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Ann. Rev. Physiol. 1987. 49:209-19

Copyright © 1987 by Annual Reviews Inc. All rights reserved

ERYTHROCYTE MEMBRANE
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ELASTICITY AND VISCOSITY

Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

R. M. Hochmuth

Department of Mechanical Engineering and Materials Science, Duke University,

Durham, North Carolina 27706

R. E. Waugh

Department of Radiation Biology and Biophysics, University of Rochester, School of

Medicine and Dentistry, Rochester, New York 14642

INTRODUCTION

The classical theoryof elasticity(35) treats the material of a deformable body

as a three-dimensional continuum in which internal stresses occur as the body
is deformed by external forces acting over its surface. Although the internal
stresses are caused by the displacement of atoms or molecules from an
original state of equilibrium, the molecular character of the material is
ignored. This means that every volume element within the material must
contain enough molecules to guarantee that the thermal fluctuation of anyone
molecule does not effect the local state of stress.
Since biomembranes in general and red cell membranes in particular are
only a few molecules thick, they can form a continuum only in the plane of
the membrane. Thus, the methods of classical, three-dimensional continuum
mechanics must be compressed into a two-dimensional world in which "stress
resultants" or "tensions" (force per unit width of membrane surface) are
defined on the surface of the membrane (8, 25, 48). Measurement of the
surface stress resultants and the corresponding surface deformations permits
the material properties of the membrane surface to be calculated (15, 16, 20).
These surface properties represent a summation, over the thickness of the
membrane, of the properties of the lamellar, molecular structures that form
the membrane.

209
0066-4278/87/0315-0209$02.00
 210 HOCHMUTH & WAUGH

External forces acting over the surface of an elastic body readily deform
and stretch it. When the external forces of deformation are removed, an
elastic body recovers its original undeformed shape, i.e. it has "memory." As
the membrane deforms, viscous dissipation can occur within the membrane
material and in the surrounding fluid. Since the cytoplasm of the normal
human red cell is a newtonian hemoglobin solution, the shape of the cell
comes from the natural shape of the membrane, and the elastic response of the
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cell is determined by the elasticity of the membrane. However, the viscous

response of the cell can be governed by the viscosities of the cytoplasm,
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

membrane, and external plasma or saline solutions. Surprisingly, dissipation

within the membrane usually dominates the process of cell deformation, and
thus, dissipation in the cytoplasm and external medium can be neglected (13,
33).

MEMBRANE ELASTICITY

Although cell and membrane deformation can be quite complex in general,

for a two-dimensional, incompressible, elastic material like the red cell
membrane, any deformation can be expressed in terms of three fundamental,
independent deformations (16, 20). The deformations are (a) an elongation or

"shear" of the membrane without either increasing the surface area or bending
it, (b) a dilation (isotropic expansion) of the membrane surface without either
shearing or bending it, and (c) a bending of the membrane without either
shearing or expanding it. Each of these fundamental elastic deformations is
characterized by an elastic modulus: (a) a shear modulus JL with units of N/m,
(b) an area expansion modulus K with units of N/m, and (c) a bending
modulus B with units of N m. In general, a larger modt!lus indicates a greater
resistance to that particular form of deformation.

Shear Elasticity
For the constant area extension of a two-dimensional material, the maximum
shear resultant, Tg, occurs along a line at 45° to the direction of extension.
Shear and extension represent the same phenomenon and are characterized by
a single elastic constant-the shear modulus JL. The relation between the
shear resultant Ts and the extension ratio A (extended lengthloriginal length) is
(9, 15):

1.

