(674b) Integration of Electrodes into Polymer Scaffolds for Near-Uniform Electric Field Distribution during Irreversible Electroporation

Irreversible electroporation (IRE) is an emerging ablation technology for cancer therapy targeting solid tumors. In order to facilitate application of IRE to disseminating cancer cells, we sought to integrate electrodes into microporous poly(caprolactone) (PCL) scaffolds that have previously been shown to recruit metastasizing cancer cells in vivo. Application of a conventional two-probe electrode results in establishment of a heterogeneous electric field within the treated tissue. While parallel plate electrodes offer the most uniform electric field distribution, facilitating uniform killing of cells throughout the tissue, incorporation of such electrodes into these scaffolds would be impractical as they would block the majority of the scaffold surface and thus impede cellular infiltration. We hypothesized that a metal mesh could be used in place of solid plates to enable infiltration while providing a more uniform electric field than the two-probe method. After identifying IRE parameters for complete in vitro ablation of B16 melanoma cells within polymer scaffolds (99 pulses with 100 μs pulse duration at 1 Hz and 1500-2000 V∙cm^-1field strength), COMSOL modeling was utilized to predict the spatial profile of electric field strength within the scaffold as a function of electrode design. When the simulation was constrained such that the average electric field strength across the scaffold for each electrode geometry was 2000 V∙cm^-1, the resulting volume-averaged electric field strength was 2000 ± 1012 V∙cm^-1for the two-probe electrode geometry, as compared to 2000 ± 150 V∙cm^-1for the parallel plate electrodes, with the lower standard deviation for the parallel plate geometry indicating a more uniform field distribution. Metal mesh electrodes with 0.348 mm aperture with 0.16 mm wire diameter provided a volume-averaged electric field strength of 2000 ± 210 V∙cm^-1, which was much closer to the uniformity of the parallel plate electrodes than the two-probe geometry. Importantly, as field strengths greater than 1500 V∙cm^-1 were required to kill B16 cells in vitro, the parallel plate and metal mesh electrodes were both predicted to established electric fields that would induce cell death throughout the entire treated scaffold. To experimentally test this metal mesh electrode geometry, we fabricated composite PCL-IRE scaffolds by placing cylindrical PCL scaffolds with 5 mm diameter, 2 mm height, and 250-425 µm pore size in between two PCL dip-coated 304 stainless steel #50 woven wire meshes with 5 mm diameter and the same aperture and wire diameter as in the simulation. When implanted in the dorsal subcutaneous region in mice, the PCL-IRE scaffolds exhibited no difference in cell infiltration compared to PCL scaffolds. In addition, upon application of the electric field in vivo, the cells infiltrating the PCL-IRE scaffolds were successfully ablated, as determined by histological analysis of the scaffolds three days post-treatment. Current efforts are focused on modifying the polymer to achieve inducible release of soluble factors upon application of the electric field in order to achieve local immune modulation of the scaffold site at the time of IRE-mediated ablation to enhance the response to treatment.