PSI - Issue 49

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2nd International Conference on Medical Devices: Materials, Mechanics and Manufacturing (ICMD3M 2023)

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Medical Devices: Materials, Mechanics and Manufacturing Editorial Sotiris Korossis*, Vadim V. Silberschmidt Medical Devices: Materials, Mechanics and Manufacturing Editorial Sotiris Korossis*, Vadim V. Silberschmidt

© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers © 2023 The Authors. Published by ELSEVIER B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers Keywords: Medical devices; materials; manufacturing; mechanics © 2023 The Authors. Published by ELSEVIER B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers Keywords: Medical devices; materials; manufacturing; mechanics Even in ancient times, medical devices were utilised in Mesopotamia, Egypt, Greece and Rome to aid patient survival and rehabilitation in peace and war. The American Civil war, just before the second industrial revolution, saw a dramatic progress in the development of medical devices to assist the thousands of soldiers wounded in the conflict. In the 20 th century, and through the third and fourth industrial revolutions, there has been a boom of a plethora of medical devices for the musculoskeletal, cardiovascular, nervous, endocrine, respiratory, digestive, urinary, and reproductive systems. Medical devices are a success story of modern engineering, with implantable hip and knee joints, heart valves, vascular stents and grafts, artificial hearts and pacemakers, as well extracorporeal devices, such as artificial lungs and orthotic devices, being routinely used in the clinical setting towards the end of the 20 th century. These advancements also generated a booming industrial sector, especially in the Western world, with an annual global medical devices market size of some USD 500 billion by the turn of the century. The past few decades saw the development of novel emerging technologies and concepts in the form of tissue engineering and regenerative medicine, stem cells, additive manufacturing and bioprinting, biofabrication, bioreactors, in vitro studies and in silico modelling that are not only aimed at developing smarter and personalised therapeutic Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, Leicestershire, LE11 3TU, United Kingdom Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, Leicestershire, LE11 3TU, United Kingdom Even in ancient times, medical devices were utilised in Mesopotamia, Egypt, Greece and Rome to aid patient survival and rehabilitation in peace and war. The American Civil war, just before the second industrial revolution, saw a dramatic progress in the development of medical devices to assist the thousands of soldiers wounded in the conflict. In the 20 th century, and through the third and fourth industrial revolutions, there has been a boom of a plethora of medical devices for the musculoskeletal, cardiovascular, nervous, endocrine, respiratory, digestive, urinary, and reproductive systems. Medical devices are a success story of modern engineering, with implantable hip and knee joints, heart valves, vascular stents and grafts, artificial hearts and pacemakers, as well extracorporeal devices, such as artificial lungs and orthotic devices, being routinely used in the clinical setting towards the end of the 20 th century. These advancements also generated a booming industrial sector, especially in the Western world, with an annual global medical devices market size of some USD 500 billion by the turn of the century. The past few decades saw the development of novel emerging technologies and concepts in the form of tissue engineering and regenerative medicine, stem cells, additive manufacturing and bioprinting, biofabrication, bioreactors, in vitro studies and in silico modelling that are not only aimed at developing smarter and personalised therapeutic

* Corresponding author. Tel.: +44 1509 227651. E-mail address: s.korossis@lboro.ac.uk * Corresponding author. Tel.: +44 1509 227651. E-mail address: s.korossis@lboro.ac.uk

2452-3216 © 2023 The Authors. Published by ELSEVIER B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers 2452-3216 © 2023 The Authors. Published by ELSEVIER B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers

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solutions and care for the individual patient, moving away from the currently dominant one-size-fits-all or even stratified medicine approaches, but also to generate important multiscale model systems to interrogate biological processes in health and disease, and predict the postoperative performance of medical devices prior to their clinical application in the individual patient, without relying on animal testing. This special issue features a cohort of studies that were presented in the 2 nd International Conference on Medical Devices: Materials, Mechanics and Manufacturing (ICMD3M 2023) in Corfu, Greece, and were focused on the development of underpinning technologies for the manufacturing and assessment of a number of different medical devices, ranging from stents and tissue engineering scaffolds to catheters, microfluidic devices and orthotic systems. Most of the featured studies were based on computational and/or in vitro simulations, whilst the manufacturing approaches investigated included additive manufacturing and biofabrication. Specifically, Zhang et al. reported on the development of computational fluid dynamics models for assessing the performance of 3D printed tissue scaffolds within a perfusion bioreactor, whilst Elenskaya et al. modelled the degradation process in TPMS-based polymer PLA scaffolds. Moreover, Moetazedian et al. reported on a novel biofabrication process that was based on microfluidics, Ahmed et al. utilised extrusion additive manufacturing to design and classify compliant geometries in orthotics systems, while Fazzini et al. correlated metal fused filament fabrication parameters and material properties of sintered 17-4PH stainless steel. Mechanical testing of 3D-printed devices was discussed by Marinopoulos et al., using a transtibial prosthetic socket as an example. Patient-specific computational simulations were reported by Ramella et al., Bates et al. and McLennan et al. for planning thoracic endovascular aortic repair, designing cardiac procedures, and assessing the impact of calcification stress during endovascular aortic aneurysm repair, respectively. Using a hybrid in silico/in vitro approach, Stratakos et al. reported on coating transfer in drug-coated balloon angioplasty, while Bridio et al. presented a novel methodology for modelling catheter aspiration in high-fidelity thrombectomy simulations. Finally, Cao et al. developed numerical models for analysis of the high-temperature behaviour of magnesium-hydroxyapatite metal matrix composites. This collection of studies clearly demonstrates the diversity of approaches and the complementarity of methods that underpin the development of medical devices. As the field moves into the era of more personalised solutions for tissue/organ repair/replacement and patient care and rehabilitation, biofabrication, underpinned by computational simulations and additive manufacturing, is poised to generate truly smart devices, with enhanced function and durability, reducing the need for costly revisions and ultimately improving patient experience and therapy.

