When high-amplitude, short-duration pulsed electric fields are applied to cells and tissues, the permeability of the cell membranes and tissue is increased. This increase in permeability is currently ...explained by the temporary appearance of aqueous pores within the cell membrane, a phenomenon termed electroporation. During the past four decades, advances in fundamental and experimental electroporation research have allowed for the translation of electroporation-based technologies to the clinic. In this review, we describe the theory and current applications of electroporation in medicine and then discuss current challenges in electroporation research and barriers to a more extensive spread of these clinical applications.
Electrochemotherapy is a local treatment of cancer employing electric pulses to improve transmembrane transfer of cytotoxic drugs. In this paper we discuss electrochemotherapy from the perspective of ...biomedical engineering and review the steps needed to move such a treatment from initial prototypes into clinical practice. In the paper also basic theory of electrochemotherapy and preclinical studies in vitro and in vivo are briefly reviewed. Following this we present a short review of recent clinical publications and discuss implementation of electrochemotherapy into standard of care for treatment of skin tumors, and use of electrochemotherapy for other targets such as head and neck cancer, deep-seated tumors in the liver and intestinal tract, and brain metastases. Electrodes used in these specific cases are presented with their typical voltage amplitudes used in electrochemotherapy. Finally, key points on what should be investigated in the future are presented and discussed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Electrochemotherapy is a local ablative therapy that increases the cytotoxicity of either bleomycin or cisplatin by applying electric pulses (electroporation) to tumors. It has already been widely ...used throughout Europe for the treatment of various types of human and veterinary cutaneous tumors, with an objective response rate ranging from 70%-90%, depending on the tumor histotype. Recently, electrochemotherapy was introduced for the treatment of primary liver tumors, such as hepatocellular carcinoma (HCC). The complete response rate was 85% per treated lesion, with a durable response. Therefore, electrochemotherapy could become a treatment of choice for HCC, especially after achieving a transition from an open surgery approach to a percutaneous approach that uses dedicated electrodes. Electrochemotherapy elicits a local immune response and can be considered an in situ vaccination. HCC, among others, is a potentially immunogenic tumor; thus, electrochemotherapy could boost adjuvant immunotherapy to achieve a better and longer-lasting antitumor response. Therefore, therapeutic strategies that combine electrochemotherapy with immune checkpoint inhibitors or adjuvant treatment with cytokines are indicated for HCC. Immunogene therapy using electroporation as a delivery system for plasmid DNA coding for interleukin-12 is a highly promising approach. This electroporation approach has shown efficacy in preclinical settings and veterinary oncology and is awaiting translation for the treatment of liver tumors,
HCC.
Biofilm contamination on an implanted medical device represents a particularity resilient reservoir of infection that inevitably leads to device failure. In this study, we demonstrate that an ...atmospheric pressure air plasma treatment can simultaneously eradicate biofilm contamination while beneficially functionalizing the underlying surface, creating long-lasting characteristics that inhibit microbial recolonization and promote fibroblast proliferation. By comparing two contrasting plasma treatments the interplay between plasma generated reactive species, biofilm contamination and the underlying surface was uncovered. The composition, wettability and topography of titanium surfaces were characterized using X-ray photoelectron spectroscopy, water contact angle measurements and atomic force microscopy. Exposure to plasma generated chemical species created nanoscale surface features and the introduction of oxygen and nitrogen containing functional groups, resulting in changes to the surface wettability. Using a polymicrobial biofilm model comprising of E. coli and S. epidermidis, it was shown that plasma can effectively eliminate biofilm contamination from the surface, while simultaneously functionalizing the surface to inhibit recolonization. To assess the biocompatibility of treated surfaces the adhesion and proliferation of murine fibroblasts was assessed using fluorescent microscopy, cell viability assays and flow cytometry. It was shown that plasma exposure led to surface characteristics that promote fibroblast adhesion and proliferation.
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•Low temperature plasma simultaneously decontaminates and functionalizes titanium.•Plasma exposure creates nanoscale features and superhydrophilic characteristics.•Plasma exposure is highly effective in eliminating polymicrobial biofilms.•Plasma treated surface inhibits microbial recolonization and biofilm formation.•Biocompatibility improved through enhanced cell adhesion and proliferation.
•HI-PEMF facilitated delivery of plasmid DNA in muscle, skin and tumors.•HI-PEMF induced less infiltration of inflammatory mononuclear cells compared to EP.•Antitumor effectiveness using HI-PEMF for ...silencing MCAM was demonstrated.
High-Intensity Pulsed Electromagnetic Fields (HI-PEMF) treatment is an emerging noninvasive and contactless alternative to conventional electroporation, since the electric field inside the tissue is induced remotely by external pulsed magnetic field. Recently, HI-PEMF was applied for delivering siRNA molecules to silence enhanced green fluorescent protein (EGFP) in tumors in vivo. Still, delivered siRNA molecules were 21 base pairs long, which is 200-times smaller compared to nucleic acids such as plasmid DNA (pDNA) that are delivered in gene therapies to various targets to generate therapeutic effect. In our study, we demonstrate the use HI-PEMF treatment as a feasible noninvasive approach to achieve in vivo transfection by enabling the transport of larger molecules such as pDNA encoding EGFP into muscle and skin. We obtained a long-term expression of EGFP in the muscle and skin after HI-PEMF, in some mice even up to 230 days and up to 190 days, respectively. Histological analysis showed significantly less infiltration of inflammatory mononuclear cells in muscle tissue after the delivery of pEGFP using HI-PEMF compared to conventional gene electrotransfer. Furthermore, the antitumor effectiveness using HI-PEMF for electrotransfer of therapeutic plasmid, i.e., silencing MCAM was demonstrated. In conclusion, feasibility of HI-PEMF was demonstrated for transfection of different tissues (muscle, skin, tumor) and could have great potential in gene therapy and in DNA vaccination.
