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ANNUAL
REVIEWS Further Fluid Mechanics of the Eye
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Annual Reviews content online,
including:
Jennifer H. Siggers and C. Ross Ethier
• Other articles in this volume Department of Bioengineering, Imperial College London, London SW7 2AZ,
• Top cited articles United Kingdom; email: j.siggers@imperial.ac.uk, r.ethier@imperial.ac.uk
• Top downloaded articles
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
347
FL44CH15-Siggers ARI 18 November 2011 14:2
1. INTRODUCTION
The eye is a remarkable organ, capable of transducing photons into neural signals with high
Intraocular pressure efficiency under a wide range of operating conditions. The retina, containing the specialized
(IOP): the pressure cells that carry out this transduction process, is aided in its function by many supporting tissues.
within the eye, which The development and proper function of this complex system depend critically on biomechanical
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is generated by the
factors, as has been summarized elsewhere (Ethier et al. 2004a). Here we focus specifically on
production and
drainage of the the fluid mechanical aspects of the eye, of which there are many. We begin with an overview of
aqueous humor relevant anatomy and physiology.
There are a number of processes within the eye in which fluid flow is important. Perhaps the
most evident of these are the production, circulation, and drainage of aqueous humor, a clear,
colorless fluid that is secreted at a flow rate of 2 to 2.5 μL min−1 (Brubaker et al. 1989) by a
specialized tissue known as the ciliary processes, located just posterior to the iris (the colored part
of the eye) (Figure 1). In view of the very small flow rates and modest dimensions, the flow of
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
aqueous humor is creeping and inertia can be neglected. The aqueous humor itself is a very dilute
protein solution and thus can be treated as Newtonian with viscosity nearly identical to that of
saline (Beswick & McCulloch 1956, Moses 1979). It flows into and fills a small region anterior to
the lens but behind the iris, known as the posterior chamber (see Figure 2a), then passes anteriorly
through the pupil (the aperture in the central part of the iris), and enters the anterior chamber,
where it circulates while bathing the iris and the inner surface of the cornea (the clear part of the
eye). Eventually the aqueous humor drains from the eye via specialized tissues located in the angle
of the anterior chamber, where the iris, cornea, and sclera (the white part of the eye) meet (see
also Figure 2 and Sections 2.1 and 2.2). These specialized tissues have a significant hydrodynamic
flow resistance, and the drainage of the aqueous humor out of the eye therefore requires that there
be a positive pressure within the eye itself, the so-called intraocular pressure (IOP).
Vortex vein
Sclera
Cornea
Choroid
Zonules
Iris RPE
Lens Retina
Retinal vessels
Optic
Ciliary processes nerve
Ciliary muscle
Anterior
chamber
Figure 1
Overview of a human eye with major anatomical structures identified. Abbreviation: RPE, retinal pigment
epithelium. Figure modified from Krey & Bräuer (1998), copyright c MSD SHARP & DOHME GMBH
Germany with kind permission.
meshwork
Iris
Cornea
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
Posterior
chamber
Trabecular
meshwork Ciliary
processes
Schlemm’s
canal Ciliary
muscle
Figure 2
Illustration of aqueous humor flow patterns in the anterior chamber and key drainage tissues. (a) Cross-sectional view through the
anterior eye. The arrows show typical thermal convection patterns of aqueous humor in the anterior chamber for an upright subject in
an ambient temperature less than 37◦ C and also drainage pathways from the anterior chamber into Schlemm’s canal and thence into
the aqueous veins/collector channels (bottom-most and top-most arrows). (b) Anterior-posterior view of Schlemm’s canal (thick green ring),
collector channels (thin green structures), aqueous veins (light blue), and adjacent arterioles. Figure modified from Krey & Bräuer (1998),
copyright c MSD SHARP & DOHME GMBH Germany with kind permission.
The flow of the aqueous humor performs two important physiological functions. First, the
positive pressure that it generates stabilizes the otherwise flaccid eye, ensuring accurate positioning
of the optical elements of the eye and hence clarity of vision. Second, aqueous humor supplies
Glaucoma: an
nutrients and removes waste products from the avascular lens and the central cornea, without ophthalmic condition,
which the cells in these tissues would die. Some models of aqueous humor flow in health are usually characterized
presented in Section 3. However, unfortunately (as explained below), impairment in the drainage by raised intraocular
of this fluid leads to an elevation in IOP, which is a major risk factor for the disease known as pressure, which leads
eventually to blindness
glaucoma, the second-most-common cause of blindness in the world (Quigley & Broman 2006)
by the death of retinal
(see Section 2). In glaucoma, a specialized type of cell known as the retinal ganglion cell is damaged ganglion cells
and eventually dies (Qu et al. 2010). These cells are responsible for carrying visual information
Mass transport:
from the retina to the brain, and therefore any insult to them can result in vision loss. As shown in transport of a defined
Section 2.3, mechanical factors are believed to play a central role in this disease (Burgoyne et al. species within a fluid
2005), and consideration of flow and mass transport effects in the retinal ganglion cell axons may or solid that is driven
be a promising new way to understand the pathogenesis of glaucoma. by convection,
diffusion, and
The cornea combines the attributes of mechanical strength and optical transparency, which
destruction/
is achieved by an extremely regular planar arrangement of collagen fibers (see Figure 3); in production (through
particular, corneal transparency depends sensitively on fiber spacing and hence on the hydration chemical reactions)
state of the cornea. There is a continuous flux of fluid in and out of the cornea, and the body
0.5 µm
Figure 3
Normal human cornea of a 62-year-old male patient, showing the regular arrangement of collagen fibers
within the corneal stroma. Figure taken from Langham, Maurice E., ed. The Cornea: Macromolecular
Organization of a Connective Tissue. Papers from a Symposium Held in Kyoto, Japan, 1967, under the Auspices of the
Department of Ophthalmology, Osaka University, p. 124, figure 7-1. Copyright c 1969 by The Johns Hopkins
Press, reprinted with permission.
therefore has developed sophisticated mechanisms to control this transport. Specifically, water is
actively and continually pumped out of the corneal stroma (the central layer of the cornea) by
the corneal endothelium, a specialized layer of cells lining the interior corneal surface. The net
effect is that the stroma is in a continual state of thermodynamic disequilibrium with respect to
its adjacent bathing fluids, namely the tear film anteriorly and aqueous humor posteriorly (see
Section 3.4).
