OpenEP: an open-source simulator for electroporation-based tumor treatments

Electroporation (EP), the increase of cell membrane permeability due to the application of electric pulses, is a universal phenomenon with a broad range of applications. In medicine, some of the foremost EP-based tumor treatments are electrochemotherapy (ECT), irreversible electroporation, and gene electrotransfer (GET). The electroporation phenomenon is explained as the formation of cell membrane pores when a transmembrane cell voltage reaches a threshold value. Predicting the outcome of an EP-based tumor treatment consists of finding the electric field distribution with an electric threshold value covering the tumor (electroporated tissue). Threshold and electroporated tissue are also a function of the number of pulses, constituting a complex phenomenon requiring mathematical modeling. We present OpenEP, an open-source specific purpose simulator for EP-based tumor treatments, modeling among other variables, threshold, and electroporated tissue variations in time. Distributed under a free/libre user license, OpenEP allows the customization of tissue type; electrode geometry and material; pulse type, intensity, length, and frequency. OpenEP facilitates the prediction of an optimal EP-based protocol, such as ECT or GET, defined as the critical pulse dosage yielding maximum electroporated tissue with minimal damage. OpenEP displays a highly efficient shared memory implementation by taking advantage of parallel resources; this permits a rapid prediction of optimal EP-based treatment efficiency by pulse number tuning.Fil: Marino, Matias Daniel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Computación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física del Plasma. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física del Plasma; ArgentinaFil: Luján, Emmanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física del Plasma. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física del Plasma; ArgentinaFil: Mocskos, Esteban Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Simulación Computacional para Aplicaciones Tecnológicas; ArgentinaFil: Marshall, Guillermo Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física del Plasma. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física del Plasma; Argentin

Spatio temporal dynamics of direct current in treated anisotropic tumors

The inclusion of a diffusion term in the modified Gompertz equation (Cabrales et al., 2018) allows to describe the spatiotemporal growth of direct current treated tumors. The aim of this study is to extend the previous model to the case of anisotropic tumors, simulating the spatiotemporal behavior of direct current treated anisotropic tumors, also carrying out a theoretical analysis of the proposed model. Growths in the mass, volume and density of the solid tumors are shown for each response type after direct current application (disease progression, partial response, stationary partial response and complete remission). For this purpose, the Method of Lines and different diffusion tensors are used. The results show that the growth of the tumor treated with direct current is faster for the shorter duration of the net antitumor effect and the higher diffusion coefficient and anisotropy degree of the solid tumor. It is concluded that the greatest direct current antitumor effectiveness occurs for the highly heterogeneous, anisotropic, aggressive and hypodense malignant solid tumors

Thermal ablation of biological tissues in disease treatment: A review of computational models and future directions

Percutaneous thermal ablation has proved to be an effective modality for treating both benign and malignant tumors in various tissues. Among these modalities, radiofrequency ablation (RFA) is the most promising and widely adopted approach that has been extensively studied in the past decades. Microwave ablation (MWA) is a newly emerging modality that is gaining rapid momentum due to its capability of inducing rapid heating and attaining larger ablation volumes, and its lesser susceptibility to the heat sink effects as compared to RFA. Although the goal of both these therapies is to attain cell death in the target tissue by virtue of heating above 50 oC, their underlying mechanism of action and principles greatly differs. Computational modelling is a powerful tool for studying the effect of electromagnetic interactions within the biological tissues and predicting the treatment outcomes during thermal ablative therapies. Such a priori estimation can assist the clinical practitioners during treatment planning with the goal of attaining successful tumor destruction and preservation of the surrounding healthy tissue and critical structures. This review provides current state-of- the-art developments and associated challenges in the computational modelling of thermal ablative techniques, viz., RFA and MWA, as well as touch upon several promising avenues in the modelling of laser ablation, nanoparticles assisted magnetic hyperthermia and non- invasive RFA. The application of RFA in pain relief has been extensively reviewed from modelling point of view. Additionally, future directions have also been provided to improve these models for their successful translation and integration into the hospital work flow

