Perspective pubs.acs.org/Macromolecules
Hydration Lubrication: The Macromolecular Domain Sabrina Jahn and Jacob Klein* Department of Materials and Interfaces, Weizmann Institute of Science, 76100 Rehovot, Israel ABSTRACT: Macromolecules, which adsorb or intrinsically form boundary layers at surfaces sliding past each other in aqueous media, are ubiquitous both in technology and in biological systems and can form effective boundary lubricants. Over the past decade or so, hydration layersrobustly bound water molecules that surround charges or zwitterionic groups of different macromolecular specieshave been identified as remarkable lubricating elements, sustaining high loads while exhibiting a fluid-like response to shear with extremely low friction. This modification of frictional forces in aqueous systems, based on the behavior of water molecules confined to hydration shells, is the central idea behind the hydration lubrication mechanism, which is presented and discussed in detail in the current Perspective. We describe the nature of hydration under confinement and the underlying experiments revealing this mechanism, focusing in particular on synthetic and biological macromolecules attached to surfaces and on phospholipid assemblies. We also emphasize these recent findings in relation to physiological environments and functions of the human body, such as cartilage lubrication, in which hydration lubrication is believed to play an important role.
1. INTRODUCTION
Many physiological situations require low friction to allow for the healthy functioning and performance of certain tissues. A prominent example is articular cartilage of the major mammalian synovial joints such as hips and knees, which is able to withstand high pressures and load while articulating. In a healthy state, articulation occurs with extremely low friction and wear, with sliding friction coefficients μ (μ = (force to slide the surfaces)/ (load compressing them)) in the range μ ≈ 0.001−0.01 at pressures to over 100 atm and shear rates from rest to ca. 106/ s. 22,23 Different macromolecules at the outer cartilage surfaces24,25 or as components of the synovial fluid26−30 have been proposed to be the key boundary molecules leading to the extremely low friction, though a major difficulty has been to identify the underlying mechanism on a molecular or nanotribological level. Recently, much progress has been made in our understanding of the means by which hydrated, surface-attached macromolecules modify frictional forces in aqueous systems. Several studies have shown that water molecules when tightly bound to charged or zwitterionic groups of synthetic or biological macromolecules have the ability to reduce friction coefficients down to extremely low values, around μ ≈ 10−4, under pressures up to hundreds of atmospheres.8,11,31,32 The proposed boundary lubrication model is based on the hydration lubrication mechanism, which, in the context of polymers and other macromolecular assemblies, is the central theme of this Perspective. In the following sections, we first consider the nature of hydration water at macromolecular interfaces and under confinement compared to water in bulk. We then describe the underlying experiments, focusing on the surface force balance
Attempts to reduce friction between sliding surfaces have been documented since antiquity.1,2 Modern understanding of friction as due to irreversible processes between sliding surfaces dates to Prandtl3 and Tomlinson4 and others and has been especially emphasized by David Tabor and co-workers.5−7 Friction is thus most fruitfully considered in terms of different energy dissipation pathways as the contacting surfaces move past each other, while lubrication, either by thin fluid films or, for surfaces in contact, by molecular species forming boundary layers, is the means by which friction and wear are reduced. Macromolecular surface phases in particular have been shown to provide a promising route by which frictional dissipation may be lessened.8−14 The structure (e.g., size and flexibility) of the adsorbed or grafted macromolecules/polymers and the nature of their interactions with the surfaces, with the solvent, and with each other are the central determinants of the lubrication. The way in which the chain-like nature of polymeric layers affects frictional forces, specifically the configurational entropy of chains on the one hand and their topological entanglement on the other, has been considered and is reasonably well understood,15−19 particularly in neutral (organic) solvents where charge effects are absent. Aqueous systems, however, are of especial interest. This is because water is nature’s solvent for most molecular and surface interactions,20 and being the ultimate “green” solvent, it is increasingly used in technological applications to replace traditional organic fluids.21 Various systems, both man-made and in nature, ranging from micro/nanoelectromechanical systems and biomedical devices to articulating joints or the eye, require surfaces in contact to slide past each other in aqueous environments. Friction between such surfaces may be strikingly modified by the adsorption to or intrinsic growth of flexible polymer chains or other macromolecular species at the surfaces. © XXXX American Chemical Society
Received: February 14, 2015 Revised: June 16, 2015
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relaxation of the layer and a fluid-like behavior under shear. Typical values of ωexchange range from 109 s−1 for the alkali metal ions to ca. 10−4 s−1 for Cr3+ ions.37 In the present context, the essential feature of hydration shells is that they may be very tenaciously bound on the one hand, thus resisting being squeezed out even under high compression, while being very labile on the other hand due to their rapid relaxation dynamics, so that they may behave in a fluid manner under shear, as discussed later. This provides such hydration layers with the ability to act as very efficient lubricating elements, underlying the hydration lubrication mechanism. Most biological macromolecules expose charges or charge patches and thus are often at least partially hydrated, as discussed later for hydrophobins. Hydration shells around proteins are typically 2−3 water molecular diameters (4−8 Å) thick.38 When hydration layers, whether surrounding monomers, proteins, or simple ions, are sheared, as in any frictional process, they dissipate energy and hence lead to friction. Spectroscopic approaches may in addition provide an interesting probe of the lubricating effects of water, as in molecular machines and other systems.39 In the present Perspective, we emphasize rather the insights derived from direct nanomechanical measurements such as with the SFB. Very recently, as described below, energy dissipation in sheared hydration layers was measured directly,40 revealing the relation between the relaxation rate of the hydration shells and the viscous losses on shearing them. Forces between surfaces, or macromolecular surface phases, may best be directly measured, as has been done in our group and others, using a surface force balance,41 which measures the forces between parallel, molecularly smooth substrates, with or without surface-attached boundary layers. The SFB approach has a number of advantages over optical tweezers or tip-based approaches based on scanning probe microscopy (SPM). These include better sensitivity and resolution (below) as well as the ability to measure the absolute separation D between two surfaces rather than relative distances between them (as for optical tweezers or SPM) and the refractive