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Electrochemotherapy Effectiveness Loss due to Electric Field Indentation between Needle Electrodes: A Numerical Study

Electrochemotherapy Effectiveness Loss due to Electric Field Indentation between Needle... Hindawi Journal of Healthcare Engineering Volume 2018, Article ID 6024635, 8 pages https://doi.org/10.1155/2018/6024635 Research Article Electrochemotherapy Effectiveness Loss due to Electric Field Indentation between Needle Electrodes: A Numerical Study 1,2 3 Jose´ Alvim Berkenbrock, Rafaela Grecco Machado, and Daniela Ota Hisayasu Suzuki Department of Electrical and Computer Engineering, University of Saskatchewan, Saskatoon, Canada Department of Electrical and Electronics Engineering, Institute of Biomedical Engineering, Federal University of Santa Catarina, Florianopolis, SC, Brazil Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK, Canada Correspondence should be addressed to Daniela Ota Hisayasu Suzuki; suzuki@eel.ufsc.br Received 30 January 2018; Revised 26 April 2018; Accepted 8 May 2018; Published 2 July 2018 Academic Editor: Terry K. K. Koo Copyright © 2018 Jose ´ Alvim Berkenbrock et al. 0is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Electrochemotherapy is an anticancer treatment based on applying electric field pulses that reduce cell membrane selectivity, allowing chemotherapy drugs to enter the cells. In parallel to electrochemotherapy clinical tests, in silico experiments have helped scientists and clinicians to understand the electric field distribution through anatomically complex regions of the body. In particular, these in silico experiments allow clinicians to predict problems that may arise in treatment effectiveness. 0e current work presents a metastatic case of a mast cell tumor in a dog. In this specific treatment planning study, we show that using needle electrodes has a possible pitfall. 0e macroscopic consequence of the electroporation was assessed through a mathematical model of tissue electrical conductivity. Considering the electrical and geometrical characteristics of the case under study, we modeled an ellipsoidal tumor. Initial simulations were based on the European Standard Operating Procedures for electrochemotherapy suggestions, and then different electrodes’ arrangements were evaluated. To avoid blind spots, multiple applications are usually required for large tumors, demanding electrode repositioning. An effective treatment electroporates all the tumor cells. Partially and slightly overlapping the areas increases the session’s duration but also likely increases the treatment’s effectiveness. It is worth noting that for a single application, the needles should not be placed close to the tumor’s borders because effectiveness is highly likely to be lost. facilitates the uptake of chemotherapy drugs (e.g., bleomycin 1. Introduction and cisplatin) by the cells and the selective death of tumor Electrochemotherapy is an anticancer treatment based on cells [1, 3]. When this delivery method is used, the cyto- pulsed electric fields and chemotherapy drugs. 0e electric toxicity of bleomycin increases 300–700 times [3]. However, field reduces the cell membrane’s selectivity, promoting the irreversible electroporation induces membrane disruption cell’s intake of chemotherapy drugs [1–3]. 0is biophysical and consequently indiscriminate cell death [2]. In this phenomenon of decreasing cell membrane selectivity through sense, the ability to achieve the right parameters for targeting electric field imposition is called electropermeabilization. tumor cells has imposed challenges. 0ese challenges are 0e most accepted theory to explain such permeabilization mainly consequences of the anatomical complexity and considers that pores are induced around the cell membrane nonhomogeneous structures of which our tissues, organs, [4]. 0is process is called electroporation and considers that and bodies are composed. the membrane permeabilization can be reversible or irre- 0e electric field distribution in biological tissues has versible depending on the membrane’s capability of resealing been studied for decades, and recent in silico experiments the pores after the removal of the electric field [2, 5]. have taken advantage of years of bioelectrical impedance 0e reversible or irreversible electroporation can lead to analysis [6, 7] and powerful processors. 0rough in silico different treatment outcomes. Reversible electroporation experiments, several different scenarios can be run, which 2 Journal of Healthcare Engineering Stratum corneum Electrodes and epidermis Tumor (d) Dermis Muscle (b) 40 mm 40 mm (a) (c) (e) Figure 1: Schematic for modeling the tumor under study. From left to right, the target tumor, the geometrical parameters extraction and anatomical characterization, and the 3D insertion into the simulation environment. (a) A mast cell tumor in a 3-year-old male dog. 0e arrow indicates the modeled tumor. Scale: 10 mm. (b) Skin with three layers (stratum corneum with epidermis, dermis, and muscle), the tumor, and two representative electrode needles. (c) Approximated geometry and dimensional parameters of the tumor. (d) 0e three types of tested electrodes. (e) 0e 3D geometry model under study. 0e ellipsoid represents the tumor seeded on the skin layers, and the cylinders are the electrode needles. have allowed scientists and clinicians to understand and stained with May–Grunwald–Giemsa ¨ (MGG) dye for a histopathology examination. 0e patient was diagnosed with predict problems in treatment effectiveness. 0e clinical treatment of electrochemotherapy has been used in in silico a metastatic mast cell tumor, and surgical removal was studies for years. In this therapy approach, there are three recommended. basic electrode types: (I) two parallel plates, (II) needles in 0e electrochemotherapy treatment was suggested as two parallel rows, and (III) needles in the vertices of a potentially curative treatment option, and the patient was a hexagon—like a honeycomb [1]. Examples of the close forwarded to the veterinary clinic that collaborated with this relationship between in silico experiments and electro- study. In Figure 1(a), the tumor chosen to be modeled is chemotherapy are found in studies on how to insert the indicated with the arrow. 0is tumor was chosen because of needle electrodes for deeply seeded tumors [8, 9], for its expressiveness rather than the others. 0e tumor di- nonsymmetrical tumors [10], and for large tumors on the mensions were 20 mm along its longest diameter and 10 mm skin’s surface [11–13]. on the other superficial diameter (orthogonal axis). Many earlier in silico studies did not consider electro- poration as a factor influencing membrane conductivity and 2.2. In Silico Modeling assumed a constant tissue electrical conductivity [14–16]. However, more recent studies have demonstrated the im- 2.2.1. Geometry and Tissue Properties. 0e data were made portance of considering such an effect for cancer treatment available by the clinic and patient owner. 0e tumor under planning [9, 17, 18]. In the present work, a case of a met- study (Figure 1(a)) was 3D modeled in the simulation astatic mast cell tumor in a dog is studied. Mast cell tumors, environment (Figure 1(e)), considering the parameters or mastocytomas, are common tumors in the skin of dogs, shown in the Figures 1(b) and 1(c). 0e tumor had its shape and many of them are prone to local recurrence and me- approximated to an ellipsoidal mass, with a, b, and c equal tastasis [19]. We started this report with a specific treatment to 20 mm, 10 mm, and 1.25 mm, respectively (Figure 1(c)). planning study to demonstrate the potential for efficiency 0e two orthogonal surface diameters were a and b. 0e loss when needle electrodes are used. tumor depth c was estimated through the following equation [1]: 2. Materials and Methods 4 π Vol � πabc � ab . (1) 3 6 2.1. In Vivo Diagnosis. 0e patient was a 3-year-old male pitbull mixed-breed dog, 32 kg, with spontaneous nodular 0e skin tissue was modeled with a surface area of formations on the right posterior limb. 0e samples were 40 × 40 mm, and it was divided into three different layers. collected from the right inguinal lymph node and were 0e deepest layer was the muscle with 10 mm of thickness; Journal of Healthcare Engineering 3 Table 1: Tissue electrical parameters [17]. values for σ are often extrapolations from measures held at 10–100 Hz [6, 18, 20]. During the application of pulses Tissue σ (S/m) σ /σ E (kV/m) E (kV/m) 0 max 0 rev irrev intense enough to produce electroporation (i.e., above E ), rev SC + epidermis 0.008 100 40 120 the tissue electrical conductivity varies as described by (2) Dermis 0.250 4 30 120 [20]. Tissue electrical conductivity, as a function of the Muscle 0.135 2.5 20 80 electric field, reaches a constant value, called σ , inasmuch max Tumor 0.300 2.5 40 80 as the local electric field approaches E (Figure 2). irrev 0e postelectroporation conductivity (σ ) values are max usually estimated through mathematical modeling with data from ex vivo or in vivo experiments [7, 20]. In this 0.9 work, the tissues were characterized by using the values from Table 1 in (2)–(4). 0.8 0.7 2.2.2. Numerical Modeling. 0e electric field distributions 0.6 of the tissues were computed through the finite element 0.5 method simulations with COMSOL Multiphysics (v5.0, COMSOL AB, Sweden). 0e software was run on a personal 0.4 computer (Intel Core i5-2500, 3 GHz CPU, 4 GB RAM) 0.3 with a Windows 7 (x64, Microsoft, Inc., USA) operating 0.2 system. 0e geometry presented (Figure 1(e)) was automatically 0.1 divided into a mesh of ∼162 thousand tetrahedral elements forming the calculation domains. 0e electric field distri- 0 20 40 60 80 100 120 140 160 180 200 bution developed by the applied electric potential on the Local electric f ield (kV/m) tissues is governed by Laplace’s equation (3), and it was SC + epidermis Muscle solved for static electric currents as follows: Dermis Tumor −∇ · (σ ·∇V) � 0, (5) Figure 2: Curves for tissue conductivity dependent on the local electric field. where σ and V are tissue electric conductivity (S/m) and electric potential (V), respectively. 0e considerations for boundary conditions were that all external surfaces are above it, was the dermis layer with 1 mm, followed by the insulated (Neumann’s boundary condition). For the contact stratum corneum (SC) and epidermis layer with 0.05 mm tissue electrodes, Dirichlet’s boundary condition, consid- of thickness (Figure 1(b)). 0e distance between the anode ering a constant potential on the surface of all the electrodes, and the cathode for the parallel rows (D ) was 10 mm. 0e was applied. needles in the same row were (D ) 7 mm apart, and their radius was 0.64 mm. All tissues were considered homogeneous, and the 2.3. Treatment Planning Simulation. 0e treatment effec- electrical conductivity assigned to each skin layer and tiveness depends on the capacity of the system to produce tumor is listed in the first column of Table 1. 0e mac- a local electric field high enough to open pores around the roscopic consequence of the electroporation is the increase entire tumor [8–10, 12]. In the simulation environment, the in electrical conductance. Such behavior may be repre- local electric field indicates whether the electroporation of sented by the following mathematical model with a sigmoid the tumor cells is theoretically viable. Whenever the local shape (Figure 2) [20]: electric field was in the range of 35 kV/m–100 kV/m [18], it σ − σ max 0 was assumed that the pores were open, allowing the influx of σ(E) � σ + (2) −(E−A/B), 1 + 10 · e the chemotherapy drugs. In regions where the local electric field is lower than 35 kV/m, the induced transmembrane E + E irrev rev (3) voltage is not considered sufficient to trigger pore formation A � , [5, 18]. In other words, there is a loss of effectiveness when regions of the target tissue (i.e., tumor cells) are exposed to E − E irrev rev (4) B � , a local electric field lower than 35 kV/m during an elec- trochemotherapy session. 0e regions with no pore for- where E and E are the thresholds for electroporation mation are shown in black in the results (Figures 3–5). rev irrev (kV/m) and irreversible electroporation (kV/m), re- Irreversible electroporation areas are represented in white, spectively, σ represents the maximum electrical con- and they indicate that the cells in these areas lost the ability max ductivity reached during the tissue electroporation (S/m), to reseal. Irreversible electroporated cells may also die but and σ is the basal (or initial) tissue electrical conductivity not due to the action of the chemotherapy drugs [2, 11]; (S/m), which is measured with low amplitude pulses. 0e therefore, an investigation into the death of these cells is Tissue conductivity (S/m) 4 Journal of Healthcare Engineering E < E E < E < E E > E E < E E < E < E E > E E < E E < E < E E > E rev rev irrev irrev rev rev irrev irrev rev rev irrev irrev (a) (b) (c) Figure 3: Typical options for the application of electrochemotherapy using (a) parallel plates, type I (b) parallel needles, type II, or (c) hexagonal needles, type III. Simulations show the electric field distribution for the minimum and sufficient applied voltage for electroporation (a) 75 kV/m, (b) 110 kV/m, and (c) 127.5 kV/m. 0e local electric field is in black and is insufficient for electroporation, the electroporated area is on gray, and the irreversible electroporated areas are in white. 