Redefining Dry Eye Disease Management: Emerging Pharmacologic and Device-Based Therapies in the Era of Precision Care: A Narrative Review

Abstract

Dry eye disease (DED) is a common, chronic ocular condition marked by tear film instability and surface inflammation that impairs comfort, vision, and overall quality of life. In the last decade, major advances have reshaped therapeutic strategies across four domains: novel pharmacological agents, device-based treatments, patient stratification, and long-term care models. New pharmacotherapies include next-generation anti-inflammatory drugs such as lifitegrast and improved cyclosporine formulations, along with short-term corticosteroid suspensions for acute flares. Secretagogues and biologics have broadened treatment options. Nasal varenicline spray is now approved to stimulate endogenous tear production through neurostimulation, while perfluorohexyloctane is the first topical therapy targeting evaporative DED, which acts by reducing excessive tear evaporation. Regenerative approaches, including autologous serum and platelet-rich plasma eye drops, are increasingly used in severe cases to deliver growth factors that support epithelial healing. Device-based therapies have also advanced significantly. Thermal pulsation platforms (LipiFlow, iLux, TearCare) apply controlled heat and pressure to meibomian glands to relieve obstruction more effectively than standard warm compresses. Adjunctive technologies, such as intense pulsed light (IPL), improve tear film stability and reduce inflammation in refractory meibomian gland dysfunction. Neurostimulator devices, both intranasal and external, enhance tear secretion through targeted trigeminal pathway activation. Sustained-release drug delivery systems, including investigational punctal inserts, aim to improve adherence and long-term treatment consistency. Given DED’s heterogeneity, personalized and phenotype-driven management is becoming central to clinical practice. Point-of-care diagnostics, including tear osmolarity testing, matrix metalloproteinase-9 (MMP-9) inflammatory marker assays, and meibography, allow more precise classification of aqueous-deficient, evaporative, or mixed disease, enabling tailored therapy selection. Long-term management increasingly follows a chronic-disease model emphasizing maintenance therapy, environmental modifications, digital health tools for symptom tracking, and proactive patient education to enhance adherence. By integrating innovative treatments with individualized management strategies, clinicians are now better equipped to disrupt the cycle of inflammation and tear film instability, ultimately improving outcomes for patients with dry eye disease.

Key Summary Points

Multiple novel dry eye therapies have emerged, including next-generation immunomodulators (advanced cyclosporine, lifitegrast) and a short-term corticosteroid for flares. A nasal spray secretagogue (varenicline) now stimulates natural tear production. Perfluorohexyloctane has become the first approved anti-evaporative drop targeting lipid-deficient tear film.

Device-based therapies for dry eye are expanding, with thermal pulsation systems (LipiFlow, iLux, TearCare) and intense pulsed light improving meibomian gland function. Neurostimulator devices may be intranasal or external and enhance tear secretion for patients intolerant to drops. Emerging sustained-release platforms, such as cyclosporine-eluting punctal inserts, aim to improve long-term adherence.

Personalized dry eye care now emphasizes phenotyping using point-of-care tests (tear osmolarity, matrix metalloproteinase-9 (MMP-9)) and imaging, such as meibography, to classify patients as aqueous-deficient, evaporative, or mixed. Treatment is increasingly tailored, targeting inflammation in MMP-9-positive cases or lipid therapies for meibomian gland dysfunction (MGD) to improve outcomes.

Long-term dry eye care now follows a chronic-disease model, emphasizing maintenance therapy, periodic follow-up, and lifestyle or environmental modifications to reduce flares. Digital health tools, including symptom-tracking apps, treatment reminders, and blink-training programs, support self-management and adherence.

Future dry eye therapy is expected to advance through biologics, including cytokine inhibitors and tear-protein analogues, with recombinant Tumor necrosis factor-stimulated gene 6 (TSG-6) derivatives showing promising corneal healing and anti-inflammatory effects in preclinical models. Telemedicine and home-monitoring tools may further enable proactive, personalized treatment adjustments.

Introduction

Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a common and complex disorder of the tear film and ocular surface [1]. It affects an estimated 5–10% of the population (hundreds of millions of people worldwide), especially older adults and women. Patients with DED experience symptoms of dryness, burning, grittiness, fluctuating vision, and ocular pain that can significantly impair daily activities and quality of life [2]. The pathophysiology of dry eye involves a self-perpetuating cycle of tear film instability, hyperosmolarity, and inflammation leading to epithelial damage on the ocular surface. DED is traditionally classified into aqueous-deficient dry eye and evaporative dry eye, although mixed forms are frequent [3]. Key risk factors include autoimmune disorders such as Sjögren’s syndrome, along with environmental exposures and modifiable lifestyle factors; in clinical practice, prolonged digital screen use is increasingly recognized as a significant contributor to dry eye disease, particularly among younger and working-age patients [4]. Indeed, increased digital device time has been associated with reduced blink rates and meibomian gland dysfunction, with one report projecting an annual 10% increase in DED incidence among young adults attributable to screen exposure [5]. Management of dry eye has evolved from simply treating symptoms with over-the-counter tear supplements to a more comprehensive strategy targeting underlying mechanisms [6]. Conventional therapy often follows a stepped approach beginning with patient education, environmental modifications, and artificial tears, and progressing to pharmacologic and procedural interventions for moderate to severe disease [7]. The 2017 Tear Film and Ocular Surface Society’s recent Dry Eye Workshop II (TFOS DEWS II) workshop and the 2018 American Academy of Ophthalmology (AAO) consensus provided treatment algorithms that incrementally escalate therapy based on dry eye severity [8]. While these guidelines remain a useful foundation, an expanding array of new treatments and diagnostics over the past 5 years has enabled more targeted and personalized care. Notably, the TFOS DEWS III, emphasizes that rigid staging of DED (e.g., “mild” vs. “severe”) is less effective than identifying each patient’s specific disease drivers and tailoring therapy accordingly [9]. In parallel, clinicians and researchers increasingly view dry eye as a chronic disease requiring long-term management rather than a short-term inconvenience. This narrative review provides an up-to-date overview of advances in dry eye treatment and patient management strategies, focusing on four key areas: novel pharmacologic therapies, device-based interventions, patient phenotyping for personalized care, and approaches to long-term management. The discussion highlights developments from last decade, including new treatments that have expanded options for patients and expert recommendations on optimizing outcomes in this common ocular condition.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Literature Search Strategy and Selection Criteria

