Adisa et al

Tropical Journal of Pharmaceutical Research, December 2008; 7 (4): 1107-1116

© Pharmacotherapy Group,
Faculty of Pharmacy, University of Benin,
Benin City, 300001 Nigeria.
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Available online at http://www.tjpr.org

Research Article

Mathematical Modelling of Intraretinal Oxygen Partial

Pressure

R Avtar* and D Tandon

Department of Mathematics, Harcourt Butler Technological Institute, Kanpur 208002, India

Abstract
Purpose: The aim of our present work is to develop a simple steady state model for intraretinal oxygen
partial pressure distribution and to investigate the effect of various model parameters on the partial
pressure distribution under adapted conditions of light and darkness..
Method: A simple eight-layered mathematical model for intraretinal oxygen partial pressure distribution
was developed using Fick’s law of diffusion, Michaelis-Menten kinetics, and oxygen delivery in the inner
retina. The system of non-linear differential equations was solved numerically using Runge-kutta
Nystroms method.
Result: The model predicts that a decrease in the blood flow rate reduces the partial pressure of oxygen
in adapted conditions of light and darkness. It was also observed that the partial pressure of oxygen was
higher in adapted light conditions than in adapted dark conditions.
Conclusion: The partial pressure of oxygen observed in different layers of the retina was reduced by a
decrease in the blood flow rate in the inner retina. The pressure becomes minimum when there is no
blood flow in the inner retina. This minimum pressure may fall below the critical level of oxygen partial
pressure and affect the retinal function. In order to restore normal retinal function, extreme hyperoxia
may assist to make the choroid capable of supplying oxygen to the whole retina during total retinal
artery occlusion.

Keywords: Mathematical modeling, Intraretinal oxygen pressure, Retinal capillaries, Oxygen

consumption, Retinal vascular occlusion, Oxygen metabolism.

Received: 15 July 2008 Revised accepted: 15 September 2008

*Corresponding author: Email: [email protected]

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 Avtar & Tandon

INTRODUCTION Over supply of oxygen can also result in some

Oxidative metabolism in the retina is a very retinal diseases such as retinopathy. There is
important process and is an essential also evidence that oxygen toxicity plays a
metabolic requirement of living and role in degenerative retinal diseases such
1
reproducing retinal cells as well as a as retinitis pigmentosa (RP) and it has
necessity for the maintenance of ionic been suggested that manipulation of the
pump mechanisms in the retina which, in oxygen environment could be a therapeutic
turn, maintains the integrity of retina . A strategy in the management of retinal
proper oxygen environment (sufficient diseases such as RP, retinal detachment,
oxygen availability) is required for retinal and occlusive diseases of the retinal
oxidative metabolism. A physiological circulation. Even in healthy eyes, there is
oxygen environment is maintained through a very delicate balance between oxygen
a delicate balance of oxygen supply to the supply and oxygen consumption. Disruption
retina and oxygen consumption in different of this balance may cause too little or too
retinal layers of the retina. The rate of oxygen much oxygen to be present in specific
consumption is dependent on the rate of retinal layers 6. Understanding the oxygen
oxygen metabolism. The retinal layers, in requirements of different components of
which there is high rate of oxygen retina is vital if therapeutic strategies to
metabolism , have high rate of oxygen restore an appropriate oxygen environment
consumption . The oxygen metabolism and are to be developed. Normal retinal oxygen
oxygen consumption are unevenly distributed environment (i.e., normal oxygen partial
in the retina. Any interference in this activity pressure in the retina ) is influenced by
will cause tissue changes6 . several physiological factors under normal
The oxygen required for essential and pathological conditions 2. Under a
metabolism in the retina is primarily derived pathological state of central retinal
from the blood in choroidal vessels and in occlusion which makes the whole retina
the central retinal artery. The choroidal blood anoxic, the blood supply to the inner retina
vessels supply oxygen to the avascular is interrupted in proportion to the degree of
outer retina by diffusion whereas the central occlusion and hence oxygen-delivery to the
retinal artery nourishes the inner retina. As inner retina is affected. Under the normal
the oxygen enters the retina, it creates a characteristics of the choroid-retinal wall, the
minimum tension/ partial pressure in the choroidal partial oxygen pressure, which
retina. This pressure is regulated through the ensures sufficient oxygen supply to the
balance of oxygen delivery and oxygen outer retina, has a dominating effect on the
2
consumption in the retina . oxygen-environment. The states of normoxia,
Besides, retinal blood flow is strongly hyperoxia, extreme hyperoxia etc, affect
dependent on the partial pressure of oxygen. retinal oxygenation. Light - adaptation and
Most of the oxygen delivered by choroidal dark - adaptation of the retina also influence
circulation to the outer retina is consumed the oxygen partial pressure4. The oxygen
by photoreceptor segments because this consumption in different retinal layers is
layer is the location of all photoreceptor bound to affect the pressure. The effect of
mitrochoridria with the exception of those in such factors varies in different layers. The
3
the synapse . A greater proportion of the understanding of the effects of such factors
oxygen provided by the retinal circulation on the oxygen partial pressure may be
to the inner retina is utilized by its inner important in the understanding of retinal
plexiform layer. The rate of oxygen development and retinal pathology and in the
consumption varies from layer to layer and clinical management of retinal vascular
proportion of oxygen consumed by different diseases.
retinal layers is not known.

