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Lubrication of Articular
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Cartilage
Sabrina Jahn, Jasmine Seror, and Jacob Klein
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235
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Contents
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
1.1. Some Basic Concepts of Frictional Dissipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
1.2. Friction in the Major Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
1.3. Cartilage Friction and Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
1.4. Fluid Films and Boundary Layers at Cartilage Surfaces . . . . . . . . . . . . . . . . . . . . . . . 239
2. PHYSIOLOGY OF ARTICULAR CARTILAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.1. Molecular Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.2. Chondrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
3. MODES OF CARTILAGE LUBRICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
4. BOUNDARY LUBRICATION OF CARTILAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
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1. INTRODUCTION
another clear pathway for energy dissipation by friction, as are viscoelastic losses arising when soft
surfaces undergo deformation on sliding under load. Lubrication may reduce friction between
the underlying surfaces either hydrodynamically by trapped fluid films or via suitable boundary
layers. For real surfaces in aqueous media, including biological surfaces, lubrication is often in
the so-called mixed regime, where the main mechanisms, fluid-film and boundary lubrication, are
active simultaneously, as when surfaces are in contact via asperities (4).
for whole joints in vivo have been reported to range from approximately 0.001 to 0.03 (see, e.g.,
citations in Reference 5), though it is important to emphasize that friction measurements on
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intact, unperturbed, in vivo articular cartilage are, in fact, extremely challenging for two main
reasons, apart from the difficulty of manipulating the joints of live animals. First, the sliding of
cartilage surfaces is so well lubricated that any measured friction is likely to be dominated by other
energy dissipation pathways [such as viscoelastic losses arising from the distortion of adjacent
ligaments, membranes, and connective tissue (D. Dowson, personal communication)]. Indeed,
because of these additional dissipation modes, it is likely that the reported friction coefficient
values for living joints, low as they are (with μ down to ∼0.001), may be higher than the actual,
intrinsic, in vivo cartilage–cartilage friction coefficient. Second, studies on in vivo cartilage, as
well as on excised cartilage ex vivo, may be influenced by the known upregulation of cartilage-
degrading enzymes, which occurs in rapid response to “insult” of the living cartilage, including
incision and removal of the joint components, or undue strain on them (6–15). Such enzymes,
including matrix metalloproteases, phospholipases (13), and ADAMTS5 (an aggrecanase), are
likely to modify considerably the properties of the cartilage surface and near-surface regions
involved in friction processes relative to its native unperturbed state, as discussed in Section 1.3,
below. For these reasons, attempts to understand the extremely efficient lubrication of cartilage
have to date focused primarily on in vitro studies of the likely lubricants (both fluid-film and
boundary), using model substrates as well as excised cartilage, rather than on living joints (though
the surface properties of excised cartilage, too, are likely to differ significantly from the in vivo
surface). In particular, direct measurements in model systems have been made on the lubricating
role of synovial fluid (SF) and, separately or in combination, on molecules that are believed to
constitute the cartilage boundary lubricants, as we discuss below.
Collagen II
Load
Synovial
membrane
Motion
Transitional
Joint cavity
Articular
cartilage
Load
Radial
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HA
Subchondral bone
Compressive modulus
collagen X and GAG
Figure 1
Schematic of a synovial joint, the structure of cartilage, and its molecular arrangement at the articular surface. (a) Synovial joints are
composed of opposing articulating bones, which are covered with a thin layer of cartilage embedded in synovial fluid filling the joint
cavity and enclosed by a synovial membrane. (b) Cartilage tissue is functionally and structurally organized into four main zones situated
above the subchondral bone. The superficial zone exposes the articulating, lubricated surface. Chondrocytes occupy less than 10% of
the volume of the cartilage tissue. The composition of matrix constituents of the tissue, as well as its modulus, varies with depth, as
indicated for two collagen types and glycosaminoglycans (GAGs). (c) The outer cartilage surface, showing charged macromolecules.
Hyaluronic acid (HA) (blue), lubricin ( green), and aggrecans (red ) are prominent macromolecules believed to participate in lubrication.
Phospholipids are present (see Figure 8) but are not shown here. Panel b modified with permission from Reference 23. Panel c
modified with permission from Reference 149.
