Novel application of nanotechnology in the treatment and management of dry eye disease: a systematic review

Introduction

Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a chronic and multifactorial disease of the ocular surface characterised by tear film instability, visual disturbances and chronic eye pain (1-3). DED poses a major public health concern, with a worldwide prevalence of up to 50% (4) and significant impairment to quality of life (5-7).

The causes are multifactorial and can be broadly classified into two main subtypes; evaporative and aqueous deficiency, affecting 86% and 10% of patients respectively (8-10).

Regardless of aetiology, the clinical consequences of DED can be devastating. DED is accompanied by inflammation of the ocular surface, which can cause corneal ulcers and blindness in severe disease (11).

Current therapies aim to reduce ocular discomfort by encouraging lubrication and stimulation of tear production. However, these do not provide definitive and permanent treatment for DED (2,3,12,13). Conventional formulations such as ointments and gels are also reported to produce a sticky sensation, blurred vision or ocular surface discomfort (14). Furthermore, the unique physiological and anatomical structure of the eye poses challenges in diagnosis and treatment. Limitations include poor drug retention and bioavailability following topical ocular administration, poor control of drug concentration over time with nasolacrimal duct drainage, or systemic toxicity at therapeutic ocular concentrations (14). Therefore, the development of improved diagnostics and therapeutics for DED is an area of increasing attention.

Emerging nanotechnology has a role in biopharmaceutics for DED. Nanotechnology involves the controlled manipulation and study of structures and devices in nanometre scale. Miniaturisation of materials and devices to this scale offers advantages of unique novel properties and functions, with advances in achieving site-specific and sustained drug delivery (15). Previous studies have focused on elevating drug concentrations by exploring various drug delivery systems, including colloidal liposomes or carriers.

Recent developments in nanotechnology have provided promise in regenerating and restoring diseased and damaged cornea, by facilitating prolonged and consistent drug delivery using nanocarriers, including nanospheres and nanoparticles. By encapsulating drugs from degradation during transport, enhancing corneal uptake and increasing corneal bioavailability and half-life on the ocular surface, nanotechnology overcomes many of the barriers associated with previous drug delivery systems (16). DED has the potential to benefit from nanotechnology.

The current systematic review focuses on advances in the development of nanotechnology for the application of DED treatment and management. It provides a comprehensive and timely update on the burgeoning field of nanotechnology for DED. We present this article in accordance with the PRISMA reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-24-9/rc) (17).

Methods

Eligibility criteria for considering studies for review

Inclusion criteria

Prospective or retrospective studies, including ex vivo and animal studies, clinical studies and randomised controlled trials were included. For the clinical studies, the patient population had a clinical diagnosis of DED. Each included study required one or more applications of nanotechnology for the diagnosis, treatment or management of DED. One or more outcome measures were assessed: visual acuity (best corrected visual acuity or uncorrected visual acuity), ocular surface staining, tear film break-up time, ocular protection, tear secretions and patient-reported outcome measures.

Exclusion criteria

Study cohorts composed of patients who did not fulfill diagnostic criteria for DED were excluded. Review articles, letters, conference presentations and abstracts were excluded, unless they were attached to a publication.

Search methods for identifying studies

A search strategy was developed to identify all articles investigating the application of nanotechnology in ocular surface disease, and results were filtered for DED.

The following electronic databases were searched: CENTRAL, MEDLINE and MEDLINE In-Process, EMBASE, PubMed, Ovid and Scopus. All searches were carried out until December 2020 and did not include language restrictions. Translation software was used for non-English-based reports.

Study selection

Titles and abstracts were initially screened by the principal investigator (E.L.S.W.) using standardised criteria according to protocol, including study design, inclusion criteria, participant baseline characteristics and outcome data.

The search and abstract screen were repeated independently by a co-author (P.K.) and the results were combined for filtering. Duplicate publications of the same study or patient cohort were examined for additional data. Reference lists of identified studies were also screened to find any further studies which were omitted in the initial search.

Data collection and risk of bias assessment

For randomised control trial (RCT) observational arms, prospective and retrospective studies, and non-randomised experimental studies, the Joanna Briggs Institute model of evidenced-based healthcare bias assessment was used (18).

Results

Study selection and quality

The search strategy yielded 3,843 publication titles. Seventy-eight were included in this systematic review. Of the 78 included studies, there were 56 laboratory studies, 8 pre-clinical studies, and 14 clinical studies including Phase 1/2b/3/4 studies, randomised crossover trials and randomised controlled trials. The study selection process is shown in Figure 1.

Figure 1 PRISMA flow chart outlining the search process to identify relevant articles from abstract identification to full paper review and inclusion of relevant publications (19).

Results of quality assessment

Sixteen of the 78 studies included in the systematic review were randomised controlled trials, thirteen of which involved human subjects and three involved animal subjects. Selection bias was minimised in 6 of the trials, which employed simple, block or stratified randomisation. In 8 studies, the method of randomisation was not outlined.

Outcome bias was minimised in 10 of the studies, through double blinding. However, this was not applicable for animal studies.

Non-randomised studies were also included; these studies were of varying quality.

Comparability between interventional and control groups was well maintained across most included studies.

A summary of bias is provided in Tables S1,S2.

Clinical application of nanotechnology for DED

Artificial tears

Nine studies identified the use of nanotechnology to overcome the limitations of topical instillation and to enhance the residence time of conventional artificial tears.

Novel formulations of artificial tears utilising nanostructured lipid carriers or nanoliposomes have been explored in laboratory studies using animal models. Niamprem et al. investigated nanostructured lipid carriers of varying sizes and surface modifications in a porcine epithelial cell model, and concluded that smaller carriers (~40 nm) showed greater penetration across the epithelium compared to larger particles (~150 nm). Both sizes demonstrated enhancement of mucoadhesive properties, attributed to strong intrinsic surface activity, and tear film stability by increasing adhesion tension of the mucous layer and decreasing the surface tension of the tear film. This translated to marked reduction in the frequency of instillations, higher dwell time in the eye and longer controlled release of lipids through disintegration (20). Rabbit model studies (21,22) have also shown promising results. A novel artificial tear formulation utilising nanoliposomes composed of phosphatidylcholine, cholesterol, and Vitamins A and E, demonstrated good biocompatibility, high in vitro cell viability and in vivo tolerance. Neither discomfort nor clinical signs (Grade 0) were reported in the first 24 hours following the instillation of artificial tear and aqueous phase (21). When dispersed in an aqueous solution of bioadhesive sodium hyaluronate, viability values in the human corneal and conjunctival cell lines were always >80% even after liposomal formulation storage for 8 weeks. Discomfort and clinical signs after instillation in rabbit eyes were absent (22).

