Soft Focused Shock Wave Treatment of Solid Tumors. Part I: Physico-mechanical Preconditions, Parametric Simulation and Technical Applicator Design

Soft Focused Shock Wave Treatment of Solid Tumors. 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Part I: Physico-mechanical Preconditions, Parametric Simulation and Technical Applicator Design Axel Erich Theuer, Nicolas Schierbaum, Heike Niessner, Francisco Meraz-Torres, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6184724/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To explore the feasibility of targeted impairment of malignant tumors by application of soft focused shock wave treatment, the physico-mechanical preconditions are investigated. This innovative “soft” approach is different from the FDA-approved high intensity focused ultrasound (HIFU)-based histotripsy. Methods Atomic force microscopy investigation for cell mechanics, multiple parametric simulations (DICOM/FEM analysis, MATLAB conversion to PZFLEX/ONSCALE). Results Individual tumor cell evaluation of physical properties as basis for multiple parametric simulations determine the optimal treatment parameters (total energy required, energy flux density, shock wave frequency) and applicator positions; design flexibility of applicator devices for extra- and intracorporeal treatment. Conclusion The fundamental feasibility and reliability of our approach were proven in tumor cells providing a reliable basis for the translation into clinical applications. Shock wave treatment of tumors Mechanics of cancer cells Computational simulation of shock wave propagation Tumor cell response Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Our primary intention was to search for an innovative option to treat malignant tumors using a physical method which is not toxic, bears no radiation risk, is not or only mildly traumatic, relies on clear physical rules and engineering standards, and is cheap and simple enough that it can be applied in general hospitals and not only in sophisticated clinical centers. Therapeutic propagation of alternating mechanical fields – ultrasound waves or shock waves – aims to deliver high-energy pulses in a spatially coordinated manner. The aim is to transfer focused energy to target tumor tissue, whether superficially situated or deep in the human body, without causing harm to surrounding tissues. The first author, A.E. Theuer who is engineer with broad experience of computational simulation of vibration technology in industry, because of a tumor case in the family, started from a study on vibration-induced destruction of malignant cells (Theuer 1998) more than a quarter century ago. For related questions about tumor biology supported by G.F. Walter from the beginning, since 2009 various patents by the authors (Theuer and Walter 2009, 2010a, 2010b; Theuer 2016; Theuer AE and Theuer I 2023) mirror the ever-improving understanding of the biological, physico-mechanical and engineering preconditions for the treatment of tumors in alternating fields. Ultrasound is characterized by a continuous wave typically with numerous periodic oscillations within a narrow bandwidth. Shock waves, on the other hand, are represented by a single positive pressure pulse, followed by a comparatively small tensile wave of lower amplitude; such a pulse contains frequencies from a few hertz to more than 10 megahertz, the pressure amplitudes are particularly large, so that a splitting effect due to nonlinearities of the propagation medium, e.g. human tissue, occurs. Shock waves are generated by electrohydraulic, electromagnetic or piezoelectric transducers to deliver high-energy pulses in a spatially coordinated manner. Different from ultrasound waves, shock waves - due to their singular pressure pulse - have no thermal effect. This physico-mechanical difference between ultrasound or shock waves has consequences for the respective therapeutic applicability. Ultrasound has gained increasing importance as an option for the therapy of various diseases including tumors. The U.S. Food and Drug Administration recently authorized a new high intensity focused ultrasound (HIFU)-based technology called histotripsy (Bader et al.2019; Bachu et al. 2021; Xu et al. 2021; Williams et al. 2023; Matthews and Stretanski 2024) which is similar to the here presented soft focused shock wave treatment by using sound waves, but quite different with regard to the physico-mechanial approach. Histotripsy has an intended destructive impact on tumor cells by periodic oscillations at high frequencies causing cytoplasmic cavitation bubbles and, thereby as potentially unintended side effects may boil the tumor cells and lead to coagulation of tumor antigens. Soft focused shock wave treatment at low frequencies (1-30 Hz) propagates high pressure amplitudes with a steepening effect, followed by negative pressure exerting strain on the cell membranes; overstretched membranes lead to immunologically presentable cell fragments without exerting a thermal effect. Soft focused shock wave treatment relies on clear physico-mechanical rules and engineering standards, is not toxic, bears no radiation risk, is not traumatic to surrounding tissue, and avoids extensive pressure load or extremely high temperature. Based on experimental evaluation of cell mechanics and using multiple computational parametric simulation models, we aim to elucidate underlying mechanisms by which soft focused shock wave treatment exerts its optimal effects on tumor cells, and if these effects might be sufficiently effective to offer options for combination with standard cancer care regimens or even to eventually replace other modalities in comprehensive cancer care regimens. Physico-mechanical preconditions In malignant tumors, nuclear polymorphism including polyploid multinucleated giant cells occurs. In normal cells and tumor cells, the nucleus and the overall architecture of the cytoskeleton influence cell mechanics (Denais and Lammerding 2014; Grady et al. 