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3081

DYNAMICAL SYSTEMS

Volume 32, Number 9, September 2012 pp. 3081–3097

Avner Friedman

The Ohio State University

Department of Mathematics

Columbus, OH 43210, USA

servation laws of the form

∂u

+ div(Vu) = F(t, x, u) (x = (x1 , . . . , xn )) (0.1)

∂t

where u = u(t, x) is a vector (u1 , . . . , uk ), F is a vector (F1 , . . . , Fk ), V is

a matrix with elements Vij (t, x, u), and Fi (t, x, u), Vij (t, x, u) are nonlinear

and/or non-local functions of u. From a mathematical point of view one would

like to establish, first of all, the existence and uniqueness of solutions under

some prescribed initial (and possibly also boundary) conditions. However, the

more interesting questions relate to establishing properties of the solutions that

are of biological interest.

In this article we give examples of biological processes whose mathematical

models are represented in the form (0.1). We describe results and present open

problems.

tant organisms (ARO) pose an increasing serious health threat in hospitals. Factors

which contribute to the spread of ARO in hospitals are poor immune system of most

patients, close living quarters, and the contact with health care workers (HCWs)

as, for example, in patients with intravenous drip or catheter. D’Agata et al. [11]

[12] and Webb et al [40] developed a mathematical model of the growth in drug

resistance in terms of a system of dynamical equations. The population of patients

is divided into compartments: colonized, uncolonized, contaminated, uncontami-

nated, with the drug-resistant, or with non-drug resistant bacteria. The proportion

of the population in each compartment is considered as a variable, xi . A system

of differential equations for the xi is then introduced to describe bacterial trans-

mission among the various compartments and to explore optimal strategies of drug

treatment.

More recently Friedman et al. [31] developed a different model based on a system

of two conservation laws of the form (0.1) with V which depends on the dynamics of

the bacteria. The model considers two bacterial strains: non-drug resistant bacteria

b1 and drug-resistant bacteria b2 . We assume that each patient carries bacterial

strains of some load (b1 , b2 ). Denote by P (t, b1 , b2 ) the number density of patients

with bacterial load (b1 , b2 ), that is, the number of patients at time t with bacterial

load between (b1 , b2 ) and (b1 + ∆b1 , b2 + ∆b2 ) is approximately P (t, b1 , b2 )∆b1 ∆b2 ,

2000 Mathematics Subject Classification. 35K57, 35L60, 35L65, 35R35, 92C17, 92C37, 92C50.

Key words and phrases. Hyperbolic equations, reaction-diffusion equations, parabolic equa-

tions, free boundary problems, drug resistance, cell differentiation, wound healing, tumor growth.

3081

3082 AVNER FRIEDMAN

provided ∆b1 and ∆b2 are small numbers. Similarly, the number density of HCWs

with bacterial load (b1 , b2 ) is denoted by H(t, b1 , b2 ). We introduce the dynamics

of the bacteria in a patient and in a HCW, respectively, by

dbi dbi

= Ai (t, b1 , b2 , H), = Bi (t, b1 , b2 , P ), (i = 1, 2). (1.1)

dt dt

The function Ai depends on the natural growth of bi , the bacterial transmission

from H which contributes to an increase of bi , the response of the immune system

of patients to bi , the effect of drug treatment, and the mutation rate from non-drug

resistant bacteria to the drug-resistant bacteria. The function Bi depends on the

growth of bi and on the bacterial transmission from P . We assume that HCWs

undergo sterilization by the end of each shift, and, therefore, we do not include

infection, drug treatment and immune response in the dynamics of the bacteria

(b1 , b2 ) within the HCWs.

We assume that visits by HCWs, with H(t, a1 , a2 ), to the patients with P (t, b1 , b2 )

result in transmission of bacteria to patients, proportional to

H(t, a1 , a2 )(ai − bi )+ for species i,

where s+ = max{s, 0}. The dynamics of the bacteria in the patients is described

by the equations

db1

= λ1 b1 − νM1 (t, b)b1 − σ1 (t)b1 − µ(t)b1 + (1.2)

dt |{z} | {z } | {z } | {z }

growth immune response drug response mutation

Z

η1 H(t, a)(a1 − b1 )+ da ≡ A1 ,

Ω

| {z }

infection of patients by HCWs

db2

= λ2 b2 − νM2 (t, b)b2 − σ2 (t)b2 + µ(t)b1 + (1.3)

dt |{z} | {z } | {z } | {z }

growth immune response drug response mutation

Z

η2 H(t, a)(a2 − b2 )+ da ≡ A2

Ω

| {z }

infection of patients by HCWs

Similarly, the dynamics of the bacteria in the HCWs is given by

Z

db1

= λ1 b1 + η1 P (t, a)(a1 − b1 )+ da ≡ B1 , (1.4)

dt |{z}

growth Ω

| {z }

contamination of HCWs by patients

Z

db2

= λ 2 b2 + η2 P (t, a)(a2 − b2 )+ da ≡ B2 . (1.5)

dt |{z}

growth Ω

| {z }

contamination of HCWs by patients

Since HCWs undergo sterilization by the end of their shift, they do not become

infected.

