Igor Lacković

Modeling of electric field distribution in tissues during electroporation

BackgroundElectroporation based therapies and treatments (e.g. electrochemotherapy, gene electrotransfer for gene therapy and DNA vaccination, tissue ablation with irreversible electroporation and transdermal drug delivery) require a precise prediction of the therapy or treatment outcome by a personalized treatment planning procedure. Numerical modeling of local electric field distribution within electroporated tissues has become an important tool in treatment planning procedure in both clinical and experimental settings. Recent studies have reported that the uncertainties in electrical properties (i.e. electric conductivity of the treated tissues and the rate of increase in electric conductivity due to electroporation) predefined in numerical models have large effect on electroporation based therapy and treatment effectiveness. The aim of our study was to investigate whether the increase in electric conductivity of tissues needs to be taken into account when modeling tissue response to the electroporation pulses and how it affects the local electric distribution within electroporated tissues.MethodsWe built 3D numerical models for single tissue (one type of tissue, e.g. liver) and composite tissue (several types of tissues, e.g. subcutaneous tumor). Our computer simulations were performed by using three different modeling approaches that are based on finite element method: inverse analysis, nonlinear parametric and sequential analysis. We compared linear (i.e. tissue conductivity is constant) model and non-linear (i.e. tissue conductivity is electric field dependent) model. By calculating goodness of fit measure we compared the results of our numerical simulations to the results of in vivo measurements.ResultsThe results of our study show that the nonlinear models (i.e. tissue conductivity is electric field dependent: σ(E)) fit experimental data better than linear models (i.e. tissue conductivity is constant). This was found for both single tissue and composite tissue. Our results of electric field distribution modeling in linear model of composite tissue (i.e. in the subcutaneous tumor model that do not take into account the relationship σ(E)) showed that a very high electric field (above irreversible threshold value) was concentrated only in the stratum corneum while the target tumor tissue was not successfully treated. Furthermore, the calculated volume of the target tumor tissue exposed to the electric field above reversible threshold in the subcutaneous model was zero assuming constant conductivities of each tissue.Our results also show that the inverse analysis allows for identification of both baseline tissue conductivity (i.e. conductivity of non-electroporated tissue) and tissue conductivity vs. electric field (σ(E)) of electroporated tissue.ConclusionOur results of modeling of electric field distribution in tissues during electroporation show that the changes in electrical conductivity due to electroporation need to be taken into account when an electroporation based treatment is planned or investigated. We concluded that the model of electric field distribution that takes into account the increase in electric conductivity due to electroporation yields more precise prediction of successfully electroporated target tissue volume. The findings of our study can significantly contribute to the current development of individualized patient-specific electroporation based treatment planning.

Three-dimensional finite-element analysis of joule heating in electrochemotherapy and in vivo gene electrotransfer

Electrochemotherapy and electrogene therapy are new methods in molecular medicine based on electroporation-mediated introduction of foreign molecules (chemotherapeutic drugs, DNA) into target cells in vivo. Electrochemotherapy involves the injection of chemotherapeutic agent followed by a local delivery of a train of short high-voltage pulses to the tumor nodule (i.e. 8 square-wave pulses of 100 mus duration delivered at the repetition frequency of 1 Hz or several kHz, with a voltage-to-distance ratio of up to 1500 V/cm). For the transfer of DNA across a cell membrane a train of long low-voltage pulses (i.e. 8 rectangular pulses of 50 ms duration delivered at the repetition rate of 1 Hz, with a voltage-to-distance ratio up to 250 V/cm) is much more effective due to the electrophoretic effect on DNA molecule. In this paper we present a comprehensive analysis of tissue heating as a potential side effect of electric pulses used for electroporation-based treatments. The analysis is based on a coupled electrothermal model using 3-D finite-element approach. We studied two electrode geometries: parallel plates and a pair of needles. By setting the appropriate boundary conditions, we simulated driving of electrodes with short, high-voltage, electropermeabilizing pulses and with longer, lower voltage, electrophoretic pulses. We obtained time dependent solutions for electric field and temperature distribution by FEM solver. Based on the numerical simulations we analyzed the influence of tissue electrical conductivity and parameters of electric pulses (amplitude, duration, number of pulses, pulse repetition frequency) on the temperature distribution within the tissue and the electrodes. Results of our simulations show that at specific pulse parameters at least locally tissue heating might be significant (i.e. tissue temperatures to grow in excess of 43degC). For electrochemotherapy, this is not critical, but DNA electrotransfer may be unsuccessful due to heating-related DNA damage or denaturation.