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 Avtar & Tandon

In order to devise strategies to restore and Fick’s law. They investigated the effect of
optimal oxygen environment in the retina, changes in retinal blood flow under the light
there is a need to improve present and dark adapted conditions.
understanding of retinal oxygenation and The objective of the present study is to
physiological factors affecting it. Enriched formulate a simple steady-state
understanding may be useful in the mathematical model for intraretinal oxygen
development of more viable strategies for partial pressure distribution. The model treats
improving oxygen supply to ischemic retina. the retina as consisting of eight layers. The
A mathematical model that accurately oxygen consumption was assumed to follow
describes the intraretinal oxygen partial Michaelis-Menten kinetics and oxygen
pressure distribution may contribute to delivery in the inner retina was described by
4
improved understanding of retinal using Hill’s equation and Fick’s law .The
oxygenation. approximate solution to the model was
In 1999, Cringle et al.2 developed a steady obtained using an iterative technique and
state mathematical model for the oxygen Runge-Kutta Nystrom’s method5. The
partial pressure distribution in the avascular computational results of the model have been
(outer) retina . The model treats the outer presented in the Figures and are also
retina as consisting of four layers. The discussed.
oxygen consumption in the outer
photoreceptor layer and in the outer nuclear METHODS
layer was considered to be zero, while in Mathematical model
the inner photoreceptor layer and deep We considered a retina that has eight
retinal capillaries, the oxygen consumption layers (see Fig 1). Layers 1-3 constitute the
was considered to be constant. The effect outer retina and the remaining layers
of oxygen partial pressure levels under constitute the inner retina. The outer retina is
adapted light and dark conditions on the avascular and hence does not receive
oxygen partial pressure in the retina was oxygen. Layer 2 is the location of a majority of
investigated and discussed. the photoreceptor mitrochondria. Most of the
Linsenmeier and Silver3 presented a three- oxygen consumption in the outer part of
layered steady state model for the oxygen the retina seems to take place in the
partial pressure distribution in the outer photoreceptors’ inner segments1. In the inner
retina by assuming oxygen diffusion and retina (which is vascular), oxygen transport
constant oxygen consumption inside it. They to the retinal cells occurs via blood and by
fitted their experimental data to the model. diffusion. Most of the oxygen supply in the
1
In 2002, Cringle et al generalized their inner part of retina seems to take place in the
1
earlier model and presented an eight- layer 6 . The oxygen consumption and
layered steady state model in the retina. The oxygen delivery was assumed to occur in
oxygen consumption in different layers was the outer region of the inner plexiform
considered to be constant. They computed layer1.
oxygen tension in different layers of the Boundary and interface conditions
retina and compared the model’s results with The physiologically relevant and
4
experimental results. Roos presented a mathematically consistent boundary and
transient four-region model for the oxygen interface conditions are prescribed below:
partial pressure in the retina. The model In the above equations, x represents the
divides the outer retina into three regions distance from the choriocapillaries. Eq.5
and the inner retina was considered as the represents that the partial pressure of
fourth region. The oxygen-consumption was oxygen at the choridal retinal boundary and is
assumed to follow Michaelis- Menten equal to that in the choriocapillaries. Eqs
kinetics and oxygen delivery in the inner 6(a,b), 7(a,b), 8(a,b), 9(a,b), 10(a,b), 11(a,b)
retina was described using Hill’s equation and 12(a,b) represent the continuity of both