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Procedia Structural Integrity 49 (2023) 30–36

© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers Abstract Drug-Coated Balloons (DCBs) have shown great promise as a minimally invasive therapeutic option for the treatment of stenotic arteries. However, recent animal studies have highlighted the challenge of limited coating transfer onto the arterial lumen short after the treatment. On this basis, studies have shown that the local transfer of the coating is highly influenced by the interaction between the balloon and the arterial endoluminal surface during balloon inflation. This sheds light on the significance of developing ex vivo strategies for the investigation of coating transfer efficiency. Therefore, this work aimed to propose a hybrid computational and experimental methodology to assess how the Contact Pressure (CP) and concurrent Balloon Stretch (BS) conditions may affect the coating delivery to the artery during the DCB inflation. On one hand, numerical simulations of a generic angioplasty balloon were implemented to study the CP at the balloon-artery interface and simultaneous BS. On the other hand, benchtop experiments of in-house and commercial DCBs were developed to study the effectiveness of local coating delivery after compression with pig aortic endothelium under the range of pressure and stretch values estimated from the numerical simulations. Coupling the effective or non-effective delivery of the coating under specific CP and BS conditions, the numerical simulations may predict the coating transfer maps under various procedure conditions. This approach is expected to provide significant insights for manufacturers of DCBs in terms of coating formulations and angioplasty platform devices. © 2023 The Authors. Published by ELSEVIER B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers Medical Devices: Materials, Mechanics and Manufacturing A Hybrid In Silico & In Vitro Approach To Study Coating Transfer In Drug-Coated Balloon Angioplasty Efstathios Stratakos a , Gianluca Poletti a , Lorenzo Vincenzi a , Edoardo Pedrinazzi a , Francesca Berti a , Lorenza Petrini b, * and Giancarlo Pennati a a Laboratory of Biological Structure Mechanics, Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milano, Italy b Department of Civil and Environmental Engineering, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milano, Italy Abstract Drug-Coated Balloons (DCBs) have shown great promise as a minimally invasive therapeutic option for the treatment of stenotic arteries. However, recent animal studies have highlighted the challenge of limited coating transfer onto the arterial lumen short after the treatment. On this basis, studies have shown that the local transfer of the coating is highly influenced by the interaction between the balloon and the arterial endoluminal surface during balloon inflation. This sheds light on the significance of developing ex vivo strategies for the investigation of coating transfer efficiency. Therefore, this work aimed to propose a hybrid computational and experimental methodology to assess how the Contact Pressure (CP) and concurrent Balloon Stretch (BS) conditions may affect the coating delivery to the artery during the DCB inflation. On one hand, numerical simulations of a generic angioplasty balloon were implemented to study the CP at the balloon-artery interface and simultaneous BS. On the other hand, benchtop experiments of in-house and commercial DCBs were developed to study the effectiveness of local coating delivery after compression with pig aortic endothelium under the range of pressure and stretch values estimated from the numerical simulations. Coupling the effective or non-effective delivery of the coating under specific CP and BS conditions, the numerical simulations may predict the coating transfer maps under various procedure conditions. This approach is expected to provide significant insights for manufacturers of DCBs in terms of coating formulations and angioplasty platform devices. © 2023 The Authors. Published by ELSEVIER B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers Medical Devices: Materials, Mechanics and Manufacturing A Hybrid In Silico & In Vitro Approach To Study Coating Transfer In Drug-Coated Balloon Angioplasty Efstathios Stratakos a , Gianluca Poletti a , Lorenzo Vincenzi a , Edoardo Pedrinazzi a , Francesca Berti a , Lorenza Petrini b, * and Giancarlo Pennati a a Laboratory of Biological Structure Mechanics, Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milano, Italy b Department of Civil and Environmental Engineering, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milano, Italy

* Corresponding author. Tel.: +39-02-2399-4307. E-mail address: lorenza.petrini@polimi.it; * Corresponding author. Tel.: +39-02-2399-4307. E-mail address: lorenza.petrini@polimi.it;