The majority of the ocular globe is filled by a clear, colorless, gel-like material known as
vitreous humor, which occupies the vitreous chamber of the eye. The chamber is surrounded by
two tissues, the retina and the choroid, the former of which comprises many layers (see Figure 4).
Vitreous humor has complex viscoelastic properties, and although there have been several attempts
to characterize its properties experimentally (Lee et al. 1992, Nickerson et al. 2008, Swindle et al.
2008, Zimmerman 1980), its rheology is not fully understood. It is known that the vitreous humor
becomes progressively liquefied with age; approximately 20% of the vitreous humor is liquid in
14–18-year-olds, and this rises to more than 50% in subjects aged 80–90 years (Bishop 2000).
In approximately 25%–30% of subjects, liquefaction can lead to a process in which the retina
detaches, risking loss of sight. In this context, it is also important to note that the eye is not
normally stationary, even when apparently focused on a fixed point. Instead, the eye constantly
executes a series of extremely rapid angular rotations (300◦ s−1 or more) known as saccades (Rayner
Direction of
light travel
Vitreous humor
Choroid
50 µm Sclera
Figure 4
Cross section through the retina and choroid within the macula (the part of the retina with the greatest
concentration of rod and cone cells). The asterisk denotes the choriocapillaris, and the white arrowheads
point to Bruch’s membrane. Reprinted from Curcio et al. (2009) with permission of Elsevier.
1998). These have the effect of creating flow patterns within the vitreous humor, particularly if
it has liquid characteristics, as explained in Section 4. A common cause of vision loss in elderly
subjects is age-related macular degeneration, which is thought to be caused by impaired transport
across Bruch’s membrane, the membrane situated at the base of the retina, due to accumulation
of lipid particles deposited within the membrane over a period of years (see Section 5).
With the notable exception of the lens, central cornea, and the vitreous humor, the eye is
richly supplied by a complex network of blood vessels, leading to many interesting physiological
problems associated with the regulation of blood flow in the network. For example, the retina has
a remarkably high metabolic rate and a correspondingly large need for blood, which was recently
investigated by Liu et al. (2009) in a reconstructed network model to compute flow and mass
transport. Moreover, because the ocular vasculature is contained within the eye globe, which is
itself pressurized, the ocular veins can experience collapse, behaving as a Starling resistor. The
physiology of ocular blood flow has been much studied (e.g., Kiel & van Heuven 1995, Reitsamer
& Kiel 2002) but has received little attention from the fluid mechanics community. Viscoelastic fluid:
a fluid whose stress
tensor depends on
both the deformation
2. FLUID MECHANICS OF GLAUCOMA
and the rate of
Glaucoma is often, although not always, characterized by an increase in IOP, and lowering the deformation of its
pressure is the only treatment currently available. Therefore, there is significant interest in un- particles
derstanding the factors that control IOP. In almost all cases of glaucoma, the cause of the pressure
sion of outflow with attendant dramatic increases in IOP; a mathematical model of this is briefly
discussed in Section 3.1. In open-angle glaucoma, the drainage tissues remain accessible to the
aqueous humor, but they present an elevated flow resistance. There are a number of different types
of open-angle glaucoma, the most common of which is known as primary open-angle glaucoma.
This condition has puzzled researchers for many years, as there are no evident structural changes
in the drainage tissues that could explain their elevated resistance. Here we discuss some of the
modeling work that has attempted to shed light on the source of the resistance. Section 2.1 dis-
cusses changes in the trabecular meshwork, and Section 2.2 focuses on changes in the mechanics
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
of flow into and through Schlemm’s canal. Section 2.3 discusses a possible mechanism for the
death of retinal ganglion cells, which is the cause of vision loss in glaucoma.
of the hydraulic permeability of a pure biopolymer gel or of tissues with well-characterized mi-
crostructure (Ethier 1986). Application of this theory to the trabecular meshwork required the
consideration of a two-level hierarchical porous medium, in which a material (the gel) with charac-
Porous medium:
teristic length scales on the order of angstroms to nanometers and hydraulic permeability Kgel was a solid material whose
embedded within a second material (the trabecular meshwork) having pores with dimensions on small-scale structure is
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the order of micrometers to tens of micrometers. Accounting for steric hindrance and tortuosity characterized by pores
effects leads to a prediction of the overall permeability of the composite material as (Ethier 1986) filled with fluid; flow
in such materials is
εT M usually governed by
K = K gel . (2)
2 − εT M the Darcy equation
This produced a much more satisfactory agreement between theory and result, leading to what
is now known as the gel-filled meshwork theory. However, subsequent experimental data have
called this model into question; for example, treatment of the trabecular meshwork with enzymes
that are known to degrade the biopolymer gel seems to have a much smaller effect on hydraulic
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
a b
Edge of JCT
(z = L) 20
Flow
30
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24 0 1 2
21 x
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Inner wall 0
(z = 0)
10 20
Pore center x Edge of domain
(x = 0) (x = b/2)
Figure 5
(a) Normalized pressure contours obtained by numerical simulation of flow in the juxtacanalicular tissue ( JCT), treated as a porous
medium, in the neighborhood of a fenestration (pore) in the inner wall of Schlemm’s canal. The length scales are normalized by the
pore radius, the pressure is normalized by the pressure drop that would be needed to force the same volume flux through the JCT alone
(i.e., without the inner wall), b is a typical distance between neighboring pores, and L is the thickness of the JCT. (b) Illustration of the
setup considered in the model. Figure taken from Johnson et al. (1992).
canal, caused by IOP-induced deformation of the trabecular meshwork. They modeled the inner
wall as a permeable membrane supported by linear Hookean springs with constant stiffness E
(see Figure 6a). Thus the height, h(x), of the canal—the distance between the inner and outer
walls as a function of position, x, along the canal—is given by h = h 0 [1 − (IOP − Psc )/E], where
Psc (x) is the pressure in Schlemm’s canal, and h0 (assumed constant) is the height of the canal
when the transmural pressure, IOP − Psc , equals zero. The resistance to transmural flow is Rw
(assumed constant), which implies that a flux of 1/Rw times the transmural pressure drop crosses the
inner wall per unit length of wall. The authors modeled the aqueous humor as an incompressible
Newtonian fluid and assumed that |d h/d x| 1 and s h 0 , where s is the half-distance between
collector channel ostia, thus allowing them to approximate the flow using lubrication theory. The
TM
Figure 6
Schematic diagrams of the model for flow entering and within Schlemm’s canal developed by Johnson & Kamm (1983): (a) original
model and (b) model with septae included. Abbreviation: TM, trabecular meshwork. Reprinted with permission of ARVO.
Boundary conditions arise from prescribing the pressure at the collector channels, which, using
the spring condition given above, leads to
IOP − Pc c
h = h0 1 − , (5)
E
at x = s, where Pcc is the pressure in the collector channels. They solved the governing
Equation 4 numerically over the half-distance between neighboring collector channels (i.e., the
region 0 ≤ x ≤ s in Figure 6), imposing a symmetry condition at x = 0.
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
The model predicts a nonlinear dependence between the total outflow and the pressure drop,
IOP − Pc c , due to an increase in resistance to outflow. The nonlinearity occurs because the height
of Schlemm’s canal decreases when the pressure drop is large, increasing the canal’s resistance
and hence the overall resistance. Thus, to maintain a constant outflow to meet physiological
demands, the IOP must increase more than it would if the dependence were linear. Another cause
of increased IOP could be that the inner wall resistance, Rw , increases, while the other parameters
maintain constant values, which would mean the IOP must also increase to maintain the outflow.
For a normal or slightly raised IOP (up to approximately 25 mmHg), and using parameter values
suitable for the human eye, the predicted height of the canal is approximately spatially uniform, and
the predicted resistance to outflow is approximately constant as IOP increases. The approximately
uniform height of Schlemm’s canal implies an approximately spatially uniform luminal pressure,
which shows that the majority of total outflow resistance does not derive from the resistance to flow
within Schlemm’s canal. For higher IOPs, the canal begins to collapse near the collector channels,
and at IOP = 29 mmHg, there is complete collapse. However, complete or almost-complete
collapse is unrealistic because Schlemm’s canal contains septae, short structures modeled as being
of height hs , which protrude into Schlemm’s canal from the outer wall to prevent complete collapse.
With a normal or slightly raised IOP, these protrusions make no difference to the model results
because the minimum width of the canal is greater than hs . For higher IOPs, there is partial collapse
of the canal with the septae supporting the collapsed region (see Figure 6b). For still-higher IOPs,
the channel is completely supported by the septae and has constant height hs , and under these
conditions the total outflow resistance is constant. In a further extension, the authors considered
compliant septae, meaning that the height can drop below hs in the collapsed region, increasing
the resistance of Schlemm’s canal compared with the rigid septae model. A comparison of model
results with experimental data suggests that Schlemm’s canal collapse does not occur in glaucoma,
implying that glaucoma cannot be caused by weakening of the trabecular meshwork alone.
A related question concerns the flow within the lumen of Schlemm’s canal, as opposed to that
across the endothelial lining of the canal. In the vascular system, which shares many biological
similarities with Schlemm’s canal, the caliber of vessels is strongly influenced by the shear stress
exerted by the blood flowing within the vessel. However, because the volumetric flow rates in
the lumen of Schlemm’s canal are minuscule, shear stresses might, a priori, also be expected
to be too small to have physiological impact. However, a simple calculation in which the cross
section of Schlemm’s canal was treated as an ellipse showed that the estimated shear stresses
were similar to those observed in the vascular system (Ethier et al. 2004b), suggesting that the
biological mechanisms for caliber regulation in the two systems could be similar. This is potentially
important, as Schlemm’s canal is observed to be shorter in the anterior-posterior direction in
glaucomatous eyes, even though its height h is unaffected (Allingham et al. 1996). This increases
outflow resistance, and thus dysregulation of the mechanisms controlling Schlemm’s canal caliber
may play a role in glaucoma.
In glaucoma, the cause of death of the retinal ganglion cells is not fully understood (Ethier et al.
2004a, Fechtner & Weinreb 1994, Schumer & Podos 1994), and several mechanisms have been
proposed. These include mechanical insult to optic nerve head tissues and/or a failure in vascular
autoregulation to the nerve (Burgoyne et al. 2005, Morgan 2000, Pillunat et al. 1997, Riva et al.
1997, Yamamoto & Kitazawa 1998, Yan et al. 1994). Here we consider another, more fluid me-
chanically based, mechanism proposed by Band et al. (2009). Retinal ganglion cells require axonal
transport to remain viable, in which cargo-containing structures, the vesicles, are transported along
the axons by motor proteins. These motor proteins require energy for their task, which they ob-
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
tain from adenosine triphosphate (ATP) molecules, which in turn are released from mitochondria
located along the axon. ATP is distributed along the axon by a combination of diffusive and, in the
presence of flow, convective, effects. If the supply of ATP is sufficiently depleted, then active axonal
transport will be reduced or stopped. This has been shown to lead to the death of ganglion cells
in primates (Anderson & Hendrickson 1974, Balaratnasingam et al. 2007, Minckler et al. 1977).
