Computational modeling of acute myocardial infarction

This is an Accepted Manuscript of an article published by Taylor & Francis Group in Computer Methods in Biomechanics and Biomedical Engineering on October, 2016, available online at: http://www.tandfonline.com/10.1080/10255842.2015.1105965Myocardial infarction, commonly known as heart attack, is caused by reduced blood supply and damages the heart muscle because of a lack of oxygen. Myocardial infarction initiates a cascade of biochemical and mechanical events. In the early stages, cardiomyocytes death, wall thinning, collagen degradation, and ventricular dilation are the immediate consequences of myocardial infarction. In the later stages, collagenous scar formation in the infarcted zone and hypertrophy of the non-infarcted zone are auto-regulatory mechanisms to partly correct for these events. Here we propose a computational model for the short-term adaptation after myocardial infarction using the continuum theory of multiplicative growth. Our model captures the effects of cell death initiating wall thinning, and collagen degradation initiating ventricular dilation. Our simulations agree well with clinical observations in early myocardial infarction. They represent a first step toward simulating the progression of myocardial infarction with the ultimate goal to predict the propensity toward heart failure as a function of infarct intensity, location, and size.Peer ReviewedPostprint (author's final draft

Mechanics reveals the biological trigger in wrinkly fingers

The final publication is available at Springer via http://dx.doi.org/10.1007/s10439-016-1764-6Fingertips wrinkle due to long exposure to water. The biological reason for this morphological change is unclear and still not fully understood. There are two main hypotheses for the underlying mechanism of fingertip wrinkling: the ‘shrink’ model (in which the wrinkling is driven by the contraction of the lower layers of skin, associated with the shrinking of the underlying vasculature), and the ‘swell’ model (in which the wrinkling is driven by the swelling of the upper layers of the skin, associated with osmosis). In reality, contraction of the lower layers of the skin and swelling of the upper layers will happen simultaneously. However, the relative importance of these two mechanisms to drive fingertip wrinkling also remains unclear. Simulating the swelling in the upper layers of skin alone, which is associated with neurological disorders, we found that wrinkles appeared above an increase of volume of ˜10%.˜10%. Therefore, the upper layers can not exceed this swelling level in order to not contradict in vivo observations in patients with such neurological disorders. Simulating the contraction of the lower layers of the skin alone, we found that the volume have to decrease a ˜20%˜20% to observe wrinkles. Furthermore, we found that the combined effect of both mechanisms leads to pronounced wrinkles even at low levels of swelling and contraction when individually they do not. This latter results indicates that the collaborative effect of both hypothesis are needed to induce wrinkles in the fingertips. Our results demonstrate how models from continuum mechanics can be successfully applied to testing hypotheses for the mechanisms that underly fingertip wrinkling, and how these effects can be quantified.Peer ReviewedPostprint (published version

On the theories and numerics of continuum models for adaptation processes in biological tissues

The final publication is available at Springer via http://dx.doi.org/10.1007/s11831-014-9142-8Computational continuum mechanics have been used for a long time to deal with the mechanics of materials. During the last decades researches have been using many of the theoretical models and numerical approaches of classical materials to deal with biological tissue which, in many senses, are a much more sophisticated material. We aim to review the last achievements of continuum models and numerical approaches on adaptation processes in biological tissues. In this review, we are looking, in particular, at growth in terms of changes of density and/or volume as, e.g., in collagen remodeling, wound healing, arterial thickening, etc. Furthermore, we point out some of the most relevant limitations of the current state-of-the-art in terms of these well established computational continuum models. In connection with these limitations, we will finish by discussing the trend lines of future work in the field of modeling biological adaptation, focusing on the computational approaches and mechanics that could overcome the current drawbacks. We would also like to attract the attention of all those researchers in classical materials (metal, alloys, composites, etc), to point out how similar the continuum and computational models between our fields are. We hope we can motivate them for getting their expertize in this challenging field of research.Peer ReviewedPostprint (author's final draft

A theoretical model of the endothelial cell morphology due to different waveforms

Endothelial cells are key units in the regulatory biological process of blood vessels. They represent an interface to transmit variations on the fluid dynamic changes. They are able to adapt its cytoskeleton, by means of microtubules reorientation and F-actin reorganization, due to new mechanical environments. Moreover, they are responsible for initiating a huge cascade of biological processes, such as the release of endothelins (ET-1), in charge of the constriction of the vessel and growth factors such as TGF-ß and PDGF. Although a huge efforts have been made in the experimental characterization and description of these two issues the computational modeling has not gained such an attention. In this work we study the 3D remodeling of endothelial cells based on the main features of blood flow. In particular we study how different oscillatory shear index and the time average wall shear stresses modify the endothelial cell shape. We found our model fitted the experimental works presented before in in vitro studies. We also include our model within a computational fluid dynamics simulation of a carotid artery to evaluate endothelial cell shape index which is a key predictor of atheroma plaque formation. Moreover, our approach can be coupled with models of collagen and smooth muscle cell growth, where remodeling and the associated release of chemical substance are involved.Peer ReviewedPostprint (author's final draft