2016). The highly dynamic and cross-linked cytoskeletal structure of actin filaments and microtubules in the cytoplasm particularly influences cell mechanics (Ketene et al. 2012). The cytoskeletal structure is disturbed, resulting in clumped and less bundled actin filaments on the inner surface of the cell membrane (Calzado-Martin 2016). There is a distinct dynamic behavior of malignant and healthy cells. Polarized epithelial cells can undergo a transition characterized by the loss of cell-cell junctions and increased migratory activity into non-polarized invasive cells. Such transitions have been linked to cancer cell metastasis (Vargas et al. 2013). By palpation, obviously due to tumor stroma, tumors appear more rigid than their surrounding environment. Paradoxically, comparing the mechanics of individual normal and cancer cells, individual cancer cells are softer than their healthy counterparts on average (Alibert et al. 2017). Methods By atomic force microscopy (AFM) studies the mechanical properties of human cells can be quantified (Li et al. 2021; Schächtele et al. 2021). For human fibroblasts and BLM melanoma cells, imaging of single cells was performed in the force mapping mode (Jiao and Schäffer 2004) using a cantilever with a nominal spring constant of 0.02 N/m (BioLever, Olympus, Melville, NY). For each single cell a mean elastic modulus was calculated by averaging the local elastic modulus over the cell area. To minimize the influence of the underlying substrate, only elastic modulus values for cell areas with a height above 1 µm were considered. Mean elastic moduli of 19 cells were averaged to obtain one representative elastic modulus 〈 E 〉 for each cell line. Results The mean elastic modulus is significantly lower for BLM melanoma cells than for human fibroblasts (figure 1). This finding of softer cancerous cells in comparison to normal cells is in line with previous AFM studies (Schierbaum et al. 2017). Parametric Simulation Methods To ensure a broad applicability for future clinical studies in various institutions, we exclusively used commercially available established programs. First, it is essential to prepare personalized DICOM (Digital Imaging and Communications in Medicine) data with segmentation procedures and FEM (finite element model) analysis for each patient. The DICOM data for each individual patient were by MATLAB/TABLIN converted to PZFLEX/ONSCALE, an explicit time-domain solver for the analysis of shock wave propagation. Second, the DICOM tissue segmentation data generated by Synopsys-Simpleware were transferred to ANSYS Explicit Dynamics. At the tissue border, an electrohydraulic shock wave generator is incorporated into FEM through the ANSYS space-claim module. Third, the time function of pressure fields at the edges of the tumor region was applied to a micromechanics FEM model of cellular structures. The numerical solution of the FEM model provides the time function of the pressure fields at each point within the tissue. Based on the physical values and the geometry of the tumor cells determined by AFM, strains in tumor cells can be simulated. Results For the mathematical description of the complex processes of shock wave propagation, FEM models are particularly adequate since the distribution of strains during and after the shock wave propagation can be simulated on the cellular and the subcellular levels (figure 2). Simulating the DICOM/FEM data on a basis of MRI/CT data of an individual patient can be visualized for entire body regions of that patient (figure 3). The numerical solution of the FEM propagation models provides patient-specific treatment parameters, including total energy required, energy flux density, shock wave frequency, and total number and sequence of shock waves as well as the optimal applicator positions resulting from multiple parametric simulations. Technical applicator design For clinical applications, in most cases extracorporeal devices can be used. The device for soft focused shock wave treatment of malignant tumors is technically characterized by different standard components: capacitive discharge control, shock wave generator, shock wave treatment applicator, reflector, and device location system (figure 4). Transcranial application for the treatment of intracranial tumors is possible. The arrangement of multiple applicators in a ring shape can focus the energy within the tumor and minimizes the energy load in the surrounding brain tissue (figure 5). Using inner body surfaces for soft focused shock wave treatment, the technical components can be adapted depending on the anatomical tumor location for better accessibility, for instance, as miniature electrohydraulic device suitable for the direct treatment of colon carcinoma, or for indirect treatment of urothelial carcinoma with propagation of shock waves via urine (figure 6). In anatomical situations where a positioning of applicators on outer or inner body surfaces is not possible, intracorporeal applicators could also be positioned by means of minimally invasive “keyhole” surgery, Optimal positioning of the applicator can be determined by individual 3D-MRT/CT-DICOM evaluation (figure 7). Discussion The primary technical objective of the soft focused shock wave propagation calculation is to ascertain precise pressure fields at all points of the treated tumor tissue and the quantity of absorbed energy throughout the entire treatment. This prevents damage to the surrounding healthy tissue and guarantees patient safety. Computational analysis of shock wave propagation in cellular structures based on AFM-data shows that the cytoskeletal filaments of malignant tumor cells stretch significantly more than those in healthy cells after the first shock wave impingement. The rate of re-stretching of tumor cells is slower than that of healthy cells. The second and subsequent shock waves, delivered before complete re-stretching, lead to additional disruptive stretching. In malignant tumors, mechanical changes