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LABORATORY SCIENCE

Rheological behavior of commercial artificial tear solutions

Arshinoff, Steve MD; Hofmann, Ilan PhD; Nae, Hemi PhD

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Journal of Cataract & Refractive Surgery: May 2021 - Volume 47 - Issue 5 - p 649-654
doi: 10.1097/j.jcrs.0000000000000507
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The various components of artificial tears form a 3D structure that dictates the rheological properties of the fluid. As pointed out in the accompanying review in this issue, the measurement of viscosity at a single rate of shear or over a limited shear rate range does not provide adequate information about the changes in the tear film throughout the blink cycle.1 Conversely, measuring both the viscosity of the system and the normal stress difference, N1, which reflects elasticity, over a large range of shear rates may provide insight to the behavior of artificial tears from instillation, through the blink cycle and back to rest. We therefore analyzed the rheological behavior of various commercially available artificial tear solutions as a potential predictor of the most effective, longest lasting, and most comfortable solutions, and thereby as a potential tool to design future artificial tears.

Newtonian behavior is manifested by a constant viscosity as a function of shear rate, whereas non-Newtonian behavior exhibits 3 phases: the first phase is one of a higher viscosity Newtonian behaviors at very low shear rates, where viscosity η = η0 (zero-shear viscosity). This phase is present in the open eye, between blinking cycles, when the tear film is at rest. The high viscosity of the tears in this phase is desirable to resist drainage and tear-film break-up. The second phase, shear thinning, is seen with the acceleration of lid movement as the blink progresses across the cornea, applying increasing stress on the tear film, progressively reducing its viscosity to allow the tears to spread over the ocular surface and avoid damage to the epithelial surface. Ideally, the shear thinning of artificial tears should be significant to allow the tears to have low viscosity at high shear rates, similar to natural human tears. Finally, the third phase, which is a second Newtonian plateau at high shear rates, where viscosity, η = η, is the viscosity of the thin film at peak blink lid acceleration. Most artificial tears form a thicker film initially upon instillation, which becomes progressively thinner with repeated blink cycles, but remains, in many cases, thicker when compared with the normal tear film. The data discussed in our companion article this issue lead us to conclude that artificial tears with non-Newtonian and significant shear-thinning properties (typically composed with HA) will provide the patient with longer-lasting relief and comfort without excessive visual disturbances such as blurring.1 This article therefore presents the results of our study of the rheologic behavior of 20 different commercial artificial tears.

METHODS

The rheological behavior and normal stress difference, N1, of 20 commercially available eyedrops, sourced in the United Kingdom and Canada, were tested by an independent laboratory.

The list of commercial eyedrops tested is presented in Table 1. These artificial tear solutions contain various demulcents, emollients, rheological additives, thickeners, gelling agents, buffers, electrolytes, emulsifiers, preservatives, and other physically and chemically acting constituents. They were labeled according to their commercial names because generic identification may not be adequate to differentiate them as elaborated in the discussion below.

Rheological measurements were performed using a Malvern Gemini HR Nano Stress-Controlled Rheometer (Malvern Panalytical) equipped with a cone and plate or parallel plate geometries. Viscosity and normal stress difference, N1, were measured as a function of shear rate. Two stainless steel cones (4 degrees/20 mm and 1 degree/60 mm) and a 60-mm acrylic plate were used to optimize torque and axial force signals. All measurements were performed at 25°C with temperature control provided by a Peltier plate. Duplicate tests were performed on each sample, using fresh material for each test.

RESULTS

The 20 artificial tears tested were sorted into 3 different groups:

Group A, which included Systane Gel (Alcon), I-Drop MGD (I-Med Pharma Inc.), HydraSense gel (Bayer, Inc.), Vismed gel (TRB Chemedica International SA), I-Drop Pur Gel (I-Med Pharma Inc.), Hylo gel (URSAPHARM), Hylo (URSAPHARM), and Hylo Dual (URSAPHARM), exhibited significant shear-thinning behavior.

Group B, which included Lacrifresh 0.3% (Avizor), HydraSense, I-Drop Pur, Lacrifresh 0.2%, Optive Fusion (Allergan), and VisuXL (VISUfarma), exhibited moderate shear-thinning behavior.

Group C, which included TheraTears (Akorn), Vismed Multi (TRB), Thealoz Duo (Théa), Hyabak (Thea), Systane Balance (Alcon), and Thealoz (Thea), exhibited Newtonian behavior throughout the shear rate range.