0e arrows indicate electric field indentation close to the tumor edges. (b) (a) (d) (c) E < E E < E < E E > E rev rev irrev irrev Figure 4: Electric field distribution for (a) type II electrode replacement in the X-axis and (d) type III electrode with an extra needle added. Type II (b) and type III (c) were taken from Figure 1 for comparison purposes. 0e gray areas represent electroporated regions, while black and white mean the magnitude of the local electric field is under or over the respective thresholds. beyond the scope of this study. A manual optimization experiments. 0e minimization process was carried out to process was carried out, aiming to maximize the region determine the electric field sufficient to create a local electric field and high enough to electroporate the cells. 0e tri- inside the range 35 kV/m and 100 kV/m and to minimize the tumor portions under or overexposed. During this process, dimensional structure was cut into slices for the three spatial the model was rerun several times for different inputs, and planes (ZX, XY, and YZ). In these slices (e.g., Figures 3–5), the outputs were evaluated. the local electric field was considered “sufficient” when A minimization process was run to determine the suf- higher than 35 kV/m (the electroporation threshold). 0is ficient and necessary applied electric field to electroporate all process was performed for each tested arrangement of target cells with each arrangement. 0e applied voltage was needles, and the minimum values obtained are listed in minimized through several simulations. 0e initial point was Table 2. 0ese minimum values are used as classification 130 kV/m, and this value was decreased in the following parameters for the robustness of the arrangements. 0e Journal of Healthcare Engineering 5 E < E E < E < E E > E E < E E < E < E E > E rev rev irrev irrev rev rev irrev irrev (a) (b) E < E E < E < E E > E E < E E < E < E E > E rev rev irrev irrev rev rev irrev irrev (c) (d) Figure 5: Decreasing the distance between needles in the same column (same polarity) reduces the minimum required voltage. 0e sequence of panels also shows a reduction of the irreversible electroporated area in comparison with (a). 0e distance between needles was reduced to (a) 90%, (b) 75%, (c) 50%, and (d) 25% of the original 7 mm. 0e initial 1100 V minimum required voltage was reduced by approximately (a) 2%, (b) 14%, (c) 30%, and (d) 50%. classification is based on how far each minimum value is field. 0e minimum and sufficient values of the applied from the starting point (i.e., 130 kV/m). electric field found for these electrodes were 75 kV/m (Figure 3(a)), 110 kV/m (Figure 3(b)), and 127.5 kV/m (Figure 3(c)). Type I (a) presented the least electroporated 3. Results area (gray) among the healthy tissues, that is, out of the 0e electric field distribution for the three main types of ellipse. Type III (c) required the highest electric field due to electrode (Figure 3) showed that the adequate type I affects the large indentation in the corners (indicated by the ar- the healthy tissue less than the other types. 0e tested types rows), resulting in large areas of irreversibility (white). were the parallel plates (Figure 3(a)), parallel needles Variations from the basic types resulted in reduced (Figure 3(b)), and hexagonal needles (Figure 3(c)). 0e values of minimum and sufficient applied voltage for elec- regions in black represent the absence of electric field, while troporation. Figure 4(a) shows the electric field distribution those in white represent the extrapolation of the local electric when the electrode was moved from the central position 6 Journal of Healthcare Engineering TABLE 2: Necessary and sufficient voltage for electroporation. may even be run at the same time of surgery in case recalculations are needed [21, 22]. Electrochemotherapy is Voltage Arrangement ∆% Figure an anticancer treatment approach kept allied to numerical (kV) simulations since its early days [15, 20]. In this work, we use Type I 75 −31.8 3(a) a simple study case to demonstrate a treatment planning As Type II 110 3(b) procedure based on numerical simulation. 0e presented reference results allowed us to highlight the loss of potential treatment Type III 127.5 15.9 3(c) effectiveness due to the electric field indentation between Type II 0X-moved 102.5 −7 4(a) Type III + central needles with the same polarity. 80 −27 4(d) needle 0e ellipsoidal tumor presented in Figure 1(a) was Not modeled considering specific electrical and geometrical 1.10∗type II 122.5 11.4 presented characteristics (Figures 1(b) and 1(c)), and the arrangements 0.90∗type II 107.5 −2.3 5(a) of different electrodes were evaluated. Once the target tumor 0.75∗type II 95 −13.6 5(b) tissue was modeled, several simulations were run consid- 0.50∗type II 77.5 −29.5 5(c) ering variations in, for instance, the electrodes’ type, posi- 0.25∗type II 55 −50 5(d) tion, arrangement, and polarization. We followed the suggestions by the European Standard Procedure for Elec- trochemotherapy (ESOPE), which are based on the number (Figure 4(b)) and when a needle pair was placed around the and volume of the tumors [1]. For large (>8 mm) superficial tumor’s largest diameter in the Y-axis. In this last scenario, tumors, ESOPE suggests using type I or III electrodes [1]. no other needle is closer to the tumor than the pair on the Based on the in silico results presented for the three com- largest diameter. Figure 4(d) shows that the type III electrode monly used electrode types (Figure 3), all electrode types (Figure 4(d)) had one extra needle inserted in the center. 0e allowed the treatment of the tumor under study. 0is means, centered needle’s polarity was the opposite of the others, and for this tumor, all three electrodes were able to generate a large area of irreversible electroporation was observed in a local electric field sufficient to trigger electroporation. the center. However, practicality and robustness are also important To better elucidate how the distance between needles considerations in electrode choice. 0e type I electrode was with the same polarity changed the electrical field distri- shown to be the most robust because, even if the voltage bution, several in silico experiments were run. 0e original source cannot supply the appropriate voltage, this type distance between needles with the same polarity in the same provides an effective treatment with 750 V. However, type I column (d ) was 7 mm. Four variations in d were tested N N is also the electrode that drains the highest current from the and are presented in Figure 4. 