Efstathios Stratakos et al. / Procedia Structural Integrity 49 (2023) 30–36 Efstathios Stratakos et al./ Structural Integrity Procedia 00 (2023) 000 – 000

Keywords: Keywords: Drug-coated balloon angioplasty; Coating transfer; finite element analysis; bench-top experiments

1. Intoduction Cardiovascular diseases are the leading cause of death worldwide, primarily attributed to atherosclerosis, which is a pathological condition affecting the intimal layer of large and medium-sized arteries. Atherosclerosis leads to the development of atheromatous plaque, resulting in the thickening of the arterial wall, narrowing of the arteries and restricting the blood flow through the vessels. To address arterial stenosis, DCBs have emerged as a promising minimally invasive therapeutic intervention. DCBs deliver various types of drugs to the arterial wall to prevent restenosis, initially, during their short inflation time (typically 30-180 seconds), with the aim of inhibiting the proliferation of smooth muscle cells. After balloon deflation, these devices are designed to transfer the drug-coating formulation onto the diseased vessel's endoluminal surface, which acts as a long-term drug repository for the lesion area (Bukka et al. (2018)). The morphological structure of DCBs has the potential to facilitate complete contact between the DCB surface and the stenosed vessel (Tesfamariam, (2016)), enabling uniform drug delivery on the lesion, which is suggested to hinder restenosis (Fanelli et al. (2014)). Despite promising results from certain clinical trials, a number of studies disclosed restrained drug delivery to the vessel (Kempin et al. (2015); Petersen et al. (2013); Seidlitz et al. (2013)). Loss of the balloon’s drug-coating can occur during transportation to the target area, resulting in incomplete coverage of the balloon surface prior to inflation (Speck et al. (2016)). Once inflated in the lesion, the interaction between the DCB and the arterial wall plays a critical role in the efficacy of local coating delivery (Cao et al. (2022)). Recent animal studies have shown limited coating adherence to the luminal wall shortly after DCB intervention (Tzafriri et al. (2020)), indicating the need for further enhancement of the treatment. Improving the device itself and optimizing the chemical formulation of the drug coating have been the primary focuses of research and development efforts (Rykowska et al. (2020)). However, only a few studies have so far examined the DCB interaction with arterial vessels (Azar et al. (2020); Chang et al. (2019); Galan et al. (2018); Lee et al. (2021)). In light of this, the efficacy of coating transfer is considered an underexamined aspect in DCB angioplasty, while studies suggest that the restrained coating transfer may limit the efficacy of DCB angioplasty (Shazly et al. (2022)). The Contact Pressure (CP) between the balloon's external surface and the endoluminal surface of the artery has been identified as a crucial parameter influencing coating transfer. Higher CP enhances coating transfer, potentially increasing drug delivery to the vascular tissue. Previous studies have proposed that micromechanical indentation pressure, developed during the interaction of the coating with the vessel, is responsible for coating transfer (Chang et al. (2019); Tzafriri et al. (2020)), driven by macro-mechanical CP. Nevertheless, in vivo evaluation of CP is deemed unachievable, and the utilization of numerical methods can provide advantages in its measurement. However, the development of a numerical model capable of accurately computing the micro-mechanical aspects of CP resulting from the interaction between the coating and the artery would be highly complex. Therefore, this study aimed to propose a coupled in silico and in vitro pipeline to investigate the effectiveness of the drug-coating transfer from the balloon's external surface onto the artery's endoluminal surface, during DCB angioplasty. The numerical simulations are conducted on a macroscale, i.e. the device-artery interaction, to analyze the overall mechanical behavior of the DCB in interaction with the arterial vessel during balloon inflation and concurrent circumferential Balloon Stretching (BS). On the other hand, the in vitro experiments are planned to be carried out on a mesoscale, where the complex artery wall/coating material interaction is investigated to examine the efficacy of coating detachment from DCB specimens obtained from drug-coated patches or commercial DCBs, and attachment of the detached coating onto the endothelial layer of pig arteries. These experiments are conducted using the calculated conditions of CP and BS derived from numerical simulations, as applied loadings. The experiments aim to investigate the complex mechanical and chemical/biological interactions between the coating and the artery as opposed to relying solely on intricate numerical simulations. By employing this hybrid approach, in the future we may evaluate the effect of CP and BS during the balloon expansion of a DCB to deduce the optimal characteristics for balloon and coating features.

Efstathios Stratakos et al. / Procedia Structural Integrity 49 (2023) 30–36 Author name / Structural Integrity Procedia 00 (2023) 000 – 000

2. Methodology The rationale underlying the approach employed in this study is illustrated in Figure 1. The focus of this research is to investigate the phenomenon of coating transfer, and it is examined at two distinct scales. At the macro/device scale, the macromechanical behavior of the DCB during its expansion within the vessel is analyzed. During the treatment, by applying inflation pressure to the internal surface of the DCB, the folded balloon initially expands until it reaches its fully distended configuration. As the inflation pressure continues to rise, the diameter of the balloon progressively increases, primarily through circumferential BS. Eventually, the expanded balloon comes into contact with the inner

Figure 1. The rationale behind the coupled numerical and experimental approach to study the drug-coating transfer during the DCB expansion inside arterial vessels. The first raw presents the two scales of the problem, while the second and third raw depict the suggested methodological approach for each aspect and the respective expected output. The fourth raw represents the objective of the study, by merging the two techniques output to predict the coating transfer efficacy.