are driven by expansion of the growing tumor mass as well as by alterations to the material properties of the surrounding extracellular matrix. Tumors often tend to be stiffer than the surrounding uninvolved tissue, yet the tumor cells themselves are often softer than the healthy cells. The stretching rate is critical in the apoptotic impairment of tumor cells. Furthermore, shock waves lead not only to cell membrane stretching, but also to tumor cell fragmentation and, thereby, to release of still viable tumor antigens within the cell fragments, which eventually may initiate an activation of the adaptive immune system. This question is tested and proven in animal experiments and investigated in the clinical application of soft focused shock wave treatment (Theuer et al., 2025 ). Conclusions Soft focused shock wave treatment reliably induces overstretching of tumor cell membranes leading to disruptive impairment of tumor cells and eventually to apoptosis. It is possible to determine optimal treatment parameters by computational simulation. Soft focused shock wave treatment may be seen as an additional option for comprehensive cancer care, either in combination with existing treatment modalities or eventually as single treatment option. Declarations Competing Interests The authors declare that they have no competing interest. Funding The development of specific simulation programs by A.E. Theuer was supported by AiF Arbeitsgemeinschaft industrieller Forschungsvereinigungen (grant number KF3356302AK4), and Zentrales Innovationsprogramm Mittelstand (grant number ZF4803001BA9). Author Contribution A.E. Theuer and G.F. Walter, with support from F. Lang, initiated investigations into the treatment of cancer in alternating mechanical fields.A.E. Theuer elaborated the computational parameters for simulation and drew up the engineering preconditions for the construction of application devices.A.E. Theuer and G.F. Walter conceptualized and proved the principal biological feasibility of the treatment of cancer in alternating mechanical fields comparing the behavior of tumor cells and healthy cells in cell cultures and tissue samples.N. Schierbaum and T. Schäffer performed and evaluated the atomic force measurements.H. Niessner, T. Sinnberg and F. Meraz-Torres evaluated cell reactions to shock wave treatment by flow cytometric analysis and provided clinical background for the design of application devices.H. Niessner, T. Sinnberg, F. Meraz-Torres, T.K. Eigentler transformed the conception into the actual clinical application of soft focused shock wave treatment for patients suffering from malignant tumors.G.F. Walter wrote the manuscript.All authors reviewed the manuscript. Data Availability The data supporting the findings of experimental results are available from the corresponding author upon reasonable request. References Alibert C, Goud B, Manneville JB (2017) Are cancer cells really softer than normal cells? Biol Cell 109:167–189. https://doi.org/10.1111/boc.201600078 Bachu VS, Kedda J, Suk I, Green JJ, Tyler B (2021) High-intensity focused ultrasound: a review of mechanisms and clinical applications. Ann Biomed Eng 49:1975–1991. https://doi.org/10.1007/s10439-021-02833-9 Bader KB, Vlaisavljevich E, Maxwell AD (2018) For Whom the Bubble Grows: Physical Principles of Bubble Nucleation and Dynamics in Histotripsy Ultrasound Therapy. Ultrasound Med Biol 45:1056–1080. https://doi.org/10.1016/j.ultrasmedbio.2018.10.035 Bilodeau GG (1992) Regular pyramid punch problem. J Appl Mech 59:519–523 Calzado-Martín A, Encinar M, Tamayo J, Calleja M, San Paulo A (2016) Effect of actin organization on the stiffness of living breast cancer cells revealed by peak-force modulation atomic force microscopy. ACS Nano 10:3365–3374. https://doi.org/10.1021/acsnano.5b07162 Denais C, Lammerding J (2014) Nuclear mechanics in cancer. Adv Exp Med Biol 773:435–470. https://doi.org/10.1007/978-1-4899-8032-8_20 Grady ME, Composto RJ, Eckmann DM (2016) Cell elasticity with altered cytoskeletal architectures across multiple cell types. J Mech Behav Biomed Mater 61:197–207. https://doi.org/10.1016/j.jmbbm.2016.01.022 Jiao Y, Schäffer TE (2004) Accurate height and volume measurements on soft samples with the atomic force microscope. Langmuir 20:10038–10045. https://doi.org/10.1021/la048650u Ketene AN, Roberts PC, Shea AA, Schmelz EM, Agah M (2012) Actin filaments play a primary role for structural integrity and viscoelastic response in cells. Integr Biol (Camb) 4:540–549. https://doi.org/10.1039/c2ib00168c Li M, Xi N, Wang YC, Liu LQ (2021) Atomic force microscopy for revealing micro/nanoscale mechanics in tumor metastasis: from single cells to microenvironmental cues. Acta Pharmacol Sin 42:323–339. https://doi.org/10.1038/s41401-020-0494-3 Matthews MJ, Stretanski MF (2024) Ultrasound Therapy. StatPearls Publishing, Treasure Island (FL). PMID: 31613497 Schächtele M, Kemmler J, Rheinlaender J, Schäffer TE (2021) Combined high-speed atomic force and optical microscopy shows that viscoelastic properties of melanoma cancer cells change during the cell cycle. Adv Mater Technol 2021:2101000. https://doi.org/10.1002/admt.202101000 Schierbaum N, Rheinlaender J, Schäffer TE (2017) Viscoelastic properties of normal and cancerous human breast cells are affected differently by contact to adjacent cells. Acta Biomater 55:239–248. https://doi.org/10.1016/j.actbio.2017.04.006 Theuer AE (1998) Selektive, schwingungsinduzierte Zerstörung maligner Zellen [Selective, vibration-induced destruction of malignant cells]. Biomed Tech (Berl) 43:304–305. https://doi.org/10.1515/bmte.1998.43.s1.304 . German Theuer AE (2016) Device for treating malignant diseases with the help of tumor-destructive mechanical pulses (TMI). U.S. Patent 20200038694. https//patents.justia.com/inventor/axel-erich-theuer Theuer AE, Walter GF (2009) Device and arrangement for destroying tumor cells and tumor tissue. German Patent WO002009156156A1. https://depatisnet.dpma.de/DepatisNet/depatisnet?action=bibdat&docid=WO002009156156A1 