Cationic nanoemulsion vs. 0.15% sodium hyaluronate artificial tears in the healing process following modern surface keratorefractive surgery

Abstract

Purpose

The aim of this study was to investigate the influence of artificial tears containing either cationic nanoemulsion (CCN) or sodium hyaluronate artificial tears (SH) on early postoperative healing after modern surface refractive surgery.

Materials and Methods

In this multicenter, prospective, double-masked, parallel-group (1:1), comparative study, 129 patients (n = 255 eyes) were randomized to receive CCN (n = 128) or SH (n = 127) as an adjuvant treatment after either transepithelial photorefractive keratectomy (transPRK) or Epi-Bowman keratectomy (EBK). The patients’ perspectives were gathered using the Ocular Surface Disease Index (OSDI) questionnaire, and uncorrected (UCVA), and corrected (BCVA) visual acuity were assessed before and one week and one month after the procedure. In addition, corneal epithelization and subjective assessment of visual blur and eye irritation on drop instillation were assessed at one week postoperatively.

Results

No statistically significant differences were found between two groups in age, spherical equivalent refractive error, UCVA, BCVA or OSDI scores before the procedure. There was also no difference between groups in UCVA one week and one month after the procedure. However, statistically significantly lower OSDI scores were found one week and one month after the procedure in the CCN group. Moreover, blurred vision after use of the eye drops was observed less frequently in the CCN group than in the SH group.

Conclusions

The CCN and SH groups had similar postoperative UCVA. However the significantly lower OSDI scores and less frequently blurred vision after application of the eye drops in the CCN group suggest better subjective outcomes in this group.

Keywords

Surface refractive surgery myopia myopic astigmatism cationic nanoemulsion sodium hyaluronate ocular surface disease index

Introduction

Surface keratorefractive surgery with the use of excimer laser was introduced more than 30 years ago, and remains widely used.¹ Studies have demonstrated the efficacy and safety of different kinds of surface refractive surgery including photorefractive keratectomy (PRK), laser-assisted subepithelial keratectomy (LASEK), transepithelial photorefractive keratectomy (transPRK) or EpiBowman blunt keratectomy (EBK).^2–5 Modern surface ablation techniques such as transPRK and EBK are associated with rapid healing and visual recovery and are often preferred over LASIK in cases of thin cornea due to their lower risk of corneal ectasia.⁶ In the transPRK technique, excimer laser devices are used to ablate the epithelium and then perform refractive ablation of the underlying stroma.⁷ During the EBK procedure, mechanical epithelial delamination is performed using an Epi-Clear epikeratome, a single-use blunt device.

Unfortunately, every type of refractive surgery decreases goblet cell populations, damages corneal nerves resulting in loss of corneal sensation, and induces ocular surface inflammation.^8,9 This leads to reduced tear secretion, blinking and ocular surface moisture.¹⁰ These changes contribute to the development of dry eye syndrome (DES), the occurrence of which is estimated at approximately 30% among patients after the LASIK procedure and 8.9%–34.8% after PRK.^11,12 Moreover, various studies have shown that preexisting DES may lead to severe post-operative DES.^13–17

There is no gold standard treatment for this condition. First-line non-invasive treatment usually includes topical application of artificial tears (AT), which hydrate and lubricate the corneal surface. The most common AT contain 0.15% sodium hyaluronate (SH). Numerous studies have demonstrated their efficacy indicating properties of water retention, enhancement of corneal wound healing, and viscoelasticity.¹⁸ In addition to the standard AT, autologous serum eye drops are effective in postoperative DES treatment.¹⁹ A recently developed preservative free AT known as Cationorm® contains cationic nanoemulsion with nonpolar and polar lipids (i.e., a surfactant) has been found to stabilize the impaired lipid layer of the tear film.^20,21 Previous studies have shown its safety and efficiency in DES treatment.^22,23 Postoperative DES is considered a ubiquitous issue which impedes the healing process and reduces patients’ satisfaction. Due to the lack of clear guidelines for AT selection, it is challenging to find the best option which not only relieves symptoms for patients with postoperative DES but also supports the postoperative healing process.

This study is the first attempt to compare the efficacy of AT containing cationic nanoemulsion (CCN) with those containing SH in the management of DES and in promoting the corneal healing process after modern surface keratorefractive surgery.

Patients and methods

This is a two-center, prospective, randomized, double-masked, parallel-group (1:1), comparative study. Patients scheduled for surface refractive surgery were randomized to receive reference AT containing 0.15% sodium hyaluronate (Biolan, Penta Arzneimittel, Stulln Germany) or cationic nanoemulsion (Cationorm, Santen, Osaka, Japan). Refractive surgery procedures were performed by surgeons experienced in use of the excimer laser Amaris 750 (Schwind, Kleinostheim, Germany) or MEL 80 (Zeiss, Oberkochen, Germany). One hundred and twenty-nine patients (255 eyes) with myopia and myopic astigmatism with mean spherical equivalent (EQS) of −4.0 ± 2.26 Diopters (D) scheduled either for transPRK or EBK were randomized to receive CCN (64 patients, 128 eyes) or SH (65 patients, 127 eyes). Patients’ demographic and baseline preoperative characteristics are shown in Table 1. Moreover, the both groups consists of patients with similar mean EQS, which results in comparable depths of the ablation: 75.18 ± 41.50 μm in CCN group and 75.71 ± 41.73 μm in SH group (p > 0.05). The optic zone treated was also similar between groups: 6.99 ± 0.46 mm in CCN group and 7.16 ± 0.44 mm in SH group (p > 0.05).²⁴ Furthermore, average keratometry was 7.49 ± 0.24 mm in CCN group, 7.46 ± 0.27 mm in SH group, and there was no statistically significant difference between groups (p > 0.05).

Table 1.

Demographic and other baseline characteristics.

	Overall	SH Group	CCN Group	P-value
Patients/eyes [N]	129/255	65/127	64/128
Mean Age [years] (range)	33 (21–56)	34 (22–53)	32 (21–56)	0.315
Mean Sph. [D] (SD)	−3.55 (2.25)	−3.58 (2.53)	−3.53 (1.95)	0.891
Mean Cyl. [D] (SD)	−0.89 (1.13)	−0.89 (1.17)	−0.88 (1.09)	0.855
Mean EQS [D] (SD)	−4.00 (2.26)	−4.02 (2.49)	−3.97 (2.02)	0.974
Mean UCVA[logMAR] (SD)	0.77 (0.77)	0.77 (0.74)	0.74 (0.82)	0.391
Mean BCVA [logMAR] (SD)	−0.06 (0.6)	−0.06 (0.62)	−0.06 (0.59)	0.9
Mean OSDI (SD)	4.73 (11.00)	4.67 (8.35)	4.78 (13.14)	0.268

Inclusion criteria were: myopia, myopic astigmatism, age > 21 years, stable refractive error for more than 2 years, and approval to undergo corneal excimer laser refractive surgery. Exclusion criteria were as follows: hyperopia, ocular trauma or previous intraocular surgery, active inflammatory eye disease, monocular best corrected visual acuity (BCVA) poorer than 0.3logMAR before surgery, and significant ophthalmic pathology other than mild DES.

Preoperative examination

Medical history and medication use was obtained from each patient preoperatively. All patients underwent standard ocular examination before the procedure including manifest refraction, uncorrected visual acuity (UCVA) and BCVA, slit-lamp examination, measurement of intraocular pressure (IOP), fundus examination after pupil dilation, and assessment of DES severity using the Ocular Surface Disease Index questionnaire (OSDI).²⁵ They were then randomly assigned to the CCN or SH group.

