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Mechanism of Tear Film Rupture and Formation of Dry Spots on Cornea A. SHARMA AND E. RUCKENSTEIN l Department of Chemical Engineering, State University of New York, Buffalo, New York 14260 Received June 8, 1984; accepted October 4, 1984 The rupture of the tear film covering the cornea and the formation of dry spots is of importance in various pathological states associated with a dry eye. The purpose of this paper is to identify its mechanism and to compute the time required for such a rupture. A two-step, double-film model is proposed which accounts for the real structure of the tear film as composed of a mucous layer and an aqueous layer. The mechanism identifies the key step in the process of rupture to be the instability and eventual rupture of the mucous layer of about 200 to 500 A thickness, which covers the epithelium, due to the dispersion interactions. This in turn exposes the aqueous layer of the tear film to the hydrophobic cornea, resulting in the observed end result of a spontaneous tear-film rupture or "beading-up." The proposed mechanism is shown to be consistent with the range of observed breakup times and other clinically observed characteristics of the tear-film rupture. The implications of this mechanism in the normal wearing and tolerance of contact lenses are also indicated. © 1985 Academic Press, Inc. INTRODUCTION than 10 s is usually considered abnormal and may have mild to serious consequences, such as: an instantaneous sensation of local irritation, a persistent feeling of ocular irritation, or a foreign body sensation. In severe cases, a breakup time of less than the interblink period may result in an irreversible dewetting of cornea, epithelial damage, and corneal ulceration. An abnormally rapid tear breakup also plays an important role in determining the contact lens tolerance. It has been shown to be responsible for the adhesion of the lens to cornea (and consequent epithelial damage) and excessive, rapid deposit formation on the anterior lens surface (12, 13). The measurement of BUT thus plays an important role in the characterization and differentiation of a normal cornea from a pathological one. In view of this, it is not surprising that the clinical measurements of BUT are widespread in assessing the severity of conditions associated with a dry eye. It is, however, surprising that in spite of its significance, none of the models proposed for the instability of the tear film address the issue of the time of rupture. This information may The stability of the lacrimal liquid film covering the cornea (or the contact lens) has attracted much attention (1-11) because of the important role it plays in the optimal conditions of vision; both from the optical and physiological points of view. The normal tear film forms a continuous smooth cover over the corneal surface. The structural integrity of this continuous film is maintained by involuntary periodic blinking, with a normal interblink interval of about 5 to 10 s. If, however, the eyelids are held open for a longer time period, the stability of the tear film is threatened, resulting in the eventual formation of randomly distributed holes in the lacrimal liquid. The average time elapsed between a blink and the first hole to appear is defined as the tear breakup time (BUT). This is found to be in the range of 20 to 50 s for a normal adult eye (2). For a pathological eye, however, BUT is found to be considerably less than the normal BUT. A breakup time of less To whom correspondence should be addressed. 12 0021-9797/85 $3.00 Copyright © 1985 by Academic Press, Inc. All rights of reproduction in any form reserved. Journal of Colloid and Interface Science, Vol. 106, No. 1, July 1985 TEAR FILM be used as an important criterion for model discrimination. The following two mechanisms have been suggested as possible causes for the rupture of the tear film. MARANGONI INSTABILITY It has been suggested that the lipids secreted from the tarsal glands decrease the overall wetting ability of the aqueous layer which rests on a mucus-coated corneal epithelium (12-15). The tear film consists of a mucous layer covering the epithelium, an aqueous layer and a lipid-mucin bilayer located at the air-tear interface (a brief exposure to the structure of the tear film is provided later). In a series of papers, Holly and his associates (1-3, 12-17) have advanced a mechanism of film rupture based on the assumption that the lipids present at the tear-air interface migrate rather rapidly to the mucous-aqueous interface and eventually overwhelm the protective capacity of the mucous layer, thus creating areas of high hydrophobicity. The surface-tension driven motion (Marangoni effect) was thought to be responsible for such a process (14). This may happen if the convective motion along the lipid-air interface (from the regions of low surface tension to those with high surface tension) is in the same direction as the convective flow induced by the interfacial perturbations. However, any uneven distribution of interfacial lipids, due to interfacial perturbations, has a tendency to equilibriate. This is so, because the surface-tension gradient driven Marangoni motion is in the direction opposite to the convective flow caused by interfacial perturbations. This stabilizing effect of surface active agents on the stability of a falling film (18) and a thin film subjected to dispersion forces (19) has been reported. It should however be noted that even in the absence of Marangoni convection, the diffusion of lipids in the aqueous layer is present. Based on the magnitudes of the thickness of aqueous layer (ho 6-9/~m) and the diffusion coefficient, D 10-5 cm2/s., the penetration time (hg/D), 13 RUPTURE for the lipids is easily shown to be of the order of 10 -2 s. Thus the aqueous layer becomes saturated with lipids in less than a second. The solubility of lipids, which are made of waxy and cholesteryl esters (2), in the aqueous medium is rather low. In addition, since the lipids are much less surface active than the mucous material covering the epithelium, their adsorption on the mucousaqueous interface is thermodynamically unfavorable, viz., it increases the mucousaqueous interfacial tension. As shown later, an increased mucous-aqueous interfacial tension makes the mucous layer more resistant to the interfacial