Maura Casciola

• PhD in Electronic Engineering and Chemistry
• Fellow at U.S. Food and Drug Administration

Exposing cells to intense and brief electric field pulses can modulate cell permeability, a phenomenon termed electroporation. When applied in medical treatments of diseases like cancer and cardiac arrhythmias, depending on level of cellular destruction, it is also referred to as irreversible electroporation (IRE) or Pulsed Field Ablation (PFA). Fo...

Introduction Pulsed Field Ablation (PFA) is a novel non-thermal method for cardiac ablation, relying on irreversible electroporation induced by high-energy pulsed electric fields (PEFs) to create localized lesions in the heart atria. A significant challenge in optimizing PFA treatments is determining the lethal electric field threshold (EFT), which...

Introduction Cardiac contractility modulation (CCM) is a medical device‐based therapy delivering non‐excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e...

Introduction: Pulsed electric field (PEF) cardiac ablation has been recently proposed as a technique to treat drug resistant atrial fibrillation by inducing cell death through irreversible electroporation (IRE). Improper PEF dosing can result in thermal damage or reversible electroporation. The lack of comprehensive and systematic studies to select...

Cardiac contractility modulation (CCM) is a medical device therapy whereby non-excitatory electrical stimulations are delivered to the myocardium during the absolute refractory period to enhance cardiac function. We previously evaluated the effects of the standard CCM pulse parameters in isolated rabbit ventricular cardiomyocytes and 2D human induc...

Introduction: Catheter cardiac ablation is a standard treatment for atrial fibrillation for patients that do not respond to drugs. Pulsed electric field (PEF) cardiac ablation has been proposed as a nonthermal technology to cause cell death by irreversible electroporation (IRE). IRE has shown to minimize off target damage. The lack of systematic st...

Two of the most prominent organ systems, the nervous and the cardiovascular systems, are intricately connected to maintain homeostasis in mammals. Recent years have shown tremendous efforts toward therapeutic modulation of cardiac contractility and electrophysiology by electrical stimulation. Neuronal innervation and cardiac ganglia regulation are...

Pulse electric field-based (PEF) ablation is a technique whereby short high-intensity electric fields inducing irreversible electroporation (IRE) are applied to various tissues. Here, we implemented a standardized in vitro model to compare the effects of biphasic symmetrical pulses (100 pulses, 1-10 μs phase duration (d), 10-1000 Hz pulse repetitio...

Background: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical simulations to the heart during the absolute refractory period to enhance cardiac function. We previously evaluated the acute effects of CCM in isolated rabbit-CM and 2D hiPSC-CM monolayers, on flexible substrate, and found enha...

Cardiac contractility modulation (CCM) is an intracardiac therapy whereby nonexcitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. We previously evaluated the effects of CCM in isolated adult rabbit ventricular cardiomyocytes and found a transient increase in calcium and contractility. In the pr...

The Cardiovascular Research Program in OSEL at the FDA consists of a diverse group of engineers and scientists who seek to drive innovation in cardiovascular device technology through development and standardization of pre-clinical test methods using in vitro, in vivo, and in silico models. The goal is to improve the pre- and post-market regulatory...

Exposures to short-duration, strong electric field pulses have been utilized for stimulation, ablation, and the delivery of molecules into cells. Ultrashort, nanosecond duration pulses have shown unique benefits, but they require higher field strengths. One way to overcome this requirement is to use trains of nanosecond pulses with high repetition...

The Gram-positive anaerobic bacterium Cutibacterium acnes (C. acnes) is a commensal of the human skin, but also an opportunistic pathogen that contributes to the pathophysiology of the skin disease acne vulgaris. C. acnes can form biofilms; cells in biofilms are more resilient to antimicrobial stresses. Acne therapeutic options such as topical or s...

Cardiac contractility modulation (CCM) is a cardiac therapy whereby non-excitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. CCM is indicated for patients with heart failure (Class III/IV) and reduced ejection fraction. We previously evaluated the effects of CCM and found isolated adult rabbit...

Irreversible Electroporation (IRE) has gained significant interest as an alternative treatment for atrial fibrillation (AF). Typically, to terminate AF, thermal energy is delivered to the arrhythmic tissue causing rare but serious damage to surrounding areas. IRE is a non-thermal approach that has the potential to be faster yet more targeted. We ar...

The principal bioeffect of the nanosecond pulsed electric field (nsPEF) is a lasting cell membrane permeabilization, which is often attributed to the formation of nanometer-sized pores. Such pores may be too small for detection by the uptake of fluorescent dyes. We tested if Ca2+, Cd2+, Zn2+, and Ba2+ ions can be used as nanoporation markers. Time-...

Depending on the initiating stimulus, cancer cell death can be immunogenic or non-immunogenic. Inducers of immunogenic cell death (ICD) rely on endoplasmic reticulum (ER) stress for the trafficking of danger signals such as calreticulin (CRT) and ATP. We found that nanosecond pulsed electric fields (nsPEF), an emerging new modality for tumor ablati...