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 Avtar & Tandon

partial pressure of oxygen and flux at the epithelium is so low that it does not
junctions between adjacent layers of the influence the shape of the oxygen profile.
retina. Eq (13) prescribes absence of oxygen 3. Since oxygen supply and consumption
flux at the retina – vitreous boundary. are intermingled in layers 4 and 8,
absolute level of oxygen consumption
cannot be quantified1. Oxygen supply and
oxygen consumption in layers 4 and 8
can counterbalance each other. Therefore,
oxygen consumption and oxygen supply
in layers 4 and 8 can be assumed
negligible.
4. All oxygen transport occurs by one-
dimensional diffusion and the retina is
assumed to be homogenous with no
diffusion parallel to the retinal layers.
5. The process of oxygen transport, oxygen
consumption, and oxygen delivery in the
retina is steady.

Governing equation
The steady state local partial pressure of
oxygen in the retina is governed by the
diffusion equation:

Fig.1: Schematic diagram of oxygen distribution ∇.( Dox ∇p ) − q ox + s ox = 0 (1)

across the eight layers of the retina1. Layer 1 =
outer segments of the photoreceptor layer; layer 2 In view of the above- mentioned
= inner segments of the photoreceptor layer; layer assumptions, eq. (1) reduces to a one-
3 = outer nuclear layer ; layer 4 = deep retinal dimensional form:
capillaries; layer 5 = inner nuclear layer; layer 6 = d 2 pi
outer region of the outer plexiform layer; layer 7 = Di − qi + si = 0 i=1,2,---- (2)
inner region of the inner plexiform layer; and layer 8 dx 2 --8
= ganglion cell / nerve fiber layer and the superficial
where pi is the partial pressure of
retinal capillaries.
th
oxygen in the i layer, Di the diffusion
Assumptions
th
To this end, the following assumptions are coefficient of oxygen in the i layer, qi the
introduced: th
oxygen consumption term in the i layer, s i
1. Oxygen gradient at the retina -vitreous
boundary is negligible. This assumption th
the oxygen delivery term in the i layer.
is based on the very low oxygen According to Michaelis- Menten kinetics, the
consumption of the vitreous and the consumption term for oxygen [16] is given
relatively by:
large distance across the vitreous to
any other oxygen sources or sinks.
pi .(q ox max ) i
qi = (3)
2. Layers 1, 3, 5 and 7 were assumed to pi + k i
have negligible oxygen consumption
where ( qox max ) i is the maximal rate of
due to the known properties of layers 1
1 th
and 3 . In particular, the oxygen oxygen consumption in the i layer and k i
consumption of the retinal pigment
the partial pressure of oxygen at half maximal

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 Avtar & Tandon

bf ( p blood ) n ( β pi ) n Hb.δ (4)

blood
si = [( p − β p i ) + ( blood n n
− n n
) ]
60 (p ) + (khem) ( β pi ) + (khem) α1
( p1 ) x =0 = pc (5)

dp 2 dp 6(a,b)
( ) x = L1 = ( 1 ) x = L1
( p 2 ) x = L1 = ( p1 ) x = L1 dx dx

( p3 ) x = L2 = ( p 2 ) x = L2 dp3 dp
( ) x = L2 = ( 2 ) x = L2
dx dx 7(a,b)

dp 4 dp 8(a,b)
( ) x = L3 = ( 3 ) x = L3
( p 4 ) x = L3 = ( p3 ) x = L3 dx dx

9(a,b)
( p5 ) x = L4 = ( p 4 ) x = L4 dp5 dp
( ) x = L4 = ( 4 ) x = L4
dx dx

( p 6 ) x = L5 = ( p5 ) x = L5 dp 6 dp 10(a,b)
( ) x = L5 = ( 5 ) x = L5
dx dx

( p 7 ) x = L6 = ( p 6 ) x = L6 dp 7 dp 11(a,b)
( ) x = L6 = ( 6 ) x = L6
dx dx

dp8
( ) x =L8 = 0
dx (13)

consumption speed in the i layer. Since a

th oxygen consumption rate in this layer will be
greater proportion of the oxygen consumption 90 mm Hg −1 in light and 170 mm Hg −1 in
occurs in the layer 2, therefore, maximal dark. For the inner retina, the value of