deformations and thus contributes to its stability. In addition, it may be noted that the presence of lipids is not necessary for the tear film breakup which is observed even in the event of a complete destruction of meibomian gland openings (2). Based on an upper estimate for the mucinconcentration gradient between the epithelium and the air-tear interface, Lin and Brenner (5) show that a mucin-concentration driven Marangoni motion may exist in the aqueous tear film. The presence of surfaceactive agents (in this case, interfacial lipids), however, makes it less likely. RUPTURE DUE TO DISPERSION FORCES Lin and Brenner (6) carded out a linear stability analysis of a nondraining, micrometer-sized tear film, under the influence of retarded van der Waals dispersion forces. The thickness of neutrally stable tear film was computed for various values of the retarded Hamaker constant, by taking the wavelength of the perturbation to be the same as the linear dimension of the eye ( ~ 1 cm). A tear film with a thickness less than this critical thickness eventually ruptures because of the dominance of the dispersion forces over the viscous and surface tension resistances of the fluid to any interfacial deformation. Additional information about the time of rupture is, however, needed for the purpose of model differentiation. Journal of Colloid and Interface Science. Vol. 106. No. 1. July 1985 14 SHARMA AND RUCKENSTEIN The main purpose of this work is thus to air-tear interface is a lipid-mucin layer, which formulate a mechanism of the tear-film rup- is about 1000 to 2000 A thick (2). Lipids ture which is consistent with the observed present in this layer retard the evaporation breakup times and other characteristics of of the aqueous phase so that only about 7% the rupture process. For this purpose, we of the aqueous layer evaporates in 1 min establish a unified linear instability criterion under the normal circumstances (13). An which incorporates the van der Waals inter- increased rate of evaporation has an adverse actions and the hydrodynamics of the tear effect both on the thinning of the tear film flow. An estimate for the time of rupture is and the dehydration of cornea. In the presobtained from this linear stability analysis. ence of a normal lipid layer, the drying of An application of this formalism to the entire the epithelial surface cannot be caused by micrometer-sized tear film (considered as a the evaporation, since it would take about homogeneous film) shows that such a rupture 10 to 20 min. Underneath this lipid layer is cannot occur within the observed breakup an aqueous electrolyte middle phase which times. Therefore a different mechanism of is about 6-9 ~tm thick immediately after the tear-film rupture is required to explain blinking. The thickness then decreases in an the observed BUT. The fact that the tear almost linear manner because of evaporation film is, in reality, composed of a hydrophobic and osmotic transfer of tears across the corepithelium, a mucous layer, and an aqueous nea, and in approximately 20 to 50 s (BUT), layer, naturally suggests a mechanism which its thickness is reduced to about 4 #m. At should incorporate this heterogeneity. The this point, the film has been observed to cause for the instability of the entire tear film rupture almost instantaneously (4). Sandis sought in the instability and the rupture wiched between the aqueous phase and the of the thin mucous layer, which covers the corneal epithelium is a mucoid layer, which, epithelium, under the influence of van der in a normal eye, is about 200 to 500 A thick Waals dispersion forces. This mechanism is (2). Most of the mucous material covering shown to be consistent with the observed the superficial epithelium originates in the breakup times and other characteristics of conjunctival goblet cells and is distributed the rupture process. In addition, it aids in a over the preocular surface by the shear created rational understanding of a diversity of clin- by the lid motion during blinking. The reical observations about the pathological con- newal rate of this layer is very small and ditions of a mucus-deficient eye and the only a small fraction of it is removed during tolerance of contact lens. A clear understand- each blink. In addition to serving such vital ing of the proposed mechanism and model functions as the maintenance of corneal and differentiation thus necessitates a brief expo- conjunctival surfaces in the proper state of sure to the structure and functioning of the hydration and lubrication, the mucous layer tear film, as well as to the observed charac- provides a hydrophilic base for an even teristics of the rupture process. This is fol- spreading of the aqueous tear film (15). lowed by linear stability analysis and deriThe corneal and conjunctival surfaces are vation of expressions for BUT. The impli- highly hydrophobic and indeed, they are cations of the suggested mechanism are then incapable of sustaining a continuous, aqueous tear film without the presence of the mucous discussed. layer coating the epithelium (2, 3, 15). There is even some experimental evidence for a THE STRUCTURE AND THE RUPTURE highly hydrophobic lipid monolayer sandCHARACTERISTICS OF A TEAR FILM wiched between the epithelium and the muThe tear film which covers conjunctiva cous layer (14). The presence of the mucous and cornea consists of at least three distinct layer is thus necessary to effectively mask the fluid layers. The outermost layer making the hydrophobic character of the epithelial surface Journal of Colloidand Interface Science, Vol. 106, No. 1, July 1985 TEAR FILM RUPTURE and to impart a stable, hydrophilic base to the tear film. Experiments of Dolhman et al. (8) also demonstrate that a reduction in the glycoproteins contents (a mucous-layer constituent) is associated with a decrease in the tear-film breakup time and was detected in some pathological states of the dry eye. The various components of a typical, normal tear film are depicted in Fig. 1. The production rate of tear is approximately 1.2 #1/min, which is drained continuously between each blink. Calculations based on the cross-sectional area of the tear film ( ~ 2 × 10-3 cm 2) and the production rate give an average tear velocity of about 10 -2 cm/s for such a flow (6). Perhaps, it is also important to note that a meniscus extends along the entire margin o