A comprehensive literature search was performed across five major databases—PubMed/MEDLINE, Scopus, Web of Science, the Cochrane Library, and Google Scholar—to ensure inclusion of both peer-reviewed and gray literature relevant to emerging dry eye therapies. The search covered the period from January 2015 to December 2025, reflecting a decade of significant advancements in anti-inflammatory, neurostimulatory, secretagogue-based, and lipid-modulating treatments. All records identified (n = 1354) underwent initial screening for duplication, relevance, and methodological sufficiency, after which 1014 articles were excluded, leaving 340 studies for full-text eligibility assessment. Inclusion priorities followed a structured evidence-hierarchy model that ranked randomized controlled trials, systematic reviews, meta-analyses, and international guidelines as highest-level evidence, supplemented by product-specific pivotal trial data. Moderate-priority sources included prospective cohort and case–control studies, as well as authoritative narrative reviews. Emerging therapies—such as neurostimulation devices, intense pulsed light (IPL), thermal pulsation, autologous serum/ Platelet-rich plasma (PRP), and novel immunomodulators—were assessed based on mechanistic innovation, regulatory milestones, phase 3 outcomes, reproducibility across studies, and overall strength of evidence. Lower-tier evidence (expert consensus, early exploratory trials, and real-world data) was incorporated only when higher-level evidence was unavailable. Two independent reviewers carried out the screening and eligibility process, resolving conflicts through consensus to optimize reliability. Ultimately, 206 studies met eligibility criteria and were included in the qualitative synthesis, following a PRISMA-inspired approach designed to maximize transparency, reproducibility, and methodological rigor, even though the review was not conducted as a full systematic review (Fig. 1).

Fig. 1.

Depicts the PRISMA-style schematic illustrating the literature search and study selection process from January 2015 to December 2025 across major databases. Of 1354 records identified, 340 underwent full screening, and 206 studies met eligibility criteria. Included studies represent prioritized evidence from randomised control trials, guidelines, cohort data, and emerging therapies

Evidence Grading Approach

To strengthen the methodological rigor of this narrative review, all referenced studies were evaluated using the SIGN (Scottish Intercollegiate Guidelines Network) evidence-grading system. This framework assigns levels of evidence based on study design, methodological quality, and risk of bias. Randomized controlled trials and meta-analyses were categorized as high-level evidence (SIGN levels 1++ to 1+), while prospective cohort studies, case–control studies, and large observational datasets were classified as moderate-level evidence (SIGN levels 2++ to 2+). Early-phase trials, pilot studies, expert consensus statements, and mechanistic reports were graded as lower-level evidence (SIGN levels 3–4). For each therapeutic category (anti-inflammatory agents, secretagogues, neuromodulators, thermal devices, regenerative therapies, etc.), the predominant SIGN evidence level is now explicitly indicated. This structured approach improves interpretability and allows clinicians to appraise the relative strength of supporting data across pharmacologic, device-based, and emerging interventions.

Novel Pharmacologic Treatments for Dry Eye Disease

A variety of pharmacological therapies have emerged in recent years to address the inflammatory and tear-film components of dry eye disease. These novel agents build upon the foundation of traditional treatments (like artificial tears and ointments) by targeting specific pathways in DED pathogenesis (Fig. 2) (Table 1) [10].

Fig. 2.

Depicts the pathophysiology-driven therapeutic target in dry eye disease. PRP Platelet-rich plasma, IPL intense pulsed light

Table 1.

Depicts the novel pharmacologic therapies for dry eye disease

S. no	Therapy class	Agent	Mechanism of action	Key indication	Evidence highlights
1	Anti-inflammatory	Lifitegrast 5%	LFA-1/ICAM-1 inhibition → ↓ T-cell inflammation	Inflammatory DED	Improves symptoms and signs; rapid onset
2	Anti-inflammatory	Cyclosporine 0.09%	Calcineurin inhibition → ↓ T-cell activation	Moderate–severe DED	Better penetration vs. 0.05%; ↑ tear production
3	Short-term steroid	Loteprednol 0.25%	Soft steroid with rapid inactivation	Acute DED flares	STRIDE trials: symptom relief with minimal IOP risk
4	Secretagogue	Varenicline nasal spray	Trigeminal nerve stimulation → reflex tearing	Aqueous-deficient DED	↑ Schirmer scores; drop-free option
5	Anti-evaporative	Perfluorohexyloctane	Lipid layer supplementation → ↓ evaporation	Evaporative DED (MGD)	First FDA-approved anti-evaporative drop

LFA-1 lymphocyte function-associated antigen-1, ICAM-1 interaction with intercellular adhesion molecule-1 (LFA-1/ICAM-1), DED dry eye disease, MGD meibomian gland dysfunction

Advanced Anti-Inflammatory and Immunomodulatory Therapies

Chronic ocular surface inflammation is a key driver of dry eye disease signs and symptoms, and newer therapies target this immune dysregulation [11]. Lifitegrast ophthalmic solution 5% was among the first next-generation agents approved in 2016, blocking lymphocyte function-associated antigen-1 (LFA-1) interaction with Intercellular Adhesion Molecule-1 (ICAM-1) to reduce T-cell-mediated inflammation [12]. Clinical trials have demonstrated improvement in both symptoms and objective signs with a favorable safety profile. Cyclosporine A remains a cornerstone therapy, with newer formulations improving bioavailability and corneal penetration [13]. Cyclosporine 0.09% in a nanomicellar vehicle has shown significant gains in tear production and ocular surface staining compared with earlier emulsions. Another important advance is loteprednol etabonate 0.25%, a soft corticosteroid approved for short-term treatment of dry eye flares. Its mucus-penetrating nanoparticle formulation allows effective inflammation control with minimal adverse effects. Collectively, these agents expand treatment options for patients globally [14].