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arterial surface. At this stage, the inflation pressure serves dual purposes: it stretches the balloon circumferentially and generates CP on the balloon-artery interface due to the radial resistance of the artery. After the balloon deflation, the coating may: i) remain on the balloon surface, ii) attach to the surface of the artery or iii) fragment and get partially transferred. Observing the phenomenon from a meso scale, the developed CP and BS during the maximum inflation of the balloon are suggested to influence the coating transfer to the arterial wall. To approach the problem at a macro scale, we developed a finite element code in Abaqus/Explicit (Dassault Systemes Simulia Corp, Johnston RI) to simulate the folding and unfolding of a semi-compliant angioplasty balloon within simplified arterial vessels, as representative of healthy arteries which is the typical case during animal studies. The balloon was simulated as a bilinear elastoplastic material (Young’s modulus =1150 MPa, Yield stress = 30 MPa and Plastic modulus =158 MPa ) and the artery as 5 parameter Mooney Rivlin hyperelastic material (Prendergast et al. (2003)). The balloon-to-artery diameter ratio was 1.2. The folding of the balloon followed the method described by Geith (Geith et al. (2019)). Two different scenarios of balloon expansion were considered, one with 3 folds and the other with 5 folds. To analyze the simulations, we visualized the circumferential BS of the balloon at a nominal inflation pressure of 7 atm, and the CP experienced by the inner surface of the artery at the same pressure using 2D heat map representation, where the intensity of the colors reflected the values of the variables. To gain insights into the transfer of drug coating in the context of the DCB interaction with the artery, it is essential to approach the phenomenon from a material perspective. However, due to the intricate nature and computational complexity associated with incorporating numerical simulations to investigate the meso scale interaction between the DCB and the artery, a series of in vitro experiments are recommended. Conventionally, a compression experiment has been employed in the literature to study drug transfer to the arterial endothelium(Azar et al. (2020); Chang et al. (2019); Galan et al. (2018); Lee et al. (2021)). This experiment involves compressing a DCB patch (“flat stamping”) onto an arterial endothelium. However, this method is limited to flat DCB specimens. Longitudinal cutting of commercial DCBs may lead to damage to the drug-coating layer due to remaining circumferential tension of the balloon. Hence, the authors propose an alternative technique that utilizes cylindrical commercial DCB specimens (“cylindrical stamping”) . The objective of these experiments is to subject the DCB patches to a range of circumferential BS and compress them onto an arterial endothelium using a force that generates a similar range of CP as calculated in the numerical simulations. Following controlled compression for a duration equivalent to the DCB inflation time during treatment, the DCB patch is retracted, and both the DCB patch and the arterial endothelium are examined using laser microscopy to quantify the percentage of coating transferred to the vessel. To test the feasibility of the experiment, preliminary testing using commercial angioplasty balloons was performed. For the sample preparation, various types of resin and techniques were employed to expand the balloons and obtain solid cylindrical structures, which were then mounted onto the developed apparatus. By establishing a correlation between the experimental effectiveness of coating transfer and the CP and BS values developed during DCB expansion, the proposed methodology aims to integrate the outcomes of the experimental approaches into the results of the numerical simulations. This integration allows the transformation of CP and BS maps obtained from the numerical simulations into coating transfer maps.

3. Results and Discussion 3.1. Numerical simulations

The results of the finite element analysis simulations demonstrated significant heterogeneity in both CP and circumferential BS at an inflation pressure of 7 atm, where the balloon and the artery have a circular cross-section (Figure 2). The values and patterns of these variables were heavily influenced by the number of folds incorporated in each simulation, showing a similar range of values. This suggests that the artery tracks initial contact with the balloon. In the case of the 5-folded balloon, it was observed that the areas with maximum balloon stretch corresponded to regions where the contact pressure was minimal. In parallel, regions with intermediate values of contact pressure exhibited significantly low levels of balloon stretch. This phenomenon can be attributed to the frictional interaction between the external surface of the balloon and the arterial endoluminal surface. When the balloon unfolds, certain areas of the balloon come into contact with the arterial wall first, resulting in these regions being obstructed by the

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vessel. This obstruction increases the contact pressure and hampers the stretching of the balloon in those particular areas.

Figure 2. Results from the numerical simulations of balloon expansion inside the idealized vessels. The column of endoluminal CP depicts the CP map at the balloon-artery interface for the 3- and 5- folded balloon during the maximum balloon inflation. The column of circumferential BS represents the concurrent stretch on the balloon for the 3- and 5- folded balloon respectively. “A” and “C” on the bottom of the graphs denote the axial and circumferential directions respectively.

3.2. “Flat stamping” To investigate the impact of the calculated CP and BS on the effectiveness of coating transfer, we developed an experimental setup capable of compressing arteries onto flat DCB specimens (Figure 3). The setup was specifically designed to be compatible with the uniaxial testing machine. The lower part of the setup consisted of a system that securely held the flat DCB patch at its ends, allowing for manual stretching of the specimen by a rotating screw. In the upper part of the setup a pig aorta was glued with the endothelium exposed on the underside. Numerical simulations were employed to assess the uniformity of the stretch caused by the grips and to calculate the required force for applying the range of CPs determined by the simulations. Following the compression process, both the balloon and the arterial patches are planned to be subjected to coating quantification using a confocal laser microscope. 3.3. “Cylindrical stamping” A cylindrical stamping setup was developed to facilitate the utilization of commercial DCB devices and enable the testing of coating transfer efficacy on a large number of specimens (Figure 4). For sample preparation, a polyurethane resin was injected into the inner surface of the balloon. The volume expansion of the injected resin during solidification determined the extent of balloon expansion and circumferential balloon size. Once the resin solidified, it was cut into 1cm long DCB patches. A stereolithography 3D printed setup was specifically designed to be compatible with a uniaxial testing machine, allowing for the stamping experiment to be conducted on the cylindrical DCB specimens. After the specimens were cut, they were clamped laterally, and compression was performed between them and a flat pig aorta, which had the endothelium exposed on the top surface. The force applied during the compression was estimated through numerical simulations to correspond with the calculated CP derived from the balloon expansion simulations. So far, an angioplasty balloon was utilized to assess the feasibility of this experimental procedure.

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Figure 3. The flat “stamping” setup previously presented in literature with the addition of a stretching system facilitates the investigation of CP and BS to the coating transfer efficacy, The figure presents the system’s design able to stretch a flat DCB patch and compress an arterial endothelium on the coated area of the patch.

4. Conclusion This study presented a comprehensive approach combining numerical simulations and experimental methods to investigate the transfer of coating during balloon expansion in DCB angioplasty, conducted at two different scales. The numerical simulations performed on balloon expansion within simplified blood vessels demonstrated notable irregularities in CP and BS, indicating a wide range of values. To translate these results in coating transfer efficacy, Figure 4. Experimental procedure to perform the “cylindrical stamping” experiment: A. The commercial DCB is initially inflated using a needle filled with a polyurethane resin and once solidified, cut in a number of specimens perpendicular to its longitudinal axis, B. the developed setup able to grab and compress DCB specimens on pig arteries and C. The feasibility of the experiment was tested with commercial angioplasty balloons.

