Low-intensity Electric Fields Research Articles

The polarization reverse of diode-like conical nanopore under pH gradient

In the past decade, with the improvement of nanofabrication technology, silica nanopores and nanochannels have been widely used in the fields of ion pumps, energy conversion, ion channels, metal ion detection, and biosensors. Although both potential and pH gradient can significantly change the performance of ion current rectification in nanoscale, the potential mechanism is still not fully understood. In this study, the ion current rectification, surface charge distribution and ion selectivity of silica nanopore under different background salt concentration and pH gradient were discussed by an analytical model, which takes into account the effects of electroosmotic flow, multiple ionic species, and the acid base neutralization. The results show that the polarity of nanopore rectifier can be changed by changing the acidity and alkalinity at both ends of the nanopore. For the first time, we find that the rectification polarity of silica conical nanopore exhibits different performances under high and low electric field intensity. One case in this study shows the rectification ratio curve of the nanopore will have a maximum or minimum value and the extreme point is near the zero of the ion current. With the increase of the concentration of background salt solution, the voltage at the zero point of ion current approaches the zero point, and then the maximum or minimum point moves to the left. The extreme point offset and polarity reversal phenomena may have potential application value in nanopore-based sensing devices.

Fabrication of High-Aspect-Ratio Cylindrical Micro-Structures Based on Electroactive Ionogel/Gold Nanocomposite

We present a fabrication process to realize 3D high-aspect-ratio cylindrical micro-structures of soft ionogel/gold nanocomposites by combining replica molding and Supersonic Cluster Beam Deposition (SCBD). Cylinders’ metallic masters (0.5 mm in diameter) are used to fabricate polydimethylsiloxane (PDMS) molds, where the ionogel is casted and UV cured. The replicated ionogel cylinders (aspect ratio > 20) are subsequently metallized through SCBD to integrate nanostructured gold electrodes (150 nm thick) into the polymer. Nanocomposite thin films are characterized in terms of electrochemical properties, exhibiting large double layer capacitance (24 μF/cm2) and suitable ionic conductivity (0.05 mS/cm) for charge transport across the network. Preliminary actuation tests show that the nanocomposite is able to respond to low intensity electric fields (applied voltage from 2.5 V to 5 V), with potential applications for the development of artificial smart micro-structures with motility behavior inspired by that of natural ciliate systems.

Optimization of multi-electrode implant configurations and programming for the delivery of non-ablative electric fields in intratumoral modulation therapy.

Application of low intensity electric fields to interfere with tumor growth is being increasingly recognized as a promising new cancer treatment modality. Intratumoral modulation therapy (IMT) is a developing technology that uses multiple electrodes implanted within or adjacent tumor regions to deliver electric fields to treat cancer. In this study, the determination of optimal IMT parameters was cast as a mathematical optimization problem, and electrode configurations, programming, optimization, and maximum treatable tumor size were evaluated in the simplest and easiest to understand spherical tumor model. The establishment of electrode placement and programming rules to maximize electric field tumor coverage designed specifically for IMT is the first step in developing an effective IMT treatment planning system. Finite element method electric field computer simulations for tumor models with 2 to 7 implanted electrodes were performed to quantify the electric field over time with various parameters, including number of electrodes (2 to 7), number of contacts per electrode (1 to 3), location within tumor volume, and input waveform with relative phase shift between 0 and 2π radians. Homogeneous tissue specific conductivity and dielectric values were assigned to the spherical tumor and surrounding tissue volume. In order to achieve the goal of covering the tumor volume with a uniform threshold of 1V/cm electric field, a custom least square objective function was used to maximize the tumor volume covered by 1V/cm time averaged field, while maximizing the electric field in voxels receiving less than this threshold. An additional term in the objective function was investigated with a weighted tissue sparing term, to minimize the field to surrounding tissues. The positions of the electrodes were also optimized to maximize target coverage with the fewest number of electrodes. The complexity of this optimization problem including its non-convexity, the presence of many local minima, and the computational load associated with these stochastic based optimizations led to the use of a custom pattern search algorithm. Optimization parameters were bounded between 0 and 2π radians for phase shift, and anywhere within the tumor volume for location. The robustness of the pattern search method was then evaluated with 50 random initial parameter values. The optimization algorithm was successfully implemented, and for 2 to 4 electrodes, equally spaced relative phase shifts and electrodes placed equidistant from each other was optimal. For 5 electrodes, up to 2.5cm diameter tumors with 2.0V, and 4.1cm with 4.0V could be treated with the optimal configuration of a centrally placed electrode and 4 surrounding electrodes. The use of 7 electrodes allow for 3.4cm diameter coverage at 2.0V and 5.5cm at 4.0V. The evaluation of the optimization method using 50 random initial parameter values found the method to be robust in finding the optimal solution. This study has established a robust optimization method for temporally optimizing electric field tumor coverage for IMT, with the adaptability to optimize a variety of parameters including geometrical and relative phase shift configurations.