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maximal oxygen consumption rate will be solve the nonlinear equation for po 2 in the
−1
26 mm Hg in both light and dark which is second layer based on Runge-Kutta
a value within the range reported by Nystrom’s method. In order to find an
others5,6 . In layers 1, 3, 5, 7 and 8, oxygen improved solution for po 2 in (i + 2) layer,
th
consumption was assumed to be zero. The
oxygen consumption in the outer retina was (i=1,2—6) we determine ( p ) x = Li +1 and
confined to the inner segment of the dp
photoreceptor layer. In the inner retina, ( ) x = Li +1 from the solution for po 2 in
oxygen consumption was assumed to occur dx
in the outer region of the outer plexiform layer. (i + 1) th layer as initial conditions when we
The amount of oxygen transported locally th
from the blood to tissue is given by4: solve differential equation for po 2 in (i + 2)
where β is a constant , pi the local partial layer by Runge-Kutta Nystrom’s method. This
th blood dp8
pressure of oxygen in the i layer , p procedure is repeated until ( ) x= L8 is less
the partial pressure in arterial blood, Hb the
dx
−5
hemoglobin concentration in blood, α1 the than a prescribed tolerance ( 10 ) or tends to
zero. Here, three iterations are sufficient to
solubility of oxygen in blood, δ the oxygen yield satisfactory result for all the cases under
carrying capacity of hemoglobin, n Hill consideration.
coefficient and b f blood flow rate in the inner
RESULTS
retina. In the outer retina oxygen delivery was
The computational results of the model for
assumed to be zero since the outer retina
the partial pressure of oxygen in the
does not have any blood flow. In the inner
retina were obtained by using typical
retina, oxygen delivery occurs only in the
values of model parameters for a
outer region of the outer plexiform layer .
representative eye given in Table 1.
Solution to the model
The distributions of oxygen partial pressure
The system of second-order differential
in a hyperoxic and light adapted condition
equations governing the partial pressure of
for different values of blood flow rate in
oxygen in different layers of the retina is non-
the inner retina are shown in Fig. 2. It is
linear, due to the presence of non-linear
evident from the plots in Fig 3 that the
consumption term in the equation for po 2 in partial pressure of oxygen decreases along
the second layer and non-linear consumption the retinal depth.
and delivery terms in the equation for po 2 in The partial pressure of oxygen is
maximum at the choroidal side and
the sixth layer. The system of equations is
decreases sharply in the outer and inner
linearized by considering zero order
photoreceptor layers. This occurs as a result
consumption of oxygen in the second and the
of the oxygen consumption in the inner
sixth layers and non-delivery of oxygen to the
photoreceptor layer. Due to the oxygen
sixth layer, and so approximate solution to the
consumption and oxygen supply in the
system of equations is obtained. In order to
inner plexiform layer, there was less
improve the approximate solution for po 2 in reduction in the remaining layers. It was
dp 2 observed from the plots that as blood flow
the second layer, we determine p 2 and rate in the inner retina increased, the
dx partial pressure of oxygen increases.
at x = L1 from the solution for po 2 in the first The oxygen partial pressure profiles in the
layer through the interface condition 6(a,b) retina at a hyperoxic and dark adapted
which serves as initial condition when we condition are shown in Fig 3. The various
plots in Fig 4 show that the partial pressure of

