Abstract
Molecular sampling with vacuum-assisted tissue electroporation is a novel, minimally invasive method for molecular profiling of solid lesions. In this paper, we report on the design of the battery-powered pulsed electric field generator and electrode configuration for an electroporation-based molecular sampling device for skin cancer diagnostics. Using numerical models of skin electroporation corroborated by the potato tissue phantom model, we show that the electroporated tissue volume, which is the maximum volume for biomarker sampling, strongly depends on the electrode’s geometry, needle electrode skin penetration depths, and the applied pulsed electric field protocol. In addition, using excised human basal cell carcinoma (BCC) tissues, we show that diffusion of proteins out of human BCC tissues into water strongly depends on the strength of the applied electric field and on the time after the field application. The developed numerical simulations, confirmed by experiments in potato tissue phantoms and excised human cancer lesions, provide essential tools for the development of electroporation-based molecular markers sampling devices for personalized skin cancer diagnostics.
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Dua, R., D. G. Beetner, W. V. Stoecker, and D. C. Wunsch. Detection of basal cell carcinoma using electrical impedance and neural networks. IEEE Trans. Biomed. Eng. 51:66–71, 2004.
Doran, C. M., et al. Estimating the economic costs of skin cancer in New South Wales, Australia. BMC Public Health. 15:952, 2015.
Mofidi, A., et al. The economic burden of occupational non-melanoma skin cancer due to solar radiation. J. Occup. Environ. Hyg. 15:481–491, 2018.
Chan, B. A., and B. G. M. Hughes. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl. Lung Cancer Res. 4:36–54, 2015.
Augustine, R., et al. 3D bioprinted cancer models: revolutionizing personalized cancer therapy. Transl. Oncol.14:101015, 2021.
Cipriani, C., et al. Personalized irradiation therapy for NMSC by rhenium-188 skin cancer therapy: a long-term retrospective study. J. Dermatol. Treat. 33:969–975, 2022.
Smit, A. K., et al. Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial. Genet. Med. 23:2394–2403, 2021.
Coleman, A. J., et al. Histological correlates of optical coherence tomography in non-melanoma skin cancer. Skin Res. Technol. 19:e10–e19, 2013.
Borsari, S., et al. Clinical indications for use of reflectance confocal microscopy for skin cancer diagnosis. JAMA Dermatol. 152:1093–1098, 2016.
Ibrahim, O., B. Gastman, and A. Zhang. Advances in diagnosis and treatment of nonmelanoma skin cancer. Ann. Plast. Surg. 73(5):615–619, 2014.
Chen, Z.-T., et al. High-frequency ultrasound for differentiation between high-risk basal cell carcinoma and cutaneous squamous cell carcinoma. Skin Res. Technol. 28:410–418, 2022.
Qin, J., et al. Usefulness of high-frequency ultrasound in differentiating basal cell carcinoma from common benign pigmented skin tumors. Skin Res. Technol. 27:766–773, 2021.
Elston, D. M., E. J. Stratman, and S. J. Miller. Skin biopsy: biopsy issues in specific diseases. J. Am. Acad. Dermatol. 74:1–16, 2016.
Longo, C., et al. Classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy. J. Am. Acad. Dermatol. 71:716-724.e1, 2014.
Gerlach, S., et al. Needle insertion planning for obstacle avoidance in robotic biopsy. Curr. Dir. Biomed. Eng. 7:779–782, 2021.
Daskalopoulou, D., et al. Cytologically interesting cases of primary skin tumors and tumor-like conditions identified by fine-needle aspiration biopsy. Diagn. Cytopathol. 19:17–28, 1998.
Yarmush, M. L., A. Golberg, G. Serša, T. Kotnik, and D. Miklavčič. Electroporation-based technologies for medicine: principles, applications, and challenges. Annu. Rev. Biomed. Eng. 16:295–320, 2014.
Golberg, A., J. Sheviryov, O. Solomon, L. Anavy, and Z. Yakhini. Molecular harvesting with electroporation for tissue profiling. Sci. Rep. 9:15750, 2019.
Genish, I., et al. Electroporation-based proteome sampling ex vivo enables the detection of brain melanoma protein signatures in a location proximate to visible tumor margins. PLoS ONE. 2022. https://doi.org/10.1371/journal.pone.0265866.
Vitkin, E., et al. Molecular harvesting of proteins with electroporation in vivo facilitates the profiling of spatial differential protein expression in tumors. Sci. Rep. 2022. https://doi.org/10.1038/s41598-022-19984-x.
Vitkin, E., et al. Proteome sampling with e-biopsy enables differentiation between cutaneous squamous cell carcinoma and basal cell carcinoma. medRxiv. 2022. https://doi.org/10.1101/2022.12.22.22283845.
Daugimont, L., et al. Hollow microneedle arrays for intradermal drug delivery and DNA electroporation. J. Membr. Biol. 236:117–125, 2010.
Quaglino, P., et al. Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases. Ann. Surg. Oncol. 15:2215, 2008.
