in-silico-clinical-trials-for-cardiovascular-disease

<em>In Silico</em> Clinical Trials for Cardiovascular Disease

The SILICOFCM project mainly aims to develop a computational platform for in silico clinical trials of familial cardiomyopathies (FCMs). The unique ...

University of Kragujevac

Due to the relative ease of producing nanofibers with a core⁻shell structure, emulsion electrospinning has been investigated intensively in making nanofibrous drug delivery systems for controlled and sustained release. Predictions of drug release rates from the poly (d,l-lactic-co-glycolic acid) (PLGA) produced via emulsion electrospinning can be a very difficult task due to the complexity of the system. A computational finite element methodology was used to calculate the diffusion mass transport of Rhodamine B (fluorescent drug model). Degradation effects and hydrophobicity (partitioning phenomenon) at the fiber/surrounding interface were included in the models. The results are validated by experiments where electrospun PLGA nanofiber mats with different contents were used. A new approach to three-dimensional (3D) modeling of nanofibers is presented in this work. The authors have introduced two original models for diffusive drug release from nanofibers to the 3D surrounding medium discretized by continuum 3D finite elements: (1) A model with simple radial one-dimensional (1D) finite elements, and (2) a model consisting of composite smeared finite elements (CSFEs). Numerical solutions, compared to experiments, demonstrate that both computational models provide accurate predictions of the diffusion process and can therefore serve as efficient tools for describing transport inside a polymer fiber network and drug release to the surrounding porous medium.

A Computational Model for Drug Release from PLGA Implant.

Mass transport represents the most fundamental process in living organisms. It includes delivery of nutrients, oxygen, drugs, and other substances from the vascular system to tissue and transport of waste and other products from cells back to vascular and lymphatic network and organs. Furthermore, movement is achieved by mechanical forces generated by muscles in coordination with the nervous system. The signals coming from the brain, which have the character of electrical waves, produce activation within muscle cells. Therefore, from a physics perspective, there exist a number of physical fields within the body, such as velocities of transport, pressures, concentrations of substances, and electrical potential, which is directly coupled to biochemical processes of transforming the chemical into mechanical energy and further internal forces for motion. The overall problems of mass transport and electrophysiology coupled to mechanics can be investigated theoretically by developing appropriate computational models. Due to the enormous complexity of the biological system, it would be almost impossible to establish a detailed computational model for the physical fields related to mass transport, electrophysiology, and coupled fields. To make computational models feasible for applications, we here summarize a concept of smeared physical fields, with coupling among them, and muscle mechanics, which includes dependence on the electrical potential. Accuracy of the smeared computational models, also with coupling to muscle mechanics, is illustrated with simple example, while their applicability is demonstrated on a liver model with tumors present. The last example shows that the introduced methodology is applicable to large biological systems.

Smeared Multiscale Finite Element Models for Mass Transport and Electrophysiology Coupled to Muscle Mechanics.

Coronary artery disease (CAD), one of the leading causes of death globally, occurs due to the growth of atherosclerotic plaques in the coronary arteries, causing lesions which restrict the flow of blood to the myocardium. Percutaneous transluminal coronary angioplasty (PTCA), including balloon angioplasty and coronary stent deployment is a standard clinical invasive treatment for CAD. Coronary stents are delivered using a balloon catheter inserted across the lesion. The balloon is inflated to a nominal pressure, opening the occluded artery, deploying the stent and improving the flow of blood to the myocardium. All stent manufacturers have to perform standard in vitro mechanical testing under different physiological conditions. In this study, partially and fully bioresorbable vascular scaffolds (BVS) from Boston Scientific Limited have been examined in vitro and in silico for three different test methods: inflation, radial compression and crush resistance. We formulated a material model for poly-L-lactic acid (PLLA) and implemented it into our in-house software tool. A comparison of the different experimental results is presented in the form of graphs showing displacement-force curves, diameter - load curves or diameter - pressure curves. There is a strong correlation between simulation and real experiments with a coefficient of determination (R) > 0.99 and a correlation coefficient (R) > 0.99. This preliminary study has shown that in-silico tests can mimic the applicable ISO standards for mechanical in vitro stent testing, providing the opportunity to use data generated using in-silico testing to partially or fully replacing the mechanical testing required for regulatory submission.

In vitro and in silico testing of partially and fully bioresorbable vascular scaffold.

Bioresorbable vascular scaffolds (BVS), made either from polymers or from metals, are promising materials for treating coronary artery disease through the processes of percutaneous transluminal coronary angioplasty. Despite the opinion that bioresorbable polymers are more promising for coronary stents, their long-term advantages over metallic alloys have not yet been demonstrated. The development of new polymer-based BVS or optimization of the existing ones requires engineers to perform many very expensive mechanical tests to identify optimal structural geometry and material characteristics.  mechanical testing opens the possibility for a fast and low-cost process of analysis of all the mechanical characteristics and also provides the possibility to compare two or more competing designs. In this study, we used a recently introduced material model of poly-l-lactic acid (PLLA) fully bioresorbable vascular scaffold and recently empowered numerical InSilc platform to perform  mechanicals tests of two different stent designs with different material and geometrical characteristics. The result of inflation, radial compression, three-point bending, and two-plate crush tests shows that numerical procedures with true experimental constitutive relationships could provide reliable conclusions and a significant contribution to the optimization and design of bioresorbable polymer-based stents.

Article	Year
A Computational Model for Drug Release from PLGA Implant. Materials (Basel, Switzerland)\| PubMed ID: 30501079	2018
Smeared Multiscale Finite Element Models for Mass Transport and Electrophysiology Coupled to Muscle Mechanics. Frontiers in bioengineering and biotechnology\| PubMed ID: 31921800	2019
In vitro and in silico testing of partially and fully bioresorbable vascular scaffold. Journal of biomechanics\| PubMed ID: 33360181	2021
Application of Platform for the Development and Optimization of Fully Bioresorbable Vascular Scaffold Designs. Frontiers in medical technology\| PubMed ID: 35047953	2021

Miljan Milosevic

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