of lubrication, and the disruption of lubrication in turn causes progressive structural and functional
damage of the cartilage tissue and the subchondral bone. A possible scenario correlates friction
with OA as follows: High friction [or some other initiating event, such as sport or accident traumas
(19)] leads to increased shear strain of the cartilage, which transmits itself to the chondrocyte cells
embedded within it (Figure 1b) and may cause upregulation of cartilage-degrading enzymes via
mechanotransduction (6–10, 14). Degraded tissue is then abraded and removed by the friction
upon articulation, with the resulting degraded cartilage surface exhibiting higher friction, and
thus higher shear strains on sliding, and so on in a self-reinforcing cycle. Figure 2 illustrates this
process schematically: For the sliding friction coefficient μ, pressure P, and shear modulus K, the
shear strain ε on the lower material as the top surface slides past it is given by ε = (μP/K). At typical
mean walking pressures [P ≈ 5 MPa, though this value can vary substantially over the cartilage
surface (1)] and a shear modulus of the cartilage K ≈ 5 × 105 N/m2 [though this value may vary
significantly with depth (20)], a sliding friction coefficient μ = 0.01 would lead to strains around
10% (Figure 2a), whereas μ = 0.001 would result in a 1% strain [though as the modulus increases
(20), the strain would fall with depth from the surface]. Assuming the strain is transmitted to and
sensed by the enclosed near-surface (chondrocyte) cells, the higher μ value would readily elicit
a mechanotransductive response (21, 22) and possible enzyme upregulation (9, 14), whereas the
lower μ value is less likely to do so (22). Although this is a simplified picture, its main elements
μ = 0.001 μ = 0.01
(Roughly to scale)
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Modulus Modulus
K = 5 × 105 N/m2 K = 5 × 105 N/m2
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Figure 2
Schematic illustration (where the cartilage strain is indicated roughly to scale) showing how sliding friction,
with different friction coefficients μ, between upper and lower surfaces can lead to different shear strain ε of
the cartilage and of embedded entities within it. The orange disk represents a chondrocyte cell embedded in
the cartilage network and distorting affinely with it. Realistic values are given for the cartilage modulus K
(assumed constant over the region shown) and maximal normal cartilage pressures P during walking. The
shear strain in steady sliding is given by ε = μP/K.
are correct and illustrate how a friction coefficient that is significantly higher (say, μ ≈ 0.01 or
higher) than that associated with healthy cartilage (where μ ≈ 0.001 or lower) could be correlated
with the onset of OA.
polysaccharide, which is complexed with aggrecans (schematically shown in Figure 1c) and satu-
rated with water and mobile ions, whose osmotic pressure helps counter loads on the cartilage. An
elastin network also contributes to the matrix properties, particularly in the outer superficial zone
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(Figure 1b) (32), as does the presence of fibronectin (33). Highly specialized cells, chondrocytes
(which synthesize the cartilage components), are embedded in the matrix (34). The cartilage is
avascular and alymphatic and lacks innervations (35). Although all synovial joints consist of the
same basic components, the thickness, matrix composition, and cell density of the articular carti-
lage, and thus its mechanical properties, can vary (as schematically depicted in Figure 1b) within
the same joint and among joints or species (18). Curiously, however, mean pressures at cartilage
surfaces, a crucial determinant in cartilage lubrication, appear rather uniform independently of
mammalian species, apparently with good reason, as discussed further in Section 2.2., below. Char-
acteristic values of the cartilage shear modulus (from a study on bovine joints) have been measured
in the range 0.1–1.5 MPa, where the modulus increases with depth from the outer superficial zone
(20). Figure 1 shows a schematic of a synovial joint, its composition, and the structure of articular
cartilage.
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Seror Klein
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2.2. Chondrocytes
Articular chrondrocytes are responsible for synthesizing and maintaining the matrix infrastructure
by which they are surrounded. They form only 1–5% by volume of the cartilage without cell-to-
cell contacts (44). Chondrocytes are capable of sensing changes in the composition of the ECM
due to the degradation of macromolecules and demands at the interface. Thus, they respond by
synthesizing the required molecules in appropriate amounts, such as type II collagen, proteoglycan
aggregates, and other specific noncollagenous proteins (18).
The behavior of chondrocytes is highly regulated by load and pressure and by the way in which
these vary dynamically, although the precise mechanisms (and, for example, why they appear
to differ for shear as opposed to normal stressing of the cells) are not yet fully understood (9,
21, 39). Clearly, chondrocyte behavior relates closely to the effect of pressure and friction at
the cartilage surface, as considered above with respect to transmitted strains. Depending on the
distinct zones of the cartilage, chondrocytes differ in their size, shape, and metabolic activity.
Various studies (see Reference 18) have suggested that the primary cilium of chondrocytes plays a
crucial role in recognizing mechanical changes, such as those that might be caused by strain in the
cartilage induced in turn by friction during articulation. It might act as a mechanotransductory
sensory feedback loop translating extracellular information to the cell in order to facilitate the
secretion of ECM (18). We emphasize the issue of the mechanosensitivity of chondrocytes within
the cartilage in this review of friction at the articular cartilage surface, precisely because of the
relation, mentioned briefly above, between friction/lubrication and the development of OA. There
is an increasing realization that the degradation of cartilage in OA, for decades considered to be a
wear-and-tear disease, may be a consequence of the upregulation of specific cellular enzymes such
as metalloproteinases, collagenases, and phospholipases known to degrade the ECM, in response
to specific mechanical stimuli (8–15), including friction-induced ones.