Postoperative regimen

All eyes underwent uneventful transepithelial photorefractive keratectomy (transPRK) or Epi-Bowman keratectomy (EBK) with use of the excimer laser Amaris 750 or MEL 80. After sequential binocular surgery, a bandage contact lens was applied (Acuvue Oasis, Johnson &Johnson, USA) for 7 days. The postoperative regimen included 0.3% tobramycin drops twice daily, 0.1%, diclofenac drops and dexamethasone drops once per day for the first week in addition to masked AT every two hours. In the second week dexamethasone drops were applied three times per day, diclofenac drops once per day and masked AT five times per day. During the third and fourth weeks 0.1% fluorometholone and 0.3% tobramycin were applied twice per day and masked AT five times per day.

Postoperative examinations

Postoperative examinations were scheduled at one day, one week and one month after surgery. Every examination included manifest refraction, BCVA, UCVA, slit-lamp examination, measurement of IOP and completion of the OSDI questionnaire. In addition, at the week one examination, the completeness of corneal epithelization was assessed during slit-lamp examination and described as “large”, when it covered >2 mm², “small” when it covered up to 1 mm², and “none” in cases with completed epithelization. A subjective questionnaire on blurred vision and eye irritation after eye drop application was also completed during the one week examination. All procedures performed in this study involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. A signed declaration of informed consent to participate in this study was collected from all included patients.

Statistical analysis

The summary statistics are presented as mean ± standard deviation (SD) or as a median and range. The Shapiro‒Wilk test was used to test the normality of data distribution. Differences between continuous variables were analyzed using the Wilcoxon test for demographic data and by the clustered Wilcoxon rank sum test for ocular data. Differences between categorical variables were tested using the chi-square or Fisher exact test for independence. The results were considered statistically significant at p-value < 0.05. The statistical analysis was performed using R-software version 3.6.2.

Results

No statistically significant differences were found between the CCN and SH groups in preoperative UCVA (p = 0.391), BCVA (p = 0.9), OSDI score (p = 0.268), EQS (0.974), or age (p = 0.315) (Table 1).

At 7days after the procedure the prevalence of severe DES (OSDI >32) in SH and CCN groups was 92.1% and 73.4%, respectively (p < 0.001). At 30 days after the procedure, the overall prevalence of severe DES was 9.4%, while in SH and CCN groups it was at 15.7% and 3.1%, respectively (p < 0.001; Table 2).

Table 2.

OSDI questionnaire scores in groups.

OSDI score		Overall	SH Group	CCN Group
OSDI score		N (%)	N (%)	N (%)	P-value
		Day7
	0–12	6 (2.4)	2 (1.6)	4 (3.1)	<0.001
	13–22	16 (6.3)	0 (0)	16 (12.5)
	23–32	22 (8.6)	8 (6.3)	14 (10.9)
	>32	211 (82.7)	117 (92.1)	94 (73.4)
		Day30
	0–12	173 (67.8)	67 (52.8)	106 (82.8)	<0.001
	13–22	40 (15.7)	38 (29.9)	2 (1.6)
	23–32	18 (7.1)	2 (1.6)	16 (12.5)
	>32	24 (9.4)	20 (15.7)	4 (3.1)

No significant difference between the two groups was found in UCVA, BCVA or completeness of corneal epithelization at 7 and 30 days after surface refractive surgery (Table 3). However, significantly lower OSDI questionnaire scores were found at 7 (p = 0.016) and 30 days (p < 0.001) after the procedure in the CCN group than the SH group (Figure 1, Table 3)

Figure 1.

Boxplots showing OSDI scores in both groups before, one week and a month after the procedure (p = 0.016 on the 7th day; p < 0.001 at 30th day by the Wilcoxon test).

Table 3.

Analysis of UCVA, BCVA, OSDI values, and corneal erosion in studied groups, by time point.