When the portion of the membrane at the dimple of a flaccid cell is aspirated
into a pipette of radius Rp, the relation between the aspiration pressure P
(relative to the pressure outside the cell) and the extension up the pipette L is
(5, 57):
 MEMBRANE ELASTICITY AND VISCOSITY 211

From Equation 2 it is readily seen that J1, is proportional to the slope of the P
versus L line. This slope can be measured accurately. The majpr uncertainty
in the determination of a value for J1, is the uncertainty in the measurement of a
value for the pipette radius Rp. A 20% error in the measurement of Rp (say 0.2
J1,m out of 1. 0 11m) gives about a 40% error in the value for J1,. Based upon a
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single datum point for two different human red cells at room temperature,
Evans (9) first obtained a value for J1, of 5 x 10-3 mN/m. This value agrees
with the value for J1, obtained from a study of the shear deformation of
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

point-attached red cells (9, 30, 48). Since the original measurements (9),
many investigators have measured values for J1, (5, 17, 36, 42, 44, 49, 56,
57). Values range from about 4 x 10-3 mN/m (5, 17) to 10 X 10-3 mN/m
(56). The typical value is J1,= 6-7 X 10-3 mN/m. Recently,however,Evans
et al (19) accurately measured the inner diameter of their pipettes from the
insertion depth of a tapered microneedle that had been calibrated with the
scanning electron microscope. Their value is J1, = 9 ± 1. 7 x 10-3 mN/m.
Because this value is based on an accurate measurement for Rp, it must be
given greater weight. Thus, for human red cells at room temperature, J1, =

6-9 X 10-3 mN/m. For a given pipette and a given sample of cells from the
same donor, the standard deviation in the measurement of J1, is about ± 20%.
This is caused either by cell-cell variability or by errors in measurement of the
slope of the P versus L line. Experimental data indicate that J1" as defined by
Equation 1, is constant, although Fischer et al (24) suggest that the value for J1,
could decrease by a factor of 2.5 at very small membrane strains. Such small
strains cannot be measured with present techniques.
The shear modulus is affected by changes in the membrane environment.
Over a temperature range from 5 to 45°C, J1, decreases from 8.0 x 10-3 to 5.2
X 10-3 mN/m (57). Thus, the reversible change with temperature in the value
for JL is -6 X 10-5 mN/mrC (57). Cells heated to 47-48°C for 6-7 min and
then rapidly cooled to room temperature undergo a permanent, irreversible
two- to threefold increase in the value for J1, (43, 46).
Metabolic depletion caused by 24-hr incubation of red cells at 37°C causes
either no change in the value for J1, (39) or a slight (15%) decrease in its value
when calcium is present (1). Decreasing pH causes a significant increase in
the value for J1" while increasing pH above 7.2 has little effect on its value
(6). Elevated concentrations of 2,3-diphosphoglycerate appear to have no
effect on the value for J1" except at low ionic strengths, where the value for J1,
decreases (54).
For normal cells, the value for J1, is independent of the cytoplasmic hemo­
globin concentration (19, 36,40, 44). Cells with hemoglobin removed (pink
resealed ghosts) have a modulus indistinguishable from that of controls (54).
However, the membrane shear elasticity of sickle cells begins to increase
 212 HOCHMUTH & WAUGH

when the hemoglobin concentration exceeds about 0.38 kg/liter (19). At 0.45
kg/liter, the value for fL is about two and one-half times that of normal cells
(19). According to Nash et al (40), the very dense, irreversibly sickled cell
(ISC) has a value for fL that is about twice that of normal cells. Surprisingly,
prior to morphological sickling, the shear elasticity of sickle cell membrane
does not appear to change, even when the cells are deoxygenated to oxygen
concentrations as low as 20 mm Hg (41).
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The shear modulus is also affected by chemical alteration of the membrane.

Small concentrations of membrane-permeable, bifunctional sulfhydryl re­
agents ( e.g. diamide, tetrathionate) decrease the elongation of human red cells
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

freely suspended in a shear field (23), which probably indicates an increase in

the value of fL. Above a certain threshold level (0. 1 fLg/ml/cell), small
concentrations of the lectin wheat germ agglutinin (WGA) cause a stiffening
of the membrane (18) because of the binding ofWGA to glycophorin (3, 37).
At higher concentrations (2 fLg/mllcell), a thirtyfold increase in the value for
fL occurs, and individual cells respond in an inelastic, plasticlike manner (18).
Cholesterol enrichment and depletion of membrane have no effect on the
value for fL (2).
In hereditary spherocytosis, the value for fL is smaller than normal (58). A
strong correlation is observed between the surface density of the structural
membrane protein spectrin and the value for fL (55). This observation supports
the idea that spectrin is primarily responsible for the shear elasticity of the
membrane. However, there is little correlation between the value for fL and
abnormalities associated either with the membrane protein band 4. 1 or with
the number of high-affinity ankyrin binding sites (55). The elasticity of red
cells from males with Duchenne muscular dystrophy and female carriers is
slightly elevated (45).

