Introduction to simulation of living systems

Modeling and simulation is the investigation of real world systems. They are utilized in
many fields of applications, especially technical sciences, physics, chemistry, economy,
medicine, biology and others.

Biosimulation play a fundamental role because it provide a method to test our

understanding of the biological system built from experimental data and observations via
models generally in a simplified versions.

From the view of a scientific-engineering approach the human-world interaction is based

on abstraction and formal models. Through observation and experimentation the scientist
attempts to create abstract representations and laws that formalize verified hypotheses
concerning real world phenomena. The formal models are only useful if they represent the
essential features of the real system. After the model-building stage simulation
experiments based on the models are performed and the results are interpreted on the
real world system.
 living Systems: It can be represented based on:
• Biology
• Math
• Computer science
• Engineering
• Chemistry
• Physics
• Statistics
There are two possible motivations for the development of a model:
problem

• The investigation of a real world system and the creation of a formal model increase
the insight of the structure of the problem. This provides a better understanding of
the system and the causality between the input and the output.
• The development of a control strategy for the real system based on the results of the
control
real experiments. In this case it is more important that the model emulates the
behavior of the system, but it is not necessary that it represents the internal
structure.
The Circulation of modeling and simulation
In human medicine modeling and simulation is limited by the complexity of the
investigated biological process and by the difficulties of gaining data for an individual
patient.

1. The complexity of the process complicates the first step of modeling , because very
often it is not clear where to draw the line between the parts that must be included
in the model and those that are negligible for a certain problem. Therefore in medical
modeling a combination of black and white box models are used very often.

2. The limited availability of data demands sometimes a down sizing of too complex
models to smaller ones, which can be identified with less data. But the unavailability
of data is not the only problem, because some data can only be gained from in-vivo
measurements, which are very complicated in most cases, so that in fact only a few
measurements can be performed, and those are often imprecise.
So there is a thin line between complex models, which represent the structural
information, but need too many parameters for identification, and simplified models,
which can be identified using easy available data at the cost of structural information.

Therefore the use of complex medical simulation not only for research but also for
assisting physicians in their daily work, depends very much on the further development of
measuring instruments and diagnostic tools.
Steps In Simulation and Model Building

1. Define an achievable goal.

2. Put together a complete mix of skills on the team.
3. Involve the end-user.
4. Choose the appropriate simulation tools.
5. Model the appropriate level(s) of detail.
6. Start early to collect the necessary input data.
7. Provide adequate and on-going documentation.
8. Develop a plan for adequate model verification.
9. Develop a plan for model validation.
10. Develop a plan for statistical output analysis.
Components of system

• Entity
An object of interest in the system : Heart in the circulation system
• Attribute
The property of an entity : heart beats, pressure
• Activity
A time period of specified length : ECG time wave
• State
A collection of variables that describe the system in any time.
• Event
A instantaneous occurrence that might change the state of the system: diseases.
• Endogenous
Activities and events occurring with the system.
• Exogenous
Activities and events occurring with the environment.
Flow chart of the steps in Simulation
 Case study 1: Simulation of blood flow in human artery
Blood is subject to the laws of mechanics; and the physical principles underlying the
motion of blood into vessels are particularly useful in the detection of abnormalities.
Specifically, in the last decades there is a growing interest towards the details of the flow
behavior of blood in the human vascular system, e.g. blood dynamics called hemodynamics.
Understanding of blood flow hemodynamics has great importance in testing the hypothesis
of disease pathogenesis, assessment and diagnosis of the cardiovascular disease, vascular
surgery planning, modeling the transport of drugs through the circulatory systems and
determining their local concentrations, predicting the performance of cardiovascular
equipment or instruments that have not yet been built such as heart valves, stents, probes,
etc., and devising better therapies of mainly coronary artery occluding, atherosclerosis,
thrombosis, vasculitis or varicose, aneurysms, etc.
The human cardiovascular system is very complex, it consists of blood, blood vessels, and
the heart.
Blood acts as a transport mechanism to the cells for carrying nutrients and wastes.
Blood vessels provide a tubular network to channel the blood to every possible region of the
body.
And the heart creates the pressure required to push blood through the vessels.
The current trend for blood flow modeling is to use non-Newtonian models to describe
blood flow behavior, as blood is actually a collection of cells suspended within plasma and
therefore does not exhibit Newtonian properties under normal conditions. Another recent
development is the incorporation of Fluid-Structural Interaction (FSI), which allows a
coupling between fluid and solid models. This method allows for a study of the vessel wall
behavior and flow response to wall deformation, factors which previously have been
neglected. This provides a valuable tool in determining critical areas where plaque rupture
or wall-collapse is likely to occur.
The constituents of blood.
The blood vessels structure
 An average cardiac output of (5.5 L) per minute:
Cardiac Output = Stroke Volume × Cardiac Rate
(ml/min) (ml/beat) (beats/min)
Arterial Fluid Biomechanics
The flow of blood through a vessel depends in part on the difference in pressure at the
two ends of it. If the pressure at both ends of the vessel is the same, there will be no flow. If the
pressure at one end is greater than at the other, blood will flow from the region of higher to the
region of lower pressure. The rate of blood flow is proportional to the pressure difference (P1 –
P2) between the two ends of the vessel.
Blood flow is directly proportional to the pressure difference (∆P) between the two ends of
the vessel but is inversely proportional to the frictional resistance to blood flow through the
vessels:
 ∆𝑷
𝑸 ∝
𝑹
Where:
Q = Blood flow, R = Vascular resistance