Retinal ganglion cells contain axoplasm, a fluid that has approximately Newtonian properties.
The walls of these cells are permeable to the axoplasm; therefore, in the presence of a pressure
gradient, it is possible for the axoplasm to flow along the axon, as it can be replenished by transmural
flow. In the proposed mechanism, the rise in IOP leads to a significant axial flow of the axoplasm,
and this causes convection of the ATP toward the brain. If the convection of ATP is stronger
than diffusion, it will prevent ATP from diffusing in the upstream direction, leading to a region
of washout along the axon. Band et al. (2009) developed a mathematical model of the flow in the
axons and used it to estimate the relative strengths of convection and diffusion, characterized by
the Péclet number. They demonstrated that their suggested mechanism is plausible because the
flow is likely to begin to occur for elevations of IOP on the scale of those observed in glaucoma.
The model is illustrated in Figure 7. Each ganglion cell axon lies partly within the eye globe
and partly within the optic nerve bundle. In the eye globe, the flux of fluid through the axon
Sclera
Cell bodies at z = −M
Pressure
p−(z;r) Site of lamina cribrosa
Pressure p+(r,z)
Flux of axoplasm
r Axis of
symmetry
Figure 7
Mathematical model to analyze flow in retinal ganglion cells. Abbreviations: AAT, active axonal transport;
CSF, cerebrospinal fluid. Figure taken from Band et al. (2009).
wall is assumed to be proportional to the local pressure drop across the axon wall. In the optic
nerve, the axons are treated as a bundle of fibers whose cross sections form a hexagonal lattice,
and flux between neighboring axons is also proportional to the pressure difference between the
Homogenization:
fluids in them. Flow along the length of the axon is driven by the axial pressure gradient. These a technique used to
assumptions were used to homogenize the model, leading to a relationship between the axial flux analyze multiple-scales
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and pressure gradient along the axons, which can be solved to find the flow and pressure in the problems; quantities
form of sums of an infinite series of Bessel functions. are averaged over the
small scale, leading to
If the IOP is elevated to levels commonly seen in glaucoma, the Péclet number for ATP
simplified large-scale
predicted by the model is greater than one within substantial extraocular regions of the axons. equations
This suggests there will be significant depletion of ATP in these regions, illustrating the potential
importance of the proposed mechanism.
Cornea: z = h(x,y) T = T0
y
a
x
−a a
−a
Pupil
aperture
T = T1
Flow w0(x,y) Iris: z = 0
Figure 8
Sketch of the model developed by Canning et al. (2002) to investigate flow in the anterior chamber.
Reprinted with permission of Oxford University Press.
to be purely normal to the plane of the iris and given by a prescribed function w0 (x, y), with no-slip
velocity applied on the other boundaries, except that drainage occurs at the angles of the domain.
Canning et al. (2002) used experimental measurements to argue that the aspect ratio of the
Buoyancy-driven
flow: flow driven by model is small (h a) (see Figure 8) and also estimated the reduced Reynolds number to be
spatial density small. In the formal mathematical limit in which these quantities are small, and also neglecting
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gradients in the fluid, viscous dissipation, time dependence, and convection of heat, they derived a simplified system of
frequently due to equations. They were able to manipulate these and reduce them to the single differential equation
temperature variations
in the fluid ∇ H · h 3 ∇ H P = −12μw0 , (6)
where ∇ H = ex ∂/∂ x + e y ∂/∂ y in Cartesian coordinates, P is the deviation in the pressure from
the hydrostatic pressure profile, and μ is the viscosity at the temperature T0 .
The authors estimated the size of w0 and concluded that, typically, it is likely to be small
compared to the thermally driven velocity, and therefore they considered the case w0 = 0, which
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
allows an exact solution of Equation 6. Estimation of the stress induced by this flow suggests it is
unlikely to be strong enough to cause particle or cell detachment from the iris. A comparison of
the transit time of the solution with the time it would take a particle in the aqueous humor to settle
under gravity shows that the convective velocity is several times faster than the settling velocity.
Calculation of the Stokes drag allows a full model of particle transport to be developed. The model
showed that particles remain in the vertical plane that contains them and that is also perpendicular
to the iris. The authors solved the model numerically and used their results to comment on
features that would be present in a number of clinical conditions. This work was extended by
Fitt & Gonzalez (2006) to include inflow (w0 = 0), to consider other directions of gravity with
respect to the model (e.g., a supine patient), to investigate vibrations of the lens as the head or
eye moves (phakodenesis), and to investigate the flow produced by rapid eye movements during
sleep. Their results showed that the buoyancy-driven flow typically exceeds the flow driven by
other mechanisms by orders of magnitude and plays a dominant role in several medical conditions
of the anterior chamber.
the lens position is, the greater the likelihood of iris-lens contact, which leads to a greater pressure
difference between the posterior and anterior chambers. Conversely, decreasing the diameter of
the anterior chamber leads to a smaller angle between the iris and the cornea, which is likely to
increase the flow resistance of the aqueous outflow pathway. However, testing their model for
different pupil diameters suggests that the condition is most severe when the pupil is small. This
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contradicts clinical tests that suggest the condition is most serious in dark environments when the
pupil is large.
only been elucidated over the past decade or so, despite the fact that the circulation of aqueous
humor has been reasonably well understood for a century.
