Dry eye disease (DED) is rising in prevalence globally, driven by factors such as aging populations, screen-based lifestyles and other environmental stressors. The rapid development of new therapies, from advanced biologics to innovative devices, often overshadows established treatments. This creates a challenge for clinicians to stay current while retaining previous foundational knowledge. For optometrists in the role of primary eyecare providers, success hinges on integrating both traditional and emerging treatments into practice. This article summarizes time-tested strategies and cutting-edge advancements, equipping clinicians to navigate the evolving landscape of dry eye management with confidence.
Often, the first line of defense requires no Rx, no equipment—no direct intervention at all. Lifestyle modifications are the simplest, yet some of the most important, changes a clinician can educate their patients about incorporating into their daily routine. Modifications such as a healthy anti-inflammatory diet, taking breaks from digital device use and avoiding smoke exposure can play a role in supplementing the improvement of symptoms in patients with any type of DED. Obesity and dry eye rates have continually been increasing in tandem. Studies have shown decreased physical activity and more time sedentary have been linked to DED.1 Obesity has been linked to higher Ocular Surface Disease Index (OSDI) scores, increased rates of meibomian gland dysfunction (MGD) and reduced tear break-up-time (TBUT).2,3
It takes as little as two months of lifestyle interventions to produce subjective improvement of dry eye symptoms.4 Recommending exercise and good eating habits will not only help a patient’s dry eye symptoms but will also have positive effects on their entire body.
Maintaining healthy habits, such as smoking cessation, proper makeup hygiene and appropriate contact lens practices, can significantly mitigate DED over the long-term. Smoking, a modifiable risk factor, destabilizes the tear film, reduces TBUT and increases corneal staining.4-6 Clinicians should emphasize smoking cessation to patients to improve dry eye symptoms and overall health.
Similarly, makeup use correlates with heightened dry eye symptoms, particularly in individuals who neglect proper removal techniques, highlighting the importance of educating patients on thorough makeup cleansing.8 The leading cause of contact lens dropout is discomfort at the end of the day, driven by dryness.9-10 Contact lens wearers must adhere to hygiene protocols to avoid exacerbating dryness. It is evident that contact lens wearers are more likely to have worse OSDI scores, MGD and reduced TBUT.11-12 By addressing these modifiable risk factors, clinicians empower patients to treat their DED through their own actions.
Eyelid hygiene plays a significant role in the overall homeostasis of the ocular surface. Lid margin inflammation and microbial overproliferation can both results in changes in meibum quality and decrease meibum secretions.13,14 These changes lead to one of the most common causes of dry eye: MGD. This in turn can cause an unstable tear film, leading to damage of the corneal epithelial cells, hyperosmolarity and increase in inflammatory cytokines.15 This inflammatory cycle leads to further exacerbation of MGD and the patient’s symptoms.16
At-home maintenance therapy is a great primary start for all patients, especially those who have MGD and anterior blepharitis. This includes warm compresses with massage, lid wipes, eyelid cleaners and/or eyelid brushes. These can be a great addition once the initial diagnosis is made and before the patient returns for a comprehensive dry eye exam. These treatments are also increasingly seen as critical to the success of ocular surgery outcomes and should be added to a patient’s routine before and after procedures such as cataract or refractive surgery.
Tear substitutes are the therapy most prescribed to patients by eyecare providers. They are also the broadest category, with many different types of options available. Most often, artificial tears are paired with initial at-home therapy (mentioned in the previous section) to help patients obtain temporary relief and establish chronic habits to help establish good ocular hygiene. Most artificial tears are aqueous based and contain viscosity-enhancing agents that provide extended lubrication to the ocular surface. They may also include oils, osmotic agents, antioxidants, preservatives and electrolytes.17
Preservative-free lubricants are a great option for patients with any type of dry eye, as they can help stabilize the tear film without causing toxicity.18 Patients who suffer from aqueous-deficient dry eye may benefit most from these, as they will help supplement the reduced tears. They are also very helpful to debulk allergens from the ocular surface in symptomatic patients, as a means of tamping down the exacerbation of dry eye that seasonal allergies can induce.
Some studies have shown lipid-based artificial tears are more effective in patients with evaporative dry eye and help stabilize the superficial lipid layer. Hyaluronic acid, a water-soluble compound, is a common ingredient in many artificial tears. Although technically considered an inactive ingredient by the FDA, it has shown protective qualities from BAK toxicity, UV radiation and chemical burns, along with anti-inflammatory and analgesic effects.19,20
In addition to artificial tear eye drops, preservative-free products such as gels, ointments and hydroxypropyl cellulose inserts offer extended lubrication for patients requiring longer-lasting tear supplementation.21 While these options can be used at any time, ointments are typically reserved for nighttime use due to their thick, occlusive texture, which can temporarily blur vision. These formulations are particularly beneficial for patients with moderate-severe aqueous-deficient dry eye, compromised lid closure or anatomical lid abnormalities that impair tear distribution or retention. Gels and inserts provide sustained extended daytime relief without significant visual disruption, whereas ointments excel in overnight protection, forming a protective barrier to prevent corneal exposure and desiccation during sleep. Together, these products address patient specific diverse needs in ocular surface management.
Over-the-counter dietary supplements are a valuable early adjunct in dry eye disease management. Omega-3 fatty acids (O3FAs), despite mixed opinions in the literature, exhibit anti-inflammatory effects and may improve meibum composition in MGD.22 A study analyzing meibum in Sjögren’s syndrome patients found more homogeneity in the lipid profile within the meibum of subjects taking O3FAs, supporting their role in assisting MGD management.23 Given their scarcity in Western diets and systemic anti-inflammatory benefits, O3FA supplements remain a valuable early recommendation.
Even though omega-6 fatty acids (O6FAs) are generally known to be proinflammatory, not all are. One formulation, gamma-linolenic acid (GLA), has been found to have anti-inflammatory properties.24 To benefit from the anti-inflammatory properties, it is important to consume GLA with EPA/DHA, for its conversion into an anti-inflammatory molecule.
