<title>Physiological imaging of electrical trauma and therapeutic responses</title>
Chin-Tu ChenK. MatthewsJohn N. AarsvoldRobert A. MintzerN.J. YasilloJürgen HannigM. Capelli-SchellpfeferMalcolm CooperRaphael C. Lee
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In victims of electrical trauma, electroporation of cell membrane, in which lipid bilayer is permeabilized by thermal and electrical forces, is thought to be a substantial cause of tissue damage. It has been suggested that certain mild surfactant in low concentration could induce sealing of permeabilized lipid bilayers, thus repairing cell membranes that had not been extensively damaged. With an animal model of electrically injured hind limb of rats, we have demonstrated and validated the use of radiotracer imaging technique to assess the physiology of the damaged tissues after electrical shock and of their repairs after applying surfactant as a therapeutic strategy. For example, using Tc-99m labeled pyrophosphate (PYP), which follows calcium in cellular function and is known to accumulate in damaged tissues, we have established a physiological imaging approach for assessment of the extent of tissue injury for diagnosis and surgical planning, as well as for evaluation of responses to therapy. With the use of a small, hand-held, miniature gamma camera, this physiological imaging method can be employed at patient's bedside and even in the field, for example, at accident site or during transfer for emergency care, rapid diagnosis, and prompt treatment in order to maximize the chance for tissue survival.Keywords:
Electrical Injuries
Irreversible Electroporation
Abstract When high pulsed electric fields (PEFs) are applied to the brain electroporation occurs. Depending on the electric fields strength, irreversible electroporation, inducing necrotic cell death or reversible electroporation, inducing BBB disruption may occur. We have developed a unique minimally-invasive setup for treating brain tumors employing a single insulated intracranial electrode with an exposed tip placed within the tumor and an external surface electrode. This unique setup, termed point-source electroporation, provides intratumoral irreversible-electroporation (inducing necrosis) with surrounding reversible BBB disruption, enabling efficient delivery of systemically administered drugs into the infiltrating zone. Treatment duration is 1–2 min. An efficacy study conducted with 120 glioma-bearing rats resulted in suppressed tumor growth rates in the electroporation+Cisplatin group (1.1±0.1) relative to growth rates in the control group (5.2±1.0), p< 0.047, and in the Cisplatin-only group p< 0.012 (3.92±1.0) (Welch’s F(2,12.73)=10.84; p< 0.002; ω2=0.28). Kaplan-Meir analysis revealed that electroporation+Cisplatin prolonged survival significantly (χ2=7.54; p< 0.006). Immunofluorescence analysis revealed significant infiltration of peripheral macrophages and CD8+ cells in the residual tumor. A finite elements simulation demonstrated the feasibility for obtaining clinically-relevant treatment volumes (~6cm diameter) using a single 3mm (diameter) intracranial catheter. Additionally, we discovered that low PEFs, an order of magnitude lower than electroporation threshold, can also transiently disrupt the BBB by a different mechanism, enabling penetration of both small (Gd/NaF) and large (Evans blue bound to serum albumin) molecules and immune cells, non-invasively. The extent of BBB disruption, measured in mice using delayed-contrast MRI, was found to be linearly dependent both on the electric field strength (r2=0.9,p< 0.03) and on the number of applied pulses (r2=0.94,p< 0.003). These results demonstrate the feasibly of applying combined systemic chemotherapy with point-source electroporation, a minimal-invasive/rapid treatment of PEFs, for obtaining significant antineoplastic effects. Furthermore, low PEFs may be applied non-invasively, rapidly and repeatedly for obtaining reversible BBB disruption.
Irreversible Electroporation
Infiltration (HVAC)
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Advances of Electroporation-Related Therapies and the Synergy with Immunotherapy in Cancer Treatment
Electroporation is the process of instantaneously increasing the permeability of a cell membrane under a pulsed electric field. Depending on the parameters of the electric pulses and the target cell electrophysiological characteristics, electroporation can be either reversible or irreversible. Reversible electroporation facilitates the delivery of functional genetic materials or drugs to target cells, inducing cell death by apoptosis, mitotic catastrophe, or pseudoapoptosis; irreversible electroporation is an ablative technology which directly ablates a large amount of tissue without causing harmful thermal effects; electrotherapy using an electric field can induce cell apoptosis without any aggressive invasion. Reversible and irreversible electroporation can also activate systemic antitumor immune response and enhance the efficacy of immunotherapy. In this review, we discuss recent progress related to electroporation, and summarize its latest applications. Further, we discuss the synergistic effects of electroporation-related therapies and immunotherapy. We also propose perspectives for further investigating electroporation and immunotherapy in cancer treatment.
Irreversible Electroporation
Electrochemotherapy
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Electrochemotherapy
Irreversible Electroporation
Cancer Therapy
Tumor ablation
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Nonthermal irreversible electroporation is a new tissue ablation technique that consists of applying pulsed electric fields across cells to induce cell death by creating permanent defects in the cell membrane. Nonthermal irreversible electroporation is of interest because it allows treatment near sensitive tissue structures such as blood vessels and nerves. Two recent articles report that electrolytic reaction products at electrodes can be combined with electroporation pulses to augment and optimize tissue ablation. Those articles triggered a concern that the results of earlier studies on nonthermal irreversible electroporation may have been tainted by unaccounted for electrolytic effects. The goal of this study was to reexamine previous studies on nonthermal irreversible electroporation in the context of these articles. The study shows that the results from some of the earlier studies on nonthermal irreversible electroporation were affected by unaccounted for electrolysis, in particular the research with cells in cuvettes. It also shows that tissue ablation ascribed in the past to irreversible electroporation is actually caused by at least 3 different cytotoxic effects: irreversible electroporation without electrolysis, irreversible electroporation combined with electrolysis, and reversible electroporation combined with electrolysis. These different mechanisms may affect cell and tissue ablation in different ways, and the effects may depend on various clinical parameters such as the polarity of the electrodes, the charge delivered (voltage, number, and length of pulses), and the distance of the target tissue from the electrodes. Current clinical protocols employ ever-increasing numbers of electroporation pulses to values that are now an order of magnitude larger than those used in our first fundamental nonthermal irreversible electroporation studies in tissues. The different mechanisms of cell death, and the effect of the clinical parameters on the mechanisms may explain discrepancies between results of different clinical studies and should be taken into consideration in the design of optimal electroporation ablation protocols.
Irreversible Electroporation
Electrochemotherapy
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Numerical study of the electroporation pulse shape effect on molecular uptake of biological cellsBackground. In order to reduce the side-effects of chemotherapy, combined chemotherapy-electroporation (electrochemotherapy) has been suggested. Electroporation, application of appropriate electric pulses to biological cells, can significantly enhance molecular uptake of cells due to formation of transient pores in the cell membrane. It was experimentally demonstrated that the efficiency of electroporation is under the control of electric pulse parameters. However, the theoretical basis for these experimental results is not fully explained. In order to predict the outcome of experiments and optimize the efficiency of electroporation before each treatment, we developed a model to investigate the effect of pulse shape on efficiency of electroporation.Results. Our model is based on a developed chemical-kinetics scheme and trapezium barrier model, while selfconsistency was taken into account. This model is further supplemented with a molecular transport model to acquire the molecular uptake of cells. The investigated pulse shapes in this study were unipolar rectangular pulses with different rise and fall times, triangular, sinusoidal and bipolar rectangular pulses and also sinusoidal modulated unipolar pulses with different percentages of modulation. The obtained results from our modelling and simulations are in good agreement with previously published
Electrochemotherapy
Irreversible Electroporation
Cell membrane
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Abstract Background Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning. Material and methods Cell death and BBB disruption models were developed based on the Peleg-Fermi model in combination with numerical models of the electric field. The model calculates the electric field thresholds for cell kill and BBB disruption and describes the dependence on the number of treatment pulses. The model was validated using in vivo experimental data consisting of rats brains MRIs post electroporation treatments. Results Linear regression analysis confirmed that the model described the IRE and BBB disruption volumes as a function of treatment pulses number (r 2 = 0.79; p < 0.008, r 2 = 0.91; p < 0.001). The results presented a strong plateau effect as the pulse number increased. The ratio between complete cell death and no cell death thresholds was relatively narrow (between 0.88-0.91) even for small numbers of pulses and depended weakly on the number of pulses. For BBB disruption, the ratio increased with the number of pulses. BBB disruption radii were on average 67% ± 11% larger than IRE volumes. Conclusions The statistical model can be used to describe the dependence of treatment-effects on the number of pulses independent of the experimental setup.
Electrochemotherapy
Irreversible Electroporation
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Electrochemotherapy
Irreversible Electroporation
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Electrochemotherapy
Irreversible Electroporation
Biological tissue
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Electroporation, the increased permeability of cell membranes due to a large transmembrane voltage, is an important clinical tool. Both reversible and irreversible in vivo electroporation are used for clinical applications such as gene therapy and solid malignant tumor ablation, respectively. The primary advantage of in vivo electroporation is the ability to treat tissue in a local and minimally invasive fashion. The drawback is the current lack of control over the process. This paper is the first report of a new method for real-time three-dimensional imaging of an in vivo electroporation process. Using two needle electrodes for irreversible electroporation and a set of electrodes for reconstructing electrical impedance tomography (EIT) images of the treated tissue, we were able to demonstrate electroporation imaging in rodent livers. Histology analysis shows good correlation between the extent of tissue damage caused by irreversible electroporation and the EIT images. This new method may lead the way to real-time control over genetic treatment of diseases in tissue and tissue ablation.
Irreversible Electroporation
Electrical Impedance Tomography
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Irreversible electroporation has raised great interest in the past decade as a means of destroying cancers in a way that does not involve heat. Irreversible electroporation is a novel ablation technology that uses short high-voltage electrical pulses to enhance the permeability of tumor cell membranes and generate irreversible nano-sized structural defects or pores, thus leading to cell death. Irreversible electroporation has many advantages over thermal therapies due to its nonthermal mechanism: (1) reduced risk of injury to surrounding organs and (2) no “heat-sink” effect due to nearby blood vessels. However, so far, it has been difficult for irreversible electroporation to completely ablate large tumors (eg, >3 cm in diameter). In order to overcome this problem, many preclinical and clinical studies have been performed to improve the efficacy of IRE in the treatment of large size of tumors through a chemical perspective. Due to the distribution of electric field, irreversible electroporation region, reversible electroporation region, and intact region can be found in the treatment of irreversible electroporation. Thus, 2 types of chemical enhancements of irreversible electroporation were discussed in the article, such as the reversible electroporation region enhanced and the irreversible electroporation region enhanced. Specifically, the state-of-the-art results regarding the following approaches that have the potential to be used in the enhancement of irreversible electroporation were systematically reviewed in the article, including (1) combination with cytotoxic drugs, (2) calcium electroporation, (3) modification of cell membrane, and (4) modification of the tumor cell microenvironment. In the end, we concluded with 4 issues that should be addressed in the future for improving irreversible electroporation further in a chemical way.
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