The essential fact driving the difference between water and protein transport in the anterior
eye is that the lining epithelium of the ciliary processes, the tissue responsible for secretion of
the aqueous humor, is highly impermeable to proteins. Therefore, proteins naturally present
in the ciliary body are prevented from entering the posterior chamber and instead build up in
the extravascular space of the ciliary body to create a reservoir of plasma proteins. Proteins then
diffuse anteriorly from this reservoir, leaking into the anterior chamber from the anterior iris. This
mechanism has been confirmed by an elegant series of tracer studies in various species (Barsotti
et al. 1992, Bert et al. 2006, Freddo et al. 1990), complemented by theoretical models of protein
mass transport with predictions that show a reasonable agreement with experimental data (Barsotti
et al. 1992).
a 1 mm
b
A
hc
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xc
x 1.20
dh/dx
Thickness, h
Thickness (mm)
Loss of fluid 1.00
0.80
0.60
hc
Gain of fluid 0.40 48 h
24 h
0.20 7h
0h
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0
xc 0 1 2 3 4 5 6 7 8 9 10 11 12
Position along strip, x Position along strip (mm)
Figure 9
Experimental work using a pachometer by Hedbys & Mishima (1962) to investigate water transport in the cornea. (a) Illustration of
water movement along the corneal strip. The upper panel depicts the sample, and the lower panel shows the thickness of the sample, h,
over time (the darker area represents the loss of fluid from the swollen part, and the lighter area the gain by the dry part).
(b) Experimentally measured heights of the corneal strip at different times, which indicate that there is a point, xc , at which the height,
denoted hc , is approximately constant in time. The fluid movement is calculated across the area A, shown in the upper panel of (a),
which is located at the point xc . Reprinted with permission of Elsevier.
of the head and rotation of the eyeball within the socket). Deformation of the vitreous chamber,
due for example to a head impact, lens movement during focusing or pulsation of retinal blood
vessels, also gives rise to forces. However, in the absence of any deformation, purely translational
motion does not result in any relative motion of the humor within the vitreous chamber because
the accelerations involved can be balanced by a pressure gradient, whereas rotational motion does
induce the relative motion of the humor. The fastest motions occur when the vitreous humor is
liquefied, which can be the case either following the process of liquefaction described in Section
1 or following vitrectomy, a surgical procedure in which some vitreous humor is removed and
replaced with another fluid, often silicone oil or a gas bubble. In this case, the fluid filling the
vitreous chamber is approximately Newtonian. Several authors have developed mathematical and
experimental models of the flow in the vitreous humor, which we discuss in this section. We
first discuss models of the dynamics that approximate the vitreous chamber as a rotating sphere,
including a viscoelastic model (Section 4.1), and then consider extensions of this work to account
for the effects of the geometry of the chamber, while also simplifying to the case of a Newtonian
fluid (Section 4.2). We then focus on the potential effects of dynamic deformation of the vitreous
chamber by considering woodpeckers, whose eyes are subjected to enormous accelerations during
pecking and which appear to have a number of special protective adaptations (Section 4.3). This has
potential applications to understanding the mechanism of damage in shaken baby syndrome. We
then discuss models of partially liquefied vitreous humor (Section 4.4) and finally the implications
for mass transport in the vitreous humor, which has important implications for drug delivery to
the retina (Section 4.5).
viscoelastic model proposed by Lee et al. (1992) to characterize the rheological behavior of the
vitreous humor. The angular displacement was modeled as cos ωt, and the assumption of small
oscillations allowed them to linearize the model and seek solutions proportional to e iωt . This led to a
Steady streaming:
linear relationship between the shear stress and the shear strain, whose constant of proportionality the time average of a
was the complex modulus, G, dependent on ω. In terms of spherical polar coordinates (r, θ, fluctuating flow,
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φ), centered on the sphere and with the axis parallel to the axis of the oscillations, the velocity arising because of a
field is nonconservative body
force, Reynolds
i R3 ω[sin(ar/R) − (ar/R) cos(ar/R)]
u=− sin θ eiωt e φ + c.c., (7) stresses, or boundary
2r 2 (sin a − a cos a) effects
where R is the radius of the sphere; a = αc e −iπ/4 ; α c is the complex Womersley number, given by
iρω2 R2
αc = ; (8)
G
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
ρ is the fluid density; eφ is the unit vector in the direction of increasing φ; and c.c. denotes the
complex conjugate. Thus for small values of |α c |, the fluid moves almost as a rigid body, whereas
for large |α c |, the motion becomes confined to a Stokes boundary layer of width |α c |−1 and
the fluid in the center of the sphere remains stationary. Their results show that for myopic eyes,
which usually have a larger radius, the shear stress generated by the vitreous humor on the retina
is typically larger than for nonmyopic eyes.
Repetto et al. (2005) studied vitreous fluid dynamics experimentally by creating an enlarged
model of the vitreous chamber in the form of a perspex cylinder containing a spherical cavity.
They mounted the cylinder on a motor that could perform prescribed torsional rotations about
the vertical axis and observed the resulting motion of the fluid on the horizontal mid-plane of the
model using particle image velocimetry. Under periodic forced rotations of prescribed amplitude
and frequency, the behavior was characterized by two dimensionless parameters: the Womersley
number, α, and the angular amplitude of the oscillations, . Their results were shown to agree well,
both qualitatively and quantitatively, with the theoretical predictions of David et al. (1998). The
authors also considered angular displacements based on measurements of realistic saccades, that
is, a single rotation through a fixed angle starting from an initially stationary fluid. At each point
in space, they measured the maximum over time of the absolute value of the azimuthal component
of the fluid velocity and also the timescale over which it was achieved. By decomposing the
time dependence of the angular displacement into a linear superposition of Fourier modes, they
compared these measurements with the theory of David et al. (1998), finding good agreement
even though the flow is not periodic, whereas David et al.’s model assumes periodicity. They used
their results to show that the shear stress is not strongly dependent on the angle through which
the eye moves in a saccade. Thus, because small-angle saccades are much more frequent than
large-angle saccades, small-angle saccades are responsible for generating the majority of the shear
stress on the retina when integrated over time.
