Advances in Therapeutic Electroporation to Mitigate Muscle Contractions

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.

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“…The first efforts in this direction have been done by suggesting application of high-frequency bipolar electroporation pulses [113]. …”

Section: Introductionmentioning

confidence: 99%

Electrochemotherapy: from the drawing board into medical practice

et al. 2014

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“…Electrical stimulation has always been a concern among researchers and clinicians working in the field of electroporation (Arena and Davalos 2012). Fortunately, quite early it was identified a mechanism to prevent the risk of ventricular fibrillation: to synchronize the voltage pulses with the electrocardiogram signal to deliver the pulses when all myocardium cells are in the absolute refractory period (Okino et al 1992, Mali et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Avoiding nerve stimulation in irreversible electroporation: a numerical modeling study

et al. 2017

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Electroporation based treatments consist in applying one or multiple high voltage pulses to the tissues to be treated. As an undesired side effect, these pulses cause electrical stimulation of excitable tissues such as nerves and muscles. This increases the complexity of the treatments and may pose a risk to the patient. To minimize electrical stimulation during electroporation based treatments, it has been proposed to replace the commonly used monopolar pulses by bursts of short bipolar pulses. In the present study, we have numerically analyzed the rationale for such approach. We have compared different pulsing protocols in terms of their electroporation efficacy and their capability to trigger action potentials in nerves. For that, we have developed a modeling framework that combines numerical models of nerve fibers and experimental data on irreversible electroporation. Our results indicate that, by replacing the conventional relatively long monopolar pulses by bursts of short bipolar pulses, it is possible to ablate a large tissue region without triggering action potentials in a nearby nerve. Our models indicate that this is possible because, as the pulse length of these bipolar pulses is reduced, the stimulation thresholds raise faster than the irreversible electroporation thresholds. We propose that this different dependence on the pulse length is due to the fact that transmembrane charging for nerve fibers is much slower than that of cells treated by electroporation because of their geometrical differences.

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“…One challenge with delivering unipolar electric pulses for nonthermal ablation or BBB disruption is that they result in signifi cant muscle contractions 20 . As electrically induced movement could compromise electrode positioning, IRE procedures typically require that patients receive a neuromuscular blocker and general anesthesia.…”

Section: Introductionmentioning

confidence: 99%

Focal blood-brain-barrier disruption with high-frequency pulsed electric fields

et al. 2014

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The blood-brain-barrier (BBB), a network of tight junctions that impedes large molecule transport, limits the usefulness of systemic chemotherapeutic delivery for the treatment of malignant gliomas and other neurological diseases. Here, we present a tool for BBB disruption that uses bursts of sub-microsecond bipolar pulses to enhance the transfer of large molecules to the brain. Blunt needle electrodes were advanced into the motor cortex of anesthetized adult rats, and a series of 90-900 bursts were delivered with voltage-to-distance ratios of 250 or 2000 V/cm, a total programmed energized time of 100 µs, and a repetition rate of 1 Hz. BBB disruption was assessed via a gadolinium-Evans blue albumin tracer, and all experimental conditions were found to cause BBB disruption immediately following treatment without inducing local or distal muscle contractions. The lowest energy condition, 300 bursts consisting of 850 ns bipolar pulses, resulted in signifi cant BBB disruption (0.51 cm 3 ), without displaying necrotic or apoptotic damage to neurological tissue. INNOVATIONTh e Vascular Enabled Integrated Nanosecond pulse (VEIN pulse) platform is a new technology for reversibly opening the blood-brain-barrier (BBB) to facilitate the treatment of brain cancer. Our experiments reveal that the delivery of bipolar sub-microsecond pulses eliminates the electrically induced movement associated with longer duration unipolar pulses used in irreversible electroporation and electrochemotherapy treatments. Th erefore, it may be possible in the future to perform these procedures while patients are under conscious sedation and assess cognitive function as the therapy is being delivered. Th e sub-lethal nature of these bursts indicates that this modality may be useful for treating other neurological disorders, such as Parkinson's disease and epilepsy, in which certain therapeutics show eff ectiveness in in vitro models of disease, but fail to reach their therapeutic target in vivo. Generation of these waveforms is possible using solid-state electronics, enabling the creation of compact systems that can easily be scaled for human clinical applications.

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Advances in Therapeutic Electroporation to Mitigate Muscle Contractions

Abstract: There is a growing effort among researchers to develop unique ways to apply pulsed electric fields for therapeutic applications that reduce the intensity or extent of muscle contractions in order to eliminate the use of muscle relaxants in clinical practice.

Cited by 16 publications

References 41 publications

Electrochemotherapy: from the drawing board into medical practice

Electrochemotherapy: from the drawing board into medical practice

Avoiding nerve stimulation in irreversible electroporation: a numerical modeling study

Focal blood-brain-barrier disruption with high-frequency pulsed electric fields

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