Golberg, A., et al. Skin regeneration with all accessory organs following ablation with irreversible electroporation. J. Tissue Eng. Regen. Med. 12:98–113, 2018.
Castiello, M., et al. A new grid electrode for electrochemotherapy treatment of large skin tumors. IEEE Trans. Dielectr. Electr. Insul. 21:1424–1432, 2014.
Cvetkoska, A., E. Pírc, M. Reberšek, R. Magjarević, and D. Míklavčič. Towards standardization of electroporation devices and protocols. IEEE Instrum. Meas. Mag. 23:74–81, 2020.
Bertacchini, C., et al. Design of an irreversible electroporation system for clinical use. Technol. Cancer Res. Treat. 6:313–320, 2007.
Campana, L. G., F. Dughiero, M. Forzan, C. R. Rossi, and E. Sieni. A prototype of a flexible grid electrode to treat widespread superficial tumors by means of Electrochemotherapy. Radiol. Oncol. 50:49–57, 2016.
Golberg, A., et al. Preventing scars after injury with partial irreversible electroporation. J. Investig. Dermatol. 136:2297–2304, 2016.
Golberg, A., et al. Pulsed electric fields for burn wound disinfection in a murine model. J. Burn Care Res. 36:7–13, 2015.
Golberg, A., et al. Skin rejuvenation with non-invasive pulsed electric fields. Sci. Rep. 5:1–18, 2015.
Lin, F., et al. A novel prototype device for electroporation-enhanced DNA vaccine delivery simultaneously to both skin and muscle. Vaccine. 29:6771–6780, 2011.
Ghosh, S., A. Gillis, J. Sheviryov, K. Levkov, and A. Golberg. Towards waste meat biorefinery: extraction of proteins from waste chicken meat with non-thermal pulsed electric fields and mechanical pressing. J. Clean. Prod. 208:220–231, 2019.
Golberg, A., J. Sheviryov, O. Solomon, L. Anavy, and Z. Yakhini. Molecular harvesting with electroporation for tissue profiling. Sci. Rep. 2019. https://doi.org/10.1038/s41598-019-51634-7.
Agnass, P., et al. Mathematical modeling of the thermal effects of irreversible electroporation for in vitro, in vivo, and clinical use: a systematic review. Int. J. Hyperth. 37:486–505, 2020.
Beitel-White, N., et al. Multi-tissue analysis on the impact of electroporation on electrical and thermal properties. IEEE Trans. Biomed. Eng. 68(3):771–782, 2021.
Čorović, S., L. M. Mir, and D. Miklavčič. In vivo muscle electroporation threshold determination: realistic numerical models and in vivo experiments. J. Membr. Biol. 245:509–520, 2012.
Davalos, R. V., B. Rubinsky, and L. M. Mir. Theoretical analysis of the thermal effects during in vivo tissue electroporation. Bioelectrochemistry. 61:99–107, 2003.
Yarmolenko, P. S., et al. Thresholds for thermal damage to normal tissues: an update. Int. J. Hyperth. 2011. https://doi.org/10.3109/02656736.2010.534527.
Kranjc, M., F. Bajd, I. Serša, M. de Boevere, and D. Miklavčič. Electric field distribution in relation to cell membrane electroporation in potato tuber tissue studied by magnetic resonance techniques. Innov. Food Sci. Emerg. Technol. 37:384–390, 2016.
Isles, M. G., C. McConkey, and H. M. Mehanna. A systematic review and meta-analysis of the role of positron emission tomography in the follow up of head and neck squamous cell carcinoma following radiotherapy or chemoradiotherapy. Clin. Otolaryngol. 33:210–222, 2008.
Pavšelj, N., and D. Miklavčič. Numerical modeling in electroporation-based biomedical applications. Radiol. Oncol. 42:159–168, 2008.
Rubinsky, B. Irreversible electroporation in medicine. Technol. Cancer Res. Treat. 6:255–260, 2007.
Golberg, A., and B. Rubinsky. A statistical model for multidimensional irreversible electroporation cell death in tissue. Biomed. Eng. Online. 9:13, 2010.
Maor, E., A. Ivorra, and B. Rubinsky. Non thermal irreversible electroporation: novel technology for vascular smooth muscle cells ablation. PLoS ONE. 2009. https://doi.org/10.1371/journal.pone.0004757.
Rubinsky, B., G. Onik, and P. Mikus. Irreversible electroporation: a new ablation modality—clinical implications. Technol. Cancer Res. Treat. 6:37–48, 2007.
Neal, R. E., P. A. Garcia, J. L. Robertson, and R. V. Davalos. Experimental characterization and numerical modeling of tissue electrical conductivity during pulsed electric fields for irreversible electroporation treatment planning. IEEE Trans. Biomed. Eng. 59:1076–1085, 2012.
Ivorra, A., L. M. Mir, and B. Rubinsky. Electric field redistribution due to conductivity changes during tissue electroporation: experiments with a simple vegetal model. In: IFMBE Proceedings, vol. 25, 2009.