Given that chondrocytes are similar in articular cartilage coatings of mammalian joints of
different species, it is interesting to inquire how their known regulation by pressure relates to the
fact that, across the animal kingdom, animals vary by many orders of magnitude in mass, so that
their major joints (e.g., legs or hind paws) support very different loads. For a mammal of size L, say,
one expects its mass M to vary as its volume, that is, roughly as M ∼ L3 , and the load-bearing area
A of its joints to vary roughly as A ∼ L2 . The pressure P on the cartilage coating the load-bearing
joints might then be expected to vary as P = (animal weight/animal joint area) = M/A ∼ L3 /L2
∼ L ∼ M1/3 . Because M can vary between, say, Mcow ≈ 600 kg to Mmouse ≈ 30 g, the ratio of the
load-bearing pressure in a cow’s leg joint to that in the joint of the hind leg of a mouse might
be expected to vary by a factor (Mcow /Mmouse )1/3 ≈ 25. In fact, in a comparative study (45) of the
pressures in the joints of different animals ranging from cows to sheep, dogs, rats, and mice, the
joint pressure varied at most by a factor of three or so. Indeed there was barely a 20% difference
in pressure between cow and mouse joints, rather than the ∼25-fold variation that simple physical
scaling might suggest. Physically, this arises because the load-bearing cartilage areas of the lighter
animals were much smaller than an M2 scaling would predict, so that the pressure was correspond-
ingly much higher. We believe this may be due to evolutionary selection, as the chondrocytes in
articular cartilage across species operate optimally under similarly high pressures (39).
times. One of the first publications, by the sixteenth-century physician Paracelsus, who coined the
word synovia for the fluid, described the oily character of the liquid in the joint space (46). In 1691,
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Havers (47) reported the chemical, physical, and lubrication properties of mammalian SF. More
systematically, over the past 80 years or so, many concepts and theories of how the synovial joint
is lubricated have been proposed (see, e.g., References 28, 41, 43, and 48–57) based on fluid-film
or boundary lubrication or on a mixed regime of the two (see References 4 and 17 for some recent
reviews).
Much of the early work on cartilage lubrication concerned fluid-film models, stimulated by re-
search on hydrodynamic lubrication of journal bearings in machine tribology by Osborne Reynolds
(1842–1912) and others (4, 58). In 1932, the anatomist MacConaill (59) made the first attempt
to develop a coherent theory about joint lubrication based on hydrodynamic theory, and shortly
afterward Jones (60) performed the first detailed experimental study on joint friction by mounting
a horse knee joint as a fulcrum in a pendulum machine. Pioneering work in the 1960s on hydrody-
namic (61, 62), elastohydrodynamic (61, 63), and microelastohydrodynamic (49) joint lubrication
took into account the deformability of articular cartilage—soft relative to the rigid surfaces for
which the original hydrodynamic models were developed. Further important developments in
fluid-film lubrication included the squeeze-film mechanism (64, 65) and the idea that the lubri-
cant is retained between the loaded surfaces due to some specific properties of the SF and the
articular cartilage. The latter idea was explored through Walker’s mechanism of boosted lubrica-
tion (66), Maroudas’s ultrafiltration theory (51, 67), and particularly by McCutchen’s concept of
weeping lubrication (52, 68). This model invoked the porosity of the cartilage tissue in a mech-
anism maintaining interstitial fluid pressure supporting joint load and lubrication (69), although
the nature of fluid flow/transport through cartilage tissue has been debated (48, 70, 71). Other
models included biphasic/triphasic (41) and mixed and multimode lubrication (72, 73). A more
detailed description of these and other fluid-film lubrication ideas is beyond the scope of this
article; a review is given in Reference 4.
The fluid-film theories noted above represent mixed modes of lubrication characterized by the
coexistence of interfacial regions operating under fluid-film and boundary lubrication conditions,
implying that multiple lubrication regimes might occur simultaneously. Experimental evidence
has generally supported mixed or boundary lubrication regimes rather than full hydrodynamic
lubrication (74). Thus, friction in joints has typically been measured as either independent of
velocity (indicative of boundary lubrication) (53) or decreasing with increasing velocity (indicative
of mixed lubrication) (75). A direct experimental indication that boundary contact occurs between
opposing, compressed cartilage layers is provided by measurements of the pressure distribution
across the cartilage in human hip joints. These have been carried out either in vivo, using a hip
242 Jahn · ·
Seror Klein
BE18CH10-Klein ARI 15 June 2016 8:39
implant incorporating pressure sensors in the femoral head, or on cadavers, with pressure-sensitive
film (1, 76). Such measurements reveal that the pressure distribution over the cartilage surface is
very nonuniform and that adjacent areas of the cartilage support highly unequal pressures, strongly
suggesting that the high-pressure regions are in boundary contact (as the fluid between them is
rapidly squeezed out to adjacent lower-pressure regions). The associated boundary lubrication on
sliding in contrast to fluid-film models must clearly take into account the detailed biochemical
and macromolecular composition and structure at the articular cartilage surface itself (17). Indeed,
much of the effort of the past decades to understand articular cartilage lubrication has been devoted
to identifying the nature of the molecular boundary layers. The following sections provide an
overview of some of this work and, in particular, describe our understanding of cartilage boundary
lubrication in the light of the recently emergent hydration lubrication paradigm.
