In-vivo porcine studies on the effect of nanosecond high-voltage pulses on liver tissue have shown that cell death can be induced in well-defined tissue volumes without damaging collagen-predominant structures. Comparison of the experimental results with the results of a 3-D finite element model allowed us to determine the threshold electric field for cell death. For 30, 100-ns-long pulses this was found to be in the range from 12 to 15 kV/cm. Modeling of the temperature distribution in the tissue using Pennes' bioheat equation showed that the lethal effect of nanosecond pulses on cells is nonthermal. Muscle contractions, generally caused by high-voltage pulses, were significantly reduced for the 100-ns pulses compared to microsecond-long pulses. The results of these studies indicate that high-voltage nanosecond pulses reliably kill normal liver cells in vivo, and therefore, may be useful for liver tumor treatments.
"The high voltage pulses were delivered to the centre needle  . The tumour is surrounded by the electrode array thereby establishing a well-define treatment zone minimising damage to surrounding tissue . The margins of safety are determined by tumour size and electrode design. "
[Show abstract][Hide abstract] ABSTRACT: Strategies for treating liver cancer using radiation, chemotherapy combinations and tyrosine kinase inhibitors targeting specific mutations have provided longer survival times, yet multiple treatments are often needed and recurrences with new malignant phenotypes are not uncommon. New and innovative treatments are undoubtedly needed to successfully treat liver cancer. Over the last decade, nanosecond pulsed electric fields (nsPEFs) have shown promise in pre-clinical studies; however, these have been limited to treatment of skin cancers or xenographs in mice. In the present report, an orthotopic hepatocellular carcinoma (HCC) model is established in rats using N1-S1 HCC cells. Data demonstrate a response rate of 80-90% when 1000 pulses are delivered with 100ns durations, electric field strengths of 50kV/cm and repetition rates of 1Hz. N1-S1 tumours treated with nsPEFs expressed significant number of cells with active caspase-3 and caspase-9, but not caspase-8, indicating an intrinsic apoptosis mechanism(s) as well as caspase-independent mechanisms. Most remarkably, rats with successfully ablated tumours failed to re-grow tumours when challenged with a second injection of N1-S1 cells when implanted in the same or different liver lobe that harboured the original tumour. Given this protective effect, infiltration of immune cells and the presence of granzyme B expressing cells within days of treatment suggest the possibility of an anti-tumour adaptive immune response. In conclusion, NsPEFs not only eliminate N1-S1 HCC tumours, but also may induce an immuno-protective effect that defends animals against recurrences of the same cancer.
European journal of cancer (Oxford, England: 1990) 07/2014; 50(15). DOI:10.1016/j.ejca.2014.07.006 · 5.42 Impact Factor
"Confining the treatment only to cancer cells may be obtained by placing the electrodes in the cancerous tissue and in the meantime creating a large electric field gradient from cancerous tissue to normal tissue using needle electrodes. As a result, a relatively well-defined ablation zone may be expected . The correlation of electric field intensity and cell death become a priori in order to define the effective treatment zone and spare normal tissue. "
[Show abstract][Hide abstract] ABSTRACT: It is hypothesized that high frequency components of nanosecond pulsed electric fields (nsPEFs), determined by transient pulse features, are important for maximizing electric field interactions with intracellular structures. For monopolar square wave pulses, these transient features are determined by the rapid rise and fall of the pulsed electric fields. To determine effects on mitochondria membranes and plasma membranes, N1-S1 hepatocellular carcinoma cells were exposed to single 600 ns pulses with varying electric fields (0-80 kV/cm) and short (15 ns) or long (150 ns) rise and fall times. Plasma membrane effects were evaluated using Fluo-4 to determine calcium influx, the only measurable source of increases in intracellular calcium. Mitochondria membrane effects were evaluated using tetramethylrhodamine ethyl ester (TMRE) to determine mitochondria membrane potentials (ΔΨm). Single pulses with short rise and fall times caused electric field-dependent increases in calcium influx, dissipation of ΔΨm and cell death. Pulses with long rise and fall times exhibited electric field-dependent increases in calcium influx, but diminished effects on dissipation of ΔΨm and viability. Results indicate that high frequency components have significant differential impact on mitochondria membranes, which determines cell death, but lesser variances on plasma membranes, which allows calcium influxes, a primary determinant for dissipation of ΔΨm and cell death.
PLoS ONE 12/2012; 7(12):e51349. DOI:10.1371/journal.pone.0051349 · 3.23 Impact Factor
"As a result, electroporation of both the plasma membrane and intracellular structures can occur for electric field strengths on the order of 10-100 kV/cm [46,47]. These nanosecond pulsed electric fields (nsPEFs) have shown great promise as a cancer therapy due to their ability to induce cell death through apoptotic mechanisms and reduce muscle contractions . One challenge associated with nsPEFs that further distinguishes them from IRE is that the field strength required to induce electroporation of intracellular vesicles and organelles, such as the nucleus, is an order of magnitude greater (40 kV/cm) . "
[Show abstract][Hide abstract] ABSTRACT: Therapeutic irreversible electroporation (IRE) is an emerging technology for the non-thermal ablation of tumors. The technique involves delivering a series of unipolar electric pulses to permanently destabilize the plasma membrane of cancer cells through an increase in transmembrane potential, which leads to the development of a tissue lesion. Clinically, IRE requires the administration of paralytic agents to prevent muscle contractions during treatment that are associated with the delivery of electric pulses. This study shows that by applying high-frequency, bipolar bursts, muscle contractions can be eliminated during IRE without compromising the non-thermal mechanism of cell death.
A combination of analytical, numerical, and experimental techniques were performed to investigate high-frequency irreversible electroporation (H-FIRE). A theoretical model for determining transmembrane potential in response to arbitrary electric fields was used to identify optimal burst frequencies and amplitudes for in vivo treatments. A finite element model for predicting thermal damage based on the electric field distribution was used to design non-thermal protocols for in vivo experiments. H-FIRE was applied to the brain of rats, and muscle contractions were quantified via accelerometers placed at the cervicothoracic junction. MRI and histological evaluation was performed post-operatively to assess ablation.
No visual or tactile evidence of muscle contraction was seen during H-FIRE at 250 kHz or 500 kHz, while all IRE protocols resulted in detectable muscle contractions at the cervicothoracic junction. H-FIRE produced ablative lesions in brain tissue that were characteristic in cellular morphology of non-thermal IRE treatments. Specifically, there was complete uniformity of tissue death within targeted areas, and a sharp transition zone was present between lesioned and normal brain.
H-FIRE is a feasible technique for non-thermal tissue ablation that eliminates muscle contractions seen in IRE treatments performed with unipolar electric pulses. Therefore, it has the potential to be performed clinically without the administration of paralytic agents.
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