablation area in potato slices in vitro using a pulsed field with a bias DC field (constant voltage). We call this protocol electrolytic irreversible electroporation (E-IRE). The area over which the electrolytic effect induced a pH change was also measured. The results show that decreasing the pulse frequency using IRE alone is found to enlarge the ablation area. The ablation area generated by E-IRE is significantly larger than that generated by using IRE or EChT alone. The ablation area generated by E-IRE at 1 Hz is 109.5% larger than that generated by IRE, showing that the reversible electroporation region is transformed into an ablation region by electrolysis. The area with a pH change produced by E-IRE is larger than that produced by EChT alone. Decreasing the pulse frequency in the E-IRE protocol can further enlarge the ablation area. The results of this study are a preliminary indication that the E-IRE protocol can effectively enlarge the ablation area and enhance the efficacy of traditional IRE for use in ablating large tumors.

A fundamental theoretical study on the different effect of electroporation on tumor blood vessels and normal blood vessels.

Electroporation achieved by the application of pulsed electric field is successfully used for clinical tumor ablation. Electrochemotherapy (ECT) and irreversible electroporation (IRE), which are two protocols based on electroporation, have been shown to ablate only tumor cells while preserving the function of normal blood vessels. However, the mechanism of this unique advantage is still not fully understood. This study first built a multilayer dielectric model of both normal and tumor blood vessels to study the electroporation effect. Since endothelial cells are the main component of normal and tumor blood vessels, this study mainly analyzed the electroporation effect on endothelial cells. The rich vascular smooth muscle cells (VSMCs), could play a protective function, allowing endothelial cells to suffer less electroporation effect in normal blood vessels. Interestingly, the endothelial cells in tumor blood vessel sustained a stronger electroporation effect than those in normal blood vessels due to the lack of VSMCs. This study may provide a conceivable explanation for why the structure of endothelial cells in normal blood vessels is preserved during electroporation treatment. This study also demonstrates that ECT or IRE may also damage both tumor blood vessels and cells while preserving normal blood vessels, which benefits complete tumor ablation.