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two benchtop experiments were proposed: one utilizing DCB patches developed in-house, and the other employing commercially available DCBs. The authors conducted a proof-of-concept study for these experimental approaches and plan to carry out a future experimental campaign that integrates the computational and laboratory findings to evaluate coating transfer under various procedural conditions. Acknowledgements The project leading to this application has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska -Curie grant agreement No 956470. References Azar, D., Lott, J. T., Jabbarzadeh, E., Shazly, T., & Kolachalama, V. B., 2020. Surface Modification Using Ultraviolet-Ozone Treatment Enhances Acute Drug Transfer in Drug-Coated Balloon Therapy. Langmuir, 36(17), 4645 – 4653. Bukka, M., Rednam, P. J., & Sinha, M., 2018. Drug-eluting balloon: Design, technology and clinical aspects. Biomedical Materials, 13(3), 032001. Cao, Z., Li, J., Fang, Z., Feierkaiti, Y., Zheng, X., & Jiang, X., 2022. The factors influencing the efficiency of drug-coated balloons. Frontiers in Cardiovascular Medicine, 9, 947776. Chang, G. H., Azar, D. A., Lyle, C., Chitalia, V. C., Shazly, T., & Kolachalama, V. B., 2019. Intrinsic coating morphology modulates acute drug transfer in drug-coated balloon therapy. Scientific Reports, 9(1), 6839. Fanelli, F., Cannavale, A., Gazzetti, M., Lucatelli, P., Wlderk, A., Cirelli, C., d’Adamo, A., & Salvatori, F. M. , 2014. Calcium Burden Assessment and Impact on Drug-Eluting Balloons in Peripheral Arterial Disease. CardioVascular and Interventional Radiology, 37(4), 898 – 907. Galan, A., Bidinger, E., Godoy, F., & Patel, S. S., 2018. Increasing Drug Delivery Efficacy of Drug-Coated Balloons. https://www.semanticscholar.org/paper/Increasing-Drug-Delivery-Efficacy-of-Drug-Coated-Galan Bidinger/68b670760e1ae9ca71c0b7df6defca4080e0f03d Geith, M. A., Swidergal, K., Hochholdinger, B., Schratzenstaller, T. G., Wagner, M., & Holzapfel, G. A., 2019. On the importance of modeling balloon folding, pleating, and stent crimping: An FE study comparing experimental inflation tests. International Journal for Numerical Methods in Biomedical Engineering, 35(11), e3249. Kempin, W., Kaule, S., Reske, T., Grabow, N., Petersen, S., Nagel, S., Schmitz, K.-P., Weitschies, W., & Seidlitz, A., 2015. In vitro evaluation of paclitaxel coatings for delivery via drug-coated balloons. European Journal of Pharmaceutics and Biopharmaceutics, 96, 322 – 328. Lee, H.-I., Rhim, W.-K., Kang, E.-Y., Choi, B., Kim, J.-H., & Han, D.-K., 2021. A Multilayer Functionalized Drug-Eluting Balloon for Treatment of Coronary Artery Disease. Pharmaceutics, 13(5), Article 5. Petersen, S., Kaule, S., Stein, F., Minrath, I., Schmitz, K.-P., Kragl, U., & Sternberg, K., 2013. Novel paclitaxel-coated angioplasty balloon catheter based on cetylpyridinium salicylate: Preparation, characterization and simulated use in an in vitro vessel model. Materials Science and Engineering: C, 33(7), 4244 – 4250. Prendergast, P. J., Lally, C., Daly, S., Reid, A. J., Lee, T. C., Quinn, D., & Dolan, F., 2003. Analysis of Prolapse in Cardiovascular Stents: A Constitutive Equation for Vascular Tissue and Finite-Element Modelling. Journal of Biomechanical Engineering, 125(5), 692 – 699. Rykowska, I., Nowak, I., & Nowak, R., 2020. Drug-Eluting Stents and Balloons — Materials, Structure Designs, and Coating Techniques: A Review. Molecules, 25(20), 4624. Seidlitz, A., Kotzan, N., Nagel, S., Reske, T., Grabow, N., Harder, C., Petersen, S., Sternberg, K., & Weitschies, W., 2013. In Vitro Determination of Drug Transfer from Drug-Coated Balloons. PLoS ONE, 8(12), e83992. Shazly, T., Torres, W. M., Secemsky, E. A., Chitalia, V. C., Jaffer, F. A., & Kolachalama, V. B., 2022. Understudied factors in drug‐coated balloon design and evaluation: A biophysical perspective. Bioengineering & Translational Medicine. Speck, U., Stolzenburg, N., Peters, D., & Scheller, B., 2016. How does a drug-coated balloon work? Overview of coating techniques and their impact. The Journal of Cardiovascular Surgery, 57(1), 3 – 11. Tesfamariam, B., 2016. Local arterial wall drug delivery using balloon catheter system. Journal of Controlled Release, 238, 149 – 156. Tzafriri, A. R., Muraj, B., Garcia-Polite, F., Salazar-Martín, A. G., Markham, P., Zani, B., Spognardi, A., Albaghdadi, M., Alston, S., & Edelman, E. R., 2020. Balloon-based drug coating delivery to the artery wall is dictated by coating micro-morphology and angioplasty pressure gradients. Biomaterials, 260, 120337.

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Procedia Structural Integrity 49 (2023) 67–73

© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers Abstract The development of high-fidelity in silico simulations of the endovascular thrombectomy (EVT) procedure, the treatment for acute ischemic stroke, is gaining importance for the possibility of investigating the causes of failure of the clinical procedure and optimizing the treatment. This work proposed a novel methodology for a realistic modeling of the thrombus aspiration in a combined EVT procedure, with stent-retriever and proximal aspiration catheter. In the combined EVT procedure, the thrombus is entrapped in the stent struts and is retrieved towards the aspiration catheter. During the retrieval, the thrombus may rotate, and therefore different portions of its surface are subjected to aspiration forces. An automatic algorithm is implemented allowing to redefine the portion of the thrombus surface subjected to the aspiration pressure in different time points of a high-fidelity finite element EVT simulation. The algorithm updates at each iteration the loaded portion of thrombus surface, by selecting elements aligned with the vascular centerline. The algorithm is applied in a high-fidelity EVT simulation in a patient-like vascular model, demonstrating the ability of obtaining a realistic simulation of thrombus aspiration. © 2023 The Authors. Published by ELSEVIER B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0) Peer-review under responsibility of ICMD3M 2023 organizers Keywords: thrombectomy; aspiration catheter; finite-element; automatic algorithm. Medical Devices: Materials, Mechanics and Manufacturing A novel methodology for the modeling of catheter aspiration in high-fidelity thrombectomy simulations Sara Bridio a *, Giulia Luraghi a , Anushree Dwivedi b , Ray McCarthy b , Jose Felix Rodriguez Matas a , Francesco Migliavacca a a Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo Da Vinci 32, 20133, Milan, Italy b Cerenovus, Neuro Technology Center, Ballybrit Business Park, H91 K5YD, Galway, Ireland

* Corresponding author. Tel.: +39 02 2399 3399. E-mail address: sara.bridio@polimi.it