A novel nanodispersion eye ointment, using petrolatum and lanolinum as the excipients dispersed in polyvinyl pyrrolidone solution, was tested in a mouse model. Compared to commercial polymer-based artificial tears (Tears Natural R Forte), the optimised formulation contained higher concentrations of ointment matrix with therapeutic improvement in tear break-up time and fluorescein staining reported. Histological evaluation demonstrated that normal corneal and conjunctival morphology was restored, supporting that the nanodispersion was likely to be non-cytotoxic and safe for ophthalmic application (23).

Large clinical studies have also demonstrated the efficacy and tolerability of nanoemulsion lubricating eye drops. In a 2019 RCT comparing the safety, efficacy, tolerability and acceptability of a nano-emulsion formulation (OM3), containing trehalose, flaxseed oil and polysorbate 80, with a marketed emulsion artificial tear (Refresh Optive^® Advanced Preservative-Free Lubricant Eye Drops), OM3 was non-inferior in reducing DED severity after 3 months of treatment. Significantly better scores in combined corneal and conjunctival staining scores with OM3 at follow-up time points of day 30 and day 90, particularly in subjects with a baseline ocular surface disease index score of ≤32 (non-severe symptoms) and a short tear break-up time (<5 seconds), were observed. Importantly, the frequency of reported blurred vision and instillation site pain was less in the OM3 group (24).

Similarly, two Phase 4, multicentre trials evaluated symptom relief in patients with DED following a single drop of propylene glycol-hydroxypropyl guar (PG-HPG) nanoemulsion (Systane^® Complete) lubricant eye drops (9,25). The nanoemulsion formulation with HPG and borate improved retention of the demulcent (PG) on the aqueous/mucin and moisture content of the deficient aqueous tear film by forming a cross-linked protective viscoelastic barrier. The anionic phospholipid barrier in PG-HPG created an interface between the outer non-polar lipids and the underlying aqueous phase, thereby restoring the complete tear film structure. Controlled release of lipid into the tear film was also exhibited. Both studies found that PG-HPG nanoemulsion was effective and well tolerated in participants with DED and all its subtypes (9,25), and that PG-HPG provided immediate and sustained symptom relief for 8 hours post-single application (9). This improvement was continued through to day 28 (25).

In a study by Rangarajan et al., HP-guar nanoemulsion-treated corneal epithelial cells demonstrated increased hydration protection of 32 to 40-fold, and 3 to 5.5 times greater desiccation protection compared to vehicle. There was less uptake of 5,6-carboxyfluorescein by intact rabbit corneas and faster recovery of normal barrier function following chemical damage by benzalkonium chloride. By combining the unique properties of gellable polymer, HP-guar and nanoparticle delivery technology, the HP-guar nanoemulsion formulation promoted longer hydration retention, improved barrier protection and reduced surface friction with increased elastic strength in corneal epithelium models in a simulated blinking model (26).

A prospective, double-masked, randomised crossover trial, found that instillation of both lipid and non-lipid containing hydroxypropyl-guar-based nanoparticle eye drops enhanced the subjective comfort of DED subjects (27). However, lipid-based drops demonstrated superior prophylactic efficacy in a simulated adverse exposure environment than non-lipid drops, as indicated by sustained objective improvements in tear film stability and lipid layer grade. These findings suggest that novel lipid-delivering nanotechnology provides prophylactic benefits following adverse environmental exposure (27). However, in a crossover comparison and one month observational study, changes in lipid layer thickness from the nanoemulsion were limited to the short term. No significant effects were observed 15 minutes post-instillation, or after a month of instillation four times daily, in patients who already had high baseline lipid layer thickness levels (≥50 nm), although it is noted that the study cohort was small (n=5) (28).

Indeed, artificial tears relieve symptoms of DED and contribute to the hydration, lubrication, stability and optical properties of the ocular surface with low side effects. Nanotechnology may improve patient compliance by decreasing the frequency of instillation and increasing the duration of action.

Cyclosporine A

Recent clinical studies have investigated the incorporation of nanotechnology to facilitate the delivery of cyclosporine A (CsA), an established DED therapy. These novel delivery systems incorporate nanotechnology through 0.05% nanoemulsions and 0.09% nanomicellar formulations.

Nanoemulsion 0.05%

An in vitro and in vivo study optimised a CsA loaded polymeric mucoadhesive nanoemulsion to assess drug concentration on the ocular surface over time (29). Corneal retention of the mucoadhesive nanoparticle was confirmed by gamma scintigraphy and surface biodistribution determined by ultraperformance liquid chromatography and mass spectrometry. The CsA nanoemulsion drug concentration peaked at 30 minutes, with sustained maximum therapeutic concentration of drug (50–300 ng/g) in the cornea and conjunctiva over 24 hours in comparison to the controls (CsA suspension and optimised composition). The concentration of the nanoemulsion in the cornea was adequate to modulate the local immune response and suppress inflammatory processes. Minimal systemic drug absorption and penetration into the inner ocular tissues were also observed. There was a higher CsA payload and improved ocular retention, corneal and conjunctival bioavailability with the nanoemulsion (29).

CsA nanoparticles prepared with poly-lactide-co-glycolide (PLGA) and a mixture of PLGA with Eudragit^® RL coating with Carbopol^® have also demonstrated improved drug retention (30,31). These preparations increased drug entrapment efficiency from 58.35% to 95.69%, and exhibited a biphasic drug release pattern with an initial burst followed by a very slow drug release. The total cumulative release up to 24 hours ranged from 69.83% to 91.92% (32).

An in vitro study by Aksungur et al. investigated improving the poor water solubility of CsA by incorporating CsA into a complex with hydroxypropyl-beta-cyclodextrin using an organic emulsification solvent evaporation preparation method. The release of CsA was significantly enhanced by the complex formation, showing high CsA encapsulation efficiency (88%) and production yield (89%), and the release rate was observed to be up to 96% (33).

When comparing the efficacy and safety of a novel topical CsA 0.05% nanoemulsion to a conventional emulsion in primary Sjögren’s syndrome for DED, two Korean prospective, RCTs found that the novel CsA nanoemulsion demonstrated faster improvement of ocular surface staining scores than the conventional emulsion (34,35). Furthermore, in a non-inferiority clinical study comparing a 0.05% CsA nanoemulsion with previously used 0.05% CsA emulsion formulations and 3% diquafosol, nanoemulsions showed an equivalent effect in DED treatment and a significant decrease in conjunctival staining. However, there was increased reporting of a ’stickiness sensation’ in the nanoemulsion group, caused by xanthan gum as a mucoadhesive polymer and carboxymethylcellulose as a viscosity increasing agent (36). Nanoemulsified CsA also resolved inflammation more effectively, compared to conventional anionic CsA solution (Restasis) (37).

Nanomicellar formulations 0.09%

The safety and superior efficacy of nanotechnology for CsA delivery were supported by two American randomised, multi-centre, vehicle-controlled, double masked clinical trials utilising a novel aqueous nanomicellar formulation of CsA (0.09%) [OTX-101] in DED treatment (38,39). In one study, with a randomised patient sample of 744 (40), 16.6% of eyes in the OTX-101 treatment group achieved an increase of greater than or equal to 10 mm in the Schirmer test score at day 84, compared to 9.2% in the vehicle control group (P<0.001). While global symptom scores were reduced across both groups, the OTX-101 group also demonstrated significant improvements in corneal and conjunctival staining; adverse reactions were considered mild in intensity. While both studies demonstrated a reduction in global symptom score in both treatment groups of up to 30%, this was not significant (38,39). A phase 1 open-label, single-arm study also concluded that OTX-101 was well-tolerated with negligible systemic exposure or accumulation in healthy volunteers following twice-daily ocular administration (41). This was consistent with an animal study in white rabbits demonstrating extensive distribution of CsA in the cornea and conjunctiva, while systemic exposure was negligible (42). Furthermore, three pooled analyses of Phase 2b/3 and Phase 3 studies found that instillation site pain was reported to be 4.0% in patients receiving OTX-101 compared to 21.8% in the vehicle control group (40) and that OTX-101 improved tear production and conjunctival staining compared to vehicle control (43,44).

Subconjunctival implantation of nanoparticle-loaded systems for sustained-release CsA delivery has also been researched, using poly(lactide-co-glycolide) or poly-e-caprolactine (PCL) (45,46). These are reported to provide constant drug concentration at the target site, due to dual drug release profiles, simultaneously delivering both a loading and maintenance dose. Tissue distribution studies indicated that CsA was present in ocular tissues, such as the cornea, sclera and lens even 90 days after application. Blood CsA was also lower than ocular tissue. Efficacy studies in murine models showed that the application of CsA-loaded fibre implant formulation resulted in faster recovery based on their staining scores (46).

Yenice et al. compared CsA concentration in rabbit corneas following the instillation of poly-epsilon-caprolactone/benzalkonium chloride nanospheres, with and without hyaluronic acid coating, versus a castor oil control. While there was no significant difference between the two nanosphere groups, both nanosphere groups achieved a 10- to 15-fold increase in CsA concentration compared to control (47).

Other promising modes of CsA delivery for DED using nanotechnology include methoxy poly(ethylene glycol)-hexylsubstituted poly(lactates) micelle nanocarriers (48), and lipid nanocapsules (49). Mucoadhesive nanoparticles have also been proposed to prolong the ocular retention of topical drugs, thus facilitating treatment using reduced dosing frequency of drugs (50).

Anti-inflammatory agents

Nanomedicine treatments for ocular surface inflammation in DED show promising results. A Spanish study instilled cationised gelatin-based nanoparticles loaded with a plasmid coding a modified MUC5AC glycoprotein in healthy and experimental DED mice. Improved fluorescein staining and tear production compared to control and a decrease in CD4⁺ T cell infiltration, consistent with reduced inflammation, were shown (51).

Another laboratory study investigated novel anti-oxidative nanoparticles targeted at mitochondria to scavenge reactive oxygen species (ROS) in situ for environmental DED. These were prepared with a charge-driven self-assembly strategy utilising heat to prepare negatively charged hyaluronic acid and positively charged MitoQ. The nanoparticles exhibited higher drug encapsulation capacity and loading efficiency compared to the traditional self-assembly method. The addition of heat treatment enhanced the interaction between the charged hyaluronic acid and MitoQ molecules, facilitating a more compact structure and uniform spherical morphology in the resultant nanoparticles. Overall, the MitoQ demonstrated stronger mitochondrial ROS scavenging activity, a better curative effect against environment-induced DED symptoms, ROS accumulation on the eye surface and enhanced down-regulation of gene suppression of inflammation-related factors in vivo (52).

Several in vitro and in vivo studies investigated novel drug delivery systems; polymeric nanoparticles loaded with natural and synthetic mixtures of oleanolic acid and ursolic acid which presented no toxicity and significant anti-inflammatory efficacy (53); poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles to encapsulate hydrocortisone which were not cytotoxic on bovine keratocytes, nor altering to corneal transparency or permeability (54); and a dexamethasone drug eluting system using a methylcellulose polymer (55). The methylcellulose nanowafer contained patterned arrays of nanoreservoirs loaded with a drug, slowly released over several hours. It exhibited advantages of good biocompatibility, water solubility, transparency and mucoadhesive properties.

While Bian et al. found that treatment with dexamethasone nanowafers once daily was as efficacious as dexamethasone eye drops four times daily (55), Coursey et al. found that treatment with nanowafers on alternate days during a five-day treatment period was comparable to topical eye drops applied twice a day in an experimental murine model (56). Nonetheless, nanowafers provided sustained release of dexamethasone and improved clinically graded corneal clarity. They were also effective in downregulating the expression of inflammatory cytokines (TNF-alpha, INF-gamma), chemokines (CXCL-10 and CCL-5), MMP-3 (56) and decreasing neutrophil infiltration in the cornea (55).

Dukovski et al. developed and optimised a functional cationic nanoemulsion formulation containing ibuprofen, 0.05% chitosan, and lecithin, to circumvent solubility issues, prolong drug residence time on the ocular surface and to stabilise the tear film. The formulation was found to have physiochemical properties adequate for ophthalmic application, mucoadhesive character and excellent biocompatibility (57).

Phospho-sulindac formulated in nanoparticles has also been investigated to be an effective formulation (58). Topical application to the eye was effectively delivered to targeted tissues in the anterior segment, and the nanoparticle formulation was superior to a standard solution in drug delivery (58).

Moreover, other nanomedicine materials made of biodegradable polymer (gelatin-HA) loaded with epigallocatechin gallate (59), and poly(catechin) capped-gold nanoparticles carrying amfenac (60), were successful in clinical improvement of DED clinical signs and reducing inflammatory cytokines. In the capped-gold study (59), the synergistic dual-function nano eyedrops delivered amfenac and acted as an antioxidant to suppress ROS-mediated processes (60). To ameliorate epithelial healing and hydrogen formation ability in corneal injuries due to DED, TEMPO-oxidised sacchachitin nanofibers combined with platelet rich plasma have been proposed in severe DED (61).

Other drugs

Nanotechnology has a role in overcoming challenges in drug delivery and enhancing drug activity. Nanomicellar formulations of hydrophobic drugs, for example, pimecrolimus, were shown to improve drug permeability and bioavailability in the treatment of DED. These exhibited sustained-release behaviour with higher drug encapsulation capability (62,63). Epigallocatechin gallate lipid nanoparticles were found to enhance antioxidant, anti-cancer, anti-inflammatory, anti-bacterial and antiviral activity (64). Pterostilbene-peptide prodrug nanomedicine with potent anti-oxidant capacity and anti-inflammatory efficacy (65) and cerium oxide loaded glycol chitosan nano-systems, which can stabilise the tear film, scavenge ROS and promote corneal and conjunctival cell growth and integrity (66), have also been explored.

In an experimental DED mouse model, a nanocomplex of poly(ethylene glycol) and catechin effectively induced an increase in tear production, stabilisation of the corneal epithelium, increase in conjunctival goblet cells, and an improvement in inflammation in a PEG dose-dependent manner (67). A Japanese study designed a novel sustained-release drug delivery system for DED therapy utilising rebamipide nanoparticles, which were delivered into the tear film through the meibomian glands. The study found increased mucin levels in the tear film and improved tear film break-up levels in an N-acetylcysteine-treated rabbit model (68). Moreover, the ocular distribution of a coumarin-6-labelled nanostructured lipid carrier with chitosan-N-acetylcysteine coating was evaluated in another rabbit model; a broad distribution and absorption by aqueous humour, with greater absorption in the cornea than conjunctiva was found (69).

Other applications

Other applications of nanotechnology to enhance the bioavailability of therapeutic agents on the ocular surface are nanoparticle embedded contact lenses. Choi et al. incorporated ceria nanoparticles, which have efficient ROS scavenging properties mimicking the activities of superoxide dismutase and catalase, into polyhydroxyethyl methacrylate-based contact lenses. In addition to excellent extracellular ROS-scavenging properties, the viability of human conjunctival epithelial cells and human Meibomian gland epithelial cells were significantly enhanced (70).

To overcome the rapid washout of drugs on the ocular surface from tear clearance, peptide-based nanoparticles targeting receptor-mediated transcytosis of the lacrimal gland, have been explored (71).

Furthermore, gold nanoparticles have been incorporated into a hydrogen based mini-eye patch for relieving DED with a light-emitting screen using a photothermal conversion hydrogel. After being pasted to the lacrimal gland, the patch converted various light irradiations into heat and stimulated the lacrimal gland to produce tears to relieve DED (72).

Nanotechnology has also been considered for diagnostic purposes, including hydrogel-coated gold nanoshells in localised surface plasmon resonance-based biosensing to screen for chronic DED (73), visualisation and quantification of nanoparticle transport across mucosal surfaces in DED to guide drug delivery (74), and the investigation of auto-immune mediated DED through a multivalent intercellular adhesion molecule 1 (ICAM-1) binding nanoparticle which inhibits the interaction between ICAM-1 and lymphocyte function-associated 1 antigen (75).

Discussion

A systematic review synthesising 78 laboratory, preclinical and clinical studies was reported and provided an update on the current applications of nanotechnology in the diagnosis, treatment and management of DED. The current review utilised the PRISMA framework to systematically evaluate the literature across multiple evidenced-based databases. The focus was on clinical applications for treatment and management with the potential for patient application.

Nanotechnology demonstrated applications in artificial tears, enhancing the penetration and residence time of conventional formulations, increasing control of CsA delivery through a nanoemulsion of 0.05% or nanomicellar formulation of 0.09%, and working synergistically with anti-inflammatory agents to reduce ocular inflammation in DED. There have also been studies investigating nanoparticle embedded contact lenses, and nanoparticle treatments targeting receptors in the lacrimal glands.

The studies included in this review demonstrated non-inferiority or improvement of outcome measures with nanotechnology compared to control. Indeed, preliminary pre-clinical and clinical studies support that nanotechnology offers promise for site-specific and sustained drug delivery, with consistent findings across laboratory, animal studies and Phase I to IV clinical studies.

Integration of nanostructured lipid carriers or nanoliposomes within artificial tears, the first line therapy for DED, has the potential to effectively circumvent the anatomical and physiological barriers of the eye, leading to sustained delivery, less frequent applications, and improved patient compliance. Strong mucoadhesiveness to the corneal epithelium, higher dwell time in the eye and the ability to release active drug ingredients through disintegration over a much longer period, is facilitated by binding to the glycocalyx coating the surface of the corneal epithelium. Subsequently, lipid contents are slowly released, to be absorbed and to penetrate the tear film lipid layer. This mechanism of action was confirmed through Meibomian lipid films spread on an aqueous buffer in a Langmuir trough (20). Absorption into corneal and conjunctival cells is facilitated if particles are smaller than 200 nm, and if particles are hydrophobic in nature (32,76).

Nanoemulsion formulations demonstrated a broad range of applications for lubricating eye drops, CsA delivery and as a vehicle for drug delivery of other agents. These biphasic systems, composed of oil, surfactants, cosurfactants and an aqueous phase, were characterised by a higher solubilisation capacity and greater stability and dispersibility than coarse emulsions (26). In particular, a cationorm cation nanoemulsion was shown to enhance tear film stability at the ocular surface, increasing film elasticity and thickness, and potentially compensating for moderate meibum deficiency (8). In the included studies, localised discomfort and systemic side effects of nanoemulsion lubricating eye drops were minimal, with one study describing that the incidence of reported blurred vision and instillation site pain was less (24). Superior efficacy in desiccation protection compared to vehicle was also confirmed, with symptom relief being sustained for up to 28 days (25). However, changes in lipid layer thickness from the nanoemulsion did not demonstrate long term effects in patients with a higher baseline lipid layer thickness levels (≥50 nm) (28).

Furthermore, delivery of CsA, an immunosuppressive selective interleukin-2 gene transcription inhibitor, has focused on hydrophobic peptide CsA loaded in nanoparticles. As a hydrophobic particle, CsA typically presents poor biopharmaceutic properties for delivery, like low solubility and permeability, rendering challenges in the formulation and efficient drug delivery for topical application. Systemic application is also associated with unwanted side effects, for example, immune suppression, nephrotoxicity and hypertension. Hydrophobic peptide CsA loaded in nanoparticles are thought to have a number of advantages, including drug encapsulation and protection capabilities, improved tolerance, penetration efficiency and increased corneal uptake. Furthermore, there was an increase in residence time of the drug in the precorneal area, improving its therapeutic effect for ocular disease (21-43).

Nanomedicine treatments have been exhibited to work synergistically with anti-inflammatory agents. In a mouse model (51) and bovine keratocytes (54), nanoparticles were effective in targeting inflammatory mediators with decreased CD4⁺ T cell infiltration and increased ROS scavenging activity, with no alteration in corneal transparency or permeability. The review also outlines that nanotechnology has a role as a carrier in enhancing drug delivery of other agents in DED and in the diagnosis of DED.

There has been one review previously published, exploring the role of nano-ophthalmology in treating DED from the United Arab Emirates (76). This summarised the nanocarrier systems that were evaluated by in vitro, ex vivo and in vivo means for DED, using PubMed to identify the use of nanocarrier technology for delivering therapeutic agents. With many preclinical studies, the review article found that although the current therapies represent a significant advancement in DED treatment, clinical applications had not advanced adequately to promote the entry of nanocarrier systems into the pharmaceutical market on a large scale.

Limitations

Outcome measures and efficacy assessments of most included studies were based on signs and symptoms. Signs included unanaesthetised Schirmer tear test, corneal and conjunctival staining, and symptoms included global symptom score. Safety evaluations included adverse events, visual acuity, intraocular monitoring, slit lamp, dilated ophthalmoscopy and fundus examinations. Using patient-reported symptoms as an outcome measure may impact reliability, as symptoms are largely a subjective experience and it is challenging to standardise symptom experiences across studies.

Furthermore, clinical tests measuring tear deficiency and ocular surface damage are, in general, only weakly correlated with patient symptoms. The global clinician grade of DED correlates more highly with patient symptoms than clinical signs, suggesting that patient symptoms influence DED diagnoses and grading more than clinical test results (77). Many studies included used animal subjects, rendering it challenging to measure subjective symptoms of DED. This may affect the significance and validity of clinical conclusions drawn.

As the literature search was confined to articles found in PubMed, EMBASE, Scopus and Web of Science, applications of nanotechnology to DED presented in conference abstracts and grey literature were omitted.

Poor methodological and reporting quality of primary studies included in a review has the potential to introduce the risk of confounding, selection bias, and information bias. This was minimised by applying the Joanne Briggs Institute model of evidence-based healthcare bias assessment tool (18). Valid assessment of study quality was undertaken by two independent reviewers to increase accuracy and generalisability.

Other limitations included the small number of clinical studies for each application with heterogeneous designs. The causes of DED are multifactorial and subgroup analysis was not possible with the number of studies included in each treatment type.

To address these limitations, a potential area for future research would be the creation of a standardised set of outcome measures to allow for easy comparison and meta-analyses of newly developed therapeutics. Such a standardised set of outcome measures should ideally include a readily quantifiable objective measure of disease severity, functional assessment, and a measure of symptom severity. Acknowledging the heterogeneity of DED, corneal staining has been proposed as an objective and meaningful outcome measure that should be included in all studies investigating DED (78). No consensus has yet been reached for measures of function or symptom severity. Dry eye registries could be used to collect key outcome measures once new technologies reach the clinic (79,80). The Save Sight Dry Eye Registry is the first cross-disciplinary registry able to collect outcomes data from everyday clinical practice, including patient reported outcomes (81). This registry may have a future role in assessing dry eye nano-based therapeutics.

Conclusions

Drug delivery to the eye remains a challenge. Nanotechnology has a role in delivering site specific, controlled and prolonged release of therapeutics, which may lead to increased patient compliance and improved clinical outcomes for patients with DED.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-24-9/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-24-9/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-24-9/coif). S.L.W. was supported by the Sydney Medical School Foundation. She is a Co-Deputy Director of Industry, Innovation, and Commercialisation, at Sydney Nano. P.K. received Medical Scientific Liaison with Novartis and Apellis Pharmaceuticals. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017;15:276-83. [Crossref] [PubMed]
2. Ballesteros-Sánchez A, Sánchez-González JM, Tedesco GR, et al. Evaluating GlicoPro Tear Substitute Derived from Helix aspersa Snail Mucus in Alleviating Severe Dry Eye Disease: A First-in-Human Study on Corneal Esthesiometry Recovery and Ocular Pain Relief. J Clin Med 2024;13:1618. [Crossref] [PubMed]
3. Borroni D, Mazzotta C, Rocha-de-Lossada C, et al. Dry Eye Para-Inflammation Treatment: Evaluation of a Novel Tear Substitute Containing Hyaluronic Acid and Low-Dose Hydrocortisone. Biomedicines 2023;11:3277. [Crossref] [PubMed]
4. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II Epidemiology Report. Ocul Surf 2017;15:334-65. [Crossref] [PubMed]
5. Gayton JL. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol 2009;3:405-12. [Crossref] [PubMed]
6. Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea 2011;30:379-87. [Crossref] [PubMed]
7. Yang W, Luo Y, Wu S, et al. Estimated Annual Economic Burden of Dry Eye Disease Based on a Multi-Center Analysis in China: A Retrospective Study. Front Med (Lausanne) 2021;8:771352. [Crossref] [PubMed]
8. Georgiev GA, Yokoi N, Nencheva Y, et al. Surface Chemistry Interactions of Cationorm with Films by Human Meibum and Tear Film Compounds. Int J Mol Sci 2017;18:1558. [Crossref] [PubMed]
9. Silverstein S, Yeu E, Tauber J, et al. Symptom Relief Following a Single Dose of Propylene Glycol-Hydroxypropyl Guar Nanoemulsion in Patients with Dry Eye Disease: A Phase IV, Multicenter Trial. Clin Ophthalmol 2020;14:3167-77. [Crossref] [PubMed]
10. Niamprem P, Milla TJ, Schuett BS, et al. Interaction of nanostructured lipid carriers with human meibum. International Journal of Applied Pharmaceutics 2019;11:35-42. [Crossref]
11. Swilem AE, Elshazly AHM, Hamed AA, et al. Nanoscale poly(acrylic acid)-based hydrogels prepared via a green single-step approach for application as low-viscosity biomimetic fluid tears. Mater Sci Eng C Mater Biol Appl 2020;110:110726. [Crossref] [PubMed]
12. Ali M, Byrne ME. Challenges and solutions in topical ocular drug-delivery systems. Expert Rev Clin Pharmacol 2008;1:145-61. [Crossref] [PubMed]
13. Lakhani P, Patil A, Majumdar S. Recent advances in topical nano drug-delivery systems for the anterior ocular segment. Ther Deliv 2018;9:137-53. [Crossref] [PubMed]
14. Calonge M. The treatment of dry eye. Surv Ophthalmol 2001;45:S227-39. [Crossref] [PubMed]
15. Mudgil M, Gupta N, Nagpal M, et al. Nanotechnology: A new approach for ocular drug delivery system. Int J Pharm Pharm Sci 2012;4:105-12.
16. Janagam DR, Wu L, Lowe TL. Nanoparticles for drug delivery to the anterior segment of the eye. Adv Drug Deliv Rev 2017;122:31-64. [Crossref] [PubMed]
17. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372: [PubMed]
18. Checklist for systematic reviews and research syntheses Internet. 2017. Available online: https://jbi.global/sites/default/files/2019-05/JBI_Critical_Appraisal-Checklist_for_Systematic_Reviews2017_0.pdf
19. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. [Crossref] [PubMed]
20. Niamprem P, Teapavarapruk P, Srinivas SP, et al. Impact of Nanostructured Lipid Carriers as an Artificial Tear Film in a Rabbit Evaporative Dry Eye Model. Cornea 2019;38:485-91. [Crossref] [PubMed]
21. Acar D, Molina-Martínez IT, Gómez-Ballesteros M, et al. Novel liposome-based and in situ gelling artificial tear formulation for dry eye disease treatment. Cont Lens Anterior Eye 2018;41:93-6. [Crossref] [PubMed]
22. Vicario-de-la-Torre M, Caballo-González M, Vico E, et al. Novel Nano-Liposome Formulation for Dry Eyes with Components Similar to the Preocular Tear Film. Polymers (Basel) 2018;10:425. [Crossref] [PubMed]
23. Zhang W, Li X, Ye T, et al. Nanostructured lipid carrier surface modified with Eudragit RS 100 and its potential ophthalmic functions. Int J Nanomedicine 2014;9:4305-15. [PubMed]
24. Downie LE, Hom MM, Berdy GJ, et al. An artificial tear containing flaxseed oil for treating dry eye disease: A randomized controlled trial. Ocul Surf 2020;18:148-57. [Crossref] [PubMed]
25. Yeu E, Silverstein S, Guillon M, et al. Efficacy and Safety of Phospholipid Nanoemulsion-Based Ocular Lubricant for the Management of Various Subtypes of Dry Eye Disease: A Phase IV, Multicenter Trial. Clin Ophthalmol 2020;14:2561-70. [Crossref] [PubMed]
26. Rangarajan R, Ketelson H. Preclinical Evaluation of a New Hydroxypropyl-Guar Phospholipid Nanoemulsion-Based Artificial Tear Formulation in Models of Corneal Epithelium. J Ocul Pharmacol Ther 2019;35:32-7. [Crossref] [PubMed]
27. Muntz A, Marasini S, Wang MTM, et al. Prophylactic action of lipid and non-lipid tear supplements in adverse environmental conditions: A randomised crossover trial. Ocul Surf 2020;18:920-5. [Crossref] [PubMed]
28. Weisenberger K, Fogt N, Swingle Fogt J. Comparison of nanoemulsion and non-emollient artificial tears on tear lipid layer thickness and symptoms. J Optom 2021;14:20-7. [Crossref] [PubMed]
29. Akhter S, Anwar M, Siddiqui MA, et al. Improving the topical ocular pharmacokinetics of an immunosuppressant agent with mucoadhesive nanoemulsions: Formulation development, in-vitro and in-vivo studies. Colloids Surf B Biointerfaces 2016;148:19-29. [Crossref] [PubMed]
30. Aksungur P, Demirbilek M, Denkbaş EB, et al. Development and characterization of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies. J Control Release 2011;151:286-94. [Crossref] [PubMed]
31. Hermans K, Van Den Plas D, Schreurs E, et al. Cytotoxicity and anti-inflammatory activity of cyclosporine A loaded PLGA nanoparticles for ocular use. Pharmazie 2014;69:32-7. [PubMed]
32. Wagh VD, Apar DU. Cyclosporine A Loaded PLGA Nanoparticles for Dry Eye Disease: In Vitro Characterization Studies. Journal of Nanotechnology 2014. doi: 10.1155/2014/68315310.1155/2014/683153
33. Aksungur P, Demirbilek M, Denkbaş EB, et al. Comparative evaluation of cyclosporine A/HPβCD-incorporated PLGA nanoparticles for development of effective ocular preparations. J Microencapsul 2012;29:605-13. [Crossref] [PubMed]
34. Kang MJ, Kim YH, Chou M, et al. Evaluation of the Efficacy and Safety of A Novel 0.05% Cyclosporin A Topical Nanoemulsion in Primary Sjögren's Syndrome Dry Eye. Ocul Immunol Inflamm 2020;28:370-8. [Crossref] [PubMed]
35. Kim HS, Kim TI, Kim JH, et al. Evaluation of Clinical Efficacy and Safety of a Novel Cyclosporin A Nanoemulsion in the Treatment of Dry Eye Syndrome. J Ocul Pharmacol Ther 2017;33:530-8. [Crossref] [PubMed]
36. Park CH, Kim MK, Kim EC, et al. Efficacy of Topical Cyclosporine Nanoemulsion 0.05% Compared with Topical Cyclosporine Emulsion 0.05% and Diquafosol 3% in Dry Eye. Korean J Ophthalmol 2019;33:343-52. [Crossref] [PubMed]
37. Bang SP, Yeon CY, Adhikari N, et al. Cyclosporine A eyedrops with self-nanoemulsifying drug delivery systems have improved physicochemical properties and efficacy against dry eye disease in a murine dry eye model. PLoS One 2019;14:e0224805. [Crossref] [PubMed]
38. Tauber J, Schechter BA, Bacharach J, et al. A Phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease. Clin Ophthalmol 2018;12:1921-9. [Crossref] [PubMed]
39. Goldberg DF, Malhotra RP, Schechter BA, et al. A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease. Ophthalmology 2019;126:1230-7. [Crossref] [PubMed]
40. Malhotra R, Devries DK, Luchs J, et al. Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies. Cornea 2019;38:1259-65. [Crossref] [PubMed]
41. Karpecki PM, Weiss SL, Kramer WG, et al. A phase 1, open-label, single-arm study evaluating the ocular safety of OTX-101 and systemic absorption of cyclosporine in healthy human volunteers. Clin Ophthalmol 2019;13:591-6. [Crossref] [PubMed]
42. Weiss SL, Kramer WG. Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits. J Ocul Pharmacol Ther 2019;35:395-402. [Crossref] [PubMed]
43. Sheppard J, Kannarr S, Luchs J, et al. Efficacy and Safety of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, for the Treatment of Keratoconjunctivitis Sicca: Pooled Analysis of a Phase 2b/3 and Phase 3 Study. Eye Contact Lens 2020;46:S14-9. [Crossref] [PubMed]
44. Smyth-Medina R, Johnston J, Devries DK, et al. Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Conjunctival Staining in Patients with Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and 3 Clinical Trials. J Ocul Pharmacol Ther 2019;35:388-94. [Crossref] [PubMed]
45. Pehlivan SB, Yavuz B, Çalamak S, et al. Preparation and in vitro/in vivo evaluation of cyclosporin A-loaded nanodecorated ocular implants for subconjunctival application. J Pharm Sci 2015;104:1709-20. [Crossref] [PubMed]
46. Yavuz B, Bozdağ Pehlivan S, Kaffashi A, et al. In vivo tissue distribution and efficacy studies for cyclosporin A loaded nano-decorated subconjunctival implants. Drug Deliv 2016;23:3279-84. [Crossref] [PubMed]
47. Yenice I, Mocan MC, Palaska E, et al. Hyaluronic acid coated poly-epsilon-caprolactone nanospheres deliver high concentrations of cyclosporine A into the cornea. Exp Eye Res 2008;87:162-7. [Crossref] [PubMed]
48. Di Tommaso C, Torriglia A, Furrer P, et al. Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers. Int J Pharm 2011;416:515-24. [Crossref] [PubMed]
49. Zhang A, Sun R, Ran M, et al. A Novel Eyes Topical Drug Delivery System: CsA-LNC for the Treatment of DED. Pharm Res 2020;37:146. [Crossref] [PubMed]
50. Liu S, Dozois MD, Chang CN, et al. Prolonged Ocular Retention of Mucoadhesive Nanoparticle Eye Drop Formulation Enables Treatment of Eye Diseases Using Significantly Reduced Dosage. Mol Pharm 2016;13:2897-905. [Crossref] [PubMed]
51. Contreras-Ruiz L, Zorzi GK, Hileeto D, et al. A nanomedicine to treat ocular surface inflammation: performance on an experimental dry eye murine model. Gene Ther 2013;20:467-77. [Crossref] [PubMed]
52. Zheng Q, Li L, Liu M, et al. In situ scavenging of mitochondrial ROS by anti-oxidative MitoQ/hyaluronic acid nanoparticles for environment-induced dry eye disease therapy. Chemical Engineering Journal 2020;398:125621. [Crossref]
53. Alvarado HL, Abrego G, Garduño-Ramirez ML, et al. Design and optimization of oleanolic/ursolic acid-loaded nanoplatforms for ocular anti-inflammatory applications. Nanomedicine 2015;11:521-30. [Crossref] [PubMed]
54. Álvarez-Álvarez L, Barral L, Bouza R, et al. Hydrocortisone loaded poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles for topical ophthalmic administration: Preparation, characterization and evaluation of ophthalmic toxicity. Int J Pharm 2019;568:118519. [Crossref] [PubMed]
55. Bian F, Shin CS, Wang C, et al. Dexamethasone Drug Eluting Nanowafers Control Inflammation in Alkali-Burned Corneas Associated With Dry Eye. Invest Ophthalmol Vis Sci 2016;57:3222-30. [Crossref] [PubMed]
56. Coursey TG, Henriksson JT, Marcano DC, et al. Dexamethasone nanowafer as an effective therapy for dry eye disease. J Control Release 2015;213:168-74. [Crossref] [PubMed]
57. Jurišić Dukovski B, Juretić M, Bračko D, et al. Functional ibuprofen-loaded cationic nanoemulsion: Development and optimization for dry eye disease treatment. Int J Pharm 2020;576:118979. [Crossref] [PubMed]
58. Wen Z, Muratomi N, Huang W, et al. The ocular pharmacokinetics and biodistribution of phospho-sulindac (OXT-328) formulated in nanoparticles: Enhanced and targeted tissue drug delivery. Int J Pharm 2019;557:273-9. [Crossref] [PubMed]
59. Huang HY, Wang MC, Chen ZY, et al. Gelatin-epigallocatechin gallate nanoparticles with hyaluronic acid decoration as eye drops can treat rabbit dry-eye syndrome effectively via inflammatory relief. Int J Nanomedicine 2018;13:7251-73. [Crossref] [PubMed]
60. Li YJ, Luo LJ, Harroun SG, et al. Synergistically dual-functional nano eye-drops for simultaneous anti-inflammatory and anti-oxidative treatment of dry eye disease. Nanoscale 2019;11:5580-94. [Crossref] [PubMed]
61. Lin HL, Wu TH, Ho HO, et al. TEMPO-Oxidized Sacchachitin Nanofibers (TOSCNFs) Combined with Platelet-Rich Plasma (PRP) for Management of Dry Eye Syndrome. Int J Nanomedicine 2020;15:1721-30. [Crossref] [PubMed]
62. Yingfang F, Zhuang B, Wang C, et al. Pimecrolimus micelle exhibits excellent therapeutic effect for Keratoconjunctivitis Sicca. Colloids Surf B Biointerfaces 2016;140:1-10. [Crossref] [PubMed]
63. Lin S, Ge C, Wang D, et al. Overcoming the Anatomical and Physiological Barriers in Topical Eye Surface Medication Using a Peptide-Decorated Polymeric Micelle. ACS Appl Mater Interfaces 2019;11:39603-12. [Crossref] [PubMed]
64. Fangueiro JF, Andreani T, Fernandes L, et al. Physicochemical characterization of epigallocatechin gallate lipid nanoparticles (EGCG-LNs) for ocular instillation. Colloids Surf B Biointerfaces 2014;123:452-60. [Crossref] [PubMed]
65. Hu L, Hu Z, Yu Y, et al. Preparation and characterization of a pterostilbene-peptide prodrug nanomedicine for the management of dry eye. Int J Pharm 2020;588:119683. [Crossref] [PubMed]
66. Yu F, Zheng M, Zhang AY, et al. A cerium oxide loaded glycol chitosan nano-system for the treatment of dry eye disease. J Control Release 2019;315:40-54. [Crossref] [PubMed]
67. Lee H, Shim W, Kim CE, et al. Therapeutic Efficacy of Nanocomplex of Poly(Ethylene Glycol) and Catechin for Dry Eye Disease in a Mouse Model. Invest Ophthalmol Vis Sci 2017;58:1682-91. [Crossref] [PubMed]
68. Nagai N, Ishii M, Seiriki R, et al. Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles. Pharmaceutics 2020;12:155. [Crossref] [PubMed]
69. Liu D, Li J, Cheng B, et al. Ex Vivo and in Vivo Evaluation of the Effect of Coating a Coumarin-6-Labeled Nanostructured Lipid Carrier with Chitosan-N-acetylcysteine on Rabbit Ocular Distribution. Mol Pharm 2017;14:2639-48. [Crossref] [PubMed]
70. Choi SW, Cha BG, Kim J. Therapeutic Contact Lens for Scavenging Excessive Reactive Oxygen Species on the Ocular Surface. ACS Nano 2020;14:2483-96. [Crossref] [PubMed]
71. Hsueh PY, Edman MC, Sun G, et al. Tear-mediated delivery of nanoparticles through transcytosis of the lacrimal gland. J Control Release 2015;208:2-13. [Crossref] [PubMed]
72. Pang Y, Wei C, Li R, et al. Photothermal conversion hydrogel based mini-eye patch for relieving dry eye with long-term use of the light-emitting screen. Int J Nanomedicine 2019;14:5125-33. [Crossref] [PubMed]
73. Culver HR, Wechsler ME, Peppas NA. Label-Free Detection of Tear Biomarkers Using Hydrogel-Coated Gold Nanoshells in a Localized Surface Plasmon Resonance-Based Biosensor. ACS Nano 2018;12:9342-54. [Crossref] [PubMed]
74. Ensign LM, Henning A, Schneider CS, et al. Ex vivo characterization of particle transport in mucus secretions coating freshly excised mucosal tissues. Mol Pharm 2013;10:2176-82. [Crossref] [PubMed]
75. Hsueh PY, Ju Y, Vega A, et al. A Multivalent ICAM-1 Binding Nanoparticle which Inhibits ICAM-1 and LFA-1 Interaction Represents a New Tool for the Investigation of Autoimmune-Mediated Dry Eye. Int J Mol Sci 2020;21:2758. [Crossref] [PubMed]
76. Natesan S, Boddu SHS, Krishnaswami V, et al. The Role of Nano-ophthalmology in Treating Dry Eye Disease. Pharm Nanotechnol 2020;8:258-89. [Crossref] [PubMed]
77. Begley CG, Chalmers RL, Abetz L, et al. The relationship between habitual patient-reported symptoms and clinical signs among patients with dry eye of varying severity. Invest Ophthalmol Vis Sci 2003;44:4753-61. [Crossref] [PubMed]
78. Hirabayashi KJ, Akpek EK, Ahmad S. Outcome Measures to Assess Dry Eye Severity: A Review. Ocul Immunol Inflamm 2022;30:282-9. [Crossref] [PubMed]
79. Khoo P, Downie LE, Stapleton F, et al. Clinical Registries in Dry Eye Disease: A Systematic Review. Cornea 2022;41:1572-83. [Crossref] [PubMed]
80. Tan JCK, Ferdi AC, Gillies MC, et al. Clinical Registries in Ophthalmology. Ophthalmology 2019;126:655-62. [Crossref] [PubMed]
81. Watson SL, Aguas MPC, Downie LE, et al. The Save Sight Dry Eye Registry: One year capture of real-world data for dry eye. Invest Ophthalmol Vis Sci 2022;63:1520-A0245.