Hjouj, M., and B. Rubinsky. Magnetic resonance imaging characteristics of nonthermal irreversible electroporation in vegetable tissue. J. Membr. Biol. 236:137–146, 2010.
Lee, E. W., C. T. Loh, and S. T. Kee. Imaging guided percutaneous irreversible electroporation: ultrasound and immunohistological correlation. Technol. Cancer Res. Treat. 6:287–293, 2007.
Rubinsky, B., G. Onik, and P. Mikus. Irreversible electroporation: a new ablation modality—clinical implications. Technol. Cancer Res. Treat. 6(1):37–48, 2007. https://doi.org/10.1177/153303460700600106.
Onik, G., P. Mikus, and B. Rubinsky. Irreversible electroporation: implications for prostate ablation. Technol. Cancer Res. Treat. 6:295–300, 2007.
Wardhana, G., J. P. Almeida, M. Abayazid, and J. J. Fütterer. Development of a thermal model for irreversible electroporation: an approach to estimate and optimize the IRE protocols. Int. J. Comput. Assist. Radiol. Surg. 16(8):1325–1334, 2021.
Miklovic, T., E. L. Latouche, M. R. DeWitt, R. V. Davalos, and M. B. Sano. A comprehensive characterization of parameters affecting high-frequency irreversible electroporation lesions. Ann. Biomed. Eng. 45(11):2524–2534, 2017.
Jeong, S., et al. Evaluation of electroporated area using 2,3,5-triphenyltetrazolium chloride in a potato model. Sci. Rep. 2021. https://doi.org/10.1038/s41598-021-99987-2.
Yao, C., Y. Lv, S. Dong, Y. Zhao, and H. Liu. Irreversible electroporation ablation area enhanced by synergistic high-and low-voltage pulses. PLoS ONE. 2017. https://doi.org/10.1371/journal.pone.0173181.
Luo, X., Y. Zhou, T. Smart, D. Grossman, and B. Sanchez. Electrical characterization of basal cell carcinoma using a handheld electrical impedance dermography device. JID Innov.2:100075, 2022.
Sieni, E., et al. Effect of tissue inhomogeneity on electric field intensity for electrochemotherapy treatment. In: 2018 Electrostatics Joint Conference: Electrostatics Society of America, Boston, MA, USA, 2018, pp. 1–10.
Yarmush, M. L., A. Golberg, T. Kotnik, and D. Miklavčič. Electroporation-based technologies for medicine: principles, applications, and challenges. Annu. Rev. Biomed. Eng. 2014. https://doi.org/10.1146/annurev-bioeng-071813-104622.
Golberg, A., and B. Rubinsky. Towards electroporation based treatment planning considering electric field induced muscle contractions. Technol. Cancer Res. Treat. 11:189–201, 2012.
Garcia, P. A., et al. Predictive therapeutic planning for irreversible electroporation treatment of spontaneous malignant glioma. Med. Phys. 44:4968–4980, 2017.
Kos, B., et al. Robustness of treatment planning for electrochemotherapy of deep-seated tumors. J. Membr. Biol. 236:147–153, 2010.
Groselj, A., et al. Coupling treatment planning with navigation system: a new technological approach in treatment of head and neck tumors by electrochemotherapy. Biomed. Eng. Online. 14:S2, 2015.
Zupanic, A., B. Kos, and D. Miklavcic. Treatment planning of electroporation-based medical interventions: electrochemotherapy, gene electrotransfer and irreversible electroporation. Phys. Med. Biol. 2012. https://doi.org/10.1088/0031-9155/57/17/5425.
Kos, B., P. Voigt, D. Miklavcic, and M. Moche. Careful treatment planning enables safe ablation of liver tumors adjacent to major blood vessels by percutaneous irreversible electroporation (IRE). Radiol. Oncol. 49:234–241, 2015.
Acknowledgments
The authors thank the Israel Ministry of Science and Technology, the TAU SPARK Fund, the TAU Zimin Center for Technologies for Better Life, and the EuroNanoMed MATISSE Project for their support.
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BG: experiment, numerical modeling, manuscript drafting, KL: engineering, device development, experiment, AB: experiments, samples collection, pathology, clinics, EV: statistical analysis, OS: experiments, samples collection, pathology, clinics, JW: experiments, protein sampling, and analysis, AS: conceptualization, critical manuscript review, AG: conceptualization, experiment, data analysis, manuscript drafting.
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A patent application was filed to protect the electroporation-based sampling technology described herein as invented by AG, JW, EV, AS, KL. The authors have no relevant financial or non-financial interests to disclose.
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Gabay, B., Levkov, K., Berl, A. et al. Electroporation-Based Biopsy Treatment Planning with Numerical Models and Tissue Phantoms. Ann Biomed Eng 52, 71–88 (2024). https://doi.org/10.1007/s10439-023-03208-y
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DOI: https://doi.org/10.1007/s10439-023-03208-y