Computational Modeling in Bioengineering and Bioinformatics

(ESAO).

Preface

Nenad Filipovic, Full Professor and Head of Center for Bioengineering, University of Kragujevac, Kragujevac, Serbia

The current medicine treatment relies exclusively on diagnostic imaging data to define the present state of the patient, biomarkers, and experience of the medical doctors to evaluate the efficacy of prior treatments for similar patients. Computational methods may give opportunity for a patient-specific model in order to improve the prediction for the disease progression.

The book Computational Modeling in Bioengineering and Bioinformatics promotes complementary disciplines that hold great promise for the advancement of research and development in complex medical and biological systems, environment, public health, drug design, and so on. It provides a common platform for the cross-fertilization of ideas and shaping knowledge and scientific achievements by bridging these two very important and complementary disciplines into an interactive and attractive forum. The chapters includes 12 chapters varying from modeling of atherosclerosis, data mining, cancer modeling, stent design, lab-on-a-chip modeling, aortic dissection modeling, bone biomechanics, computational chemistry, modeling of DPIs for pulmonary drug delivery, cochlea biomechanics, microfluidic chips, abdominal aortic aneurysm, and sport biomechanics.

The book is also prepared to be useful for researchers in various fields related to bioengineering and other scientific fields, including medical applications. The book provides basic information about how a bioengineering (or medical) problem can be modeled, which computational models can be used, and what is the background of the applied computer models. Each of the bioengineering problems treated in this book has been analyzed elsewhere from different aspects, with more details and particular theoretical considerations. We have referred to these analyses to a certain extent, but this referring is far from being complete, since the field of computer modeling in bioengineering is vast and consistently expanding.

The chapters are results of many international projects of the authors over a number of years, in area of bioengineering and bioinformatics of the Faculty of Engineering of the University of Kragujevac, and Research and Development Center for Bioengineering BioIRC from Serbia.

Chapter 1

Computational modeling of atherosclerosis

Nenad Filipovic¹,²    ¹ Faculty of Engineering, University of Kragujevac, Kragujevac, Serbia

² Bioengineering Research and Development Center (BioIRC), Kragujevac, Serbia

Abstract

In this chapter, the model of atherosclerosis has been described. The inflammation and lipid accumulation in the arterial wall represent a progressive disease known as atherosclerosis. This disease begins with endothelial dysfunction, which favors lipid and cell elements crossing inside blood vessel wall. An important hemodynamic parameter in interaction between fluid and vessel wall is the wall shear stress, which is the mechanical force imposed on the endothelium by the flowing blood. In this study, a numerical model of plaque progression was presented. Fluid domain (blood) was modeled using Navier-Stokes equations in conjunction with continuity equation, while the solid domain (arterial wall) was modeled using Darcy's law. Kedem-Katchalsky equations were used for coupling fluid and solid dynamics. Coupled finite element method with dissipative particle dynamics was used for simulation of plaque formation and development. The specific biomolecular parameters for each patient such as LDL, HDL, and triglycerides are incorporated in the model. Experimental data from pigs submitted to a high-cholesterol diet for 2 months are compared with computational model. We also used real clinical cases with baseline and follow-up for the coronary artery CT scan for validation of our model. The results for wall shear stress, plaque concentration for animal, and patients with plaque progression in the coronary arteries are presented.

Keywords

Coronary artery; Computational fluid dynamics; DPD; FE; Wall shear stress; Plaque progression; Biomolecular parameters

Contents

1Theoretical background

2Methods

2.1Blood flow simulation

2.2Plaque formation and progression modeling—Continuum approach

2.3Discrete approach

2.4DPD modeling of oxidized LDL particle adhesion to the wall

3Results

3.1Animal pig experiments

3.2Comparison experimental and numerical results for pigs data

3.3Fitting parameters of ODE model for pigs

3.4Coupled model of atherosclerosis

3.5Plaque concentration distribution in the coronary artery

4Conclusions

Acknowledgments

References

Further reading

Acknowledgments

Serbian Ministry of Education, Science and Technological Development III41007, ON174028 and EC HORIZON2020 689068 SMARTool project.

1 Theoretical background

Atherosclerosis is becoming the number one cause of death worldwide as a progressive disease characterized in particular by the accumulation of lipids and fibrous elements in artery walls. It is characterized by dysfunction of endothelium; vasculitis; and accumulation of lipid, cholesterol, and cell elements inside blood vessel wall. The process of atherosclerosis develops in arterial walls (Loscalzo and Schafer, 2003). It starts to develop from oxidized low-density lipoprotein (LDL) molecules. When oxidized LDL evolves in plaque formations within an artery wall, a series of reactions occur to repair the damage to the artery wall caused by oxidized LDL (Libby, 2002). The body's immune system responds to the damage to the artery wall caused by oxidized LDL by sending specialized white blood cells—macrophages (MPHs)—to absorb the oxidized LDL forming specialized foam cells (Meyer et al., 1996). Macrophages accumulate inside arterial intima. Also, smooth muscle cell (SMC) accumulates in the atherosclerotic arterial intima, where they proliferate and secrete extracellular matrix to form a fibrous cap (Begent and Born, 1970). Unfortunately, macrophages are not able to process the oxidized LDL and ultimately grow and rupture, depositing a larger amount of oxidized cholesterol into the artery wall. The schematic process of atherosclerosis has been shown in Fig. 1.1.

Fig. 1.1 Atherosclerotic plaque development. Adapted from Loscalzo J., Schafer A. I., 2003, Thrombosis and Hemorrhage, third ed. Lippincott Williams & Wilkins, Philadelphia.

Formerly focused on luminal narrowing due to the bulk of atheroma, the current concepts recognize the biological attributes of the atheroma as key determinants of its clinical significance (Libby, 2002). Inflammatory process starts with penetration of low-density lipoproteins (LDL) in the intima. This penetration, if too high, is followed by leucocyte recruitment in the intima. This process may participate in the formation of the fatty streak, in the initial lesion of atherosclerosis, and then in formation of a plaque (Meyer et al., 1996).

Several mathematical models have described the transport of macromolecules, such as low-density lipoproteins, from the arterial lumen to the arterial wall and inside the wall (e.g., Tarbell, 2003; Zunino, 2002; Prosi et al., 2005; Quarteroni and Valli, 1999; Quarteroni et al., 2002). It is now well known that the early stage of the inflammatory disease is the result of interaction between plasma low-density lipoproteins that filtrate through endothelium into the intima, cellular components (monocytes/macrophages, endothelial cells, and smooth muscle cells), and the extracellular matrix of the arterial wall (Libby, 2002; Ross, 1993).

Low endothelial wall shear stress (WSS) promotes the development of early fibroatheromas, which evolution follows an individualized natural history of progression. In vivo assessment of the local WSS, extent of vascular inflammation, and arterial remodeling response, all responsible for individual plaque evolution, in combination with systemic biomarkers of vascular inflammation, may all together improve risk stratification of individual early atherosclerotic plaques, thereby personalizing the therapeutic strategies.

The purpose of this study was to determine wall shear stress with computational fluid dynamics in the coronary arteries using patient-specific data obtained from computed tomography. Also, plaque concentration in the arterial wall was calculated. Coronary geometries of several patients were used. Two time periods were analyzed: baseline and follow-up. Plaque progression was performed using numerical approach. Mass transport of low-density lipoprotein through the arterial wall was firstly described. Fluid motion in the lumen domain is described with Navier-Stokes equations, the fluid filtration with the Darcy law, while the Kedem-Katchalsky equations (Kedem and Katchalsky, 1958, 1961) is used for the solute flow between the lumen domain, endothelium, and the first layer of the vessel wall—intima. Also, we used coupled approach for modeling of blood flow with the collection of dissipative particle dynamic (DPD) particles (Boryczko et al., 2003; Haber et al., 2006; Filipovic et al., 2006, 2008a, 2008b, 2010). Motion of each DPD particle is governed by Newton's law equation. At the end, some discussion related to shear stress distribution and plaque growth was given.

