Quantitative Physiology Amr A.

Sharawi

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Foreword

It can be argued that of all the biological sciences, physiology is the one in which mathematics has played the greatest role. Since the nineteenth century, physiologists have repeatedly used mathematical methods and models to help their understanding of physiological processes. Yet, there are always barriers to communication between physiology and 4/28/12

Foreword

But times are changing, and it is rapidly becoming apparent that applied mathematics and physiology have a great deal to offer one another. It is our view that teaching physiology without a mathematical description of the underlying dynamical processes is like teaching planetary motion to physicists without mentioning or using Keplers laws; you can observe that there is a full moon every 28 days, but without Keplers 4/28/12 laws you cannot determine when the next

Course Objectives

This course highlights some of the work that lies on the border between mathematics and physiology; it describes some of the ways in which mathematics may be used to give insight into physiological questions, and how physiological questions can, in turn, lead to new mathematical problems. In this sense, it is truly an interdisciplinary course, which, hopefully, may be appreciated by physiologists interested in 4/28/12

Course Objectives

More importantly, it emphasizes the concept to the applied mathematician (engineer) that mathematical modeling of normal physiological function is just an invaluable tool for the design of manmade system intended to assist or support life or to compensate for dysfunction.

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Course Topics

Basic physiology Mathematical models Cardiovascular system Respiratory system

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References

A.C. Guyton, J.E. Hall: Textbook of Medical Physiology, 11th ed., ElsevierSaunders, 2006. E.P. Widmaier, H. Raff, K.T. Strang: Human Physiology: The Mechnisms of Body Function, 9th ed., Mc. Graw Hill, 2004. J.D. Bronzino: The Biomedical Engineering HandBook, Second Edition, CRC Press, LLC, 2000. J. Keener, J. Sneyd: Mathematical
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BASIC PHYSIOLOGY

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Aim of Physiology

The goal of physiology is to explain the physical and chemical factors that are responsible for the origin, development, and progression of life.

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The Scope of Physiology

The scope of physiology is extremely broad. At one end of the spectrum, it includes the study of individual moleculesfor example, how a particular proteins shape and electrical properties allow it to function as a channel for sodium ions to move into or out of a cell. At the other end, it is concerned with complex processes that depend on the
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Physiologists are unique among biologists

They are always interested in function and integrationhow things work together at various levels of organization and, most importantly, in the entire organism. Many areas of function are still only poorly understood (for example, how the workings of the brain produce the phenomena we associate with conscious thought and memory). There is much to 4/28/12 say about the future of physiology

The Relationship between Physiology and Medicine

Some disease states can be viewed as physiology gone wrong, or pathophysiology. For this reason an understanding of physiology is essential for the study and practice of medicine. Indeed, many physiologists are themselves actively engaged in research on the physiological bases of a wide 4/28/12 range of diseases.

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Types of Cells

About 200 distinct kinds of cells can be identified in the body in terms of differences in structure and function. When cells are classified according to the broad types of function they perform, however, four categories emerge:

muscle cells nerve cells epithelial cells

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Muscle Cells

They are specialized to generate the mechanical forces that produce movement. There are three types of muscle cells which differ from each other in shape, in the mechanisms controlling their contractile activity, and in their location in the various organs of the body. These are

Skeletal muscles Smooth muscles

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Nerve Cells

They are specialized to initiate and conduct electrical signals, often over long distances. A signal may initiate new electrical signals in other nerve cells, or it may stimulate secretion by a gland cell or contraction of a muscle cell.

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Epithelial Cells

They are specialized for the selective secretion and absorption of ions and organic molecules, and for protection. They are located mainly at the surfaces that

(1) cover the body or individual organs or (2) line the walls of various tubular and hollow structures within the body.

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Connective Tissue Cells

They connect, anchor, and support the structures of the body.