CONSERVATION LAWS IN MATHEMATICAL BIOLOGY 3083

If we assume that patients enter or leave the hospital with total balance F (F

may be positive or negative) then, by conservation law,

∂P

+ div(AP ) = F (1.6)

∂t

where A = (A1 , A2 ) is defined in (1.2)-(1.3). Similarly,

∂H

+ div(BH) = 0 (1.7)

∂t

if the number of HCWs remains unchanged.

Patients are observed for a 6 weeks period and are given a drug when the bacterial

load b1 + b2 exceeds a threshold TH . Both TH and the duration of the treatment

are viewed as control variables, but the total amount of drug given over the 6 weeks

period is fixed. Mutation from the non-resistant strain b1 to the resistant strain b2 ,

resulting from the use of the drug, are included in the mutation term in (1.2)-(1.3).

We are interested in evaluating the bacterial loads

Z

Qi (t) = bi P (t, b)db (i = 1, 2),

Ω

The model predicts that as soon as drug is administered, the average non-

resistant load Q1 (t) will decrease and eventually (i.e., after 6 weeks) will reach

a very low level. However, the average load Q2 (t) of the drug-resistant bacteria

will decrease, immediately after treatment, but then will bounce back and remain

at a high level, dropping off eventually only if the total amount of drug to kill the

bacteria (or, alternately, the strength of this drug) is large enough. This result

agrees qualitatively with experimental results [4] [33] that underdosing increases

the drug-resistant bacteria.

The model also predicts that lower values for Q2 (t) are obtained if the (total fixed

amount of) drug is administered for a period of two weeks instead of one week.

2. T cell differentiation. Lymphocytes are white blood cells that play important

roles in the immune system. T cells and B cells are two major types of lympho-

cytes. B cells produce antibodies against pathogens while T cells are involved in

autoimmunity. Th lymphocytes represent a subtype of T cells that are identified

by the presence of surface antigens called CD4; they are referred to as CD4+ T

cells. Other subtypes of T cells include cytotoxic T cells (CD8+ ) and regulatory

T cells. Th cells are the most numerous of the T cells in a healthy person. After

an initial antigenic stimulation, Th lymphocytes differentiate into either one of two

distinct types of cells called Th1 and Th2. Th1 cells produce IFNγ that combat

intracellular pathogens; and this immune response, if abnormal, is associated with

inflammatory and autoimmune diseases. Th2 cells produce cytokines that activate

B cells to produce antibodies against extracellular pathogens; this response, if ab-

normal, is associated with allergies such as asthma. Whether a precursor Th cell

becomes Th1 or Th2 depends on ‘polarizing’ signals. Yates et al. [43] developed a

model of Th differentiation based on the interaction and competition between two

transcription factors, T-bet and GATA-3. High protein level of T-bet or GATA-3

corresponds to the Th1 phenotype or the Th2 phenotype. We shall denote by S1

and S2 the Th1 and Th2 polarizing cytokines, and by x1 and x2 the concentrations

3084 AVNER FRIEDMAN

is described by

xn

dx1 S1 1

= −µx1 + α1 n 1 n + σ1 · + (2.1)

dt k1 + x1 ρ1 + S1 1 + x2 /γ2

β1 ≡ f1 (x1 , x2 , S1 ),

xn2

dx2 S2 1

= −µx2 + α2 n n + σ2 · + (2.2)

dt k2 + x 2 ρ2 + S2 1 + x1 /γ1

β2 ≡ f2 (x1 , x2 , S2 ),

where n ≥ 2. The first term on the right-hand side of each equation represents the

rate of protein degradation. The last term βi is the constant basal rate of protein

synthesis. The second term on the right-hand side represents autoactivation of

the transcription factor xi plus exogeneous signal, and both are inhibited by the

competing transcription factor xj (j 6= i). Si is given by

R

Ci (t) + xi φ(t, x1 , x2 )dx1 dx2

Si (t) = R , i = 1, 2, (2.3)

φ(t, x1 , x2 )dx1 dx2

R

where Ci (t) is non-T cell signal whereas xi φ(t, x1 , x2 )dx1 dx2 is the component of

the signal produced by the population of Th cells weighted by the density of xi ;

here φ(t, x1 , x2 ) denotes the population density of CD4+ T cells with concentration

(x1 , x2 ) at time t; the above integrals are taken over a rectangular domain

Ω = {(x1 , x2 ), 0 ≤ x1 ≤ A1 , 0 ≤ x2 ≤ A2 }.

By conservation of mass,

∂φ ∂ ∂

+ (f1 φ) + (f2 φ) = gφ (2.4)

∂t ∂x1 ∂x2

in Ω, where f1 , f2 are defined in (2.1)-(2.2), and g is a growth term, and

φ|∂Ω = 0, φ(0, x1 , x2 ) is prescribed.

Friedman, Kao and Shih [26] proved that, with appropriate choice of A1 , A2 ,

this problem has a unique solution, and they proceeded to study the behavior of

the solution as t → ∞.

Under some conditions on the parameters of the system they proved: If g → 0

fast enough as t → ∞, and lim Ci (t) exists for i = 1, 2, then as t → ∞ the Th cells

t→∞

aggregate in one, two or four peaks about points ai = (ai1 , ai2 ). More precisely,

n

X

φ(t, x1 , x2 ) → µi δai where n = 1, 2 or 4, µi > 0, (2.5)

i=1

If ai1 > ai2 the cell tends to differentiate into Th1, and when the expression of

ai1 is high enough it will indeed differentiate into Th1. Conversely, if ai2 > ai1

CONSERVATION LAWS IN MATHEMATICAL BIOLOGY 3085

the cell will tend to differentiate into Th2. It is thus important to determine the

coordinates of ai .

Proof of (2.5). A basic idea in proving (2.5) is the introduction of upper and

lower dynamical systems

dx̂i dx̌i

= fˆi (x̂1 , x̂2 , Ŝi ), = fˇi (x̌1 , x̌2 , Ši ) (2.6)

dt dt

where x̂i (0) = x̌i (0) = xi (0) and

Initially we take

!

xn Ŝi

fˆi (x1 , x2 , Ŝi ) = −µi xi + αi n i n + σi + βi

ki + xi ρi + Ŝi

xni

Ši 1

fˇi (x1 , x2 , Ši ) = −µi xi + αi n n + σi + βi

ki + xi ρi + Ši 1 + Aj /γj

where j 6= i, and

R

Ĉi + Ai φ(t, x1 , x2 )dx1 dx2

Ŝi = R

φ(t, x1 , x2 )dx1 dx2

Či

Ši = R ,

φ(t, x1 , x2 )dx1 dx2

and

lim x̌i (t) = b̌i , lim x̂i (t) = b̂i (0 < b̌i < b̂i < Ai )

t→∞ t→∞

We next use (2.7) to introduce sharper upper and lower dynamics for t > t1 ,

namely,

!

n

x Ŝi 1

fˆi (x1 , x2 , Ŝi ) = −µi xi + αi n i

+ σi + βi

ki + xni ρi + Ŝi 1 + ( b̌j − )/γj

xn

Ši 1

fˇi (x1 , x2 , Ši ) = −µi xi + αi n i n + σi + βi

ki + xi ρi + Ši 1 + (b̂j + )/γj

3086 AVNER FRIEDMAN

where j 6= i, and

R

Ĉi + (b̂i + )φ(t, x1 , x2 )dx1 dx2

Ŝi = R ,

φ(t, x1 , x2 )dx1 dx2

R

Či + (b̌i − )φ(t, x1 , x2 )dx1 dx2

Ši = R ,

φ(t, x1 , x2 )dx1 dx2

Repeating the above process we get

či − < xi (t) < ĉi + for all t ≥ t2 .

where b̌i < či < ĉi < b̂i .

Proceeding step-by-step in the same manner, we obtain a decreasing sequence of

rectangles Rk , whose limit R is either a rectangle or a single point. Under some

parameters regime one can prove that R is a single point a1 = (a1 , a2 ), and this

proves the assertion (2.5) with n = 1.

Under other parameters regimes each of the systems (2.6) has either two (or four)

stable equilibrium points. In this case the limit R is again a rectangle. Furthermore,

as proved in [26], each of the rectangles Rk contains two (or four) subrectangles

Rki (Rmi ⊂ Rki if m > k) such that, for any initial condition (x1 (0), x2 (0)),

(x1 (t), x2 (t)) belongs to one of the rectangles Rki for all t > tk ,

and the k’s are the same for a given i, i.e., tranjectories do not switch from Rki to

Rk+1,j where j 6= i. Furthermore, as k → ∞ the rectangles Rki decrease to a point

ai , and this completes the proof of (2.5).

The above ideas extend to more complex models. Consider an extension of the

above model which includes the fact that the transmission factor xi is prescribed

by mRNA yi . Following Mariani et al. [32], the autocatalytic process which the xi

are undergoing is given by the equation

dxi

= νi yi − τi xi

dt

where νi , τi are constants, coupled with the equations for the mRNA

xni

dyi Si 1

= −µi yi + αi n + σi · + βi ,

dt ki + xni ρi + Si 1 + xj /γj

for (i, j) = (1, 2) and (i, j) = (2, 1).

Introducing the population density of cells with concentration (x1 , x2 , y1 , y2 ) at

time t, φ(t, x1 , x2 , y1 , y2 ), the mass conservation law then yields,

2 X 2

∂φ X ∂ dxi ∂ dyi

+ φ + φ = gφ.

∂t i=1

∂xi dt i=1

∂yi dt

In this case again it was proved by Friedman, Kao and Shih [27] that, for some

parameters regimes, as t → ∞

n

X

φ(t, x1 , x2 , y1 , y2 ) → µi δai

i=1

CONSERVATION LAWS IN MATHEMATICAL BIOLOGY 3087

where ai = (ai1 , ai2 , ai3 , ai4 ) and n = 1, 2 or 4. However, the proof that trajectories

cannot wander from Rki to Rk+1,j (j 6= i) for all k large enough is far more com-

plicated. It requires very careful analysis of the phase portrait in four dimensions.

3. Tumors. We assume that the tumor includes three types of cells: proliferating

cells with (mass) density p(x, t), quiescent cells with density q(x, t), and dead cells

with density n(x, t).

Following [36], we assume that quiescent cells become proliferating at a rate

KP (c) which depends on the concentration of nutrients c, and they become necrotic

at death rate KD (c). We also assume that proliferating cells become quiescent at

a rate KQ (c) and their death rate is KA (c). The density of proliferating cells is

increasing at a rate KB (c). Finally, we assume that dead cells are removed from

the tumor (by macrophages) at a constant rate KR .

We also assume that all the cells are physically identical in volume and mass and

that their density is constant throughout the tumor. Then

p + q + n = const. = θ. (3.1)

Due to the proliferation and removal of cells, there is a continuous motion of cells

within the tumor. We shall represent this movement by a velocity field v. We can

then write the conservation of mass law for the densities of the proliferating cells

p, the quiescent cells q, and the dead cells n within the tumor region Ω(t) in the

following form:

∂p

+ div(pv) = [KB (c) − KQ (c) − KA (c)]p + KP (c)q, (3.2)

∂t

∂q

+ div(qv) = KQ (c)p − [KP (c) + KD (c)]q, (3.3)

∂t

∂n

+ div(nv) = KA (c)p + KD (c)q − KR n. (3.4)

∂t

If we add equations (3.2)-(3.4) and use (3.1), we get

and we may replace (3.4) by (3.5). The tumor tissue will be treated as a porous

medium and the moving cells as fluid flow. In a porous medium, the velocity of v

of fluid flow is related to the fluid pressure σ by means of Darcy’s law.

v = −∇σ (3.6)

We assume that the nutrient concentration satisfies the diffusion equation

∂c

0 = ∆c − λ(p + q) in Ω(t). (3.7)

∂t

Eliminating n from (3.5) by (3.1) and taking, for simplicity, θ = 1, and recalling

(3.6), we obtain, in addition to (3.7), the following equations:

∂p

− ∇σ · ∇p = f (c, p, q) in Ω(t), t > 0, (3.8)

∂t

∂q

− ∇σ · ∇q = g(c, p, q) in Ω(t), t > 0, (3.9)

∂t

∆σ = −h(c, p, q) in Ω(t), t > 0, (3.10)

3088 AVNER FRIEDMAN

where

f (c, p, q) = [KB (c) − KQ (c) − KA (c)]p + KP (c)q − h(c, p, q)p,

g(c, p, q) = KQ (c)p − [KP (c) + KD (c)]q − h(c, p, q)q,

h(c, p, q) = −KR + [KB (c) + KR ]p + KR q.

The system (3.2)-(3.3), or (3.8)-(3.9), is a conservation law with velocity v which

depends non-locally on the variables p,q through the solution of the diffusion equa-

tions (3.7) and (3.10). In order to close the system we must give boundary condi-

tions.

We denote the boundary of Ω(t) by Γ(t) and impose the following boundary

conditions:

σ = γκ on Γ(t), t > 0, (3.12)

where c is a constant, γ is a surface tension coefficient representing the cell-to-cell

adhesion, and κ is the mean curvature (κ = R1 if Ω(t) is a ball of radius R). The

boundary of the tumor varies in time; it is a ‘free boundary’. We assume that its

normal velocity Vn is the same as the normal velocity v·n of the cells in the outward

normal direction n, i.e.,

∂σ

= −Vn on Γ(t), t > 0. (3.13)

∂n

Since the velocity Vn of the free boundary coincides with v · n where v is the

velocity in the conservation laws (3.2)-(3.3), we do not need to assign boundary

conditions for p and q.