In addition to the behavior just described, there is also a steady component of flow in the
vitreous humor [steady streaming (e.g., see Riley 2001)]. For small-amplitude oscillations, this
component is much smaller in magnitude than the leading-order oscillatory flow, but even so
it can play an important role in mass transport because the transport it induces does not tend
to cancel over a period of the oscillatory motion. Therefore, Repetto et al. (2008) studied this
steady streaming flow analytically in a similar system, i.e., a torsionally oscillating sphere filled
with a Newtonian viscous and incompressible fluid, assuming rotations of small angular amplitude
. They formulated the solution as a series expansion in powers of the small parameter : u =
u1 + 2 u2 + · · · , p = p 1 + 2 p 2 + · · · . The leading-order solutions u1 and p1 have frequency
ω and are also given by Equation 7, but with α c replaced by the Womersley number α. The first
corrections u2 and p2 are driven by the nonlinear term u1 · ∇u1 in the Navier-Stokes equation
(2)
and are thus a superposition of a solution with frequency 2ω and a steady solution, denoted u2 ,
(2) (0) (0) (0) (2) (0) (2)
p 2 and u2 , p 2 , respectively [thus u2 = u2 + u2 and p 2 = p 2 + p 2 ]. Because the steady
solution is more important in terms of its implication for mass transport, the authors calculated
(0) (0) (2) (2)
u2 and p 2 , but neglected u2 and p 2 . The solution took the form of a sum of terms whose
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dependence on θ and φ was found exactly, but whose dependence on r was an integral that had
to be computed numerically. In the limit α 1, the integral could be calculated analytically,
in which case the velocity can be shown to be proportional to α 6 and thus grows very slowly
as α increases. The integral can also be found analytically in the limit α 1, and in this case
the velocity tends to a constant value. The authors also performed experiments using the same
apparatus as Stocchino et al. (2007) but taking images only once per period to reveal the average,
rather than the instantaneous, velocity. The theoretical and experimental results showed good
agreement for small amplitudes (within 10% for = 0.0885) over the whole range of α (from 3.1
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
to 15.9).
4.2. Flow in Models that Account for the Real Shape of the Vitreous Chamber
The vitreous chamber is not perfectly spherical, and the most prominent feature is an indentation
into the chamber caused by the presence of the lens. To investigate the effect of the shape,
Stocchino et al. (2007) used an experimental model similar to the spherical model of Repetto
et al. (2005), but with a modified shape. Based on their analysis of several ultrasound and magnetic
resonance scans, the authors modeled the lens as a spherical indentation into the sphere, with both
spheres having the same radius. This introduces a further nondimensional parameter, δ, equal to
the maximum depth of the indentation divided by the vitreous cavity radius R. Again they subjected
this apparatus to periodic, torsional rotations and, approximately at each of the times when the
angular velocity reached its maximum absolute value, observed a circulation structure generated at
the back of the indentation. This structure then traveled toward the center of the sphere and was
annihilated. The path taken by the structure depended on the value of the Womersley number,
α. For small α, it traveled approximately in a straight line to the center of the vitreous cavity. For
large α, the circulation structure initially took the same path as in the low-α case but then diverged
from the low-α track as it moved away from the lens. This experimental work was extended by
Stocchino et al. (2010), who used particle image velocimetry with images separated by a multiple
of the oscillation period to find a steady streaming flow on the plane of symmetry orthogonal to the
axis of rotation. For moderate α, this revealed two large, counter-rotating steady circulation cells.
As α was increased, a complicated sequence of topological changes took place in the flow, and for
the largest value of α considered (α = 45.7), the most obvious circulations were a counter-rotating
pair with the a sense of rotation opposite to those visible for small α.
There has also been analytical progress on this problem. Repetto (2006) assumed the flow to
be incompressible and irrotational. Thus the governing equations reduce to Laplace’s equation
for the velocity potential, subject to no-penetration boundary conditions, and time enters the
problem only as a parameter. In a perfect sphere, the velocity equals zero because there is no stress
at the boundary to drive a flow. Motivated by this, the author assumed the indentation to be small,
δ 1, and linearized the problem. He found the potential as a sum of the spherical harmonic
functions each multiplied by a function of the radial coordinate. The linearized unsteady Bernoulli
equation was used to find the pressure.
However, this solution did not reproduce the circulations seen in the experiments, as they are
not irrotational. To model these circulations, Repetto et al. (2010) dropped the assumption of
potential flow and considered Newtonian viscous flow in an indented sphere. They also assumed
that δ is small and expanded the velocity as a double series u = (δ 0 u10 + δu11 + · · ·) + 2 (δ 0 u20 +
δu21 + · · ·) + · · ·, and similarly for the pressure. The component u10 and the steady streaming
(0) (0)
component of u20 , denoted u20 , equal the components u1 and u2 of the solution for the flow
(0)
in a true sphere described in Section 4.1. The calculation of u11 and u21 (the steady streaming
component of u21 ) is performed in terms of vector spherical harmonics, which are a basis of
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(0)
pairwise orthogonal, vector-valued functions of θ and φ. The components u11 and u21 are written
as a sum of an unknown function of r times a vector spherical harmonic times a known function
(0)
of t. The analysis also shows that u11 and u21 , which arise as a result of the deformed geometry,
grow rapidly as α increases and become increasingly important in the overall flow structure. Thus
the method is not expected to predict the velocity accurately for large α.
Plotting u10 + δu11 reveals a circulation that forms every half-period behind the indentation,
moves to the center of the sphere, and is annihilated. This reproduces the features of the exper-
imentally observed circulations for low α but not the path of the circulations for high α, which
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
is to be expected as the series expansion is not accurate for large α. Examination of the steady
component arising because of the deformation, u21 , reveals that there are two large steady circu-
lations on the horizontal mid-plane (the plane of symmetry perpendicular to the axis of rotation)
just inside the indentation. The wall shear stress is maximal on the apex of the indentation and
has two additional smaller maxima on either side of this point.
where α m is the m-th positive zero of the Bessel function J1 of the radial coordinate, and e m (t) are
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functions to be determined. The velocity potential satisfies Laplace’s equation, and they expand
it as
∞
d e m (t)
ϕ= ψm (r, θ) sin φ + [χ (r, θ) sin φ eiωt + c.c.], (10)
m=1
d t
where the second term involving the function χ is only needed in the case of forced oscillations.
The analysis for free motions yields the natural frequencies of the system, which are the frequencies
associated with each of the functions em . These are found to be substantially lower than the natural
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
frequencies of the membrane in the absence of fluid. With forced oscillations, there is an infinite
response at each of the natural frequencies, suggesting that, for a viscous fluid, there will be a large
but finite response at the natural frequencies. Such a response could in turn lead to the generation
of large shear stresses on the retina, potentially leading to damage and subsequent detachment.
Repetto et al. (2011) studied a circular model of the vitreous chamber filled with partially
liquefied vitreous humor. They modeled the liquefied component as a Newtonian incompress-
ible fluid and the gel component as a homogeneous isotropic viscous elastic incompressible solid,
characterized by a Mooney-Rivlin strain energy function, and assumed that the two components
were separated by an elastic membrane. They solved a numerical model to find the solid deforma-
tion and fluid flow. Their results showed oscillations of the vitreous humor for sufficiently large
values of the elastic modulus of the solid. The stresses were particularly high near the points of
attachment of the membrane to the retina, which could account for the increased risk of retinal
detachment at these locations.
considered a model consisting of three regions: the vitreous chamber, the retinal pigment epithe-
lium (surrounding the vitreous chamber on its posterior surface), and the choroid (surrounding
the retinal pigment epithelium). They used Darcy’s law and the convection-diffusion equation
to model the fluid flow and the drug transport, respectively (with different diffusivities in each
region). In the vitreous humor, there was assumed to be no source or uptake of the drug, while, to
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model the active transport within the retina, there was an additional transport term kact ·∇c , where
c is the drug concentration and kact is a vector in the radially outward direction. In the choroid,
there was no additional transport, but they added a rate-of-uptake term γ (c − c bl ), where cbl is
the drug concentration in the blood and γ is constant. The boundary conditions were as follows:
At the lens, they applied no penetration of fluid and no mass flux of drug; at the anterior hyaloid
membrane (the anterior surface of the vitreous humor immediately posterior to the lens) and at
the surface of the sclera, they set the pressures (with an approximate drop of 5 mmHg between
them driving the flow); and at both the hyaloid membrane and at the sclera, they assumed a rate
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
of uptake proportional to the amount of drug available, but with different constants of propor-
tionality in the two regions. The authors solved the system numerically to obtain concentration
profiles of the drug and compared the loss rates by each of the three mechanisms.
Repetto et al. (2010) also used their calculated flows to estimate a Péclet number quantifying the
degree of mixing that occurs because of convective mass transport in the vitreous humor. Because
(0)
the flow components u10 , u11 , and u20 all consist of closed streamlines, these components do not
induce mixing, and thus the estimate of the Péclet number is based on the maximum magnitude
(0)
of u21 . For fluorescein, a commonly used tracer in ophthalmology, this gives an estimated Péclet
number of approximately 1,000. This would suggest that the strength of the convection induced
by saccades is typically much greater than diffusion, and thus convection should not be neglected
in a model of drug transport. Stocchino et al. (2010) calculated the particle trajectories associated
with the steady component of the flow and used these to find typical distances traveled by a particle
over time. They found that the value of the Womersley number has a significant effect on mass
transport, with flows at high Womersley numbers transporting the fluid significantly further after
a fixed number of periods (see Figure 10).
a d
1 1
0.75 0.75
0.50 b2 0.50 b2
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0.020 0.050
0.25 0.016 0.25 0.040
0.012 0.030
y/R0 0 0.008 y/R0 0 0.020
0.004 0.010
–0.25 –0.25
0 0
–0.50 –0.50
–0.75 –0.75
–1.00 –1.00
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
0.75 0.75
0.50 b2 0.50 b2
0.080 0.150
0.25 0.064 0.25 0.120
0.048 0.090
y/R0 0 0.032 y/R0 0 0.060
0.016 0.030
–0.25 –0.25
0 0
–0.50 –0.50
–0.75 –0.75
–1.00 –1.00
–1.00 –0.50 0 0.50 1.00 –1.00 –0.50 0 0.50 1.00
x/R0 x/R0
c f
1 1
0.75 0.75
0.50 b2 0.50 b2
0.50 0.80
0.25 0.40 0.25 0.64
0.30 0.48
y/R0 0 0.20 y/R0 0 0.32
0.10 0.16
–0.25 –0.25
0 0
–0.50 –0.50
–0.75 –0.75
–1.00 –1.00
–1.00 –0.50 0 0.50 1.00 –1.00 –0.50 0 0.50 1.00
x/R0 x/R0
Figure 10
Contour plots of the nondimensional absolute square particle displacement, b2 (which is scaled by the square of the radius of the
domain, R2 0 ), in two experiments by Stocchino et al. (2010). They used nondimensional maximum indentation depth δ = 0.3,
amplitude of the sinusoidal rotations = 0.17 rad, and Womersley number α = 3.8 in panels a–c and α = 45.7 in panels d–f. The
panels show the displacement after (a,d ) 50, (b,e) 100, and (c,f ) 500 cycles. Reprinted with permission of the IOP.
embedded, approximately uniformly, by lipid spheres with volume fraction ϕ (volume of spheres
per unit total volume).
