The first observations of the effects of pulsed electric fields on biological material
date more than 250 years back. But in the past two decades applications of
electroporation emerged in medicine, food processing, and biotechnology. The
phenomenon of electroporation leads to increased cell membrane permeability. Due
to exposure to high voltage electric pulses, the cell membrane becomes permeable to
molecules, which otherwise can not cross the membrane. A pulsed power generator
termed as electroporator and electrodes are used to expose cells to a pulsed electric
field. Electroporator generates electrical pulses with a specific shape, amplitude,
duration, number, repetition rate and sequence (bursts of pulses). By applying
electrical pulses to the electrodes, which are in direct contact with the tissue, an
electric field is generated in tissue with specific distribution and intensity.
In order to properly understand the current situation and trends of development
on the electroporation field, a thesis begins with a review of commercially available
devices, their characteristics, limitations, and weaknesses. Also, expert opinion
about the electroporation devices used in skin electroporation was provided. The
electroporation device manufacturers are currently hindering the development of
electroporation field by concealing the output pulse parameters of their devices,
designing them in a way to disable output pulse measuring, specifying characteristics
which device cannot deliver, and making devices that do not warn the
user when pulse delivery fault occurs. The quality of the pulse delivery was
evaluated, by checking if the delivered pulses were adequately addressed and
measured in the electroporation studies, with the focus on the field of nanosecond
electroporation, where the delivery and measuring are the most challenging. Additionally,
recommendations for standardization, mainly focusing on the evaluation
of electroporators proper or improper operation were proposed and electronic
emulator of the biological load during electroporation, which enables constant and
sustainable testing and unbiased comparison of different electroporators operation,
was developed.
Secondly, we developed a high-frequency high voltage generator by using and
improving the latest pulse generator designs. The developed 4 kV pulse generator,
generates high voltage pulses with minimized switching time between positive and
negative pulse. The minimal pulse duration is 200 ns and maximal repetition rate
2 MHz, it is also able to generate asymmetrical bipolar pulses. The developed
device was tested in first in vivo high-frequency electrochemotherapy (HF-ECT),
in which HF-ECT with bleomycin and cisplatin was proved to be as effective as
well established "classical" ECT with bleomycin and cisplatin.
Third, the cost-effectiveness of electrochemotherapy of stage IV and IIIc skin
melanoma was calculated for patients treated at the Institute of Oncology in
Ljubljana using the Cliniporator device and associated electrodes. The probability
of ECT (with hospitalization) being cost-effective for the patient with stage IV and
IIIc skin melanoma is just above 50 %, which implies the prices of the device and
electrodes should be reduced for successful implementation into clinical practice.
However, if patients have bleeding lesions the ECT can be assumed cost-effective
(probability rises to 0.97).
|