The system (3.7)-(3.13) with initial conditions on c, p and q was investigated

mathematically. Local existence and uniqueness of a solution with prescribed initial

data was proved in [1] [7]. Under radially symmetric data, global existence of a

radially symmetric solution was proved and asymptotic estimates were derived on

the free boundary Γ(t) = {r = R(t)} as t → ∞ [10]. There are only partial results

on the existence and uniqueness of a radially symmetric stationary solution and on

its asymptotic stability [9] [6]. However, in the case of only one population of cells

(i.e., p ≡ 1, q ≡ n ≡ 0) it was proved that there exists a unique radially symmetric

stationary solution [28]; it is asymptotically stable for all γ < γ∗ (for some γ∗ > 0)

but not for γ > γ∗ [2] [17]; see also [41]. Furthermore, there are symmetry-breaking

bifurcation branches of solutions initiating from points γ2 , γ3 , . . . , γn , . . . , where

γ2 ≥ γ∗ [29] [13] [18] [22].

So far we have assumed that the velocity v in the conservation laws (3.2)-(3.4)

is given by Darcy’s law for porous media. In general, the tissue where the tumor

develops is very heterogeneous and complex, so the Darcy’s law is just one of several

possible approximations. For some tumors, for example those that originate in the

mammary gland, it is more realistic to assume that the tissue is fluid-like, and model

it by Stokes equation.

In this case the relation between the velocity v and the pressure σ is given by

− ν∇2 v + ∇σ = f , (3.14)

div v = g (3.15)

where f = − ν3 ∇g, and the boundary condition (3.12) is replaced by

CONSERVATION LAWS IN MATHEMATICAL BIOLOGY 3089

where

2ν

T (v, σ) = ν(∇v + ∇vT ) − (σ + div v)I,

3

ν is the viscosity coefficient, I is the unit matrix, and g is the proliferation rate,

given by the right-hand side of (3.5). Local existence and uniqueness of a solution

with prescribed initial data was proved in [14]. In the case of one population of

cells (p ≡ 1, q ≡ n ≡ 0) the existence of a unique stationary solution with radially

symmetric free boundary was proved in [14] and its asymptotic stability if γ < γ∗∗

(for some γ∗∗ > 0), but not if γ > γ∗∗ , was proved in [21]. As in the case of

porous medium, here too there exists a sequence of symmetry-breaking bifurcation

branches of solutions [20].

region

where W0 (t) is the surface of the wound, lying in {x3 = 0}. Healing occurs as W0 (t)

and h(x1 , x2 , t) decrease in t. Taking a fixed cylindrical domain

q

R = {(x1 , x2 , x3 ); x21 + x22 < L, −H < x3 < 0}

such that W (0) ⊂ R, we view the tissue undergoing healing, as occupying the region

Let ρ denote the density of the extracellular matrix (ECM). During the healing

process ρ is increasing until, with complete recovery, it reaches the density ρ0 of

healthy normal tissue.

Wound healing is a complex biological process which involves several overlapping

stages and several types of cells and signaling molecules. It includes interactions

among blood platelets, macrophages, endothelial cells that line up the inner layer of

blood capillaries, and fibroblasts. Fibroblasts secrete collagen, which is the primary

component of the ECM. Among the various mathematical models of wound healing,

the articles [34] [35] [5] [39] emphasize the critical role of oxygen, which is tightly

connected to angiogenesis, that is, to the formation of new blood capillaries that

move toward the wound.

Here we consider a more recent model developed by Xue et al. [42] and Friedman

and Xue [30]. Since healing entails a movement of newly formed collagen within

the healing tissue Ω(t), we introduce a velocity field v in the ECM and assume that

cells and signaling molecules are moving with velocity v. By conservation of the

ECM mass we then have,

∂ρ

+ div(ρv) = G (4.1)

∂t

where

kw ρ

G= f 1− − λρ. (4.2)

w+K ρmax

Here w is the concentration of oxygen, and f is the concentration of fibroblasts.

3090 AVNER FRIEDMAN

law. To determine such a law we note that the ECM in Ω(t) is a growing collagen

matrix which is elastic on a short time scale and viscous on a long time scale. We

shall model it as upper convected Maxwell (viscoelastic) fluid with isotropic pressure

depending on its density.

For an upper convected Maxwell fluid, the stress-strain relationship is given by

Dτ

λ − (∇v)τ − τ (∇v)T + τ = η(∇v + ∇vT ),

Dt

where η is the shear viscosity, and, as shown in Xue et al. [42], the first term on

the left-hand side is very small, so after dropping it we obtain,

We next consider the momentum equation

∂(ρv)

+ ∇ · (ρv ⊗ v) = ∇ · σ,

∂t

where σ is the total stress. We can write σ = −P I + τ where P is the isotropic

pressure and τ is the deviatoric stress. Since healing is a slow, or quasi-stationary

process with negligible inertia, the last equation may be approximated by ∇ · σ = 0,

or

− ∇P + ∇ · τ = 0. (4.4)

For compressible material the isotropic pressure is a function of the density, i.e.,

P = P (ρ), and we take

ρ

P = βF −1 , (4.5)

ρ0

where β, ρ0 are positive constants, and F is a smooth approximation to the Heavi-

side function.

Taking the gradient in (4.3) and using (4.4), (4.5), we find that v = (v1 , v2 , v3 )

satisfies the elliptic system

η∇ · (∇v + ∇vT ) − ∇P = 0 in Ω(t), (4.6)

or

3

X ∂ ∂vj ∂vi ∂P

η + − = 0 in Ω(t), (j = 1, 2, 3). (4.7)

i=1

∂xi ∂xi ∂xj ∂xj

We denote by Γ(t) the part of the boundary of Ω(t) which lies in {x3 < 0}. It is

natural to assume that there is no stress at the free boundary Γ(t). Hence

3

X ∂vj ∂vi

η + νi − P νj = 0 on Γ(t), (j = 1, 2, 3). (4.8)

i=1

∂xi ∂xj

The boundary conditions for v at the fixed boundaries are

∂v1 ∂v2

= / W0 (t), x21 + x22 < L2 }.

= 0, v3 = 0 on {x3 = 0, (x1 , x2 ) ∈

∂x3 ∂x3

CONSERVATION LAWS IN MATHEMATICAL BIOLOGY 3091

We assume that the free boundary moves in the normal direction with velocity

Vn = v · n. We can represent this relation in the form

ψt + v · ∇ψ = 0 on Γ(t) (4.10)

where Γ(t) is given by the zero set of ψ, i.e., by ψ(t, x) = 0 where x = (x1 , x2 , x3 ).

It was proved by Friedman, Hu and Xue [25] that, given a smooth Γ(0) and a

smooth function P (t, x), there exists a unique smooth solution to the free boundary

problem (4.7)-(4.10) for a small time interval.

Of course P is not a given function!; it depends on ρ which in turn depends on

w and f , and, in fact, the variables ρ, w, f and v are involved in a larger system of

drift-diffusion equations which includes several cell types and several growth factors.

The existence and uniqueness of a solution for the complete system was also proved

in [25] for a small time interval. Here one of the critical steps consists in proving

that for any smooth P there exists a solution (v, ψ) of the free boundary problem

(4.7)-(4.10) for a small time t, and

x,t x,t x,t

In the 2-dimensional radially symmetric case with free boundary r = R(t), it

was proved by Friedman, Hu and Xue [24] that R(t) is strictly decreasing in t,

unless the oxygen supply from the healthy tissue is mostly blocked due to vascular

damage, which indeed is often the case in chronic wounds. In this latter case

R(t) = const. > 0 for all t > t0 , for some finite time t0 .

Nothing is known about the behavior of the free boundary in the 3-dimensional

case. In fact, already the following special problem is open: Find conditions on

the function P and on Γ(0) such that for the solution of (4.7)-(4.10) there holds:

Ω(0) ⊂ Ω(t) for sufficiently small t.

system of hyperbolic equations

n

X

{∂t pi + ∂x (vi pi )} = kij pj , i = 1, 2, · · · , n (n ≥ 2), (5.1)

j=1

We assume that the kij are constants,

n

X

kij ≥ 0 if i 6= j, kij = 0 for j = 1, 2, · · · , n, (5.2)

i=1

and

i0 = j1 , i1 = j` and kjm jm+1 > 0 for 1 ≤ m ≤ ` − 1.

Under these conditions, the null space of the matrix (kij )ni,j=1 is one dimensional,

and there exists a unique vector λ = (λ1 , · · · , λn ) such that

3092 AVNER FRIEDMAN

n

X n

X

kij λj = 0, 0 < λi < 1 for i = 1, 2, · · · , n, and λj = 1. (5.4)

j=1 j=1

The system (5.1)-(5.3) arises in several models of biological processes. One ex-

ample, with vi = const., arises in modeling the transport of neurofilaments along

the axon of a neuron. The neurofilaments are needed to fill in the space in the

interior of the axon. These proteins are made near the nucleus of the neuron and

are then transported, as cargo, along microtubules. The cargo is “loaded onto”, or

attached to, motor proteins that carry it along microtubules. There are two kinds

of motor proteins, kinesin and dynein. Kinesin motor proteins move forward to-

ward the synaptic terminal (anterograde motion), and dynein motor proteins move

backward (retrograde motion). We assume that neurofilaments are only capable of

movement in the longitudinal dimension of the axon when they are on track along

a microtubule, but they can switch on and off track.

When off track, neurofilaments pause for long periods until they get back on

track. When on track, neurofilaments alternate between short bouts of movement

and short pauses. Thus we divide the on track population of neurofilaments into

those that are moving and those that are making a short pause. We designate

separately the population of anterograde moving neurofilaments and the population

of retrograde moving neurofilaments. In this manner, the neurofilaments are divided

into five different populations:

moving anterogradely, on track,

u1 : neurofilaments bound to anterograde motors, pausing, on track,

u0 : neurofilaments bound to anterograde or retrograde,

motors, pausing, off track,

u−1 : neurofilaments bound to retrograde motors

pausing, on track,

u−2 : neurofilaments bound to retrograde motors,

moving retrogradely, on track.

For simplicity we shall also denote by u−2 , u−1 , u0 , u1 , u2 the concentrations of

these five populations of neurofilaments. Following Craciun et al. [8] we assume that

neurofilaments can reverse direction (i.e. switch motors) when they are pausing, off

track. Thus we obtain the following diagram of possible transitions between the

five neurofilament populations:

u−2 u−1 u0 u1 u2

If we denote by ki,j the rate of change from ui to uj , then we have

u−2 u−1 u0 u1 u2 .

k−2,−1 k−1,0 k1,0 k2,1

CONSERVATION LAWS IN MATHEMATICAL BIOLOGY 3093

These relations, together with mass conservation laws yield the following dynamical

system for 0 < x < L, where L is the length of the axon:

∂u2 ∂u2

= −vA + k1,2 u1 − k2,1 u2 ,

∂t ∂x

∂u1

= k2,1 u2 + k0,1 u0 − (k1,2 + k1,0 )u1 ,

∂t

∂u0

= k1,0 u1 + k−1,0 u−1 − (k0,1 + k0,−1 )u0 , (5.5)

∂t

∂u−1

= k0,−1 u0 + k−2,−1 u−2 − (k−1,0 + k−1,−2 )u−1 ,

∂t

∂u−2 ∂u−2

= vR + k−1,−2 u1 − k−2 u−2 ,

∂t ∂x

where vA is the velocity of neurofilaments moving anterograde, and vR is the velocity

of neurofilaments moving retrograde.

The model parameters were obtained in vitro experiments, by Brown et al. [3],

and the model simulation were shown, in [8], to be in good agreement with in vivo

experiments.

It was discovered by Reed et al. [37] that formally, as → 0, the densities pi (x, t)

in (5.1), behave like approximate traveling wave solutions in the following sense: If

we set

n

x − vt X

s= √ where v = λ i vi (5.6)

i=1

then the functions

Qi (s, t) = pi (x, t) (5.7)

converge to λi Q0 (s, t) where Q0 satisfies a diffusion equation

∂Q0 ∂ 2 Q0

− σ2 = 0 in − ∞ < s < ∞, t > 0, (5.8)

∂t ∂s2

and σ 2 > 0.

In the special case of (5.5), this asymptotic behavior was rigorously proved by

Friedman and Craciun [15] [16].

The following more general result is due to Friedman and B. Hu [19].

Theorem 5.1. Consider the problem (5.1)-(5.4) for 0 < x < ∞, with

x

pi (x, 0) = λi q0 √ , 0 < x < ∞, j = 1, . . . , n,

pj (0, t) = λj for all j for which vj > 0,

and assume that not all the vj coincide. Then

where Q0 satisfies (5.8) with the initial condition

(

1 if − ∞ < s < 0

Q0 (s, 0) =

q0 (s) if 0 < s < ∞.

3094 AVNER FRIEDMAN

and the kij .

There are biological models for which the vi are functions of x, while −∞ < x <

∞. For example, suppose x is the position of a molecular motor along a microtubule,

which it is transporting a load. Let Si represent different i-states of the motor, and

vi = V (x, t, Si ) denote the velocity of the motor in state i. The states Si could stand

for different attachment/detachment states or phosphorylation states, for example,

and the velocities and transitions between states could be dependent on the local

(chemical) environment (for example, ATP concentration, or concentrations of other

signaling molecules).

A second example is that of a neuron whose transmembrane potential is x and

changes of which are driven by various transmembrane ionic currents, Ij . In the

usual Hodgkin-Huxley formulation

dx X

Cm =− Ij − Iapp ,

dt j

where Cm is membrane capacitance and Iapp is the applied current. If the membrane

patch is small, then the ionic currents fluctuate randomly with the opening and

closing of individual ion channels. Thus, the ionic currents should be written as

Ij = gj Sj (x − Xj ),

where gj is the single channel conductance, Xj is the Nernst potential, and Sj is

the number of open channels of type j, a randomly fluctuating integer. Markov

models of ion channels typically have voltage-dependent, hence non-autonomous,

transitions between open and closed states. A recent article by Friedman, B. Hu

and Keener [23] provides references for these two examples. In this article Theorem

5.1 was extended to the case where vi = vi (x, t) is a smooth function, and

x

pi (x, 0) = λi q0 √ for − ∞ < x < ∞.

Let g(x, t) be the solution of

g(x, 0) = x, −∞ < x < ∞

where

n

X

v(x, t) = λi vi (x, t),

i=1

and set

1

Qi (s, t) = pi (x, t), s = √ g(x, t).

n

(vi (x, t) − v(x, t))2 ≥ const. > 0, then

P

It was proved in [23] that, if

i−1

where

∂Q0 ∂ 2 Q0

− σ 2 (t) − b(t)Q0 = 0, −∞ < s < ∞, t > 0 (5.10)

∂t ∂s2

Q0 (s, 0) = q0 (s), −∞ < s < ∞.

CONSERVATION LAWS IN MATHEMATICAL BIOLOGY 3095

The proof of this result, as well as that of Theorem 5.1, involve estimating higher

order derivatives of the form

∂` ∂k

`+k/2−1 ` Q

∂t ∂sk i

and proving that such terms converge to zero as → 0.

Extension of these results to the case where the kij are variable functions remains

an open problem. We mention here one special case of a system that arise in gas

kinetics:

∂p1 1 ∂p1 1

+ = 2 (p1 + p2 )α (p2 − p1 ), (5.11)

∂t ∂x

∂p2 1 ∂p2 1

− = 2 (p1 + p2 )α (p1 − p2 )

∂t ∂x

where 0 ≤ α ≤ 1; by scaling, this system can be rewritten in the form (5.1) with kij

multiplied by (p1 + p2 )α . In this model the pi (i = 1, 2) represent the concentration

of two gases. It was established (see [38] and the references therein) that, under

appropriate initial data, pi → u as → 0 where u satisfies the diffusion equation

∂u ∂ 1 ∂u

= .

∂t ∂x uα ∂x

the main theme of the present article is conservation laws in mathematical biology,

these laws, as we have seen, are strongly coupled to other systems, such as ODEs

with nonlocal or nonlinear coefficients, elliptic equations, and parabolic equations,

sometimes with free boundary. The questions we explored include asymptotic be-

havior of solutions as t → ∞ or as → 0, and the behavior of the free boundary.

Historically the physical sciences motivated many mathematical ideas and theories.

Today the biological sciences have become another major source for mathematical

explorations.

REFERENCES

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Application to a model of tumor growth, Comm. in PDE, 28 (2003), 517–560.

[2] B. Bazaliy and A. Friedman, Global existence and stability for an elliptic-parabolic free bound-

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of antibiotic exposure and other interventions on the endemic prevalence of vancomycin-

resistant enterococci, The Journal of Infectious Diseases, 192 (2005), 2004–2011.

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equations modeling tumor growth, Interfaces & Free Boundaries, 8 (2006), 247–261.

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model, J. Diff. Eqs., 227 (2006), 598–639.

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arising in a tumor model, Arch Rat. Mech. Anal., 180 (2006), 293–330.

[19] A. Friedman and B. Hu, Uniform convergence for approximate traveling waves in linear

reaction-hyperbolic systems, Indiana Univ. Math. J., 56 (2007), 2133–2158.

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Stokes equation, SIAM J. Math. Anal., 39 (2007), 174–194.

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modeling tumor growth by Stokes equation, J. Math. Anal. Appl., 327 (2007), 643–664.

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reaction-hyperbolic equations, submitted.

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wounds, SIAM J. Math. Anal., 42 (2010), 2013–2040.

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computation, Discrete and Continuous Dynamical Systems Series B, to appear.

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care workers, Math. Biosciences and Engineering, 7 (2010), 779–792.

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differentiation: Insights from helper T lymphocytes, Biophys. Mol. Biol., 86 (2004), 45–76.

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emerging resistance, Clin. Microbiol. Infect. 11 Suppl., 5 (2005), 4–16.

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angiogenesis in soft tissue, Mathematical Biosciences, 136 (1996), 35–63.

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in wound healing, Proc. R. Soc. Lond. B, 263 (1996), 1487–1493.

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linearity, 18 (2005), 1223–1248.

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epidemics in hospitals, PNAS, 102 (2005), 13343–13348.

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modeling the growth of tumors with fluid tissues, SIAM J. Math. Anal., 41 (2009), 391–414.

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E-mail address: afriedman@math.ohio-state.edu

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