2 Methods

2.1 Blood flow simulation

The blood can be considered as an incompressible homogenous viscous fluid for flow in large blood vessels. Also, the laminar flow is dominant in physiological flow environment. Therefore, the fundamental laws of physics that include balance of mass and balance of linear momentum are applicable here. These laws are expressed by continuity equation and the Navier-Stokes equations.

We here present the final form of these equations to emphasize some specifics related to blood flow. The incremental-iterative balance equation of a finite element for a time step "n and equilibrium iteration i" has a form

   (1.1)

where n + 1V(i − 1) n + 1P(i − 1) are the nodal vectors of blood velocity and pressure, with the increments in time step ΔV(i) and ΔP(i) (the index blood is used to emphasize that we are considering blood as the fluid), Δt is the time step size and the left upper indices "n and n + 1" denote start and end of time step, and the matrices and vectors are defined in (Kojic et al., 2008; Filipovic et al., 2006). Note that the vector n + 1Fext(i − 1) of external forces includes the volumetric and surface forces. In the assembling of these equations, the system of equations of the form (Eq. 1.1) is obtained, with the volumetric external forces and the surface forces acting only on the fluid domain boundary (the surface forces among the internal element boundaries cancel).

The specifics for the blood flow are that the matrix n + 1K(i − 1) may include variability of the viscosity if non-Newtonian behavior of the blood is considered. We have that

   (1.2)

where μ(i − 1) corresponds to the constitutive law for the last known conditions (at iteration "i − 1"). In case of use of the Cason relation (1.2), the second invariant of the strain rate DII(i − 1) is to be evaluated when computing μ(i − 1).

We note here that the penalty method can also be used, as well as the ALE formulation in case of large displacements of blood vessel walls (Kojic et al., 2008; Filipovic et al., 2006; Filipovic et al., 2010).

In addition to the velocity and pressure fields of the blood, the distribution of stresses within the blood can be evaluated. The stresses tσij at time "t" follow from

   (1.3)

where

   (1.4)

is the viscous stress. Here, tμ is viscosity corresponding to the velocity vector tv at a spatial point within the blood domain. The field of the viscous stresses is given by Eq. (1.4).

Further, the wall shear stress at the blood vessel wall is calculated as

   (1.5)

where tvt denotes the tangential velocity and n is the normal direction at the vessel wall. Practically, we first calculate the tangential velocity at the integration points near the wall surface and then numerically evaluate the velocity gradient ∂tvt/∂ n; finally, we determine the viscosity coefficient tμ using the average velocity at these integration points. In essence, the wall shear stress is proportional to the shear rate γ at the wall and the blood dynamic viscosity μ.

For a pulsatile flow, the mean wall shear stress within a time interval T can be calculated as (Taylor et al., 1998)

   (1.6)

Another scalar quantity is a time-averaged magnitude of the surface traction vector, calculated as

   (1.7)

where the vector tt is given by the Cauchy formula.

2.2 Plaque formation and progression modeling—Continuum approach

Continuum-based methods are an efficient way for modeling the evolution of plaque. In our model, LDL concentration is first introduced into the system of partial differential equations as a boundary condition. The model simulates the inflammatory response formed at the initial stages of plaque formation.

Regarding the particle dynamics, the model is based on the involvement of LDL/oxidized LDL, monocytes and macrophages, and foam cells and extracellular matrix. Reaction-diffusion differential equations are used to model these particle dynamics. The adhesion rate of the molecules depends on the local hemodynamics, which is described by solving the Navier-Stokes equations. Intima LDL concentration is a function of the wall shear stress, while the adhesion of monocytes is a function of shear stress and VCAM. Finally, the alterations of the arterial wall are simulated. A finite element solver is used to solve the system of the equations. The lumen is defined as a 2D domain, while the intima is simplified as 1-D model due to its thin geometry. First, the LDL penetration to the arterial wall and the wall shear stress is calculated. Then, the concentration of the various components of the model is calculated to simulate the intima fattening in the final step.