Non-equilibrium molecular dynamics simulations of water transport through plate- and hourglass-shaped CNTs in the presence of pressure difference and electric field

In the present work, the water transport dynamics and properties within CNT membranes are studied under the effect of pressure and electric field, using non-equilibrium molecular dynamics (NEMD) simulations. To reduce the pressure loss at the entrance and exit regions, the pore mouth shape has been changed to an hourglass shape for CNT membranes of (6,6), (8,8) and (12,12), inspired by aquaporins, which are capable of high water permeation. It is shown that as the pressure difference increases, the water flux enhancement due to change of pore mouth from plate to hourglass increases rapidly. Furthermore, it is found that the hourglass-shaped geometry has the highest impact on the reduction of entrance resistance within the pores with a smaller diameter. By applying an axial electric field at the entrance of the hourglass-shaped CNT membrane, the enhancement in water flux could be further improved. Interestingly, our results show that applying an electric field at the membrane entrance can cause two opposing effects on the water molecules transport: reduction of water molecules steric crowding at the entrance and increasing the average hydrogen bond numbers of the water molecules entering the tube. It seems that the former effect is dominant for low-intensity electric fields.

85‐5: Late‐News‐Paper: Real Time Dynamic Holographic Display Based on Perovskite Doped Liquid Crystal

Holographic display, which can completely reconstruct phase and amplitude information, is considered as an ideal true three‐dimensional display technology. In this work, liquid crystal doped with perovskite (CsPbBr3) works as the photorefractive material and forms diffraction grating under the interference light beams. The dependences of diffraction efficiency and response time on doping concentration, recording beam power and applied voltage are investigated. A maximum first‐order diffraction efficiency of 18% has been achieved under a low electric field intensity of ~0.5 V/μm and the shortest grating build up time is as low as 5.5 ms. The system can realize a real‐time dynamic display with 60 Hz refresh rate.

Electrokinetic transport and distribution of antibacterial nanoparticles for endodontic disinfection.

To assess a novel, noninvasive intervention capable of mobilizing charged antibacterial nanoparticles to the apical portions of the root canal system, utilizing the principles of electrokinetics. Experiments were conducted in three stages. Stage-1: A computer model was generated to predict and visualize the electric field and current density distribution generated by the proposed intervention. Stage-2: Transport of chitosan nanoparticles (CSnp) was evaluated qualitatively using a transparent microfluidic model with fluorescent-labelled CSnp. Stage-3: An ex vivo model was utilized to study the antimicrobial efficacy of the proposed treatment against 3-week-old monospecies E.faecalis biofilms. Scanning electron microscopy (SEM) was also utilized in this stage to confirm the deposition of CSnp. The results of the computer simulations predicted an electric field and current density that reach their maxima at the apical constriction of the root canal. Correspondingly, the microfluidic experiments demonstrated rapid, controlled CSnp transport throughout the simulated root canal anatomy with subsequent distribution and deposition in the apical constriction as well as periapical regions. Infected root canals when subjected to the novel treatment method resulted in a mean bacterial reduction of 2.1 log CFU. SEM analysis revealed electrophoretic deposition of chitosan nanoparticles onto the root canal dentine walls in the apical region. The findings from this study demonstrate that the combination of cationic antibacterial nanoparticles with a low-intensity electric field results in particle transportation (electrophoresis) and deposition within the root canal. This results in a synergistic antibiofilm efficacy and has the potential to enhance root canal disinfection.