Sara Bridio et al. / Procedia Structural Integrity 49 (2023) 67–73

S. Bridio et al. / Structural Integrity Procedia 00 (2023) 000–000

1. Introduction Stroke is the second leading cause of death worldwide, with more than 12 million new cases each year (Feigin et al., 2022). Over 62% of these cases are ischemic strokes, caused by an occlusion in a cerebral artery preventing the blood perfusion of downstream brain tissues. In case of a large vessel occlusion (LVO), i.e. affecting the intracranial internal carotid artery (ICA), the middle cerebral artery (MCA) or the anterior cerebral artery (ACA), the most effective treatment is the endovascular thrombectomy (EVT), a minimally-invasive mechanical treatment aiming at removing the occluding thrombus and restoring the blood flow (Phipps and Cronin, 2020). The procedure can be performed with a stent-retriever, with an aspiration catheter, or with combined techniques using both devices (Munich et al., 2019). A combined EVT technique can be performed using, in combination with the stent-retriever, a proximal aspiration catheter placed at the base of the intracranial ICA (usually a balloon guide catheter, BGC, to stop the antegrade blood flow and facilitate the procedure (Ospel et al., 2020)). In this technique, the stent-retriever, initially crimped in a microcatheter, is deployed at the occlusion location to entrap the thrombus, and is then retrieved to the BGC, whose aspiration facilitates the thrombus removal and avoids the circulation of emboli. A different combined EVT technique uses, in addition to the stent-retriever and the BGC, a distal access catheter (DAC), coaxial with the BGC and navigated to the proximal end of the thrombus. In this technique, the thrombus is entrapped both by the stent-retriever and by the aspiration of the DAC, which are retrieved together, up to the BGC (Ospel et al., 2019). Despite being currently the standard of care for stroke due to an LVO, there is still a wide interest in optimizing the EVT procedure to increase the success rate and improve the patients’ outcome (Ospel et al., 2021). Computational models of the clinical procedure can help understanding the thrombus-device interactions and the causes of failure of the procedure. In recent years, in silico models of the EVT procedure with stent-retriever have been proposed (Liu et al., 2021; Luraghi et al., 2021b; Mousavi J S et al., 2021). The credibility of the high-fidelity finite-element model (FEM) proposed in (Luraghi et al., 2021b) was demonstrated through validation with in vitro experiments and a patient-specific case (Luraghi et al., 2021a). In (Luraghi et al., 2022a), the same authors proposed a high-fidelity FEM of the combined EVT technique, both with only the BGC and with BGC and DAC. This work proposes an algorithm for a more realistic FEM modelling of the EVT procedure with stent-retriever and BGC. In (Luraghi et al., 2022a), the aspiration pressure of the BGC was applied to the surface of the proximal end of the thrombus, defined at the initial configuration. However, with this EVT technique, the thrombus entrapped in the stent struts can rotate during the retrieval, therefore the surface exposed to the BGC aspiration pressure may vary throughout the procedure. The novel proposed algorithm allows to automatically redefine the thrombus surface for the application of the aspiration pressure at different time points of the EVT simulation. The novel methodology is applied in a high-fidelity model of a combined EVT procedure in a patient-like vascular model. 2. Materials and Methods 2.1. Algorithm for thrombus aspiration modeling The algorithm for the automatic definition of the thrombus surface for the application of the catheter aspiration is based on periodically restarting the FEM aspiration simulation, solved using the finite-element solver LS-DYNA (ANSYS, USA). A schematic representation of the algorithm is provided in Fig. 1. The algorithm requires the definition of a shell mesh representing the outer surface of the thrombus, and the discretization of the vessel centerline with beam elements. Moreover, the number of simulation restarts Nr is chosen based on the desired time interval dt for the update of the thrombus surface for the application of aspiration. In the initial configuration, a set of elements is selected on the thrombus end in proximity to the aspiration catheter for the application of the aspiration pressure (details about the simulation settings will be provided in the next section). The FEM simulation is launched and stopped after a time interval dt . The generated output files are analyzed for the update of the loaded thrombus surface. This is done by following four main steps: 1) identify the closest beam element of the centerline to the thrombus surface, using the beam connectivity to select the centerline elements in the direction of the aspiration; 2) define the centerline direction using the extreme points of the identified beam element; 3) define the normal vectors to each element of the shell mesh defining the outer surface of the thrombus, and for each normal vector compute the scalar product with the centerline direction, to select the thrombus elements with angle between

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the normal vector and centerline direction below a chosen value; 4) redefine in the simulation settings the thrombus surface for the application of the aspiration pressure. The simulation is restarted from the last configuration, and runs for another interval dt . The process is repeated until the desired number of restarts Nr is reached and the simulation continues until the imposed termination time. The whole procedure is made completely automatic through Python codes, which manage both the algorithm for the redefinition of the loaded surface and the restart of the simulation in the computational facility.