Theuer AE, Walter GF (2010a) Apparatus for the destruction of tumor cells or pathogens in the blood stream. German Patent WO002010406A1. https://depatisnet.dpma.de/DepatisNet/depatisnet?action=bibdat&docid=WO002010020406A1 Theuer AE, Walter GF (2010b) Medical device for treating tumor tissue. German Patent WO 002010049176a1. https://depatisnet.dpma.de/DepatisNet/depatisnet?action=bibdat&docid=WO002010049176A1 Theuer AE, Theuer I (2023) Device for treating malignant diseases with the help of tumor-destructive mechanical pulses (TMI). U S Patent 11,752,365 B2. https//patents.justia.com/inventor/axel-erich-theuer Theuer AE, Borkmann M, Thomas I, Niessner H, Meraz-Torres F, Sinnberg TW, Lang F, Strassmann G†, Eigentler TK, Walter GF (2025) Soft focused shock wave treatment of solid tumors. Part II: Biological feasibility, clinical application and immunological abscopal effect J Cancer Res Clin Oncol (submitted) Vargas DA, Bates O, Zaman MH (2013) Computational model to probe cellular mechanics during epithelial-mesenchymal transition. Cells Tissues Organs 197:435–444. https://doi.org/10.1159/000348415 Williams RP, Simon JC, Khokhlova VA, Sapozhnikov OA, Khokhlova TD (2023) The histotripsy spectrum: differences and similarities in techniques and instrumentation. Int J Hyperth 40:2233720. https://doi.org/10.1080/02656736.2023.2233720 Xu Z, Hall TL, Vlaisavljevich E, Lee FT Jr (2021) Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound. Int J Hyperth 38:561–575. https://doi.org/10.1080/02656736.2021.1905189 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6184724","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":427948682,"identity":"276230ea-b39a-4ba9-920e-d0abab18dcd2","order_by":0,"name":"Axel Erich Theuer","email":"","orcid":"","institution":"Charité University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Axel","middleName":"Erich","lastName":"Theuer","suffix":""},{"id":427948683,"identity":"2e4d7334-9457-4b1c-b44c-ebfe06131c86","order_by":1,"name":"Nicolas Schierbaum","email":"","orcid":"","institution":"University of Tübingen","correspondingAuthor":false,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"Schierbaum","suffix":""},{"id":427948684,"identity":"3a876670-fac2-4bb7-a3fa-58251c112885","order_by":2,"name":"Heike Niessner","email":"","orcid":"","institution":"University of Tübingen","correspondingAuthor":false,"prefix":"","firstName":"Heike","middleName":"","lastName":"Niessner","suffix":""},{"id":427948685,"identity":"abcc6674-5a07-47dd-a299-f24ca1063edc","order_by":3,"name":"Francisco Meraz-Torres","email":"","orcid":"","institution":"University of Tübingen","correspondingAuthor":false,"prefix":"","firstName":"Francisco","middleName":"","lastName":"Meraz-Torres","suffix":""},{"id":427948686,"identity":"18260c65-5f54-4a40-b5a0-bbfa2d64ebf4","order_by":4,"name":"Tobias W. 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Eigentler","email":"","orcid":"","institution":"Charité University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"K.","lastName":"Eigentler","suffix":""},{"id":427948690,"identity":"f92e37e3-273d-4d3d-b289-5b381afdcf7d","order_by":8,"name":"Gerhard Franz Walter","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYDAC5gNAogCI2RvAXCK0sCUACQMDBgaeAyRrkUggUou8GwObxA+DP3LmM59f3czDYC1HUIvhMQY2yR4DA2OZ2zllN2cwpBsT1jK/ge0Gj4FB4gzpnLQbHxgOJzYQ1NLGwHbzj4FB/QzJM2k3EhgO1xPUIs/GwHYbaEuChAT7MZAtCQQdZsDG2P5bxsDYcAZPDtvNGQbphoRtaWM+bPimQk5egv34s9s8FdbyhG05wAgzlgcYOQYENQBtQbiD/QER6kfBKBgFo2AkAgCqijdnb3sHcQAAAABJRU5ErkJggg==","orcid":"","institution":"International Neuroscience Institute","correspondingAuthor":true,"prefix":"","firstName":"Gerhard","middleName":"Franz","lastName":"Walter","suffix":""}],"badges":[],"createdAt":"2025-03-08 14:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6184724/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6184724/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78913715,"identity":"689d22c4-bdea-4bdb-aae6-8ec14d542ec9","added_by":"auto","created_at":"2025-03-20 17:45:25","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":764494,"visible":true,"origin":"","legend":"\u003cp\u003eAFM investigation to compare the mechanical properties of human fibroblasts with BLM melanoma cells. \u003cstrong\u003eA, A’:\u003c/strong\u003eRepresentative images of optical fluorescence (actin green, cell nucleus blue). \u003cstrong\u003eB, B’:\u003c/strong\u003e AFM contact height. \u003cstrong\u003eC, C’:\u003c/strong\u003e AFM elastic modulus (softer regions are darker) for a human fibroblast (left column) and a BLM melanoma cell (right column). \u003cstrong\u003eD: \u003c/strong\u003eAFM force mapping principle whereby a 2D-raster pattern of force-distance curves is recorded on a cell. \u003cstrong\u003eE:\u003c/strong\u003eForce-distance curve (solid red curve) was fitted (dashed black curve) by applying Bilodeau's modified Hertz model for a pyramidal tip (Bilodeau 1992) to obtain the local elastic modulus \u003cem\u003eE\u003c/em\u003e. \u003cstrong\u003eF:\u003c/strong\u003e In comparison to human fibroblasts, the geometric mean of the elastic modulus 〈\u003cem\u003eE\u003c/em\u003e〉(\u003cem\u003en\u003c/em\u003e = 19/group) of BLM melanoma cells is significantly lower (Student’s t-test, ***p\u0026lt;0.001). Error bars denote geometric SEM. The scale bar in the images is 20 µm.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/54929013c5d63acfac3299d1.jpeg"},{"id":78914156,"identity":"5cc57168-83e3-41c7-8d92-1e1fbad79e80","added_by":"auto","created_at":"2025-03-20 17:53:25","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":773974,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAbove:\u003c/strong\u003eBLM melanoma cell structure image imported from AFM (left) to FEM nonlinear shockwave propagation model (center) and shock wave propagation through the cell structures at 9 ns after induced shock waves at FEM model border (right). \u003cstrong\u003eBelow:\u003c/strong\u003e After induced shock waves at FEM model border (left), simulation of shock wave propagation over time through cellular filamentous microstructure generating strains at t = 4 ns (center) and t = 8 ns (right).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/0b1d403232f0273fe752788a.jpeg"},{"id":78914158,"identity":"cc332096-8067-4715-b671-481a7064d1bb","added_by":"auto","created_at":"2025-03-20 17:53:25","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":373580,"visible":true,"origin":"","legend":"\u003cp\u003eSimulated effect of shock wave propagation. \u003cstrong\u003eLeft:\u003c/strong\u003e Initial situation based on MRI/CT data. \u003cstrong\u003e1-\u003c/strong\u003e patient DICOM/FEM data of an intrathoracic tumor (yellow), \u003cstrong\u003e2-\u003c/strong\u003e shock wave generator. \u003cstrong\u003eCenter:\u003c/strong\u003e Propagation of discharged shock waves. \u003cstrong\u003e1\u003c/strong\u003e- exerting positive pressure, \u003cstrong\u003e2\u003c/strong\u003e- reflector of the electrohydraulic device. \u003cstrong\u003eRight:\u003c/strong\u003e After discharge. \u003cstrong\u003e1\u003c/strong\u003e- generator, \u003cstrong\u003e2\u003c/strong\u003e- primary wave, \u003cstrong\u003e3-\u003c/strong\u003e reflected wave exerting negative strains, \u003cstrong\u003e4- \u003c/strong\u003ereflector.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/169e1038bf35c937544345ba.jpeg"},{"id":78914157,"identity":"24f8e4af-3930-4c67-bf90-2920ad4d6769","added_by":"auto","created_at":"2025-03-20 17:53:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":86931,"visible":true,"origin":"","legend":"\u003cp\u003eComponents of a device for extracorporeal soft focused shock wave treatment of pancreatic carcinoma. \u003cstrong\u003e1-\u003c/strong\u003epatient DICOM data, \u003cstrong\u003e2- \u003c/strong\u003epatient rigid body, \u003cstrong\u003e3-\u003c/strong\u003e optical localization, \u003cstrong\u003e4-\u003c/strong\u003e treatment applicator rigid body, \u003cstrong\u003e5-\u003c/strong\u003e applicator, \u003cstrong\u003e6-\u003c/strong\u003e FEM simulation model that considers the patient's specific shock wave propagation\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/22493301b881cdd5ccd6937e.png"},{"id":78913711,"identity":"832d458e-aa45-48d1-8d05-998480b057e8","added_by":"auto","created_at":"2025-03-20 17:45:25","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":742672,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAbove: \u003c/strong\u003eComponents of a device for extracorporeal soft focused shock wave treatment of brain tumors. \u003cstrong\u003e1-\u003c/strong\u003e patient DICOM data, \u003cstrong\u003e2- \u003c/strong\u003epatient rigid body, \u003cstrong\u003e3-\u003c/strong\u003e optical localization, \u003cstrong\u003e4-\u003c/strong\u003e treatment applicator rigid body, \u003cstrong\u003e5-\u003c/strong\u003e applicator, \u003cstrong\u003e6-\u003c/strong\u003e DICOM-MATLAB-ONSCALE-FEM simulation model, 7- DICOM-MATLAB-ONSCALE conversion\u003cstrong\u003e. Below left: \u003c/strong\u003eSingle applicator; patient DICOM data for the MATLAB-ONSCALE-FEM simulation analysis for shock wave propagation within the area of a frontal brain tumor (yellow). \u003cstrong\u003eRight:\u003c/strong\u003e Multiple applicators arranged in a ring shape for the treatment of intracranial tumors.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/7c6c03e50f120580dbf18cf4.jpeg"},{"id":78913716,"identity":"4b9ae38d-3f65-4b25-9462-6a2fad3f75b8","added_by":"auto","created_at":"2025-03-20 17:45:25","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":91011,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLeft: \u003c/strong\u003eComponents of a device for direct intracorporeal soft focused shock wave treatment of colon carcinoma.\u003cstrong\u003e 1- i\u003c/strong\u003entestinal wall, \u003cstrong\u003e2-\u003c/strong\u003e tumor area, \u003cstrong\u003e3- \u003c/strong\u003ehead of the shock wave miniature device with protective cover and miniature camera (not shown), \u003cstrong\u003e5-\u003c/strong\u003e endoscope for colonoscopy. \u003cstrong\u003eRight:\u003c/strong\u003e Device for indirect intracorporeal soft focused shock wave treatment of urothelial carcinoma. \u003cstrong\u003e1-\u003c/strong\u003e tumor area, \u003cstrong\u003e2-\u003c/strong\u003e urinary bladder wall, \u003cstrong\u003e3-\u003c/strong\u003eapplicator, \u003cstrong\u003e4-\u003c/strong\u003e prostate.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/5c97d2898aeb1623b01f57ce.png"},{"id":78914159,"identity":"fb87ef1b-8bb1-4a87-825b-c7299d91811e","added_by":"auto","created_at":"2025-03-20 17:53:25","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":485436,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLeft: \u003c/strong\u003eIndividual 3D-MRT/CT-DICOM determination for positioning (1, 2, 3) of the treatment applicator. \u003cstrong\u003eRight:\u003c/strong\u003e Treatment situation with extracorporeal device for soft focused shock wave treatment.\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/537296c55b8308e330bb51b4.jpeg"},{"id":79181177,"identity":"d4ffe59c-cc08-4826-89b9-af5073c5332a","added_by":"auto","created_at":"2025-03-25 10:32:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3836818,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6184724/v1/9f79a912-f393-4d9e-b67a-5da11e21d2c3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Soft Focused Shock Wave Treatment of Solid Tumors. Part I: Physico-mechanical Preconditions, Parametric Simulation and Technical Applicator Design","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOur primary intention was to search for an innovative option to treat malignant tumors using a physical method which is not toxic, bears no radiation risk, is not or only mildly traumatic, relies on clear physical rules and engineering standards, and is cheap and simple enough that it can be applied in general hospitals and not only in sophisticated clinical centers.