The LDL penetration is defined by the convection-diffusion equation, while the endothelial permeability is shear stress dependent. This model produces results about the initial stages of the atherosclerotic plaque formation. More specifically, concentration of LDL is calculated on the artery wall and in the next step the oxidized LDL. Furthermore, monocytes and their modified form (macrophages) are also counted. Solution to the system provides to the user the concentration of foam cells created when a threshold on LDL concentration is reached.

The previous model describes the initial stages of atherosclerosis. However, atherosclerosis is characterized by the proliferation of SMCs. A medical user needs a prediction for the plaque formation that is based on the concentration of SMCs, the necrotic core, and the extracellular matrix. In this respect, a new approach to count the concentration of SMCs is being developed. The user is also provided with results regarding the formation of plaque in an overall manner.

The fluid is assumed to be steady, incompressible, and laminar for modeling fluid dynamics in the lumen. Navier-Stokes equations were used (Eqs. 1.8 and 1.9):

   (1.8)

   (1.9)

where ul is blood velocity, pl is pressure, μ is blood dynamic viscosity, and ρ is blood density.

Darcy`s law was used to model mass transfer across the wall (transmural flow) of the blood vessel:

   (1.10)

   (1.11)

where uw is transmural velocity, pw is pressure in the arterial wall, μp is viscosity of blood plasma, and k is the Darcian permeability coefficient of the arterial wall (Eqs. 1.10 and 1.11). Convective diffusion equations were occupied for modeling mass transfer in the lumen (Eq. 1.12):

   (1.12)

where cl represents blood concentration in the lumen and Dl is diffusion coefficient of the lumen.

Convective diffusion reactive equations (1.13) were used for modeling mass transfer in the wall, which are related to transmural flow:

   (1.13)

where cw is solute concentration in the arterial wall, Dw is diffusive coefficient of solution in the wall, K is solute lag coefficient, and rw is consumption rate constant.

The coupling of fluid dynamics and solute dynamics at the endothelium was achieved by the Kedem-Katchalsky equations (Kedem and Katchalsky, 1958, 1961) (Eqs. 1.14 and 1.15):

   (1.14)

   (1.15)

where Lp is the hydraulic conductivity of the endothelium, Δc is the solute concentration difference across the endothelium, Δp is the pressure drop across the endothelium, Δπ is the oncotic pressure difference across the endothelium, σd is the osmotic reflection coefficient, σf is the solvent reflection coefficient, P is the mean endothelial concentration (Nanfeng et al., 2006).

The inflammatory process is modeled using three additional reaction-diffusion partial differential equations (Filipovic et al., 2011, 2012, 2013):

   (1.16)

where O is the oxidized LDL in the wall; M and S are concentrations in the intima of macrophages and cytokines, respectively; d1, d2, d3 are the corresponding diffusion coefficients; λ and γ are degradation and LDL oxidized detection coefficients; and vw is the inflammatory velocity of plaque growth (Filipovic et al., 2011, 2013).

2.3 Discrete approach

Blood flow in the small coupled domain within finite element mesh is viewed as a motion of the collection of DPD particles. Motion of each DPD particle is described by Newton's law equation:

   (1.17)

where mi is the mass of particle "iis the particle acceleration as the time derivative of velocity; FijC, FijD, and FijR are the conservative (repulsive), dissipative, and random (Brownian) interaction forces, which particle "j exerts on particle i, respectively, provided particle j" is within the radius of influence rc of particle "i"; and Fiext is the external force exerted on particle "i," which usually represents gradient of pressure or gravity force as a driving force for the fluid domain (Boryczko et al., 2003). Hence the total interaction force Fij (Fig. 1.2) between the two particles is

   (1.18)

Fig. 1.2 Interaction forces in the DPD approach.