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cartilage articulation. For this reason, the focus of most recent studies has shifted from using fluid-
film-based models (Section 3.1) to identifying the nature of the molecular boundary layer coating
the articular cartilage surface, and the mechanism that might lead to the very low friction between
two such surfaces as they slide under load (77, 78). As indicated in the introduction, the main
molecules that have been implicated in forming these lubricating boundary layers, either alone or
in combination, are HA (55, 57, 79–86) (though in earlier studies there was sometimes ambiguity
between HA as a component of SF and its role as a boundary lubricant); aggrecans (87–90); lubricin
(25, 56, 91–96); and PLs (27, 29, 30, 43, 86, 97–103). The role of other molecules present in the
synovial joint has also been examined (78, 104–109). It is appropriate to inquire concerning the
relation of these studies—most of which involve measuring friction between boundary layers of
the molecules on smooth, hard substrates, very different to articular cartilage—to their boundary
lubrication in living joints. The point is that in boundary friction the energy dissipation on sliding,
which manifests itself as the measured friction force, arises from the dynamic interaction between
the contacting boundary layers themselves, and is independent of the substrate. For rough, soft,
or viscoelastic substrates (such as cartilage) there may be additional dissipation pathways that
will manifest as additional friction, but the boundary friction itself will be a function only of the
interaction between the opposed molecular boundary layers, and thus well represented by the
studies cited above. In the following subsections, we briefly survey some direct studies of these
molecules as boundary lubricants.
4.1. Hyaluronan
HA is a high-molecular-weight, highly charged polysaccharide ubiquitous both in SF (where it
accounts for its high viscosity at low shear rates) and in articular cartilage (where, together with ag-
grecan, it contributes to the osmotic pressure giving the collagen network its mechanical resilience)
(17, 33). It was originally considered the molecule responsible for the lubricity of SF (79, 80, 110),
until it was demonstrated that HA enzymatic digestion made little difference to SF lubrication
ability (91, 111). Nonetheless, HA has often been, and is still, used as an intra-articularly injected
viscosupplement to alleviate OA symptoms.1 This is curious in view of the fact that HA solutions
1
As of 2013, the American Academy of Orthopedic Surgeons “cannot recommend” the use of HA viscosupplements for OA
symptoms (see http://www.aaos.org/news/aaosnow/jun13/cover1.asp).
P (atm)
0 9 11 12 14 17 20
0.3
a b P = 8.2 atm
40 μ = 0.3
Shear (friction) FII (mN)
Damage at point A: Fs
0.2 P ~ 3.0 atm, 30 μ = 0.1
D ~ 400 Å Fs
Fs (µN)
20
A
0.1 μ = FII /F = 0.19
10 μ = 0.01
P ~ 1.5 atm,
D ~ 500 Å
0
0
0 0.2 0.4 0.6 0.8 0 50 100 150 200 400 600
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Figure 3
Sliding friction mediated by hyaluronic acid (HA) boundary layers: friction forces as a function of normal force measured with surface
force balance. (a) Friction between a bare mica surface and a mica surface bearing HA layers on top of a lipid bilayer. The friction
coefficient (μ) is 0.19, increasing sharply when damage occurs at point A. When HA faces HA, the behavior is similar, or with a slightly
higher μ (∼0.3) (84). (b) Friction between two mica surfaces bearing attached HA layers (open triangles, stars). The friction, which may
also be influenced by bridging effects, corresponds to μ ≈ 0.3. Friction forces between surface layers consisting of complexes of HA and
aggrecan are also shown ( full and crossed symbols). Complexation of the HA with aggrecan reduces the friction coefficient substantially at
lower pressures (10 atm) relative to HA alone. Panel a modified with permission from Reference 84. Panel b modified with permission
from Reference 90.
at the concentrations in SF (and in viscosupplements) are highly shear-thinning, and at the typical
shear rates across the sliding articular cartilage surfaces (which can reach 105−6 /s) their viscosity
becomes comparable to that of water (112). In recent years HA has been examined as a boundary
lubricant, as it is known to be at the outer cartilage surface (Figure 1c) (see Section 6, below). Direct
measurements have been carried out using a variety of approaches, including surface force balance
(SFB) methods (84, 89, 90, 113) and friction force (colloid-tipped) microscopy (FFM) techniques
(82) for HA attached to model substrates, as well as torque-based methods using articular cartilage
samples (55, 57), although these were at rather low normal stresses [some 100-fold lower than
maximal pressures in joints (1)]. Friction coefficients measured directly using an SFB method (84,
89, 90, 114) reveal that HA is a rather poor boundary lubricant at high pressures (above several at-
mospheres), with μ ≈ 0.2–0.5 (Figure 3). Linking aggrecan molecules to the surface-attached HA
(Figure 3b) improves the lubrication, with μ ≈ 0.01, but again only up to several atmospheres of
pressure, beyond which the value of μ increases sharply. These values are far above the low friction
(μ down to 0.001 or less) at the high maximal pressures (up to 100 atm or more) in the major joints.