f both the upper and lower eyelids. Similar menisci are present surrounding the bubbles and debris found in the tear film (11) and contact lenses. The locally thin areas, the socalled "black lines," appear adjacent to these thick menisci. Such locally thin (couple of micrometers thick) areas have been thought to be instrumental in accelerating the process of film rupture (6). With this brief exposure to the tear film, we now proceed to derive a stability criterion for a tear film. THE INSTABILITY CRITERION AND THE TIME OF RUPTURE OF A THIN FILM From the geometry and the dimensions of eye as shown in Fig. 2, it is readily shown that the angle/30 is less than 1 10 °. Thus the deviation of the tear film from a vertical film (/30 = 7r/2) is only slight and the small curvature of the vertical plane may be neglected. Thus we essentially consider the stability of the tear film on a two-dimensional cylindrical surface as shown in Fig. 3. The AIR LIPID LAYER 15 ANTERIOR CORNEAL ~ EPITHELIUM ~ / ho --I : TEAR FILM ! / FIG. 2. Side view of a human eye. relevant equations describing the hydrodynamics are the Navier-Stokes equations which include the van der Waals dispersion forces acting on the tear film as a body force. This body force becomes important when the film is thinner than the range of interaction of the dispersion forces between the epithelium and the film resting on it. The effect of van der Waals dispersion forces is incorporated by using a Hamaker-type approximation, which has been used by Scheludko (20), Ruckenstein and Jain (19), and G u m e r m a n and Homsey (21), with many others for various problems of thin-film stability. For thin films (h0< 500 A), the van der Waals dispersion forces acting on a unit volume located at the interface are derived from the potential 49' = ,~/67rh'3, [ 1] where A is an effective Hamaker constant and h' is the thickness of the film. For films of higher thicknesses, the retardation effect has to be included. Consequently, while investigating the stability of the micrometer- ~ ho EAR FILM z i000-2000 A AQUEOUS LAYER 4-8/,trn v~a:,'.c:c:zi.:c,~:.:~:c~;:~':~;~• MUCOUS LAYER,200-500 r EPITHELIUM FIG. 1. Structure of the precorneal tear film. FIG. 3. Definition sketch. Journal of Colloid and Interface Science, Vol. 106, No. 1, July 1985 16 SHARMA AND RUCKENSTEIN sized homogeneous tear film, the following retarded potential may be used: dp' = B/h '4, Selecting the initial film thickness, h0, and the free interface velocity of a film flowing down a flat vertical wall, v~0 = pgh2/2#, as the basic units of length and velocity, the time and pressure may be scaled by ho/v~o and pv~, respectively. In this way, one obtains the following nondimensional form of the Navier-Stokes equations in the cylindrical coordinates [2] where B = B~ - B I 2 and B o is the retarded Hamaker constant for the interactions between molecules of type i and j (1 refers to the tear film and 2 to the epithelium). OUr _1_ OUr 1)0 OVr , 0-7 + r-ff + _ 031)r 1)2 a-7- r op o, ±(o vr Or 1 1921)r 021)r ~ Or + R e \ o r 2 + ~ - ~ 1 20Vo 01.) r +-~z 2 + r Or r 2 ao vr~ ~5), [31 Vo 01)o + OVo + "1)rVo OVo + Vr OVo + -0-7 -fir r-ffff Vz-~z r = - 1 8p ~704~+ r O0 r O0 1 (a2Vo R-e l~Or 2 021)0 10Vo 20Vr + ~15 02vo -~+~ +'+ r Or r 2 O0 VO~ ) -~ [4] and O1)z + 1)rOVz + Vo OV~ + Vz OVz o-7 -fir r 2 Re Op Oz Od~ 1 [02Vz 1 02Vz 02Vz 10v~ nOz+ Re\~rZ + ~ + Oz----2+r Or]" [5] The continuity equation is Ovr vr 1 OVo Ov~ O--r- + --r + - r - ~ + ~ = 0. at [61 r : (ao/ho) : a, 13r = VO = Vz = 0. [7] The following three boundary conditions are to be satisfied at the tear-air interface, viz., at r = a + h(z, O, t): two conditions of zero shearing stresses, In Eqs. [3] to [6], vr, Vo, v=, and p are the three nondimensional velocity components and the nondimensional pressure, respectively. The coordinate system is shown in O (Oh~21 Fig. 3. The Reynolds number, Re, is defined pr._.zrOho_._+pr°[ r 1---\aO] I as pv~oho/~. Although the interaction potential 4~ is in general a function of the spatial Pr~ Oh Oh poz Oh Oh coordinates, it is only the potential at the r O00z r O0 poz-~z = 0 [8] film interface that is required within the framework of the approximation employed and h e r e (Appendix A). At the interface, the Oh Pro Oh Oh parameter • is given by B'/h~pv2zo and q~ = 1/ Prr OZ r Oz O0 h c. The quantity 4~ is related to the potential 4J = B'/h '~ by the relation 4~ = h~c#/B'. Clearly, B' = B and c = 4 apply to the + prz 1 kOzl l r O0 retarded case, and B' = .~/67r and c = 3 to Oh the nonretarded case. Here h is the nondi- P~z --~ = O, [91 mensional thickness of the film. On the anterior epithelium, the following and the relation between the pressure jump and the surface tension adhesion conditions are satisfied: -~21 [_(oh 21 Journalof ColloidandInterfaceScience,Vol. 106, No. 1, July 1985 TEAR FILM RUPTURE IPrr_.} Poo(Oh]2 [Oh~ 2 r2 \-~] 2p~oOh+2po~OhOh r O0 r O00z +Pzz~oz,] \-~](Oh] 2 __ S ~po ~75 1[1 r + - + (Ohm21 \-~zl J 1 02h [1 + (Oh] l - -r 2 -002 - 02h [ Oz 2 Here Po is the static nondimensional pressure of the nonviscous, semi-infinite medium (air), S is a nondimensional parameter defined as S = a/pho v 2 , and a is the interfacial tension. Finally, the description of the interface is made complete by adding the kinematic condition Oh Ot Vo Oh Oh Vr + r O0 + Vz Oz O, at r=a+h. [11] For a Newtonian fluid, the various components of the nondimensional pressure tensor are related to the velocity gradients by the following constitutive relations: P,r=-P 2 Ov~ + Re Or' poo = - p + ~ -gr + ' 20v~ Pz~ = - P + R e Oz ' Pro = ~ - ~ + Or ' 1 (Ovo l OVz] l (Ovr OVz] Prz = ~ 17 2 Oh Oh \-~z] [ + r 2 O00z O00z 1 Oh 2 1 (Oh~ 2 (0h]21-3/2 [lO] where the subscript b denotes the base case velocity and pressure distributions. Now in order to investigate the instability of the basic solution [13], which is caused by the dispersion forces and flow, we make use of a perturbation approach similar to that of Shlang and Sivashinsky (22). This approach has the advantage of yielding a nonlinear equation of evolution for the interface, from which the information about the linear stability of the interface may also be extracted. In what follows, we make use of the fact that S = ~/phov~ is a large parameter for thin liquid films (S ~ 108 for the tear film) and thus defining S = l/e 2, the estimate e ~ 1 holds. This may be referred to as the "largesurface tension approximation" combined with the "thin-film approximation." At this stage, the problem involves two time scales which are related to the deformation of the free surface at a given cross section and to the vertical wave motion, respectively. This complication may be circumvented by introducing a moving coordinate system and thus eliminating the time scale associated with the vertical wave motion z' = z + 7t, [12] [14] \ OZ + Or] " The domain of the solution is bounded by the layer a <~ r <~ a + h(z, O, t). where 2/is a nondimensional velocity, which is determined in what follows. The following space-time stretching transformations are now introduced The basic, steady, laminar flow solution to the set of Eqs. [3] to [12] is given by x = r - a, '/-)rb O0b = 0, 1 2 ~)zb = y(r -- a 2) --(1 +a)21n(r/a), h= 1 [13a] and Pb = PO + S/(1 + a), [ 13b] Z1 ~ 6Z', O~ = ar, y = aO, T = E2t. [15] The film thickness, velocities, and the pressure may thus be expanded around their base values as the following power series perturbation expansions JournalofColloidandInterfaceScience,Vol. 106, No. 1, July 1985 18 SHARMA AND RUCKENSTEIN h =- 1 + ~ Enhn(y, Z1, T), [16a] n=l T), [ 16b] Vo -- ~ e"Vo,(X, y, zl, T), [16c] l)r -~" ~ ~nVrn(X, y~ Z I , n=l n-I 1)z = Vzb(X , e) + E enl)zn(X, Y, Z1, T ) , [16d] n=l and P -- Pb(~) + Z ~"P,- The dispersion potential, q~, is, however, not expanded in power series, since we wish to retain the dispersion nonlinearities in the subsequent derivation. The derivation pursued here retains both the convective and the dispersion force contributions to the instability of the film and allows one to study the synergism between the two. Transforming to the coordinate system [14]-[15] and equating the like powers of e, one obtains a hierarchy of perturbed equations, which are solved successively for the deviation in the film thickness, hi. Details of these calculations are given in Appendix A. The nonlinear equation of evolution for the deviation in the film thickness, hi, is obtained, 2 Oh1 3a Oz t X V2hl + 4hi Ohi + 8Re 02hi + R e Oz' 15 OZ t2 3a 2 S 1/2 Ren V4hl - ~qZ V2q~ = 0, [17] where v 2= hi ~ exp(flt + ik'z' + il'O), [ 16e] n=l Ohl Ot available presently for various parameters and the breakup times to be predicted, an estimate of the breakup times obtained by linearizing Eq. [ 17] is deemed satisfactory for model discrimination. The linear stability of the interface is determined by examining the response of the interface to a Fourier component of an arbitrary traveling wave perturbation, viz., . This may be solved numerically to obtain an accurate information about the kinetics of rupture, for a given initial interfacial disturbance. We, however, do not undertake this calculation here, since such an endeavor demands that an equally accurate information be available for various physical parameters (most crucially, the Hamaker constant) and the amplitude of interracial perturbations. As only an order of magnitude information is Journal of Colloidand InterfaceScience, Vol. 106, No. 1, July 1985 [18] where k' and l' are the wavenumbers of the disturbances in the z' and 0 coordinates. Note that k' is dimensionless. Substituting [18] in Eq. [17] and discarding the nonlinear terms in Eq. [ 17], one arrives at the dispersion relation in terms of the original variables, _- 2 / 3\ k ao] 1 + [g8 hov2p +~ - a{(kho) 2 + (Iho)2} × {(kh0)2 + (lh0)a}, [19] where l = (/'/ao), k = (k'/h0), fl is the rate of instability parameter, and k and l are the wavenumbers of perturbations in the dimensional coordinates corresponding to z' and 0 coordinates, respectively. Any arbitrary perturbation imposed on the surface may be Fourier-decomposed into various wave-like components (Eq. [18]) with different wavenumbers. We seek to determine the wavenumber for which the growth rate, /3, is a maximum. The waves with these wavenumbers are selectively amplified at a faster rate, thus causing the eventual rupture of the film. The wavenumber of this fastest growing perturbation is thus obtained by maximizing the real part of fl with respect to (k 2 + /2), viz., from dfl/d(k 2 + l 2) = 0. [20] Denoting the wavenumbers of the most dangerous perturbations by km and Im and noting that for the parameters of tear film (Table I), (~) pho ~ 8 hoGp, ~- TEAR FILM RUPTURE 19 TABLE I The expression, V~o = ogh2/2#, has been used in the derivation of Eq. [23]. As is expected, our results without the van Property Average value Ref. der Waals interactions (B' = 0) recover the results of Benjamin (23), who considered the Maximum thickness of the stability of the flow of a viscous liquid film tear film 7.8 #m (2, 4, 5) Minimum thickness of the down a vertical plate. For a nonretarded tear film 4.0/~m (4) potential, viz., C = 3 and B' = A/67r and in Mucous layer thickness 200-500 A (2) the absence of flow, it reduces to the result Surface tension for the air-tear interface (a) 40 dyn/cm (5) derived by Ruckenstein and Jain (19) for the Density (o) of the tear film 1.0 g/cm 3 (5) rupture of thin films. It may be pointed out Viscosity (t~) of the tear that the interfacial instability of the film due film 0.035 g/cm-s (5) (t~a) for the mucous layer 1.0 dyn g/cmZ-s to the flow (which is reflected in the first S (dimensionless) 5.1 × 108 term of the denominator of Eq. [23]) does Re(dimensionless) 3.1 × 10-4 not lead to the film rupture, but results in a stable self-fluctuating wave or the formation of ripples on the film surface (22). The van one obtains der Waals dispersion forces on the other hand are capable of rupturing a thin film. cB' 2 [21] This happens because, although the surface free energy increases with the increasing surAll of the two-dimensional wave disturbances face area associated with the deformation of which satisfy Eq. [21] are now selectively the interface, the total free energy of the amplified at the fastest rate. A characteristic system decreases due to van der Waals diswavelength for these perturbations may be persion interactions. Williams and Davis (24) obtained the time defined by letting lm ~ 0 (one-dimensional disturbance) in which case of rupture of a nonflowing, thin film with a ~km = 27r/km. [22] nonretarded potential (C = 3, B' = .