2.4 DPD modeling of oxidized LDL particle adhesion to the wall

When an oxidized LDL comes close to the wall and if shear rate allows, it binds to the wall. However, when adhered LDL particles are exposed simultaneously to other forces stronger than the binding forces, the bonds break. To incorporate LDL adhesion to vessel walls, we introduce an attractive (bonding) force, (Fija), in addition to the conservative, viscous, and random interaction forces. As an approximation, we model the attractive force with a linear spring attached to the LDL's surface. The spring is attached to the vessel wall or to an already adhered LDL particle. The effective spring constant for LDL adhesion on the vessel wall, or to another stationary LDL particle, is denoted by kbw.

The additional parameter involved in the model is the size of the domain from the LDL coated wall (Lmaxwall) for which the action of attractive force needs to be considered. We take the attractive force as

   (1.19)

where Lw is the distance of the oxidized LDL from the wall.

3 Results

3.1 Animal pig experiments

In this section, a model of plaque formation on the pig left anterior descending coronary artery (LAD) is simulated numerically using a specific animal data obtained from IVUS and histological recordings. The 3D blood flow is described by the Navier-Stokes equations, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modeled by a convection-diffusion equation. The LDL transports in lumen of the vessel and through the vessel tissue (which has a mass consumption term) are coupled by Kedem-Katchalsky equations (Kedem and Katchalsky, 1958, 1961). The inflammatory process is modeled using three additional reaction-diffusion partial differential equations. A full three-dimensional model was created that includes blood flow and LDL concentration, as well as plaque formation. Matching of IVUS and histological animal data is performed using a 3D histological image reconstruction and 3D deformation of elastic body.

We used experimental data from pigs submitted to a high-cholesterol diet for 2 months. Specific software for 3D reconstruction of lumen domain and wall artery (coronary artery) was developed. Matching of histological data and IVUS slices has been applied. A 3D reconstruction was performed from standard IVUS and angiography images. After that, a full three-dimensional finite element analysis was performed using our in-house finite element code to find low and oscillatory WSS zones. The LAD was selected for this analysis. The process of matching with IVUS images was achieved by 2D modeling of tissue deformation for a number of cross sections recorded by histological analysis; those cross sections are deformed until the internal lumen circumferential lengths in IVUS images are reached. Volume of the plaque obtained from histological analysis (after 2 months of high-fat diet for plaque formation) was fitted by employing a nonlinear least-square analysis (Chavent, 2010), to determine material parameters in Section 2.

We examined experimental data obtained for the LAD artery of a pig after 2 months of high-fat diet, to determine material parameters of the computer model. Matching computed plaque location and progression in time with experimental observations demonstrates a potential benefit for future prediction of this vascular disease by using computer simulation.

The results for shear stress distribution for pig are shown in Fig. 1.3. It can be observed that there are low wall shear stress zones < 5 dyne/cm² that are indicated in Fig. 1.3 in the proximal zones of the coronary arteries which is in good agreement with histological measurement from CNR.

Fig 1.3 Shear stress distribution for pig.

3.2 Comparison experimental and numerical results for pigs data

In this section, the comparison of numerical and experimental results for high-fat diet pig is presented. We tried to match first of all lesion and foam cell (FC) lipids. The initiator for plaque formation is shear stress function.

We choose four characteristic pigs to fit model parameters and compare it with experimental measurement from CNR described in WP4. These data for four pigs are HF6, HF9, HF11, and LIHF2, and their experimental data for flow, pressure, and blood analysis are given in Tables 1.1 and 1.2.

Table 1.1

Table 1.2

Experimental histological data for these four pigs together with WSS are presented in Table 1.2. We concentrated on the FC lipids, lesion area, CXCR4, and MIF signals.

For a specific pig HF9, we tried to fit lesion area function with WSS obtained from simulation. The function has four parameters (a,b,c,d)

   (1.20)

The fitted values for a, b, c, d are 100.95, 1.0, 0.00773, and − 0.8849, respectively (Fig. 1.4).

Fig. 1.4 Four parameters a, b, c, d were fitted.

The comparison of numerical and experimental data for pig HF9 is presented in Figs. 1.5, 1.6, and 1.7. CXCR4 is considered to be initiator and plaque formation together with WSS distribution. The system of reaction-diffusion Eq. (3.7) (Parodi et al., 2012) is now

   (1.21)

Fig. 1.5 Numerical results for HP9. Foam cell (FC) lipid percentage area inside lesion area 26.2 %. Histological data per some characteristic cross sections and comparison with numerical data. Numerical cross-sectional dimension.

