J. Math. Biol. (1986) 24:279289
Journal of
9 SpringerVerlag 1986
A numerical study of oxygen diffusion in a spherical cell with the MichaelisMenten oxygen uptake kinetics
Gary A. Sod
Department of Mathematics, Tulane University, New Orleans, LA 70118, USA
Abstract. A numerical method is presented for the solution of reaction diffusion systems in biology. The method is used to reexamine the oxygen diffusion in a spherical cell with the MichaelisMenten oxygen uptake kinetics.
Key words: Random choice method  Dictionary method
1.
Introduction
A numerical method has been developed (see Sod [14] and [16] that has applica tion to time dependent and steadystate reaction diffusion systems arising in biology. The method is based on a technique, the random choice method, developed for hyperbolic conservation laws. The method decomposes the solution into normal modes which consist of elementary waves and steadystate waves. The steadystate waves are sampled to provide left and right states for the Riemann problems solved in the random choice method. The diffusion and reaction terms are taken into account simultaneously, thereby preserving the natural balance that exists between these two processes. As an example we consider the oxygen diffusion in a spherical cell, which is assumed to consist of a surface membrane and protoplasm and where external diffusion effects are neglected. Enzymes are compartmentalized in the protoplasm and act as catalysts for the metabolic reactions which provides the energy for the cell. The oxygen, acting as a substrate for the metabolic reactions, plays a central role. An oxygen uptake kinetics of the MichaelisMenten type is assumed, (see Michaelis and Menten [10]). The consumption rate of oxygen in a cell is a function of the oxygen tension (see Prosser and Brown [11]). The time dependent reactiondiffusion equation for the oxygen tension P(R, "r) in a spherical coordinates with spherical symmetry
is
_{P}_{+}_{K}_{~}_{'}
0~<R<~Ro, 7~>0,
with boundary conditions
ORP = 0
at R
= 0,
MP
+ DORP = MPo
at R = Ro,
(1.1a)
(1.1b)
(1.1c)
280 
G.A. Sod 

and with initial condition 

P(R, 0) = 0, 
(1.1d) 
where R is the spatial coordinate measuring the distance from the center of the cell, r is the time coordinate, D is the diffusion coefficient of oxygen in the cell, V is the maximum reaction rate, Km is the MichaelisMenten constant, R0 is the radius of the cell, and M is the permeability of the cell membrane of R = Ro. Introduce dimensionless variables
P 
rD 
R 

C 
Po' 
t=R2' 
r=Ro, 

VR 2o 
Km 
M Ro 

ot = 
'" 
km = 
m= 
. 

PoD' 
Po' 
D 
With this choice of dimensionless variables, the initial boundaryvalue problem (1.1) for C(r, t) becomes
a,c = a~C +2 a~c
r
ac
C+k='
0<~r<~l, t~>0
with boundary conditions
and with initial condition
OrC =0
at r=0,
mC+OrC=m
at r=
1,
C(r,
0) = 0.
(1.2a)
(1.2b)
(1.2c)
(1.2d)
In this paper the method is extended to reactiondiffusion equations with spherical (or cylindrical) symmetry. The singularity at the origin, due to this symmetry, is a major source of difficulty. Lin [8] solved the time dependent initial boundaryvalue problem (1.2) using the CrankNicolson method. The steadystate boundaryvalue problem obtained from (1.2) was solved by McElwain [9] using a shooting technique with a fourth order RungeKutta method and by Anderson and Arthurs [1] using a variational principle. The results obtained by McElwain and Anderson and Arthurs are in excellent agreement. However, the results obtained by Lin differ greatly. In Lin [8] it is not stated how the singular term in (1.2a) was treated nor how the nonlinear reaction term in (1.2a) was treated so that a linear system of equations was obtained. However, it is likely that the mishandling of one or both of these terms resulted in the erroneous solution obtained by Lin.
2. The random choice method
In Sod [14] and [16] a random choice type method was developed for reaction diffusion equations. The random choice method was introduced by Glimm [6] for the construction of solutions of systems of nonlinear hyperbolic conservation laws. The method was developed for l~ydrodynamics by Chorin [2], [3] and further developed by Colella [4], Glaz and Lin [5], and Sod [12][16].
Numerical study of oxygen diffusionin a spherical cell
281
Consider Eq. (1.2a). The term 2/r 0rC, which arises from writing the Laplacian operator in spherical coordinates, can also be viewed as an advection term. This will be fundamental in the removal of the singularity at r = 0. The homogeneous equation obtained by omitting the reaction and the diffusion terms becomes
OtC _2
r
arC = 0,
(2.1)
which is formally a hyperbolic equation with wave speed 2/r. The steadystate part of Eq. (1.2a) is
+2 orc
r
C+ Km
o.
However, we shall consider the steadystate equation omitting the advection terms (for justification see Sod [16])
O~C=O. aC
C + K,,
(2.2)
Divide time into intervals of length k and space into intervals of length h.
Let r approximate the solution C(ih, nk)
to (1.2), where
i, n =0,
1,2, ....
Given the approximate solution c~ for each grid point ih, consider the sequence of twopoint boundaryvalue problems
aC 