index of the material between the surfaces; these, crucially, enable close monitoring of the surface-attached layers. Most importantly, however, in the context of frictional studies, is the following: friction between sliding surfaces may, as noted earlier, be a convolution of several energy dissipation effects. Boundary lubrication, in which we are primarily interested, concerns the dissipation at the molecular level as the molecules on the opposing surfaces rub past each other. Other modes may include viscoelastic losses due to largerscale distortions of a soft substrate or local viscoelastic effects when an AFM tip “ploughs” through a surface layer, or they may include plastic deformation and wear of the underlying surface at asperity contacts.42 The SFB, where two essentially parallel, molecularly smooth substrates slide past each other, is able to measure the boundary friction between two surface-attached layers in the “cleanest” fashion, unconvoluted with additional dissipation pathways, as would occur with e.g. macroscopic tribometers or AFM tips. The SFB allows for the study of normal and shear forces between molecularly smooth mica surfaces at separations D from contact up to many hundreds of nanometers or more with an absolute spatial resolution in distance D down to ±2−3 Å41,43 and state-of-the-art sensitivity and resolution in measuring normal and shear stresses between the surfaces, i.e., force/unit area (up to some 500-fold better than tipped AFM).41 This enables in particular to probe the very weak shear forces arising when friction coefficients are μ = 0.001 or smaller, as is often the
(SFB) approach, which reveal hydration repulsion effects and shed light on the mechanism of hydration lubrication. After that, we briefly discuss general polymer interactions in the context of lubrication and present different macromolecular systems in aqueous environments where hydration lubrication plays a dominant role. Among them are neutral, charged, and zwitterionic polymer brushes as well as proteins, phospholipid bilayers, and liposomes. Following this, we discuss hydration lubrication by biological macromolecules in the context of biolubrication processes, with reference both to high-stress environments, such as the articulation in the major synovial joints (hips or knees), and to low-pressure sliding such as blinking of the eye.
2. NATURE OF HYDRATION The unique properties of water arise largely from its dipolar nature, illustrated in Figure 1. Although water is overall neutral,
Figure 1. Illustration of a water molecule with its large dipole (A). The atoms of the molecule form a polar bond due to the difference in electronegativity. The oxygen attracts the electrons more strongly than the hydrogen. As the electrons do not completely transfer, the hydrogens keep a partially positive charge and the oxygen a partially negative charge. Numbers refer to the residual charges in units of e (electronic charge) (B). Adjacent positive charges undergo repulsive interactions of steric origin due to an overlap of hydration shells. Reproduced with permission from ref 33. Copyright 2013 Springer.
its large dipole, with positive charged H atoms and a negative O atom, leads to the formation of layers, or shells, of so-called hydration water that surround charges in aqueous media, with the dipole pointing (on average) as indicated, depending on the charge. The hydration shells reduce the self-energy (Born energy) of the enclosed charges34 and as a result may be very tenaciously attached and require large energies to be removed. The dehydration energy per water molecule in the hydration shell, ΔGhyd1, provides a measure of this removal energy; for example,35 for the Na+ ion, ΔGhyd1(Na+) ≈ 80 ± 20 kJ/mol (≈ 33kBT/water molecule). As a result of these large energies required to displace hydration water, overlap of hydration shells may be strongly resisted, leading to (hydration) repulsion between hydrated species, over and above any other interactions (such as electrostatic or dispersive36). At the same time, the exchange rate ωexchange of water molecules in the hydration shell with water in the surrounding bulk may be very rapid, leading to rapid B
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Figure 3. Normal force (Fn) vs surface separation D of two approaching bare mica surfaces across pure water, measured using the SFB and normalized as Fn/R with R ≈ 1 cm being the surface radius of curvature. The profiles display long-ranged electrostatic double layer repulsion (the broken line corresponds to eq 1) with appropriate parameters. The inset magnifies the region when the surfaces jumped infrom ca. 4.5 nmto adhesive contact due to vdW forces. The jump time enables an estimate of the effective water viscosity in the thin (150 atm. In both water and 0.1−0.2 M salt solutions, the resulting friction coefficients went down to remarkably low values μ ≈ 10−4−10−5 up to such pressures, as shown in Figure 7 (these values are 1−2 orders of magnitude lower than with PEG brushes, showing clearly the added benefit of the hydration lubrication over and above other factors such as the weak brush interpenetration). The density and swelling of these grafted-from pMPC brushes are captured by the ratio L/s, where L is the brush thickness and s the mean brush spacing, and reached L/s ≈ 50 in the Tairy et al. study, compared to L/s ≈ 15 in the earlier Chen et al. study (and compared to physisorbed brushes with L/s ≈ 6−872), implying a reduced relative interpenetration of the brushes under compression. Indeed, the denser pMPC brushes resulted in significantly better
hydration lubrication (Figure 7C), as described in more detail in ref 19. In a recent SFB study94 of friction reduction by bottle-brush molecules, exposing pMPC moieties, quite low friction (μ ≈ 3 × 10−3) was measured, likely arising from the lubrication by the highly hydrated phosphocholine groups exposed. The friction between such bottle-brush boundary layers is higher than that between extended brush layers, likely as a result of additional dissipation pathways arising from the rougher nature of the bottle-brush pMPC array relative to a uniform pMPC brush, and also from the lower density of the pMPC moieties on the bottlebrush structure.94 Indeed, this value of μ is similar to that with the adsorbed PLL-g-PEG bottle brushes described earlier,89 which benefited much less from hydration effects but where the brush chains were considerably denser along the grafting backbone and so benefited more from a weaker interpenetration. In different macrotribological studies, which investigated frictional forces of pMPC brushes grown from silicon wafers or polyethylene, relatively high friction coefficients in the range of 0.01−0.1 were measured at pressures around 108 Pa.9,14,104 The discrepancy in the friction coefficient values between the SFB studies described above and these macroscopic studies may be attributed to G
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Figure 8. Structural properties of liposomes. (A) Illustration of a phospholipid bilayer forming the shell of vesicular liposomes. Liposomes are able to entrap hydrophobic molecules (red spheres) within the hydrophobic tail domains and hydrophilic molecules (green star) in its inner compartment. The lipid head contains the zwitterionic phosphocholine group. Reproduced with permission from ref 122. Copyright 2012 Nature Publishing Group. (B) SEM micrograph of surface-adsorbed liposomes in water. (C) Chemical structure of hydrogenated soy phosphatidylcholine lipid (HSPC). Reproduced with permission from ref 31. Copyright 2011 Elsevier.