Numerous controlled studies with GLA in the dry eye supplement HydroEye (Science Based Health) have shown significantly positive effects in improving aqueous-deficient dry eye, post-PRK dry eye, Sjögren’s syndrome KCS, contact lens–induced dry eye, evaporative dry eye and patients with MGD, mild-to-moderate dry eye and a post-menopausal dry eye study in women.2-31
A new formulation of lutein, zeaxanthin isomers and curcuminoids (Blink NutriTears, Bausch + Lomb) shows improved Schirmer’s scores, TBUT, osmolarity and OSDI scores. These antioxidants reduce oxidative stress and inflammation, correlating with reduced corneal staining and symptomatic relief.32,33 Such supplements address both structural and inflammatory components of DED, making it valuable, especially for any dry eye patient.
Increased inflammation is closely linked with dry eye as both a cause and an effect of the condition. The Tear Film and Ocular Surface Society (TFOS) DEWS II report elegantly described how the “vicious cycle” of inflammation perpetuates dry eye. As such, elevated inflammatory markers, such as MMP-9, are to be expected in the tear film. Irrigation of the ocular surface has shown to reduce MMP-9 and improve symptoms of DED. A randomized clinical trial showed irrigation of the eye resulted in 68% reduction of the OSDI score compared to artificial tears use.34 Another study shows daily irrigation of the eye improved OSDI and reduced MMP-9 levels.35,36
A recently introduced irrigation device called Rinsada also performs eyelid retraction, which allows the aiming of fluid towards the fornix with pressure. When compared to standard irrigation, performance with the eyelid retracted showed significantly more reduction of MMP-9.37
Eyelid debridement, meibomian gland expression and microblephroexfoliation (MBE) are great primary in-office treatments for managing anterior blepharitis and MGD. Lid debridement involves gentle mechanical removal of biofilm, keratinized epithelium and debris from the lid margin using a gold spud, which restores gland orifice opening and facilitates meibum flow. This procedure, combined with manual meibomian gland expression, is recommended as a first-line intervention during initial dry eye evaluations and follow-ups. Together, they provide critical diagnostic insights into gland obstruction severity, biofilm burden and meibum quality, helping tailor further therapies.
MBE, an advanced form of debridement, enhances outcomes by thoroughly exfoliating the lid margin, helping remove biofilm and anterior blepharitis accumulation.38 A clinical study demonstrated that MBE significantly improved subjective symptoms, enhanced meibomian gland secretion quality and reduced inflammatory biomarkers such as matrix MMP-9 in patients with moderate-to-severe MGD.39 MBE is a great tool to be used early in the treatment pyramid for patients with MGD and anterior blepharitis.
Once a mainstay of dry eye management, punctal occlusion is now considered a second-tier treatment by TFOS DEWS II. It becomes indicated once there is an insufficient volume of tears, often seen in aqueous-deficient dry eye. It allows the retention of natural tears on the ocular surface, improving tear film quality, quantity and stability. Punctal occlusion can be achieved through several methods, including permanent plugs, dissolvable plugs—especially the new tapered 180-day plugs (Oasis Medical)—canalicular gel made from cross-linked HA (Lacrifill, Nordic Pharmaceuticals) or cauterization. After some control of inflammation has been achieved, punctal occlusion results in improvement in subjective symptoms, ocular staining, tear film stability and a decrease in artificial tear use.40
A proper seal of the upper and lower eyelids is essential to maintain overnight ocular surface hydration, especially since tear production already is reduced at nighttime.41 In many patients, the lids can come together but not seal, resulting in inefficient moisture seal despite apparent lid contact. This is different than nocturnal lagophthalmos, where the lid separation is apparent during the ocular exam and often noticed by a family member.42
Diagnosis is made by morning symptoms as these patients will report issues upon awakening.43 Moisture-retaining or lid closure therapies such as lid tapes or seals (SleepTite, SleepRite), moisture goggles and lid weights allow patients to prevent overnight dryness. Addressing nighttime exposure and pairing it with daytime therapies can really improve the quality of life of our patients.
Corticosteroids are a valuable short-term adjunct in the long-term management of DED, particularly during periods of heightened ocular inflammation, such as dry eye flares or more severe initial presentations. This inflammatory component is seen in both aqueous-deficient and evaporative dry eye, driving symptoms such as discomfort, hyperemia and epithelial damage.44 Steroids exert their anti-inflammatory effects by inhibiting phospholipase A2 at the cellular membrane, thereby blocking the arachidonic acid cascade and reducing proinflammatory cytokine release.45 Their relatively rapid action makes them ideal for acute flares or bridging with sustained therapies like topical immunomodulators (e.g., cyclosporine, lifitegrast).
Objective metrics such as tear osmolarity MMP-9 testing can help identify patients with active inflammation, while corneal/conjunctival staining visually confirms inflammatory damage. Clinical studies demonstrate that short-term steroid use improves OSDI scores, staining severity, tear film stability (via TBUT), meibum quality and meibomian gland expressability.46 However, due to risks of elevated intraocular pressure or cataract formation with prolonged use, steroids should be transitioned to maintenance therapies, such as immunomodulators or therapies that address the root cause of the inflammation, such as antievaporative medications.
Modifying the physiological immune response by targeting inflammatory mediators to reduce damage to ocular surface tissues has been the backbone of prescription drug therapy for dry eye for over two decades.47 This class of medications includes cyclosporine and lifitegrast, which can be initiated as early as stage 2 (moderate severity) of DED.48 Despite their differing mechanisms, both reduce inflammation and help restore ocular surface homeostasis.
Clinical evidence supports their efficacy once a treatment effect manifests after an initial ramp-up period. A study of 0.05% cyclosporine (Restasis, Abbvie) demonstrated increased goblet cell density in the bulbar conjunctiva after two to three months, enhancing mucin production critical for tear film stability.49 Higher concentrations of cyclosporine include a 0.09% with a nanomicellar vehicle (Cequa, Sun Pharmaceuticals) allowing for significantly greater drug concentrations in the cornea.50
Similarly, the OPUS trials revealed that lifitegrast significantly improved both signs and symptoms of DED vs. placebo.51 These agents are particularly effective for aqueous-deficient dry eye associated with chronic inflammation, such as Sjögren’s syndrome or autoimmune-related dry eye.