4.2. Lubricin
In 1968, Linn & Radin (115) showed that digesting HA from the cartilage surfaces of canine
joints does not affect the lubrication. In contrast, following trypsin digestion, which decomposes
proteins present on the articular surface, an increase in the friction coefficient was observed (115).
On the basis of this observation, the authors claimed that a protein is a necessary component of
the lubricant (or the mucin, as they called it), and interestingly, they conjectured that this protein
might work together with HA, possibly linking HA to the cartilage (115). [Several later studies,
using a number of approaches, directly indicated that such an interaction indeed exists (82, 85,
244 Jahn · ·
Seror Klein
BE18CH10-Klein ARI 15 June 2016 8:39
94–96).] Subsequently, Radin et al. (91) suggested that an HA-free fraction of SF contains the
actual lubricant, which was later identified as a glycoprotein and named lubricin by Swann et al.
(92) in 1981. Later still, this glycoprotein was shown to be identical to SZP or PRG4 (24, 25) and
present both in the outer superficial zone of cartilage and in SF. It is worth remarking that the
original study (91), based on which lubricin was claimed to be the boundary lubricant, showed
a rather moderate reduction in friction—relative to saline or HA-containing solution without
lubricin—of only a factor of two or so. Since then, many investigations (see, e.g., References 24,
93, 94, 111, and 116–118), including studies showing somewhat increased cartilage friction and
wear in lubricin-lacking mice (111, 116), have indicated that lubricin plays a role in the lubrication
of articular cartilage, and that its absence may be related to joint diseases. Direct measurements of
friction between lubricin boundary layers, however, reveal that lubricin per se is not an especially
efficient boundary lubricant, particularly in the context of the known low friction at high pressures
of articular cartilage, and its precise mechanistic role in articular cartilage lubrication remains far
Annu. Rev. Biomed. Eng. 2016.18:235-258. Downloaded from www.annualreviews.org
between two hydrophilic surfaces bearing lubricin is relatively low (μ = 0.02–0.04) only under
low pressures (up to ∼4 atm) and increases to μ ≈ 0.2 under the higher pressures typical of
synovial joints (Figure 4a). Using colloidal-probe friction force microscopy, Chang et al. (82,
96) showed friction coefficient values of ∼0.1 between lubricin boundary layers, much higher
than what is expected for articular cartilage. Furthermore, these authors studied the interaction
30
a Mica: friction at high loads b
28 Hydrophobized mica
1.2 26 1 mg/mL mucin
Rinsed, 0.1 M Na+
24
Rinsed, pure water
1.0 22 Filled: compression
20 Open: μ ≈ 0.2–0.3
Friction force, f (mN)
μ = 0.6 decompression
0.8 18
Fs* (µN)
30
0.6
14
μ = 0.2 12
0.4
10
0.2 8 μ ≈ 0.01–0.02
6
0.0 4
0 1 2 3 4 5 2
Load, F (mN) 0
0 50 100 150 200
Fn (µN)
Figure 4
Sliding friction mediated by boundary layers of different mucins. (a) Friction force f as a function of the load F between sliding
lubricin-bearing mica surfaces immersed in lubricin solutions of different concentrations or following surface attachment or rinsing
(different symbols refer to the different conditions). Up to ∼4 atm the friction is low (μ ≈ 0.02–0.04), but at higher pressures the friction
is high and falls within the shaded area within the range μ = 0.2–0.6. (b) Friction force Fs∗ as a function of load Fn (both compression
and decompression) between mica surfaces bearing porcine gastric mucin, both in mucin solution and rinsed, in both water and salt
solution, as indicated. Up to pressures between the surfaces of ∼7–10 atm the friction is low (μ ≈ 0.01–0.02), increasing at higher
pressures to μ ≈ 0.2–0.3. Panel a modified with permission from Reference 56. Panel b modified with permission from Reference 106.
between lubricin and HA (82, 96) and found that, once mixed together, the lubrication between
the surfaces does not improve (82). Other studies showed that boundary layers consisting of
lubricin together with other macromolecules [including HA (95, 121) and fibronectin (109)] led
to friction coefficients at physiological pressures that were some one to two orders of magnitude
higher than in living joints. A recent SFB study (106) on the boundary-lubricating properties of a
model mucin is also of interest, as lubricin is a glycoprotein with its dominant linear central region
possessing the characteristic mucin structure (122). This model mucin (Figure 4b) has boundary
lubrication properties very similar to those of lubricin: At low pressures (up to 7–10 atm) it leads
to relatively low friction, μ ≈ 0.01–0.02, whereas at higher pressures the friction increases sharply
(μ ≈ 0.1–0.2), much as for lubricin (Figure 4a).
4.3. Phospholipids
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A different concept for boundary lubrication of articular cartilage was proposed in 1984 by Hills &
Butler (27) on the basis of what they called surface-active phospholipids (SAPLs). Such SAPLs are
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generally phosphatidylcholines (PCs), with diacyl tails and a phosphocholine head group; they form
the major component of the lipids present in SF and at the surface of articular cartilage (43), and
are present on other tissues (such as lungs). Hills and Butler’s basic idea (Figure 5a) assumes that
the PC lipids behave much as synthetic surfactant-based boundary lubricants do in classic machine
tribology (2). That is, the zwitterionic phosphocholine head groups are supposed to attach to the
underlying, negatively charged cartilage substrate, with the acyl tails extending out and rubbing
past each other as the surfaces slide under compression (Figure 5a). Such a mechanism—where
frictional dissipation occurs via shearing of relatively weak van der Waals bonds at the interface
a b
– – – –
– –
+ + – +
– – + – – + –
– – –
+– – –
+
–
O O O O
– + – – +
–
O
P
O
–
O
P
O
–
O
P
O
–
O
P
O
– + + – O O O O
– –
Cohesive Synovial
bonds fluid – Hydrophobic N+ N+ N+ N+
– – palmitoyl chains
– + + + – N+ N+ N+ N+
Slip
+ – – – + plane
– – –
– O O O O
– + – + – O O O O
– P P P P
+ – – – O– O– O– O–
+ + + O O O O
– –
– – Articular surface – –
Figure 5
Proposed mechanisms for cartilage lubrication by phosphatidylcholine (PC) lipids. (a) Lipid monolayers adsorb to the negatively
charged cartilage surface via their dipolar head groups, exposing the diacyl (fatty acid) chains to the interface, while frictional
dissipation on sliding occurs as the chains slide past each other at the slip plane, much as in the classic boundary lubrication of metal
surfaces by surfactants. Such a mechanism is known to lead to friction coefficients (μ) of approximately 0.05–0.1 (2). (b) In the hydration
lubrication mechanism, assemblies of PCs (whether monolayers, bilayers, or vesicles attached or complexed at the cartilage surface)
exposing their phosphocholine head groups slide past each other. Frictional dissipation takes place through shear of the hydration
layers at the slip plane. This mechanism leads to low friction coefficients (μ ≈ 0.001 or less) up to high pressures (∼100 atm or more)
(29, 100, 126–128). Panel a modified with permission from Reference 27.
between the tails—is known to result in friction coefficients of ∼0.05–0.1 (2, 123), that is, some
50–100-fold larger than in joints. At the same time, lubrication by such surfactant-like boundary
layers in aqueous environment—as in joints—is known to occur via a very different mechanism
involving hydration lubrication (124), as discussed further in the following sections. Hills (98)
also found that a mixture of HA and dipalmitoylphosphatidylcholine (DPPC) lipids, probably in
a multilamellar vesicle form, when added to saline, led to rather low friction (μ ≈ 0.004) between
sliding quartz surfaces, although at pressures of 3 atm, some 50-fold lower than maximal joint
pressures (1). The same study (98) found that adding DPPC alone to quartz surfaces in saline
resulted in only modest lubrication (μ ≈ 0.01–0.1). In a different (SFB) study, Yu et al. (114)
found that adding dioleoylphosphatidylcholine (DOPC) lipids to surfaces bearing HA in aqueous
media resulted in rather high friction coefficients (μ > 0.5). Direct measurements (125) between
sliding surfaces bearing lipid bilayers showed that DPPC bilayers (but not DOPC bilayers) could
reduce friction to low values (μ ≈ 0.002), but only up to rather low pressures (3 atm). Mirea et al.
Annu. Rev. Biomed. Eng. 2016.18:235-258. Downloaded from www.annualreviews.org
(103) used similarly low pressures to examine friction at other liquid-phase bilayers. In a separate
study, Wang et al. (86) found relatively low friction (μ ≈ 0.02) between surfaces bearing layers
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of DPPC and HA, at pressures of ∼600 atm, although this study was not able (because of large
scatter) to measure friction in the range of physiological pressures of interest (up to, say, 150 atm).
Clearly, an understanding of the boundary lubrication of articular cartilage must, as noted
above, be able to reproduce its main features. These include especially the physiologically low
friction coefficient of articular cartilage (down to μ ≈ 10−3 or lower) up to the maximal joint
pressures (100–200 atm or higher), with known components of the synovial joint, over a wide range
of shear rates and shearing times. From these facts we may conclude that few, if any, of the above
studies, which directly measured friction between surfaces bearing the main molecular candidates
that have been proposed as cartilage lubricants, alone or in combination, appear to provide a
realistic model for cartilage boundary lubrication. Indeed, HA and lubricin by themselves (or in
combination) are rather poor boundary lubricants. A key to further understanding lies instead in
the concept of hydration lubrication, a paradigm for reduction of friction in aqueous media that
has emerged over the past decade or so.