\u003c/p\u003e\n\u003cp\u003eTherapeutic propagation of alternating mechanical fields – ultrasound waves or shock waves – aims to deliver high-energy pulses in a spatially coordinated manner.\u0026nbsp;The aim is to transfer focused energy to target tumor tissue, whether superficially situated or deep in the human body, without causing harm to surrounding tissues.\u003c/p\u003e\n\u003cp\u003eThe first author, A.E. Theuer who is engineer with broad experience of computational simulation of vibration technology in industry, because of a tumor case in the family, started from a study on\u0026nbsp;vibration-induced destruction of malignant cells\u0026nbsp;(Theuer 1998) more than a quarter century ago. For related questions about tumor biology supported by G.F. Walter from the beginning, since 2009 various patents by the authors (Theuer and Walter 2009, 2010a, 2010b; Theuer 2016; Theuer AE and Theuer I 2023) mirror the ever-improving understanding of the biological, physico-mechanical and engineering preconditions for the treatment of tumors in alternating fields.\u003c/p\u003e\n\u003cp\u003eUltrasound is characterized by a continuous wave typically with numerous periodic oscillations within a narrow bandwidth. Shock waves, on the other hand, are represented by a single positive pressure pulse, followed by a comparatively small tensile wave of lower amplitude; such a pulse contains frequencies from a few hertz to more than 10 megahertz, the pressure amplitudes are particularly large, so that a splitting effect due to nonlinearities of the propagation medium, e.g. human tissue, occurs. Shock waves are generated by electrohydraulic, electromagnetic or piezoelectric\u0026nbsp;transducers to deliver high-energy pulses in a spatially coordinated manner.\u0026nbsp;Different from ultrasound waves, shock waves - due to their singular pressure pulse - have no thermal effect.\u0026nbsp;This physico-mechanical difference between ultrasound or shock waves has consequences for the respective therapeutic applicability.\u003c/p\u003e\n\u003cp\u003eUltrasound has gained increasing importance as an option for the therapy of various diseases including tumors. The U.S. Food and Drug Administration recently authorized a new high intensity focused ultrasound (HIFU)-based technology called histotripsy (Bader et al.2019; Bachu et al. 2021; Xu et al. 2021; Williams et al. 2023; Matthews and Stretanski 2024) which is similar to the here presented soft focused shock wave treatment by using sound waves, but quite different with regard to the physico-mechanial approach. Histotripsy has an intended destructive impact on tumor cells by periodic oscillations at high frequencies causing cytoplasmic cavitation bubbles and, thereby as potentially unintended side effects may boil the tumor cells and lead to coagulation of tumor antigens.\u003c/p\u003e\n\u003cp\u003eSoft focused shock wave treatment at low frequencies (1-30 Hz) propagates high pressure amplitudes with a steepening effect, followed by negative pressure exerting strain on the cell membranes; overstretched membranes lead to immunologically presentable cell fragments without exerting a thermal effect. Soft focused shock wave treatment relies on clear physico-mechanical rules and engineering standards, is not toxic, bears no radiation risk, is not traumatic to surrounding tissue, and avoids extensive pressure load or extremely high temperature.\u003c/p\u003e\n\u003cp\u003eBased on experimental evaluation of cell mechanics and using multiple computational parametric simulation models, we aim to elucidate underlying mechanisms by which soft focused shock wave treatment exerts its optimal effects on tumor cells, and if these effects might be sufficiently effective to offer options for combination with standard cancer care regimens or even to eventually replace other modalities in comprehensive cancer care regimens.\u003c/p\u003e"},{"header":"Physico-mechanical preconditions","content":"\u003cp\u003eIn malignant tumors, nuclear polymorphism including polyploid multinucleated giant cells occurs. In normal cells and tumor cells, the nucleus and the overall architecture of the cytoskeleton influence cell mechanics (Denais and Lammerding 2014; Grady et al. 2016). The highly dynamic and cross-linked cytoskeletal structure of actin filaments and microtubules in the cytoplasm particularly influences cell mechanics (Ketene et al. 2012). The cytoskeletal structure is disturbed, resulting in clumped and less bundled actin filaments on the inner surface of the cell membrane (Calzado-Martin 2016). There is a distinct dynamic behavior of malignant and healthy cells. Polarized epithelial cells can undergo a transition characterized by the loss of cell-cell junctions and increased migratory activity into non-polarized invasive cells. Such transitions have been linked to cancer cell metastasis (Vargas et al. 2013). By palpation, obviously due to tumor stroma, tumors appear more rigid than their surrounding environment. Paradoxically, comparing the mechanics of individual normal and cancer cells, individual cancer cells are softer than their healthy counterparts on average (Alibert et al. 2017).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBy atomic force microscopy (AFM) studies the mechanical properties of human cells can be quantified (Li et al. 2021; Sch\u0026auml;chtele et al. 2021). For human fibroblasts and BLM melanoma cells, imaging of single cells was performed in the force mapping mode (Jiao and Sch\u0026auml;ffer 2004) using a cantilever with a nominal spring constant of 0.02 N/m (BioLever, Olympus, Melville, NY).\u0026nbsp;For each single cell a mean elastic modulus was calculated by averaging the local elastic modulus over the cell area. To minimize the influence of the underlying substrate, only elastic modulus values for cell areas with a height above 1 \u0026micro;m were considered. Mean elastic moduli of 19 cells were averaged to obtain one representative elastic modulus\u0026nbsp;〈\u003cem\u003eE\u003c/em\u003e〉\u0026nbsp;for each cell line.