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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
∂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.
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
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
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
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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
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
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
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
= −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
∂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
∂(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
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
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:
u−2 u−1 u0 u1 u2
If we denote by ki,j the rate of change from ui to uj , then we have
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
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
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
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3096 AVNER FRIEDMAN
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