5. HYDRATION LUBRICATION
Most of the studies described above attempted to identify the nature of the lubricating boundary
layer on the articular cartilage, rather than the detailed frictional mechanism—that is, the mecha-
nism by which energy is dissipated as two such layers slide past each other in the aqueous environ-
ment of the joint. Understanding this mechanism, as we discuss further below, can lead to deep
insight into the boundary lubrication of cartilage. In 2002, on the basis of SFB measurements, it was
proposed (126) that hydrated charges in an aqueous medium may provide extremely efficient lubri-
cating elements. This is because water in the hydration shell surrounding a charge, on the one hand,
is very tenaciously held (due essentially to the interaction of the large water dipole with the en-
closed charge) and, on the other hand, may be very rapidly relaxing (due to ultrafast exchange rates
of up to 109 /s, depending on the nature of the enclosed charge, with surrounding water molecules).
These twin attributes mean that it is difficult to squeeze the hydration water out under compression
between two surfaces but that, when sheared, the hydration shells respond in a fluidlike manner
and the surfaces may slide easily past each other. This combination of supporting a large compres-
sive load together with easy sliding enables hydration layers to act as excellent lubrication elements
in aqueous surroundings (resembling molecular ball bearings, as it were), especially in biological
systems (127, 128). This mechanism, termed hydration lubrication, was extended to several bound-
ary lubrication systems. These include different hydrated ions (126, 129–132), charged polymer
brushes (133–135), boundary layers of surfactants under water (124), polyzwitterionic brushes
(136–138), and in particular, liposomes or bilayers of PC lipids, exposing phosphocholine groups
at their outer surfaces (26, 29, 97, 100, 125). The energy dissipation mechanism as hydration layers
slide past each other has also been examined in detail, and can be accounted for by the viscous losses
within the subnanometer hydration shells themselves as they are compressed and sheared (139).
In the context of biological lubrication, the most interesting finding within the hydration
lubrication paradigm is that phosphocholine groups—the head groups of PC lipids, which are
known to be highly hydrated with up to ∼15 water molecules in the primary hydration shell (136)—
constitute extremely efficient lubrication elements. The high hydration arises from the particular
zwitterionic structure of the phosphocholine groups (140). Indeed, boundary layers based on such
phosphocholine elements, whether in the form of polymer brushes (136, 137), bilayers (26), or
surface layers of PC liposomes (26, 29, 97, 100), provided remarkably low friction (μ values down
to 10−4 or less) at pressures up to 200 atm or more, over extended sliding periods, and over orders
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of magnitude in sliding velocity. A subtle interplay between the extent of hydration, the lipid phase
nature (i.e., gel or liquid phase), and the robustness of the lipid bilayer structures, along with the
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possibility of their self-healing, plays an important role in the comparative lubricating ability of
different PC lipids (26, 29, 97, 100, 141); this topic, however, is beyond the scope of this review. The
lubrication itself—for example, between PC bilayer assemblies or between PC vesicles adsorbed
on surfaces—takes place at the interface between the hydrated phosphocholine head groups as they
slide past each other (Figure 5b). The coefficient-of-friction values—μ values down to 10−4 or
less at pressures up to 200 atm or more—are very much consistent with the lubrication properties
of living joints. Because PC lipids are ubiquitous in joints, this finding strongly suggests that
such lipids must play an important role in cartilage lubrication. Indeed, very recent SFB studies
of friction between boundary layers of PLs extracted from human and bovine SF and cartilage
showed that PC lipids provide similarly good lubrication (μ values down to 10−3 ) up to high
pressures (up to 100 atm or more) ( J. Seror, Y. Merkher, A. Maroudas & J. Klein, manuscript
submitted).
248 Jahn · ·
Seror Klein
BE18CH10-Klein ARI 15 June 2016 8:39
b
DPPC
HA
Biotin
Avidin
a
450
1.5
1.0
0.5
400
nm
nm
0.0
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–0.5
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–1.0
350
–1.5
low friction coefficients (μ ≈ 10−3 ) up to pressures well over 100 atm (Figure 7a). This observation
is in line with measurements of PC vesicles [in their gel phase (29, 100)], although with somewhat
higher friction, probably due to the rougher nature of the HA–lipid surface complexes. Crucially, it
exhibits the low friction at the high pressures characteristic of articular cartilage. The contrast with
the high frictional forces (μ ≈ 0.3) between the HA layers alone prior to the introduction of the
lipids (e.g., Figure 3) is particularly striking. Moreover, the low friction was essentially constant
over some three orders of magnitude in sliding velocity (Figure 7b), indicative of boundary rather
than fluid-film lubrication, and the surface complexes were robust and lubricious over at least 1 h
of back-and-forth sliding at high pressure (Figure 7c).
These results (30) have clear implications for the mechanism of cartilage boundary lubrication.