Due to their delayed onset, immunomodulators are often paired with short-term corticosteroids for rapid symptom control—a synergistic strategy to address acute flare-ups while establishing long-term anti-inflammatory environment.
The newest immunomodulator (Vevye, Harrow) combines a higher concentration of cyclosporine (0.1%) with a perfluorobutylpentane vehicle; like previous cyclosporine formulas, it is preservative-free. However, this particular formulation has no water, and thus no pH, making it far more comfortable. It also has been shown to increase cyclosporine concentration in the ocular surface by 22 times over 0.5% cyclosporine (Restasis).52 In the clinical studies, it showed statistically significant improvement in total corneal fluorescein staining and symptoms as early as day 15 that continued to the study’s end at 113 days.53
The quintessential problem in evaporative dry eye is the presence of an inadequate, unstable lipid layer. The somewhat new drug perfluorohexyloctane (Meibo, Bausch + Lomb) mimics artificial tears but employs a distinct mechanism to alleviate dry eye symptoms, stabilizing the tear film by supplementing the lipid layer.54 By forming a protective barrier over the ocular surface, Meibo helps reduce tear evaporation and shields the eye from environmental stressors.
FDA trials demonstrated significant improvement in corneal staining and DED symptoms within eight weeks of perfluorohexyloctane use.55 Measurements were taken at day 15 and day 57; improvement in corneal fluorescein staining at day 15 was two times greater than the vehicle.56,57 Symptoms of eye dryness improved 1.5 times over vehicle at day 15 and day 57 as well. This dry eye medication was also found to be the most tolerable on the market, with only one patient out of 614 dropping out of the study due to adverse events, while three noted mild burning and 13 noted mild blur upon instillation.
Perfluorohexyloctane’s unique physicochemical properties make it particularly beneficial for patients with evaporative dry eye, offering sustained relief while maintaining clarity of vision.
Blepharitis is a progressive, chronic inflammatory condition of the eyelids that drives ocular surface irritation and secondary dry eye disease.58 Up to 50% of chronic blepharitis cases involve ectoparasite infestation (e.g., Demodex mites), which exacerbate inflammation through mechanical blockage of meibomian glands, direct tissue damage and bacterial overgrowth.59-61 Demodex mites trigger immune responses via their exoskeletons, waste products and aiding microbial proliferation, perpetuating a cycle of inflammation, gland dysfunction and even gland loss.62,63 Demodex infestation has also been correlated with ocular rosacea, suggesting a shared pathogenic mechanism such as immune dysregulation or microbial dysbiosis, which may contribute to both facial and ocular inflammatory manifestations.
We’re now fortunate to have access to lotilaner ophthalmic solution 0.25% (Xdemvy, Tarsus Pharmaceuticals), a selective parasiticide that targets Demodex by inducing paralysis and death.64 Clinical trial data demonstrated that twice-daily use for six weeks achieves near-complete mite eradication and significantly reduces collarettes.65 By eliminating the parasitic burden, lotilaner disrupts the inflammatory cascade, enabling restoration of proper gland function and tear film stability, allowing patients to experience reduction in lid margin inflammation and symptoms like itching and burning.66
Recent studies have suggested that lotilaner may be beneficial in the management of MGD associated with Demodex blepharitis, improving the number of meibomian glands producing liquid secretion by 78% at day 85 and statistically significant improvements in fluctuating vision, burning, itching and redness.
Tea tree oil, historically the mainstay treatment for Demodex, remains an option for mild cases or limited-resource settings, used in scrubs or diluted solutions.67 Note, however, that it may have some level of toxicity to the meibomian glands.68 These two therapies—lotilaner and tea tree oil—provide a targeted approach to reducing Demodex burden while supporting ocular surface and adnexal health. Okra extract applied to the eyelids also can show good efficacy in controlling Demodex infestations. Some studies have also explored the role of agents such as esterase inhibitors, sulfur ointment and mercury ointment, but these are rarely employed in clinics.
A good long-term maintenance therapy that does not expose patients to potential toxicity is Manuka extract in a lid scrub that also contains aloe and coconut oil (MyboClean, Denali Ocular Creations). Manuka is a natural antiparasitic known for its effects on Demodex blepharitis. In addition, coconut oil has also been found to be effective.69
Patients with ocular rosacea can experience ocular surface effects as well. In such patients, topical ivermectin 1% cream (Soolantra, Galderma), applied to the face and adnexal areas, may be of value.
Soft contact lenses play a vital role in managing various corneal complications, including DED. Bandage lenses, particularly those made from silicone hydrogel (SiHy), provide comfort and protection in ocular surface disorders such as chemical burns, Stevens-Johnson syndrome (SJS), recurrent corneal erosions, abrasions and postsurgical complications.70,71
A study on Sjögren’s syndrome patients demonstrated that SiHy lenses were as effective as autologous serum tears, with both groups showing significant improvements in visual acuity, OSDI scores and TBUT. Notably, the contact lens group exhibited lower corneal staining scores after six weeks of treatment.72 Another study highlighted that continuous wear of SiHy lenses for one month reduced dry eye symptoms and improved visual acuity, underscoring their therapeutic potential.73
Scleral contact lenses have in recent years become another cornerstone in managing severe dry eye, particularly in exposure keratopathy, SJS, Sjögren’s and post-refractive surgery dry eye.74,75 According to the DEWS II guidelines, scleral lenses are recommended at step 3 of the treatment algorithm, reserved for advanced or refractory cases. Clinical studies have shown improvements in OSDI scores, corneal staining and symptomatic relief with scleral lens use.76,77 By vaulting the cornea and maintaining a fluid reservoir, these lenses provide unparalleled protection and hydration, making them a great tool for patients with severe ocular surface disease.
Doxycycline (a tetracycline derivative) and azithromycin (a macrolide) are commonly used in conditions like blepharitis and MGD for their dual antimicrobial and anti-inflammatory properties.78-80 Some comparative studies between doxycycline and azithromycin suggest azithromycin may achieve more superior clinical outcomes in certain cases.81,82
Oral nicergoline—originally used for the treatment of cognitive impairment, degenerative dementia and strokes—is emerging as a promising off-label therapy for certain ocular surface diseases.83,84 Animal studies have suggested a mechanism involving the upregulation of nerve growth factor and acetylcholine within the cornea and lacrimal gland. Nerve growth factor promotes epithelial cell proliferation and differentiation, leading to healing of persistent epithelial defects. The epithelial healing has been shown in several animal studies and recently in human subjects as well.85,86 These healing properties make this a great option for patients with neurotrophic keratitis (NK).
Energy-based interventions for DED use light or radiofrequency (RF) pulses to target MGD and evaporative dry eye. Intense pulsed light (IPL) devices deliver a broad spectrum of light, while low-level light therapy (LLLT) uses a single wavelength, typically red or blue. Thermal pulsation devices apply heat and pressure, and radiofrequency (RF) treatment generates electromagnetic waves to generate localized heat. These modalities improve eyelid margin health, addressing inflammation and MGD to effectively treat DED. Telangiectasia, commonly seen in patients with MGD and rosacea, contributes to inflammation and gland dysfunction. This further highlights the importance of energy-based treatments for evaporative dry eye associated with MGD and lid disease.87,88
IPL has a notable limitation—its efficacy and safety are influenced by skin pigmentation. It is primarily recommended for patients with Fitzpatrick skin types I-III. Newer IPL systems have self-cooling heads that don’t require coupling gel, and so in some cases type IV skin types and even occasionally type V can be treated. Patients with darker skin tones (types V-VI) risk depigmentation at the treatment site. For these individuals, alternative therapies such as LLLT, RF and thermal pulsation are effective options.
IPL delivers light energy that achieves multiple therapeutic results, including thrombosis of superficial blood vessels, liquefaction of meibum, photobiomodulation, reduction of Demodex mites and decreased ocular surface inflammation.89-93 Similarly, LLLT has demonstrated efficacy in preclinical and clinical studies, through its photobiomodulatory and anti-inflammatory properties to treat ocular surface disease.94,95
Combining IPL with LLLT offers further benefit, with clinical trials reporting significant improvements in OSDI scores, TBUT, Schirmer’s scores and meibomian gland expression.96,97 While beneficial for a broad range of dry eye patients, these therapies are particularly effective for patients with MGD and patients with ocular rosacea, addressing both gland obstruction and inflammation.
Radiofrequency systems generate electromagnetic waves via an oscillatory electrical field to charge tissue particles. This leads to the vibration of the particles, causing heat generation within the tissue. When applied to the lid margin, RF energy enables targeted heating of meibomian glands, aiding in the treatment of MGD by unclogging obstructed glands, stimulating heat-shock protein expression and reducing inflammation.98 RF can also complement IPL therapy. Together, they synergistically improve both signs and symptoms of DED. Frequent RF application can raise concerns for periocular tissue hollowing, so this procedure is not intended to be performed indefinitely.
Thermal expression (TearCare, Sight Sciences) and thermal pulsation (LipiFlow, Johnson & Johnson; iLux, Alcon) are two additional in-office therapies for MGD. Thermal expression involves heating the lid margin followed by manual gland expression to clear obstructions. In contrast, thermal pulsation combines heating with pulsatile pressure to massage and unclog glands simultaneously.99
Controlled studies show thermal pulsation improves gland secretions, TBUT, Schirmer’s test scores and symptom relief compared to traditional home therapies.100 The therapeutic response to thermal expression and thermal pulsation seems to be similar.101 However, studies on thermal expression with the TearCare system have shown it provided a statistically superior and sustained improvement in TBUT and multiple measures of meibomian gland expression compared to an arm that maintained cyclosporine drops BID.102
For patients with complex ocular surface diseases, amniotic membranes are a great therapeutic tool for restoring homeostasis and catalyzing the healing response. They offer mechanical protection as well as anti-inflammatory, anti-scarring and pro-regenerative properties.103,104 Options are available in cryopreserved, dehydrated and powder forms.
Amniotic membranes are particularly beneficial for patients with severe aqueous-deficient DED, SJS, filamentary keratitis, NK, limbal stem cell deficiency, recurrent corneal erosion and exposure keratopathy.105-107 Cryopreserved membrane (Prokera, Biotissue) has been shown to promote corneal nerve regeneration and resolve keratitis in clinical studies.108 Dehydrated membranes demonstrate significant improvements in OSDI scores, corneal nerve density and epithelial staining.109 A new ringless cryopreserved amniotic membrane (CAM 360, BioTissue) was recently introduced that can also be used within a disposable collagen shield (Oasis Medical).
Amniotic membranes provide a multifunctional approach in managing severe ocular surface disorders that is essential to any dry eye clinic.
The trigeminal parasympathetic pathway regulates approximately one-third of basal tear secretion.110Activation of this can be achieved via electromechanical devices that stimulate the nasolacrimal reflex or through use of varenicline nasal spray, which activates nicotinic acetylcholine receptors in the nasal mucosa to trigger tear secretion.111 Varenicline in particular has shown significant improvements in Schirmer’s test scores and subjective symptoms.112 Neurostimulation offers an innovative, mechanism-driven approach for aqueous-deficient dry eye. Patient education on proper administration is important to success.
Cenegermin, an FDA-approved topical biologic for neurotrophic keratitis, promotes corneal healing by restoring corneal nerve function and epithelial integrity. Clinical trials have shown about 70% of patients achieve complete corneal healing within eight weeks of use, with restored sensitivity, transparency and structural transparency.113,114
For aqueous-deficient dry eye, insulin and insulin-like growth factor drops offer regenerative benefits, enhancing corneal epithelial proliferation, nerve regeneration and ATP production.115,116 While their exact mechanism remains unclear, insulin drops show efficacy in NK, along with aqueous-deficient and to a lesser degree evaporative dry eye. Patients with dry eye instilling insulin drops have shown improving symptoms, conjunctival hyperemia and corneal staining.117,118
Autologous serum tears and platelet-rich plasma (PRP) tears are blood-derived therapies with different places in the dry eye regimen. Serum tears mimic natural tears in pH, osmolarity and biomechanical properties aiding autoimmune-related, keratoconjunctivitis sicca and inflammatory dry eye.119,120 Concentrations of 40% QID to Q2H are most often recommended.
PRP tears are rich in growth factors from concentrated platelets, which accelerates tissue repair in evaporative dry eye, aqueous-deficient dry eye and NK.121-124 PRP’s superior growth factor profile makes it more effective for severe ocular surface repair, while serum tears are typically more for advanced cases involving SPK, keratoconjunctivitis sicca, NK or LSCD.125
A mucolytic agent, N-acetylcysteine effectively breaks down abnormal mucus strands. This property makes it a good therapy for filamentary keratitis.126,127 It also holds anti-inflammatory properties, which stem from its ability to neutralize free radicals and inhibit reactive acid metabolites.128 Clinical studies highlight N-acetylcysteine’s value in managing moderate-to-severe dry eye characterized by thickened mucous discharge, where it reduces mucus accumulation, promotes corneal epithelialization and improves symptoms.129 By targeting both structural and inflammatory components, N-acetylcysteine offers therapeutic benefits for filamentary keratitis and complex dry eye cases.
The agent requires QID dosing and has an unpleasant odor, both of which can lead to patient nonadherence, but those who tolerate the therapy can achieve good results.
Intraductal meibomian gland probing (MGP) is based on the theory that MGD involves periductal fibrosis and ductal stenosis, and that mechanically dilating gland orifices and ducts with a probe may restore glandular function. However, clinical evidence supporting MGP remains limited, as existing studies lack a randomized controlled trial and show inconsistent results.130 Despite this, MGP is clinically offered for MGD, though its efficacy and role in treatment algorithms remains questionable.
Tarsorrhaphy involves partial or complete eyelid closure using sutures, adhesives or botulinum toxin–induced levator muscle paralysis to shorten the palpebral fissure. This limits environmental exposure, enhancing lubrication and protection of the ocular surface.131 The procedure is usually reserved for patients with severe dry eye, often with persistent epithelial defects, corneal ulcers and those at risk of corneal perforation, as it can severely limit vision. In one study of non-healing persistent epithelial defects, tarsorrhaphy achieved >75% complete healing rates.132,133
Surgical correction of structural abnormalities (e.g., ectropion, entropion, floppy eyelids, Salzmann’s nodules, pterygia) is critical, as these conditions exacerbate DED. For severe aqueous-deficient dry eye, advanced options include salivary/submandibular gland transplantation and mesenchymal stem cell (MSC) injections, which promote tear production and ocular surface regeneration are available. However, these procedures are less commonly performed.
Dry eye can be exacerbated by conditions such as benign essential blepharospasm and hemifacial spasm. Botulinum toxin A (BTX-A) injections can be very beneficial for patients with these conditions and are also emerging as a promising treatment for DED alone. When injected into the lower lid, BTX-A temporarily paralyzes the orbicularis oculi muscle, reducing tear drainage and enhancing ocular surface lubrication.134 Additionally, BTX-A can also help regulate tear secretion and influence the tear film stability through its effects on lacrimal gland activity.135 A recent meta-analysis showed BTX-A can help increase TBUT, tear stability, OSDI scores, Schirmer results and tear lake.136 With these promising findings, this could possibly be a viable advanced treatment for patients with advanced DED.
Although the above categories give us no shortage of options to consider, research continues to pursue new treatment avenues for dry eye. There are dozens of products in development but we’ll highlight a few especially intriguing ones.
The Eye Lipid Mobilizer is a mechanical mask designed for in-office and home use to manage MGD. The thought is that by combining targeted heat and vibrational energy, it should facilitate the liquefaction and expression of obstructed meibum, improving gland function and tear film stability.
Acoltremon, a selective transient receptor potential melastatin 8 (TRPM8) agonist, activates cold-sensitive ion channels involved in trigeminal nerve signaling.137 TRPM8 receptors, which respond to temperature, osmolarity or pharmacological agonists like acoltremon, trigger membrane depolarization and action potentials that stimulate basal tear production.138 Clinical trials demonstrate promising results, including improved subjective symptoms, increased Schirmer’s scores and reduced ocular surface staining.139 This therapy will be particularly beneficial for patients with aqueous-deficient dry eye, exposure keratopathy or postsurgical dry eye.
Reproxalap targets reactive aldehyde species (RASP), key mediators of proinflammatory signaling cascades linked to ocular surface diseases.140 Elevated RASP levels are observed in conditions such as Sjögren’s syndrome, anterior uveitis, allergic conjunctivitis and DED.141-144 Clinical studies demonstrate that reproxalap reduces RASP concentrations, improving patient comfort, normalizing tear osmolarity and decreasing ocular surface staining. These findings suggest that reproxalap may be a promising therapeutic option for managing inflammatory ocular surface disorders, including inflammatory dry eye. Unfortunately, reproxalap did not demonstrate efficacy against dry eye symptoms in its FDA trials. The manufacturer plans to resubmit its application with new data later this year. The company recently shared topline data from a trial conducted in a dry eye chamber that showed encouraging results.145
In the near future, there is also the potential for an OTC product derived from silk fibroin, which would be our first protein-based therapeutic. Besides its strong anti-inflammatory effects, evident via NFkB inhibition, silk-derived protein (SDP-4) also has mucomimetic properties. In clinical trials, SDP-4 significantly increased TFBUT vs. the vehicle control (p<0.05) at days 28 and 56 as well as patient symptoms by 46% based on SANDE Visual Analog Scale scores at day 84. Patients with more severe DED symptoms experienced a significantly greater amount of relief than when compared to patients with moderate forms of dry eye.146 All treatment groups were well-tolerated with a 2.6% discontinuation rate. Especially impressive is this agent’s ability to treat conjunctival staining and its 100% natural composition.
Dry eye disease is a complex, multifactorial condition that demands a precision clinical approach. Successful management hinges on identifying the underlying etiology and tailoring treatments accordingly. As novel therapies emerge, clinicians must prioritize evidence-based, stepwise protocols while remaining adaptable to new therapies. By understanding available treatments and tailoring them to specific patient profiles, managing dry eye can become more streamlined.
Dr. Shah graduated from Illinois College of Optometry and completed a residency in ocular disease at Center for Sight and Dry Eye Institute in Carmel, IN. He is currently a clinical assistant professor at University of Houston College of Optometry and a fellow of the American Academy of Optometry. His primary focus is in perioperative care, glaucoma, and ocular surface disease. He has no financial disclosures.
Dr. Karpecki is director of cornea and external disease at the Kentucky Eye Institute in Lexington KY. He is the Chief Clinical Editor for Review of Optometry and chair of the New Technologies & Treatments conferences and the and the Ocular Surface Symposia. A fixture in optometric clinical education, he consults for a wide array of ophthalmic clients, including ones discussed in this article. Dr. Karpecki’s full disclosure list can be found here.
1. Kawashima M, Uchino M, Yokoi N, et al. The association between dry eye disease and physical activity as well as sedentary behavior: results from the Osaka study. J Ophthalmol. 2014;2014:943786.
2. Baser G, Yildiz N, Calan M. Evaluation of meibomian gland dysfunction in polycystic ovary syndrome and obesity. Curr Eye Res. 2017;42:661-665.
3. Kawashima M, Uchino M, Yokoi N, et al. Associations between subjective happiness and dry eye disease: a new perspective from the Osaka study. PLoS One. 2015;10(4):e0123299.
4. Kawashima M, Sano K, Takechi S, Tsubota K. Impact of lifestyle intervention on dry eye disease in office workers: a randomized controlled trial. J Occup Health. 2018;60(4):281-288.
5. Mohidin N, Jaafar AB. Effect of smoking on tear stability and corneal surface. J Curr Ophthalmol. 2020;32:232-237.
6. Bhutia P, Sen S, Nath T, Shamshad MA. The effect of smoking on ocular surface and tear film based on clinical examination and optical coherence tomography. Indian J Ophthalmol. 2021;69:1693-1696.
7. Yoon K-C, Song B-Y, Seo M-S. Effects of smoking on tear film and ocular surface. Korean J Ophthalmol. 2005;19:18-22.
8. O’Dell L, Periman L, Sullivan A, et al. An evaluation of cosmetic wear habits correlated to ocular surface disease symptoms. Invest Ophthalmol Vis Sci. 2017;58(8):495.
9. Begley CG, Chalmers RL, Mitchell GL, et al. Characterization of ocular surface symptoms from optometric practices in North America. Cornea. 2001;20:610-618.
10. Riley C, Young G, Chalmers R. Prevalence of ocular surface symptoms, signs and uncomfortable hours of wear in contact lens wearers: the effect of refitting with daily-wear silicone hydrogel lenses (senofilcon a). Eye Contact Lens. 2006;32:281-286.
11. Henriquez AS, Korb DR. Meibomian glands and contact lens wear. Br J Ophthalmol. 1981;65:108-111.
12. Craig JP, Willcox MD, Argueso P, et al. The TFOS International Workshop on Contact Lens Discomfort: report of the contact lens interactions with the tear film subcommittee. Invest Ophthalmol Vis Sci. 2013;54:TFOS123-TFOS156.
13. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and discomfort in patients with meibomian gland dysfunction. Arch Ophthalmol. 1995;113:1266-1270.
14. Lee SH, Oh DH, Jung JY, et al. Comparative ocular microbial communities in humans with and without blepharitis. Investig Ophthalmol Vis Sci. 2012;53:5585-5593.
15. Mizoguchi S, Iwanishi H, Arita R, et al. Ocular surface inflammation impairs structure and function of meibomian gland. Exp Eye Res. 2017;163:78-84.
16. Baudouin C, Messmer EM, Aragona P, et al. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016;100(3):300-306.
17. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628.
18. Gomes JAP, Azar DT, Baudouin C, et al. TFOS DEWS II iatrogenic report. Ocul Surf. 2017;15(3):511-538.
19. Kojima T, Nagata T, Kudo H, et al. The effects of high molecular weight hyaluronic acid eye drop application in environmental dry eye stress model mice. Int J Mol Sci. 2020;21(10):3516.
20. Gomis A, Pawlak M, Balazs EA, et al. Effects of different molecular weight elastoviscous hyaluronan solutions on articular nociceptive afferents. Arthritis Rheumatol. 2004;50(1):314-326.
21. Tong L, Petznick A, Lee S, et al. Choice of artificial tear formulations for patients with dry eye: where do we start? Cornea. 2012;31 Suppl 1:S32-S36.
22. Omega-3 fatty acids fact sheet for consumers. National Institutes of Health. Updated July 18, 2022. Accessed March 14, 2024.
23. Sullivan BD, Cermak JM, Sullivan RM, et al. Correlations between nutrient intake and the polar lipid profiles of meibomian gland secretions in women with Sjögren’s syndrome. Adv Exp Med Biol. 2002;506(Pt A):441-447.
24. Vasquez A. Reducing pain and inflammation naturally. Part II: new insights into fatty acid supplementation and its effect on eicosanoid production and genetic expression. Nutr Perspect. 2005;28(1):5-16.
25. Barabino S, et al. Systemic linoleic and gamma-linolenic acid therapy in dry-eye syndrome with inflammatory component. Cornea. 2003;22(2):97-101.
26. Macri A, Giuffrida S, Amico V, et al. The effect of LA and GLA on tear production, tear clearance and on the ocular surface after PRK surgery. Graefes Arch Clin Exp Ophthalmol. 2003;241:561-566.
27. Aragona P, et al. Systemic omega-6 essential fatty acid treatment and PGE1 tear content in Sjogren’s syndrome patients. Invest Ophthalmol Vis Sci. 2005;46:4474-4479.