Figure 1 is a log–log plot of the viscosity of group A members as a function of increasing shear rate. All artificial tears in group A exhibited a low shear rate Newtonian plateau, a significant shear-thinning behavior zone, and a second Newtonian plateau at high shear rates. From the various mathematical models describing the viscosity as a function of shear rate, we found that the best fit describing the non-Newtonian behavior for group A was the Cross model2–6:η=η+(η0η)/(1+Kγ.n)where η is the viscosity, η0 is the viscosity of the first Newtonian plateau at low shear rates, η is the viscosity of the second Newtonian plateau at high shear rates, γ˙ is the shear rate, and K and n are constants. A correlation coefficient, r, is usually calculated to express the best-fit correlation of the variables. Using a mathematical model enables the prediction of η0 and η and the shear thinning of the system over a large range of shear rates.

Table 1. - List of Commercial Eye Drops Tested.
Product name Manufacturer Key ingredients, % Others
HA CMC HPG CARBOMER
1 Hyabak Laboratoires Thea 0.15
2 HydraSense Bayer/TRB Chemedica 0.15
3 HydraSense Gel Bayer/TRB Chemedica 0.30
4 Hylo URSAPHARM 0.10
5 Hylo Dual URSAPHARM 0.05 Ectoine
6 Hylo Gel URSAPHARM 0.20
7 I-Drop MGD I-MED Pharma 0.20 PC, GLY
8 I-Drop Pur I-MED Pharma 0.18 GLY
9 I-Drop Pur Gel I-MED Pharma 0.30 GLY
10 Lacrifresh 0.20% Avizor 0.20 GLY PVP 90
11 Lacrifresh 0.30% Avizor 0.30 GLY PVP 90
12 Optive Fusion Allergan, Inc. 0.10 0.50 GLY
13 Systane Balance Alcon Laboratories, Inc. 0.4 PG, mineral oilPolyoxyl 40 stearate
14 Systane Gel Alcon Laboratories, Inc. Unknown PG 400, PPG
15 Thealoz Laboratoires Thea Trehalose
16 Thealoz Duo Laboratoires Thea 0.15 0.3 Trehalose
17 TheraTears Akorn Pharmaceutical 0.25 Trehalose
18 Vismed Gel TRB Chemedica 0.30
19 Vismed Multi TRB Chemedica 0.18
20 VisuXL VISUfarma 0.10a CoQ10, Vit E
CARBOMER = cross-linked acrylic polymer, GLY = glycerin; HA = hyaluronan; HPG = hydroxypropyl guar; PG = polyethylene glycol; PPG = polypropylene glycol; PC = phosphorylcholine; PVP = polyvinylpyrrolidone.
aCross-linked hyaluronan.

Figure 1.
Figure 1.:
Shear-thinning behavior—group A. All artificial tears included in group A clearly demonstrated low and high shear Newtonian plateaus separated by a zone of significant shear thinning, but some exhibited higher overall viscosity than others.

The extent of shear thinning may be described by a Relative Shear-Thinning Index (RSTI), RSTI = (η0 − η)/η0.

The various parameters for the Cross model and the extent of shear thinning of group A are summarized in Table 2. The correlation of the Cross model to the measured parameters is listed.

The artificial tears in group B exhibited moderate shear-thinning behavior and may be generally described by either the Cross model or the power law model. The power law model describes the stress (σ) as a function of shear rate7:σ=Kγ.nwhere K and n are constants. HydraSense and VisuXL seemed to be described better by the power law model rather than by the Cross model. Figure 2 is a log–log plot of the shear-thinning behavior of group B artificial tears as a function of increasing shear rate. The calculated parameters for the power law and Cross models of group B are shown in Table 3 along with the correlation coefficients of the models to the measured data and the RSTI.

Table 2. - Parameters for Cross Model and the Extent of Shear Thinning for Group A.
Sample Model η0 (mPas) η (mPas) K n r RSTI
Systane Gel Cross 1693 29.34 0.169 0.7762 0.999 0.9827
I-Drop MGD Cross 345.6 5.71 0.3386 0.4803 0.9996 0.9835
HydraSense Gel Cross 126.1 7.25 0.04775 0.7219 1.00 0.9425
Vismed Gel Cross 102.6 1.86 0.04065 0.6766 0.9984 0.9819
I-Drop Pur Gel Cross 99.38 6.08 0.03731 0.7184 1.00 0.9389
Hylo Gel Cross 130 14.87 0.02423 1.00 0.9474 0.8856
Hylo Cross 83.41 9.02 0.02594 0.8734 0.9999 0.8919
Hylo Dual Cross 21.45 4.16 0.01358 1.008 0.9998 0.8062
η0 = zero shear viscosity, the viscosity at the first, low-shear, Newtonian plateau, η = high shear viscosity at the second, high-shear, Newtonian plateau.
K and n = constants, r = correlation coefficient between the Cross model used and the measured data.
RSTI = relative shear thinning index, an indication of how much the measured fluid shear thins compared with its original viscosity [RSTI = (η0 − η)/η0].

Figure 2.
Figure 2.:
Shear-thinning behavior—group B. Group B artificial tears demonstrated rheological behavior similar to those in group A (Figure 1), but the rheological curves exhibited lower initial viscosity and moderate shear-thinning behavior.

The artificial tears in group C exhibited Newtonian behavior where the viscosity remains constant as the shear rate was increased. The artificial tears in group C did not exhibit shear thinning, and their zero-shear viscosity and high shear viscosity were the same across the shear rate range. Figure 3 shows the Newtonian behavior for group C. The Newtonian viscosity of the artificial tears in group C is shown in Table 4.

Table 3. - Parameters for the Power Law and the Cross Models and the Extent of Shear Thinning for Group B.
Sample Model η0 (mPas) η (mPas) K n r RSTI
Lacrifresh 0.3% Power law 0.0909 0.7923 0.9991
Lacrifresh® 0.3% Cross 44.15 15.03 0.003575 1.021 0.9999 0.6596
I-Drop Pur Power law 0.0486 0.7831 0.9993
I-Drop Pur Cross 21.72 9.64 0.001271 1.269 0.9983 0.5560
HydraSense Power law .0266 0.8924 0.9977
HydraSense Cross 26.79 13.91 NA NA 0.9937 0.4809
Lacrifresh 0.2% Power law 0.037 0.8404 0.9996
Lacrifresh 0.2% Cross 17.47 10.73 0.0001 1.545 0.9982 0.3858
Optive Fusion Power law 0.0283 0.8694 0.9997
Optive Fusion Cross 16.9 10.21 0.0026 1.08 0.9921 0.3959
VisuXL Power law 0.005 0.9102 0.9994
VisuXL Cross 3.88 2.99 0.0023 1.423 0.9241 0.2289
η0 = zero shear viscosity, the viscosity at the first, low-shear, Newtonian plateau, η = high shear viscosity at the second, high-shear, Newtonian plateau.
K and n = constants, r = correlation coefficient between the model used and the measured data.
RSTI = relative shear thinning index; an indication of how much the measured fluid shear thins compared with its original viscosity [RSTI = (η0 − η)/η0].

Figure 3.
Figure 3.:
Newtonian behavior—group C. All members of group C demonstrated no change in viscosity with increasing shear rate and therefore illustrate typical Newtonian behavior.

In addition to a significant shear-thinning effect of viscosity, the artificial tears in group A also exhibited an increase in the normal stress difference, N1, with increasing shear rate, indicative of elastic behavior. Figure 4 is a log–log plot illustrating the dependence of both viscosity and N1 as a function of increasing shear rates for I-Drop MGD. The viscosity curve here, in dark blue, is taken from Figure 3, and N1 is shown in red. The graph illustrates decreasing viscosity (shear thinning) and increasing elasticity (N1) with increasing shear rate of a typical group A artificial tear.

Table 4. - Viscosity of Members of Group C.
Sample Model η (mPas)
TheraTears Newtonian 12.30
VismedMulti Newtonian 7.32
Thealoz Duo Newtonian 2.48
Hyabak Newtonian 2.03
Systane Balance Newtonian 1.75
Thealoz Newtonian 1.00
η = viscosity, mPas = milliPascal seconds

Figure 4.
Figure 4.:
Viscosity and normal stress difference, N1, as a function of shear rate—I-Drop MGD. The non-Newtonian viscosity of group A member, I-Drop MGD, decreased with increasing shear rate (taken from figure 1). The normal stress difference, N1, of the same preparation was seen to increase with increasing shear rate, demonstrating its elasticity.

Figure 5 shows the increase in the normal stress difference, N1, as a function of increasing shear rate for the artificial tears in group A. This relationship may be described by a power law model: σ=AN1mwhere σ is the shear stress, N1 is the normal stress difference, and A and m are constants.

Figure 5.
Figure 5.:
Normal stress difference N1 as a function of shear rate—group A. N1, the normal stress difference is shown for group A artificial tears, indicating significant increase in N1 as shear rates increased.

Figure 6 shows the increase in N1 as a function of increasing shear rate for the artificial tears in group B. The increase in N1 with increasing shear rate for group B may be best described by a power law model. Group B exhibited much lower normal stress difference as compared with group A, indicating less elasticity of the solutions tested in this group.

Table 5. - Normal Stress Difference (N1) at 1000 1/s for Groups A and B.
Sample N1 at 1000 1/s (Pa) Group
Systane Gel 63.95 A
I-Drop MGD 31.4 A
Hylo Gel 19.2 A
I-Drop Pur Gel 17.8 A
Vismed Gel 16.0 A
Hylo 13.2 A
HydraSense Gel 9.6 A
Lacrifresh 0.3% 9.0 B
I-Drop Pur 5.3 B
Hylo Dual 4.4 A
Lacrifresh 0.2% 3.7 B
Optive Fusion 2.6 B
HydraSense 2.3 B
VisuXL 0 B

Figure 6.
Figure 6.:
Normal stress difference as a function of shear rate—group B. The artificial tears in group B demonstrate lower N1 with increasing shear compared with the artificial tears in group A. VisuXL is not shown as it did not ever go above baseline for N1. It can be seen in Figure 4 that VisuXL is almost Newtonian in behavior. We included it in group B because it demonstrated slight shear-thinning viscous behavior with increasing shear.

Members of group C exhibited Newtonian behavior and therefore do not exhibit any normal stress (N1 = 0), so no figure is shown.

Normal stress difference (N1) at the high shear rate of 1000 s−1 for groups A and B are shown in Table 5. We divided the groups based on their viscosity profiles. It can be seen that in some cases, using N1 as the primary factor for grouping would lead to different group assignment. For example, Hylo Dual would change from group A to group B. VisuXL, which was included in group B in the viscosity study, exhibited the lowest viscosity in that group. However, VisuXL did not exhibit any significant N1 throughout the shear rate range. This indicates that although there was some structure break up due to shear, it did not develop any elasticity with increasing shear rate and would be classed into group C if we based grouping on elasticity rather than shear-thinning behavior.

DISCUSSION

We studied 20 different artificial tear formulations and present a method to estimate their viscosity, η0, at the low shear rate Newtonian plateau, the extent of shear thinning, the viscosity, η, at the high shear rate Newtonian plateau, and the elasticity as reflected by the normal stress difference, N1. We used trade names rather than generic names because one company's formulation may contain a substance (e.g., HA) having the same generic name and concentration as in another manufacturer's formulation, but they may be significantly different rheologically from each other, as with ophthalmic viscosurgical devices, likely because of mass average molecular weight and its polydispersion differences. For example, Lacrifresh 0.3% and I-Drop Pur gel both have 0.3% hyaluronan and glycerin, but the η0 values for these two products are 44.15 mPas and 99.38 mPas, respectively. From this, it seems most likely that the chain length of the hyaluronan ingredient in I-Drop Pur gel is significantly longer than that for Lacrifresh 0.3% or that there is an interaction between the HA and other ingredients in the commercial products, emphasizing our point that studies on artificial tears and ophthalmic viscosurgical devices must use trade names to specify the solutions we are talking about.

The low shear rate viscosity, η0, for members of group A ranges from 1692 mPas to 21.72 mPas. This first Newtonian plateau is associated with the viscosity at rest, either after instillation or when the system recovers its viscosity after being sheared through the blink cycle. The high shear rate viscosity, η, for members of group A ranges from 29.34 mPas to 1.86 mPas. This second Newtonian plateau is associated with the peak acceleration of the blink.

The transformation of artificial tears from high viscosity at low shear rates to low viscosity at high shear rates (shear thinning) is a result of the alteration of the formulation's 3D structure because of the blinking cycle, as explained in our companion article this issue.1 The extent of this alteration may be evaluated by the RSTI illustrated in Table 2, https://links.lww.com/JRS/A273, and Table 3, https://links.lww.com/JRS/A274, which show that the RSTI for group A tears is much higher than that of group B members. The RSTI is a single numerical indicator of the shape of the viscosity shear-thinning behavior curves.

The elastic component of viscoelastic nature of fluids may be estimated by measuring the normal stress difference (N1) as a function of increasing shear rate. It is important that the macromolecular structure giving the tears their viscoelasticity can survive blink cycles, returning to their initial state, or else the tears will not perform their desired function for very long. Elasticity is required to facilitate recoil of the tear structure to the original. Measuring both the dependence of viscosity and normal force difference, N1, on the shear rate provides insight into the effect of the blink cycle on artificial tears.