A structural approach including the behavior of collagen cross-links to model patient-specific human carotid arteries

The final publication is available at Springer via http://dx.doi.org/10.1007/s10439-014-0995-7The objective of this work is to develop a remodeling model for biological matter coupling two different processes in a 3D framework: reorientation of the preferential direction of a given fibered structure and reorientation of the fibrils or filaments that make up such a structure. This work uses the microsphere-based approach to take into account the micro mechanics involved in biological fibered structures regarding both their passive behavior and the reorientation of their micro constituents. Moreover, the macro behavior of the material as a whole is obtained by means of homogenizing the underlying micro response. We associate the orientation space of the integration directions to the physical space of micro-fibrils. To approximate the directional distribution of the fibrils within each fiber bundle, a Bingham probability orientation density function is introduced into the Helmholtz energy function. With all these assumptions, the problem is studied from an energetic point of view, describing the dissipation inherent to remodeling processes, and the evolution equations for both reorientations (change in preferential direction of the network and change in shape of the fibril distribution) re obtained. The model is included in a finite element code which allows computing different geometries and boundary value problems. This results in a complete methodology for characterizing the reorientation evolution of different fibered biological structures, such as cells. Our results show remodeling of fibered structures in two different scales, presenting a qualitatively good agreement with experimental findings in cell mechanics. Hierarchical structures align in the direction of the maximum principal direction of the considered stimulus and narrow in the perpendicular direction. The dissipation rates follows predictable trends although there are no experimental findings to date for comparison. The incorporation of metabolic processes and an insight into cell-oriented mechano-sensing processes can help to overcome the limitations involved.Peer ReviewedPostprint (author's final draft

A multi-scale clutch model for adhesion complex mechanics

Cell-matrix adhesion is a central mechanical function to a large number of phenomena in physiology and disease, including morphogenesis, wound healing, and tumor cell invasion. Today, how single cells respond to different extracellular cues has been comprehensively studied. However, how the mechanical behavior of the main individual molecules that form an adhesion complex cooperatively responds to force within the adhesion complex is still poorly understood. This is a key aspect of cell adhesion because how these cell adhesion molecules respond to force determines not only cell adhesion behavior but, ultimately, cell function. To answer this question, we develop a multi-scale computational model for adhesion complexes mechanics. We extend the classical clutch hypothesis to model individual adhesion chains made of a contractile actin network, a talin rod, and an integrin molecule that binds at individual adhesion sites on the extracellular matrix. We explore several scenarios of integrins dynamics and analyze the effects of diverse extracellular matrices on the behavior of the adhesion molecules and on the whole adhesion complex. Our results describe how every single component of the adhesion chain mechanically responds to the contractile actomyosin force and show how they control the traction forces exerted by the cell on the extracellular space. Importantly, our computational results agree with previous experimental data at the molecular and cellular levels. Our multi-scale clutch model presents a step forward not only to further understand adhesion complexes mechanics but also to impact, e.g., the engineering of biomimetic materials, tissue repairment, or strategies to arrest tumor progression.We acknowledge funding from the Spanish Ministry of Science and Innovation (Grant PID2019-11094GB-100 funded by MCIN/ AEI /10.13039/501100011033 to P.S.), the European Commission (H2020-FETPROACT-01-2016- 731957 to C.V. and P.S), the Generalitat de Catalunya (2017-SGR-1278 to P.S. and FI AGAUR 2018 for C.V. salary). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer ReviewedPostprint (published version

On the use of the Bingham statistical distribution in microsphere-based constitutive models for arterial tissue

Constitutive models for arterial tissue have been an active research field during the last years. The main micro-constituents of blood vessels are different types of cells and the extra-cellular matrix formed by an isotropic high water content ground substance and a network composed of elastin and collagen fibres. Usually the arterial tissue has been modelled as a hyperelastic material within the framework of continuum mechanics, whereas inclusion of structural tensors into constitutive laws is the most widely used technique to introduce the anisotropy induced by the fibres. Though the different existing fibre bundles present a clear preferential direction, the dispersion inherent to biological tissue advices using of constitutive models including representative structural information associated to the spatial probabilistic distribution of the fibres. Lately, microsphere-based models have demonstrated to be a powerful tool to incorporate this information. The fibre dispersion is incorporated by means of an Orientation Density Function (ODF) that weights the contribution of each fibre in each direction of the micro-sphere. In previous works the rotationally symmetric von Mises ODF was successfully applied to the modelling of blood vessels. In this study, the inclusion of the Bingham ODF into microsphere-based model is analysed. This ODF exhibits some advantages with respect to the von Mises one, like a greater versatility and a comparable response to simple tension and equibiaxial tension tests.Peer ReviewedPostprint (author's final draft