HA, which, as described above, is ubiquitous in both cartilage and SF, is exposed at the cartilage
outer surface and complexes with PCs, which are likewise ubiquitous, to form robust boundary lay-
ers that are capable of providing the low friction (μ ≈ 10−3 ) at the physiologically high pressures (up
to 100 atm or more) of the major joints. The attachment of the HA at the cartilage surface may be
due to either physical entanglements with the near-surface network or its interactions with lubricin,
as noted elsewhere (82, 85, 94–96), or both acting together. In this scenario, therefore (Figure 8)
a μ = 3 × 10 –3
70
P ≈ 122 atm
μ = 7 × 10 –3
60 P ≈ 160 atm
–3
10
50 1.5 ×
μ=
Fs (µN)
40
30
μ = 6 × 10 –4
P ≈ 220 atm
20
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10
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0
0 5 10 15 20 25 30 35
Fn (mN)
30 60
b c
20
Fs (µN)
Fs (µN)
50
10 40
0 30
0.01 0.1 1.0 0 20 40 60
Vs (µm/s) Time (min)
Figure 7
Friction up to physiologically high pressures between sliding surfaces bearing boundary layers of
surface-attached hyaluronic acid (HA) to which dipalmitoylphosphatidylcholine small unilamellar vesicles
(DPPC SUVs) had been added, as indicated in Figure 6. (a) Friction forces Fs as a function of load Fn ,
measured with the surface force balance method. The shaded area includes all the Fs versus Fn profiles under
water. The black symbols represent the limiting profiles across water (highest and lowest μ values at the high
pressure indicated; the broken line indicates the mean value over all measurements). The red symbols
represent Fs versus Fn profiles across a 0.15 M salt solution. (b) Friction force Fs as function of sliding
velocity v s under pressure P ≈ 160 atm, showing little change over three orders of magnitude in v s .
(c) Friction force as a function of sliding time, showing little change following 1 h of sliding at v ≈ 0.4 μm/s
and P ≈ 60 atm. These results show that such HA–lipid complexes achieve the low friction coefficients
(down to μ ≈ 0.001) of articular cartilage up to physiologically high pressures of more than 100 atm. Figure
modified with permission from Reference 30.
(30), all three of the main synovial joint components, which have been widely conjectured to act
independently as the cartilage boundary lubricant, are observed to act together, each with a very
different role, to provide the lubrication characteristic of healthy joints. Lubricin in the outer super-
ficial zone (25), or possibly adsorbed from SF at the articular surface (122), interacts with and immo-
bilizes HA at the cartilage surface, which in turn complexes with PC lipids to provide the boundary
lubrication at the exposed phosphocholine groups via the hydration lubrication mechanism. This
picture can naturally account for the healing of the boundary layers as they wear, given that all three
of the components, as described above, are widely present both in cartilage and in SF, and are thus
readily available to replenish and heal any lubricin–HA–PC surface-attached complexes as they are
250 Jahn · ·
Seror Klein
BE18CH10-Klein ARI 15 June 2016 8:39
PC
Bilayer Monolayer
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Figure 8
Structure of the cartilage boundary lubricant layer, proposed by Seror et al. (30), based on results shown in
Figure 6 and 7 and described in detail in Reference 30. Lubricin ( purple) in the outer superficial zone and at
the cartilage surface interacts with and immobilizes hyaluronic acid (HA) at the surface ( gray); the surface-
attached HA in turn complexes with phosphatidylcholine (PC) lipids to form monolayer ( green) or bilayer
(blue) assemblies exposing phosphocholine groups. These exposed groups slide past similar groups from the
opposing surface with low friction (μ values down to 10−3 ) up to high pressures (100 atm or more) via the
hydration lubrication mechanism (Figure 5b).
naturally removed by friction. Moreover, this scenario emphasizes the importance of all three com-
ponents working together in the lubrication and may account, for example, for the fact that lubricin
deficiency can affect joint friction (116), even if lubricin itself is not the actual lubricating molecule.
treatment and clinical implications for OA. As an example, such treatment might involve replacing
the often-used HA-based viscosupplement intra-articular injections (see footnote 1 on p. 243,
above) by injections introducing suitable PC/polymer-based lubricants to augment or repair the
body’s natural biolubrication mechanisms.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
J.K. thanks Tonia Vincent for useful discussions and Duncan Dowson for correspondence. We
Annu. Rev. Biomed. Eng. 2016.18:235-258. Downloaded from www.annualreviews.org
thank the European Research Council (Advanced Grant HydrationLube), the McCutchen Foun-
dation, the Petroleum Research Fund of the American Chemical Society (grant 55089-ND10),
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the Israel Science Foundation, and the Israel Science Foundation–Natural Science Foundation
of China joint research program (grant 875/13) for support of the work described in this review.
J.S.’s current affiliation is CollPlant Ltd., Weizmann Science Park, Ness-Ziona 74140, Israel.
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