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean elastic modulus is significantly lower for BLM melanoma cells than for human fibroblasts (figure 1). This finding of softer cancerous cells in comparison to normal cells is in line with previous AFM studies (Schierbaum et al. 2017).\u0026nbsp;\u003c/p\u003e"},{"header":"Parametric Simulation","content":"\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure a broad applicability for future clinical studies in various institutions, we exclusively used commercially available established programs.\u003c/p\u003e\n\u003cp\u003eFirst, it is essential to prepare personalized DICOM (Digital Imaging and Communications in Medicine) data with segmentation procedures and FEM (finite element model) analysis for each patient. The DICOM data for each individual patient were by MATLAB/TABLIN converted to PZFLEX/ONSCALE, an explicit time-domain solver for the analysis of shock wave propagation.\u003c/p\u003e\n\u003cp\u003eSecond, the DICOM tissue segmentation data generated by Synopsys-Simpleware were transferred to ANSYS Explicit Dynamics. At the tissue border, an electrohydraulic shock wave generator is incorporated into FEM through the ANSYS space-claim module.\u003c/p\u003e\n\u003cp\u003eThird, the time function of pressure fields at the edges of the tumor region was applied to a micromechanics FEM model of cellular structures. The numerical solution of the FEM model provides the time function of the pressure fields at each point within the tissue. Based on the physical values and the geometry of the\u0026nbsp;tumor\u0026nbsp;cells\u0026nbsp;determined by AFM, strains in tumor cells can be simulated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the mathematical description of the complex processes of shock wave propagation, FEM models are particularly adequate since the distribution of strains during and after the shock wave propagation can be simulated on the cellular and the subcellular levels (figure 2).\u003c/p\u003e\n\u003cp\u003eSimulating the DICOM/FEM data on a basis of MRI/CT data of an individual patient can be visualized for entire body regions of that patient (figure 3).\u003c/p\u003e\n\u003cp\u003eThe numerical solution of the FEM propagation models provides patient-specific treatment parameters, including total energy required, energy flux density, shock wave frequency, and total number and sequence of shock waves as well as the optimal applicator positions resulting from multiple parametric simulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTechnical applicator design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor clinical applications, in most cases extracorporeal devices can be used. The device for soft focused shock wave treatment of malignant tumors is technically characterized by different standard components: capacitive discharge control, shock wave generator, shock wave treatment applicator, reflector, and device location system (figure 4).\u003c/p\u003e\n\u003cp\u003eTranscranial application for the treatment of intracranial tumors is possible. The arrangement of multiple applicators in a ring shape can focus the energy within the tumor and minimizes the energy load in the surrounding brain tissue (figure 5).\u003c/p\u003e\n\u003cp\u003eUsing inner body surfaces for soft focused shock wave treatment, the technical components can be adapted depending on the anatomical tumor location for better accessibility, for instance, as miniature electrohydraulic device suitable for the direct treatment of colon carcinoma, or for indirect treatment of urothelial carcinoma with propagation of shock waves via urine (figure 6).\u003c/p\u003e\n\u003cp\u003eIn anatomical situations where a positioning of applicators on outer or inner body surfaces is not possible, intracorporeal applicators could also be positioned by means of minimally invasive \u0026ldquo;keyhole\u0026rdquo; surgery,\u003c/p\u003e\n\u003cp\u003eOptimal positioning of the applicator can be determined by individual 3D-MRT/CT-DICOM evaluation (figure 7).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe primary technical objective of the soft focused shock wave propagation calculation is to ascertain precise pressure fields at all points of the treated tumor tissue and the quantity of absorbed energy throughout the entire treatment. This prevents damage to the surrounding healthy tissue and guarantees patient safety.\u003c/p\u003e \u003cp\u003eComputational analysis of shock wave propagation in cellular structures based on AFM-data shows that the cytoskeletal filaments of malignant tumor cells stretch significantly more than those in healthy cells after the first shock wave impingement. The rate of re-stretching of tumor cells is slower than that of healthy cells. The second and subsequent shock waves, delivered before complete re-stretching, lead to additional disruptive stretching.\u003c/p\u003e \u003cp\u003eIn malignant tumors, mechanical changes are driven by expansion of the growing tumor mass as well as by alterations to the material properties of the surrounding extracellular matrix. Tumors often tend to be stiffer than the surrounding uninvolved tissue, yet the tumor cells themselves are often softer than the healthy cells. The stretching rate is critical in the apoptotic impairment of tumor cells.\u003c/p\u003e \u003cp\u003eFurthermore, shock waves lead not only to cell membrane stretching, but also to tumor cell fragmentation and, thereby, to release of still viable tumor antigens within the cell fragments, which eventually may initiate an activation of the adaptive immune system. This question is tested and proven in animal experiments and investigated in the clinical application of soft focused shock wave treatment (Theuer et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eSoft focused shock wave treatment reliably induces overstretching of tumor cell membranes leading to disruptive impairment of tumor cells and eventually to apoptosis. It is possible to determine optimal treatment parameters by computational simulation.