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Tissues

Most specialized cells are associated with other cells of a similar kind to form tissues. A tissue is formally defined as an aggregate of a single type of specialized cell. However, it is also commonly used to denote the general cellular fabric of any organ or structure, for example, kidney tissue or lung tissue, each of which in fact 4/28/12 usually contains all four classes of tissue

Organs

Organs are composed of the four kinds of tissues arranged in various proportions and patterns like for example

sheets tubes layers bundles strips

Many organs are organized into small, similar subunits often referred to as 4/28/12

Organ Systems

Organ systems are a collection of organs that together perform an overall function. For example, the kidneys, the urinary bladder, the tubes leading from the kidneys to the bladder, and the tube leading from the bladder to the exterior constitute the urinary system. There are 10 organ systems in the body.

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BODY FLUID COMPARTMENTS

Fluid compartments of the body. Volumes are for an average 70-kg (154-lb) person. 4/28/12

Extracellular FluidThe Internal Environment

About 60 per cent of the adult human body is fluid, mainly a water solution of ions and other substances. Although most of this fluid is inside the cells and is called intracellular fluid, about one third is in the spaces outside the cells and is called extracellular fluid. This extracellular fluid is in constant motion throughout the body. It is transported rapidly in the circulating 4/28/12

Extracellular FluidThe Internal Environment

In the extracellular fluid are the ions and nutrients needed by the cells to maintain cell life. Thus, all cells live in essentially the same environmentthe extracellular fluid. For this reason, the extracellular fluid is also called the internal environment of the body.
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Homeostasis

The term homeostasis is used by physiologists to mean maintenance of nearly constant conditions in the internal environment. Essentially all organs and tissues of the body perform functions that help maintain these constant conditions. The preservation of these constant conditions is effected by means of control systems.
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Homeostatic Control Example: Thermoregulation

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The Human as an Automaton

The human being is actually an automaton The fact that we are sensing, feeling, and knowledgeable beings is part of this automatic sequence of life These special attributes allow us to exist under widely varying conditions.

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The human body has thousands of control systems in it. The most intricate of these are the genetic control systems that operate in all cells to help control intracellular function as well as extracellular function. Many other control systems operate within the organs to control functions of the individual parts of the organs. Other systems operate throughout the 4/28/12 entire body to control the interrelations

Control Systems of the Body

Negative feedback nature of most control systems Positive feedback does not lead to stability but to instability. It can cause serious diseases and often death.

Characteristics of Control Systems

Yet in a few cases positive feedback can sometimes be useful. Blood clotting is an example

More complex types of control systems are called Adaptive Control

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Recovery of heart pumping caused by negative feedback after 1 liter of blood is removed from the circulation. Death is caused by positive feedback when 2 liters of blood are removed. 4/28/12

Examples of Body Control Systems

The respiratory system, operating in association with the nervous system, regulates the concentration of carbon dioxide and oxygen in the extracellular fluid, thus replenishing the oxygen used by the cells. The kidneys regulate concentrations of hydrogen, sodium, potassium, phosphate, and other ions in the extracellular fluid. The liver and pancreas regulate the 4/28/12 concentration of glucose in the

Regulation of Body Functions

The hallmark of vertebrate physiology is the fine control of physioIogical states by negative feedback systems. For this to be effective, there must be mechanisms to turn off operating processes and to turn on dormant processes. This requires that there be body-wide communication among system components that signals the state of 4/28/12

The coordinated interaction of the central nervous system and hormones is one of the most important mechanisms by which negative feedback is achieved. Thus the two main control systems of body functions are:

Regulation of Body Functions

Nervous System (fast response) Hormonal System of Regulation (slow response)

Thus, the hormones are a system of 4/28/12 regulation that complements the nervous

Nervous System

The nervous system is composed of three major parts:

the sensory input portion, the central nervous system (or integrative portion) the motor output portion.

Sensory receptors detect the state of the body or the state of the surroundings.
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Nervous System

The central nervous system is composed of the brain and spinal cord. The brain can store information, generate thoughts, create ambition, and determine reactions that the body performs in response to the sensations. Appropriate signals are then transmitted through the motor output portion of the nervous system to carry out ones 4/28/12 desires.