~/67r), by solving a nonlinear equation which they The above definition is chosen only for con- derived by a long-wavelength approximation. venience, since only an order of magnitude Their results indicate that the rupture times for the wavelength is desired. An alternate computed after retaining the nonlinearities choice such as km ~ lm may also be used to are no more than a factor of two lower than define the characteristic wavelength. We that derived from a linear theory, even for compute this characteristic wavelength to amplitudes of perturbations as large as oneshow that the wavelength of the fastest grow- third of the film thickness. It is in view of ing perturbation is smaller than the linear this, and of the fact that only an order of magnitude is available for the Hamaker condimension of the eye. Substituting the wavenumbers of the fastest stant, that Eq. [23] can be used to evaluate growing perturbations (Eq. [21]), in the real the breakup time, ~-m. part of 13, the maximum growth coefficient, /3m, may be obtained. Finally, an estimate R U P T U R E O F A H O M O G E N E O U S T E A R F I L M for the time of rupture is obtained from rm /3m~, which leads to the expression for the Equation [23] is now applied to the entire time of rupture: tear film considered as a homogeneous film of several micrometers in thickness. The shaded region in Fig. 4 depicts the feasible ~-m = 12#aho 1'1"2 + h~--~. ] . [23] ranges for the retarded Hamaker constant Physical Properties of the Tear Film c.,l Journal of Colloid and Interface Science, Vol. 106, No. I, July 1985 20 SHARMA AND RUCKENSTEIN a model of rupture predicts a continuous process of thinning prior to the rupture and thus cannot explain the observed instantaneous rupture or "beading-up" of tear film at a thickness of about 4 ~zm (4). Finally, it fails to recognize the key role played by the mucous layer in determining the stability characteristics of the tear film. This last point is amply supported by various experiments (8, 29) and clinical tests (12-17). Thus, although the instability of the air-tear interface due to the dispersion forces and flow exists, it is not sufficient to cause the observed rapid rupture. 10 -12 5x.lO-~3 r m =15 sec B 10-ts (ergs- cm) "rm = 14-0 sec 5x10 -14 10 -14 5x10 -15 10 -t5 5x10 - 1 2 5 4, 5 6 7 8 ho (/~m) FIG. 4. Feasible region for the tear-film rupture in the H a m a k e r constant-tear-film thickness parameter space. (B) and the tear-film thickness which are consistent with the observed breakup times. Although the retarded Hamaker constant has not been measured for the epithelium-tear fluid or the contact lens-tear fluid systems, various experiments for other substances indicate an upper bound of 10-19 erg-cm for B (25-28). Thus even assuming local micrometer-sized inhomogenities in the tear film and a rather large time for the tear breakup (-~ 140 s), the estimated Hamaker constant by this mechanism is about three orders of magnitude higher than that expected. For a more realistic tear-film thickness of 4 ~m and a breakup time of 50 s, the rupture of the tear film requires a Hamaker constant of about 3 × 10 -13 erg-cm, which is about six orders of magnitude higher than that reported. In other words, even assuming a retarded Hamaker constant of 10 -18 erg-cm and a micrometer-sized local inhomogenity in the tear film, Eq. [23] predicts the time of rupture of such a film to be about 3 years! In view of these considerations, it may be concluded that the retarded van der Waals interactions are not strong enough to break the micrometer-sized tear films within the observed times of rupture. In addition, such Journal of Colloid and Interface Science, Vol. 106, No. 1, July 1985 THE R U P T U R E OF U N D E R L Y I N G M U C O U S LAYER: A N E W M E C H A N I S M OF TEAR-FILM INSTABILITY It is well known that the presence of the mucous layer on the epithelium is absolutely necessary for the wetting of cornea (2, 1416, 30). These studies indicate that the epithelial mucus is capable of adsorbing onto the low-energy surfaces, converting them into hydrophilic surfaces. Even Teflon, which cannot be rendered hydrophilic by any commercially available surfactant, becomes water wettable when exposed to a layer of mucin. The experiments of Doughman et al. (17) and Padday (31) demonstrate the rupture of aqueous films of several hundred micrometers thick on hydrophobic surfaces such as Teflon, paraffin, and polyethylene. The hydrophobicity and water-wetting characteristics of a clean (without mucus) anterior epithelium are found to be similar (32). The tear film is seen to rupture spontaneously only after it thins from its initial thickness of 7 to about 4/zm. This is much smaller than the critical thickness of water over hydrophobic surfaces at which rupture occurs (17, 31) and much too large for the retarded dispersion forces to cause a rupture within observed BUT. A plausible mechanism which emerges from this discussion is that the initially mucus coated cornea converts its wettability characteristics within the observed breakup times, thus effectuating a spontaneous rupture of the aqueous layer. 21 TEAR FILM RUPTURE The rupture of the thin mucous layer, which coats the hydrophobic epithelium and provides a hydrophilic base for the aqueous tears, due to dispersion interactions indeed leads to such a hydrophilic-hydrophobic transition. The issue whether the time of rupture of the mucous layer is consistent with the observed range of BUT is addressed next. The thickness of the aqueous film is at least two orders of magnitude larger than the mucous layer, and hence a slow deformation of the air-aqueous interface may be neglected while investigating the stability of the mucous-aqueous interface. The superficial epithelial cell walls, which are coated by the mucous layer, have a complex structure of protrusions known as microvilli (2). The characteristic dimensions of these protrusions are, however, about an order of magnitude larger than the thickness of the mucous layer (2) and thus the mucous-epithelial interface may be considered to be planar while investigating the rupture of the mucous layer. In other words, we consider the instability of a thin (200-500 A) mucous layer sandwiched between epithelium and a semi-infinite viscous, aqueous phase (Fig. 1). Since the film is thin, the following potential is used for the dispersion forces: 49' = A/67rh '3. [24] The effective Hamaker constant for this geometry is given by [25] where A 0 is the Hamaker constant for the interaction between the