In the first model, they used a unit-cell approach, in which a single rigid sphere was surrounded
by a larger concentric spherical volume of the porous medium, such that the volume fraction of
the rigid sphere equaled ϕ. They assumed that the velocity on the outer surface of the porous
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sphere was the average velocity in the medium. In this assumption, the outer surface is sufficiently
far from the rigid sphere that the velocity on it is approximately uniform, and therefore ϕ must
be small for it to be valid. The resulting model can be solved exactly to find the pressure field,
and a comparison of the spatially averaged pressure gradient with Darcy’s law yielded the effective
hydraulic conductivity, K:
1−ϕ
K = Km . (11)
1 + ϕ/2
The second way to estimate K started with the rigid sphere embedded in the porous sphere of
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
the first model and used the calculated pressure distribution to find the total force on the rigid
sphere, which was
4 1 1
πra3 μV 0 − . (12)
3ϕ K Km
Comparing this with the formula derived by Brinkman for the force on a sphere in a porous
medium, they obtained the relationship
1 1 9ϕ ra r2
= + 2 1+ √ + a , (13)
K Km 2ra (1 − ϕ) K 3K
which agrees with Equation 11 to first order in ϕ in the limit K ra2 (which was relevant for their
experiments).
The authors tested these theoretical results by conducting experiments. They used Matrigel,
a material that has similar properties to those of Bruch’s membrane. After the addition of latex
nanospheres to the Matrigel, the measured values of the effective hydraulic conductivities agreed
well with those predicted by the theory. However, with embedded spheres of low-density lipopro-
tein instead of latex nanospheres, the effective hydraulic conductivity decreased significantly more
than the theory would predict, a phenomenon that has not been satisfactorily explained.
6. DISCUSSION
Our aim in writing this article was to show that the eye presents a wealth of interesting and
challenging problems in fluid mechanics. Several of these problems have been tackled; however,
there remain many outstanding unsolved fluid mechanical problems. We recommend this area to
the reader as a source of interesting and accessible research questions that have potential impacts
on our most important sense.
SUMMARY POINTS
1. The combined resistance of the trabecular meshwork filled with biopolymer together
with the inner lining of Schlemm’s canal are estimated to be sufficient to be the primary
source of resistance to the outflow of aqueous humor in health. The observed increase in
IOP during glaucoma could result partially from faulty caliber regulation in Schlemm’s
canal but does not result from the collapse of Schlemm’s canal per se.
2. Using a mathematical model, it is possible to show that typical raised IOP values in
glaucoma can drive a sufficiently large flow along the axons of the retinal ganglion cells
to cause washout of energy-providing ATP in the cells, which could promote cell death
and vision loss.
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3. Thermal convection is typically the dominant mechanism driving flow in the anterior
chamber.
4. The iris deforms as a result of the mechanical forces acting on it, leading to a complicated
fluid-structure interaction problem, which is relevant for closed-angle glaucoma and
recovery after a transient deformation of the iris position.
5. The transport of proteins within the anterior eye does not follow the same path as the
flow of aqueous humor itself.
Annu. Rev. Fluid Mech. 2012.44:347-372. Downloaded from www.annualreviews.org
6. Fluid transport in the cornea is anisotropic owing to the arrangement of fibers within
the corneal stroma.
7. If the vitreous humor is treated as viscoelastic, the vitreous chamber is assumed to be
spherical, and movements of the eyeball are assumed to be torsional and sinusoidal, the
linearized equations can be solved exactly to find the primary azimuthal component of
the flow. If the fluid is additionally assumed to be Newtonian, then a secondary streaming
component of flow can be found semianalytically.
8. The departure from perfect sphericity in the real shape of the vitreous cavity has a
significant effect on the flow, leading to additional circulation structures in both the
primary flow and in the steady streaming flow. Transient temporal deformations in the
shape of the vitreous cavity are likely to have a large effect on the flow and pressure,
which is not fully understood.
9. Nonhomogeneous properties of the vitreous humor can lead to additional stresses. A
membrane separating the cavity into two regions could lead to the possibility of resonance
at particular frequencies of oscillation. Alternatively, if the vitreous cavity is occupied by
a hemispherical region of elastic solid and a hemispherical region of viscous fluid, with
the two parts separated by a membrane, then the stress is particularly high at the points
of attachment of the membrane.
10. In the case of liquefied vitreous humor, mass transport typically primarily results from
convection induced by flow due to eye movements. The steady streaming component
of the flow plays one of the dominant roles in transport. In addition, mass transport is
significantly affected by both the shape of the chamber and the frequency of oscillation.
11. Impaired transport through Bruch’s membrane, thought to be responsible for macular
degeneration, can be partially understood by considering a homogenized mathematical
model of lipid particles embedded in a membrane.
FUTURE ISSUES
1. Open-angle glaucoma is known to be caused by increased resistance in the outflow path-
way of the aqueous humor. However, the exact locations and causes of the change in
resistance are not understood.
2. Closed-angle glaucoma results from the iris physically blocking the outflow of aqueous
humor. The mechanisms underlying this condition have not been fully resolved.
3. Glaucoma results in the death of retinal ganglion cells and subsequent vision loss. The
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DISCLOSURE STATEMENT
The authors are not aware of any biases that might be perceived as affecting the objectivity of this
review.
ACKNOWLEDGMENTS
C.R.E. acknowledges financial support from a Royal Society Wolfson Research Merit Award.
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Annual Review of
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Fluid Mechanics
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FL44-FrontMatter ARI 1 December 2011 22:45
Indexes
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