0e d was reduced to 90% source [15], especially when conductive gels are applied to (Figure 5(a)), 75% (Figure 5(b)), 50% (Figure 5(c)), and 25% increase the electric field’s homogeneity [8, 11, 12]. (Figure 5(d)). 0e number of needles was increased to High current peaks are the main reason for voltage minimize the spreading effect at the borders. drops, which are usually related to liquid accumulation in 0e necessary and sufficient values of the applied voltage the tumor surroundings due to bleeding or suppuration. In for the in silico experiments discussed in this work are listed addition to voltage drops, type I electrodes may be more in Table 2, with the best result seen in the last line. 0e difficult to handle than type II and III. During the early days presented values were sufficient to electroporate all the cells of electrochemotherapy, the plates used to be attached to in the region between electrodes. 0e first column indicates calipers for an easier measurement of the distance and the the tested arrangements as plates, needles, and their vari- subsequent calculation of the required voltage to be applied ations. 0e second and third columns show the obtained [23]. After a few years, predefined electrode plates with fixed values and the percentages from type II as a reference, re- distances were commercialized and became widely used spectively. Type II electrodes are most commonly employed [1, 3, 16], skipping the necessity to recalculate the applied for cutaneous tumors [3]. 0e last column indicates which voltage for each repositioning. However, the ability to figure represents each result. change the position of the plates to squeeze the tumor had Graphical visualization for the tested arrangement of already been demonstrated [16]. In this sense, the use of type electrodes is presented in the first column. 0e positive I electrodes seems to be restrained to small tumors in su- electrodes are gray and the ground electrodes are black. perficial and soft tissues, which can be accommodated be- 0ree tridimensional models can be seen in Figure 1(d). tween the plates. Type II electrode replacement reduced the minimum 4. Discussion and sufficient voltage. In one of our experiments, where the In this age of electronics, the health sciences have received position of the type II electrode was changed along the contributions from many fields, such as bioinformatics, X-axis (Figure 4(a)), a 7% decrease in the needed voltage to magnetic resonance imaging, and robotic hands for sur- cover the tumor was observed. 0is was the first indication geries. Treatment planning is a powerful tool during the of the importance of the field indentation between needles preoperative stage that allows clinicians to predict eventual with the same polarity. 0is result is important because it revealed the importance of a lateral safe margin, which was complications or loss of effectiveness [10, 21, 22]. 0anks to fast and powerful modern processors, real-time simulations exploited in the following experiments. Journal of Healthcare Engineering 7 When an extra needle was inserted into the center of the must be translated into in vitro and in vivo experiments, type III electrode (Figure 4(b)), the electric field had a dif- we showed that fundamental issues like a safe margin ferent distribution. Such an arrangement has been used for and effectiveness loss can be revealed using a validated ECT in some cases [4, 23, 24], and it is also considered a good numerical model. Even though type II electrodes are the option for commuted systems (at least two different po- most commonly used by practitioners [3], previous studies larization steps for the needles) [24]. For a single polari- have pointed out the limitations of this treatment for large zation scenario, Figure 4(b) shows that the electroporated tumors. For example, the top regions of large tumors might area is less irreversible in healthy tissue, but a large one not be electroporated without conductive gels [2, 11, 12]. around the center needle is observed (only one with the 0e literature has also considered the depth of the tumor and opposite polarization from the others). 0is electrode also the depth of needle insertion needed to avoid non- presents a significant reduction (27%) of the sufficient and electroporated areas at the tumor’s bottom [8]. We pre- necessary voltage for treatment. However, this structural sented numerical simulations that indicate the importance modification of the type III electrode might not be available of considering the electric field indentation to make the to all physicians and veterinarians. treatment as effective as possible. 0e spacing between needles is an important parameter for increasing the effective area, but based on the presented Data Availability experiments, it was observed that reducing the space be- tween needles with the same polarity in the type II electrode 0e data used to support the findings of this study are decreased the minimum required voltage and shrank the available from the corresponding author upon request. electric field indentation (Figure 5). 0ese results also imply the need to structurally modify the commercial electrodes; Conflicts of Interest however, there are extrapolations to show the electric field indentation in the region between needles with the same 0e authors declare that they have no conflicts of interest. polarity. Independent of the space between the needles in the same row (d ), the applied electric field should produce the Acknowledgments same effect in the tumor under treatment, as the electric field depends on the distance between rows (E � V/d ). However, R 0is research was supported by the Brazilian funding we observed that the applied field could be continually agencies Conselho Nacional de Desenvolvimento Cientıfico decreased for type II electrodes with a smaller distance e Tecnologico ´ (CNPq) and Coordenação de Aperfeiçoa- between the same polarity needles (<d ). 0e sufficient and mento de Pessoal de N´ ıvel Superior (CAPES) Foundation. necessary voltage is lower for smaller values of d (Table 2); N 0e authors thank M. V. Mariana Dante from the veterinary therefore, 0.25∗type II is considered the most robust elec- clinic Projeto Castração Cães and Gatos for ceding the trode. 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Electrochemotherapy Effectiveness Loss due to Electric Field Indentation between Needle Electrodes: A Numerical Study