Autonomic Nervous System

A large segment of the nervous system is called the autonomic system. It operates at a subconscious level and controls many functions of the internal organs, including

the level of pumping activity by the heart, movements of the gastrointestinal tract, secretion by many of the bodys glands

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Hormonal Control

In the body there are eight major endocrine glands that secrete chemical substances called hormones. Hormones are chemicals that are transported long distances via the blood to all parts of the body and that are capable of turning on and off processes occurring at the site of hormone action, thus to help regulate cellular function.
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Thyroid hormone increases the rates of most chemical reactions in all cells, thus helping to set the tempo of bodily activity. Insulin controls glucose metabolism; Adreno-cortical hormones control

Examples of Hormonal Control

sodium ion potassium ion protein metabolism

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MATHEMATICAL MODELS

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What is Mathematical Modeling

Mathematical modeling is the process of combining quantitative data with a qualitative understanding to produce an explanatory and predictive tool. The level of advancement from qualitative/ quantitative prediction via mathematical modeling is one measure which marks the maturity of a scientific discipline. Mathematical models are theoretical 4/28/12 constructions that allow formulation and

Mathematical Models: Definition

A mathematical model is an abstract model that uses mathematical language to describe the behavior of a system. Eykhoff (1974) defined a mathematical model as 'a representation of the essential aspects of an existing system (or a system to be constructed) which presents knowledge of that system in usable form.
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Why use models in science and technology?

Because of the ease with which they can be used to analyze real systems Because of their prominent ability to predict as yet unknown properties of the system

actually since model parameters of a mathematical or computer model can be easily altered and the system performance can be simulated three-dimensional physical

For 4/28/12 example

Typical Applications of Mathematical Models

Mathematical models are used particularly in the natural sciences and engineering disciplines (such as physics, biology, and electrical engineering). They are also used in the social sciences (such as economics, sociology and political science). Physicists, engineers, computer scientists, and economists use 4/28/12 mathematical models most extensively.

Different Forms of Mathematical Models

Mathematical models can take many forms, including but not limited to:

Dynamical systems Statistical models Differential equations Game theoretic models

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Groups of Variables to be Modeled

Decision variables Input variables State variables Exogenous (disturbance) variables Random variables Output variables
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The Mathematical Modeling Process

Identification of the problem

which must then be described using the language of mathematics. they must be solved and interpreted in the language used to describe the original problem.

Solution of the resultant equations

Comparison of the results of the mathematical problem to reality

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to identify improvements and extensions

The Modeling Process

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Upper row: Scale describing the different modeling levels with the corresponding dimensioning for biological systems beginning from the genetic/protein level up to whole system models and organisms. Middle row: Each level of modeling requires the appropriate method for describing the related mathematical behavior of the system. Lower row: Scale describing time constants reaching from molecular events up to a human lifetime. Abbreviations: ODEs = ordinary differential equations, PDEs = partial differentia equations, 4/28/12 ML = model, Anat = anatomical, Physio = physiological

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Why don't we use modeling in all biomedical fields?

The number of variables required to define the state of a system may become prohibitive. The interactions between these variables which determine system function may become extremely complex. The characteristic space and time scales of these systems require a certain level of technological development before 4/28/12 experiments to measure the variables are

Mechanical Models

Mechanical models consisting of combinations of springs and dashpots are very popular in numerous disciplines. They have been used to model the mechanical behavior of viscoelastic materials. In a linear spring the force is proportional to the change in length or the strain. But the force in a dashpot is proportional to the rate of change in strain.
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Mechanical Models

Consider a mass supported by a spring and dashpot in parallel. Application of Newtons law results in:
d 2x dx F = m 2 + b + kx dt dt (1A)

where x = elongation w.r.t. steady state value b = constant of the dashpot k = spring constant
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Mechanical Models

It should be pointed out that this mechanical equation is similar to the electrical equation:
L di 1 + Ri + i dt = E dt C (1B)

where L = inductance, R = resistance, C = capacitance, i = current, E = voltage This equation can be expressed in terms of the charge instead of the current as follows: 2

d q dq 1 L 2 +R + q=E dt dt C

(1C)

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Mechanical Models

Equations (1A), (1B) & (1C) are similar. Thus

A mass is similar to an inductor A dashpot is similar to a resistor A spring is similar to a capacitor Charge is similar to deformation or elongation Current is similar to velocity Force is similar to voltage