Lifitegrast

Improvements were primarily symptom-driven, with clinically meaningful OSDI reductions (typically 7–12 points) and modest but reproducible gains in conjunctival hyperemia and corneal staining. Trials were vehicle-controlled, with benefits emerging by 2–4 weeks and maintained with continuous daily use [12].

Cyclosporine (CsA Formulations)

Most studies demonstrate meaningful improvements in both signs and symptoms, including tear breakup time (TBUT) gains of 1–3 s and reductions in staining. Benefits typically manifest after 4–12 weeks of continuous use. Comparators included vehicle or artificial tears. Long-term therapy is required to maintain effect [14].

Loteprednol

Provides rapid symptom and staining improvement, often within 2–4 weeks, in vehicle-controlled studies. Primarily sign-based improvement; used short-term or as induction therapy before CsA/lifitegrast [8].

Secretagogues and Tear Stimulatory Treatments

Enhancing endogenous tear production represents an important therapeutic strategy, particularly for aqueous-deficient dry eye disease [15]. Traditional oral cholinergic secretagogues such as pilocarpine and cevimeline have been used in severe conditions like Sjögren syndrome, but newer topical and nasal agents have expanded treatment options [16]. Varenicline solution nasal spray is a first-in-class tear secretagogue approved in 2021 that stimulates nicotinic acetylcholine receptors within trigeminal afferent pathways, triggering reflex lacrimal gland secretion [17]. Clinical trials demonstrated improvements in Schirmer scores and patient-reported symptoms, with onset of benefit within weeks. Because it bypasses the ocular surface, nasal varenicline causes local irritation and can be used without contact lens removal [18]. Another important agent is diquafosol tetrasodium 3%, a P2Y₂ receptor agonist used in East Asia, which enhances water and mucin secretion from conjunctival epithelial and goblet cells, improving tear film stability [19]. Alongside rebamipide 2%, a mucin secretagogue with goblet cell-enhancing and anti-inflammatory properties, these agents underpin tear film-oriented therapy. Randomized trials show both drugs improve tear breakup time, ocular surface staining, and symptoms, with rebamipide also increasing aqueous tear secretion. Overall, secretagogues provide clinically meaningful benefit in selected dry eye populations. Secretagogues improve TBUT, staining, and mucin secretion with daily dosing. The duration of benefit is dependent on continued use. Most trials use vehicle comparators [20].

Lipid Layer Replacement and Tear Film Stabilizers

One major advancement in dry eye therapy is the approval of perfluorohexyloctane ophthalmic solution 100% (MIEBO™) in May 2023, the first prescription drop specifically indicated for evaporative dry eye due to meibomian gland dysfunction [21]. This semi-fluorinated alkane spreads over the tear film, supplementing the lipid layer and reducing evaporation. In two phase 3 trials {Global Ocular Benefit Index- (GOBI) and Measure of Ocular JAuVEnile Dry Eye (MOJAVE)}, MIEBO significantly improved tear breakup time, ocular surface staining, and symptoms over 57 days compared to placebo [22]. It is preservative-free and water-free, minimizing irritation in sensitive patients. Its ability to reduce evaporation directly addresses a key driver of evaporative DED. Miebo’s approval marks a shift in therapy from anti-inflammatories alone to lipid-layer stabilization [23]. Other tear stabilizers like glycerin- or lipid-based artificial tears, trehalose, and ectoine are in use or development, but MIEBO stands out with regulatory approval and robust clinical trial data for prescription use in evaporative dry eye [24].

Biologic and Regenerative Therapies

For patients with severe dry eye, particularly with ocular surface damage, biologic tear substitutes are gaining importance. Autologous serum eye drops, rich in growth factors and anti-inflammatory mediators, have shown benefits in epithelial healing, symptom relief, and goblet cell density, especially in Sjögren’s syndrome and refractory cases [25]. Platelet-rich plasma (PRP), another blood-derived product, has also been explored as eye drops or periocular injections [26]. A 2024 meta-analysis of 16 trials confirmed that blood-based therapies (serum, PRP, umbilical cord serum) significantly outperform artificial tears in improving tear film stability and ocular integrity. PRP improved corneal staining and symptom scores, while umbilical cord serum was effective in enhancing tear breakup time [27]. These therapies harness the body’s natural repair mechanisms and are personalized and biocompatible. While limited by cost and processing availability, their use is expanding in advanced dry eye centers and clinical guidelines. These demonstrate sign-dominant improvement (staining, epithelial integrity) with moderate symptom benefit. Requires repeated cycles. Evidence is primarily observational, with variability in concentrations and endpoints. Other biologics in development include recombinant lubricin, pigment epithelium-derived factor (PEDF) fragments combined with steroids, and thymosin beta 4 [10]. A novel tumor necrosis factor-stimulated Gene-6 (TSG-6) fusion protein has shown superior efficacy over cyclosporine in preclinical studies by reducing inflammation and promoting tissue repair [28]. Together, these innovations in last decade empower personalized therapy. Inflammatory cases may benefit from lifitegrast or cyclosporine, while evaporative DED responds to perfluorohexyloctane. Ongoing research will refine therapy combinations and sequencing. These therapies are generally well tolerated, filling critical gaps in modern dry eye management [29].

Device-Based Therapies in Dry Eye Management

In parallel with pharmacological innovations, device-based therapies have become integral to dry eye disease management [30]. These technologies often address the anatomical or physical aspects of tear film dysfunction especially meibomian gland health and tear film stability and can be used in conjunction with medical treatments [31]. Key device-based interventions include thermal pulsation systems, intense pulsed light for meibomian gland dysfunction, neurostimulation devices, and novel drug delivery tools (Fig. 3) (Table 2).

Fig. 3.

Depicts the device-based therapies mapped to tear film anatomy in dry eye disease

Table 2.

Depicts the device-based therapies in modern dry eye management

S. no	Device category	Examples	Primary target	Key benefits	Typical duration of effect
1	Thermal pulsation	LipiFlow, iLux, TearCare	Meibomian gland obstruction	Restores lipid secretion	6–12 months
2	Intense pulsed light (IPL)	OptiLight	MGD + inflammation	Improves TBUT, reduces telangiectasia	6–12 months
3	Neurostimulation (intranasal/external)	TrueTear*, iTear 100	Lacrimal reflex	Drop-free tear stimulation	On-demand
4	Drug-delivery devices	Cyclosporine punctal inserts	Adherence & sustained therapy	Long-acting anti-inflammation	Up to 16 weeks
5	Lid hygiene devices	BlephEx, ZEST	Biofilm/Demodex	Improves lid health	Maintenance dependent

MGD meibomian gland dysfunction, TBUT tear breakup time, ZEST Zocular Eyelid System Treatment

Thermal Pulsation and Eyelid Warming Devices

Meibomian gland dysfunction is a key cause of evaporative dry eye. In-office thermal pulsation devices provide more effective gland therapy than warm compresses. LipiFlow® was the first FDA-approved system, applying 42 °C heat to the inner eyelids with pulsatile pressure to express glands [32]. Competing devices like iLux^® and TearCare^® have since emerged. All aim to melt thickened meibum and restore lipid secretion. Studies show a single treatment improves tear breakup time and symptoms, with effects lasting 6–12 months [33]. A 2022 review found LipiFlow, iLux, and TearCare similarly effective in improving symptoms and gland output, though long-term outcomes are still under evaluation. Practical differences include TearCare’s external heating with blinking, iLux’s handheld single-lid treatment, and LipiFlow’s simultaneous bilateral treatment [34]. Cost and equipment availability can limit access. At-home warming masks are emerging, but in-office systems offer more thorough clearance in one session. For patients unresponsive to basic compresses, thermal pulsation offers a powerful option to rehabilitate meibomian gland function [35]. LipiFlow produces objective TBUT improvement (2–4 s) and meibomian gland secretion enhancement. The benefit lasts 9–12 months in many patients. The comparators include warm compresses and symptoms typically improve within 2–6 weeks [35].

Intense Pulsed Light (IPL) Therapy

Originally used for rosacea, IPL is now applied to treat dry eye associated with meibomian gland dysfunction (MGD). IPL delivers pulses of filtered broad-spectrum light (500–600 nm) to the eyelid skin [36]. It reduces pro-inflammatory mediators by ablating telangiectatic vessels, heats meibomian glands to improve meibum quality, and may lower bacterial load and demodex [36]. A 2021 meta-analysis showed IPL improves tear breakup time and symptom scores more than warm compresses or thermal pulsation. A Cochrane review confirmed IPL provides meaningful symptom relief in patients with MGD with acceptable safety. Usually delivered in 3–4 sessions over 2–4 weeks, benefits can last 6–12 months [37]. IPL is especially effective in patients with rosacea or lid telangiectasia. Proper shielding and appropriate skin selection minimize risks such as burns or pigmentation changes. Newer devices like OptiLight (FDA approved in 2023) include safety features. IPL complements other therapies and is increasingly combined with thermal expression. Its growing use reflects its efficacy in stabilizing tear film and reducing drop dependence. IPL leads to improvement in TBUT (≈ 2–3 s), meibum quality, and symptoms. Often requires 3–4 initial sessions, with retreatment every 4–6 months. Studies vary in comparators and endpoints [38].

Neurostimulation Devices

Technological advances have introduced neurostimulation devices that promote tear secretion without drugs. The first such device was the TrueTear^® Intranasal Tear Neurostimulator (Allergan), FDA-approved in 2017 [39]. Inserted into the nostrils, it delivered electrical pulses stimulating the ophthalmic trigeminal nerve, triggering tear production. Studies showed that intranasal stimulation increased Schirmer scores and improved symptoms over 6–12 weeks, though side effects like tingling or sneezing were common [40]. Although TrueTear was discontinued for business reasons, it paved the way for newer technologies. In 2020, the iTear^® 100 (Olympic Ophthalmics) received FDA clearance. Applied externally to the side of the nose, it activates the nasolacrimal reflex through the skin, providing a user-friendly, non-invasive alternative [41]. Early data show improvements in basal tear production and symptoms similar to intranasal methods. These drug-free devices are especially beneficial for patients intolerant to eye drops or wearing contact lenses [42]. They avoid preservatives and can be used on demand. As technology evolves, smaller wearable neurostimulators may emerge. Though still early in clinical adoption and requiring user motivation, neurostimulation broadens the dry eye treatment toolkit by leveraging neural pathways to restore natural tear secretion. These devices improve symptoms rapidly (within minutes to hours) with modest improvement in TBUT. Effects are transient and require ongoing use. Comparators include sham stimulation [43]. Neurostimulation therapies should be considered within a clearly defined clinical context, as their benefits are not uniform across all dry eye phenotypes. Current evidence suggests that the greatest improvement is observed in aqueous-deficient dry eye (ADDE), particularly in patients with impaired lacrimal gland stimulation but preserved neural pathways [44]. Individuals with mixed-mechanism disease may also experience symptomatic relief; however, improvements in objective signs such as TBUT or staining are generally more modest compared to purely ADDE populations. Appropriate patient selection therefore requires confirming that meibomian gland dysfunction is not the dominant driver of symptoms, and that adequate neural integrity is present to permit reflex tear stimulation [45].

Several practical barriers limit widespread clinical adoption. Neurostimulation devices may be cost-prohibitive for some patients, are inconsistently available across regions, and often require ongoing user adherence for sustained benefit, as their effects are typically short-acting and necessitate repeated daily application [46]. The field has also evolved with changes in device availability: TrueTear^® (Allergan), the first FDA-approved intranasal neurostimulator, has been discontinued, and current options primarily include external neurostimulation platforms, which vary in mechanism, regulatory approval, and clinical evidence. Importantly, neurostimulation is not recommended as a universal therapy. Patients with severe ocular surface inflammation, significant neuropathic ocular pain, or advanced MGD are less likely to benefit. Evidence to date supports a role for neurostimulation as an adjunctive option in carefully selected patients with ADDE rather than a broadly adopted primary treatment [40].

Innovations in Drug Delivery and Punctal Plugs

Another device-based strategy in dry eye involves enhancing drug delivery. Sustained-release inserts, like punctal plugs placed in the lacrimal duct, offer continuous therapy by slowly releasing medications [47]. One example is the cyclosporine intracanalicular insert (OTX-CSI), which in a phase 2 trial showed improved signs and symptoms of dry eye for up to 16 weeks after a single 12-week delivery. Similarly, Dextenza^®, a dexamethasone-impregnated plug approved for post-surgical use, may be adapted for dry eye flares [48]. Other innovations include mucus-penetrating particle drops (e.g., loteprednol 0.25%) and liposomal sprays for closed eyelid application. Drug-eluting contact lenses, such as those delivering vitamin A or anti-inflammatories, are under study. “Smart” lenses that monitor tear osmolarity and respond with drug release remain experimental [49]. Lid hygiene devices also play a vital role. BlephEx® and Zocular Eyelid System Treatment (ZEST) reduce biofilm and demodex on lashes, improving meibomian gland function. The 2023 approval of lotilaner 0.25% (XDEMVY™) adds a pharmacologic option for demodex blepharitis [50]. Comprehensive dry eye care often combines thermal pulsation, IPL, lid hygiene, and medications. This multi-modal approach helps disrupt the cycle of inflammation and dysfunction. The TFOS DEWS III (2025) report now includes many such devices in its recommendations, underscoring their established role in standard dry eye management [51].

Clinical vs. Emerging Diagnostic Tools

The commonly used clinical diagnostics are differentiated from emerging or investigational tools to improve clarity regarding real-world applicability. Currently available point-of-care tests include tear osmolarity, matrix metalloproteinase-9 (MMP-9) immunoassays, and meibography, all of which have established clinical workflows and reproducibility suitable for routine practice [52]. These tools assist in identifying tear film hyperosmolarity, ocular surface inflammation, and meibomian gland structural compromise, respectively, and are supported by validated performance characteristics in everyday clinics. In contrast, several investigational or emerging diagnostic approaches—such as tear proteomic panels, cytokine profiling, neuromodulatory pathway biomarkers, and high-resolution lipid layer interferometry beyond standard devices—remain largely research-based [53]. These modalities show promise for phenotyping dry eye disease with greater biological precision but currently face limitations related to cost, accessibility, standardization, and interlaboratory reproducibility [54].

Patient Stratification and Tailored Management Strategies

Given the multifactorial nature of dry eye disease, a “one-size-fits-all” approach to treatment is suboptimal. Recent years have seen a growing emphasis on patient stratification – that is, identifying clinically relevant subtypes or phenotypes of DED in order to personalize therapy. Stratification involves characterizing each patient’s specific tear film deficiencies, eyelid and meibomian gland status, inflammatory profile, and even neuropathic pain components, then selecting targeted interventions accordingly [55].

Phenotyping by Dry Eye Subtype

Distinguishing between aqueous-deficient (ADDE) and evaporative dry eye (EDE) remains key to therapy. ADDE, due to causes like Sjögren’s syndrome or medications, presents with low Schirmer scores and benefits from tear substitutes or punctal plugs. EDE, often linked to meibomian gland dysfunction or contact lens use, features normal tear volume but high evaporation, needing lipid-enhancing treatments [56]. Objective diagnostics now aid in phenotyping. Tear osmolarity > 308 mOsm/l or inter-eye differences > 8 mOsm/l signal instability and severity. The InflammaDry^® test detects matrix metalloproteinases-9 (MMP-9), an inflammatory marker—positive results support early anti-inflammatory use. Some patients with neuropathic ocular pain (severe symptoms but minimal signs) may need systemic neuromodulators. These tools help clinicians move from generic treatment to tailored, phenotype-driven management, improving outcomes across diverse dry eye profiles (Fig. 4) [57].

Fig. 4.

Depicts the phenotype-based diagnostic and treatment flowchart in dry eye disease. DED dry eye disease, PRP Platelet-rich plasma, IPL intense pulsed light

Advanced Diagnostic Tools for Stratification

Emerging diagnostics support precise dry eye stratification. Meibography visualizes gland dropout and truncation, helping classify MGD severity. Non-invasive breakup time and interferometry assess lipid deficiency, guiding treatment choices like LipiFlow or IPL [58]. Tear protein biomarkers are a growing frontier—elevated interleukin-1 (IL-1), interleukin-6 (IL-6), TNF-α, metalloproteinases-3 (MMP-3), and MMP-9 levels may signal inflammatory subtypes requiring immunomodulation [59]. Digital phenotyping is another innovation: apps like DryEyeRhythm track blink rate, screen time, and symptoms to classify subtypes and triggers. Integrating this with genomics could enable early risk prediction for severe disease. Though not yet routine, these tools point to a future where dry eye is managed through personalized, data-driven approaches, moving beyond symptom-based treatment to targeted, phenotype-guided care [60].

Although numerous inflammatory cytokines and tear-film biomarkers—including IL-1β, IL-6, IL-17, TNF-α, ICAM-1, and matrix metalloproteinases—provide valuable insight into the immunopathogenesis of dry eye disease, it is important to note that most of these markers remain research-based tools rather than routine clinical diagnostics [11]. At present, only a limited subset, such as tear osmolarity and point-of-care MMP-9 testing, has sufficient standardization and clinical accessibility to support widespread use. For the majority of cytokine assays, variability in sampling techniques, lack of assay harmonization, high cost, and limited reproducibility across laboratories continue to restrict their applicability in daily practice [61]. Accordingly, references to these biomarkers in this review are intended to enhance mechanistic understanding rather than imply their necessity for routine evaluation. Future advances in assay standardization and point-of-care platforms may enable broader clinical adoption, but current evidence supports a conservative and context-specific role for biomarker testing in dry eye disease [62].

Tailoring Treatment Regimens

Personalizing medicine in dry eye targets the key pathophysiology for each patient. In autoimmune ADDE, like Sjögren’s, treatment emphasizes tear stimulation (e.g., secretagogues, serum drops), immunosuppressants, and systemic coordination with rheumatology [63]. Conversely, evaporative dry eye from MGD may require lipid-enhancing therapies and gland-directed interventions like IPL or thermal pulsation. A stratified approach often leads to combination therapy—tackling multiple drivers simultaneously. The TFOS DEWS III report recommends identifying and managing all clinically relevant contributors rather than following a strict stepwise model [64]. For example, a patient with poor lipid layer and allergic conjunctivitis should receive lipid therapy and anti-allergic agents concurrently. Treatment plans must also consider lifestyle. A professional who forgets midday drops may benefit from longer-lasting options like gel-based drops or punctal plugs [65]. Patients with neuropathic features may require serum drops or neuromodulators (e.g., gabapentin) to address nerve dysfunction. Though formal trial data remain limited, real-world evidence and expert opinion support stratified treatment for faster symptom relief and fewer ineffective interventions [66]. Tailored regimens improve adherence, build patient trust, and align better with the multifactorial nature of DED. Looking ahead, artificial intelligence (AI) may integrate diagnostic inputs (osmolarity, meibography, symptom profiles) to recommend optimal therapy [67]. While still evolving, this precision-based, phenotype-guided care is becoming the new standard. In the meantime, clinicians are encouraged to move beyond uniform protocols and adopt a phenotype-first mindset when managing dry eye (Table 3).

Table 3.

Depicts the phenotype-driven stratification and targeted therapy in dry eye disease

S. no	DED phenotype	Key diagnostic features	Point-of-care tests	Targeted treatment strategy
1	Aqueous-deficient DED	Low Schirmer, conjunctival staining	Schirmer, osmolarity	Secretagogues, serum drops, punctal plugs
2	Evaporative DED (MGD)	Normal volume, ↓ TBUT	Meibography, interferometry	Lipid drops, thermal pulsation, IPL
3	Inflammatory DED	Hyperemia, burning	MMP-9 positive	Lifitegrast, cyclosporine, short steroid
4	Neuropathic pain	Severe symptoms, minimal signs	Symptom–sign mismatch	Serum drops, neuromodulators
5	Mixed DED	Overlapping features	Combined testing	Combination therapy

DED dry eye disease, MGD meibomian gland dysfunction, TBUT tear breakup time, IPL intense pulsed light, MMP-9 matrix metalloproteinase-9

Long-Term Management and Patient Support Strategies

Managing dry eye disease is a long-term endeavor. As a chronic condition with fluctuating severity, DED requires not only acute symptom relief but also sustained maintenance therapy and regular monitoring. Recent advances reflect this chronic disease management perspective, focusing on improving treatment adherence, patient education, and utilization of technology to track disease over time (Fig. 5) [68].

Fig. 5.

Depicts the chronic disease management model for dry eye disease. DED dry eye disease

Chronic Disease Model of Care

Dry eye is now being treated like a chronic disease just like glaucoma or diabetes. Patients need to know it’s not a one-time fix. They’ll need consistent care over years. Clinicians, in turn, should stop “as-needed” plans and instead set regular follow-ups maybe every 3 to 6 months – to monitor symptoms, inflammation markers, and tweak treatment [69]. Long-term care often includes maintenance therapy like cyclosporine or lifitegrast, even when symptoms improve. Bland ointments and punctal plugs help with exposure-related issues [70]. During flare-ups like allergy season or screen-heavy weeks, short steroid courses (like loteprednol) or more lubricants may be needed. This approach is like asthma: daily control plus rescue plans. Educating patients to recognize flares and act early is key. Managing DED this way prevents severe relapses and supports long-term ocular surface stability (Table 4) [71].

Table 4.

Depicts the long-term dry eye management: Chronic disease mode. QoL Quality of Life

S. no	Domain	Strategy	Clinical rationale
1	Maintenance therapy	Long-term immunomodulators	Prevents inflammatory relapse
2	Flare control	Short steroid bursts	Rapid symptom suppression
3	Lifestyle modification	Blink training, screen breaks	Reduces evaporative stress
4	Adherence support	Digital reminders, apps	Improves long-term compliance
5	Follow-up model	Scheduled 3–6-month reviews	Enables proactive adjustment
6	Psychosocial care	Patient education, counseling	Improves satisfaction and QoL

Lifestyle and Environmental Management

Long-term non-pharmacologic strategies significantly influence dry eye control. Regular breaks from screens, conscious blinking, and using humidifiers or wraparound glasses can reduce evaporative stress [72]. Omega-3 supplements show mixed results but may help some patients, and anti-inflammatory diets are encouraged. Adequate hydration and minimizing caffeine/alcohol can support tear production. Managing systemic diseases (e.g., thyroid, RA) helps control ocular symptoms [73]. Reviewing medications (antihistamines, isotretinoin) that worsen DED is crucial. Lid hygiene is vital for MGD daily warm compresses and lid scrubs (with baby shampoo, hypochlorous acid sprays, or commercial pads) help prevent recurrence. Such lifelong habits complement medical treatments and promote sustained symptom relief [74].

Improving Adherence and Patient Education

One of the greatest challenges in chronic dry eye management is poor adherence. Many treatments like artificial tears or lid hygiene require frequent use, but patients often reduce or stop them once symptoms ease [75]. Studies show many do not use drops as prescribed or discontinue therapy within a month. Reasons include cost, inconvenience, side effects (e.g., burning), or lack of immediate benefit [76]. To improve compliance, clinicians must educate patients early: explain that dry eye is chronic, consistent therapy yields long-term relief, and inflammation control is vital. Simple explanations (“this drop reduces hidden inflammation”) help motivate use [77]. Written action plans, virtual tools, or mobile apps that remind and track drop usage have shown positive outcomesnews-medical.net. Behavioral tips like pairing drop use with daily routines or setting alarms can also help. Regular follow-ups increase accountability, especially if outcomes (e.g., corneal staining) are monitored. Tailoring regimens like using preservative-free drops or punctal plugs—can address side effects and reduce treatment burden [78].

Digital Monitoring and Telemedicine

Digital tools are emerging in dry eye care. Apps now help patients track symptoms, assess blink rate via phone cameras, or do blink training. For example, the free MyDryEye app reminds patients to blink, log symptoms, and track screen time [79]. A study found it reduced symptoms and incomplete blinks within 2 weeks. Apps act as digital coaches with daily prompts. Clinics now use remote monitoring patients complete Ocular Surface Disease Index (OSDI) forms online or use home devices (e.g., blink sensors, osmolarity readers) to send data to providers [80]. Teleconsults manage routine follow-ups, offering convenience and sustained care. During COVID-19, many patients benefited from virtual dry eye visits. Going forward, hybrid care models—combining in-person and remote visits may improve patient engagement, adherence, and outcomes in chronic dry eye management [81]. Current literature suggests that digital health interventions—such as smartphone-based reminders, treatment-tracking apps, automated instillation alerts, and tele-ophthalmology follow-up—may enhance patient engagement and reinforce routine treatment behaviors. However, robust data demonstrating sustained long-term adherence or significant clinical outcome improvements remain limited [82]. Most published studies report improved symptom logging, increased patient–clinician communication, or short-term gains in medication compliance, rather than definitive reductions in disease severity. Furthermore, the heterogeneity of study designs, variable endpoints, and lack of standardized adherence metrics make cross-comparison challenging [83].

Psychosocial Support and Patient Centered Care

Chronic dry eye can have a significant psychological impact, particularly in severe cases, leading to frustration, anxiety, and reduced quality of life. Recognizing this burden is an important component of long-term management [84]. Validating symptoms and acknowledging their daily impact helps build trust and improve the therapeutic relationship. Some practices assess how dry eye affects routine activities and emotional well-being to guide care [85]. Patient-centered management also involves aligning treatment with individual goals. For example, avid readers may prioritize therapies that improve reading comfort, while contact lens users may focus on extending comfortable wear time [86]. Creating a sustainable management plan requires education, flexibility, and ongoing support. Although new treatments and monitoring tools are valuable, long-term success ultimately depends on a strong partnership between patient and clinician. With active patient participation and tailored strategies, even severe dry eye can be effectively controlled rather than debilitating [86].

To strengthen interpretability and ensure consistency across therapeutic descriptions, the present review differentiates between statistically significant improvements and outcomes that are clinically meaningful for patients with dry eye disease. For each intervention, the type of outcome demonstrating benefit is explicitly stated—whether primarily symptom-based (e.g., Ocular Surface Disease Index [OSDI], Dry Eye Questionnaire-5 [DEQ-5]) or sign-based (e.g., tear breakup time [TBUT], corneal/conjunctival staining, Schirmer test values) [87]. Where available, commonly accepted thresholds for clinical relevance are provided, such as a ≥ 10-point reduction in OSDI indicating a meaningful symptomatic improvement, or a ≥ 3-s increase in TBUT reflecting functional tear-film stabilization. Trial comparators are also clarified on a study-by-study basis, distinguishing vehicle-controlled trials from those using active comparators such as artificial tears, topical corticosteroids, or alternate immunomodulators, thereby allowing accurate interpretation of relative therapeutic magnitude [88].

Because therapeutic durability and retreatment needs vary substantially across pharmacologic and device-based options, the review specifies the expected onset and duration of effect for each modality. Chronic immunomodulators (e.g., cyclosporine, lifitegrast) typically require continuous daily dosing to maintain benefits, whereas device-based interventions such as intense pulsed light (IPL), thermal pulsation, or meibomian gland heating systems may produce improvements that persist for several months, though retreatment is often required at 4–12-month intervals depending on disease severity and glandular function [89]. Neurostimulation therapies generally provide rapid symptomatic relief but with shorter duration, necessitating repeated or ongoing use. Outcome variability across clinical studies is also acknowledged, particularly differences in follow-up duration, study design, inclusion criteria, and choice of endpoints (OSDI, TBUT, fluorescein staining, lissamine green staining, Schirmer testing) [90]. In instances where evidence is limited to early-phase studies, small cohorts, or exploratory device evaluations, these limitations are stated explicitly to avoid overstating therapeutic efficacy. Collectively, the review provides transparent and clinically meaningful assessment of therapeutic effectiveness, enabling clinicians to understand not only whether an intervention is beneficial, but the type, degree, and durability of benefit expected based on current evidence (Table 5) [91].

Table 5.

Depicts the dry eye therapies: mechanism, phenotype target, evidence level, and regulatory status (USA, EU, India)

S. no	Therapy	Mechanism of action	Phenotype target	Evidence level	Regulatory status (USA/EU/India)
1	Cyclosporine 0.05–0.1%	Calcineurin inhibitor reducing T-cell-mediated inflammation	Inflammatory, aqueous-deficient	Strong (Multiple RCTs, long-term data)	Approved in all three regions
2	Lifitegrast 5%	LFA-1/ICAM-1 blockade reducing inflammatory cell recruitment	Inflammatory	Strong (phase 3 + real-world evidence)	Approved USA; limited EU access; India approval variable, mostly tertiary-center use
3	Loteprednol (Low-dose)	Corticosteroid suppressing inflammatory cytokines	Acute inflammation flares	Moderate–Strong	Approved in all three regions
4	Omega-3 fatty acids	Anti-inflammatory, lipid enhancement	Evaporative/lipid	Moderate (mixed RCT results)	Widely available OTC worldwide
5	Punctal Plugs	Reduces tear drainage to increase aqueous volume	Aqueous deficient	Moderate (cohort + RCTs)	Approved in all three regions
6	Autologous Serum/PRP Drops	Growth factor–rich biologic supporting epithelial healing	Severe aqueous deficiency, neurosensory	Moderate (observational + small RCTs)	USA/EU: regulated as biologics; India: widely available in hospital banks
7	Thermal Pulsation (LipiFlow®)	Heat + pulsation to clear meibomian glands	Evaporative/MGD	Strong (multiple RCTs)	Approved USA/EU; widely available in India in metro centers
8	Intense Pulsed Light (IPL)	Reduces peri-meibomian inflammation, improves lipid layer	Evaporative/inflammatory	Moderate–Strong	Approved USA/EU for MGD; India widely available
9	Neurostimulation devices	Stimulates trigeminal pathways to increase basal tear secretion	Aqueous deficiency	Moderate (device trials)	USA FDA-cleared; limited EU; India – niche availability
10	Neuromodulators (e.g., Gabapentin, Pregabalin)	Alters corneal pain signaling	Neuropathic ocular pain	Moderate (RWE, cohort)	Approved for neurologic pain; off-label in all regions
11	Rebamipide 2% (Asia)	Mucin secretagogue improving tear stability	Aqueous + mucin deficiency	Strong (Asian RCTs)	Japan/Asia approved; not approved in USA/EU; available in India through select distributors
12	Tavilermide (MIM-D3)	TrkA agonist enhancing mucin secretion	Mucin deficiency	Early evidence	Not approved; phase 2 data only
13	Rivenprost (Prostanoid EP2 agonist)	Improves goblet cell density and tear function	Aqueous + mucin deficiency	Early–moderate	Under investigation globally
14	TSG-6 derivatives	Anti-inflammatory and extracellular matrix–modulating	Severe inflammatory DED	Early	Pre-clinical/phase 1 only
15	Regenerating Agents (RGTA®)	Matrix mimetic promoting epithelial healing	Severe ocular surface damage	Moderate evidence	EU/India availability; not FDA-approved
16	PEDF-derived peptides	Anti-inflammatory, epithelial regeneration	Severe DED, neurotrophic	Early	Investigational globally
17	Platelet-derived formulations (PRP variants)	EGF, NGF-rich biologics promoting healing	Severe DED, post-LASIK neural deficits	Moderate evidence	Allowed in all three regions as in-house biologic preparations
18	Gene therapy candidates	Target mucin/goblet cell biology	Severe refractory DED	Preclinical only	Not approved anywhere

RCT randomized control trial, LFA-1 lymphocyte function-associated antigen-1, ICAM-1 interaction with intercellular adhesion molecule-1 (LFA-1/ICAM-1), OTC over the counter, PRP platelet-rich-plasma, MGD meibomian gland dysfunction, RWE real-world evidence, MIM-D3 mimetic peptide D3 [aka tavilermide], TrkA tropomyosin receptor kinase A, EP2 prostaglandin E₂ receptor subtype 2, EGF epidermal growth factor, NGF nerve growth factor, LASIK laser-assisted in situ keratomileusis

Conclusions

Dry eye disease management has evolved significantly in the 2020s. New pharmacologic agents—such as immunomodulators, corticosteroid suspensions, nasal sprays, and tear film stabilizers—have expanded options beyond artificial tears. At the same time, device-based treatments like thermal pulsation, intense pulsed light, and neurostimulation offer alternatives targeting meibomian gland dysfunction and tear production. These advances enable mechanism-specific care tailored to individual patient profiles. A major shift is underway toward personalized, long-term strategies based on patient phenotyping and continuous care. Diagnostic innovations, including tear biomarkers and imaging, help identify key disease drivers to guide targeted treatment. Recognizing dry eye as a chronic disease, experts now recommend maintenance regimens and digital tools to support adherence. The combined use of pharmacologic and device therapies offers the potential to disrupt the cycle of inflammation and tear instability, improving outcomes through a comprehensive, individualized, evidence-based approach.

Author Contributions

Bharat Gurnani: Conceptualization of the review, study design, development of the search strategy, data acquisition and interpretation, manuscript drafting, figure preparation, and critical revision for important intellectual content. Kirandeep Kaur: Methodology refinement, verification of extracted data, literature synthesis, preparation of tables and graphical summaries, manuscript editing, and critical review of the final manuscript. Both authors approved the final version of the manuscript, contributed substantially to its intellectual content, and agree to be accountable for all aspects of the work.

Funding

No funding or sponsorship was received for this study or publication of this article. No external support, either public or private, was received for the conduct of this study.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Bharat Gurnani is an Editorial Board member of Ophthalmology and Therapy. Bharat Gurnani was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Kirandeep Kaur has nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.