UC Berkeley

Non-thermal irreversible electroporation (IRE) is a new minimally invasive surgical technique that is part of the emerging field of molecular surgery which holds the potential to treat diseases with unprecedented accuracy. IRE utilizes electrical pulses delivered to a targeted area, producing irreversible damage to the cell membrane. While electroporation is not fully understood to date, evidence indicates that this damage is induced by the increased transmembrane potential due to high voltage pulses affecting the lipid bilayer. Because IRE does not cause thermal damage, the integrity of all other molecules and only effects cellular structures, collagen and elastin in the targeted area is preserved.

Previous theoretical studies have only examined IRE in homogeneous tissues. However, tissues can be heterogeneous in two different capacities: 1) they can be intrinsically heterogeneous due to anatomy, and 2) they can be extrinsically heterogeneous due to external factors. This investigation of heterogeneous tissues studies both cases in order to expand the depth and breadth of the field of electroporation.

Intrinsic Heterogeneous Tissues

Because biological structures are complex collections of diverse tissues it becomes imperative to consider intrinsic heterogeneities. In order to develop electroporation as a precise treatment in clinical applications, realistic models for pre-surgical planning are necessary. In this way, the study of heterogeneous tissues will enable refinement of electroporation as a treatment. In this chapter, three different intrinsic heterogeneous structures were taken into account: nerves, blood vessels and lactiferous ducts. The subsequent results made it clear that heterogeneities significantly impact both the temperature and electrical field distribution in surrounding tissues, indicating that heterogeneities should not be neglected. While the surrounding tissue experienced a high electrical field, the axon of the nerve, the interior of the blood vessel and the ducts experienced no electrical field. This indicates that blood vessels, nerves and lactiferous ducts adjacent to a tumor treated with electroporation have the potential to survive, while the cancerous lesion is ablated. This clearly demonstrates the importance of considering heterogeneity in IRE applications.

Extrinsic Heterogeneous Tissues

Extrinsic heterogeneous tissues can be induced by various external factors. One such factor is an applied temperature gradient. Two different temperature gradients were considered in this investigation: 1) subzero temperatures, induced by cryosurgery, and 2) cooling temperatures.

Cryosurgery, tissue ablation by freezing, is a well-established minimally invasive surgical technique. The goal of this investigation was to study extrinsic heterogeneous tissues induced by externally applied subzero temperatures by combining cryosurgery and electroporation. Analysis of the electric field and temperature distribution during simultaneous tissue treatment with cryosurgery and irreversible electroporation (cryoIRE) was used to study the effect of tissue freezing on electric fields. The results indicate that this combination may resolve some of the major disadvantages that occur in each technology when used alone. Because of decreased electrical conductivity in the frozen tissue, this region experienced temperature induced magnified electric fields in comparison to IRE delivered to unfrozen tissue, the control case. This suggests that freezing confines and magnifies the electric fields to those regions; a targeting capability unattainable in traditional electroporation. This analysis also shows how temperature induced magnified and focused IRE can be used to ablate cells in the high subzero freezing region of a cryosurgical lesion, in which cells can be resistant to freezing damage.

The next heterogeneous tissues that were studied were heterogeneities extrinsically produced by cooling. This chapter explores the hypothesis that non-subzero temperature dependent electrical parameters of tissue can also be used to modulate the outcome of IRE protocols, providing a new means for controlling and optimizing this minimally invasive surgical procedure. This chapter investigates two different applications of cooling temperatures applied during IRE. The first case utilizes an electrode which simultaneously delivers electric fields and cooling temperatures. The subsequent results demonstrate that changes in electrical properties due to temperature produced by this configuration can substantially magnify and confine the electric fields in the cooled regions while almost eliminating electric fields in surrounding regions. This method can be used to increase precision in IRE procedures, and eliminate muscle contractions and damage to adjacent tissues. The second configuration considered introduces a third probe that is not electrically active and only applies cooling boundary conditions. This second configuration demonstrates that with this probe geometry the temperature induced changes in electrical properties of tissue substantially reduce the electric fields in the cooled regions. This novel treatment can potentially be used to protect sensitive tissues from the effect of IRE.

Perhaps the most important conclusion of this investigation is that temperature is a powerful and accessible mechanism to modulate and control electric fields in biological tissues and can therefore be used to optimize and control IRE treatments.