The resistance to blood flow through a vessel is directly proportional to the length of
the vessel and to the viscosity of the blood. Of particular physiological importance, the
vascular resistance is inversely proportional to the fourth power of the radius of the
vessel:
𝑳µ
𝑹 ∝ 𝟒
𝒓
Where:
L = length of the vessel
r = radius of the vessel
µ = viscosity of the blood
Blood flow in most healthy
(b)
situations should be laminar, or at least not turbulent. In fact,
the flow in most arteries would be most properly classified somewhere in between laminar
and turbulent.

Velocity profile for laminar flow (uniform) (a), (non- uniform) (b), and for turbulent flow
(c).
 The pulsatile nature of the cardiac output is also an important factor in determining
blood flow patterns. The most important parameter in describing pulsatile flows is the
Womersley parameter:
𝝎𝝆
𝜶=𝒓
𝝁

Where: ω = the radian frequency of the heart beat.

The velocity profiles tend to be nearly parabolic in shape. At higher Womersley parameter
values, unsteady effects become more important, and the velocity profiles may take on
complex m-shapes, with a core of nearly in viscid (plug) flow in the middle.
The flow instabilities created by branches are also present with pulsatile flow.
However, like turbulent fluctuations, they tend to be less prevalent when the flow is
accelerating.
 As with the non-Newtonian behavior of blood, the importance of vessel wall compliance
depends on the type of information desired. Fluid in contact with the vessel wall will travel
at the same velocity as the wall under the ‘no slip’ condition imposed on the boundary.

This causes a non-zero velocity gradient, (du/dy) where u and y are the velocity
components in the direction of the flow and the space coordinate normal to the flow
direction respectively as shown:

Diagram showing the velocity component u, in the

direction of the flow and the space coordinates x and y
for a ‘no slip’ condition applied on the vessel wall.
 The mathematical relationship between the wall shear stress (τ ) and the viscosity (μ )
of the blood is shown below:
𝒅𝒖
𝝉=𝝁
𝒅𝒚

