Research Papers

Principles of Tissue Engineering With Nonthermal Irreversible Electroporation

[+] Author and Article Information
Mary Phillips

Department of Mechanical Engineering, University of California, Berkeley, 6124 Etcheverry Hall, Berkeley, CA 94720mary_phillips@berkeley.edu

Elad Maor

Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA 94720eladmaor@gmail.com

Boris Rubinsky

Department of Mechanical Engineering and Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA 94720brubinsky@gmail.com

J. Heat Transfer 133(1), 011004 (Sep 27, 2010) (8 pages) doi:10.1115/1.4002301 History: Received February 25, 2010; Revised March 19, 2010; Published September 27, 2010; Online September 27, 2010

Nonthermal irreversible electroporation (NTIRE) is an emerging tissue ablation modality that may be ideally suited in developing a decellularized tissue graft. NTIRE utilizes short electric pulses that produce nanoscale defects in the cell membrane lipid bilayer. The electric parameters can be chosen in such a way that Joule heating to the tissue is minimized and cell death occurs solely due to loss in cell homeostasis. By coupling NTIRE with the body’s response, the cells can be selectively ablated and removed, leaving behind a tissue scaffold. Here, we introduce two different methods for developing a decellularized arterial scaffold. The first uses an electrode clamp that is applied to the outside of a rodent carotid artery and the second applies an endovascular minimally invasive approach to apply electric fields from the inner surface of the blood vessels. Both methods are first modeled using a transient finite element analysis of electric and thermal fields to ensure that the electric parameters used in this study will result in minimal thermal damage. Experimental work demonstrates that both techniques result in not only a decellularized arterial construct but an endothelial regrowth is evident along the lumen 7 days after treatment, indicating that the extracellular matrix was not damaged by electric and thermal fields and is still able to support cell growth.

Copyright © 2011 by American Society of Mechanical Engineers
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Figure 1

Electrodes used to apply NTIRE. The electrode clamp (top image) consists of two printed circuit boards with disk electrodes at the end. When used on the rat carotid artery, the electrodes are held apart by approximately 0.4 mm. The electrode catheter (bottom image) is shown in its inflated state. When in use, the four electrodes are pressed gently against the inner wall of the artery.

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Figure 2

Schematic of model geometry for the electrode clamp and carotid artery. The artery is shown here in cross-section pressed between the two electrodes. The artery was modeled as 0.4×3 mm2 and the copper electrodes are 0.1 mm thick. The printed circuit boards were modeled as having the material properties of Flame Retardant 4 (FR4) and have the dimensions of 1.6×3 mm2. The artery-clamp system was modeled as being surrounded by a 3×3 cm2 block of air.

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Figure 3

Two-dimensional geometry for the endovascular device. The four electrode nickel titanium wire electrodes (0.5×0.4 mm2 in cross-section) run parallel to the longitudinal axis of the artery and lay pressed against the inner artery wall (2.5 mm in diameter). The electrodes are insulated from the arterial lumen space and the whole construct is modeled as being embedded in a very large block of tissue (not shown in full). Dimensions shown here are in millimeters.

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Figure 4

Two-dimensional electric field distribution. The resulting electric field is shown for the catheter electrode device. The outermost contour corresponds to 1000 V/cm and the electric field increases by 1000 V/cm for each contour moving in toward the electrodes. A spike in the electric field is seen at the corner of the electrodes due to edge effects. The model dimensions are shown in meters.

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Figure 5

Transient solution of the maximum tissue temperature. The maximum temperature obtained for each time step over the course of the simulation is plotted for the clamp electrode design (left), indicating that the overall peak temperature is reached immediately after the final electrical pulse as expected. The maximum temperature obtained for the first 200 μm of the biological tissue domain are shown for the endovascular device (right).

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Figure 6

H&E staining results for both clamp electrodes and endovascular device experiments. H&E staining shows that the NTIRE-treatment of the rat carotid artery using the clamp electrode device resulted in an artery that was almost completely decellularized (top right) when compared with the control (top left). Treatment of the rabbit iliac artery using the endovascular electrode device resulted in the complete absence of VSMC at one week after treatment (bottom right) as compared with the control (bottom left).

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Figure 7

Masson’s trichrome stain for both clamp electrodes and endovascular device experiments. Masson’s trichrome stain demonstrates absence of cell nuclei (stained dark brown) and VSMC fibers (red) 7 days after NTIRE-treatment using both the clamp electrode device (upper right) and the endovascular device (lower right) when compared with their respective controls (upper left and lower left). These images also indicate that an abundance of collagen fibers remains after both treatment methods (stained blue).

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Figure 8

EVG staining for both clamp electrodes and endovascular device experiments. EVG staining demonstrates that the elastin fibers of the arteries treated by both the clamp electrode device (top right) and the endovascular device (bottom right) are undamaged 7 days after the NTIRE-treatment when compared with their respective controls (top left and bottom left).




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