The permeabilized condition of the cell membrane after electroporation can last minutes but the underlying mechanisms remain elusive. Previous studies suggest that lipid peroxidation could be responsible for the lasting leaky state of the membrane. The present study aims to link oxidation within the plasma membrane of live cells to permeabilization...

The initiation of action potentials (APs) by membrane depolarization occurs after a brief vulnerability period, during which excitation can be abolished by the reversal of the stimulus polarity. This vulnerability period is determined by the time needed for gating of voltage-gated sodium channels (VGSC). We compared nerve excitation by ultra-short...

A unique aspect of electrostimulation (ES) with nanosecond electric pulses (nsEP) is the inhibition of effects when the polarity is reversed. This bipolar cancellation feature makes bipolar nsEP less efficient at biostimulation than unipolar nsEP. We propose to minimize stimulation near pulse-delivering electrodes by applying bipolar nsEP, whereas...

Intense nanosecond pulsed electric field (nsPEF) is a novel modality for cell activation and nanoelectroporation. Applications of nsPEF in research and therapy are hindered by a high electric field requirement, typically from 1 to over 50 kV/cm to elicit any bioeffects. We show how this requirement can be overcome by engaging temporal summation whe...

Poly-unsaturated fatty acids of the plasma membrane are a primary target for reactive oxygen species. Oxidative stress at the membrane can significantly affect its properties and thus, the intracellular transport and cell homeostasis. Currently, most of the protocols to detect membrane lipid peroxidation are characterized by low specificity/resolut...

Introduction Opening of voltage‐gated sodium channels takes tens to hundreds of microseconds, and mechanisms of their opening by nanosecond pulsed electric field (nsPEF) stimuli remain elusive. This study was aimed at uncovering the mechanisms of how nsPEF elicits action potentials (APs) in cardiomyocytes. Methods and Results Fluorescent imaging o...

We compared membrane permeabilization by nanosecond pulsed electric field (nsPEF) in HEK293 cells with and without assembled CaV1.3 L-type voltage-gated calcium channel (VGCC). Individual cells were subjected to one 300-ns pulse at 0 (sham exposure); 1.4; 1.8; or 2.3 kV/cm, and membrane permeabilization was evaluated by measuring whole-cell current...

Intense electric shocks of nanosecond (ns) duration can become a new modality for more efficient but safer defibrillation. We extended strength-duration curves for excitation of cardiomyocytes down to 200 ns, and compared electroporative damage by proportionally more intense shocks of different duration. Enzymatically isolated murine, rabbit, and s...

Bipolar cancellation refers to a phenomenon when applying a second electric pulse reduces ("cancels") cell membrane damage by a preceding electric pulse of the opposite polarity. Bipolar cancellation is a reason why bipolar nanosecond electric pulses (nsEP) cause weaker electroporation than just a single unipolar phase of the same pulse. This study...

Decreasing the time gap between two identical electric pulses is expected to render bioeffects similar to those of a single pulse of equivalent total duration. In this study, we show that it is not necessarily true, and that the effects vary for different permeabilization markers. We exposed individual CHO or NG108 cells to one 300-ns pulse (3.7-11...

Nanosecond pulsed electric fields are emerging as a new modality for tissue and tumor ablation. We previously reported that cells exposed to pulsed electric fields develop hypersensitivity to subsequent pulsed electric field applications. This phenomenon, named electrosensitization, is evoked by splitting the pulsed electric field treatment in frac...

Modern technologies enable deep tissue focusing of nanosecond pulsed electric field (nsPEF) for non-invasive nerve and muscle stimulation. However, it is not known if PEF orders of magnitude shorter than the activation time of voltage-gated sodium channels (VGSC) would evoke action potentials (APs). One plausible scenario requires the loss of membr...

Nanosecond pulsed electric fields (nsPEFs) are emerging as a novel modality for cell stimulation and tissue ablation. However, the downstream protein effectors responsible for nsPEF bioeffects remain to be established. Here we demonstrate that nsPEFs activate TMEM16F, (or anoctamin 6), a protein functioning as a Ca(2+)-dependent phospholipid scramb...

Electroporation (EP), also known as electropermeabilization, is a widely used technology employed primarily for intracellular delivery of drugs and genes, likewise for tissue and tumor destruction. The majority of the studies on EP hypothesize that the boost in permeability of cell membranes, following the application of pulsed electric fields, to...

In most applications of electroporation in biology, medicine, and industry, the desired effect is achieved by the delivery of multiple pulses. The pulse repetition rate (PRR) is one of the key factors which determine the efficiency of such treatments. Despite intense research, the impact of PRR has not been fully understood and remains one of the m...

Cellular effects caused by nanosecond electric pulses (nsEP) can be reduced by an electric field reversal, a phenomenon known as bipolar cancellation. The reason for this cancellation effect remains unknown. We hypothesized that assisted membrane discharge is the mechanism for bipolar cancellation. CHO-K1 cells bathed in high (16.1mS/cm; HCS) or lo...

