Dry eye disease (DED) is a complex multifactorial disease that affects an increasing number of patients worldwide. Close to 30% of the population has experienced dry eye (DE) symptoms and presented with some signs of the disease during their lifetime. The significant heterogeneity in the medical background of patients with DEs and in their sensitivity to symptoms renders a clear understanding of DED complicated. It has become evident over the past few years that DED results from an impairment of the ocular surface homeostasis. Hence, a holistic treatment approach that concomitantly addresses the different mechanisms that result in the destabilization of the tear film (TF) and the ocular surface would be appropriate. The goal of the present review is to compile the different types of scientific evidence (from in silico modeling to clinical trials) that help explain the mechanism of action of cationic emulsion (CE)-based eye drop technology for the treatment of both the signs and the symptoms of DED. These CE-based artificial tear (AT) eye drops designed to mimic, from a functional point of view, a healthy TF contribute to the restoration of a healthy ocular surface environment and TF that leads to a better management of DE patients. The CE-based AT eye drops help restore the ocular surface homeostasis in patients who have unstable TF or no tears.

Biointerfaces and Biomaterials Laboratory Department of Optics and Spectroscopy School of Optometry Faculty of Physics St Kliment Ohridski University of Sofia Sofia Bulgaria

CHNO des Quinze Vingts IHU FOReSIGHT INSERM DGOS CIC 1423 Paris France and Sorbonne Universités INSERM CNRS Institut de la Vision Paris France

Department of Clinical Pharmacology Medical University of Vienna Vienna Austria

Department of Neuroscience Ophthalmology Unit University of Padua Padua Italy

J Heyrovsky Institute of Physical Chemistry Czech Academy of Sciences Prague Czech Republic

Novagali Innovation Center Santen SAS Evry France

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Baudouin C. The pathology of dry eye. Surv. Ophthalmol. 45 Suppl 2:S211–S220, 2001 PubMed

Bron A.J. The Biology of Eye Disease. 2010

Wei Y., and Asbell P.A.. The core mechanism of dry eye disease is inflammation. Eye Contact Lens. 40:248–256, 2014 PubMed PMC

Baudouin C. A new approach for better comprehension of diseases of the ocular surface. J. Fr. Ophtalmol. 30:239–246, 2007 PubMed

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., Uchino Y., Yokoi N., Zoukhri D., and Sullivan D.A.. TFOS DEWS II pathophysiology report. Ocul. Surf. 15:438–510, 2017 PubMed

Yokoi N., and Georgiev G.A.. Tear film–oriented diagnosis and tear film–oriented therapy for dry eye based on tear film dynamics TFOD and TFOT. Invest. Ophthalmol. Vis. Sci. 59:DES13–DES22, 2018 PubMed

Tsubota K., Yokoi N., Watanabe H., Dogru M., Kojima T., Yamada M., Kinoshita S., Kim H.M., Tchah H.W., Hyon J.Y., Yoon K.C., Seo K.Y., Sun X., Chen W., Liang L., Li M., Tong L., Hu F.R., Puangsricharern V., Lim-Bon-Siong R., Yong T.K., Liu Z., Shimazaki J., and Members of The Asia Dry Eye, Society. A new perspective on dry eye classification: proposal by the Asia Dry Eye Society. Eye Contact Lens. 46 Suppl 1:S2–S13, 2020 PubMed PMC

Lallemand F., Daull P., Benita S., Buggage R., and Garrigue J.S.. Successfully improving ocular drug delivery using the cationic nanoemulsion Novasorb. J. Drug Deliv. 2012:604204, 2012 PubMed PMC

Daull P., Lallemand F., and Garrigue J.S.. Benefits of cetalkonium chloride cationic oil-in-water nanoemulsions for topical ophthalmic drug delivery. J. Pharm. Pharmacol. 66:531–541, 2014 PubMed PMC

Robert P.-Y., Cochener B., Amrane M., Ismail D., Garrigue J.-S., Pisella P.-J., and 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. 26:546–555, 2016 PubMed

Leonardi A., Van Setten G., Amrane M., Ismail D., Garrigue J.-S., Figueiredo F.C., and 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. 26:287–296, 2016 PubMed

Hwang S.B., Park J.H., Kang S.S., Kang D.H., Lee J.H., Oh S.J., Lee J.Y., Kim J.Y., and Tchah H.. Protective effects of cyclosporine A emulsion versus cyclosporine A cationic emulsion against desiccation stress in human corneal epithelial cells. Cornea. 39:508–513, 2020 PubMed

Leonardi A., Doan S., Amrane M., Ismail D., Montero J., Németh J., Aragona P., and Bremond-Gignac D.. A randomized, controlled trial of cyclosporine A cationic emulsion in pediatric vernal keratoconjunctivitis: the VEKTIS Study. Ophthalmology. 126:671–681, 2019b PubMed

Willcox M.D.P., Argueso P., Georgiev G.A., Holopainen J.M., Laurie G.W., Millar T.J., Papas E.B., Rolland J.P., Schmidt T.A., Stahl U., Suarez T., Subbaraman L.N., Ucakhan O.O., and Jones L.. TFOS DEWS II tear film report. Ocul. Surf. 15:366–403, 2017 PubMed PMC

Georgiev G.A., Eftimov P., and Yokoi N.. Structure-function relationship of tear film lipid layer: a contemporary perspective. Exp. Eye Res. 163:17–28, 2017 PubMed

Yokoi N., Takehisa Y., and Kinoshita S.. Correlation of tear lipid layer interference patterns with the diagnosis and severity of dry eye. Am. J. Ophthalmol. 122:818–824, 1996 PubMed

Butovich I.A. Tear film lipids. Exp. Eye Res. 117:4–27, 2013 PubMed PMC

Lam S.M., Tong L., Duan X., Petznick A., Wenk M.R., and Shui G.. Extensive characterization of human tear fluid collected using different techniques unravels the presence of novel lipid amphiphiles. J. Lipid Res. 55:289–298, 2014 PubMed PMC

Brown S.H., Kunnen C.M., Duchoslav E., Dolla N.K., Kelso M.J., Papas E.B., Lazon de la Jara P., Willcox M.D., Blanksby S.J., and Mitchell T.W.. A comparison of patient matched meibum and tear lipidomes. Invest. Ophthalmol. Vis. Sci. 54:7417–7424, 2013 PubMed

Butovich I.A. Meibomian glands, meibum, and meibogenesis. Exp. Eye Res. 163:2–16, 2017 PubMed PMC

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

Cwiklik L. Tear film lipid layer: a molecular level view. Biochim. Biophys. Acta. 1858:2421–2430, 2016 PubMed

Wizert A., Iskander D.R., and Cwiklik L.. Organization of lipids in the tear film: a molecular-level view. PLoS One. 9:e92461, 2014 PubMed PMC

Lam S.M., Tong L., Yong S.S., Li B., Chaurasia S.S., Shui G., and Wenk M.R.. Meibum lipid composition in Asians with dry eye disease. PLoS One. 6:e24339, 2011 PubMed PMC

Nencheva Y., Olzynska A., Melcrova A., As Georgiev G., Daull P., Garrigue J.-S., and Cwiklik L.. Improving stability of tear film lipid layer via concerted action of two drug molecules: a biophysical view. Biophys. J. 114:104a, 2018 PubMed PMC

Georgiev G.A., Yokoi N., Nencheva Y., Peev N., and Daull P.. Surface chemistry interactions of cationorm with films by human meibum and tear film compounds. Int. J. Mol. Sci. 18:E1558, 2017 PubMed PMC

Georgiev G.A., Yokoi N., Ivanova S., Tonchev V., and Daull P.. Surface chemistry of the interactions of cationic nanoemulsions with human meibum films. ARVO poster 6188-A0091, Seattle, 2016

Cwiklik L., Melcrova A., Daull P., and Garrigue J.. Tear film break-up: a molecular level view by employing in silico approach. ARVO poster 472-A0397, Baltimore, 2017

Cwiklik L., Melcrova A., Daull P., and Garrigue J.S.. A proposed mechanism for tear film breakup: a molecular level view by employing in-silico approach. J. Model. Ophthalmol. 1:19–23, 2018

Wizert A., Iskander D.R., and Cwiklik L.. Interaction of lysozyme with a tear film lipid layer model: a molecular dynamics simulation study. Biochim. Biophys. Acta Biomembr. 1859:2289–2296, 2017 PubMed

Garhofer G., Werkmeister R., Messmer A., Dos Santos V., Stegmann H., Schmidl D., Fondi K., and Schmetterer L.. Short-term reproducibility of interferometry based tear film lipid layer thickness measurements in humans. ARVO poster 4398-A0237, Baltimore, 2017

Aranha dos Santos V., Schmetterer L., Stegmann H., Garhofer G., Schmidl D., and Werkmeister R.M.. Quantification of the tear film lipid layer using optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 59:271, 2018

Mochizuki H., Yamada M., Hatou S., and Tsubota K.. Turnover rate of tear-film lipid layer determined by fluorophotometry. Br. J. Ophthalmol. 93:1535–1538, 2009 PubMed PMC

Amrane M., Creuzot-Garcher C., Robert P.Y., Ismail D., Garrigue J.S., Pisella P.J., and 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. 37:589–598, 2014 PubMed

Leonardi A., Messmer E.M., Labetoulle M., Amrane M., Garrigue J.S., Ismail D., Sainz-de-la-Maza M., Figueiredo F.C., and Baudouin C.. Efficacy and safety of 0.1% ciclosporin A cationic emulsion in dry eye disease: a pooled analysis of two double-masked, randomised, vehicle-controlled phase III clinical studies. Br. J. Ophthalmol. 103:125–131, 2019a PubMed PMC

Baudouin C., Aragona P., Messmer E.M., Tomlinson A., Calonge M., Boboridis K.G., Akova Y.A., Geerling G., Labetoulle M., and Rolando M.. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul. Surf. 11:246–258, 2013 PubMed

Lemp M.A., Bron A.J., Baudouin C., Del Castillo J.M., Geffen D., Tauber J., Foulks G.N., Pepose J.S., and Sullivan B.D.. Tear osmolarity in the diagnosis and management of dry eye disease. Am. J. Ophthalmol. 151:792–798.e1, 2011 PubMed

Li D.Q., Chen Z., Song X.J., Luo L., and Pflugfelder S.C.. Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells. Invest. Ophthalmol. Vis. Sci. 45:4302–4311, 2004 PubMed

Luo L., Li D.Q., Corrales R.M., and Pflugfelder S.C.. Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface. Eye Contact Lens. 31:186–193, 2005 PubMed

Potvin R., Makari S., and Rapuano C.J.. Tear film osmolarity and dry eye disease: a review of the literature. Clin. Ophthalmol. 9:2039–2047, 2015 PubMed PMC

Craig J.P., Nelson J.D., Azar D.T., Belmonte C., Bron A.J., Chauhan S.K., de Paiva C.S., Gomes J.A.P., Hammitt K.M., Jones L., Nichols J.J., Nichols K.K., Novack G.D., Stapleton F.J., Willcox MDP, Wolffsohn J.S., and Sullivan D.A.. TFOS DEWS II report executive summary. Ocul. Surf. 15:802–812, 2017 PubMed

Suzuki M., Massingale M.L., Ye F., Godbold J., Elfassy T., Vallabhajosyula M., and Asbell P.A.. Tear osmolarity as a biomarker for dry eye disease severity. Invest. Ophthalmol. Vis. Sci. 51:4557–4561, 2010 PubMed

Gilbard J.P. Human tear film electrolyte concentrations in health and dry-eye disease. Int. Ophthalmol. Clin. 34:27–36, 1994 PubMed

Beck R., Stachs O., Koschmieder A., Mueller-Lierheim Wolfgang G.K., Peschel S., and van Setten G.-B.. Hyaluronic acid as an alternative to autologous human serum eye drops: initial clinical results with high-molecular-weight hyaluronic acid eye drops. Case Rep. Ophthalmol. 10:244–255, 2019 PubMed PMC

Holly F.J., and Lamberts D.W.. Effect of nonisotonic solutions on tear film osmolality. Invest. Ophthalmol. Vis. Sci. 20:236–245, 1981 PubMed

Corrales R.M., Luo L., Chang E.Y., and Pflugfelder S.C.. Effects of osmoprotectants on hyperosmolar stress in cultured human corneal epithelial cells. Cornea. 27:574–579, 2008 PubMed

Chen W., Zhang X., Li J., Wang Y., Chen Q., Hou C., and Garrett Q.. Efficacy of osmoprotectants on prevention and treatment of murine dry eye. Invest. Ophthalmol. Vis. Sci. 54:6287–6297, 2013 PubMed

van Setten G.B. Osmokinetics: a new dynamic concept in dry eye disease. J. Fr. Ophtalmol. 42:221–225, 2019 PubMed

Simmons P., Chang-Lin J.-E., Chung Q., Vehige J., and Welty D.. Effect of compatible solutes on transepithelial electrical resistance and uptake in primary rabbit corneal epithelial cell layers model. Invest. Ophthalmol. Vis. Sci. 48:428, 2007

Warcoin E., Clouzeau C., Roubeix C., Raveu A.L., Godefroy D., Riancho L., Baudouin C., and Brignole-Baudouin F.. Hyperosmolarity and benzalkonium chloride differently stimulate inflammatory markers in conjunctiva-derived epithelial cells in vitro. Ophthalmic Res. 58:40–48, 2017 PubMed

Bron A.J., Evans V.E., and Smith J.A.. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 22:640–650, 2003 PubMed

Daull P., Feraille L., Barabino S., Cimbolini N., Antonelli S., Mauro V., and Garrigue J.S.. Efficacy of a new topical cationic emulsion of cyclosporine A on dry eye clinical signs in an experimental mouse model of dry eye. Exp. Eye Res. 153:159–164, 2016 PubMed

Quentric Y., Daull P., Feraille L., Elena P.P., and Garrigue J.S.. Efficacy of a preservative-free cationic emulsion vehicle eye drop in a mouse model of dry eye. ARVO poster 422-D0131, Seattle, 2016

Liang H., Baudouin C., Daull P., Garrigue J.S., and Brignole-Baudouin F.. In vitro and in vivo evaluation of a preservative-free cationic emulsion of latanoprost in corneal wound healing models. Cornea. 31:1319–1329, 2012 PubMed

Daull P., Feraille L., Elena P.P., and Garrigue J.S.. Comparison of the anti-inflammatory effects of artificial tears in a rat model of corneal scraping. J. Ocul. Pharmacol. Ther. 32:109–118, 2016 PubMed PMC

Daull P., Guenin S., and Garrigue J.-S.. Mechanism of action of cationic emulsions in the management of ocular surface inflammation and wound healing. ARVO poster 5053-B0259, Seattle, 2016

Daull P., Guenin S., Hamon de Almeida V., and Garrigue J.S.. Anti-inflammatory activity of CKC-containing cationic emulsion eye drop vehicles. Mol. Vis. 24:459–470, 2018 PubMed PMC

Liang H., Brignole-Baudouin F., Rabinovich-Guilatt L., Mao Z., Riancho L., Faure M.O., Warnet J.M., Lambert G., and Baudouin C.. Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits. Mol. Vis. 14:204–216, 2008 PubMed PMC

Liang H., Baudouin C., Faure M.O., Lambert G., and Brignole-Baudouin F.. Comparison of the ocular tolerability of a latanoprost cationic emulsion versus conventional formulations of prostaglandins: an in vivo toxicity assay. Mol. Vis. 15:1690–1699, 2009 PubMed PMC

Liang H., Baudouin C., Daull P., Garrigue J.S., and Brignole-Baudouin F.. Ocular safety of cationic emulsion of cyclosporine in an in vitro corneal wound healing model and an acute in vivo rabbit model. Mol. Vis. 18:2195–2204, 2012 PubMed PMC

Daull P., Raymond E., Feraille L., and Garrigue J.S.. Safety and tolerability of overdosed artificial tears by abraded rabbit corneas. J. Ocul. Pharmacol. Ther. 34:670–676, 2018 PubMed PMC

Chen Z., Li Z., Basti S., Farley W.J., and Pflugfelder S.C.. Altered morphology and function of the lacrimal functional unit in protein kinase C{alpha} knockout mice. Invest. Ophthalmol. Vis. Sci. 51:5592–5600, 2010 PubMed PMC

Antal J.M., Divis L.T., Erzurum S.C., Wiedemann H.P., and Thomassen M.J.. Surfactant suppresses NF-kappa B activation in human monocytic cells. Am. J. Respir. Cell Mol. Biol. 14:374–379, 1996 PubMed

Thomassen M.J., Antal J.M., Divis L.T., and Wiedemann H.P.. Regulation of human alveolar macrophage inflammatory cytokines by tyloxapol: a component of the synthetic surfactant Exosurf. Clin. Immunol. Immunopathol. 77:201–205, 1995 PubMed

Kuo J.H., Lin Y.L., and Tseng J.W.. Interactions between U-937 human macrophages and tyloxapol. Colloids Surf. B Biointerfaces. 64:208–215, 2008 PubMed

Wolffsohn J.S., Arita R., Chalmers R., Djalilian A., Dogru M., Dumbleton K., Gupta P.K., Karpecki P., Lazreg S., Pult H., Sullivan B.D., Tomlinson A., Tong L., Villani E., Yoon K.C., Jones L., and Craig J.P.. TFOS DEWS II Diagnostic Methodology report. Ocul. Surf. 15:539–574, 2017 PubMed

Labetoulle M., Rolando M., Baudouin C., and van Setten G.. Patients' perception of DED and its relation with time to diagnosis and quality of life: an international and multilingual survey. Br. J. Ophthalmol. 101:1100–1105, 2017 PubMed

Tuisku I.S., Konttinen Y.T., Konttinen L.M., and Tervo T.M.. Alterations in corneal sensitivity and nerve morphology in patients with primary Sjogren's syndrome. Exp. Eye Res. 86:879–885, 2008 PubMed

Bron A.J., Yokoi N., Gafney E., and Tiffany J.M.. Predicted phenotypes of dry eye: proposed consequences of its natural history. Ocul. Surf. 7:78–92, 2009 PubMed

Benitez-Del-Castillo J.M., Acosta M.C., Wassfi M.A., Diaz-Valle D., Gegundez J.A., Fernandez C., and Garcia-Sanchez J.. Relation between corneal innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye. Invest. Ophthalmol. Vis. Sci. 48:173–181, 2007 PubMed

Xu K.P., Yagi Y., and Tsubota K.. Decrease in corneal sensitivity and change in tear function in dry eye. Cornea. 15:235–239, 1996 PubMed

Labbe A., Liang Q., Zhang Y., Wang Z., Xu L., Baudouin C., and Sun X.. Corneal nerve structure and function in patients with non-Sjogren dry eye: clinical correlations. Invest. Ophthalmol. Vis. Sci. 54:5144–5150, 2013 PubMed

Adatia F.A., Michaeli-Cohen A., Naor J., Caffery B., Bookman A., and Slomovic A.. Correlation between corneal sensitivity, subjective dry eye symptoms and corneal staining in Sjogren's syndrome. Can. J. Ophthalmol. 39:767–771, 2004 PubMed

Improving Stability of Tear Film Lipid Layer via Concerted Action of Two Drug Molecules: A Biophysical View