Computational Fluid Dynamic (CFD) Technique

The physical aspects of any fluid flow are governed by three fundamental principles:
1. Mass is conserved;
2. Newton's second law of motion (force = mass × acceleration);
3. Energy is conserved;
 These fundamental physical principles can be expressed in terms of basic
mathematical equations, which in their most general form are either integral equations or
partial differential equations.
CFD is the art of replacing the integrals or the partial derivatives (as the case may be) in
these equations with discretized algebraic forms, which in turn are solved to obtain numbers
for the flow field values at discrete points in time and/or space.
The field of CFD has a broad range of applicability. Independent of the specific application
under study, the following sequence of steps generally must be followed in order to obtain a
satisfactory solution:
1. Problem specification and geometry preparation.
The first step involves the specification of the problem, including the geometry, flow
condition, and the requirements of the simulation.
2. Selection of governing equations and boundary conditions.
Once the problem has been specified, an appropriate set of governing equations and
boundary conditions must be selected.
The success of the simulation depends greatly on the engineering insight involved in
selecting the governing equations and physical models based on the problem specification.
3.Selection of gridding strategy and numerical method.
Next a numerical method and a strategy for dividing the flow domain into cells, or
elements, must be selected. Furthermore, the grid can be altered on the solution in an
approach known as solution-adaptive gridding. The numerical methods generally used in
CFD can be classified as finite-difference, finite-volume, finite element, or spectral
methods. Here again, the success of the simulation can depend on appropriate choices for
the problem or class of the problems of interest.
4. Assessment and interpretation of results.
Finally, the results of the simulation must be assessed and interpreted. This step can
require post-processing of data.
Biofluid Applications in CFD
Extension of CFD methods to blood flow has been of interest to biomedical researchers
for many years. However, lack of a complete analysis capability kept it from making
significant impacts on medical research and practices for many years. The human circulatory
system is like a huge tree with many branches of various sizes. Therefore, many
computational studies have been performed using a truncated geometric model. One difficulty
in simulating a truncated arterial system results from setting proper boundary conditions,
especially at the downstream boundary.
Because of its importance in biomedical research, modeling and simulation of the
cardiovascular system has been the subject of many investigations.
Another interesting application of blood flow simulation is related to artificial devices such
as artificial hearts, ventricular assist devices (VADs), and heart valves. Because the demand
for transplant organs far exceeds the number of donors, the need for artificial devices to be
used either as a temporary device or as a permanent replacement for a natural organ-
becomes increasingly high. Accurate quantification of blood flow plays a crucial role in
developing these devices.
All such blood flow computations may be regarded as a branch of CFD. The number
of CFD applications for blood flow and biomedical problems is increasing rapidly, and the
work cited here represents only a small sample of the vast amount of ongoing work.
A) Cell-Free Marginal Layer Model
Haynes has presented a model for characterizing the laminar flow called cell-free marginal
layer model. Consider steady flow of blood through a circular tube of radius a as shown in
Figure below. The tube cross section can be divided into a core region and a cell-free plasma
region near the wall.
The governing equations for both regions can be given by the following equations:

where and represent the viscosities of the core and periphery, respectively.
and represent the velocities of the core
and periphery, respectively.
The boundary conditions used to obtain a solution for the two differential equations are
(1) the velocity gradient is zero at the center of the tube. ( )
(2) no slip occurs at the tube wall. ( )
(3) the velocity and the shear stress is continuous at the interface between the two zones.
(at , )
The equations can be integrated with the above boundary conditions to solve for the
velocity components and to obtain an expression for the flow rate as given below:

By comparison, the expression for the flow rate for a homogeneous fluid (Poiseuille’s
Equation) was derived earlier as:
Comparing these two equations, if Poiseuille’s law was applied to calculate the viscosity of
blood, the apparent viscosity could be written as:

In the limit as , , as would be expected. When the ratio is small, the higher
order terms containing the ratio can be neglected and the relationship for the apparent
viscosity reduces to:
B) Sigma Model

The Sigma effect theory, however, states that when blood flows through a small diameter
tube, the assumption of a continuum is not valid. For example, assume that the tube
diameter is so small that there is only room for five red blood cells to move abreast. Then,
the ensuing velocity profile would not be continuous and would consist of concentric
laminae moving axially as demonstrated in Figure below:
An apparent viscosity can be derived for this case by the following analysis. The expression
for flow rate from the Poiseuille solution:

or:

Applying the “no slip” condition at the wall, the first integral on the right side will be
identically equal to zero. From the parabolic velocity profile characteristic of Poiseuille flow,
the expression for the velocity gradient will be given by:

Substituting this velocity gradient into the flow integral, we obtain

Now, if we assume that flow occurs in N concentric laminae, each of thickness
then the radius R of the tube will be equal to N and any general radius r can be
replaced by n , where n = 1,2 ... N.
If r = n , then since is equal to unity.
Hence, the integration can be replaced by a summation as:

Since and

Then ,

and the apparent viscosity can be given by the formula: