Deciphering mechanical regulation of chondrogenesis in fibrin-polyurethane composite scaffolds enriched with human mesenchymal stem cells: a dual computational and experimental approach.

Fibrin-polyurethane composite scaffolds support chondrogenesis of human mesenchymal stem cells (hMSCs) derived from bone marrow and due to their robust mechanical properties allow mechanical loading in dynamic bioreactors, which has been shown to increase the chondrogenic differentiation of MSCs through the transforming growth factor beta pathway. The aim of this study was to use the finite element method, mechanical testing, and dynamic in vitro cell culture experiments on hMSC-enriched fibrin-polyurethane composite scaffolds to quantitatively decipher the mechanoregulation of chondrogenesis within these constructs. The study identified compressive principal strains as the key regulator of chondrogenesis in the constructs. Although dynamic uniaxial compression did not induce chondrogenesis, multiaxial loading by combined application of dynamic compression and interfacial shear induced significant chondrogenesis at locations where all the three principal strains were compressive and had a minimum magnitude of 10%. In contrast, no direct correlation was identified between the level of pore fluid velocity and chondrogenesis. Due to the high permeability of the constructs, the pore fluid pressures could not be increased sufficiently by mechanical loading, and instead, chondrogenesis was induced by triaxial compressive deformations of the matrix with a minimum magnitude of 10%. Thus, it can be concluded that dynamic triaxial compressive deformations of the matrix is sufficient to induce chondrogenesis in a threshold-dependent manner, even where the pore fluid pressure is negligible.

A multi-scale mechanobiological model of in-stent restenosis: deciphering the role of matrix metalloproteinase and extracellular matrix changes.

Since their first introduction, stents have revolutionised the treatment of atherosclerosis; however, the development of in-stent restenosis still remains the Achilles' heel of stent deployment procedures. Computational modelling can be used as a means to model the biological response of arteries to different stent designs using mechanobiological models, whereby the mechanical environment may be used to dictate the growth and remodelling of vascular cells. Changes occurring within the arterial wall due to stent-induced mechanical injury, specifically changes within the extracellular matrix, have been postulated to be a major cause of activation of vascular smooth muscle cells and the subsequent development of in-stent restenosis. In this study, a mechanistic multi-scale mechanobiological model of in-stent restenosis using finite element models and agent-based modelling is presented, which allows quantitative evaluation of the collagen matrix turnover following stent-induced arterial injury and the subsequent development of in-stent restenosis. The model is specifically used to study the influence of stent deployment diameter and stent strut thickness on the level of in-stent restenosis. The model demonstrates that there exists a direct correlation between the stent deployment diameter and the level of in-stent restenosis. In addition, investigating the influence of stent strut thickness using the mechanobiological model reveals that thicker strut stents induce a higher level of in-stent restenosis due to a higher extent of arterial injury. The presented mechanobiological modelling framework provides a robust platform for testing hypotheses on the mechanisms underlying the development of in-stent restenosis and lends itself for use as a tool for optimisation of the mechanical parameters involved in stent design.

A multiscale mechanobiological modelling framework using agent-based models and finite element analysis: application to vascular tissue engineering.

Computational models of mechanobiological systems have been widely used to provide insight into these systems and also to predict their behaviour. In this context, vascular tissue engineering benefits from further attention given the challenges involved in developing functional low calibre vascular grafts with long-term patency. In this study, a novel multiscale mechanobiological modelling framework is presented, which takes advantage of lattice-free agent-based models coupled with the finite element method to investigate the dynamics of VSMC growth in vascular tissue engineering scaffolds. The results illustrate the ability of the mechanobiological modelling approach to capture complex multiscale mechanobiological phenomena. Specifically, the framework enabled the study of the influence of scaffold compliance and loading regime in regulating the growth of VSMCs in vascular scaffolds and their role in development of intimal hyperplasia (IH). The model demonstrates that low scaffold compliance compared to host arteries leads to increased luminal ingrowth and IH development. In addition, culture of a tissue-engineered blood vessel under a pulsatile luminal pressure reduced luminal ingrowth and enhanced collagen synthesis within the scaffold compared to non-pulsatile culture. The mechanobiological framework presented provides a robust platform for testing hypotheses in vascular tissue engineering and lends itself to use as an optimisation design tool.

Simulation of a balloon expandable stent in a realistic coronary artery-Determination of the optimum modelling strategy.

Computational models of stent deployment in arteries have been widely used to shed light on various aspects of stent design and optimisation. In this context, modelling of balloon expandable stents has proved challenging due to the complex mechanics of balloon-stent interaction and the difficulties involved in creating folded balloon geometries. In this study, a method to create a folded balloon model is presented and utilised to numerically model the accurate deployment of a stent in a realistic geometry of an atherosclerotic human coronary artery. Stent deployment is, however, commonly modelled by applying an increasing pressure to the stent, thereby neglecting the balloon. This method is compared to the realistic balloon expansion simulation to fully elucidate the limitations of this procedure. The results illustrate that inclusion of a realistic balloon model is essential for accurate modelling of stent deformation and stent stresses. An alternative balloon simulation procedure is presented however, which overcomes many of the limitations of the applied pressure approach by using elements which restrain the stent as the desired diameter is achieved. This study shows that direct application of pressure to the stent inner surface may be used as an optimal modelling strategy to estimate the stresses in the vessel wall using these restraining elements and hence offer a very efficient alternative approach to numerically modelling stent deployment within complex arterial geometries. The method is limited however, in that it can only predict final stresses in the stented vessel and not those occurring during stent expansion, in which case the balloon expansion model is required.

Determination of the influence of stent strut thickness using the finite element method: implications for vascular injury and in-stent restenosis.

Many clinical studies, including the ISAR-STEREO trial, have identified stent strut thickness as an independent predictor of in-stent restenosis where thinner struts result in lower restenosis than thicker struts. The aim of this study was to more conclusively identify the mechanical stimulus for in-stent restenosis using results from such clinical trials as the ISAR-STEREO trial. The mechanical environment in arteries stented with thin and thicker strut stents was investigated using numerical modelling techniques. Finite element models of the stents used in the ISAR-STEREO clinical trial were developed and the stents were deployed in idealized stenosed vessel geometries in order to compare the mechanical environment of the vessel for each stent. The stresses induced within the stented vessels by these stents were compared to determine the level of vascular injury caused to the artery by the stents with different strut thickness. The study found that when both stents were expanded to achieve the same initial maximum stent diameter that the thinner strut stent recoiled to a greater extent resulting in lower luminal gain but also lower stresses in the vessel wall, which is hypothesised to be responsible for the lower restenosis outcome. This study supports the hypothesis that arteries develop restenosis in response to injury, where high vessel stresses are a good measure of that injury. This study points to a critical stress level in arteries, above which an aggressive healing response leads to in-stent restenosis in stented vessels. Stents can be designed to reduce stresses in this range in arteries using preclinical tools such as numerical modelling.