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InSilc: In-silico trials for drug-eluting BVS design, development and evaluation

Periodic Reporting for period 2 - InSilc (InSilc: In-silico trials for drug-eluting BVS design, development and evaluation)

Reporting period: 2019-05-01 to 2021-04-30

The InSilc project was funded by the European Commission within the Horizon 2020 Research and Innovation program with 5.8M EUR. Thirteen partners from ten different countries, including universities, medical centres, research centres and enterprises, participated in the project, providing the necessary experience to ensure the success of the project in all stages of development.
Coronary artery disease remains the leading cause of mortality worldwide. Coronary stents are currently the most widely used devices for treating symptomatic coronary disease. The success of this treatment depends on optimal device designs and suitable implantation procedures by the interventional cardiologists.
In designing a new coronary stent, there are several key aspects of performance that the device must fulfill. This presents a challenging design problem, particularly when it is considered that these functions must be fulfilled across a diverse patient population, whose coronary anatomies vary significantly. In the design and development process of new coronary stents, rare adverse effects may take years to manifest while a high number of treated patients is required. Computer modelling and simulations can address this challenge and assist in avoiding these pitfalls even before any patient is treated, thanks to the possibility of testing the device in virtual patients.
InSilc enables virtual trials for coronary stents by using, integrated in a single platform, computational models to provide detailed predictions of implanted device performance. To achieve this, InSilc has developed integrated modules that provide predictions of stent performance, functionalities and operation in the pre-operative, acute, short-, medium- and long-term phases of the device lifetime.
InSilc developed several modules/tools were developed and well validated following the ASME V&V 40 standard. In particular:

1) The Mechanical Modelling module enables the virtual in vitro bench testing of coronary stents.
2) The 3D reconstruction and plaque characterization tool is a standalone software tool that accurately reconstructs parts of the arterial tree including the lumen, the outer wall, as well as plaque components.
3) The Deployment module enables the in silico reproduction of the implantation procedure for coronary stents. T
4) The Fluid dynamics module enables predictions of patient-specific velocity and wall shear stress patterns in human coronary arteries following the scaffold implantation.
5) The Drug delivery module generates simulation-based predictions of drug distribution and uptake by the vessel wall, following the scaffold implantation.
6) The Myocardial perfusion module allows for more realistic simulation of post-operative coronary flow in patients by describing the local response of the cardiac muscle and the coronary autoregulation system.
7) The Degradation module enables predictions of long-term degradation and mechanical performance of drug-eluting bioresorbable vascular scaffolds (BVS).
8) The Virtual population, which includes pre-implantation arterial and plaque geometries, representative of a real clinical trial population, with a variety in type of lesions, plaques, comorbidities and medication.

The InSilc modules have been integrated into a single web-based cloud platform that enables the users to set up, monitor, visualize and analyse the results of virtual scenarios for coronary stents. For the implementation of the virtual scenarios, the InSilc modules are applied in the InSilc Virtual population. The Virtual population includes virtual arterial and plaque geometries and clinical data, representative of the population enrolled in the real clinical trials with a variety of characteristics (arterial morphology, composition, comorbidities) that could play a significant role in scaffold performance.
From the beginning of the project, successful exploitation of the project results was one of the main focuses of the consortium. For each InSilc exploitable result (platform and separate modules), an individual exploitation plan has been described by the module developers. The time required to perform each simulation was analyzed and compared in terms of time required to perform the real clinical intervention to provide evidence on how the adoption of InSilc could contribute to significant savings in resources and time. Barriers to enter the market were analyzed and a plan for their mitigation was also considered.
The InSilc project has been disseminated widely through various channels. The project has resulted in 18 journal articles already published, with 3 further manuscripts under review and 13 manuscripts in preparation. Additionally, project results have been published and presented at over 70 conferences reaching National, European and international audiences. Awareness toward the stent industry has been raised through participation in eleven events/exhibitions, which have included poster presentations, delivery of keynote talks and one-on-one meetings with industry representatives.
The InSilc platform provides the unique opportunity to pose a wide range of “what if” questions on stent performance, which can facilitate useful insight in device behaviour during the design and development phase of coronary stents. For example, this capability allows users to compare the performance of different stents and/or stent designs implanted in the same artery or compare outcomes of clinical different procedures to treat the same stenotic artery, something which is obviously impossible to do in real cases. Conversely, the same stent can be used to treat two different virtual patient anatomies, where direct side-by-side comparisons of performance outcomes in Deployment, Fluid dynamic and Drug delivery modules are visible.
Economic assessment of the InSilc platform was considered in three applications: bench tests, animal tests and clinical trials. Three economic models were built. Our analysis showed that the recourse to in silico medicine tools, such as the InSilc platform, allows savings in terms of costs for those adopting them (about 50% for bench tests, a more moderate 16% for clinical trials). Moreover, even if not quantified in our economic analysis, it is worth mentioning that, besides the reported cost saving, the platform gives the possibility to virtually test, in a very short time and with a significantly lower cost, concepts in an initial development phase, specifically before prototype production and during the preclinical and clinical tests phases. When dealing with clinical trials, it is important to highlight three additional important aspects: the undoubtful advantage of reducing the number of real individuals running the risks of a clinical trial, the possibility to estimate, in a very short time, long term efficacy and safety endpoints that would otherwise require years-long real trials, and the possibility to focus on specific critical typologies of patients (sometimes rarely findable in real trials).
In conclusion, based on the economic evaluation, all the opportunities analyzed demonstrated that the adoption of InSilc platform can improve the exploratory phase and increase the innovation capacity of a company, with added consequent potential advantages for target patients.
The InSilc Modules
InSilc Cloud platform
InSilc architecture
Benefits of InSilc in silico clinical trials
Virtual Scenario that examines the performance of vascular stent in different arterial anatomies