Hierarchical micro-adaptation of biological structures by mechanical stimuli

Remodeling and other evolving processes such as growth or morphogenesis are key factors in the evolution of biological tissue in response to both external and internal epigenetic stimuli. Based on the description of these processes provided by Taber, 1995 and Humphrey et al., 2002 for three important adaptation processes, remodeling, morphogenesis and growth (positive and negative), we shall consider the latter as the increase/decrease of mass via the increase/decrease of the number or size of cells, leading to a change in the volume of the organ. The work of Rodriguez et al. (1994) used the concept of natural configuration previously introduced by Skalak et al. (1982) to formulate volumetric growth. Later, Humphrey et al. (2002) proposed a constrained-mixture theory where changes in the density and mass of different constituents were taken into account. Many other works about biological growth have been presented in recent years, see e.g. Imatani and Maugin, 2002, Garikipati et al., 2004, Gleason and Humphrey, 2004, Menzel, 2004, Amar et al., 2005, Ganghoffer et al., 2005, Ateshian, 2007, Goriely et al., 2007, Kuhl et al., 2007, Ganghoffer, 2010a, Ganghoffer, 2010b and Goktepe et al., 2010. Morphogenesis is associated to changes in the structure shape (Taber, 1995 and Taber, 2009) while remodeling denotes changes in the tissue microstructure via the reorganization of the existing constituents or the synthesis of new ones with negligible volume change. All these processes involve changes in material properties. Although remodeling and growth can, and usually do, occur simultaneously, there are some cases where these processes develop in a decoupled way. For example, Stopak and Harris (1982) reported some experimental results showing remodeling driven by fibroblasts, with no volume growth. We will assume this scenario in this contribution, focusing exclusively on remodeling processes and on the reorientation of fibered biological structures. It is well known that biological tissue remodels itself when driven by a given stimulus, e.g. mechanical loads such as an increase in blood pressure, or changes in the chemical environment that control the signaling processes and the overall evolution of the tissue. Biological remodeling can occur in any kind of biological tissue. In particular, the study of collagen as the most important substance to be remodeled, in all its types (preferentiallyPeer ReviewedPostprint (author's final draft

Computational modeling of hypertensive growth in the human carotid artery

The final publication is available at Springer via http://dx.doi.org/10.1007/s00466-013-0959-zArterial hypertension is a chronic medical condition associated with an elevated blood pressure. Chronic arterial hypertension initiates a series of events, which are known to collectively initiate arterial wall thickening. However, the correlation between macrostructural mechanical loading, microstructural cellular changes, and macrostructural adaptation remains unclear. Here, we present a microstructurally motivated computational model for chronic arterial hypertension through smooth muscle cell growth. To model growth, we adopt a classical concept based on the multiplicative decomposition of the deformation gradient into an elastic part and a growth part. Motivated by clinical observations, we assume that the driving force for growth is the stretch sensed by the smooth muscle cells. We embed our model into a finite element framework, where growth is stored locally as an internal variable. First, to demonstrate the features of our model, we investigate the effects of hypertensive growth in a real human carotid artery. Our results agree nicely with experimental data reported in the literature both qualitatively and quantitatively.Peer ReviewedPostprint (author's final draft

Mathematical modeling of collagen turnover in biological tissue

The final publication is available at Springer via http://dx.doi.org/10.1007/s00285-012-0613-yWe present a theoretical and computational model for collagen turnover in soft biological tissues. Driven by alterations in the mechanical environment, collagen fiber bundles may undergo important chronic changes, characterized primarily by alterations in collagen synthesis and degradation rates. In particular, hypertension triggers an increase in tropocollagen synthesis and a decrease in collagen degradation, which lead to the well-documented overall increase in collagen content. These changes are the result of a cascade of events, initiated mainly by the endothelial and smooth muscle cells. Here, we represent these events collectively in terms of two internal variables, the concentration of growth factor TGF-$\beta$ and tissue inhibitors of metalloproteinases TIMP. The upregulation of TGF-$\beta$ increases the collagen density. The upregulation of TIMP also increases the collagen density through decreasing matrix metalloproteinase MMP. We establish a mathematical theory for mechanically-induced collagen turnover and introduce a computational algorithm for its robust and efficient solution. We demonstrate that our model can accurately predict the experimentally observed collagen increase in response to hypertension reported in literature. Ultimately, the model can serve as a valuable tool to predict the chronic adaptation of collagen content to restore the homeostatic equilibrium state in vessels with arbitrary micro-structure and geometry.Peer ReviewedPostprint (author's final draft