		Overall	SH Group	CCN Group
		N = 255	N = 127	N = 128	P-value
Day 7
Mean UCVA[logMAR] (SD)		0.15 (0.51)	0.17 (0.48)	0.13 (0.55)	0.402
Mean OSDI(SD)		44.89 (17.12)	47.36 (14.15)	42.45 (19.38)	0.016
Corneal erosion (%)	None	229 (89.8)	112 (88.2)	117 (91.4)	0.384
	Small	21 (8.2)	11 (8.7)	10 (7.8)
	Large	5 (2)	4 (3.1)	1 (0.8)
Day 30
Mean UCVA [logMAR] (SD)		0.06 (0.60)	0.07 (0.62)	0.05 (0.57)	0.958
Mean BCVA [logMAR] (SD)		−0.02 (0.72)	−0.01 (0.72)	−0.03 (0.72)	0.745
Mean OSDI (SD)		13.86 (12.56)	16.92 (15.08)	10.83 (8.44)	<0.001

While no significant differences in eye irritation were found between the groups, the occurrence of blurred vision after eye drop instillation was significantly lower in the CCN group than the SH group (p = 0.048) (Table 4).

Table 4.

Prevalence of eye irritation and blurred vision after eye drop instillation in studied groups.

	OverallN (%)	SH GroupN (%)	CCN GroupN (%)	P-value
Eye irritation after eye drop instillation
None	214 (83.9)	105 (82.7)	109 (85.2)	0.613
Minor	41 (16.1)	22 (17.3)	19 (14.8)	0.613
Blurred vision after eye drop instillation
None	211 (82.7)	99 (78)	112 (87.5)	0.048
Minor	44 (17.3)	28 (22)	16 (12.5)	0.048

Discussion

Patients may experience DES soon after keratorefractive surgery, and this can persist for some time postoperatively. DES is a complex disease of the ocular surface and tears resulting in discomfort, impaired vision and potential damage to the cornea, accompanied by inflammation.²⁶ It is characterized by reduced tear production and increased evaporation of the tear film.²⁷ Efforts to understand the mechanism underlying DES have contributed to development of new AT. Novel types of AT, including CCN are designed to address the above issues and to relieve patients’ symptoms. CCN contains preservative-free cationic nanoemulsion, which is composed of cetalkonium chloride, poloxamer 188, glycerol trishydrochloride, and tyloxapol. It also includes Novasorb, an aqueous emulsion which is produced by cationic nanoemulsion technology and contains positively-charged lipid nanodroplets which cause attraction to the negatively-charged ocular surface^20,28 and are responsible for its sustained presence on the ocular surface with prolonged relief of symptoms. The primary aim of the present study was to compare the effect of AT containing cationic nanoemulsion with well-established lubricant 0.15% hyaluronic sodium drops in terms of DES symptoms and ocular surface healing after keratorefractive surgery. Previous studies have shown the negative impact of keratorefractive surgeon neural feedback due to damaged sensory corneal nerves resulting in reduced tear secretion, blinking rate and therefore DES, and impeded healing.^29–32 A study by Nejima et al. revealed decreased epithelial barrier function, reduced tear film stability, and lower tear secretion in patients’ eyes after PRK and LASIK.³³ Prevalence of postkeratorefractive surgery DES varies from 8.9% to 34.8%, depending on the surgical approach,^11,12 patients’ age, gender, and preoperative contact lens wear.³² Establishment of an effective treatment for post-keratorefractive surgery DES is crucial, due in part to a high proportion of patients with a history of contact lens wear (44.9% according to a study by Li et al.) who are predisposed to this condition.³⁴ In addition, the high postoperative DES prevalence, its impact on the healing process, and a lack of accurate predictive tests illustrate the need to develop an effective DES treatment strategy and to find the optimal AT to form an integral part of the postoperative regimen. Previous studies have demonstrated the efficacy of a range of commercially available ATs containing hyaluronic acid, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyethylene glycol, propylene glycol, glycerine or polysorbate.^35,36

A recent meta-analysis on AT efficacy found that preserved and preservative-free forms were statistically similar.³⁷ Preservative-free ATs were used in the present study. Clinical benefits of these include faster DES symptom improvement, while side effects caused by preserved ATs are well documented.^38–40 Preservative-free drops are relatively well tolerated in glaucoma treatment³⁹ while immediate deleterious effects of preserved latanoprost (with 0.02% benzalkonium chloride) on the corneal epithelium have been reported.⁴¹