molecules of type i and j (1 refers to the aqueous phase, 2 to the mucous layer, and 3 to the anterior epithelium). The aqueous layer is viscous and thus the boundary conditions [8]-[10], which are established for a nonviscous (air) bounding medium, do not hold rigorously. However, the ratio of the viscosities of the aqueous layer and the mucous layer is much smaller than unity. In this case, the effects of the viscosity of the bounding medium on the stability of the mucous layer may be shown to be insignificant (less than 1%) (Appendix = A I 2 -]- A 2 2 - A13 - A 2 3 , B). Thus, the entire formalism developed earlier holds and we now investigate the amplification o f fluctuations or the initial nonhomogeneities arising at the mucousaqueous interface. In addition, v~0 ~ 0 since the mucous layer is very thin and viscous. The time of rupture for such a layer is derived from Eq. [23] by making use of the potential [24]. Thus the substitutions C = 3, B' = A/6~-, and g = 0 (no-flow) in Eq. [23] give rm = 48~rZ~#h~/A2. [26] This result has been derived earlier by Ruckenstein and Jain (19) by making a lubrication approximation for a thin film. The discrepancy between the time of rupture as determined from the linear and nonlinear equations depends on the magnitude of the perturbations (24). Since no a priori information is available about the amplitude of perturbations at the mucous-aqueous interface, a factor of 2 may again be used to convert the times of rupture as computed by Eq. [26] to more realistic times of rupture computed from the solution of a nonlinear equation (24). The feasible range of Hamaker's constant for the rupture of the mucous film to occur may thus be obtained by rewriting Eq. [26] as A m . . . . in = ( 2 4 a # T r 2 h ~ / r m i . . . . . )1/2. [27] The breakup time estimates "rmin = 20 S and 7ma x = 50 S are used to find the range of the Hamaker constant which is consistent with the observed BUT. These are shown as the shaded region in Fig. 5. The wavelength of the most dangerous perturbation is Xm = ( 8 7 r 3 f f / d ) l / 2 h 2 , [28] which, for the parameters values falling in the shaded region of Fig. 5, is easily verified to be several orders of magnitude smaller than the dimensions of the eye. The Hamaker constant thus obtained for a mucous-film thickness of 200 to 500 A is in the range of 10 -14 to 4 × 1 0 -13 erg. This magnitude of the Hamaker constant is realistic (19, 20, 27) and thus the dispersion forces acting on the mucous layer are indeed Journal of Colloid and Interface Science, Vol. 106, No, 1, July 1985 22 SHARMA AND RUCKENSTEIN 10"12 8x10 "15 6x10 -13 4x10 -13 A 2x10-t3 Vm=2Osec (ergs) 13 10-t4 8xlO" 6xtO "14 4xlO -t4 2x10 -14 rrn = 5 0 sec i 0 -i4 8xfO -le 6x10 -l~ normal eye. At this point, the inherent hydrophobicity of the exposed epithelium is responsible for an instantaneous (fast compared to the previous step) rupture of the aqueous tear film. Due to its sequential nature and the fact that the model incorporates the structure of the tear film as made up of two distinct films, the proposed mechanism may be referred to as a "two-step, double-film" mechanism of tear-film rupture. DISCUSSION AND IMPLICATIONS 4x10 "15 In a normal eye, tear-film rupture does not occur because the interblink time is small compared to the breakup time and the blinkl O 1 5 ~ _ _ J 100 200 500 400 500 ing is instrumental in restoring the structural o ho(A) integrity of the mucous layer. This rupture and the consequent formation of dry spots FIG. 5. Feasible region for the mucous-filmrupture in the Hamaker constant-tear-film thickness parameter on cornea, however, are crucial for a mucusspace. deficient pathological eye, for which the rupture would occur rather frequently within the interblink period. For instance, assuming capable of rupturing it within a time period an effective Hamaker constant of 10 -14 erg, consistent with the observed breakup times. an abnormally thin ( ~ 100 ~ ) mucous layer With this understanding, the basic steps of would break within 4-5 s, thus exposing the the proposed mechanism may now be sumhydrophobic epithelium to the aqueous layer. marized: This may result in the extensive dewetting (i) The blinking movement exerts shear and desiccation of cornea. Indeed, in a clinical across the thin, aqueous film located between study (3), patients with chronic conjunctival the eyelid and the ocular globe and thus inflammation were observed to have an abredistributes and smoothens the mucous layer normally short breakup time ( ~ 3 to 5 s) of on the corneal epithelium. Immediately after the tear film, despite the normal amounts of its structural integrity is restored, this mucous aqueous tears. Conjunctival biopsy revealed layer is responsible for effectively masking a marked decrease in the population of conany lipid contamination as well as the basic junctival goblet cells which are responsible hydrophobic nature of the epithelium. At for the production of conjunctival mucous. this stage, the overlying aqueous film is com- The crucial role of the mucus in the tearplete and is slowly thinning due to the evap- film stability and thus in determination of oration and the osmotic transfer across the BUT, has also correlated well in other clinical findings. The deficiency of vitamin A has cornea. (ii) Upon its restoration, the small inhom- been observed to catalyze the disappearance ogeneities of the mucous layer begin to am- of conjunctival goblet cells and the conseplify at several places under the influence of quent appearance of the dry-eye syndromes the dispersion forces. If this process is not (2). Some other conditions such as ocular reversed by an intermediate blink, the grow- pemphigoid, Stevens-Johnson syndrome, ing interfacial perturbations cause the rupture trachoma, chemical burns, and certain forms of the mucous layer in about 15 to 50 s in a of drug-induced diseases also decrease the 2x10 -15 Journal of Colloid and Interface Science, Vol. 106, No. 1, July 1985 TEAR FILM RUPTURE goblet cell population, resulting in decreased BUT, even in the presence of normal tear volume (2, 33). An important consequence of the stability of the tear film is in the normal wearing and functionality of the contact lenses (12, 13, 34). A well-fitted contact lens rests on a continuous tear film sandwiched between the epithelium and the lens and is also coated with a continuous tear film on the outside. The stability of both the prelens (in-front-ofthe-lens) and the postlens (behind-the-lens) tear film is important for good contact lens wearing performance. Most of the silicone and hydrogel lenses being used presently are not completely water wettable. Thus, it is most likely that the conjunctival mucus soon coats the anterior surface of a lens placed in the eye and contributes to the wettability of the prelens film. The premature rupture of this mucous layer would result in the prelens film breakup and the accumulation of denaturated proteins contaminated with the lipids which are observed on the lens surface (13). This arises due to the high interracial tension between the aqueous layer and the exposed (without the mucous coating) prelens surface and results in a deposition of proteins and lipids because they tend to lower the interfacial tension at the aqueous-lens interface. The strong interactions between the lens surface and the proteins give rise to multiple site adsorption, resulting in less exposure of hydrophilic groups of the proteins to the aqueous tears and consequently, their denaturation. While the interfacial tension is somewhat lowered by this process, it may not be sufficient to stabilize the aqueous tear film due to the unavailability of enough hydrophilic groups which face the tear film. Indeed, some successful attempts have been made to correlate the length of deposit-free wear time with the tear-film breakup time (35), which show that a rapid deposit formation is associated with a short BUT. This is expected from the proposed mechanism, because both the BUT and the prelens film breakup time depend on the thickness of the mucous layer coating the epithelium and the 23 lens surface, respectively. The mucus deficiency would thus decrease both the BUT and the prelens breakup time and the latter would encourage deposit formation. The cause for a condition called "giant papillary conjunctiviries" has been linked with an immune-type reaction to antigenic, denaturated proteins accumulated on the lens surface (36). Thus the stabilization of the prelens tear film by coating the lens surface with mucus or mucus-like substances seems a logical step for the prevention of lens surface contamination. According to our mechanism, the stability of postlens tear film is determined by the structural integrity of the epithelial mucous layer. As the epithelial mucous layer ruptures, the postlens film would also break if the lens surface is not wettable and the adhesion of the contact lens to cornea can take place. This may result in excessive ocular discomfort, irritation, or even epithelial damage. In fact, a clinical study (12) shows that five of the six cases of corneal erosion observed occurred under the stationary lens, which results due to the premature rupture of postlens film. In view of this, wearing of contact lens in a normally mucus-deficient eye may result in these complications. In addition, in the presence of contact lens, even a marginally mucus-deficient eye may be affected by these conditions because of two reasons: (i) contact lenses adversely affect the lid-globe congruity (13) which is important for the formation and renewal of an evenly distributed mucous layer; (ii) contact lens wearers often become lazy blinkers and in addition the blinking becomes incomplete (13), resulting in incomplete restoration of mucous layer. Both of these factors may eventually contribute toward a poor lens tolerance and various conditions of a pathological eye, because they encourage a thinner than the normal mucous layer and hence reduce its time of rupture. The only objective clinical measurement which reflects the relative stability of the tear film is the measurement of BUT under properly controlled environmental conditions. The proposed mechanism actually correlates BUT Journal of Colloid and Interface Science, Vol. 106, No. 1, July 1985 24 SHARMA AND RUCKENSTEIN with the thickness of mucous layer and the mucous-aqueous interfacial tension. Tests such as the lack of mucus in inferior fornix and the absence of goblet cells as determined by conjunctival biopsy (3), may be readily used to diagnose the mucus deficiencies. Thus, in the absence of other factors such as lipid abnormalities, large aqueous-tear deficiency, impaired lid functions, and gross irregularities in the corneal epithelium, the replacement of mucus-like substances in the eye seems to be the logical starting point for the therapy of short BUT and its consequences. Finally, the model proposed does not account for the non-Newtonian rheology of the mucous layer, since its rheological properties have never been measured. It seems likely that a better characterization of both the Hamaker constant (for epithelium-tear and contact lens-tear systems) and rheological behavior of mucous material would result in improved knowledge of the kinetics of rupture. Thus there is a need for both in vivo and in vitro experiments on the rupture of "thin" mucous layers, for this indeed appears to play a central role in the pathological states associated with a dry eye. CONCLUSIONS We have derived a nonlinear evolution equation for the interface, a dispersion relation, and an estimate for the time of rupture of a thin film. The formalism developed incorporates the effects of van der Waals dispersion forces, the convective motion of the film and the two-dimensional perturbations arising at the interface. Application of this model to the tear film, considered as a several-micrometer-thick homogeneous film, fails to predict the observed kinetics of rupture. Based on many clinical and experimental observations about the role of mucus in determining the stability characteristics of the entire tear film, we propose a new mechanisms for the formation of dry spots on the cornea. Immediately after blinking, a thin (200-500 A) mucous layer is restored on the Journal of Colloid and Interface Science. VoL 106, No. 1, July 1985 corneal epithelium. The van der Waals dispersion forces acting on the mucous layer act to destabilize this layer, resulting in its eventual rupture. This, in turn, exposes the hydrophobic epithelium to the aqueous film and to the omnipresent lipids. It is at these sites that the aqueous tear film breaks rather rapidly causing the dewetting of the cornea. The time of rupture computed by this mechanism is in agreement with