pathological consequence following total joint replacement which frequently leads to their eventual failure.
additional energy dissipation pathways involved in the different experimental setups, particularly the nature of the surface and the different pressures in the macroscopic studies, over and above those arising from shear of the hydration shells.40 Thus, in the macroscopic tribometric studies,9,14,105 the friction forces between sliding surfaces that bear pMPC boundary layers may have been dominated by (a) asperity contacts, where individual protrusions at the surface are exposed to higher pressures compared to the mean pressures across the contact area and hence experience high energy loss plastic deformation or wear, or (b) a squeeze-out and subsequent removal of the hydration layers from around the PC groups of the polymer segments at the much higher pressures used relative to the SFB studies (>108 Pa vs 107 Pa). A further study of friction between an AFM tip and pMPC brushes106 also indicated relatively high friction (μ ≈ 0.04) due almost certainly to ploughing dissipation. Surfaces grafted with dense pMPC brushes that exhibit low friction/wear and are able to withstand pressures >100 atm, comparable to those exerted in the major synovial joints while articulating, are of particular interest for biomedical applications. Moro et al. studied the use of pMPC brushes as boundary lubricants for artificial hip implants.10 With the rationale of reducing the production of wear particles originating from the prosthetic device, the authors grafted pMPC brushes onto the polyethylene surface of the prosthetic acetabular cup. Hip joint simulator experiments at physiological pressures revealed that the presence of the grafted pMPC on the PE surfaces decreased friction (somewhat) and predominantly wear (very markedly).10 The rather weak friction reduction may be attributed to additional frictional dissipation pathways (such as plastic deformation in asperity contacts) as in the macroscopic experiments described above. On the other hand, the very substantial reduction of wear particles due to reduced friction is important in lowering the periprosthetic immunological/ inflammatory response which leads to osteolysis, a major
5. LUBRICATION BY PHOSPHOLIPIDS AND THEIR ASSEMBLIES The discovery of highly hydrated phosphocholine groups as exceptionally efficient lubricating elements in synthetic pMPC brushes suggests that other macromolecular or supramolecular systems that expose phosphocholine groups may also act as very efficient boundary lubricating layers. Studies of boundary lubrication under water by surfactant layers by Briscoe et al.107 showed that an interfacial layer consisting of close-packed hydrated headgroups of the surfactant molecules can result in massive friction reduction, via hydration lubrication mediated by the 2-D hydrated headgroup array. This suggests that similar interfacial layers based on surfactants bearing phosphocholine headgroups may also act as very efficient lubricating layers. Phosphatidylcholine (PC) lipids with their amphiphilic character based on the zwitterionic phosphocholine headgroups and nonpolar fatty acid chains are indeed precisely such surfactantlike molecules and are ubiquitous in living systems. Their existence has been found in a free, multilayered24 and globularassembled108 state in various human body tissues and fluids including the synovial fluid, peritoneum, pericardium, and pleura.109 Lubrication properties of phospholipids may consequently be of physiological relevance and are proposed to be involved in the lubrication of articulating joints, first by Hills (though via a classic boundary lubrication mode which could not apply in biological systems) and others.110−117 Phospholipids in aqueous environments may also form closed vesicular structures, termed liposomes, whose membranes are lipid bilayers,118 as shown in Figure 8. They can entrap hydrophilic therapeutic or diagnostic agents in their internal aqueous compartment and hydrophobic agents within their membrane and have been widely used for drug delivery and other medical uses.119−121 H
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room temperature of the friction measurements, were substantially more robust, and hence better lubricants, than the shorter tailed liposomes which were near their solid-ordered to liquid-disordered transition temperature and were weaker and thus disrupted at the highest pressures. In a separate study,128 a detailed comparison between extended bilayers and liposomes, both formed by DSPC (C18) lipids, was carried out with respect to their lubrication properties and mechanical properties. Nanomechanical measurements of the supported bilayers showed that the structures were easily punctured via the tip of the AFM and displayed extensive hysteresis between approach and retraction force curves, while the liposomes exhibited purely elastic behavior and were not punctured.128 Figure 10 shows
Recent studies have examined the lubricating ability of lipid monolayers and bilayers (in analogy to boundary lubrication by surfactants under water).107 Trunfio-Sfarghiu et al. and others123,124 measured frictional forces between phospholipid bilayers,125 while addition of liposomes was found to reduce friction in a cartilage-on-cartilage system.126,127 Most notably, outstanding lubrication performance by close-packed liposomes layers at physiologically high pressures was discovered by means of the SFB:31,32,61,128 Goldberg et al. created 2D-close-packed, self-assembled layers of small unilamellar vesicles (SUVs) of hydrogenated soy phosphatidylcholine (HSPC) (∼65 nm in diameter) on opposing mica surfaces,31,32 as shown in Figure 8B. The sliding friction coefficient between the liposome-coated mica surfaces over a range of sliding velocities was as low μ ≈ 2 × 10−5 across water (Figure 9) and μ ≈ 6 × 10−4 across 0.15 M salt
Figure 10. Force vs indentation plots based on AFM measurements of DSPC phospholipids on mica surfaces, either arranged as a bilayer or as self-closed, spherical liposomes. Reproduced with permission from ref 128.