Area Elasticity

An isotropic dilation of the red cell membrane is produced by aspirating a

preswollen cell into a micropipette until the portion of the cell outside the
pipette forms a sphere. The isotropic tension T is given by (22, 47):

3.

where P is the aspiration pressure, Rp is the pipette radius, and Rc is the cell
radius. As the aspiration pressure is increased, the area of the cell expands
because of an increase in the isotropic tension in the membrane. The expan­
sion of the surface area is measured accurately by measuring the movement up
the pipette of the membrane "tongue" within the pipette (21, 22). Extremely
small area dilations can be measured in this way.
 MEMBRANE ELASTICITY AND VISCOSITY 213

Evans et al (22) propose a simple linear relation between the isotropic

tension in the membrane and the relative area expansion:

4.

where L1A is the increase in surface area, Au is the original area, and K is the
area expansion modulus. The value for K at room temperature is K 450
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mN/m (21, 57) with a standard deviation of about ± 15-20% (57).

The value for K decreases from about 560 mN/m at 5°C to about 320 mN/m
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

at 46°C (57). The change with temperature in the value for K is -6 mN/mtC
(57). Note that both 1L and K have roughly the same proportional decrease
with temperature (57). The unpublished results of L. Smith & R. M. Hoch­
muth indicate that the value for K is smaller by approximately a factor of two
for cells from individuals with hereditary spherocytosis. Finally, the recent,
disconcerting results of Katnik & Waugh (34) indicate that the apparent value
for K depends strongly on the strength (voltage) of the applied electrical field
across the cell. Voltages of ± 200 mV produce changes in the value for K of
± 40%. Also, the measured value for K changes with the presence of Cu2 + or
Zn2+ in solution (34).

Bending Elasticity

Although small, the membrane's resistance to bending stabilizes the bicon­

cave shape of the cell during the early phases of the swelling process (24, 60)
and during pipette aspiration (11). For a shear elastic modulus of 6 X 10-3
mN/m, the bending modulus has to be about-1O-19 N m (10-12 ergs) for the
cell to swell smoothly (without popping) from a biconcave shape into a sphere
(24, 60). This value for the bending modulus implies that bending does not
contribute significantly to the pressure required to aspirate the membrane into
a pipette (11).
In multilamellar membranes, bending resistance can occur because of the
differential expansion and compression of a given monolayer or coupled
bilayer or coupled multilayer. For a coupled bilayer, the relation between the
bending modulus B, the compressibility of the bilayer K, and the bilayer
separation distance h is (16, 20)

5.

For h =2.5 nm and K 100 mN/m, B equals 1. 6 x 10-19 N m.

=

The bending moment, M, per unit length is given by (10, 26)

6.
 214 HOCHMUTH & WAUGH

where C, and C2 are the principal curvatures and Co is the curvature in the
stress-free state. Evans (12) has designed an experiment to measure the value
for B in Equation 6. In this experiment, a cell is aspirated into a pipette until
the circumferential load on the membrane causes it to buckle. The magnitude
of the aspiration pressure at buckling depends directly on the value for Band
inversely on the cube of the pipette radius. Analysis and measurements (12,
19) indicate that B = 1.8 ± 0.2 X 10-19 N m. This value for B agrees with
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previous estimates (11, 24, 60), including the estimate based on Equation 5.
Based on measurements of the buckling pressure, Nash & Meiselman (43)
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

conclude that heat treatment of red cells causes the value for B to change little,
if at all. Also, the value for B does not change with cell hemoglobin
concentration for both normal and sickle cells (19), except at an ex­
traordinarily high value for the hemoglobin concentration (0.47 kg/liter).
Waugh (55) found a strong correlation between the reduction in spectrin and
the fractional reduction in the values for both the bending modulus B and the
shear modulus JJ.. For red cell membranes, this suggests a common molecular
basis for the values of JJ. and B, as well as for the value of K (Equation 5).