The antibacterial and cell-proliferative character of atmospheric pressure plasma jets (APPJs) helps in the healing process of chronic wounds. However, control of the plasma-biological target ...interface remains an open issue. High vacuum ultraviolet/ultraviolet (VUV/UV) radiation and RONS flux from plasma may cause damage of a treated tissue; therefore, controlled interaction is essential. VUV/UV emission from argon APPJs and radiation control with aerosol injection in plasma effluent is the focus of this research. The aerosol effect on radiation is studied by a fluorescent target capable of resolving the plasma oxidation footprint. In addition, DNA damage is evaluated by plasmid DNA radiation assay and cell proliferation assay to assess safety aspects of the plasma jet, the effect of VUV/UV radiation, and its control with aerosol injection. Inevitable emission of VUV/UV radiation from plasmas during treatment is demonstrated in this work. Plasma has no antiproliferative effect on fibroblasts in short treatments (t < 60 s), while long exposure has a cytotoxic effect, resulting in decreased cell survival. Radiation has no effect on cell survival in the medium due to absorption. However, a strong cytotoxic effect on the attached fibroblasts without the medium is apparent. VUV/UV radiation contributes 70% of the integral plasma effect in induction of single- and double-strand DNA breaks and cytotoxicity of the attached cells without the medium. Survival of the attached cells increases by 10% when aerosol is introduced between plasma and the cells. Injection of aerosol in the plasma effluent can help to control the plasma–cell/tissue interaction. Aerosol droplets in the effluent partially absorb UV emission from the plasma, limiting photon flux in the direction of the biological target. Herein, cold and safe plasma-aerosol treatment and a safe operational mode of treatment are demonstrated in a murine model.
Irreversible electroporation (IRE) is gaining importance in routine clinical practice for nonthermal ablation of solid tumors. For its success, it is extremely important that the coverage and ...exposure time of the treated tumor to the electric field is within the specified range. Measurement of electric field distribution during the electroporation treatment can be achieved using magnetic resonance electrical impedance tomography (MREIT). Here, we show improved MREIT-enabled electroporation monitoring of IRE-treated tumors by predicting IRE-ablated tumor areas during IRE of mouse tumors in vivo. The in situ prediction is enabled by coupling MREIT with a corresponding Peleg-Fermi mathematical model to obtain more informative monitoring of IRE tissue ablation by providing cell death probability in the IRE-treated tumors. This technique can potentially be used in electroporation-based clinical applications, such as IRE tissue ablation and electrochemotherapy, to improve and assure the desired treatment outcome.
In electrochemotherapy two conditions have to be met to be successful – the electric field of sufficient amplitude and sufficient uptake of chemotherapeutics in the tumor. Current treatment plans ...only take into account critical electric field to achieve cell membrane permeabilization. However, permeabilization alone does not guarantee uptake of chemotherapeutics and consequently successful treatment. We performed a feasibility study to determine whether the transport of cisplatin in vivo could be calculated based on experiments performed in vitro. In vitro, a spectrum of parameters can be explored without ethical issues. Mouse melanoma B16-F1 cell suspension and inoculated B16-F10 tumors were exposed to electric pulses in the presence of chemotherapeutic cisplatin. The uptake of cisplatin was measured by inductively coupled plasma mass spectrometry. We modeled the transport of cisplatin with the dual-porosity model, which is based on the diffusion equation, connects pore formation with membrane permeability, and includes transport between several compartments. In our case, there were three compartments - tumor cells, interstitial fraction and peritumoral region. Our hypothesis was that in vitro permeability coefficient could be introduced in vivo, as long as tumor physiology was taken into account. Our hypothesis was confirmed as the connection of in vitro and in vivo experiments was possible by introducing a transformation coefficient which took into account the in vivo characteristics, i.e., smaller available area of the plasma membrane for transport due to cell density, presence of cell-matrix in vivo, and reduced drug mobility. We thus show that it is possible to connect in vitro and in vivo experiments of electrochemotherapy. However, more experimental work is required for model validation.
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Electrochemotherapy (ECT) is a local ablative treatment that is based on the reversible electroporation and intracellular accumulation of hydrophilic drug molecules, which greatly increases their ...cytotoxicity. In mucosal head and neck cancer (HNC), experience with ECT is limited due to the poor accessibility of tumors. In order to review the experience with ECT in mucosal HNC, we undertook a systematic review of the literature. In 22 articles, published between 1998 and 2020, 16 studies with 164 patients were described. Curative and palliative intent treatment were given to 36 (22%) and 128 patients (78%), respectively. The majority of tumors were squamous cell carcinomas (79.3%) and located in the oral cavity (62.8%). In the curative intent group, complete response after one ECT treatment was achieved in 80.5% of the patients, and in the palliative intent group, the objective (complete and partial) response rate was 73.1% (31.2% and 41.9%). No serious adverse events were reported during or soon after ECT and late effects were rare (19 events in 17 patients). The quality-of-life assessments did not show a significant deterioration at 12 months post-ECT. Provided these preliminary data are confirmed in randomized controlled trials, ECT may be an interesting treatment option in selected patients with HNC not amenable to standard local treatment.
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