\u003c/p\u003e \u003cp\u003eSoft focused shock wave treatment may be seen as an additional option for comprehensive cancer care, either in combination with existing treatment modalities or eventually as single treatment option.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe development of specific simulation programs by A.E. Theuer was supported by AiF Arbeitsgemeinschaft industrieller Forschungsvereinigungen (grant number KF3356302AK4), and Zentrales Innovationsprogramm Mittelstand (grant number ZF4803001BA9).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.E. Theuer and G.F. Walter, with support from F. Lang, initiated investigations into the treatment of cancer in alternating mechanical fields.A.E. Theuer elaborated the computational parameters for simulation and drew up the engineering preconditions for the construction of application devices.A.E. Theuer and G.F. Walter conceptualized and proved the principal biological feasibility of the treatment of cancer in alternating mechanical fields comparing the behavior of tumor cells and healthy cells in cell cultures and tissue samples.N. Schierbaum and T. Sch\u0026auml;ffer performed and evaluated the atomic force measurements.H. Niessner, T. Sinnberg and F. Meraz-Torres evaluated cell reactions to shock wave treatment by flow cytometric analysis and provided clinical background for the design of application devices.H. Niessner, T. Sinnberg, F. Meraz-Torres, T.K. Eigentler transformed the conception into the actual clinical application of soft focused shock wave treatment for patients suffering from malignant tumors.G.F. Walter wrote the manuscript.All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e \u003cp\u003eThe data supporting the findings of experimental results are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlibert C, Goud B, Manneville JB (2017) Are cancer cells really softer than normal cells? Biol Cell 109:167\u0026ndash;189. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/boc.201600078\u003c/span\u003e\u003cspan address=\"10.1111/boc.201600078\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBachu VS, Kedda J, Suk I, Green JJ, Tyler B (2021) High-intensity focused ultrasound: a review of mechanisms and clinical applications. 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U S Patent 11,752,365 B2. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps//patents.justia.com/inventor/axel-erich-theuer\u003c/span\u003e\u003cspan address=\"https://patents.justia.com/inventor/axel-erich-theuer\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTheuer AE, Borkmann M, Thomas I, Niessner H, Meraz-Torres F, Sinnberg TW, Lang F, Strassmann G\u0026dagger;, Eigentler TK, Walter GF (2025) Soft focused shock wave treatment of solid tumors. Part II: Biological feasibility, clinical application and immunological abscopal effect\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ Cancer Res Clin Oncol (submitted)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVargas DA, Bates O, Zaman MH (2013) Computational model to probe cellular mechanics during epithelial-mesenchymal transition. 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Int J Hyperth 40:2233720. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/02656736.2023.2233720\u003c/span\u003e\u003cspan address=\"10.1080/02656736.2023.2233720\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu Z, Hall TL, Vlaisavljevich E, Lee FT Jr (2021) Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound. Int J Hyperth 38:561\u0026ndash;575. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/02656736.2021.1905189\u003c/span\u003e\u003cspan address=\"10.1080/02656736.2021.1905189\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Shock wave treatment of tumors, Mechanics of cancer cells, Computational simulation of shock wave propagation, Tumor cell response","lastPublishedDoi":"10.21203/rs.3.rs-6184724/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6184724/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo explore the feasibility of targeted impairment of malignant tumors by application of soft focused shock wave treatment, the physico-mechanical preconditions are investigated. This innovative \u0026ldquo;soft\u0026rdquo; approach is different from the FDA-approved high intensity focused ultrasound (HIFU)-based histotripsy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAtomic force microscopy investigation for cell mechanics, multiple parametric simulations (DICOM/FEM analysis, MATLAB conversion to PZFLEX/ONSCALE).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIndividual tumor cell evaluation of physical properties as basis for multiple parametric simulations determine the optimal treatment parameters (total energy required, energy flux density, shock wave frequency) and applicator positions; design flexibility of applicator devices for extra- and intracorporeal treatment.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe fundamental feasibility and reliability of our approach were proven in tumor cells providing a reliable basis for the translation into clinical applications.\u003c/p\u003e","manuscriptTitle":"Soft Focused Shock Wave Treatment of Solid Tumors. Part I: Physico-mechanical Preconditions, Parametric Simulation and Technical Applicator Design","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-20 17:45:20","doi":"10.21203/rs.3.rs-6184724/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"88ff0069-a13e-4b93-a7fb-fd5bc0dbfaf1","owner":[],"postedDate":"March 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-25T10:23:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-20 17:45:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6184724","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6184724","identity":"rs-6184724","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}