Measurement of gait parameters from free moving subjects

In this paper a telemetry system for real-time force measurement in the legs and crutches or cane is presented. The system provides a quantitative gait analysis of orthopaedic patients with details, which are often hidden to a visual observation. Three vertical force components in each leg are measured. For this purpose flat and pliable capacitive sensors, which are placed on the sole of the shoes, were developed. The infrared telemetry is applied to enable free and unconstrained movements of the patient inside a wide indoor environment. Measured forces, after transmission and processing on the receiver side, are presented on the computer monitor as eight channel time diagrams. An original software package (GAS) for on-line monitoring and processing of vertical force data was developed. The processing enables calculation of many diagnostically important parameters (e.g. temporal parameters, average force, force-time integral, sum of forces, etc.), spectral and time-frequency analysis and many other. As an example of clinical application, temporal parameters during ten strides for 20 normal subjects and 20 patients with lower extremities degenerative joint diseases were calculated and compared.

Challenges of the biomedical engineering education in Europe

Higher education in Europe has passed through a very dynamic period of changes during the last ten years. Since the signing of the Bologna Declaration in 1999 by the Ministers of Education from the EU states, European higher education system has aimed toward establishing harmonized programs enabling students and teachers to extensively exchange knowledge, ideas and skills. Education in the field of Biomedical Engineering has experienced changes also because of the research and development in the field which was more intensive than in other fields. Besides research in new power sources, it is the most intensive and productive research field. Much of the development in BME education in Europe is influenced by the European research policy expressed through the 7th Framework Programme where health is the major theme. In order to foster and support the changes in the European Higher Education Area (EHEA) according to the needs of research sector and the labor market, the Tempus scheme of projects was established. Tempus scheme aims to support the modernization of higher education and create an area of co-operation in the countries surrounding the EU. Our Tempus project, CRH-BME “Curricula Reformation and Harmonization in the field of Biomedical Engineering” aims to create guidelines for updating existing curricula in the field of BME in Europe in order to meet recent and future developments in the area, address new emerging interdisciplinary domains that appear as the result of the R&D progress and respond to the BME job market demands. In this paper, some policy and economic factors affecting BME education in Europe are discussed and the results of a BME education survey we prepared within the Tempus CHR-BME project are presented. The number of BME programmes in Europe has in the last decade significantly increased and there are more BME specializations as the result of growing complexity of the research and production in the field.

A Novel Approach to Wheeze Detection

Wheezing often accompanies pulmonary pathologies and its detection is considered of great importance for the diagnosis and management of respiratory diseases. Our aim was to develop a simple and robust algorithm for wheeze detection in respiratory sound spectra to be used for long-term monitoring and early stage assessment of asthma episode in children. The robustness of the algorithm enables wheezing detection in presence of noise and moving artifacts. Children cannot perform respiratory function tests such as peak-flow measurement and therefore we find continuous recording and processing of respiratory sounds as an alternative. The algorithm we used for wheeze detection is based on the idea of frequency domain peak detection proposed by Shabtai-Musih et al. because of its simplicity and scoring used for specifying the likelihood that the peaks in power spectra represent wheezes. In our algorithm, we have modified the way of searching peaks in the spectrogram. Before searching for peaks, wavelet denoising was used in order to remove the noise in spectrum without affecting the peaks that we were searching for. Using the scoring algorithm we were able to create a binary image of the spectrogram of the sounds - wheezes and score the length (duration) of connected components considered as wheezing. The components that did not meet length criterion were rejected and were not considered as wheezing. The algorithm was tested on respiratory sound signals from public signal databases and on our own signals recorded in a group of 26 asthmatic children. The algorithm successfully detected wheezes in all signals containing wheezing.