0~C 
=0, C+Km 
C(ih) 
= c7 
C((i + 1)h) = ci+l. 
ih<~r<(i+l)h, 
(2.3a) 
(2.3b) 

(2.3c) 
By omitting the advection term from the steadystate equation, the solution to (2.3) is translation invariant. Let C~(r) denote the function that is the solution to (2.3) on each subinterval. Rather than considering the Cauchy problem (2.1) with the piecewise smooth initial condition
C(r, nk)=CS(r), 
ih<r<(i+l)h, 

we consider Eq. (2.1) along with the piecewise constant initial conditions 

C(r, nk)=c,+l/2, 
ih<r<(i+l)h, 
(2.4) 

where 

n 
s 
 
1 

Ci+l/2 = 
C 
((z+~)h), 
(2.5) 
that is, CS(r) is sampled at the midpoint of the interval [ih, (i+ 1)h]. This defines a sequence of Riemann problems given by (2.1) and (2.4) that are centered at the grid points ih. If the CourantFriedrichsLewy (CFL) condition is satisfied, then the waves generated by the individual Riemann problems, one for each grid point ih, will not interact. Hence, the solution to the different Riemann problems can be combined by superposition into a single exact solution, denoted by Ce(r, t),
defined for nk ~
t < ( n + l ) k.
282
G.A. Sod
The CFL condition for the Riemann problem (2.1) and (2.4) centered at the
grid point
ih
is
2 
k 
2k 

max 
 
~= 
 
~< 
1. 

rc[(i1/2)h,(i+l/2)hl r I~ 
(i 89 
2 
(2.6)
As r> 0 the signal speed becomes infinite and by the CFL condition k> 0. This problem will be addressed in Sect. 3. Let ~, denote an equidistributed random (or quasirandom) variable in the interval ( 89 89 Define the approximate solution at the next time interval by
c7 +' = ce((i
+ ~,,)h, (n + 1)k).
The solution
C(r,
t)
to
(2.1) is constant along curves
/,2
+
4
t = const.
(2.7)
By following the curve passing through the point ((i + ~:,) h, (n + 1)k) to the point
of intersection with the line t = nk, denoted by (~, nk) 
we see 
that 

~=~/((i+ ~,,)h)2+4k. 

With this, the approximate solution (2.2) becomes 

cn+l 
fcin_l/2, 
r < ih 

[ ci+l/2, 
~> 
ih, 

that is, if the point of intersection lies to the left (right) of the 
point (ih, nk), 
the 

value of the left (right) state is assumed 
by c~'+1 (see Fig. 2.1). 
The presence of the diffusion term in Eq. (1.2a) places an additional require ment on the time step h. This has been determined in Sod [14] using the random walk solution to the diffusion equation, where the condition
h 2 

k =  
(2.8) 

8 

is obtained. 

The 
solution 
of the 
twopoint boundaryvalue 
problem 
(2.3) 
is 
the 
most 
expensive part of the algorithm as described thus far. However, only one value
(2.5) characterized by this solution is required.
((i § &)h,(n* 
1)k) 

§ 
t 
= coNst. 

(il/2)h 
c~n i1/2 
i h 7, nk) 9 cni§ 
(i§ 
t=(n+l)k 

t: 
nk 
Fig. 2.1. Sampling procedure for Riemann problem (2.1) and (2.4) 
Numerical study of oxygen diffusion in a spherical cell
283
With this choice of dimensionless variables, 0 ~< C(r, t)<~ 1 (see Hiltmann and
Lory [7]). Assume that
0<~c~'<~ 1 for all
i and
n~>0 and define
1
hD
NoI'
where No is a positive integer. Consider the twopoint boundaryvalue problem given by (2.3a) with i = 0 (due to the translation invariance, this involves no loss of generality) and the boundary conditions
Cs(O) 
= (1 
1)ho = C' 
(2.9a) 

C'(h) = 
(m 
 
1)hD = Cm 
(2.9b) 

for l, m = 1, ... , ND. Let C~,m(r) denote the solution to (2.3a) and (2.9) and define C~,~/2_ u,,  Cl,s r,,(h/2). The solutions r,s,~/2 ~t,,, form the basis of a dictionary which is a 
twodimensional table.
Given the twopoint boundaryvalue problem (2.3) with boundary conditions
C'(ih) 
and CS((i+ 1)h) satisfying 0<~ C~(ih), 
C~((i+ 
1)h) ~< 1, define 

l= Int((No  1)CS(ih))+ 1 

m 
= 
Int((No  1) CS((i+ 1)h)+ 
1, 
where Int(z) is the function yielding the integer part of the real number z. Clearly
l<~l,m<~No 
. 