Based on our measurements, group A members exhibit the best shear-thinning properties and normal stress differences of the tested artificial tears. However, Systane gel exhibits a much higher η than the other members of group A, which may lead to a thicker film at the peak acceleration of the blinking cycle possibly affecting coverage of the ocular surface, visual clarity, comfort, and residence time. If we accept that the blur threshold is 20–30 mPas (see companion article this issue), then all the products in group A with the possible exception of Systane gel fall below that upper limit of 30 mPas, for the blur threshold in their η measurements. This suggests that these products will provide comfortable relief from symptoms for the patients without excessive blurring.1,8 This difference from other group A members may account for individual patient preferences of different brands of artificial tears but remains to be confirmed clinically.

If we accept that the minimum shear viscosity of artificial tears necessary to maintain corneal coverage is 10 mPas (see companion article this issue) is correct, it could be argued that all the products tested in groups A and B, except for VisuXL, meet this minimum criterion.1 All the products in group C, except for TheraTears, fall below the 10 mPas threshold, thus possibly predicting that their precorneal residence time will be reduced. However, we believe that this assertion has a significant inherent weakness because it is based on a single viscosity measurement, probably in the mid-shear rate range. We know from our, and other similar, data that solutions exhibiting shear thinning will typically have decreasing viscosities with increasing shear rates during the blink cycle. Therefore, a single viscosity measurement may not provide a sufficiently reliable measurement to predict precorneal residence time and should be supplemented with rheological data over a broader range of shear rates before drawing such conclusions.

Based on all the above, in simplistic terms it may be concluded that non-Newtonian fluids with a steep shear-thinning slope should behave as better tear replacements than Newtonian solutions in patients not suffering from simple aqueous deficiency (volume deficiency) in their tears. Furthermore, it seems that greater N1, reflecting greater elasticity, contributes to the rapid recoil of the tear film to its preblink status after each blink, prolonging its duration of efficacy.

We studied the rheological behavior of tears, which we believe is critically important to their clinical behavior, but this study made no attempt to directly correlate our results with clinical results. Future studies should focus on the cyclical recovery of viscosity of artificial tears with successive blinks as they should regain their initial structure after each cycle. Such studies should include changes to the tear film throughout the blinking cycle. Studying the resistance to degradation of the macromolecular structure when exposed to the shear stress of blinking should help us design better tear replacements which will last longer. Clinical parameters, such as tear break-up time, tear-film thickness, tear-film osmolarity, corneal and conjunctival staining, artificial tear residence time, and patient comfort will help ascertain whether there is a good correlation between clinical measurements and the rheological profiles presented herein. If so, the rheological characterization of the dependence of viscosity and normal stress difference on the shear rate may be useful measurements in understanding the behavior of artificial tears and in the design of better formulations.

WHAT WAS KNOWN

  • Different artificial tear solutions exhibit either Newtonian or non-Newtonian rheological behaviors, with varying shear-thinning behaviors.

WHAT THIS PAPER ADDS

  • The viscous rheological profile and elastic normal stress difference, N1, of 20 commercially available artificial tear solutions permit their segregation into 3 categories based on their degree of non-Newtonian behavior.
  • Solutions with generically similar or identical contents may exhibit radically different rheological profiles.
  • Rheological assessment of artificial tears may provide a basis for predicting clinical parameters such as comfort and duration of efficacy, and can assist in the design of future artificial tear formulations.

REFERENCES

1. Arshinoff SA, Hofmann I, Nae H. The role of rheology in tears and artificial tears. J Cataract Refract Surg 2021;47:655–661
2. Bingham EC. Fluidity and Plasticity. New York, NY: McGraw-Hill; 1922
3. Cross MM. Rheology of non-Newtonian fluids: a new flow equation for pseudoplastic systems J Coll Sci 1965;20;417–437
4. Bird RB, Armstrong RC, Hassager O. Dynamics of Polymeric Liquids: Fluid Mechanics. Vol 1. New York, NY: John Wiley & Sons, Inc.; 1987
5. Barnes HA, Hutton JF, Walters K. An Introduction to Rheology. Amsterdam, The Netherlands: Elsevier Science BV; 1989
6. Nae HN Introduction to Rheology in Rheological Properties of Cosmetics and Toiletries. Laba D, ed. New York, NY: Marcel Dekker, Inc; 1993
7. Macosko CW. Rheology: Principles, Measurements and Applications. New York, NY: VCH Publishers; 1994
8. Aragona P, Simmons PA, Wang H, Wang T. Physicochemical properties of hyaluronic acid–based lubricant eye drops TVST 2019;8;1–8

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