Another meta-analysis including studies which compared 0.1% to 0.4% preparations of SH-based ATs was not able to distinguish between these due to heterogeneity between studies.⁴² In clinical practice higher concentrations of SH are used in more severe DES. In the present comparative study we used 0.15% SH as the comparator due to its demonstrated effectiveness and safety at this concentration.^43–45

González-García et al. revealed an increase in pro-inflammatory molecules such as IL-4, IL-5, IL-6, IL-13, IL-17A, and IFN-γ in tears during the weeks following surface corneal refractive surgery.⁴⁶ While ATs are effective in the relief of DES symptoms, most of them do not reduce inflammation.⁴⁷ Topical corticosteroids may be prescribed post-operatively for rapid anti-inflammatory effects, but their use is not free of adverse effects such as glaucoma or drug-induced cataract.⁴⁸ One type of AT, containing cationic emulsion of cetalkonium chloride has been found to have anti-inflammatory effects due to inhibition of IL-6, IL-8 IL-17, TNF-α, IFN-γ, and IL-2 secretion.^49,50 In addition, an animal study revealed its unique ability to increase goblet cell count by almost 40% in corneas with scraped epithelia.⁵⁰

The results of the present and above-mentioned previous studies suggest that CCN maybe beneficial compared with the standard postoperative SH treatment of DES, with improvements in the subjective parameters of DES due to its anti-inflammatory effect. Moreover, previous studies have shown preservative-free CCN to be safe for ocular surface application and efficient in the treatment of DES.^22,51–53 In addition, CCN has been described as effective in the treatment of both DES signs and symptoms as well as the new type of delivery vehicle of topically applied lipophilic drugs such as latanoprost.^20,54

The advantage of the present study is its two-center, randomized, double-masked design. However, it has some limitations. While the postoperative corneal healing period after surface keratorefractive surgery is up to 12 months, follow up in this study was for one month. We focused on the initial and most important part of the healing process, during which treatment compliance is good and changes in subjectively measured parameters such as symptoms are clear. Other limitations are the lack of objective assessment of DES severity, and the use of two similar but different surgical techniques and only one reference comparator.

Conclusion

In conclusion, the results of this study revealed significant improvement in postoperative visual acuity, and DES symptoms during the first postoperative month in both groups. In the CCN group, we observed relatively rapid improvement in DES symptoms measured subjectively and less blurred vision immediately after AT instillation, while objective results were similar in both groups. Therefore, our findings suggest benefits of CCN over 0.15% SH in the treatment of post-keratorefractive DES and the wound healing process, including an advantage in patient reported symptoms.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The professional editing of the paper and open access fee was supported by Santen EMEA Research Grant.

ORCID iDs

Damian Jaworski

Katarzyna Jadczyk-Sorek

Bartłomiej J Kałużny

References

El Bahrawy

Alió

. Excimer laser 6th generation: state of the art and refractive surgical outcomes. Eye Vis 2015; 2: 1–8. DOI:10.1186/s40662-015-0015-5

Vingopoulos

Kanellopoulos

. Epi-Bowman blunt keratectomy versus diluted EtOH epithelial removal in myopic photorefractive keratectomy: a prospective contralateral eye study. Cornea 2019; 38: 612–616. DOI:10.1097/ICO.0000000000001863.

Slade

Durrie

Binder

. A prospective, contralateral eye study comparing thin-flap LASIK (Sub-Bowman Keratomileusis) with photorefractive keratectomy. Ophthalmology 2009; 116: 1075–1082. DOI:10.1016/j.ophtha.2009.01.001.

Hatch

Moshirfar

Ollerton

, et al. A prospective, contralateral comparison of photorefractive keratectomy (PRK) versus thin-flap LASIK: assessment of visual function. Clin Ophthalmol 2011; 5: 451–457. DOI:10.2147/OPTH.S18967.