MEMBRANE VISCOSITY

The elasticity of the membrane characterizes its resistance to deformation,

and the viscosity of the membrane characterizes its resistance to a rate of
deformation. For all experiments discussed in this section, the rate of de­
formation is one of shear ( extension), and thus a shear viscosity is measured.

Viscoelastic Solid Behavior

When the membrane of a flaccid red cell is elongated by micropipette
aspiration or fluid shear deformation and then the force of deformation is
suddenly removed, the cell rapidly recovers its undeformed shape. For this
recovery process, Evans & Hochmuth (13) calculated that the viscous dissipa­
tion in the membrane is about two orders of magnitude greater than that in the
internal hemoglobin solution. Thus, the membrane is the dominant source of
viscous dissipation during the recovery process.
Evans & Hochmuth (13) accounted for the dissipation in a viscoelastic solid
membrane by the addition to Equation 1 of a dissipative term analogous to
Newton's law of viscosity:

7.

where t is time and 71 is the coefficient of surface viscosity. A characteristic

time constant tc is obtained in Equation 7 simply by dividing 71 by J.L:

8.
 MEMBRANE ELASTICITY AND VISCOSITY 215

The time required for the membrane of a red cell to recover its stress-free
state when the force of deformation is removed is given by the integration of
Equation 7 with Ts = 0 (13, 33). A best fit of this integrated equation to the
experimental data gives a value for te (33). Typically, te 0.1 s, and thus if po,
=

= 10-2 mNlm, TJ = po,te

= 10-3 mN s/m.
Rapid deformation of a red cell, produced either b y rapid aspiration of the
membrane into a pipette (5) or by "tank treading" the membrane in a fluid
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shear field (51), indicates that "shear thinning" of the membrane may occur at
high rates of deformation. Values for te and, presumably, TJ (if po, is a constant)
may decrease by as much as a factor of six from their values at a very low rate
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

of deformation (5).
The membrane viscosity TJ is strongly influenced by the concentration of
hemoglobin in the cytoplasm, probably because hemoglobin binds to the
membrane (4, 7). Surprisingly, however, the value for the shear elastic
modulus po, for normal cells is independent of hemoglobin concentration (19,
36, 40, 44, 54). Thus, TJ increases in direct proportion with te, since po, is a
constant. Red cells from the bottom 5% of a centrifuge tube have a value for te
that is about 50% larger than that of those from the top 5% (36, 44). Similar
but less dramatic changes were found by Sutera et al (50). Studies in which
cells were precisely separated into density fractions with Stractan solutions
reveal a dramatic increase in te with an increase in hemoglobin concentration
(19). For example, at 0.42 kglliter (an abnormally large value), the value for
tc is about ten times larger than its value at a normal hemoglobin concentration
of 0.32 kglliter (19). For sickle cells the value for te increases with hemoglo­
bin concentration, just as it does for normal cells (19, 40). The viscosity of the
dense, irreversibly sickled Sell (ISC) is very large because of an increase in
both the values of po, and te (40). In general, rehydration of dense cells by
swelling them in a hypotonic solution causes te and TJ to approach normal
values (19, 40).
Temperature also has a strong influence on membrane viscosity. For
example, the value for te decrem:es from 0.275 s at 6°C to 0.065 s at 37°C
(27). With Equation 8 and the data of Waugh & Evans (57), these values for te
are converted to values for TJ. At 6°C, TJ 2.1 X 10-3 mN slm, and at 37°C,
=

TJ = 0.36 X 10-3 mN slm (27).

The lectin wheat germ agglutinin (WGA) binds to glycophorin (3, 37).
Small concentrations of WGA can cause a threefold increase in the value for TJ
(49). Elevated levels of 2,3-DPG also affect the value for TJ. High 2,3-DPG
levels at physiological ionic strength cause an increase in TJ because of an
increased cellular hemoglobin concentration (54). At lower ionic strength the
value for TJ decreases with high 2,3-DPG (54). ATP depletion via incubation
at 37°C for 24 hr has no effect on the value for TJ (39). Cholesterol enrichment
and depletion of human red cell membrane have no effect on the value for TJ
(2). Ghost cells have a normal value for TJ (42). Diabetic cells have a normal
 216 HOCHMUTH & WAUGH

value for tc and, presumably, a normal value for the membrane viscosity 1/
(59). Nonmammalian nucleated cells have values for 'TI which are 10 to 30
times those for normal, mammalian cells (56). In general, the value for 11 is
reduced in inherited blood disorders involving reductions in the amount of
spectrin, reductions in the number of high-affinity ankyrin binding sites, and
abnormalities associated with the band 4. 1 membrane proteins (55).
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Yield and Continuous Flow

When the stress resultant in the membrane of a red cell exceeds a critical
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

value, the membrane material yields and flows from the cell body into a long,
thin, apparently hollow membrane filament called a "tether" (31). Evans &
Hochmuth (14) modeled this membrane flow process by assuming that the
membrane behaves as a two-dimensional version of a "Bingham plastic":

alnA/at = 0 for Ts < Ty

9.

where Ty is the value for the shear resultant at the yield point where the
membrane begins to flow, and 'TIp is the viscosity for plastic flow. If the tether
radius is between 20 and 50 nm, Evans & Hochmuth (14) calculate a value for
Ty = 1. 6-4.0 X 10-2 mN/m. A more recent measurement and calculation by
Waugh gives Ty 2 X 10-2 mN/m (52). The value for l1p (Equation 9) is
=

inversely proportional to the tether growth rate or tether velocity and directly
proportional to the stress resultant in the membrane relative to the yield stress.
At room temperature, 'TIp = 3-10 X 10-3 mN slm (14,29,32,52,58). These
values for 1/p are about ten times larger than those for 1/ discussed in the
previous section. However, the formation of a tether is a drastic process in
which the lipid component of the membrane may separate from the cytoskel­
eton.
At 12°e, 1/p =29 X 10-3 mN s/m, while at 40oe, l1p = 1. 3 X 10-3 mN
slm (52). The dependence of 1/p on temperature gives an apparent activation
energy of 18. 6 kcal/mol, while the dependence of 1/ on temperature gives only
10. 0 kcallmol (52). Surprisingly, the value for Ty does not change with
temperature.
In one Gase of hereditary spherocytosis, the value for Ty is about one-third
that of normal, whereas the value for l1p appears to be normal (58).
Abnormalities in the binding of ankyrin to the membrane do not affect the
value of Ty (53). Abnormalities associated with the function of band 4. 1 cause
a reduction in the value for Ty, but the extent of the reduction does not
correlate well with the extent of the molecular abnormality (53).
 MEMBRANE ELASTICITY AND VISCOSITY 217

Creep and Force Relaxation

Small forces applied for periods of time greater than a few minutes result in
permanent deformation of the membrane (17). This process of creep and force
relaxation in red cell membrane has been modeled analytically with an elastic
membrane component (Equation 1) in series with a linear (Newtonian)
viscous component (20). Markle et al (38) measured the permanent deforma­
tion of red cell membrane. The magnitude of the permanent deformation is
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proportional to the total time period of extension and the level of the applied
force. When the results are analyzed according to the analytical model, a
value for a "creep viscosity" can be calculated. However, the results are
Annu. Rev. Physiol. 1987.49:209-219. Downloaded from www.annualreviews.org

strongly influenced by the concentration of albumin in the suspending fluid.

For albumin concentrations of 0.0, 0.01, 0.10, and 1.0 g percent, the creep
viscosity is equal to 3.6, 15, 26, and 52 mN slm, respectively (38). These
values for the creep viscosity are approximately four orders of magnitude
greater than the values for 1] and 1]p. These extremely large values for the
membrane creep viscosity probably represent a slow and permanent molecular
reorganization of the structural membrane components (e.g. spectrin).

ACKNOWLEDGMENT

This work was supported by National Institutes of Health grants HL23728,

HL31524, and HL18208.

Literature Cited

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