force vs indentation plots of the DSPC phospholipids arranged either in form of a bilayer or as spherical liposomes. At the same time, the supported bilayers were shown to be less stable and less efficient as lubricants, with friction coefficients that while quite low (ca. 10−3) were nonetheless an order of magnitude higher (at similar pressures, ∼50 atm) than those of the SUVs. The superior stability and corresponding lubrication ability of the liposomes at high pressure and shear relative to the extended lamellar phase (bilayers) were attributed to the more defect-free nature of the liposomes (each of size ca. 60−100 nm) relative to that of the many-micron-sized supported bilayers. Taken together, this study clearly demonstrates the importance of the interplay between structural, mechanical features of phospholipids, and their ability to actvia the hydration lubrication mechanism mediated by exposed phosphocholine arraysas extremely efficient boundary lubricants.
Figure 9. Shear force Fs as a function of normal force Fn between opposing liposome-coated mica surfaces in water. The highest loads correspond to contact pressures of over 10 MPa. The gray lines I, II, and III represent friction coefficient values as follows: (I) μ = 5 × 10−4, (II) μ = 1 × 10−4, and (III) μ = 2 × 10−4. The inset depicts how the hydrated phosphocholine head groups exposed by the liposome-covered surfaces slide past other. Reproduced with permission from ref 32. Copyright 2011 Wiley.
solution at mean pressures up to 12 MPa (120 atm). Further measurements have shown that if the highly hydrated PC groups are screened by covalently attached PEG chains at the liposomal surface, friction between these PEGylated HSPC layers is much higher (μ ≈ 0.1 up to 1 MPa) compared to bare HSPC liposomes (where μ in the range of 4 × 10−4−2 × 10−5) up to 11 MPa (such PEGylation is often used to stabilize SUVs sterically against aggregation and fusion). This observation supports the concept that the highly hydrated PC headgroups are the essential building blocks to enable lubrication; screening them via a coating of less hydrated PEG chains leads to a clear increase in friction. The extreme lubricity of the bare liposome layers is attributed to the hydration lubrication mechanism acting via the tenaciously attached,102 rapidly relaxing hydration layers surrounding the PC groups (Figure 9 cartoon inset). The great robustness of the 2-D SUV assemblies, which can support stably pressures over 100 atm while being slid over similar liposome layers, is attributed to their uniformity and close packing on the surface (minimizing surface “bumps”) and their gel-phase rigidity. A recent study by Sorkin et al. examined the differences in lubrication of phospholipids of varying diacyl chain length (C14−C18) by AFM and SFB.61 It showed clearly that the longer-tailed liposomes, well into their solid-ordered (gel) phase at the
6. HYDRATION LUBRICATION IN A BIOLOGICAL CONTEXT Biological processesfrom cell signaling to joint articulation take place in aqueous environments. Hence, as part of living systems, connective tissues, cells, organelles, and macromolecules are at least partially hydrophilic or expose hydrophilic groups of ionized, polar, dipolar, or zwitterionic nature at the surface water interface.33 Consequently, these groups tend to be hydrated to a lesser or greater extent. As biological components slide past other fulfilling various physiological functions, the efficient lubrication of such sliding, particularly under conditions that involve large mechanical stresses, is crucial, and we anticipate that the hydration lubrication mechanism plays a key role in this. Several model studies on lubrication by key biological macromolecules, described below, indeed reveal that hydration lubrication provides a comprehensive framework for understanding biolubrication. I
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change rapidly.136 Indeed, any manipulation or insult to cartilage (including excision or other trauma) risks releasing cartilage degrading enzymes137,138 which may change the nature of the cartilage boundary layer providing the unperturbed lubrication in vivo. For these reasons, insight into biolubrication is best obtained by model measurements, including nanotribological studies, on boundary layers consisting of joint macromolecules that have been implicated in the interfacial modification of cartilage; such studies have been carried out by several groups.139−143 As part of a systematic study of lubrication by boundary layers of joint macromolecules (Figure 11, caption), Seror et al. investigated, using the SFB, the lubrication properties of two of the central components of cartilage, hyaluronan (HA), and aggrecans (Aggs) extracted from bovine cartilage.144,145 HA is a linear, high molecular weight, negatively charged polysaccharide along which bottle-brush-like proteoglycans, aggrecans, form supramolecular complexes (stabilized by link proteins). The aggrecans themselves expose mostly highly charged chondroitin sulfate (CS) chains as their “brush hairs”; the structure of both the HA and CS monomers are shown in Figure 12C. In vivo, both macromolecules are synthesized by chondrocytes and excreted into the cartilage space. This study145 mimicked the macromolecules extending from the cartilage surface into the synovial cavity by reconstructing complexes composed of HA or of HA to which aggrecans were attached, on a model (mica) surface, and measured normal and lateral interactions between them. Figure 12A illustrates the molecular arrangement on the surface. Shear force measurements show that hyaluronan/aggrecan complexes provide superior lubrication compared to hyaluronan alone (Figure 12B), which provided rather poor lubrication in line with earlier studies.146 In both cases the lubrication is attributed mainly to the hydration sheaths bound to the fixed negative charges on the molecules, either HA or CS. Because of the higher density of charges (see Figure 12C), the hydration is more effective on the CS-exposing aggrecan−HA complexes than on the HA surface layers alone and hence provides better lubrication. In neither case, however, was the hydration lubrication anywhere near as efficient as between the phosphocholine-exposing assemblies described in the previous sections. Friction coefficients of 0.01 over the pressure range up to 17 atm were obtained for the surface-attached HA/aggrecan complexes, with higher values for the HA layers alone (Figure 12B). This relatively high frictional dissipation is attributed to the weaker hydration of the charged −SO3− and −COO− on CS and HA groups (discussed also earlier in the context of charged brushes) relative to the phosphocholine groups on the pMPC brushes or exposed by the PC liposomes. For the adsorbed HA, bridging is also likely to play a role in the higher friction. These valuesof the HA or HA/aggrecan complexesare also significantly higher than friction coefficients of synovial joints (which are μ ≈ 0.001−0.005 up to pressures of over 100 atm), implying that HA layers or HA−aggrecan complexes by themselves cannot account for the extremely low boundary friction of cartilage. It is of interest however that at the lowest pressures P, up to P = ca. 5 atm (Figure 12B, black data points up to normal loads of ca. 50 μN), a closer examination of the friction mediated by the HA−aggrecan layers reveals a rather low coefficient of friction, around μ ≈ 0.002. This compares with the value μ ≈ 0.001 observed at low P (up to 3 atm) for the charged PMMA-b-PSGMA brushes,11 where the ion providing the hydration lubrication was also −SO3−, just as for the chondroitin sulfate moieties exposed by the aggrecan brushes (Figure 12C).