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oxygen decreases along the retinal depth. It the vitreous body. A higher decrease in the
is obvious from the plots in Figs 2 and 3 that partial pressure of oxygen in the inner
the partial pressure of oxygen is higher in light photoreceptor layer and its adjoining layers
than in the dark. than the outer photoreceptor layer and outer
The various oxygen partial pressure profiles in nuclear layer was observed. This decrease in
extreme hyperoxic, light adapted condition for oxygen partial pressure reduced the partial
different values of blood flow rate in the inner pressure of oxygen in the inner retina.
retina are depicted in Fig 4. From the plots in The oxygen partial pressure profiles at an
Fig 4, it can be appreciated that the partial extreme hyperoxic and dark adapted condition
pressure of oxygen decreases gradually are depicted in Fig 5. The different plots in Fig
across the retinal layers from the choroid to 5 demonstrate that under extreme hyperoxia

Table1: Definitions and explanations of terms/symbols

Symbol Explanation Numerical Value Referenc

e
7
The diffusion coefficient of oxygen
Di (i=1,2--- 2*10 −5 cm 2 s −1
8) in the i th layer.

8
x The thickness of the retina (cm) 0.0245
4
The maximal consumption rate of
(qox max ) i th
Layer2: 90mmHgs −1 in
oxygen in the i layer. −1
light; 170 mmHgs in
dark
−1
Layer6: 26mmHgs iiin
both light and dark
9
ki The partial pressure of oxygen, at half 2 mm Hg
th
maximal speed in the i layer.
10,11
pc The partial pressure of oxygen in the 80 mm Hg (normoxia)
choriocapillaries. 250 mm Hg (hyperoxia)
405mmHg (extrme -
hyperoxia)
12
khem A constant which equals the partial 26 mm Hg
pressure of oxygen at which
hemoglobin is 50% saturated with
oxygen.
12
n Hill coefficient 2.7
9,10
Partial pressure of oxygen in arterial 80, 250 ,405 mmHg
p blood blood.
4
Hb The hemoglobin concentration in blood.
140 ( gL−1 )
13
δ The oxygen carrying capacity of −1
0.0616 ( mmolg )
hemoglobin
5
bf The blood flow rate in inner retina 0.4, 0.3,0.2, 0.1, 0 ml g −1 min
13
The
α solubility sol solubility of oxygen in blood.
1 1.5*10−3(mM mmHg −1 )

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 Avtar & Tandon

condition the partial pressure of

oxygen is extremely high at the
choroidal side and decreases sharply
along the retinal depth. The oxygen
consumption and oxygen delivery
occurring in the inner retina diminish
the decrease in the retinal layers
beyond inner plexiform layer as is
evident from the plots in Fig 5.
Comparison of the plots in Figs 4 and
5 show that the partial pressure of
oxygen at an extreme hyperoxic and
light adapted condition is higher than
Figure 2: Partial pressure oxygen profiles in the retina for that in extreme hyperoxic and the
different values of blood flow rates at a hyperoxic, light dark adapted condition.
adapted condition
DISCUSSION
An insufficient supply of oxygen to the
retina is thought to be an important
pathogenic factor in a variety of retinal
diseases such as retinal pigmentosa,
retinal artery occlusion, etc1.
Oversupply of oxygen can also result
in retinal disease4. There is also
evidence that oxygen toxicity plays a
role in degenerative retinal diseases
and it has been suggested that
manipulation of the retinal oxygen
environment may be a therapeutic
tool in the management of retinal
diseases 1,6.
Figure 3: Partial pressure oxygen profiles in the retina at a Previous theoretical modeling of
hyperoxic, dark adapted condition.
retinal oxygenation has mostly been
focused on conditions where oxygen
availability does not limit the oxygen
4,5
consumption . Moreover, attention
has been focused on the outer retina
or conditions where there is no retinal
blood supply. However, Cringle and
Yu 1 have sought to include the inner
retina with a possible blood circulation
by introducing their oxygen
consumption model. In their model,
the layers were assumed to have
blood supply, and the oxygen delivery
and consumption were treated as a
lumped term for oxygen supply and
Figure 4: Partial pressure oxygen profiles in the retina consumption, and a curve-fitting
for different values of blood flow rates at an extreme routine was used to obtain the
hyperoxic and the light adapted condition. parameter values producing the best

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Figure 5: Partial pressure oxygen profiles for different values of blood flow rates at an
extreme hyperoxic and dark adapted condition.

fit to experimental data. This means that their ACKNOWLEDGMENT

model should be used for the interpolation of The authors gratefully acknowledge the
some aspects of experimental data. Thus, the constructive and fruitful comments of the
present work has provided theoretically reviewers of original manuscript of the paper.
derived values of po2 in the retina at different
degrees of retinal ischemia in light and REFERENCES
darkness. If the result of this work is accepted 1. Cringle SJ, Yu D, Yu PK, Su E. Intraretinal
as reasonable, it seems that more clinical oxygen consumption in the rat in vivo.
studies with different degrees of hyperoxia will Invest. Ophthalmol . Vis Sci. 2002; 43: 1922-
1927.
be required.
2. Cringle SJ, Yu D, Alder V, Su E. Light and

CONCLUSION choroidal po 2 modulation of intrare-tinal

The computational results of the model predict oxygen levels in an avascular retina. Invest.
Ophthalmol. Vis. Sci, 1999; 40 :2307-2313.
that the partial pressure of oxygen in different 3. Linsenmeier RA, Silver. LP Metabolic dependence
layers of the retina is reduced by a decrease of photoreceptors on the choroids in the
in the blood flow rate in the inner retina. The normal and detached retina. Invest.
pressure is observed as minimum when there Ophtalmol. Vis.Sci. 2000; 41: 3117-3123.
4. Roos WM. Theoretical estimation of retinal
is no blood flow in the inner retina. This oxygenation during retinal artery occlusion.
minimum pressure may fall below the critical Physiol. Meas. 2004; 25 :1523-1532.
level of oxygen partial pressure and affect the 5. Ahmed J, Braun RD, Duun R, Linsenmeier RA.
retinal function. In order to restore normal Oxygen distribution in the macaque retina.
Invest Ophthalmol. Vis. Sci. 1993, 34516-521.
retinal function, extreme hyperoxia may assist 6. Cringle Stephen J, Yu D Intraretinal oxygenation
the choroid to supply oxygen to the whole and oxygen consumption in the rabbit
retina during total retinal artery occlusion as during systemic hyperoxia. Invest Ophthalmol.
suggested by Roos4. The results also predict Vis. Sci.2004;45:3223-3228
7. Pouge BW, Paulsen KD, O’ Hara JA, Wilmot CM,
higher partial pressure of oxygen in the retina Schwartz HM. Estimation of oxygen distribution
under light adapted conditions than that under in RIF-1 tumor by diffusion model based
dark adapted conditions. Thus, light may, to Interpretation of pimonidazole hypoxia and
some extent, be beneficial in preventing ependorf measurements. Radiat. Res 2001;
155: 15-25.
ischemia caused by retinal artery occlusion, 8. Haugh LM, Linsenmeier RA , Goldstick TK.
etc. Mathematical models of the spatial
distribution of retinal oxygen tension and

1115 Trop J Pharm Res December 2008; 7 (4)

 Avtar & Tandon

consumption including changes upon in the cat. Invest Ophthamol. Vis Sci.1995;
illumination. Ann.Biomed.Eng. 1990;18:19-36 36:523- 41.
9. Ganfield RA, Nair P, Whalen WJ. Mass transfer, 12. Kavanagh B D, Secomb TW. A comparison in
storage utilization of oxygen in cat cerebral individual murine tumors of techniques for
cortex. AM. J. Physiol. 1970; 219:814-21 measuring oxygen levels Int. J. Radiat. Oncol.
10. Alder VA, Cringle SJ. PO2 profiles and oxygen Biol . Phys. 2002; 53: 172-9.
consumption in cat retina with an occulded 13. Jain M.K, Iyengar SRK, Jain RK. Numerical methods
th
retinal circulation . Invest. Ophthalmol. Vis.Sci. for scientific and engineering computation, 4
1990;31:1029-1034. edn, New Age In Pub Ltd, New Delhi, India,
11. Braun RD, Linsenmeier RA. Retinal oxygen tension 2004.
and electro retinogram during arterial occlusion

1116 Trop J Pharm Res December 2008; 7 (4)