28. Kokke KH, Morris JA, Lawrenson JG. Oral omega-6 essential fatty acid treatment in contact lens associated dry eye. Contact Lens Anterior Eye. 2008;31:141-146.
29. Pinna A, Piccinini P, Carta F. Effect of oral linoleic and gamma-linolenic acid on meibomian gland dysfunction. Cornea. 2007;26:260-264.
30. Brignole-Baudouin F, Baudouin C, Aragona P, et al. A multicentre, double-masked, randomized, controlled trial assessing the effect of oral supplementation of omega-3 and omega-6 fatty acids on a conjunctival inflammatory marker in dry eye patients. Acta Ophthalmol. 2007;89:e591-e597.
31. Sheppard J, Singh R, et al. Long-term supplementation with n-6 and n-3 PUFAs improves moderate-to-severe keratoconjunctivitis sicca: a randomized double-blind clinical trial. Cornea. 2013;32(10):1297-1304.
32. Gioia N, Gerson J, Ryan R, et al. A novel multi-ingredient supplement significantly improves ocular symptom severity and tear production in patients with dry eye disease: results from a randomized, placebo-controlled clinical trial. Front Ophthalmol. 2024;4:1362113.
33. Efficacy and safety of Nutritears in adults with dry eye syndrome. NCT05481450. Available from: https://clinicaltrials.gov/study/NCT05481450.
34. Diaz-Llopis M, Pinazo-Duran MD, Diaz-Guiñon L, et al. A randomized multicenter study comparing seawater washes and carmellose artificial tears eyedrops in the treatment of dry eye syndrome. Clin Ophthalmol. 2019;13:483-490.
35. Li X, Kang B, Eom Y, et al. The protective effect of an eye wash solution on the ocular surface damage induced by airborne carbon black exposure. Cornea. 2020;39(8):1040-1047.
36. Kim A, Postnikoff CK, Nichols KK. Non-pharmaceutical eye wash may reduce matrix metalloprotease-9 (MMP-9) in dry eye. Invest Ophthalmol Vis Sci. 2020;61(7):100.
37. Mayer N, Kondapalli SSA, Venkateswaran N, Saeed HN. The efficacy of an irrigating eyelid retractor-facilitated ocular rinse on MMP-9 expression and dry eye disease. Adv Ophthalmol Pract Res. 2024;4(3):142-146.
38. Epstein IJ, Rosenberg E, Stuber R, et al. Double-masked and unmasked prospective study of terpinen-4-ol lid scrubs with microblepharoexfoliation for the treatment of Demodex blepharitis. Cornea. 2020;39(4):408-416.
39. Moon SY, Han SA, Kwon HJ, et al. Effects of lid debris debridement combined with meibomian gland expression on the ocular surface MMP-9 levels and clinical outcomes in moderate and severe meibomian gland dysfunction. BMC Ophthalmol. 2021;21:175.
40. Yung YH, Toda I, Sakai C, et al. Punctal plugs for treatment of post-LASIK dry eye. Jpn J Ophthalmol. 2012;56:208-213.
41. Baum J. A relatively dry eye during sleep. Cornea. 1990;9:1.
42. Gauba V, Curtis ZJ. Sleep position and the ocular surface in a high airflow environment. Saudi J Ophthalmol. 2014;28:66-68.
43. Blackie CA, Korb DR. A novel lid seal evaluation. Eye Contact Lens. 2015;41(2):98-100.
44. Baudouin C. The pathology of dry eye. Surv Ophthalmol. 2001;45(Suppl 2):211-220.
45. Errasfa M, Russo-Marie F. A purified lipocortin shares the anti-inflammatory effect of glucocorticosteroids in vivo in mice. Br J Pharmacol. 1989;97:1051-1058.
46. Lee H, Chung B, Kim KS, et al. Effects of topical loteprednol etabonate on tear cytokines and clinical outcomes in moderate and severe meibomian gland dysfunction: randomized clinical trial. Am J Ophthalmol. 2014;158(6):1172-1183.
47. Radomska-Leśniewska DM, Skopiński P, Bałan BJ, et al. Angiomodulatory properties of Rhodiola spp. and other natural antioxidants. Centr Eur J Immunol. 2015;40:249-262.
48. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25:900-910.
49. Pflugfelder SC, De Paiva CS, Villarreal AL, et al. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea. 2008;27:64-69.
50. Cholkar K, Gilger BC, Mitra AK. Topical, aqueous, clear cyclosporine formulation design for anterior and posterior ocular delivery. Transl Vis Sci Technol. 2015;4(3):1-16.
51. Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology. 2016.
52. Agarwal P, Scherer D, Günther B, Rupenthal ID. Semifluorinated alkane based systems for enhanced corneal penetration of poorly soluble drugs. Int J Pharm. 2018;538(1-2):119-129.
53. Wirta DL, Torkildsen GL, Moreira HR, et al. A clinical phase II study to assess efficacy, safety and tolerability of water-free cyclosporine formulation for treatment of dry eye disease. Ophthalmology. 2019;126(6):792-800.
54. Agarwal P, Khun D, Krösser S, et al. Preclinical studies evaluating the effect of semifluorinated alkanes on ocular surface and tear fluid dynamics. Ocul Surf. 2019;17(2):241-249.
55. Tauber J, Wirta DL, Sall K, et al. A randomized clinical study (SEECASE) to assess efficacy, safety and tolerability of NOV03 for treatment of dry eye disease. Cornea. 2021;40(9):1132-1140.
56. Tauber J, Berdy GJ, Wirta DL, et al. NOV03 for dry eye disease associated with meibomian gland dysfunction: results of the randomized phase 3 GOBI study. Ophthalmology. 2023;130(5):516-524.
57. Sheppard JD, Kurata F, Epitropoulos AT, et al. NOV03 for signs and symptoms of dry eye disease associated with meibomian gland dysfunction: the randomized phase 3 MOJAVE study. Am J Ophthalmol. 2023;252:265-274.
58. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred practice pattern guidelines. Blepharitis. 2018; American Academy of Ophthalmology, San Francisco, CA, USA.