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Copyright © 2018 José Alvim Berkenbrock et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Healthcare Engineering Volume 2018, Article ID 6024635, 8 pages https://doi.org/10.1155/2018/6024635 Research Article Electrochemotherapy Effectiveness Loss due to Electric Field Indentation between Needle Electrodes: A Numerical Study 1,2 3 Jose´ Alvim Berkenbrock, Rafaela Grecco Machado, and Daniela Ota Hisayasu Suzuki Department of Electrical and Computer Engineering, University of Saskatchewan, Saskatoon, Canada Department of Electrical and Electronics Engineering, Institute of Biomedical Engineering, Federal University of Santa Catarina, Florianopolis, SC, Brazil Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK, Canada Correspondence should be addressed to Daniela Ota Hisayasu Suzuki; suzuki@eel.ufsc.br Received 30 January 2018; Revised 26 April 2018; Accepted 8 May 2018; Published 2 July 2018 Academic Editor: Terry K. K. Koo Copyright © 2018 Jose ´ Alvim Berkenbrock et al. 0is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Electrochemotherapy is an anticancer treatment based on applying electric field pulses that reduce cell membrane selectivity, allowing chemotherapy drugs to enter the cells. In parallel to electrochemotherapy clinical tests, in silico experiments have helped scientists and clinicians to understand the electric field distribution through anatomically complex regions of the body. In particular, these in silico experiments allow clinicians to predict problems that may arise in treatment effectiveness. 0e current work presents a metastatic case of a mast cell tumor in a dog. In this specific treatment planning study, we show that using needle electrodes has a possible pitfall. 0e macroscopic consequence of the electroporation was assessed through a mathematical model of tissue electrical conductivity. Considering the electrical and geometrical characteristics of the case under study, we modeled an ellipsoidal tumor. Initial simulations were based on the European Standard Operating Procedures for electrochemotherapy suggestions, and then different electrodes’ arrangements were evaluated. To avoid blind spots, multiple applications are usually required for large tumors, demanding electrode repositioning. An effective treatment electroporates all the tumor cells. Partially and slightly overlapping the areas increases the session’s duration but also likely increases the treatment’s effectiveness. It is worth noting that for a single application, the needles should not be placed close to the tumor’s borders because effectiveness is highly likely to be lost. facilitates the uptake of chemotherapy drugs (e.g., bleomycin 1. Introduction and cisplatin) by the cells and the selective death of tumor Electrochemotherapy is an anticancer treatment based on cells [1, 3]. When this delivery method is used, the cyto- pulsed electric fields and chemotherapy drugs. 0e electric toxicity of bleomycin increases 300–700 times [3]. However, field reduces the cell membrane’s selectivity, promoting the irreversible electroporation induces membrane disruption cell’s intake of chemotherapy drugs [1–3]. 0is biophysical and consequently indiscriminate cell death [2]. In this phenomenon of decreasing cell membrane selectivity through sense, the ability to achieve the right parameters for targeting electric field imposition is called electropermeabilization. tumor cells has imposed challenges. 0ese challenges are 0e most accepted theory to explain such permeabilization mainly consequences of the anatomical complexity and considers that pores are induced around the cell membrane nonhomogeneous structures of which our tissues, organs, [4]. 0is process is called electroporation and considers that and bodies are composed. the membrane permeabilization can be reversible or irre- 0e electric field distribution in biological tissues has versible depending on the membrane’s capability of resealing been studied for decades, and recent in silico experiments the pores after the removal of the electric field [2, 5]. have taken advantage of years of bioelectrical impedance 0e reversible or irreversible electroporation can lead to analysis [6, 7] and powerful processors. 0rough in silico different treatment outcomes. Reversible electroporation experiments, several different scenarios can be run, which 2 Journal of Healthcare Engineering Stratum corneum Electrodes and epidermis Tumor (d) Dermis Muscle (b) 40 mm 40 mm (a) (c) (e) Figure 1: Schematic for modeling the tumor under study. From left to right, the target tumor, the geometrical parameters extraction and anatomical characterization, and the 3D insertion into the simulation environment. (a) A mast cell tumor in a 3-year-old male dog. 0e arrow indicates the modeled tumor. Scale: 10 mm. (b) Skin with three layers (stratum corneum with epidermis, dermis, and muscle), the tumor, and two representative electrode needles. (c) Approximated geometry and dimensional parameters of the tumor. (d) 0e three types of tested electrodes. (e) 0e 3D geometry model under study. 0e ellipsoid represents the tumor seeded on the skin layers, and the cylinders are the electrode needles. have allowed scientists and clinicians to understand and stained with May–Grunwald–Giemsa ¨ (MGG) dye for a histopathology examination. 0e patient was diagnosed with predict problems in treatment effectiveness. 0e clinical treatment of electrochemotherapy has been used in in silico a metastatic mast cell tumor, and surgical removal was studies for years. In this therapy approach, there are three recommended. basic electrode types: (I) two parallel plates, (II) needles in 0e electrochemotherapy treatment was suggested as two parallel rows, and (III) needles in the vertices of a potentially curative treatment option, and the patient was a hexagon—like a honeycomb [1]. Examples of the close forwarded to the veterinary clinic that collaborated with this relationship between in silico experiments and electro- study. In Figure 1(a), the tumor chosen to be modeled is chemotherapy are found in studies on how to insert the indicated with the arrow. 0is tumor was chosen because of needle electrodes for deeply seeded tumors [8, 9], for its expressiveness rather than the others. 0e tumor di- nonsymmetrical tumors [10], and for large tumors on the mensions were 20 mm along its longest diameter and 10 mm skin’s surface [11–13]. on the other superficial diameter (orthogonal axis). Many earlier in silico studies did not consider electro- poration as a factor influencing membrane conductivity and 2.2. In Silico Modeling assumed a constant tissue electrical conductivity [14–16]. However, more recent studies have demonstrated the im- 2.2.1. Geometry and Tissue Properties. 0e data were made portance of considering such an effect for cancer treatment available by the clinic and patient owner. 