Targeted gold nanorods combined with low-intensity nsPEFs enhance antimelanoma efficacy in vitro

High-intensity nanosecond pulsed electric fields (nsPEFs) are a novel treatment with promising applications for cell stimulation and tissue ablation, and many research studies have shown that gold nanorods (GNRs) are high-conductivity nanomaterials that can enhance electroporation for biomedical applications. In addition, the folic acid (FA) receptor has been demonstrated as a valuable therapeutic target that is highly expressed in a variety of cancers. To reduce the electric field strength required to treat tumors by nsPEFs, for the first time, gold nanorods with folic acid were proposed to achieve higher antimelanoma efficacy at lower electric field intensity in this study. The surface of polyethylene glycol-gold nanorods with good biocompatibility was further modified by folic acid (FA) to provide modified gold nanorods (GNR-PEG-FA) with specific targeted recognition of A375 melanoma cells. The binding of GNRs to A375 melanoma cells was observed by dark field microscopy. After combined treatment with nsPEFs and GNRs, cell viability was evaluated by a CCK-8 assay. Flow cytometry was performed to evaluate apoptosis and the cell cycle. And active caspase 3 was also detected after treatment. The antimelanoma efficacy was enhanced in a pulsed electric field-dependent manner. More importantly, compared with the group of nsPEFs alone and gold nanorods without FA, treating cells with nsPEFs combined with GNR-PEG-FA resulted in a lower percentage of viable cells, higher percentages of necrosis and apoptosis and higher concentration of active caspase 3 and induced cell cycle arrest in S phase, effectively inhibiting the proliferation of A375 melanoma cells. nsPEFs combined with GNR-PEG-FA showed the best antimelanoma efficacy in vitro and effectively killed melanoma cells with low-intensity nsPEFs. The combined treatment of cells with nsPEFs and GNR-PEG-FA is expected to become a safer and more efficient physical treatment of melanomas.

Substrate orientation effects on nanoelectrode lithography: ReaxFF molecular dynamics and experimental study

The crystallographic orientation of the substrate is an essential parameter in the kinetic mechanism for the oxidation process. Hence, the choice of substrate surface orientation is crucial in nanofabrication industries. In the present work, we have studied qualitatively the influence of substrate orientation in nanoelectrode lithography using ReaxFF reactive molecular dynamics simulation. We have investigated the oxidation processes on (100), (110) and (111) orientation surfaces of silicon at different electric field intensities. The simulation results show the thickness of the oxide film and the initial oxygen diffusion rate follow an order of (100) > (110) > (111) at lower electric field intensities. It also confirms that surfaces with higher surface energy are more reactive at lower electric field intensity. Crossovers occurred at a higher electric field intensity (7 V nm−1) under which the thickness of the oxide film yields an order of T(110) > T(100) > T(111). These types of anomalous characteristics have previously been observed for thermal oxidation of silicon surfaces. Experimental results show different orders for the (100) and (111) substrate, while (110) remains the largest for the oxide thickness. A good correlation has been found between the oxide growth and the orientation-dependent parameters where the oxide growth is proportional to the areal density of the surfaces. The oxide growth also follows the relative order of the activation energies, which could be another controlling factor for the oxide growth. Less activation energy of the surface allows more oxide growth and vice versa. However, the differences between simulation and experimental results probably relate to the empirical potential as well as different time and spatial scales of the process.

Numerical simulation on electric field intensity and reaction pathway in the He–O2 atmospheric pressure plasma jet

In this work, a two-dimensional fluid model of the needle-plane discharge plasma has been built to numerically investigate the spatio-temporal evolution characteristics of the electric field intensity and electric potential as well as generating and consuming reaction pathways of various oxygen species in a He–O2 atmospheric pressure plasma jet. Simulation results have indicated that the region of high electric field intensity moves in the direction of the plane electrode with the formation and propagation of an ionization wave. The region of low electric field intensity exists between the needle electrode and the head of the ionization wave, and its area increases continuously. The obvious voltage drop and local electric field enhancement occur between the head of the ionization wave and the plane electrode. Electron attachment reactions e + O2 → O + O− and e + 2O2 → O2− + O2 produce negative ions O− and O2−. More than 80% of the positive ions O2+ and H2O+ come from Penning ionizations between He* and molecules O2 and H2O. e + O2 → e + O + O(1D) is the main pathway to generate O and O(1D). O(1D) + H2O → 2OH and O + H + H2O → OH + H2O produce 69.3% and 39.2% of OH, respectively. 2O2 + O → O3 + O2 is the key generating reaction of O3.