6.1. High Load Environment: The Synovial Joint. The major synovial joints such as the hip or the knee joint are coated with articular cartilage layers, which have to withstand a wide range of loading conditions over a large range of shear rates, typically from rest to ca. 106 s−1,44 and can slide past each other with very low friction (μ down to 10−3 or lower). The interactions of the synovial fluid filling the joint cavity and particularly the macromolecular boundary layers at the cartilage outer surface provide the basis for the efficient lubrication of the joint and thus enable protection from mechanical damage and wear. Moreover, as has recently become clear,129 shear stresses on the cartilage (directly related to its sliding friction) may modulate protease production by the chondrocytes in the cartilage (the cartilage-synthesizing cells) and affect the progress of osteoarthritis, a widespread joint disease. Articular cartilage consists of a macromolecular matrix framework of collagen fibers, proteoglycans, phospholipids, and other noncollagenous proteins, saturated with water and mobile ions, in which highly specialized cells, chondrocytes, are embedded. Figure 11 shows a schematic of a synovial joint, the articular cartilage, and its surface composition.
Figure 11. Illustration of a synovial joint showing the interacting bones covered with a thin layer of cartilage immersed in synovial fluid, the medium of the joint cavity. The inset schematically magnifies the outer surface of cartilage tissue with its characteristic charged macromolecules extending into the synovial cavity to form a brush-like boundary layer: hyaluronan (blue curved lines), bottle-brush aggrecans (red curved lines), and lubricins (light green curved lines). These are some of the key macromolecules for providing boundary lubrication at cartilage surfaces.130 Reproduced with permission from ref 131. Copyright 2009 AAAS.
From a tribological perspective, the synovial joint is a remarkable construct.23,132 The major human synovial joints are able to sustain loads up to 10 times body weight during daily activities such as walking or climbing stairs.133 The mean pressure during the peak of a normal walking cycle is ∼50 atm, while local contact pressures may rise up to 200 atm134,135 as measured in vivo using orthopedic implants modified with pressure sensors. The in vivo determination of the friction between sliding cartilage surfaces, however, is extremely challenging, partly because the intrinsic cartilage−cartilage friction is so low that other dissipation processessuch as adjacent tissue deformation during articulationmay dominate. At the same time, if measured ex vivo, the properties of the tissue do not resemble the native state as the physiological features may J
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Figure 12. Reconstruction of the HA−aggrecan complexes on mica for SFB studies and their interactions. (A) Schematic of the molecular configuration at the surface. The negatively charged mica surfaces are coated, step by step, with avidin (Av), biotininylated hyaluronan (bHA, biotin indicated as green circles), cartilage link proteins (LP, black circles), and aggrecans (Agg). (B) Shear forces Fs vs normal forces Fn. The top axis shows the corresponding pressures. The open symbols represent interactions between two surfaces coated with Av-bHA across pure water; crossed symbols are interactions between Av-bHA-LP-Agg bearing surfaces across PBS; closed symbols are interactions between surfaces modified with Av-bHA-LP-Agg across pure water. The shaded band shows the shear forces when an HA-Agg complex is slidat the same pressuresagainst bare mica. The value μ = 0.01 is the mean over the pressure range. (C) Monomer structures of hyaluronan (HA) and chondroitin sulfate (CS, the major component of aggrecans), showing CS to have double the charge density of HA. Reproduced with permission from ref 145.
Figure 13. Showing the synergy between HA and phospholipids in a boundary lubrication layer. (A) AFM micrograph showing the DPPC−HA complex on the mica surface; red lines are a guide to the eye of HA contours. The inset on the same scale shows a DPPC liposome, used to deliver the lipids to the surface-attached HA, prior to rupture. The cartoon illustrates the structure of the HA/DPPC complex, where the biotinylated HA is attached to the surface via biotin−avidin bonds. (B) Friction vs load between two mica surfaces bearing HA/DPPC complexes as in (A), showing friction coefficient down to μ ≈ 10−3 at high pressures. The shaded area is the range of data, while the red data is in a 0.1 M salt solution. Reproduced with permission from ref 130. Copyright 2015 Nature Publishing Group.