0e tumor under planning [9, 17, 18]. In the present work, a case of a met- study (Figure 1(a)) was 3D modeled in the simulation astatic mast cell tumor in a dog is studied. Mast cell tumors, environment (Figure 1(e)), considering the parameters or mastocytomas, are common tumors in the skin of dogs, shown in the Figures 1(b) and 1(c). 0e tumor had its shape and many of them are prone to local recurrence and me- approximated to an ellipsoidal mass, with a, b, and c equal tastasis [19]. We started this report with a specific treatment to 20 mm, 10 mm, and 1.25 mm, respectively (Figure 1(c)). planning study to demonstrate the potential for efficiency 0e two orthogonal surface diameters were a and b. 0e loss when needle electrodes are used. tumor depth c was estimated through the following equation [1]: 2. Materials and Methods 4 π Vol � πabc � ab . (1) 3 6 2.1. In Vivo Diagnosis. 0e patient was a 3-year-old male pitbull mixed-breed dog, 32 kg, with spontaneous nodular 0e skin tissue was modeled with a surface area of formations on the right posterior limb. 0e samples were 40 × 40 mm, and it was divided into three different layers. collected from the right inguinal lymph node and were 0e deepest layer was the muscle with 10 mm of thickness; Journal of Healthcare Engineering 3 Table 1: Tissue electrical parameters [17]. values for σ are often extrapolations from measures held at 10–100 Hz [6, 18, 20]. During the application of pulses Tissue σ (S/m) σ /σ E (kV/m) E (kV/m) 0 max 0 rev irrev intense enough to produce electroporation (i.e., above E ), rev SC + epidermis 0.008 100 40 120 the tissue electrical conductivity varies as described by (2) Dermis 0.250 4 30 120 [20]. Tissue electrical conductivity, as a function of the Muscle 0.135 2.5 20 80 electric field, reaches a constant value, called σ , inasmuch max Tumor 0.300 2.5 40 80 as the local electric field approaches E (Figure 2). irrev 0e postelectroporation conductivity (σ ) values are max usually estimated through mathematical modeling with data from ex vivo or in vivo experiments [7, 20]. In this 0.9 work, the tissues were characterized by using the values from Table 1 in (2)–(4). 0.8 0.7 2.2.2. Numerical Modeling. 0e electric field distributions 0.6 of the tissues were computed through the finite element 0.5 method simulations with COMSOL Multiphysics (v5.0, COMSOL AB, Sweden). 0e software was run on a personal 0.4 computer (Intel Core i5-2500, 3 GHz CPU, 4 GB RAM) 0.3 with a Windows 7 (x64, Microsoft, Inc., USA) operating 0.2 system. 0e geometry presented (Figure 1(e)) was automatically 0.1 divided into a mesh of ∼162 thousand tetrahedral elements forming the calculation domains. 0e electric field distri- 0 20 40 60 80 100 120 140 160 180 200 bution developed by the applied electric potential on the Local electric f ield (kV/m) tissues is governed by Laplace’s equation (3), and it was SC + epidermis Muscle solved for static electric currents as follows: Dermis Tumor −∇ · (σ ·∇V) � 0, (5) Figure 2: Curves for tissue conductivity dependent on the local electric field. where σ and V are tissue electric conductivity (S/m) and electric potential (V), respectively. 0e considerations for boundary conditions were that all external surfaces are above it, was the dermis layer with 1 mm, followed by the insulated (Neumann’s boundary condition). For the contact stratum corneum (SC) and epidermis layer with 0.05 mm tissue electrodes, Dirichlet’s boundary condition, consid- of thickness (Figure 1(b)). 0e distance between the anode ering a constant potential on the surface of all the electrodes, and the cathode for the parallel rows (D ) was 10 mm. 0e was applied. needles in the same row were (D ) 7 mm apart, and their radius was 0.64 mm. All tissues were considered homogeneous, and the 2.3. Treatment Planning Simulation. 0e treatment effec- electrical conductivity assigned to each skin layer and tiveness depends on the capacity of the system to produce tumor is listed in the first column of Table 1. 0e mac- a local electric field high enough to open pores around the roscopic consequence of the electroporation is the increase entire tumor [8–10, 12]. In the simulation environment, the in electrical conductance. Such behavior may be repre- local electric field indicates whether the electroporation of sented by the following mathematical model with a sigmoid the tumor cells is theoretically viable. Whenever the local shape (Figure 2) [20]: electric field was in the range of 35 kV/m–100 kV/m [18], it σ − σ max 0 was assumed that the pores were open, allowing the influx of σ(E) � σ + (2) −(E−A/B), 1 + 10 · e the chemotherapy drugs. In regions where the local electric field is lower than 35 kV/m, the induced transmembrane E + E irrev rev (3) voltage is not considered sufficient to trigger pore formation A � , [5, 18]. In other words, there is a loss of effectiveness when regions of the target tissue (i.e., tumor cells) are exposed to E − E irrev rev (4) B � , a local electric field lower than 35 kV/m during an elec- trochemotherapy session. 0e regions with no pore for- where E and E are the thresholds for electroporation mation are shown in black in the results (Figures 3–5). rev irrev (kV/m) and irreversible electroporation (kV/m), re- Irreversible electroporation areas are represented in white, spectively, σ represents the maximum electrical con- and they indicate that the cells in these areas lost the ability max ductivity reached during the tissue electroporation (S/m), to reseal. Irreversible electroporated cells may also die but and σ is the basal (or initial) tissue electrical conductivity not due to the action of the chemotherapy drugs [2, 11]; (S/m), which is measured with low amplitude pulses. 0e therefore, an investigation into the death of these cells is Tissue conductivity (S/m) 4 Journal of Healthcare Engineering E < E E < E < E E > E E < E E < E < E E > E E < E E < E < E E > E rev rev irrev irrev rev rev irrev irrev rev rev irrev irrev (a) (b) (c) Figure 3: Typical options for the application of electrochemotherapy using (a) parallel plates, type I (b) parallel needles, type II, or (c) hexagonal needles, type III. Simulations show the electric field distribution for the minimum and sufficient applied voltage for electroporation (a) 75 kV/m, (b) 110 kV/m, and (c) 127.5 kV/m. 0e local electric field is in black and is insufficient for electroporation, the electroporated area is on gray, and the irreversible electroporated areas are in white. 0e arrows indicate electric field indentation close to the tumor edges. (b) (a) (d) (c) E < E E < E < E E > E rev rev irrev irrev Figure 4: Electric field distribution for (a) type II electrode replacement in the X-axis and (d) type III electrode with an extra needle added. Type II (b) and type III (c) were taken from Figure 1 for comparison purposes. 