Engineered Extracellular Vesicles: Processing and testing of cell-derived Exos

In recent decades, endogenous nanocarrier-exosomes have received considerable scientific interest as drug delivery systems. The unique proteo-lipid architecture allows the crossing of various natural barriers and protects Exosomes cargo from degradation in the bloodstream. However, the presence of this bilayer membrane as well as their endogenous content make production and loading of exogenous molecules challenging. In the present work, we will investigate how to promote the manipulation of cellular. And vesicles curvature by a high pressure microfluidic system as ground-breaking method for both Exosomes production and encapsulation. First of all, we exploited this approach to isolate the Exosomes derived by Glioblastoma U87-MG tumoral cell line. An increased yield and purity of Exosomes have been obtained. Furthermore, we proposed a complete protein-profiling comparing traditional isolation method in cell medium and isolation by Dynamic High-Pressure Homogenization. To validate our approach for Exosomes encapsulation, we tested in vitro the prodrug Irinotecan (IRI) in U87-MG Exosomes. As a result, we obtained a high EE, up to 45%, comparable to the principal industrial methodologies used for polymer nanoparticles, shortening the processing time for the encapsulation to several days to 1 hr, improving the drug uptake, and entirely avoiding the use of permeabilization enhancers. Also, this new approach has been tested on Doxorubicin and validated on a different cell lines and 3D cells model. Finally, we performed in vitro preliminary analysis to further understand Exosomes fate and nanobiointeraction with biological environment

Gold nanoparticles meet medical radionuclides

Thanks to their unique optical and physicochemical properties, gold nanoparticles have gained increased interest as radiosensitizing, photothermal therapy and optical imaging agents to enhance the effectiveness of cancer detection and therapy. Furthermore, their ability to carry multiple medically relevant radionuclides broadens their use to nuclear medicine SPECT and PET imaging as well as targeted radionuclide therapy. In this review, we discuss the radiolabeling process of gold nanoparticles and their use in (multimodal) nuclear medicine imaging to better understand their specific distribution, uptake and retention in different in vivo cancer models. In addition, radiolabeled gold nanoparticles enable image-guided therapy is reviewed aswell as the enhancement of targeted radionuclide therapy and nanobrachytherapy through an increased dose deposition and radiosensitization, as demonstrated by multiple Monte Carlo studies and experimental in vitro and in vivo studies. (C) 2021 The Authors. Published by Elsevier Inc

Oncology and mechanics: landmark studies and promising clinical applications

Clinical management of cancer has continuously evolved for several decades. Biochemical, molecular and genomics approaches have brought and still bring numerous insights into cancerous diseases. It is now accepted that some phenomena, allowed by favorable biological conditions, emerge via mechanical signaling at the cellular scale and via mechanical forces at the macroscale. Mechanical phenomena in cancer have been studied in-depth over the last decades, and their clinical applications are starting to be understood. If numerous models and experimental setups have been proposed, only a few have led to clinical applications. The objective of this contribution is to propose to review a large scope of mechanical findings which have consequences on the clinical management of cancer. This review is mainly addressed to doctoral candidates in mechanics and applied mathematics who are faced with the challenge of the mechanics-based modeling of cancer with the aim of clinical applications. We show that the collaboration of the biological and mechanical approaches has led to promising advances in terms of modeling, experimental design and therapeutic targets. Additionally, a specific focus is brought on imaging-informed mechanics-based models, which we believe can further the development of new therapeutic targets and the advent of personalized medicine. We study in detail several successful workflows on patient-specific targeted therapies based on mechanistic modeling

Effets des champs électriques pulsés milli et nanosecondes sur cellules et tissus