Electric field pulses of nano- and picosecond duration are a novel modality for neurostimulation, activation of Ca2 + signaling, and tissue ablation. However it is not known how such brief pulses activate voltage-gated ion channels. We studied excitation and electroporation of hippocampal neurons by 200-ns pulsed electric field (nsPEF), by means of...

The emergence of nanosecond pulsed electric fields (nsPEFs) for intracellular manipulation experiments requires the use of specific miniaturized applicators. We propose the design of a versatile nsPEFs applicator, based on microwave propagating systems, suitable for in vitro exposure to undistorted 1–3 ns pulses in single and multi-cell experiments...

In most applications of electroporation in biology, medicine, and industry, the desired effect is achieved by the delivery of multiple pulses. The pulse repetition rate (PRR) is one of the key factors which determine the efficiency of such treatments. Despite intense research, the impact of PRR has not been fully understood and remains one of the m...

Electroporation (EP), also known as electropermeabilization, is a widely used technology employed primarily for intracellular delivery of drugs and genes, likewise for tissue and tumor destruction. The majority of the studies on EP hypothesize that the boost in permeability of cell membranes, following the application of pulsed electric fields, to...

In the last decades, the advances in the micro and nano fabrication techniques have led to the development of microdevices that improved the possibility of analysis at cell level. These devices can be used in different applications (e.g., cell detection and identification, manipulation, cell treatments). The requisites, that are necessary to achiev...

Electrical conductance of an aqueous pore in the lipid bilayer has an important role in the process of membrane electroporation, i.e., formation of pores induced by electric pulses. In our present study we compare the pore conductance as predicted by a theoretical model based on the continuum Poisson-Nernst-Planck theory to the pore conductance obt...

Electroporation (EP) is a technique used to affect the integrity of plasma cell membranes and/or internal organelles, consequence of the application of an external pulsed electric field of sufficient energy content, tuned by its strength and duration. It is proven by extensive indirect experimental and in silico evidences that this phenomenon resul...

The transport of chemical compounds across the plasma membrane into the cell is relevant for several biological and medical applications. One of the most efficient techniques to enhance this uptake is reversible electroporation. Nevertheless, the detailed molecular mechanism of transport of chemical species (dyes, drugs, genetic materials …) follow...

Molecular dynamics (MD) simulations have become a powerful tool to study electroporation (EP) in atomic detail. In the last decade, numerous MD studies have been conducted to model the effect of pulsed electric fields on membranes, providing molecular models of the EP process of lipid bilayers. Here we extend these investigations by modeling for th...

When studying proteins in solution it is apparent that electrostatic interactions play a role in folding, conformational stability, and other chemical-physical properties. Electrostatics considers the evaluation of the static electrical field that is formed between charged species once a rearrangement of their charge distributions has occurred due...

We report on a molecular dynamics (MD) simulation study of the electroporation of lipid bilayers at different cholesterol contents using protocols mimicking “traditional” electroporation, i.e. low intensity millisecond pulses (msEP), and high intensity nanosecond electric pulses (nsEP). The results show that addition of cholesterol in concentration...

membranes are permeabilized. Under specific conditions, EP may be reversible, in which case membranes and cells recover their initial state when the applied field is turned off. Due to the availability of corresponding electronic devices, early studies have involved applying electric pulses of microsecond duration. Under such conditions, low magnit...

Molecular dynamics (MD) simulations of electrophoretic transport of monovalent ions through field-stabilized electropores in POPC lipid bilayers permit systematic characterization of the conductive properties of lipid nanopores. The radius of the electropore can be controlled by the magnitude of the applied sustaining external electric field, which...

In this paper, an electromagnetic characterization of a moveable wire electrode microchamber for nanosecond pulse delivery is proposed. The characterization of the exposure system was carried out through experimental measurements and numerical simulations. The frequency and time domain analyses demonstrate the utility of the proposed assembly for d...

In this paper, a versatile electrode assembly for cell electroporation is proposed. For validation of the delivery system, biological cell electroporation experiments using 2.5 ns and 5 ns, 10 MV/m pulsed electric fields have been conducted. Electromagnetic, time domain, and frequency analyses demonstrate the broadband behavior of the delivery syst...

Microdosimetric models for biological cells have assumed increasing significance in the development of nanosecond pulsed electric field technology for medical applications. In this paper, novel passive element circuits, able to take into account the dielectric dispersion of the cell, are provided. The circuital analyses are performed on a set of in...

In this paper, a versatile electrode assembly for cell electroporation is proposed. For validation of the delivery system, biological cell electroporation experiments using 2.5 ns and 5 ns, 10 MV/m pulsed electric fields have been conducted. Electromagnetic, time domain, and frequency analyses demonstrate the broadband behavior of the delivery syst...