The International Conference on Health Informatics

The International Conference on Health Informatics : , The International Conference on Health Informatics : , کتابخانه دیجیتال جندی شاپور اهواز

Low-frequency dielectric properties of the oral mucosa

Low-frequency (≤ 1 MHz) electrical conductivity and permittivity spectra of the oral mucosa were reconstructed from impedance measurements at various regions (tongue, buccal mucosa, hard palate) of the oral cavity. Impedance magnitude and phase were measured with the HP4284A LCR meter in the frequency range from 30 Hz to 1 MHz. Bipolar intraoral measurement probe was used. In order to obtain conductivity and permittivity spectra from measured impedance data, the geometry factor of the probe (cell factor) was determined theoretically. Namely, numerical modeling using the finite-element method was used to calculate the geometry factor. The FEM model was also used to study the sensitivity field of the probe and the penetration depth. The results show typical dispersion characteristics observed in α-, and β-dispersion range of biological tissues. Possibilities of correcting electrode polarization, which causes error at lower frequencies are considered.

Analysis of Tissue Heating During Electroporation Based Therapy: A 3D FEM Model for a Pair of Needle Electrodes

Cancer electrochemotherapy and electro gene therapy are emerging methods in molecular medicine. Both are based on electroporation mediated introduction of foreign molecules (drugs, DNA) into target cells. Depending on the application (electrochemotherapy or DNA electrotransfer), pulse delivery protocols and electrode geometry are chosen to achieve above the permeabilization threshold electric field in the target tissue volume. In this study we present the analysis of tissue heating as a potential side effect of strong electric pulses. The analysis is based on a 3D finite-element model of tissue in which a pair of needle electrodes was inserted. By setting the appropriate boundary conditions, we simulated driving of electrodes with short, high voltage, electropermeabilizing pulses and with longer, lower voltage, electrophoretic pulses. Time dependent solutions for electric field and temperature distribution were obtained by FEM solver. The results show localized tissue heating near the electrodes. This is predominately due to the sharp radial decrease of the electric field around the needles.

Promoting harmonization of BME education in Europe: The CRH-BME Tempus project

Biomedical Engineers should be prepared to adapt to existing or forecasted needs. There is a strong pressure on education, training and life long learning programs to continuously adapt their objectives in order to face new requirements and challenges. The main objective of the TEMPUS IV, CRH-BME project is to update existing curricula in the field of Biomedical Engineering (BME) in order to meet recent and future developments in the area, address new emerging inter-disciplinary domains that appear as a result of the R&D progress and respond to the BME job market demands. The first step is to extensively review the curricula in the BME education field. In this paper, a proposal for a generic curriculum in the BME education is presented, in order to meet recent and future developments and respond to the demands of the BME job market. Adoption of the core program structure will facilitate harmonization of studies as well as student and staff exchange across Europe, thus promoting the European Higher Education Area.

Incorporating Electroporation-related Conductivity Changes into Models for the Calculation of the Electric Field Distribution in Tissue

Electroporation is a phenomenon caused by externally applied high-intensity electric field to cells that results in the increase of cell membrane permeability to ions and various molecules such as drugs or DNA. In vivo tissue electroporation is the basis for electochemotherapy and electrogenetherapy. Apart from the increased membrane permeability which is observed long after the delivery of electric pulses, there is experimental evidence that, during the application of membrane permeabilizing electric pulses electric conductivity of tissue increases. In this work we use 3D finite-element modeling approach to investigate the difference in electroporated tissue volume when tissue conductivity change due to electroporation is taken into account vs. constant conductivity case. We modeled needle electrodes and assumed that tissue has sigmoid-like conductivity dependence on electric field intensity. Our numerical studies showed that taking into account dependence of tissue conductivity on electric field intensity affects the electric field distribution in tissue and in consequence irreversibly and reversibly electroporated regions. For model validation we calculated the reaction current and compared it with results of previous study where current was measured during in vivo tissue electroporation on experimental animals. We found reasonably close match between the calculated current in our nonlinear model and current measured in the experiment.