Fig. 1.6 Comparison between experimental and numerical data for pig HF9. Baseline and model with plaque. Cross-sectional presentation of histological and numerical data.

Fig. 1.7 Numerical results for pig HF9. Percentage of the FC lipids inside lesion area. Percentage of CXCR4 inside wall area. Shear stress distribution [Pa].

Boundary condition for first equation is WSS function from Fig. 1.4. and MIF signal function for the second equation. For fluid domain, we used around 100,000 eight-node finite elements. Wall domain was modeled with around 80,000 eight-node finite elements. Boundary conditions and fitted parameters are given in Table 1.3. ALE formulation was applied for the moving mesh domains. Time domain of 2 months was achieved for each pig.

Table 1.3

Numerical and experimental results for FC lipid percentage inside lesion area are presented in Fig. 1.5. It can be observed that good accuracy was achieved for lesion area, FC lipids, and CXCR4.

Comparison of these experimental and numerical data is given in Table 1.4.

Table 1.4

3.3 Fitting parameters of ODE model for pigs

In this section, we tried to fit ODE system for plaque formation by using experimental data from two HF pigs HF9 and HF11 and two HHF pigs HHF4 and HHF10. As ODE system is in the time domain, we assumed that different types of plaque lesion correspond to different time even it is on the same pigs.

3.3.1 Hybrid genetic algorithm

We firstly described a hybrid genetic algorithm for fitting parameters of ODE model for oxidized LDL, macrophage, smooth muscle cell, and foam cell concentration evolution in time. The goal of the fitting procedure is to determine parameters of ODE model, so it agrees with experimental data as much as possible. ODE model is given with the following equations:

   1.22

where C, ϕ, ρ, and φ are concentrations of oxidized LDL, macrophages, smooth muscle cells, and foam cells, respectively; β0, β1, γ0, γ1, α, λ1,and λ2 are real positive numbers; and Φ is a wall shear stress function:

   (1.23)

where α0, α1, and α2 are also real positive numbers.

A hybrid genetic algorithm combines the power of the genetic algorithm (GA) with the speed of a local optimizer. The GA excels at gravitating toward the global minimum. It is not especially fast at finding the minimum when in a locally quadratic region. Thus, the GA finds the region of the optimum, and then the local optimizer takes over to find the minimum. Hybrid GA can take one of the following forms:

1.Running a GA until it slows down, then letting a local optimizer take over. Hopefully the GA is very close to the global minimum.

2.Seeding the GA population with some local minima found from random starting points in the population.

3.After a few iterations, running a local optimizer on the best solution or the best few solutions and adding the resulting chromosomes to the population.

The continuous GA will easily couple to a local optimizer, since local optimizers use continuous variables. Generally, the local optimizer begins its job when the GA shows little improvement after many generations. The local optimizer uses the best chromosome in the population as its starting point. We used Nelder-Mead simplex optimization algorithm as a local optimizer (Nelder and Mead, 1965).

3.3.2 Results for fitting model

For fitting ODE model, we used HF and HHF pig data. Unfortunately, we do not have data about concentration evolution in time for LDL, macrophages (MPH), smooth muscle cell (SMC), and foam cell (FC). Instead, we used different lesion types as different time steps for each pig. Instead of macrophage concentration, we used MIF concentration. Oxidized LDL concentration is not available, so we fitted our ODE model according to MIF, SMC, and FC concentrations. Available data are represented in Tables 1.5 and 1.6 for HF pigs and Tables 1.10 and 1.11 for HHF pigs.

Table 1.5

Table 1.6

Available data for pigs HF9 and HF11 are given in Tables 1.5 and 1.6.

The best fit minimizes the sum of squared residuals, where residuals represent differences between experimental and calculated concentration of MIF, smooth muscle cells, and foam cells. Function to be minimized is in the following