This similarity reinforces the conclusion that this ion (−SO3−) is relatively weakly hydrated and acts as an efficient lubricating element only up to low pressures. To obtain deeper insight into the issue of articular cartilage lubrication, and in light of the striking lubrication performance of phosphatidylcholine (PC) lipidswhich are ubiquitous in both cartilage and in the synovial fluida very recent study examined the lubrication behavior of phosphatidylcholine/hyaluronan (PC/HA) complexes on model surfaces.130 In this study130 HA molecules were attached via avidin−biotin bonds to a model
(mica) surface and spontaneously formed a surface complex with DPPC lipids (delivered to the surfaces via the corresponding liposomes). The resulting HA/DPPC boundary layers provided robust and very efficient lubrication, with friction coefficients μ down to 10−3 or lower up to pressures 100 atm or higher. This is shown in Figure 13. The very low friction is attributed to the highly hydrated phosphocholine groups exposed by the HA/lipid surface complex, actingas for the case of pMPC (Figure 7) or the case of the close-packed liposomes layers (Figure 9)via the hydration lubrication mechanism. This is the first demonstration K
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Figure 14. (A) Schematic of an “Orthana” mucin, used as a model mucin in a number of rheological and lubrication studies.157 Its structure is dumbbelllike, composed of two globular domains connected via a heavily glycosylated domain. Adapted with permission from ref 158. (B) Structure of HFBI protein, showing the hydrophobic patch and the charged residues indicated which form a hydrophilic patch. Reproduced with permission from ref 159. Copyright 2013 Royal Society of Chemistry.
surfaces (the two outermost layers of the eye facing the eyelid) during the eyelid blink.156 Harvey et al. used the SFB to study the frictional properties of adsorbed mucins on both hydrophilic and hydrophobic substrates, where they form robust boundary layers.158 The adsorbed protein layers led to lower friction between the hydrophobized surfaces than the hydrophilic surfaces. Figure 15 shows the Fs vs Fn plots for both surface scenarios in different aqueous solutions. The rather different frictional behavior in the two cases, i.e., μ ≈ 0.007 vs μ ≈ 0.03, in the load range to 50 μN (Figure 15) may be attributed to the fact that adsorbing the hydrophobic moieities of the mucin on the (hydrophobized) surface exposes relatively more of the hydrophilic, polar moieties at the outer surface of the boundary layer, and as the latter are more highly hydrated there is better lubrication via the hydration lubrication mechanism. Moreover, the hydrophobic moieties of the mucins interact more strongly with the underlying surface and allow for a denser arrangement on the hydrophobic surface in comparison to the hydrophilic substrate. As seen in Figure 15A at low loadsand thus low pressures (up to a few atm)the intrinsic friction by the mucin layers is rather low, μ < ∼0.01, suggesting that at low pressures the frictional dissipation pathways are dominated by hydration lubrication. This is of interest, as in the eye or in the bronchial tract, as well as in the oral cavity, where mucins are implicated in the lubrication, pressures between sliding surfaces are generally much less than 1 atm. The conclusion that adsorption of proteins on a hydrophobic surface tends to expose more of their hydrophilic, and thus more highly hydrated and better lubricating epitopes at the protein− water interface, was demonstrated more directly in a study by Goldian et al.159 on forces between boundary layers of the protein hydrophobin I, HFBI. This protein has a highly amphipathic structure, with one side exposing charged hydrophilic groups and the other exposing hydrophobic groups, as illustrated in Figure 14B. The results of this study show that the friction between HFBI layers on hydrophobized mica, exposing hydrophilic groups, is an order of magnitude lower than between HFBI-coated surfaces on hydrophilic surfaces, which expose the hydrophobic domains of the protein to the water interface. The greater level of hydration of the exposed outer surfaces and the resulting lower friction in the former case may clearly be attributed in terms of the hydration lubrication concept.
that molecular components that are ubiquitous in the synovial jointHA and phosphatidylcholine lipidscould complex to provide the low friction at the high pressures characteristic of living joints. On the basis of this work, Seror et al.130 propose a scenario where the three molecules, namely lubricins, HA, and phospholipids, each of which has in the past have been separately invoked as responsible for the low friction of cartilage, act synergistically, each with a different role: Hyaluronan, anchored at the outer surface of articular cartilage by lubricin molecules, complexes with joint phosphatidylcholines to provide the extreme boundary lubrication of synovial joints via the hydration−lubrication mechanism. 6.2. Low Load Environments. Effective lubrication between internal surfaces of living organisms provides the core concept to enable physiological functions of the eye,147 the bronchial tract,148 and efficient processing of food in the mouth and the gastrointestinal tract.149 Although these functions are usually accomplished under conditions dominated by low loads and mechanical contact stresses compared to the high-load scenario of the synovial joint, low friction is vital to minimize loss of energy and wear of the tissue. Mucins are a family of at least 20 large, highly glycosylated, membrane-tethered or secreted proteins (0.5−50 MDa) sharing the common features of (a) having tandem repeats of certain amino acids in their protein backbone (hydrophobic domains) and (b) extensive O-glycosylation (hydrophilic domains) that accounts for 50−80% of the mass of the molecule.150 As a consequence of their polyampholytic character, mucins are able to adhere to a wide range of surfaces via hydrophobic and electrostatic interactions and hydrogen bonding.151 The biophysical properties of mucins are primarily based on the hydrated −OH groups of the oligosaccharides, which stretch away from the protein backbone in a bottlebrush configuration,152 similarly to the aggrecans discussed earlier. The oligosaccharide side chains are most commonly composed of Nacetylglucosamine, galactosamine, galactose, and sialic acid.150 Because of the existence of sialic acid residues and sulfate groups, mucins carry a net negative charge. Figure 14A shows a schematic of a gastric porcine mucin (so-called “Orthana” mucin). Membrane-associated mucins, which are believed to extend 200−500 nm153 into the glycocalyx of a cell, are found on the apical surfaces of all wet-surfaced epithelia (cells lining the cavities and surfaces of tissue) of the human body.154 At the ocular surface, mucins exhibit a multifunctional nature and are found to be secreted by specific cells (goblet cells) of the conjunctival epithelium and the lacrimal glands into the tear film and span the membrane of the epithelium.155 They are believed to act as lubricants of the corneal and conjunctival epithelial
