Benefits of the NanoKnife System

Preservation of Critical Structures

A unique characteristic of IRE ablation that separates it from other ablative techniques is its capability of preserving vital structures within the IRE-ablated zone.1 IRE affects only the cell membrane and no other structure in the tissue.2 IRE uses a non-thermal based method of action and can be used to treat tissue near vital structures, such as the urethra, larger blood vessels, nerves, and by itself to produce tissue ablation in vivo.3

With IRE ablation, cell death is mediated by apoptosis through disruption of the cell membrane. The structures mainly formed by proteins such as vascular elastic and collagenous structures, pericellular matrix proteins are not damaged by IRE ablation. This leads to the preservation of structural scaffoldings of vessels and bile ducts. Conversely, other types of tumor ablation, these structures are completely obliterated due to the extreme temperature changes used by thermal ablation techniques, causing the denaturation of proteins. The denaturation process does not discriminate which proteins or DNA to destroy. Thus, all protein structures and cells with DNA can be damaged with the use of current thermal ablation techniques.4 Hepatocytes and central vein in the non-ablated zone, and irreversible electroporation (IRE)- ablated zone. All hepatocytes around the vessel in the IRE-ablated zone have been completely ablated and undergone cell death seen as pyknosis and karyorrhexis (H&E stain, ×40).5 In “Irreversible Electroporation of the Pancreas: Definitive Local Therapy Without Systemic Effects”, by Bower et al., (J. Surg. Oncol., 104(1): 22-28, July 2011), it was stated that “Necrosis of pancreatic cells was seen immediately adjacent to vascular structures. Venous as well as arterial structures were widely patent without any evidence of thrombosis at the 72-hr, 7-day, and 14-day time intervals.”

 Figure 1: IRE Necrosis without vessel destruction.6 Figure 2: IRE in Pancreas – vessels and structures remain patent.7

 

MRI, at 1 month, post IRE procedure. Superior aspect of tumor shows no residual enhancement of tumor, with maintained patency and appearance of the splenic artery (arrow).

A pilot study on the effect of IRE on blood vessels demonstrated that intact adventitia and lamina are visible at 2 days with no smooth muscle cells present. Reendothelialization occurs within 24–48h. The smooth muscle cells in the media are repopulated at 2 weeks. At 28 days after the procedure,the connective matrix of the blood vessels remained intact, and although the number of vascular smooth muscle cells in the arterial wall was decreased, there was no evidence of aneurysm, thrombus formation, or necrosis.8

Figure 3: IRE and vessels.9 Figure 4: IRE effects onvessels.10

(In reference to Figure 4) Top picture: Left common carotid artery seven days after IRE (animal #2). In this picture it is possible to see the scarcity of vascular smooth muscle cells nuclei at the tunica media (arrow A). The elastic fibers morphology is maintained (arrow B). Bottom picture: Right common carotid artery of the same animal (animal #2). In this picture it is possible to see the normal density of vascular smooth muscle cells in the tunica media (cells are marked with arrows).11

No Heat Sink Effect
Although safety and effectiveness of conventional thermal ablation techniques have been shown in multiple studies, several limitations and issues have surfaced. Effectiveness of thermal ablation has been hindered by the “heat sink” phenomenon as perivascular tissues are not completely ablated and lead to incomplete ablation of tumor and tumor recurrence. Lee et al., (in their publication “Imaging Guided Percutaneous Irreversible Electroporation: Ultrasound and Immunohistological Correlation” Technology in Cancer Research and Treatment, 6(4): 287-293, August 2007) demonstrated and verified that IRE can effectively cause complete tissue death even in cases where the ablation zone is juxtaposed to a large vessel.

One critical difference in IRE (versus other ablative modalities) is its ability to create cell death via non-thermal ablation. A short, but powerful electric field (range, 1,500 to 3,000 volts) is applied to the targeted area and causes a disruption of cellular homeostasis through dismantling the cell membrane wall with innumerable nanopores. This disruption of cellular homeostasis causes apoptotic cell death and necrosis. The IRE treatment uses multiple ultra- short pulses which increases therapeutic effect and decreases thermal effects. This has been investigated and optimized by Davalos et al.((“Tissue Ablation with Irreversible Electroporation”, Annals of Biomedical Engineering, 33(2); 223-231, February 2005)), who demonstrated that short pulses with brief intervals allow for cooling of tissues to avoid any thermal effect. As a result, the electric field created by IRE is devoid of any joule heating and therefore, non-thermal ablation is achieved. Since it does not depend on either heat or cold, IRE can create a focal tumor ablation area, independent of any heat or cold-sink effect.12