Effect of low-intensity electric current field and iron anode on biological nitrate removal in wastewater with low COD to nitrogen ratio from coal pyrolysis

Mixotrophic nitrate removal in wastewater from coal pyrolysis was achieved in microbial electrolysis cell with iron anode (iron-MEC). The effect of voltage, iron anode and conductivity were investigated. The effluent TN concentration was 8.35 ± 1.94 mg/L in iron-MEC when the conductivity of the wastewater was adjusted to 3.97 ± 0.08 mS/cm, which was lower than that in no-treated reactor. The increase of current density, which was resulted from the elevation of conductivity, promoted the iron corrosion and Fe2+ ion generation. Therefore, more Fe2+ ion was utilized by nitrate reducing ferrous oxidation bacteria (NRFOB) used to reduce nitrate. The microbial community analysis demonstrated that NRFOB, including Acidovorax and Bradyrhizobium, possessed a higher abundance in iron-MEC. The enrichment of Geobacter in iron-MEC might imply that the part of Fe(III) produced by ferrous oxidation was reduced by Geobacter, which established an iron cycle. Moreover, the production of N2O was decreased by the formation of Fe2+ ion.

Modeling of the second harmonic generation in a lens-shaped InAs/GaAs quantum core/shell dot under temperature, pressure and applied electric field effects

In this paper, we explore the second harmonic generation (SHG) in a lens-shaped InAs/GaAs quantum core/shell (LSQCS). The three-dimensional Schrödinger equation is given under the framework of the effective mass approximation and it is solved by using the Finite Difference Method (FDM). In this work, we have studied the effects of the structure dimensions, the applied transverse electric field, the hydrostatic pressure and the temperature on the SHG. Obtained results show that the SHG coefficient experiences an obvious red shift and an increase in magnitude with increasing the core radius. Therefore, we note that the SHG experiences a blue shift (red shift) with increasing temperature (pressure). Moreover, both resonant peaks values of the SHG are not a monotonic function of the applied electric field. Thus, SHG reaches its optimized magnitude at a low electric field intensity which is directed along one side of the cross section of the structure under investigation. Finally, at a low electric field intensity, a comparative analysis has shown that the SHG magnitude in LSQCS was 22% higher than that of the uncapped single quantum dot (SQD and a red shift has occurred.

Highly uniform in-situ cell electrotransfection of adherent cultures using grouped interdigitated electrodes

Cell electrotransfection is an effective approach for transferring exogenous molecules into living cells by electric stimulation. The existing in-situ electrotransfection micro-devices for adherent cells exhibit the drawbacks of low transfection efficiency and low cell viability. An important reason for these drawbacks is the unequal exposure of cells to the electric field. It was found that cells growing directly below the energized electrodes experience a much lower electric field intensity when compared to the cells growing below the spacing area of the electrodes, resulting in low transfection with a strip-like pattern. Therefore, a new strategy for the in-situ electrotransfection of adherent cells growing in a standard 12-well plate is proposed in this study. By sequentially energizing electrodes arranged in a nested and non-contact manner, the cells were exposed to an overall equal intensity of the electric field, and thus a higher efficiency of transfection was achieved. The seven cell lines transfected using this method exhibited high transfection efficiency and high cell viability, demonstrating the potential for studying gene function.

TMIC-54. COMPARISON OF CELLULAR FEATURES AT AUTOPSY IN GLIOBLASTOMA PATIENTS WITH STANDARD TREATMENT OF CARE AND TUMOR TREATMENT FIELDS

Abstract BACKGROUND The FDA has approved the use of tumor treatment fields (TTFields) on patients with recurrent glioblastoma (GBM). A recent clinical trial showed that the use of TTFields along with standard treatment of care resulted in increased quality of life and survival over five years. TTFields work by delivering low intensity electric fields that disrupt GBM tumor cell division. This works to slow or even stop GBM tumor cells from dividing. METHODS Brain tissue samples were taken from thirteen GBM patients, diagnosed at autopsy. Three patients underwent standard clinical treatment and ten patients underwent TTField therapy in addition to the standard. Tissue samples were acquired from regions where enhancement was seen on the last clinical T1 plus contrast MRI prior to death. Samples were paraffin embedded and stained with hematoxylin and eosin (H&E) and Ki67. The slides were digitized, allowing analysis of the cellular features. RESULTS Using the H&E stained slides we compared cellular density between both groups. We found that there was not a noticeable difference in the nuclei density in areas of tumor between the groups. The percent of positive nuclei on the Ki67 stained slides was calculated and there was increased mitotically active cells per area of tissue in patients that did not undergo TTField therapy. CONCLUSION These findings suggest there is a difference in the cellular features in areas of tumor in patients treated with TTFields compared to those with standard treatment alone. Additional research needs to be done evaluating more patients.

Influence of Pulsed Electric Fields processing at high-intensity electric field strength on the relationship between anthocyanins composition and colour intensity of Merlot (Vitis vinifera L.) musts during cold maceration

Abstract Merlot grapes have high proportion of anthocyanins protected inside cell vacuoles but the thick skins limit their extractability. This study investigated the effect of a continuous Pulsed Electric Fields (PEF at 500 kg/h) system operated at high-intensity electric field strengths (>30 kV/cm) combined with energy inputs ranging from 4.7 to 49.4 kJ/L on anthocyanins extraction and colour intensity of Merlot musts during a 4-day cold maceration. Considerable amount of anthocyanins with different chemical features was extracted instantaneously due to PEF treatment at high-intensity electric field strength, in which the amount was higher than those extracted from non PEF-treated Merlot followed by 4 days maceration. During maceration, malvidin derivatives were the most significant anthocyanins contributing (r > 0.71, p Industrial relevance text Previous PEF studies mainly investigated the effect of low-intensity electric field strength ( 30 kV/cm) using Marx generator for the first time in the literature. Marx generator has a tendency to produce high-intensity electric field strength, up to 80 kV/cm, but the impact on plant materials intended for food application are not well studied. In this study, Merlot grapes were continuously treated with PEF at high-intensity electric field strength at a flow rate of 500 kg/h while many previous studies conducted trial at approximately 100–200 kg/h in conjunction with low-intensity electric field strength ( 200 kg/h) at the commercial scale. In this study, we have successfully showed that high-intensity electric field strengths (33.1 and 41.5 kV/cm) of PEF were efficient (i.e. instantaneous extraction) in extracting all types of anthocyanins with different chemical features from the thick-grape skins of Merlot. Therefore, grape juice with more elaborated anthocyanin composition and intense colour was produced at a large scale immediately after PEF. The extracted anthocyanins were found to be stable over time after PEF treatment in which the issues on anthocyanin stability and colour development have never been considered in many previous studies, but are important quality aspects that beverage industry desired.

(Ba,Sr)TiO3 solid solutions sintered from sol-gel derived powders: An insight into the composition and temperature dependent dielectric behavior

Single-phase Ba1-xSrxTiO3 (BST) perovskite ceramics with 0.3 ≤ x ≤ 0.4 were prepared from powders synthesized via sol-gel route. The compositions have the ferroelectric-paraelectric phase transition close to room temperature. At 20 °C the BST ceramics are ferroelectric for 0.3 ≤ x ≤ 0.35 and paraelectric for x = 0.375 and x = 0.40. The study follows the relation between the structural changes produced when increasing the Sr content and the dielectric properties at low intensity electric fields. It is found that the grain size and tetragonality decreases as the Sr content increases. Analyses of complex permittivity and impedance spectroscopy reveal the temperature and frequency dependencies of the dielectric properties. The phase transitions seem to be of first order for all compositions, with a thermal hysteresis that decreases with increasing the Sr content, fact attributed to the corresponding increase of the grain boundaries weight allowing a more efficient stress relaxation in the structure during the change of the symmetry from cubic to tetragonal. The diffusiveness degree during the phase transition is increasing with Sr content, suggesting some relaxor-type contribution attributed to smaller grain size. The ac conductivity follows the universal Jonscher law, with an ac component having the power parameter s independent of Sr content, and a dc component that it is thermally activated with an activation energy of about 0.7–0.77 eV attributed to oxygen vacancies acting as donor-like defects. The fit of impedance spectra at different temperatures and frequencies is obtained by using an equivalent circuit accounting the grains, grain boundaries, electrode interfaces and the local contributions produced by reorientation of defect dipoles or defect clusters. All the component circuits have significant variations around phase transitions. These are discussed in relation to structural changes occurring during transition and considering the changes in the distribution of various charges when polarization vanishes.

P11.19 Glioblastoma cancer stem cells proliferation and cell cycle arrest under TTFields influence

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and fastest growing-type among brain tumours. The current standard of care is a combination of surgery, radio- and chemotherapy. However, GBM is characterized by a poor prognosis and an average life expectancy of 15 months under current treatment. Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly. It has been evaluated in randomized phase 3 trials in GBM and demonstrated to prolong progression-free survival and overall survival when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients. This technology represents the biggest step forward against GBM in more than a decade. METHODS Primary cultures of human glioblastoma enriched in cancer stem cells (GSCs) were stimulated using the InovitroTM System (NOVOCURE) for 72 hours. Remaining cells were collected for further experiments. RESULTS Our investigation has targeted GSCs, a subset of cells that are considered responsible for tumour recurrence and confer resistance to chemotherapy and radiotherapy. Our data show that after 72 hours of TTFields exposure, more than 60% of the cellular population are dead. The residual GSCs were able to recover proliferation as soon as TTFields application had ended. We used different combinations of TTFields exposure times and pharmacological treatments with the main objective to impair cell proliferation relapse. Prolong TTF stimulation kills more cells but survivor cells are still able to resume proliferation. The addition of 10 mM TMX increase drastically the efficacy of the TTFields treatment even if the few cells left were able to slowly form colonies in a single cell cloning assay. CONCLUSION GCSs are sensitive to TTFields and to the combining pharmacological treatment with TMZ. The strategy to optimize the antiproliferative action on GCSs relapse will be to find a best combination of anticancer drugs concentration, together with TTFields exposure.

Tumor-treating fields induce autophagy by blocking the Akt2/miR29b axis in glioblastoma cells.

Tumor-treating fields (TTFs) - a type of electromagnetic field-based therapy using low-intensity electrical fields - has recently been characterized as a potential anticancer therapy for glioblastoma multiforme (GBM). However, the molecular mechanisms involved remain poorly understood. Our results show that the activation of autophagy contributes to the TTF-induced anti-GBM activity in vitro or in vivo and GBM patient stem cells or primary in vivo culture systems. TTF-treatment upregulated several autophagy-related genes (~2-fold) and induced cytomorphological changes. TTF-induced autophagy in GBM was associated with decreased Akt2 expression, not Akt1 or Akt3, via the mTOR/p70S6K pathway. An Affymetrix GeneChip miRNA 4.0 Array analysis revealed that TTFs altered the expression of many microRNAs (miRNAs). TTF-induced autophagy upregulated miR-29b, which subsequently suppressed the Akt signaling pathway. A luciferase reporter assay confirmed that TTFs induced miR-29b to target Akt2, negatively affecting Akt2 expression thereby triggering autophagy. TTF-induced autophagy suppressed tumor growth in GBM mouse models subjected to TTFs as determined by positron emission tomography and computed tomography (PET-CT). GBM patient stem cells and a primary in vivo culture system with high Akt2 levels also showed TTF-induced inhibition. Taken together, our results identified autophagy as a critical cell death pathway triggered by TTFs in GBM and indicate that TTF is a potential treatment option for GBM.

Non-Invasive Extraction of Gabapentin for Therapeutic Drug Monitoring by Reverse Iontophoresis: Effect of pH, Ionic Strength, and Polyethylene Glycol 400 in the Receiving Medium

Background: Monitoring of plasma concentrations is a necessity for narrow therapeutic index potent drugs. Development of non-invasive methods can save the patients from the trauma of needles and hence is considered as a research priority. Introduction: Gabapentin, an anti-epileptic drug requires therapeutic monitoring because of its narrow therapeutic index. The objective of the study was to develop a suitable method for the non-invasive extraction of gabapentin for the same. Methods: Transdermal reverse iontophoresis was performed using pig ear skin as a barrier membrane. Three compartment iontophoretic cells were used for the extraction study. Extractions were carried out under low intensity electric field (current intensity- 0.5 mA/cm2, electrical field approximately 5 V). The donor compartment was charged with aqueous gabapentin (10 µg/ml in phosphate buffer of pH 7.4). For studying the effect of receiving vehicle (pH, ionic strength, and enhancer) on the extraction efficiency of gabapentin, the two receiver chambers were charged with media having varying concentration of these factors. Drug content was determined by HPLC. Results: Compared to other pHs, cumulative extraction of gabapentin at pH 5 was significantly higher at both anode and cathode (p<0.001). At low ionic strength, extraction of gabapentin increased linearly with the increase in concentration of ions up to a certain value but at very high ionic strength the pattern reversed. Similar results were obtained with enhancer (polyethylene glycol 400). Extraction increased with increase in polyethylene glycol 400 up to 3% and then decreased. Conclusion: Extraction flux can be optimized by manipulation of the receiver media.

Abstract 692: Treating spinal cord metastases with tumor treating fields

Abstract Introduction: Tumor Treating Fields (TTFields) is an anti-mitotic technology utilizing low-intensity (1-3 V/cm) electric fields within the medium frequency range (100-300 kHz) to treat solid tumors. TTFields are currently approved for the treatment of Glioblastoma (GBM). Some cancer types, such as breast cancer, lung cancer, and melanoma, frequently result in metastases to the spinal cord. Transducer array positioning used to treat abdominopelvic diseases (e.g. pancreatic cancer), in which one pair of arrays are placed on the anterior and posterior of the patient, and another pair of arrays placed on the lateral aspects of the patient have been shown to be inefficient for treating the spinal cord because the clinical threshold for field intensity of 1V/cm is not reached in the spine when these layouts. The structure of the spine, in which a relatively resistive bone structure encapsulates a highly conductive layer of fluid (cerebrospinal fluid), shunts the current delivered across the body by the arrays away from the spine, reducing the field within the spine to below the therapeutic threshold. To overcome this limitation, a new approach of array placement on the body is needed. Here we present a simulation-based study designed to identify array layouts that effectively deliver TTFields to the spine. Methods: To simulate delivery of TTFields to the spine, we used a human male 34 years old realistic computerized model (DUKE v3.1 by ITI’S, Zurich). In order to generate TTFields, an alternating current with current density of 200mA/disk with a frequency of 150 kHz was imposed on the outer surfaces of the disks of each pair of arrays. The simulations were performed using ZMT's Sim4Life v4.0 electro-quasi-static solver. Results: One of the array layouts tested was placement of a pair of arrays on the back of the patient. One array is placed above the target region in the spine to which treatment would be delivered, and the other array is placed below the region. With this configuration, a high electric field is induced within the spinal cord and surrounding CSF. Mean field intensity within the spine and nerves in between vertebrae T8-T9 at the top, and L3-L4 at the bottom were calculated at a value of 1.77 V/cm. It is important to note that the electric field is oriented along the spine in this instance (a vertical field). In general, the whole spine could be treated by placing one array on the neck, and one at the bottom of the spine. Conclusions: Placing two transducer arrays on the patient’s back allows single-direction treatment of the spinal cord and nerves. Further work should be conducted to find an effective treatment in the perpendicular direction. Citation Format: Ofir Yesharim, Ariel Naveh, Ze'ev Bomzon. Treating spinal cord metastases with tumor treating fields [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 692.

Abstract CT062: A Phase I study of the safety and immunogenicity of personalized mutation-derived tumor vaccine and treatment fields in patients with newly diagnosed glioblastoma

Abstract Glioblastoma (GBM) like other cancers generates mutation-derived tumor antigens (MTA) arising from somatic mutations such as insertions, deletions, nucleotide substitutions and gene fusions. These mutations can be recognized by the immune system, providing a specific target for antitumor therapy. The use of TTFields, a modality that utilizes low intensity electric fields that disrupt cell division, increases progression-free survival and overall survival in newly diagnosed GBM. Among several mechanisms of action, TTFields potentially induces an immunogenic cell death. Therefore, we combined this modality treatment with the standard of care of adjuvant Temozolomide chemotherapy and a personalized vaccine for newly diagnosed GBM in a single-arm, open label clinical trial. Phase Ia tests the safety and immunogenicity of MTA-vaccine and phase Ib tests the safety and immunogenicity of the vaccine in conjunction with the TTFields. RNA and DNA are extracted from tumor specimens and blood, and whole-exome sequencing and mRNASeq is performed. HLA typing is obtained for each patient. MTA are identified using a computational pipeline for prediction and ranking according to both HLA binding affinity and expression. A maximum of 10 peptides is selected for the synthesis of each patient vaccine. Patients receive 14 doses of the MTA-vaccine in combination with 14 doses of poly-ICLC, the vaccine adjuvant. We have found mutation-derived tumor antigens in all patients included in phase Ia despite a low mutational load in GBM patients. The patients that took part in phase Ia have received multiple vaccinations spanning over 6 months of treatment. The vaccine has been well tolerated without serious adverse events. Quantitative and qualitative changes in epitope-specific circulating T-cell response is currently being evaluated. Citation Format: Adilia Hormigo, Alex Rubinsteyn, Julia Kodysh, Ana Blazquez, Nina Bhardwaj. A Phase I study of the safety and immunogenicity of personalized mutation-derived tumor vaccine and treatment fields in patients with newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT062.