7. CONCLUSIONS, OPPORTUNITIES, AND CHALLENGES Hydration lubrication is an emergent paradigm for understanding friction in aqueous, particularly biological systems (rather different from the main classical modes predicated on L
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massively reduce friction between sliding surfaces. Table 1 summarizes in outline the frictional behavior and the corresponding pressures studied for different macromolecular/ supramolecular surface-boundary systems in aqueous media mentioned in this Perspective. (For more details of how the friction varies with pressure, sliding velocity, salt concentrations, and other parameters the reader is directed to the original papers.) Despite the great variety of systems described, two general observations may be made. The first is that for the case of adsorbed polymers, even if they are charged and hydrated, dissipation arising from adsorptive bridging can dominate the sliding friction, particularly at higher compressions, leading in general to higher friction than for nonbridging brushes. The second is that SFB studies reveal lower friction for a given system than either macrotribometric or tip-based scanning probe methods approaches, in line with our expectation that the latter involve more dissipation pathways than with the SFB approach. The nature of hydration, and thus the efficiency of the hydration lubrication, can vary strongly with specific charged or polar groups. Just as the Cs+ ion readily sheds its hydration layer under pressure as a result of its large ionic diameter, and therefore can provide little or no hydration lubrication,164 in contrast to smaller ions such as Na+ or K+,165 so not all ionic or polar groups are equivalent in the hydration lubrication context. Thus, as we have seen, the etheric −O− in poly(ethylene oxide), as likewise the −SO3− or −COO− ionic groups, are less efficient lubrication elements at high pressures when incorporated in their macromolecular vectors, in consequence of their weak hydration, as seen in Table 1. In contrast, the zwitterionic phosphocholine group −(PO4−)(CH2)2N+(CH3)3, whether in a polymeric context (such as pMPC) or more commonly as the headgroup of phosphatidylcholines (the most widespread phospholipids in our bodies) in liposomic or extended lamellar assemblies, acts as an extremely efficient lubrication element: This is due to its exceptionally strong hydration with some 15 water molecules in its primary hydration shell.8,102 The fact that phosphocholine groups are ubiquitous in living systems as the headgroup of phosphatidylcholine (PC) lipids suggests that PCs may play a central role in biolubrication processes. This is particularly the case in high-stress environments such as the major joints, since, as we have shown, PC assemblies such as liposomes, bilayers, or less-ordered complexes with surface-attached macromolecules can provide extremely low friction up to more than 20 MPa, exceeding the highest joint pressures. The recently discovered synergy between HA and PC lipids, both of them present in joints, in providing boundary layers whose lubrication properties mimic those of articular cartilage130 is a case in point. Hydration lubrication, however, provides an excellent framework for understanding biolubrication processes more generally, as indicated for mucins at lower stresses (such as occur in the eye). At the same time, it is important to bear in mind that the hydration lubrication mechanism is just one pathway by which friction may be modulated, albeit one with exceptionally low levels of frictional dissipation,40 and in real systemswhere surfaces are generally rougher and softer than the mica in the SFBit will in general be convoluted with other dissipation pathways. These include viscous effects associated with disentanglement of interpenetrated polymer chains8 and the “dragging” of bridging, adsorbed polymers or viscoelastic effects arising from deformation of soft materials (or liposomes) as they slide past each other. Classical dissipation processes via irreversible bond-breakage or atomhopping processes may also arise if the sliding surfaces or the
Figure 15. Shear force Fs* as a function of Fn for adsorbed mucins on STAI-hydrophobized mica (A) and on bare hydrophilic mica substrates (B) in pure water, protein solution and 0.1 M Na+ solution at a shear velocity of 400 ± 35 nm s−1. § represents an interval of 11 min, while the surfaces were in contact with no increase in load. Reproduced with permission from ref 158.
fluid film or solid-contact boundary lubrication160), in which the sub-nanometer hydration shells surrounding charged or polar groups may act as extremely efficient lubrication elements. This arises because the hydration shells may be tenaciously bound to the enclosed charges and yet be very fluid, due to the rapid exchange rate with surrounding water molecules, enabling the support of large normal stresses and at the same time a weak frictional stress on shearing. In the macromolecular/supramolecular domain, the subject of this review, hydration lubrication offers new opportunities and challenges. In particular, suitable macromolecules or supramolecular assembliessuch as surfactant bilayers or liposomesmay act as vectors to bring hydrated species to the desired interfaces, where they can M
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Table 1. Summary of Measured Sliding Friction Coefficients and Corresponding Range of Mean Contact Pressures between Surfaces Bearing Different Hydrated Macromolecular/Supramolecular Systems in Aqueous Mediaa system PEG adsorbed PEG−PL bottle brushes short end-functionalized PEG brushes chitosan-adsorbed HA-adsorbed PMMA-b-PGMAS brushes HA-aggrecan brushes pMPC brushes
pMPC bottle brushes surfactant layers PC liposomes PC lipid bilayers HA−PC complexes mucins porcine gastric (“Orthana”) mucin lubricin hydrophobins exposing hydrophobic patch exposing hydrophilic patch a
friction coeff μ 0.01−0.05 0.001−0.003 0.1 0.03 0.003−0.07 0.3 6 × 10−4 0.01 ∼10−3−10−4 0.01−0.1 0.02 ∼10−3 10−3−10−4 ∼10−4−2 × 10−5 ∼10−3 0.002 ∼10−3−10−4
pressure (atm)
ref
comments
neutral polymers ∼0.1−3 35 SFB ∼100 89 SFB ∼8000 90 macrotribometry 0.3 to ∼1 88 SFB charged and zwitterionic polymers ∼1−3 99 SFB ∼8 145 SFB 3 (max) 11 SFB; chain shear-off at higher P 17 144, 145 SFB; lower μ at P < 5 atm >150 8, 19 SFB ∼1000 9, , macrotribometry 106 FFM 21 94 SFB supramolecular 40 107 SFB; under adhesion, load estimated from the effective adhesive force 180 32, 161 SFB 50 128 SFB 10 162 macrotribometry 220 130 SFB proteins
0.01−0.4 0.02−0.04 0.2−0.6
0.1 to >10 ∼4
158 163
SFB; μ varies with load and hydrophobicity/hydrophilicity of the substrate SFB
∼0.15/∼1.4 ∼0.14
0.5 up to 18
159
SFB
SFB = surface force balance studies; FFM = friction force microscopy.