IRE is a non-thermal technology; hence incomplete treatment secondary to the “heat sink” effect and heat injuries, do not appear to be applicable to IRE.13

Figure 5: IRE – No Heat Sink Effect (Porcine Model)

No heat sink effect was evident adjacent to vessels with complete necrosis adjacent and often surrounding patent vasculature, post-IRE.14

Well-demarcated ablations

The parameters of IRE are precise; ie, an electrical pulse either causes IRE on the cell membrane or not, thus, IRE produces an extremely sharp, well-demarcated, ablation area, and the transition between healthy and ablated tissue can be observed on a cellular level. This contrasts with what is observed with other ablative modalities.15, 16, 17. 18

Figure 6: NADH-stained porcine renal tissue at 1-h after IRE.19
NADH-stained porcine renal tissue at 1-h after IRE showing complete cellular death (upper portion of photograph), with a sharp delineation from the untreated tissue (lower portion of photograph), as seen in Tracy et al., “Irreversible electroporation (IRE): a novel method for renal tissue ablation”, BJU International, 107(12): 1982-1987, June 2011.19
Figure 7: Sharp demarcation post IRE

Image from: Lavee et al., The Heart Surgery Forum, 2006-1202, 10(2), 2007

Higher magnification of an ablated area demonstrates a sharp demarcation line between the injured necrotic myocardial tissue (in purple) and the surrounding normal atrial myocardium (original magnification ×10).

Short ablation time
The speed of the procedure is impressive with the ablation occurring in seconds rather than minutes. Therefore, the time needed to complete an IRE procedure is almost solely determined by the time needed to properly place the ablation probes.20

A typical IRE procedure for a solid tumor, with a size of approximately 3 cm in diameter, uses 90 pulses with an ultra-short pulse length of 100 microseconds. A single IRE ablation session takes less than one minute. Therefore, even with three or four overlapping ablations, total IRE treatment time is under 5 minutes. This relatively short ablation time for IRE may correlate with reduced anesthesia time, reduced postablation pain, decreased ablation-related complications, decreased overall cost of ablation treatment, and as mentioned, it may provide an opportunity for treatment of multiple lesions or multiple treatments of single lesion in one session.21

1. Adapted from: Lee et al., Gut and Liver, 4 (Suppl. 1) 99- 104, Sep. 2010
2. Rubinsky et al., Technology in Cancer Research and Treatment, Vol. 6, N. 1, February 2007
3. Martin et al., Annals of Surgical Oncology, Online, Nov 6 2012
4. Adapted from: Lee et al., Gut and Liver, 4 (Suppl. 1) 99- 104, Sep. 2010
5. Lee et al., Gut and Liver, 4 (Suppl. 1) 99- 104, Sep. 2010
6. Image from: Lavee et al., The Heart Surgery Forum, 2006-1202, 10(2), 2007
7. Bagla et al., JVIR, 23:142–145, January 2012
8. Maor et al., Technology in Cancer Research and Treatment, 6(4), August 2007
9. Image: Blue Histology, School of Anatomy and Human Biology - The University of Western Australia
http://www.lab.anhb.uwa.edu.au/mb140/
10. Image from: Maor et al., Technology in Cancer Research and Treatment, 6(4), August 2007
11. Maor et al., Technology in Cancer Research and Treatment, 6(4), August 2007
12. Lee et al., Gut and Liver, 4 (Suppl. 1) 99- 104, Sep. 2010
13. Deodhar et al., Urology, 77(3): 754-760, 2011
14. Onik et al., Technology in Cancer Research and Treatment, 6(4): 1-6, August 2007
15. Lavee et al., The Heart Surgery Forum, 2006-1202, 10(2), 2007
16. Onik et al., Technology in Cancer Research and Treatment, 6(4): 1-6, August 2007
17. Rubinsky et al., Technology in Cancer Research and Treatment, Vol. 6, N. 1, February 2007
18. Lavee et al., The Heart Surgery Forum, 2006-1202, 10(2), 2007
19. Tracy et al., BJU International, 107(12): 1982-1987, June 2011
20. Onik et al., Technology in Cancer Research and Treatment, 6(4): 1-6, August 2007
21. Lee et al., Gut and Liver, 4 (Suppl. 1) 99- 104, Sep. 2010

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