Camellin

. Laser epithelial keratomileusis for myopia. J Refract Surg 2003; 19: 666–670. DOI:10.3928/1081-597X-20031101-09.

Randleman

Woodward

Lynn

, et al. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology 2008; 115: 37–48. DOI:10.1016/j.ophtha.2007.03.073

Kuboyama

Tohda

Komatsu

. Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases. Biol Pharm Bull 2014; 892: 892–897. DOI:10.1248/bpb.b14-00022.

EYW

Leung

Rao

, et al. Effect of laser in situ keratomileusis on tear stability. Ophthalmology 2000; 107: 2131–2135. DOI:10.1016/S0161-6420(00)00388-2.

Ryan

Bower

Sia

, et al. Goblet cell response after photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg 2016; 42: 1181–1189. DOI:10.1016/j.jcrs.2016.05.008.

10.

Albietz

Lenton

McLennan

. Dry eye after LASIK: comparison of outcomes for Asian and Caucasian eyes. Clin Exp Optom 2005; 88: 89–96. DOI:10.1111/j.1444-0938.2005.tb06673.x.

11.

Hong

Kim

. The changes of tear break up time after myopic excimer laser photorefractive keratectomy. Korean J Ophthalmol 1997; 11: 89–93. DOI:10.3341/kjo.1997.11.2.89.

12.

Sia

Ryan

Stutzman

, et al. Alcohol versus brush PRK: visual outcomes and adverse effects. Lasers Surg Med 2012; 44: 475–481. DOI:10.1002/lsm.22036.

13.

Lee

J-H

Han

Kim

T-H

, et al. Acupuncture for dry eye syndrome after refractive surgery: a randomized controlled pilot trial. Integr Med Res 2021; 10: 100456. DOI:10.1016/j.imr.2020.100456.

14.

Chao

Golebiowski

Stapleton

. The role of corneal innervation in lasik-induced neuropathic dry eye. Ocul Surf 2014; 12: 32–45. DOI:10.1016/j.jtos.2013.09.001.

15.

Schallhorn

Pelouskova

Oldenburg

, et al. Effect of gender and procedure on patient-reported dry eye symptoms after laser vision correction. J Refract Surg 2019; 35: 161–168. DOI:10.3928/1081597X-20190107-01.

16.

Levinson

Rapuano

Cohen

, et al. Referrals to the Wills Eye Institute Cornea Service after laser in situ keratomileusis: reasons for patient dissatisfaction. J Cataract Refract Surg 2008; 34: 32–39. DOI:10.1016/j.jcrs.2007.08.028.

17.

Jabbur

Sakatani

O'Brien

. Survey of complications and recommendations for management in dissatisfied patients seeking a consultation after refractive surgery. J Cataract Refract Surg 2004; 30: 1867–1874. DOI:10.1016/j.jcrs.2004.01.020.

18.

Gomes

JAP

Amankwah

Powell-Richards

, et al. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol 2004; 88: 821–825. DOI:10.1136/bjo.2003.027573.

19.

Noda-Tsuruya

Asano-Kato

Toda

, et al. Autologous serum eye drops for dry eye after LASIK. J Refract Surg 2006; 22: 61–66. DOI:10.3928/1081-597x-20060101-13.

20.

Lallemand

Daull

Benita

, et al. Successfully improving ocular drug delivery using the Cationic Nanoemulsion, Novasorb. J Drug Deliv 2012; 2012: 1–16. DOI:10.1155/2012/604204.

21.

Georgiev

Yokoi

Nencheva

, et al. 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.

22.

Amrane

Creuzot-Garcher

Robert

, et al. Ocular tolerability and efficacy of a cationic emulsion in patients with mild to moderate dry eye disease – A randomised comparative study. J Franc d’Ophtalmol 2014; 37: 589–598. DOI:10.1016/j.jfo.2014.05.001.

23.

Aragona

Spinella

Rania

, et al. Assessment of the efficacy of Cationorm® in patients with moderate dry eye compared with Optive® and Emustil® eye drops. Acta Ophthalmol 2011; 89: 0–0. DOI:10.1111/j.1755-3768.2011.3125.x.

24.

Chu

Zhou

, et al. Recovery of corneal sensitivity after laser-assisted subepithelial keratectomy. J Cataract Refract Surg 2006; 32: 785–788. DOI:10.1016/J.JCRS.2006.01.066.

25.

Schiffman

Christianson

Jacobsen

, et al. Reliability and validity of the ocular surface disease index. Arch Ophthalmol 2000; 118: 615–621. DOI:10.1001/archopht.118.5.615.

26.

Lemp

Baudouin

Baum

, et al. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international Dry Eye WorkShop (2007). Ocular Surf 2007; 5: 75–92. DOI:10.1016/s1542-0124(12)70081-2.

27.

Lemp

Crews

Bron

, et al. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea 2012; 31: 472–478. DOI:10.1097/ICO.0b013e318225415a.

28.

Daull

Lallemand

Garrigue

. Benefits of cetalkonium chloride cationic oil-in-water nanoemulsions for topical ophthalmic drug delivery. J Pharm Pharmacol 2014; 66: 531–541. DOI:10.1111/jphp.12075.

29.

Kobashi

Kamiya

Shimizu

. Dry eye after small incision lenticule extraction and femtosecond laser-assisted LASIK: meta-analysis. Cornea 2017; 36: 85–91. DOI:10.1097/ICO.0000000000000999.

30.

Rabina

Boguslavsky

Mimouni

, et al. The association between preoperative dry eye symptoms and postoperative discomfort in patients underwent photorefractive keratectomy. J Ophthalmol 2019; 2019: 1–6. DOI:10.1155/2019/7029858

31.

Toda

. Dry eye after lasik. Investig Ophthalmol Vis Sci 2018; 59: DES109–DES115. DOI:10.1167/iovs.17-23538.

32.

Shehadeh-Mashor

Mimouni

Shapira

, et al. Risk factors for dry eye after refractive surgery. Cornea 2019; 38: 1495–1499. DOI:10.1097/ICO.0000000000002152.

33.

Nejima

Miyata

Tanabe

, et al. Corneal barrier function, tear film stability, and corneal sensation after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol 2005; 139: 64–71. DOI:10.1016/j.ajo.2004.08.039.

34.

Zeng

, et al. A multi-center study of the prevalence of dry eye disease in Chinese refractive surgery candidates. Ophthalmic Res Published online June 2, 2020. DOI:2021; 64(2): 224–229. DOI:10.1159/000509060.

35.

Labetoulle

Benitez-Del-castillo

Barabino

, et al. Artificial tears: Biological role of their ingredients in the management of dry eye disease. Int J Mol Sci 2022; 23: 2434–2446. DOI:10.3390/IJMS23052434

36.

Albietz

McLennan

Lenton

. Ocular surface management of photorefractive keratectomy and laser in situ keratomileusis. J Refract Surg 2003; 19: 636–644. DOI:10.3928/1081-597X-20031101-05.

37.

Ribeiro

MVMR

Barbosa

Ribeiro

LEF

, et al. Effectiveness of using preservative-free artificial tears versus preserved lubricants for the treatment of dry eyes: a systematic review. Arq Bras Oftalmol 2019; 82: 436–445. DOI:10.5935/0004-2749.20190097.

38.

Astakhov

Asakhov

Lisochkina

. Assessment of dry eye signs and symptoms and ocular tolerance of a preservative-free lacrimal substitute (Hylabak®) versus a preserved lacrimal substitute (Systane®) used for 3 months in patients after LASIK. Clin Ophthalmol 2013; 7: 2289–2297. DOI:10.2147/OPTH.S50446.

39.

Economou

Laukeland

Grabska-Liberek

, et al. Better tolerance of preservative-free latanoprost compared to preserved glaucoma eye drops: the 12-month real-life FREE study. Clin Ophthalmol 2018; 12: 2399–2407. DOI:10.2147/OPTH.S176605.

40.

Nasser

Rozycka

Rendon

, et al. Real-life results of switching from preserved to preservative-free artificial tears containing hyaluronate in patients with dry eye disease. Clin Ophthalmol 2018; 12: 1519–1525. DOI:10.2147/OPTH.S160053.

41.

Inoue

Mohamed

Uematsu

, et al. Corneal damage and its recovery after instillation of preservative-free versus preserved latanoprost eye drops. Cutan Ocul Toxicol 2020; 39: 158–164. DOI:10.1080/15569527.2020.1752228.

42.

Yang

Lee

Kim

, et al. A meta-analysis of the efficacy of hyaluronic acid eye drops for the treatment of dry eye syndrome. Int J Environ Res Public Health 2021; 18: 1–14. DOI:10.3390/IJERPH18052383.

43.

van Setten

G-B

Baudouin

Horwath-Winter

, et al. The HYLAN M study: efficacy of 0.15% high molecular weight hyaluronan fluid in the treatment of severe dry eye disease in a multicenter randomized trial. J Clin Med 2020; 9: 3536. DOI:10.3390/jcm9113536.

44.

Baeyens

Bron

Baudouin

. Efficacy of 0.18% hypotonic sodium hyaluronate ophthalmic solution in the treatment of signs and symptoms of dry eye disease. J Fr Ophtalmol 2012; 35: 412–419. DOI:10.1016/j.jfo.2011.07.017.

45.

Ntonti

Panagiotopoulou

E-K

Karastatiras

, et al. Impact of 0.1% sodium hyaluronate and 0.2% sodium hyaluronate artificial tears on postoperative discomfort following cataract extraction surgery: a comparative study. Eye Vis 2019; 6: 1–9. DOI:10.1186/s40662-019-0131-8

46.

González-García

Murillo

Pinto-Fraga

, et al. Clinical and tear cytokine profiles after advanced surface ablation refractive surgery: A six-month follow-up. Exp Eye Res 2020; 193: 1–10. DOI:10.1016/j.exer.2020.107976

47.

Pflugfelder

de Paiva

. The pathophysiology of dry eye disease: what we know and future directions for research. Ophthalmology 2017; 124: S4–S13. DOI:10.1016/j.ophtha.2017.07.010.

48.

Knop

. Regulation of the inflammatory component in chronic dry eye disease by the eye-associated lymphoid tissue (EALT). Res Projects Dry Eye Syndrome 2010; 45: 23–39. DOI:10.1159/000315017.

49.

Mechanism of action of cationic emulsions in the management of ocular surface inflammation and wound healing | IOVS | ARVO Journals. Accessed April 19, 2021. https://iovs.arvojournals.org/article.aspx?articleid=2563215

50.

Daull

Feraille

Elena

, et al. Comparison of the anti-inflammatory effects of artificial tears in a rat model of corneal scraping. J Ocul Pharmacol Ther 2016; 32: 109–118. DOI:10.1089/jop.2015.0054.

51.

Kinnunen

Kauppinen

Piippo

, et al. Cationorm shows good tolerability on human HCE-2 corneal epithelial cell cultures. Exp Eye Res 2014; 120: 82–89. DOI:10.1016/j.exer.2014.01.006.

52.

Georgiev

Yokoi

Nencheva

, et al. Surface chemistry interactions of cationorm with films by human meibum and tear film compounds. Int J Mol Sci 2017; 18: 1558–1570. DOI:10.3390/ijms18071558

53.

Robert

Cochener

Amrane

, et al. 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.

54.

Daull

Buggage

Lambert

, et al. A comparative study of a preservative-free latanoprost cationic emulsion (catioprost) and a BAK-preserved latanoprost solution in animal models. J Ocul Pharmacol Ther 2012; 28: 515–523. DOI:10.1089/jop.2011.0245.