0e gray areas represent electroporated regions, while black and white mean the magnitude of the local electric field is under or over the respective thresholds. beyond the scope of this study. A manual optimization experiments. 0e minimization process was carried out to process was carried out, aiming to maximize the region determine the electric field sufficient to create a local electric field and high enough to electroporate the cells. 0e tri- inside the range 35 kV/m and 100 kV/m and to minimize the tumor portions under or overexposed. During this process, dimensional structure was cut into slices for the three spatial the model was rerun several times for different inputs, and planes (ZX, XY, and YZ). In these slices (e.g., Figures 3–5), the outputs were evaluated. the local electric field was considered “sufficient” when A minimization process was run to determine the suf- higher than 35 kV/m (the electroporation threshold). 0is ficient and necessary applied electric field to electroporate all process was performed for each tested arrangement of target cells with each arrangement. 0e applied voltage was needles, and the minimum values obtained are listed in minimized through several simulations. 0e initial point was Table 2. 0ese minimum values are used as classification 130 kV/m, and this value was decreased in the following parameters for the robustness of the arrangements. 0e Journal of Healthcare Engineering 5 E < E E < E < E E > E E < E E < E < E E > E rev rev irrev irrev rev rev irrev irrev (a) (b) E < E E < E < E E > E E < E E < E < E E > E rev rev irrev irrev rev rev irrev irrev (c) (d) Figure 5: Decreasing the distance between needles in the same column (same polarity) reduces the minimum required voltage. 0e sequence of panels also shows a reduction of the irreversible electroporated area in comparison with (a). 0e distance between needles was reduced to (a) 90%, (b) 75%, (c) 50%, and (d) 25% of the original 7 mm. 0e initial 1100 V minimum required voltage was reduced by approximately (a) 2%, (b) 14%, (c) 30%, and (d) 50%. classification is based on how far each minimum value is field. 0e minimum and sufficient values of the applied from the starting point (i.e., 130 kV/m). electric field found for these electrodes were 75 kV/m (Figure 3(a)), 110 kV/m (Figure 3(b)), and 127.5 kV/m (Figure 3(c)). Type I (a) presented the least electroporated 3. Results area (gray) among the healthy tissues, that is, out of the 0e electric field distribution for the three main types of ellipse. Type III (c) required the highest electric field due to electrode (Figure 3) showed that the adequate type I affects the large indentation in the corners (indicated by the ar- the healthy tissue less than the other types. 0e tested types rows), resulting in large areas of irreversibility (white). were the parallel plates (Figure 3(a)), parallel needles Variations from the basic types resulted in reduced (Figure 3(b)), and hexagonal needles (Figure 3(c)). 0e values of minimum and sufficient applied voltage for elec- regions in black represent the absence of electric field, while troporation. Figure 4(a) shows the electric field distribution those in white represent the extrapolation of the local electric when the electrode was moved from the central position 6 Journal of Healthcare Engineering TABLE 2: Necessary and sufficient voltage for electroporation. may even be run at the same time of surgery in case recalculations are needed [21, 22]. Electrochemotherapy is Voltage Arrangement ∆% Figure an anticancer treatment approach kept allied to numerical (kV) simulations since its early days [15, 20]. In this work, we use Type I 75 −31.8 3(a) a simple study case to demonstrate a treatment planning As Type II 110 3(b) procedure based on numerical simulation. 0e presented reference results allowed us to highlight the loss of potential treatment Type III 127.5 15.9 3(c) effectiveness due to the electric field indentation between Type II 0X-moved 102.5 −7 4(a) Type III + central needles with the same polarity. 80 −27 4(d) needle 0e ellipsoidal tumor presented in Figure 1(a) was Not modeled considering specific electrical and geometrical 1.10∗type II 122.5 11.4 presented characteristics (Figures 1(b) and 1(c)), and the arrangements 0.90∗type II 107.5 −2.3 5(a) of different electrodes were evaluated. Once the target tumor 0.75∗type II 95 −13.6 5(b) tissue was modeled, several simulations were run consid- 0.50∗type II 77.5 −29.5 5(c) ering variations in, for instance, the electrodes’ type, posi- 0.25∗type II 55 −50 5(d) tion, arrangement, and polarization. We followed the suggestions by the European Standard Procedure for Elec- trochemotherapy (ESOPE), which are based on the number (Figure 4(b)) and when a needle pair was placed around the and volume of the tumors [1]. For large (>8 mm) superficial tumor’s largest diameter in the Y-axis. In this last scenario, tumors, ESOPE suggests using type I or III electrodes [1]. no other needle is closer to the tumor than the pair on the Based on the in silico results presented for the three com- largest diameter. Figure 4(d) shows that the type III electrode monly used electrode types (Figure 3), all electrode types (Figure 4(d)) had one extra needle inserted in the center. 0e allowed the treatment of the tumor under study. 0is means, centered needle’s polarity was the opposite of the others, and for this tumor, all three electrodes were able to generate a large area of irreversible electroporation was observed in a local electric field sufficient to trigger electroporation. the center. However, practicality and robustness are also important To better elucidate how the distance between needles considerations in electrode choice. 0e type I electrode was with the same polarity changed the electrical field distri- shown to be the most robust because, even if the voltage bution, several in silico experiments were run. 0e original source cannot supply the appropriate voltage, this type distance between needles with the same polarity in the same provides an effective treatment with 750 V. However, type I column (d ) was 7 mm. Four variations in d were tested N N is also the electrode that drains the highest current from the and are presented in Figure 4. 0e d was reduced to 90% source [15], especially when conductive gels are applied to (Figure 5(a)), 75% (Figure 5(b)), 50% (Figure 5(c)), and 25% increase the electric field’s homogeneity [8, 11, 12]. (Figure 5(d)). 