The mass, the spring, the inductor and 4/28/12 the capacitor are storage units, whereas

Electric Analog Models

Electric analog models (or simply electric analogs) are a class of lumped models. They are often used to simulate flow through the network of blood vessels. These models are useful in assessing the performance of a system or a subsystem. The flow of blood is governed by:

Fluid momentum equation (KVL) Fluid continuity equation (KCL)

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Electric Analog Models

Electrical analog models have been used in the study of cardiovascular, pulmonary, intestinal, and urinary system dynamics. An electrical analog model has been also used to simulate flow through the urethera. The model consisted of a simple RLC circuit with a variable capacitor. The time-varying capacitor simulated the time-dependent relaxation of the 4/28/12

Electrical Analogy for the Fluid Momentum Equation (Conservation of Momentum) dQ a P = 2a

2

dt

wher e

Q = flow rate driving P= pressure a = vessel wall radius l = vessel length w = shear stress at wall

w =

l dQ 8l = P 4 Q 2 a dt a dQ L = P RQ 4/28/12 dt

4 Q a3

Resulting Analogy

It can be easily observed that:

Q is analogous to electric current i P is analogous to electric voltage drop E L = inertance (analogous to electrical inductance) R = resistance to flow (analogous to electrical di resistance) L = E Ri
dt

Therefore the electric circuit analogy is given by:

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Electrical Analogy for the Fluid Continuity Equation (Conservation of Mass)

V= volume Qin = inflow Qout = outflow However, the volume is a function of the transmural pressure P. dV dP
wher e

dt

=C

dt

dP C = Qin Qout dt
These equations can be used to simulate either a blood vessel segment or 4/28/12 the entire blood vessel.

Resulting Analogy

V is analogous to electric charge Q. C = compliance (analogous to electrical capacitance)

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Example: Electrical Analog of the Leg Circulation

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Electrical analog model of the circulation of the leg. PMP is the muscle pump which exerts a periodic external pressure on the blood vessels. Q is the flow rate. QLGSA is the flow through the leg small arteries, QCAP is the flow rate through the capillary. QLGVE is the flow through leg small veins. The elasticity is simulated with 4/28/12 capacitance. The

In small blood vessels, the inductance L is very low compared to the resistance term R, therefore the inductance term can be neglected in small arteries, arterioles, and capillaries. Since there is no pressure oscillation in the capillaries, the inductance term can be neglected in vessels downstream of the capillary (i.e., venules, veins, and vena cava).
4/28/12 Since the small arteries are distensible

Electrical Analog of the Leg Circulation

Venules have a resistance and a variable capacitance. This capacitance is subject to neurogenic control, since the diameter of the venule is also under neurogenic control. From the venules blood flow goes into the legs small veins which have a resistance and a variable capacitance subject to neurogenic control. The veins have valves (diodes). They 4/28/12 permit flow in only on direction.

Electrical Analog of the Leg Circulation

Electrical Analog of the Leg Circulation

Blood flow in the legs is aided by the muscle pump, which is created by periodic skeletal muscle contractions during walking, etc. These contractions produce pressure oscillations on the blood vessel walls. That muscle pump is absent in bedridden patients. Extremity pumps are therefore used for such patients to enhance blood flow through the legs.
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Lumped Mechanical Models

Lumped mechanical models have been used to analyze impact dynamics and vibration. Generally a muscle is represented by a combination of a spring and a dashpot, whereas a ligament is represented by a spring.

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Electromechanical Analogy

Any electrical system can be modeled by mechanical analogs and vice versa.

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Important Considerations

Regardless of the type of mathematical model developed, it should be validated with experimental results. Validation becomes very important in the black-box type of models, such as neural network models. Moreover, model results are valid only within certain regimes where the model assumptions are valid.
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Compartmental Systems

A compartment is an amount of some material which is homogeneously distributed. Examples:

The amount of drug in the bloodstream of a person The number of infected individuals in an epidemic of a specific disease in a uniform population.

