Article

Subnanosecond Electric Pulses Cause Membrane Permeabilization and Cell Death

Frank Reidy Research Center for Bioelectrics, Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, VA 23529, USA.
IEEE transactions on bio-medical engineering (Impact Factor: 2.35). 02/2011; 58(5):1239-45. DOI: 10.1109/TBME.2011.2112360
Source: PubMed

ABSTRACT

Subnanosecond electric pulses (200 ps) at electric field intensities on the order of 20 kV/cm cause the death of B16.F10 murine melanoma cells when applied for minutes with a pulse repetition rate of 10 kHz. The lethal effect of the ultrashort pulses is found to be caused by a combination of thermal effects and electrical effects. Studies on the cellular level show increased transport across the membrane at much lower exposure times or number of pulses. Exposed to 2000 pulses, NG108 cells exhibit an increase in membrane conductance, but only allow transmembrane currents to flow, if the medium is positively biased with respect to the cell interior. This means that the cell membrane behaves like a rectifying diode. This increase in membrane conductance is a nonthermal process, since the temperature rise due to the pulsing is negligible.

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    • "Evidently, cell death under pulse conditions which lead to considerable Joule heating is caused by a combination of heating and electric field effect. In this paper [10], the thermal and electrical parameters could not be independently controlled. However, the results show, that even with such a low electric field of 25 kV/cm (compared to those used in the 800 ps studies), the specific energy required for inducing cell death was found to be on the same order as in the 800 ps studies. "
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    ABSTRACT: The rate of trypan blue uptake of liver cancer cells, indicating cell death, when exposed to subnanosecond high electric field pulses, increased strongly when the temperature was raised above 37 °C. The exposure of Hepa 1-6 cells to 2000 pulses of 200 picosecond duration and electric field amplitudes exceeding 80 kV/cm induced cell death in almost 30% of the cells when the temperature was increased to 47 °C for the time of the pulsing. For temperatures at 37 °C and below, the same exposure to pulsed electric fields did not show any measurable effect. Even for the maximum elevated temperature of 47 °C, thermal effects were not found to cause fatalities for the time of exposure, which was, for 2000 pulses at a repetition rate of 7-9 pulses per second, on the order of 5 min. The effect of temperature on the electrical properties of the cell was measured by means of dielectric spectroscopy. The membrane voltages derived from these values were found to be too low to cause electroporation at room temperature. However, the reduced viscosity of the membrane with temperature is likely to reduce the threshold for poration, and together with the effect of multiple pulses, is considered to be the cause for the observed high death rate of the cells. This argument is supported by molecular dynamics simulations which show an increased probability for pore formation with temperature.
    Full-text · Article · Oct 2012 · IEEE Transactions on Plasma Science
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    • "Evidently, cell death under pulse conditions which lead to considerable Joule heating is caused by a combination of heating and electric field effect. In this paper [10], the thermal and electrical parameters could not be independently controlled. However, the results show, that even with such a low electric field of 25 kV/cm (compared to those used in the 800 ps studies), the specific energy required for inducing cell death was found to be on the same order as in the 800 ps studies. "
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    ABSTRACT: Nanosecond electrical pulses have been successfully used to treat melanoma tumors by using needle arrays as pulse delivery systems. Reducing the pulse duration of intense electric field pulses from nanoseconds into the subnanosecond range, and using a prolate-spheroidal reflector as part of a picosecond Impulse Radiating Antenna (IRA), allows us to focus the electromagnetic waves into biological tissue with reasonable spatial resolution. In order to achieve a spatial resolution on the order of one centimeter, pulses with duration on the order of 100 picoseconds are required. Based on the nanosecond pulse generator, a pulse generator was developed which allows us to generate 150 picosecond-long pulses. The voltage amplitude (in an improved version) reaches values of up to 120 kV. Modeling results indicate that with this pulse generator as part of an IRA, electric fields on the order of 100 kV/cm can be generated in tissue close to the body surface. In order to explore the biological effects of these ultrashort, high electric fields, a coaxial exposure chamber has been designed which is integrated into the pulse delivery system in such a way that an almost uniform electric field (based on modeling using MAGIC) can be expected. The chamber is placed in a water bath, which allows us to vary the ambient temperature from room temperature (20 C) to a physiologically relevant range (37 C to 41 C). Experiments where platelets were exposed to 150 picosecond long pulses with an electric field of 150 kV/cm indicate a pulse number dependent uptake of calcium. The experiments were performed at a temperature of 37 C. A possible synergistic effect was observed when melanoma cells were pulsed at elevated temperatures.
    Full-text · Conference Paper · Aug 2009
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    ABSTRACT: Delivery of subnanosecond pulses into biological tissue can be undertaken by an impulse radiating antenna (IRA). Previous analysis shows that it is important to add a dielectric lens, which reduces the abrupt change of dielectric constant from air to tissue and therefore increases the transmission of the pulses. As a proof of concept, we have simulated subnanosecond pulsed radiation focused into a tissue simulant which consists of homogeneous, hemisphere tissues using 3-D electromagnetic solver, CST Microwave Studio. The simulation of an IRA in conjunction of a lens indicates subnanosecond pulses can be focused 6 cm below tissue surface with a spot diameter approximately 1 cm. The focal point coincides with the geometric focus of the IRA. However, this result is only valid for a tissue with a low conductivity (σ< 0.3 S/m). For lossier tissues, the electric field decreases from the surface monotonically as the subnanosecond pulses penetrate in depth. Two approaches were proposed to solve this problem. One was to use an inhomogeneous dielectric lens, with lossy material partially filled, to attenuate the incident field in the small azimuthal angles but to spare the field in the larger azimuthal angels. A desirable focusing was observed. The second approach was to use a dipole antenna in conjunction with the impulse radiating antenna. The dipole antenna decreases the surface field intensity generated by the aperture antenna, but at the destination, the field will be mostly given by the aperture antenna, resulting in a focusing.
    No preview · Conference Paper · Jan 2012
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