Define 

/+={/+1, 
l<No 

I, 
I=ND 

and 

m+={m+l, m<ND 

m, 
m 
= 
ND, 

SO that C 1 <~ C s (ih) 
<~ C 1+ and 
Cm ~< C s (( i + 1) h) <~ Cm+. To interpolate values in 

the dictionary we use the area weighing method. The area of the cell bounded 

by C t, C t+, Cm, Cm+ is A = (C 
t+ Ct)(Cm +  Cm), where 
if I + = I then C r 
C t is 

replaced with 1 and similarly 
if 
m § 
m. Define 
At,,, = (CS(ih)  
Ct)(CS((i+ 1)h)  
C'), 

At,., + = 
(CS(ih)  
Ct)(C,,,+  CS((i+ 1)h)), 

aF,m 
= (Ct +  CS(ih))(C~(i+ 1)h)  
Cm) , 

and 

At+,,,,+ = ( C t+  
CS(ih))( Cm + CS((i+ 
1)h)). 

With this the interpolated value of ci~1/2 becomes 

n 
r 
f~s,1/2 
A 
,.~s,l/2 
A s,1/2 
s,l/2 

Ci+ l/2 = 
t 
t~ l,m .'ll+,m+r 
__ l~ l+,m/.!l,m+I C't,m+ Al+,m + C l+m+At,m) / A, 
(2.10)
(see Fig. 2.2).
284 
G.A. Sod 

CS((i+l)h.) 

1 
2 .......... 
m 
m+ 
1 .......... NO 

C1 
C2 ............ 
Cm 
Cm+l 
.......... CN D 

I I 

1 
C ~ 
t 

I 

I 

2 
C 2 
I I 

I 
I 

f 
I 

I 
I 

I 
I 

1 
,CL' S m 1/2 
~ 
S, 112 

C 
.................. 
~j rr~* 

CS(ih) 
A4m 
At,m* 
C n 

= 
LA,.,mIA.,r." 
i. 1/2 

1.1 I 
C 
1.1 ................. 
S, 1/2 Cl.,m 
_{c}_{S} 1/2 ,[~,m* 

I 

I 

I 

NDCND 
Fig. 2.2. Dictionary and area weighing interpolation
3. Boundary conditions and singularity removal
Consider a boundary at r = 1, corresponding to the cell membrane, with boundary condition
aC(1, t)+ fl arC(l, t) = m( t), 
(3.1) 

where 
a 
and/3 
are constants. Approximate Or by a centered difference 

CN+I 
 CN1 
n 

a c"N + /3 \ 
~~ 
/ 
= m 
, 

where 
t = 
nk and 
r = 
1 = Nh. The grid point corresponding to i = N 
+ 
1 lies outside 
the physical domain. We may solve this difference equation for c~+1
C~/+ 1 = 
C~/+1 +2h (m"  eL). 
(3.2) 

In order 
to 
find the 
solution at the 
next time level, 
t = 
(n + 1)k, 
at the boundary 
r = 1, we must establish a left and right state for the Riemann problem associated with the grid point at r = 1 (or i = N). The appropriate twopoint broundaryvalue problem is solved on the interval Nh <~ r ~ (N + 1) h with the right boundary value given by c~+~ in (3.2) and the appropriate twopoint boundaryvalue problem is solved on the interval (N1)h<~r<Nh. From this point we proceed as described in Sect. 2.
We now consider the boundary condition
arC(O , t)  0
(3.3)
Numerical study of oxygen diffusion in a spherical cell 
285 

and 
the 
singularity at r = 0. Approximate 
the boundary 
condition 
(3.3) 
by 
the 
forward divided difference (see Sod [15])
which gives rise to
n
C 1

h
?i
C0
=0
"
CO
=
r
"
(3.4)
where t = nk. Consider the twopoint boundaryvalue problem (2.3) on the interval
[0, h] yielding c~/2 and on the interval 
[h, 2h] yielding 
c~/=. This 
gives 
rise to 
a 

Riemann problem centered at the point r= h given by Eq. (2.1) with initial 

condition 

C(r, nk)=~C']/2, 
r<h 

[ C~/2, 
r > h. 