Fig. 1. Algorithm for the update of the thrombus surface for the application of the aspiration pressure ( i =iteration; Nr =number of simulation restarts; dt =time interval between each surface update).

2.2. Combined EVT simulation in patient-like vessel The algorithm for the update of the thrombus surface for applying the aspiration pressure was integrated in a high fidelity simulation of a combined EVT procedure, with a stent-retriever and a BGC. A computer-aided design (CAD) model of a patient-like vascular branch, complete with ICA, MCA and ACA, was provided by Cerenovus, Johnson&Johnson (Ireland) (Fig. 2a). The model was discretized with quadrilateral rigid elements of 0.35 mm average size. The vascular centerline was discretized with beam elements of 0.2 mm. A thrombus model was placed at the bifurcation of the MCA. The thrombus diameter was set to occlude 90% of the vascular lumen. The thrombus was modeled with a length of 10 mm and a 100% fibrin – 0% red blood cells composition. The quasi-hyperelastic foam material formulation available in LS-DYNA was used (Kolling et al., 2007), which determines the material parameters directly from a given stress-strain curve (Fig. 2b), interpolated from experiments carried out on human ex vivo thrombi, as detailed in (Luraghi et al., 2021a). The thrombus was discretized

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with tetrahedral elements of 0.2 mm average size (following an analysis on the element size reported in (Luraghi et al., 2022b, 2021b)). The connectivity of the triangular shell elements in the outer surface of the thrombus is stored, necessary for the surface update algorithm. The BGC (2.3 mm diameter) and the microcatheter (0.5 mm diameter) for the stent delivery (respectively black and blue in Fig. 2a) are discretized with quadrilateral rigid elements (0.35 mm average size). A model of the EmboTrap II (Cerenovus) stent-retriever was created (Fig. 2c) based on the CAD model provided by the company, and discretized with beam elements with rectangular section and 0.2 mm length (a sensitivity analysis was performed in (Luraghi et al., 2021b)). The nickel-titanium material was modeled with the shape memory material model available in LS DYNA, with parameters calibrated as explained in (Luraghi et al., 2021b). The EVT simulation is made of four main steps: 1. Stent crimping and microcatheter tracking: the stent-retriever is crimped inside a straight 0.5 mm diameter microcatheter by imposing the movement of the stent tip. At the same time, the microcatheter is displaced inside the vessel to reach the position shown in Fig. 2a, and pushes the thrombus against the vessel wall. A contact with 0.4 friction coefficient is defined between thrombus and vessel wall. 2. Stent tracking: the crimped stent is displaced inside the microcatheter to reach the thrombus position. 3. Stent deployment: the stent is deployed by progressively removing the contacts with the microcatheter. A contact with 0.2 friction coefficient is defined between stent and thrombus, and a frictionless contact between stent and vessel wall. 4. Retrieval and aspiration: the stent-thrombus complex is retrieved along the vessel towards the BGC, by imposing the movement of the stent tip. At the same time, the aspiration pressure is applied to the portion of the thrombus surface closest to the BGC. The pressure is applied as a function of the distance of the thrombus from the BGC: the applied pressure is hypothesized to start having an effect on the thrombus when it is less than 10 mm far from the BGC. From this distance, the applied pressure grows linearly from 0 to 10 kPa exerted by the BGC (in the range of catheter aspiration pressures reported in (Chitsaz et al., 2018)). Further details about the simulation settings can be found in (Luraghi et al., 2021b) and (Luraghi et al., 2022a). The algorithm for the update of the thrombus surface for the aspiration is applied with a total of Nr = 10 restarts of the simulation, with intervals dt = 50 ms starting from the retrieval phase. The loaded surface of the thrombus is selected considering elements with an angle < 30° with the centerline direction.

Fig. 2. a) Finite-element model for the combined EVT simulation in a patient-like vessel; b) Stress-strain curve for the definition of the thrombus material; c) Finite-element model of the EmboTrap II stent-retriever.

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3. Results Fig. 3 shows the results of the combined EVT simulation in the patient-like vascular model, from the deployment of the stent (frame 1) to the final retrieval of stent and thrombus inside the BGC (frame 6). These simulation frames clearly show the rotation of the thrombus during the procedure. The proposed algorithm allowed to select the proper portion of thrombus surface for the application of the aspiration pressure in each restart of the simulation (Fig. 4). The effect of the aspiration pressure on the thrombus is visible from frame 4, when the thrombus is closer to the BGC.

Fig. 3. Results of the combined EVT simulation in the patient-like vessel.

Fig. 4. Different selected portions of the thrombus for the application of the aspiration pressure in different time points of the simulation (the selected elements are contoured in black). 4. Discussion In this work, an automatic algorithm was developed for a realistic application of the aspiration pressure exerted by the BGC in a combined EVT simulation. The use of in silico simulation of the EVT procedure is gaining much relevance for the investigation of the thrombus-device interactions and for understanding the causes of unsuccessful outcomes. While several computational studies can be found in the literature replicating the EVT procedure with only

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