The tear film at the ocular surface is covered by a thin layer of lipids. This oily phase stabilizes the film by decreasing its surface tension and improving its viscoelastic properties. Clinically, destabilization and rupture of the tear film are related to dry eye disease and are accompanied by changes in the quality and quantity of tear film lipids. In dry eye, eye drops containing oil-in-water emulsions are used for the supplementation of lipids and surface-active components to the tear film. We explore in detail the biophysical aspects of interactions of specific surface-active compounds, cetalkonium chloride and poloxamer 188, which are present in oil-in-water emulsions, with tear lipids. The aim is to better understand the macroscopically observed eye drops-tear film interactions by rationalizing them at the molecular level. To this end, we employ a multi-scale approach combining experiments on human meibomian lipid extracts, measurements using synthetic lipid films, and in silico molecular dynamics simulations. By combining these methods, we demonstrate that the studied compounds specifically interact with the tear lipid film enhancing its structure, surfactant properties, and elasticity. The observed effects are cooperative and can be further modulated by material packing at the tear-air interface.

Department of Cytology and Embryology Faculty of Biology University of Sofia 1504 Sofia Bulgaria

iBB Institute for Bioengineering and Biosciences Complexo Interdisciplinar IST Universidade de Lisboa 1649 004 Lisbon Portugal

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences 16610 Prague Czech Republic

J Heyrovský Institute of Physical Chemistry Czech Academy of Sciences Dolejškova 3 18223 Prague Czech Republic

SANTEN SAS Novagali Innovation Center 1 rue Pierre Fontaine Bâtiment Genavenir 4 CEDEX F 91458 Evry France

Zobrazit více v PubMed

Willcox M.D., Argüeso P., Georgiev G.A., Holopainen J.M., Laurie G.W., Millar T.J., Papas E.B., Rolland J.P., Schmidt T.A., Stahl U. Tfos dews ii tear film report. Ocul. Surf. 2017;15:366–403. doi: 10.1016/j.jtos.2017.03.006. PubMed DOI PMC

Cwiklik L. Tear film lipid layer: A molecular level view. BBA-Biomembranes. 2016;1858:2421–2430. doi: 10.1016/j.bbamem.2016.02.020. PubMed DOI

Georgiev G.A., Eftimov P., Yokoi N. Structure-function relationship of tear film lipid layer: A contemporary perspective. Exp. Eye Res. 2017;163:17–28. doi: 10.1016/j.exer.2017.03.013. PubMed DOI

Baudouin C. The vicious circle in dry eye syndrome: A mechanistic approach. J. Fr. Ophtalmol. 2007;30:239–246. doi: 10.1016/S0181-5512(07)89584-2. PubMed DOI

Bron A.J., de Paiva C.S., Chauhan S.K., Bonini S., Gabison E.E., Jain S., Knop E., Markoulli M., Ogawa Y., Perez V. Tfos dews ii pathophysiology report. Ocul. Surf. 2017;15:438–510. doi: 10.1016/j.jtos.2017.05.011. PubMed DOI

Yokoi N., Takehisa Y., Kinoshita S. Correlation of tear lipid layer interference patterns with the diagnosis and severity of dry eye. Am. J. Ophthalmol. 1996;122:818–824. doi: 10.1016/S0002-9394(14)70378-2. PubMed DOI

Baudouin C., Messmer E.M., Aragona P., Geerling G., Akova Y.A., Benítez-del-Castillo J., Boboridis K.G., Merayo-Lloves J., Rolando M., Labetoulle M. Revisiting the vicious circle of dry eye disease: A focus on the pathophysiology of meibomian gland dysfunction. Br. J. Ophthalmol. 2016;100:300–306. doi: 10.1136/bjophthalmol-2015-307415. PubMed DOI PMC

Chan T.C.Y., Chow S.S.W., Wan K.H.N., Yuen H.K.L. Update on the association between dry eye disease and meibomian gland dysfunction. Hong Kong Med. J. 2019;25:38–47. doi: 10.12809/hkmj187331. PubMed DOI

Llorens-Quintana C., Rico-Del-Viejo L., Syga P., Madrid-Costa D., Iskander D.R. Meibomian gland morphology: The influence of structural variations on gland function and ocular surface parameters. Cornea. 2019;38:1506–1512. doi: 10.1097/ICO.0000000000002141. PubMed DOI

Garrigue J.-S., Amrane M., Faure M.-O., Holopainen J.M., Tong L. Relevance of lipid-based products in the management of dry eye disease. J. Ocul. Pharmacol. Ther. 2017;33:647–661. doi: 10.1089/jop.2017.0052. PubMed DOI PMC

Robert P.-Y., Cochener B., Amrane M., Ismail D., Garrigue J.-S., Pisella P.-J., Baudouin C. Efficacy and safety of a cationic emulsion in the treatment of moderate to severe dry eye disease: A randomized controlled study. Eur. J. Ophthalmol. 2016;26:546–555. doi: 10.5301/ejo.5000830. PubMed DOI

Daull P., Amrane M., Ismail D., Georgiev G., Cwiklik L., Baudouin C., Leonardi A., Garhofer G., Garrigue J.-S. Cationic emulsion-based artificial tears as a mimic of functional healthy tear film for restoration of ocular surface homeostasis in dry eye disease. J. Ocul. Pharmacol. Ther. 2020 doi: 10.1089/jop.2020.0011. PubMed DOI PMC

Amrane M., Creuzot-Garcher C., Robert P.-Y., Ismail D., Garrigue J.-S., Pisella P.-J., Baudouin C. Ocular tolerability and efficacy of a cationic emulsion in patients with mild to moderate dry eye disease–a randomised comparative study. J. Fr. Ophtalmol. 2014;37:589–598. doi: 10.1016/j.jfo.2014.05.001. PubMed DOI

Georgiev G.A., Yokoi N., Nencheva Y., Peev N., Daull P. Surface chemistry interactions of cationorm with films by human meibum and tear film compounds. Int. J. Mol. Sci. 2017;18:1558. doi: 10.3390/ijms18071558. PubMed DOI PMC

Tiffany J., Winter N., Bliss G. Tear film stability and tear surface tension. Curr. Eye Res. 1989;8:507–515. doi: 10.3109/02713688909000031. PubMed DOI

Nagyova B., Tiffany J.M. Components responsible for the surface tension of human tears. Curr. Eye Res. 1999;19:4–11. doi: 10.1076/ceyr.19.1.4.5341. PubMed DOI

Miller D. Measurement of the surface tension of tears. Arch. Ophthalmol. 1969;82:368–371. doi: 10.1001/archopht.1969.00990020370014. PubMed DOI

Zhao J., Wollmer P. Surface activity of tear fluid in normal subjects. Acta Ophthalmol. Scand. 1998;76:438–441. doi: 10.1034/j.1600-0420.1998.760409.x. PubMed DOI

Tiffany J. Tears in health and disease. Eye. 2003;17:923–926. doi: 10.1038/sj.eye.6700566. PubMed DOI

Zhao J., Wollmer P. Air pollutants and tear film stability–a method for experimental evaluation. Clin. Physiol. 2001;21:282–286. doi: 10.1046/j.1365-2281.2001.00329.x. PubMed DOI

Georgiev G.A., Yokoi N., Koev K., Kutsarova E., Ivanova S., Kyumurkov A., Jordanova A., Krastev R., Lalchev Z. Surface chemistry study of the interactions of benzalkonium chloride with films of meibum, corneal cells lipids, and whole tears. Investig. Ophthalmol. Vis. Sci. 2011;52:4645–4654. doi: 10.1167/iovs.10-6271. PubMed DOI

Georgiev G.A., Yokoi N., Ivanova S., Krastev R., Lalchev Z. Surface chemistry study of the interactions of pharmaceutical ingredients with human meibum films. Investig. Ophthalmol. Vis. Sci. 2012;53:4605–4615. doi: 10.1167/iovs.12-9907. PubMed DOI

Georgiev G.A., Yokoi N., Ivanova S., Dimitrov T., Andreev K., Krastev R., Lalchev Z. Surface chemistry study of the interactions of hyaluronic acid and benzalkonium chloride with meibomian and corneal cell lipids. Soft Matter. 2013;9:10841–10856. doi: 10.1039/c3sm51849c. DOI

Borchman D., Foulks G.N., Yappert M.C., Milliner S.E. Differences in human meibum lipid composition with meibomian gland dysfunction using nmr and principal component analysis. Investig. Ophthalmol. Vis. Sci. 2012;53:337–347. doi: 10.1167/iovs.11-8551. PubMed DOI PMC

Leiske D.L., Miller C.E., Rosenfeld L., Cerretani C., Ayzner A., Lin B., Meron M., Senchyna M., Ketelson H.A., Meadows D., et al. Molecular structure of interfacial human meibum films. Langmuir. 2012;28:11858–11865. doi: 10.1021/la301321r. PubMed DOI

Olżyńska A., Wizert A., Štefl M., Iskander D.R., Cwiklik L. Mixed polar-nonpolar lipid films as minimalistic models of tear film lipid layer: A langmuir trough and fluorescence microscopy study. BBA-Biomembranes. 2020:183300. PubMed

Wizert A., Iskander D.R., Cwiklik L. Organization of lipids in the tear film: A molecular-level view. PLoS ONE. 2014;9:e92461. doi: 10.1371/journal.pone.0092461. PubMed DOI PMC

Olżyńska A., Cwiklik L. Behavior of sphingomyelin and ceramide in a tear film lipid layer model. Ann. Anat. 2017;210:128–134. doi: 10.1016/j.aanat.2016.10.005. PubMed DOI

Wizert A., Iskander D.R., Cwiklik L. Interaction of lysozyme with a tear film lipid layer model: A molecular dynamics simulation study. BBA-Biomembranes. 2017;1859:2289–2296. doi: 10.1016/j.bbamem.2017.08.015. PubMed DOI

Bland H., Moilanen J., Ekholm F.S., Paananen R. Investigating the role of specific tear film lipids connected to dry eye syndrome: A study on o-acyl-ω-hydroxy-fatty acids and diesters. Langmuir. 2019;35:3545–3552. doi: 10.1021/acs.langmuir.8b04182. PubMed DOI

Paananen R.O., Viitaja T., Olżyńska A., Ekholm F.S., Moilanen J., Cwiklik L. Interactions of polar lipids with cholesteryl ester multilayers elucidate tear film lipid layer structure. Ocul. Surf. 2020;18:545–553. doi: 10.1016/j.jtos.2020.06.001. PubMed DOI

Humphrey W., Dalke A., Schulten K. Vmd: Visual molecular dynamics. J. Mol. Graph. 1996;14:33–38. doi: 10.1016/0263-7855(96)00018-5. PubMed DOI

Skrzypiec M., Georgiev G.A., Rojewska M., Prochaska K. Interaction of polyhedral oligomeric silsesquioxanes and dipalmitoylphosphatidylcholine at the air/water interface: Thermodynamic and rheological study. BBA-Biomembranes. 2017;1859:1838–1850. doi: 10.1016/j.bbamem.2017.06.012. PubMed DOI

Roylance D. Engineering Viscoelasticity. Volume 2139. Department of Materials Science and Engineering–Massachusetts Institute of Technology; Cambridge, MA, USA: 2001. pp. 1–37.

Rantamaki A.H., Seppanen-Laakso T., Oresic M., Jauhiainen M., Holopainen J.M. Human tear fluid lipidome: From composition to function. PLoS ONE. 2011;6:e19553. doi: 10.1371/journal.pone.0019553. PubMed DOI PMC

Hezaveh S., Samanta S., De Nicola A., Milano G., Roccatano D. Understanding the interaction of block copolymers with dmpc lipid bilayer using coarse-grained molecular dynamics simulations. J. Phys. Chem. B. 2012;116:14333–14345. doi: 10.1021/jp306565e. PubMed DOI

Abraham M.J., Murtola T., Schulz R., Páll S., Smith J.C., Hess B., Lindahl E. Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1:19–25. doi: 10.1016/j.softx.2015.06.001. DOI

Leonardi A., Van Setten G., Amrane M., Ismail D., Garrigue J.S., Figueiredo F.C., Baudouin C. Efficacy and safety of 0.1% cyclosporine a cationic emulsion in the treatment of severe dry eye disease: A multicenter randomized trial. Eur. J. Ophthalmol. 2016;26:287–296. doi: 10.5301/ejo.5000779. PubMed DOI

Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease