Projects / Programmes
Numerical models of skin electroporation as a method to enhance transdermal drug delivery and gene transfection of the skin
| Code |
Science |
Field |
Subfield |
| 2.06.07 |
Engineering sciences and technologies |
Systems and cybernetics |
Biomedical technics |
| Code |
Science |
Field |
| T115 |
Technological sciences |
Medical technology |
electroporation, electropermeabilization, numerical modeling, finite elements method, electrogene transfer, transdermal drug delivery, microelectrodes
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
20822 |
PhD Nataša Pavšelj |
Systems and cybernetics |
Head |
2007 - 2008 |
82 |
Organisations (1)
Abstract
Cell membrane is, in general, impermeable for larger molecules; however, the application of electric pulses to cells, either in suspension or tissue, causes the electroporation of cell membrane, increasing its permeability and making it possible for larger molecules that otherwise can not cross the membrane, such as drug molecules or DNA, to enter the cell. Electroporation can also be used to create aqueous pathways across the skin's outermost layer, the stratum corneum to enhance transdermal drug delivery. Further, skin being an attractive target tissue for in vivo gene delivery, electroporation proved effective enhancing DNA transfection after intradermal and topical DNA delivery. Within the proposed project, the electropermeabilization process in skin will be described theoretically, by means of numerical modeling, leaning on data derived from the in vivo experiments resulting from our past research activities. The numerical models will take into account the layered structure of skin and changes of its bulk electric properties during electroporation, as observed in the in vivo experiments. Also, the microscopical aspect of the skin electropermeabilization and the increased molecular transport through the stratum corneum will be studied. The theory of the creation of localized sites of increased molecular transport termed local transport regions (LTRs) and their expansion due to Joule heating will be described with numerical models, using multiphysics modeling approach, solving the model for coupled electrical-thermal phenomena. Furthermore, numerical modeling will yield guidelines for the design of new, state-of-the-art electrode design for transdermal drug and gene delivery in skin. This minimally invasive technique is based on the concept of an array of hollow microneedle electrodes piercing the upper epidermis far enough to increase skin permeability and allow drug delivery, but too short to cause any pain. Our numerical models will provide a more in-depth understanding of the process of skin electropermeabilization, allowing predicting the outcome of pulse delivery before the treatment, thus helping in optimizing/choosing the right protocols and pulse parameters and the development of macro- and micro-electrodes.
Significance for science
The results of our research yield theoretical explanation of skin tissue electroporation phenomena, observed during in vivo experiments. One of the seemingly paradoxical observations was usefulness of the external plate electrodes to permeabilize skin cells in deeper viable skin layers. Namely, the ratios of the initial conductivities of the skin layers suggest that the highest voltage drop rests across the outermost, thin dead skin layer, the stratum corneum. That would cause a very high electric field in that layer while its strength would stay below the permeabilization threshold in the layers beneath stratum corneum. However, the electrical conductivities of tissues subjected to electric pulses increase. As a result, the electric field “penetrates” deeper into the skin and permeabilizes the target cells, making electrically enhanced gene transfer possible. We described this phenomenon with numerical models, contributing to a better understanding of skin electropermeabilization.
Further, the experiments of other researchers revealed highly localized molecular transport in skin after electroporation. We thus made a model of skin with local transport regions embedded in the stratum corneum, based on the data on the size, density and electrical properties of LTRs found in the literature. We upgraded these models by including the thermal aspect of skin electroporation. We described the mechanism of the nonlinear process of skin electropermeabilization from the aspect of bulk conductivity changes and the presence of the local transport regions in the permeabilized stratum corneum. In this way, the observations derived from various in vivo experiments by different authors were confirmed theoretically. Such numerical models, further improved and validated by experiments, can be used for the simulation of permeabilization process in skin, as well as other tissues. They allow predicting the outcome of pulse delivery before the treatment and help us in optimizing/choosing the most efficient protocols and pulse parameters. Such an approach can also assist us in the development of electrodes and optimizing their placement with respect to target tissue in both electrogene transfer and transdermal drug delivery.
Our research also deals with the design of microneedle electrodes for electrogene transfer in skin and transdermal drug delivery, and further improvement of such electrodes. Different setups of microneedle electrode arrays were modeled and compared in order to get the most favorable outcome in terms of maximizing the permeabilized tissue volume, while minimizing the tissue volume permeabilized irreversibly. Our research provided the guidelines regarding shape and dimensions of the microneedle and the best polarity/geometry setting of the microneedle array and were used for the 6th FP ANGIOSKIN project (LSHB-CT-2005-512127), dealing with DNA electrotransfer in skin. Findings were taken into account for the electrode prototyping, technological limitations permitting.
Significance for the country
The results of our research are being used, and will be used in the future, in a wider context of research activities in the area of electrochemotherapy, electrically mediated gene transfer and transdermal drug delivery. The project was a continuance of the past research efforts of the project leader, as well as the research group of the Laboratory of Biocybernetics at the Faculty of Electrical Engineering, University of Ljubljana. This research group has a leading role in the field of electroporation-based treatments and technology in Europe, as well as worldwide. The continuation of active participation of Slovenian researchers in the field of electroporation means an important recognition of Slovenian science and puts us side by side with leading scientists in this research field. Further, the accumulation of knowledge and technological solutions gives an opportunity for Slovenian SMEs to be involved in the manufacture of this new technology. Cooperation with Iskra Medical, one of the leading European manufacturers of medical devices used in physiotherapy, rehabilitation, dermatology and cosmetics has already been established. The efforts of the company’s management are aimed at increasing the added value of their products to stay in the leading position in the market race by the development of devices and protocols supported by scientific theoretical and experimental results.
Further, as the research was performed at the Faculty of Electrical Engineering of the University of Ljubljana, the results and findings will be incorporated in educational process.
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