The CFL condition (2.6) with 
i 1 becomes h 2 
4'
which is satisfied by condition 
(2.8). Sampling yields the approximate solution 

at the nest time interval c~'+1 from which, using (3.4), c~ +1 is obtained. 

4. Numerical 
results 

We choose parameters Ro = 5 x 10 3 
cm, 
D 
= 2 x 10 5 cm 
2 s 1, 
Po = 155 mm 
Hg, 

M = 2 x 10 2 cm s 1, V = 94.4 mm Hg 6 1, and K,, = 4.834 mm Hg, which corre 

sponds to case (d) in McElwain 
[9] and the study of Anderson and Arthurs 
[1]. 

The dimensionless 
oxygen tension 
profiles 
in the cell when external diffusion 

effects are neglected and depicted 
in 
Fig. 
4.1. The grid spacing used to obtain 
1.0
08
0.6
r
0.4
02
0
0
0.2
O.Z,
r
0.6
0.8
1~0
Fig. 4.1. Oxygen tension profiles in the cell at equally spaced time intervals leading to a steadystate profile
286
G. A. Sod
Table 4.1. Comparison of steadystate profiles with results of Anderson and Arthurs [1]
R 
RCM 
Anderson and Arthurs 

0.0 
0.8234 
0.8276 

0.1 
0.8234 
0.8288 

0.2 
0.8271 
0.8326 

0.3 
0.8334 
0.8388 

0.4 
0.8425 
0.8474 

0.5 
0.8545 
0.8586 

0.6 
0.8693 
0.8721 

0.7 
0.8867 
0.8880 

0.8 
0.9044 
0.9062 

0.9 
0.9245 
0.9262 

1.0 
0.9483 
0.9477 

these profiles was 
h =0.1 
and 
No11. 
The transient profiles are characteristic 

of mass 
diffusion in a spherical 
domain. 
The 
steadystate 
results 
are in excellent 

agreement 
with those 
obtained 
by McElwain 
[9] and Anderson and Arthurs [1]. 

The steadystate results are compared 
with those obtained by Anderson and 

Arthurs 
[1] in Table 
4.1. 
Appendix A: Partial error estimates
Consider the equation
r 20tC 
= 
D Or(r 2 c~rC ) 

which may be written in the form 

2D 

OtC  
O~C = D O~C, 
(A.1) 

r 
where D > 0 is a constant. The steadystate equation without the advection term becomes 02~C = 0, while the homogeneous part of (A.1) is the scalar conservation law
2D 

0tC  
arC = 0. 
(A.2) 
r 
Consider the Riemann problem defined by Eq. (A.2) with initial condition
C(r, nk) =
c~ 2 !,
ci~,
r<
ih
r>
ih,
where c~+1/2 = CS((i+ 89
and CS(r) is the solution to the twopoint boundaryvalue problem (2.3)
O~Cs=O, 
ih<~r<~(i+l)h 
(A.3a) 

CS(ih) = c'] 
(A.3b) 

CS((i+ 1)h) = c~'+1. 
(A.3e) 

Since (A.3) implies that CS(r) is a 
line, CS((i+ 89189 
+ ci+l). 
The solution C(r, t) to (A.2) is constant along the characteristic curves
r 2
+
4D
t = const.
Numerical study of oxygen diffusion in a spherical cell
_{2}_{8}_{7}
The initial discontinuity propagates along the characteristic curve passing through the point (ih, nk).
Now choose a uniformly distributed random variable ~:,. If so, lies to the left of this characteristic
then c~ §
= c'/_1/2. On
the
other
hand,
if so, lies to the right of this characteristic then
c~ +1 = c'~+u2.
Let r = ih and (?, (n + 1)k) denote the point where the characteristic curve passing through the point (r, nk) intersects the line t = (n + 1)k. We see that
f=~.
(A.4)
The random variable G lies to the left of the characteristic with probability
h/2(rf)
h
(the length of the segment Pi_m/2~ normalized by the length of the interval h). Similarly, the random variable sen lies to the right of the characteristic with probability
h/2+(rY)
h
(the length of the segment ~Pi+l/2 normalized by the length of the interval h) (as depicted in Fig. A.1).
Now consider the dictionary with 0<~ C(r, t)~<
1
and
with spacing
h o = 1/(N o 
1), where
N D is
a positive integer. Using the area weighing algorithm (Sect. 2), we obtain as an approximate solution to (A.3) sampled at the midpoint of the interval c'/+u2 , where
It follows that
c7+1/2 = CS( ( i + 89
) + O( ho).
c'~ = C(ih + 71, nk) + O(h 2) + O(ho) ,
where r/= r/(t)
is a random variable which depends on
t
alone. To
see this, from (A.5)
c,%,/2 = c'( ( i +bh ) + O(
hD)
= 89
+ ~, nk) + C((i+
1)h + r/, nk)) + O(hD)
= C((i + 89
+ q, nk) + O(h 2) + O(ho) ,
(A.5)
where we have used the fact that 7/is independent of r. Thus to O(h z) + O(ho) the computed solution equals the exact solution with a random shift independent of r.
After n steps the displacement of the initial value at a point
r
is
r+
~7,
7} =
'~
i=l
~7i,
where ,}~ are independent, uniformally distributed random variables with probability distribution
[
P
h]
"qi=2
h/2+(rf)
h
= h/2(rf)
",': ...... 
h / 2+ 
(r 
7) 

i 
I 

Pi1/2 
r 

I 

r hi2 
r 
I
Pi+ 112
l 
t = (n.l) 
k 
t 
t=nk 
r.h/2
288
and
h/2+(rf)
h
The expected value and variance of ~z are then
and
E[rh] = (r
~)
var[•i]
h 2
= ~
(r
F)z.
By expanding ~ given by (A.4) in a Taylor series
2D
= rr
D 2 k~r3 k2 + O(k3)'
we see that
E[rh]=
2D
r
D 2
k~r3k2+O(k3)
and
h 2
[2D~2z
2D 3
From which we obtain
and
2D
E[rl]=
r
t + O(h 2)
var[r/] = 2Dt (1
[2D\2
hE
4 \
where k= h2/8D
(condition (2.8)where
D~
1,
Sod
[14]),
so that
G.A. Sod 

k= O(h z) 
and 
t= 
nk. 
Thus 
var[~]o 2Dr as h o 0 for fixed t and D > 0. We see that the standard deviation is ~/2D~(1 + O(h2)).
Thus as h, h o ~ 0 the computed solution converges to the exact solution.
References
1. Anderson, N., Arthurs, A. M.; Complementary variational principles for diffusion problems with MichaelisMenten kinetics. Bull. Math. Biol. 42, 131 (1980)
2. Chorin, A. J.: Random choice solution of hyperbolic systems. J. Comp. Phys. 22, 517 (1976)
3. Chorin, A. J.: Random choice methods with applications to reacting gas flows. J. Comp. Phys. 25, 253 (1977)
4. ColeUa, P.: Glimm's method for gas dynamics. SIAM J. Sci. Stat. Comp. 3, 76 (1982)
5. Glaz, H. M., Liu, T.P.: The asymptotic analysis of wave interactions and numerical calculations of transonic nozzle flow. Adv. Appl. Math. 5, 111 (1984)
6. Glimm, J.: Solutions in the large for nonlinear hyperbolic systems of equations. Comm. Pure Appl. Math. 18, 697 (1965)
7. Hiltmann, P., Lory, P.: On oxygen diffusion in a spherical cell with MichaelisMenten oxygen uptake kinetics. Bull. Math. Biol. 45, 661 (1983)
8. Lin, S. H.: Oxygen diffusion in a spherical cell with nonlinear oxygen uptake kinetics. J. Theor. Biol. 60, 449 (1976)
9. McElwain, D. L. S.: A reexamination of oxygen diffusion in a spherical cell with Michaelis Menten oxygen uptake kinetics. J. Theor. Biol. 71, 255 (1978)
Numerical study of oxygen diffusion in a spherical cell
289
10. Michaelis, L., Menten, M. L.: Die Kinetik der Invertinwirkung, Biochemz. 49, 333 (1913)
11. Prosser, C. L., Brown, F. A.: Comparative animal physiology. Saunders, Philadelphia, 1962
12. Sod, G. A.: A numerical study of converging cylindrical shock. J. Fluid Mech. 83, 78 (1977)
13. Sod, G. A.: A survey of several finite difference methods for systems of nonlinear hyperbolic conservation laws. J. Comp. Phys. 27, 1 (1978)
14. Sod, G. A.: A random choice method with application to reactiondiffusion systems in combustion. Int. J. Comp. Math. with Appl. 11 (1985); and Advances hyperbolic partial differential equations, vol. II. Witten, M. (ed.), Pergamon Press, New York (1985)
15. Sod, G. A.: Numerical methods in fluid dynamics. Cambridge University Press, New York (1985)
16. Sod, G. A.: A flame dictionary approach to unsteady combustion phenomena. Matem. Applic, Comp. 3, 157 (1984)
Received July 15, 1984/Revised May 15, 1985
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