the clinically observed tear-film breakup times of about 15 to 50 s for a healthy eye. This rupture does not occur in a normal eye because the interblink time is small compared to the time of rupture of the tear film. The mechanism proposed is also consistent with other observed characteristics of the tear-film rupture, such as the almost spontaneous rupture of the tear film after it thins from an initial thickness of about 7 #m to a thickness of 4 um, an abnormal decrease of BUT in mucus-deficient eye and the adhesion of the contact lens to the cornea in mucusdeficient patients or lazy blinkers. The mechanism proposed thus have implications for the diagnosis and treatment of pathological eye, as well as in determining the contact lens tolerance. It also lends support to a number of clinical and experimental observations about the crucial role of mucus in determining the stability characteristics of the tear film. APPENDIX A Making use of the set of transformations [14], [15] and the perturbation expansions [16a]-[16e], the set of governing Eqs. [3] to [ 12] may be manipulated to yield a hierarchy of equations. Equating the terms of order ~ gives the first nontrivial set of equations and the corresponding boundary conditions as =0, 02VOl Ox 2 = 0 , 02Vzl Ox 2 0 [la] and O/)rl Ox - 0, [lb] TEAR FILM RUPTURE 25 ch = 1 + EChl+ ' ' ' , together with Vrl=Vol=Vzt=O at x=0 [lc] and Vrl ~ 0 7 OVzl Ovol _ 0 2hl + ~ = O, Ox [ld] and 1 OJ hi Pl -- V2hl x = 1. at [le] The solution to this first approximation is immediately obtained as Vrl = vo1= O and Vzl = - 2 h l X then we would have terms ~(O4)l/Oy) and rt(O4)l/OZl), instead of ~cl(o(o/Oy) and ncl(o(o/ OZl), respectively, in the second-order equations. Such an expansion would, however, destroy the dispersion-force nonlinearities which we wish to retain in the first-order equation of evolution for the interface. The boundary conditions for the second-order problem are at at x= x = 0, 1, OVo2 _ o, 2h2+Ovz2 -~x = 0 ' Ox [2a] (3' - 1) Oh~ 3zl and 1 OJ hi - V2hl -1- nqSlx=l nq5 -t- P l -- = r/q~(y, zl) + PI(Y, zl), [3d] Vr2 = V02 = 'Oz2 = 0 Vr2 = 0. [3e] The solutions to the set of Eqs. [3a]-[3e] are Vr2 = X 20hl OZl ' [2b] where [4a] 1 Vo2 = -- -~ Re x(x - 2) As shown by Eq. [2b], the further hydrodynamic calculations require only the interaction potential at the interface, viz. at x = 1. The second approximation is obtained by equating the terms of order e2, giving X I 1~-5 Ohl -~y + V2 ~Oh1 y 0hi(1 vz2=Reoz---~l X (x - 2) O~)r2 -- + Ox _ Op~ _ Oy 0q5 1 O'Ozl Ozl = 0, 2x3 I--~ Ohl 1R -'~ Oz~ ,e 2)hl - 2Xh2, Od [3b] OVzl 3' Ozz + 2(x - 1)l)r2 q- X ( X -- 2) OVz~ OZl OZ 1 O(]) ~ E - I -OZl ~- 1 02~)z2 Re 1 OVzl -Ox - 2 -~- -aRe _Ox _ [3c1 In the derivation of [3b] and [3c], we take ~ O(1), in order to retain the dispersion force nonlinearities in the lower-order equations. This point is better understood by noting that if the potential, qS, is expanded in a power series as rle-l(Od~/Oy) and , e l(O~9/OZl) ex -1 3.~121 ] [4c] and finally, 3' = 2. Opl [4b] [3a] 1 - 0 4) +sx ~2 Ohl az---~l+ and -- -5 +-x(x- 021)02 rte-l Ov + Re ~3x 4 gx ~/C1 O~yy] , [4d] Equation [4d] reflects the well-known fact that the wave velocity for a falling film on a flat vertical plane is twice the velocity of the free interface. Going to the terms of order E3, the kinematic condition gives the following equation of evolution for the interface: _Ohl _ + 2 Oh~ _ 2hl OT OZ 1 -]- ( Ohl OZ 1 l)zllx=l Oh2 Vr3[x= 1 _ _ _ OZl ')3hl -- G ~ = 0. Journal of Colloid and Interface Science, Vol. 106, No. [5] 1, July 1985 26 SHARMA AND RUCKENSTEIN The velocity component, Vr3, appearing in the above equation is determined by equating the terms of order ~3 in the continuity equation, to obtain Oi)r3 1 Ovo2 O'l)z2 OX "[- -~ l)r2 -[- ~ y "~ --OZ1 = 0. 2 Oh1 4hl Oh---!l+ 8 Re 02hi 3a Ozl Ozl 15 Oz2 Ohl aT Re5 + 3a---- xTZh1 + Re -~- ~74hl - Re~le-lxTZffa = O. [81 [6a] For a nondimensional potential of the form With the help of boundary condition vr3=O at x = 0 , 4, = 1/h c, [6b] 2(~x3_ )Oh1 -Ozl 1 2X2 a +-- 1 2 F × LCV2hl - E2h-l(1 + X Re(3x3-x2)(-.-~V2hl-}-V4hl-t-V2q~) -- Re (~0 x5 1X42) - -6 02hl Ohzx2" Ozl + 3 x30z---~l + Making use of the expressions [2a] and [7] for vz~ and Vr3, respectively, the kinematic condition [5] is manipulated to yield the following closed-form equation of evolution for the deviation in the interface from its equilibrium value: ~effkho [ (sinh( kho)cosh( kho) 2#h0 APPENDIX B In order to evaluate the effects of viscous aqueous layer on the stability of thin mucous film, we employ the results of Jain and Ruckenstein (37). Their final dispersion relation for the linear stability of a thin film on a solid support and bounded by a semiinfinite viscous fluid is kho) + R ( sinh 2( kho) - (kho)2)] L ~5--~¥-(~-~sh(kh-~+g-~i--~o~ where ~eff = ~ + (Odf/Oh')h=ho(1/k2) and R is the ratio of the viscosities of the aqueous and mucous layers. Since the mucous film is thin and the critical wavelength is orders of magnitude higher than the film thickness, Eq. [1] may be simplified by noting that sinh(kho) ~ oh11=l C)~ oh1 + OzlJ ] " [91 (Oy Equation [8] is the desired nonlinear equation of evolution which retains both the convective and the dispersion-forces nonlinearities and may be solved numerically for a given initial disturbance. [7] /3- (kho) 3 (kho) + - - These estimates simplify Eq. [1] to (kho)2 I _d /3 - 3#ho ] 2 ~ oz - ¢(kh°)2 (1 + The wavenumber of the fastest growing perturbation is the solution of dfl/dk = 0, viz., RoA 2 Journalof Colloidand InterfaceScience,Vol. (kho) < 0.3. 106, No. 1, July 1985 1 2R(kho)) [3] - 27rh----~km (kho) 2 for [1] 3' (3aRha)k3m + (2ah02)k~ 6 and cosh(kho) ~ 1 + - ch-(l+c) V2q~ = (02/Oy 2 + 02/0Z2)~ = the solution to Eq. [6a] is given by l)r3 = - - __ 7z~b in Eq. [8] is determined as [2] A 2~rh----~- 0, [4] which in the event of an inviscid semiinfinite fluid gives the well-known result TEAR FILM RUPTURE lim kern - R~O 4~rah 4 " [5] The other limit of infinitely viscous, semiinfinite fluid is easily shown to be lim k 2 - - R~oo 6~r~h4" [6] Thus the fastest growing wavenumber is bounded by 0-41 ( A _ _) ha ~ J 1/2 ~ < k m ~ <0"5 -- (~zl) __ 1/2 ho2 ~ / for all R E (0, ~ ) . For the tear film, R < 1, and its inclusion in Eq. [3] makes negligible contribution to the final result. REFERENCES 1. Holly, F. 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