0e number of needles was increased to High current peaks are the main reason for voltage minimize the spreading effect at the borders. drops, which are usually related to liquid accumulation in 0e necessary and sufficient values of the applied voltage the tumor surroundings due to bleeding or suppuration. In for the in silico experiments discussed in this work are listed addition to voltage drops, type I electrodes may be more in Table 2, with the best result seen in the last line. 0e difficult to handle than type II and III. During the early days presented values were sufficient to electroporate all the cells of electrochemotherapy, the plates used to be attached to in the region between electrodes. 0e first column indicates calipers for an easier measurement of the distance and the the tested arrangements as plates, needles, and their vari- subsequent calculation of the required voltage to be applied ations. 0e second and third columns show the obtained [23]. After a few years, predefined electrode plates with fixed values and the percentages from type II as a reference, re- distances were commercialized and became widely used spectively. Type II electrodes are most commonly employed [1, 3, 16], skipping the necessity to recalculate the applied for cutaneous tumors [3]. 0e last column indicates which voltage for each repositioning. However, the ability to figure represents each result. change the position of the plates to squeeze the tumor had Graphical visualization for the tested arrangement of already been demonstrated [16]. In this sense, the use of type electrodes is presented in the first column. 0e positive I electrodes seems to be restrained to small tumors in su- electrodes are gray and the ground electrodes are black. perficial and soft tissues, which can be accommodated be- 0ree tridimensional models can be seen in Figure 1(d). tween the plates. Type II electrode replacement reduced the minimum 4. Discussion and sufficient voltage. In one of our experiments, where the In this age of electronics, the health sciences have received position of the type II electrode was changed along the contributions from many fields, such as bioinformatics, X-axis (Figure 4(a)), a 7% decrease in the needed voltage to magnetic resonance imaging, and robotic hands for sur- cover the tumor was observed. 0is was the first indication geries. Treatment planning is a powerful tool during the of the importance of the field indentation between needles preoperative stage that allows clinicians to predict eventual with the same polarity. 0is result is important because it revealed the importance of a lateral safe margin, which was complications or loss of effectiveness [10, 21, 22]. 0anks to fast and powerful modern processors, real-time simulations exploited in the following experiments. Journal of Healthcare Engineering 7 When an extra needle was inserted into the center of the must be translated into in vitro and in vivo experiments, type III electrode (Figure 4(b)), the electric field had a dif- we showed that fundamental issues like a safe margin ferent distribution. Such an arrangement has been used for and effectiveness loss can be revealed using a validated ECT in some cases [4, 23, 24], and it is also considered a good numerical model. Even though type II electrodes are the option for commuted systems (at least two different po- most commonly used by practitioners [3], previous studies larization steps for the needles) [24]. For a single polari- have pointed out the limitations of this treatment for large zation scenario, Figure 4(b) shows that the electroporated tumors. For example, the top regions of large tumors might area is less irreversible in healthy tissue, but a large one not be electroporated without conductive gels [2, 11, 12]. around the center needle is observed (only one with the 0e literature has also considered the depth of the tumor and opposite polarization from the others). 0is electrode also the depth of needle insertion needed to avoid non- presents a significant reduction (27%) of the sufficient and electroporated areas at the tumor’s bottom [8]. We pre- necessary voltage for treatment. However, this structural sented numerical simulations that indicate the importance modification of the type III electrode might not be available of considering the electric field indentation to make the to all physicians and veterinarians. treatment as effective as possible. 0e spacing between needles is an important parameter for increasing the effective area, but based on the presented Data Availability experiments, it was observed that reducing the space be- tween needles with the same polarity in the type II electrode 0e data used to support the findings of this study are decreased the minimum required voltage and shrank the available from the corresponding author upon request. electric field indentation (Figure 5). 0ese results also imply the need to structurally modify the commercial electrodes; Conflicts of Interest however, there are extrapolations to show the electric field indentation in the region between needles with the same 0e authors declare that they have no conflicts of interest. polarity. Independent of the space between the needles in the same row (d ), the applied electric field should produce the Acknowledgments same effect in the tumor under treatment, as the electric field depends on the distance between rows (E � V/d ). However, R 0is research was supported by the Brazilian funding we observed that the applied field could be continually agencies Conselho Nacional de Desenvolvimento Cientıfico decreased for type II electrodes with a smaller distance e Tecnologico ´ (CNPq) and Coordenação de Aperfeiçoa- between the same polarity needles (<d ). 0e sufficient and mento de Pessoal de N´ ıvel Superior (CAPES) Foundation. necessary voltage is lower for smaller values of d (Table 2); N 0e authors thank M. V. Mariana Dante from the veterinary therefore, 0.25∗type II is considered the most robust elec- clinic Projeto Castração Cães and Gatos for ceding the trode. Based on these results, we highlight the impact of the patient data for this study. field indentation between needles with the same polarity. For clinical use, needle electrodes are potentially vulnerable to References losses in treatment effectiveness due to voltage drops, es- pecially in cases where the tumor boundaries are close to the [1] L. M. Mir, J. Gehl, G. Sersa et al., “Standard operating pro- needles. 0is finding is contrary to what has been suggested cedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or for plate electrodes, where the tumor should be squeezed locally and electric pulses delivered by the Cliniporator by between the electrodes [16]. 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