L'électroperméabilisation est une technique permettant, entre autre, l'entrée de molécules cytotoxiques dans les tumeurs. Elle consiste en la perméabilisation transitoire de la membrane plasmique suite à l'application de champs électriques pulsés. Certaines conditions électriques permettent le transfert de gène, ouvrant le champ d'application de la technique à la thérapie génique. Cette thèse s'est intéressée à étudier les effets des champs électriques sur cellules et tissus, dans le cas de l'électro-transfert de gène. En effet, la compréhension mécanistique de ce transfert est indispensable à l'optimisation de la technique pour les futures applications cliniques. Dans ce contexte, nous nous sommes attachés à étudier les 3 barrières rencontrées par le gène lors de son transfert, à savoir la complexité de l'environnement multicellulaire au niveau du tissu, la membrane plasmique et l'enveloppe nucléaire au niveau de la cellule. i) L'efficacité de l'electrotransfer de gène a été étudié sur le modèle de tumeur in vitro/ex vivo dit sphéroïde. Dans un premier temps ce modèle a été validé pour l'étude de l'électrotransfection et dans un deuxième temps les raisons de l'absence d'efficacité en structure tissulaire ont été mises en évidence et l'optimisation de la technique a été amorcée. ii) Une deuxième partie a été dédiée à l'étude nano-mécanique des cellules à l'échelle de la membrane plasmique par microscopie à force atomique. La microscopie à force atomique a été utilisée afin d'imager et mesurer par spectroscopie de force l'effet de l'électroperméabilisation sur la membrane plasmique. Nous avons imagé la perturbation membranaire et mesuré une diminution d'élasticité membranaire suivant l'application des champs électriques. Ce phénomène a été relié aux effets secondaires de l'électroperméabilisation affectant l'actine corticale. iii) Une dernière partie s'est intéressée aux effets des nanopulses. Ces impulsions très courtes (ns) et intenses (plusieurs kV/cm) représentent la nouvelle génération d'impulsions, dont les effets sont encore peu décrits, mais pourraient permettre une déstabilisation spécifique de l'enveloppe des organelles. L'impact de ses impulsions nanosecondes sur la membrane ont été analysée par Patch-Clamp pour déterminer l'implication du cytosquelette d'actine dans la forme des nanopores créés. Dans un deuxième temps leur impact sur l'enveloppe nucléaire a été étudié, dans le but de déterminer d'éventuels effets néfastes sur le fonctionnement cellulaire, et la potentielle augmentation de transfection résultant d'une déstabilisation de la deuxième barrière rencontré par le gène lors de son transfert. Il est montré que l'actine ne joue pas de rôle dans la formation des nanopores, et que les impulsions nanosecondes ne permettent pas d'augmenter l'efficacité de transfection. En conclusion ces travaux ont apporté de nouveaux éléments dans la compréhension du mécanisme d'électroporation et des barrières au transfert de gène. Des protocoles, modèles, et outils ont été mis en place et sont aujourd'hui validés et disponibles pour une investigation poussée des effets des champs électriques sur le vivantElectropermeabilization is a physical technique first developed to transfer cytotoxic drugs in tumor. It consists in the transient permeabilization of the plasma membrane following electric field application. In specific electric conditions using long pulses of several milliseconds, the membrane destabilization can allow transferring plasmid DNA into the cell, thus allowing the development of gene therapy. For now, one clinical trial has been published using gene eletro-transfer and several others are ongoing. However the efficiency of the technique remains low compared to other transfer methods. This thesis gets interested in how pulsed electric fields affect cell membranes, in the concrete situation of gene transfer by electroporation. The comprehension of electro-gene transfer process need to be well understood in order to optimize it. In this context, we focus on the 3 barriers that DNA is confronted to during its transfer: first at the cell level: plasma membrane and nuclear envelope, second at the tissue level: the complexity of a multicellular environment. i) We first studied the efficiency of gene transfer on multicellular spheroid model. This work allowed the validation of this model for electro-transfection study, and the further optimization of the technique by raising some of the failures encountered in gene transfer in tissue. ii) The second part of the work has been dedicated to study plasma membrane destabilization due to electroporation by Atomic Force Microscopy. We used both innovating imaging modes and spectroscopy modes to analyze the effects on living cells, which resulted in the measurement of a decrease in elasticity, linked to side effects of electric fields on actin cytoskeleton destabilization. iii) The last part has been dedicated to the effects of nanopulses (nsEP) on both plasma membrane and the second barrier encountered by gene during its transfer, namely nuclear envelope. The effects of these very short (ns) and intense (several kV/cm) pulses have been indeed shown to affect both cell membrane and internal envelope (organelles ones). We first study their effect on membrane using patch-clamp to discriminate in the implication of actin cytoskeleton in nanopores formation. We secondly aimed to study how these nanopulses affect the special structure that is nuclear envelope during gene transfer, for validating their potential use on humans, and their possible role in optimization for gene transfer. P-clamp study revealed that actin is not involved in nanopores formation, and gene transfer one that nsEP do not affect positively transfection efficiency. Altogether this thesis brings new insights in electropermeabilization mecanisms understanding and barriers for gene transfer in tissue. Methods, models and tools have been set and validated. They are now usable for investigating electric field effect on living organism