coatings of catheters or other biomedical devices. In a different context, a very recent study has shown that when glucosamine sulfate, a charged monosaccharide, which is extensively used as a treatment for osteoarthritis (OA, the most widespread joint disease, affecting many millions), is encapsulated within liposomes, the vesicles are stable upon shear at high compressions (>100 atm) and provide very good lubrication.167 Hence, this system demonstrates the possibility of incorporating a therapeutic substance while still maintaining the efficient lubrication properties of the liposomal vectors. Further, as pathological conditions of OA may be associated with the shear (frictional) stresses at articulating cartilage,129 specific macromolecular systems such as the liposomes reported above bearing appropriate hydration layers might potentially be used as therapeutic lubrication vectors. Indeed, the recently discovered hyaluronic acid (HA)/phospholipid hydration lubrication synergy,130 together with new means of attaching HA to cartilage,142 suggest additional sophisticated approaches to modulating articular cartilage lubrication to alleviate OA.
boundary vectors themselves are sufficiently strongly coupled, i.e., in contact unmediated by hydration shells, at high compressions.40 These effects of additional dissipation pathways are seen in Table 1 for different systems, particularly when comparing nanotribometric (e.g., SFB) with macrotribometric measurements. In light of these findings, there are several future challenges and opportunities in the macro/supramolecular domain where the hydration lubrication paradigm may be studied or exploited. These include understanding the interplay between the different frictional dissipation modes, such as hydration lubrication and viscous losses between interpenetrated or interentangled macromolecular surface phases, including the shear rate dependence of segmental relaxation vs hydration shell relaxation in hydrated polymers. The design and de novo synthesis of molecules or assemblies to be functionalized with particular hydrated groups, e.g., phosphocholinated, and that may then either act as vectors bringing hydrated groups to a desired interface or be incorporated in new supramolecular assemblies (micelles or vesicles) that may serve as lubrication vectors, is a clear direction. Hydration lubrication via interfacial modification of suitable soft vectors such as hydrogels166 is of clear relevance for biomedical devices as well as tissue engineering scaffolds. Indeed, the development of such biomimetic and biocompatible, clinically applicable surfaces with the capability of substantially reducing friction might have a large impact, not only for total joint replacement10 but also as a platform technology in other biomedical contexts, in which lubrication plays a role, e.g.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] (J.K.). Notes
The authors declare no competing financial interest. N
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(Advanced Grant HydrationLube), the Israel Science Foundation (ISF), the Petroleum Research Fund (Grant 55089-ND10), The Minerva Foundation, the ISF-National Science Foundation China joint program, and the McCutchen Foundation. S.J. acknowledges a Minerva Fellowship and thanks her medical service dog “Kai” for assistance. This work was partly enabled by the historic generosity of the Harold Perlman family.
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REFERENCES
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Sabrina Jahn received her MPhil in Biotechnology from Cambridge University (UK) in 2007. She continued her studies at Cambridge, working on polymer-driven colloidal assemblies, at the Cavendish Laboratory obtaining her PhD in Physics in 2011. Since 2011, she is a postdoctoral researcher at the Weizmann Institute, Israel, under the guidance of Prof. Jacob Klein. Her current research interests focus on the interfacial behavior of hydrated proteins, light−matter interactions, and applications based thereon.
Jacob Klein is the Herman Mark Professor of Polymer Physics at the Weizmann Institute in Israel. Klein gained his BA in Physics at the University of Cambridge, where in 1977 he also received his M.A. and PhD at the Cavendish Laboratory. He did his postdoc at the Weizmann Institute in Israel and from 1980 to 1984 was a Senior Scientist at the Weizmann Institute and a University Demonstrator at the Cavendish Laboratory. In 1984, he was appointed Professor at the Weizmann Institute (full Professor from 1987) and subsequently headed its Polymer Research department and was Chairman of its Scientific Council. From 2000 to 2007 Klein was the Dr. Lee’s Professor of Chemistry at the University of Oxford and Head of its Physical and Theoretical Chemistry Laboratory (2000−2005). His interests in soft matter have ranged from the dynamics and interfacial properties of polymers to the behavior of confined fluids and biological lubrication and, more recently, tissue engineering. Klein has published some 250 papers, including over 20 in Science and Nature. His honors include the High Polymer Physics Prize of the American Physical Society (1995), the 2010 Prize of the Israel Chemical Society, the 2011 Soft Matter and Biophysical Chemistry Award of the UK Royal Society of Chemistry, and the 2012 Tribology Gold Medal.
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ACKNOWLEDGMENTS We thank Jasmine Seror for useful information. We appreciate financial support of this work by the European Research Council O
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