A compartment is usually represented diagramatically by a square or a circle with arrows pointing towards and/or away from 4/28/12 the compartment.

Compartmental Systems

A compartmental system is a group of compartments that are connected by arrows. The system diagram represents all the flows into or out of the system, as well as the flows inside the system. Therefore it is called a connectivity diagram for the system. 1
1 2

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Compartmental Models

The concept of a compartmental model assumes that the system can be divided into a number of homogeneous wellmixed compartments. Various characteristics of the system are determined by the movement of material from one compartment to the other. Compartmental models have been used to describe:

blood flow distribution to various organs population dynamics

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A one-compartment model of the human body to analyze the patient-dialyzer interactions for the prescription of treatment 4/28/12 protocols for dialysis by an artificial kidney device

Single Compartment Model of a Dialyzer

The purpose of dialysis is to bring the blood urea nitrogen level (BUN) in a patient closer to normal. In an artificial kidney blood flows on one side of the dialyzer membrane and the dialysate flows on the other side. Mass transfer across the dialyzer membrane occurs by diffusion due to the concentration difference across the membrane.
4/28/12 In a one-compartment model of the tissue

Single Compartment Model of a Dialyzer

Mass balance demands that the rate of accumulation of mass in the body be equal to the net rate of mass coming into the body from the dialyzer + metabolic production rate. Thus
Ci dC V = m Q( Co Ci ) = m QCo 1 C dt o
wher e

V = tissue volume + blood volume Q = blood flow rate to the kidney m = metabolic waste production rate in the body

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Single Compartment Model of a Dialyzer

Regardless of the dialyzer type, the extraction ratio can be expressed as the fraction of a substance removed from the blood flowing through the kidney. It is calculated using the ratio of the substance concentrations in kA Ci the arterial and venous renal plasma.
E = 1 Co = 1 exp Q
wher e

A = membrane surface area for mass exchange k = permeability of membrane for a solute species (e.g., urea) Q is not scheduled to change during dialysis. k and A are design parameters. Therefore the extraction ratio, E remains constant.
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Also, it should be noted that the solute concentration Co going out of the body is the same as its concentration inside the body C, since we have assumed that the entire body (blood and tissue) constitutes a homogeneous wellmixed compartment. Thus
Ci dC V = Q( Ci Co ) + m = QCo 1 + m = QCo E + m = QCE + m C dt o

Single Compartment Model of a Dialyzer

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When the dialyzer is turned on, the metabolic production rate (m) can be neglected when compared to the other term in the equation, and the integration will result in QE C = C o exp t V Co = initial urea concentration This means that when the patient is on dialysis the urea concentration tends to decay exponentially. On the other hand, when the patient is not on dialysis, the blood flow to the dialyzer is zero. dC m =V The rate of waste mass production in the body is then given dt by: Thus when the patient is not on dialysis, the concentration of the urea will increase linearly if the metabolic rate is constant, or will increase exponentially if the metabolic rate is a linear function of the concentration.
In this way the treatment protocol can be prescribed after simulating different on/off 4/28/12 times (e.g. turn on the dialyzer for 4 hours every 3 days) to bring the

Single Compartment Model of a Dialyzer

Two Compartment Model of a Dialyzer

C1 C 1 Intracellul ar

C 2 Extracellu lar

Dialyz er

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Two Compartment Model of a Dialyzer

Intracellular pool (Compartment (1)) Extracellular pool (Compartment (2)) Urea is produced in the intracellular pool and is transported across the cell membrane into the interstitial fluid (extracellular pool) and then into the blood stream.
dC Mass1 balance 1for 2these two compartment is V1 = m kA( C C ) dt given by:
dC 2 V2 = kA( C1 C 2 ) QC 2 E dt

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where

Two Compartment Model of a Dialyzer

V1 and V2 refer to the volumes of compartments (1) and (2), respectively. C1 and C2 refer to the urea concentrations in compartments (1) and (2), respectively. Let V = V1 + V2 = total distribution volume for the solute C = C2 = concentration of solute passing into the bloodstream Adding both equations we get: dC V = m QCE dt

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