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J. Math. Biol. (1986) 24:279-289

Journal of

### Wology

9 Springer-Verlag 1986

A numerical study of oxygen diffusion in a spherical cell with the Michaelis-Menten 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 re-examine the oxygen diffusion in a spherical cell with the Michaelis-Menten oxygen uptake kinetics.

Key words: Random choice method -- Dictionary method

1.

Introduction

A numerical method has been developed (see Sod  and  that has applica- tion to time dependent and steady-state 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 steady-state waves. The steady-state 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 Michaelis-Menten type is assumed, (see Michaelis and Menten ). The consumption rate of oxygen in a cell is a function of the oxygen tension (see Prosser and Brown ). The time dependent reaction-diffusion 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 Michaelis-Menten 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 boundary-value 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 reaction-diffusion equations with spherical (or cylindrical) symmetry. The singularity at the origin, due to this symmetry, is a major source of difficulty. Lin  solved the time dependent initial boundary-value problem (1.2) using the Crank-Nicolson method. The steady-state boundary-value problem obtained from (1.2) was solved by McElwain  using a shooting technique with a fourth order Runge-Kutta method and by Anderson and Arthurs  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  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  and  a random choice type method was developed for reaction diffusion equations. The random choice method was introduced by Glimm  for the construction of solutions of systems of nonlinear hyperbolic conservation laws. The method was developed for l~ydrodynamics by Chorin ,  and further developed by Colella , Glaz and Lin , and Sod -.

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 steady-state part of Eq. (1.2a) is

+2 orc-

r

C+ Km

-o.

However, we shall consider the steady-state equation omitting the advection terms (for justification see Sod )

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 two-point boundary-value 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 steady-state 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

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 Courant-Friedrichs-Lewy (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[(i--1/2)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 quasi-random) 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

### cin_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  using the random walk solution to the diffusion equation, where the condition

 h 2 k = -- (2.8) 8 is obtained. The solution of the two-point boundary-value 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. (i-l/2)h c~n i-1/2 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 ). Assume that

0<~c~'<~ 1 for all

i and

n~>0 and define

1

hD----

No-I'

where No is a positive integer. Consider the two-point boundary-value 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

two-dimensional table.

Given the two-point boundary-value 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
 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)

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

cS 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 -- CN--1 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 two-point broundary-value 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 two-point boundary-value problem is solved on the interval (N-1)h<~r<-Nh. From this point we proceed as described in Sect. 2.

We now consider the boundary condition

 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 )

which gives rise to

n

C 1

--

h

?i

C0

=0

"

CO

=

r

"

(3.4)

where t = nk. Consider the two-point boundary-value 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. 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  and the study of Anderson and Arthurs . 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 steady-state profile

286

G. A. Sod

Table 4.1. Comparison of steady-state profiles with results of Anderson and Arthurs 

 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 No--11. The transient profiles are characteristic of mass diffusion in a spherical domain. The steady-state results are in excellent agreement with those obtained by McElwain  and Anderson and Arthurs . The steady-state results are compared with those obtained by Anderson and Arthurs  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 steady-state 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 two-point boundary-value 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

287

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-(r-f)

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+(r-Y)

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+(r-f)

h

= h/2-(r-f)

 ",': ...... h / 2+ (r- 7) i- I Pi-1/2 r I r -hi2 r

-I

Pi+ 112

 l t = (n.l) k t t=nk

r.h/2

288

and

h/2+(r-f)

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

= r---r

D 2 k-~r3 k2 + O(k3)'

we see that

E[rh]=

-2D

r

D 2

k-~r3k2+O(k3)

and

### var[,7,]=4-~--7) k +~-g3+o(g4).

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

),

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 ~/2-D~(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 Michaelis-Menten 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 Michaelis-Menten 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 re-examination 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 reaction-diffusion 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