59. Zhao Y-E, Wu L-P, Hu L, Xu J-R. Association of blepharitis with Demodex: a meta-analysis. Ophthalmic Epidemiol. 2012;19(2):95-102.
60. Liu J, Sheha H, Tseng SC. Pathogenic role of Demodex mites in blepharitis. Curr Opin Allergy Clin Immunol. 2010;10:505-510.
61. Hung KH, Lan YH, Lin JY, et al. Potential role and significance of ocular demodicosis in patients with concomitant refractory herpetic keratitis. Clin Ophthalmol. 2020;14:4469-4482.
62. Fromstein SR, Harthan JS, Patel J, Opitz DL. Demodex blepharitis: clinical perspectives. Clin Optom. 2018;10:57-63.
63. Cheng S, Zhang M, Chen H, Fan W, Huang Y. The correlation between the microstructure of meibomian glands and ocular Demodex infestation: a retrospective case-control study in a Chinese population. Medicine (Baltimore). 2019;98:e15595.
64. Dourmishev AL, Dourmishev LA, Schwartz RA. Ivermectin: pharmacology and application in dermatology. Int J Dermatol. 2005;44:981-988.
65. Gaddie IB, Donnenfeld ED, Karpecki P, et al. Lotilaner ophthalmic solution 0.25% for Demodex blepharitis: randomized, vehicle-controlled, multicenter, phase 3 trial (Saturn-2). Ophthalmology. 2023;130(10):1015-1023.
66. Li J, Wei E, Reisinger A, et al. Comparison of different anti-Demodex strategies: a systematic review and meta-analysis. Dermatology. 2023;239(1):12-31.
67. Kheirkhah A, Blanco G, Casas V, Tseng SC. Fluorescein dye improves microscopic evaluation and counting of Demodex in blepharitis with cylindrical dandruff. Cornea. 2007;26:697-700.
68. Chen D, Wang J, Sullivan DA, et al. Effects of terpinen-4-ol on meibomian gland epithelial cells in vitro. Cornea. 2020;39(12):1541-1546.
69. Wong K, Flanagan J, Jalbert I, Tan J. The effect of Blephadex eyelid wipes on Demodex mites, ocular microbiota, bacterial lipase and comfort: a pilot study. Cont Lens Anterior Eye. 2019;42(6):652-657.
70. Montero J, Sparholt J, Mely R. Retrospective case series of therapeutic applications of a lotrafilcon A silicone hydrogel soft contact lens. Eye Contact Lens. 2003;29(1 Suppl):S54-S56.
71. Rashad R, Weed MC, Quinn N, Chen VM. Extended wear bandage contact lenses decrease pain and preserve vision in patients with epidermolysis bullosa: case series and review of literature. Ocul Immunol Inflamm. 2020;28:379-383.
72. Li J, Zhang X, Zheng Q, et al. Comparative evaluation of silicone hydrogel contact lenses and autologous serum for management of Sjogren syndrome-associated dry eye. Cornea. 2015;34:1072-1078.
73. Russo PA, Bouchard CS, Galasso JM. Extended-wear silicone hydrogel soft contact lenses in the management of moderate to severe dry eye signs and symptoms secondary to graft-versus-host disease. Eye Contact Lens. 2007;33:144-147.
74. Bavinger JC, DeLoss K, Mian SI. Scleral lens use in dry eye syndrome. Curr Opin Ophthalmol. 2015;26:319-324.
75. Chaudhary S, Ghimire D, Basu S, et al. Contact lenses in dry eye disease and associated ocular surface disorders. Indian J Ophthalmol. 2023;71:1142-1153.
76. La Porta Weber S, Becco de Souza R, Gomes JAP, Hofling-Lima AL. The use of the Esclera scleral contact lens in the treatment of moderate to severe dry eye disease. Am J Ophthalmol. 2016;163:167-173.e1.
77. Moon J, Lee SM, Hyon JY, et al. Large diameter scleral lens benefits for Asians with intractable ocular surface diseases: a prospective, single-arm clinical trial. Sci Rep. 2021;11:2288.
78. Greene JB, Jeng BH, Fintelmann RE, Margolis TP. Oral azithromycin for the treatment of meibomitis. JAMA Ophthalmol. 2014;132(1):121-122.
79. Igami TZ, Holzchuh R, Osaki TH, et al. Oral azithromycin for treatment of posterior blepharitis. Cornea. 2011;30(10):1145-1149.
80. Lindsley K, Matsumura S, Hatef E, et al. Interventions for chronic blepharitis. Cochrane Database Syst Rev. 2012;2012(5):Cd005556.
81. De Benedetti G, Vaiano AS. Oral azithromycin and oral doxycycline for the treatment of meibomian gland dysfunction: a 9-month comparative case series. Indian J Ophthalmol. 2019;67(4):464-471.
82. Kashkouli MB, Fazel AJ, Kiavash V, et al. Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomized double-masked open-label clinical trial. Br J Ophthalmol. 2015;99(2):199-204.
83. Ogawa N, Asanuma M, Hirata H, et al. Cholinergic deficits in aged rat brain are corrected with nicergoline. Arch Gerontol Geriatr. 1993;16:103-110.
84. Giardino L, Giuliani A, Battaglia A, et al. Neuroprotection and aging of the cholinergic system: a role for the ergoline derivative nicergoline (Sermion). Neuroscience. 2002;109:487-497.
85. Kim SY, Choi JS, Joo CK. Effects of nicergoline on corneal epithelial wound healing in rat eyes. Invest Ophthalmol Vis Sci. 2009;50:621-625.
86. Lee YC, Kim SY. Treatment of neurotrophic keratopathy with nicergoline. Cornea. 2015;34(3):303-307.
87. Viso E, Rodríguez-Ares MD, Oubiña B, Gude F. Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain. IOVS. 2012;53(6):2601-2606.
88. Toyos R, McGill W, Briscoe D. Intense pulsed light treatment for dry eye disease due to meibomian gland dysfunction: a 3-year retrospective study. Photomed Laser Surg. 2015;33(1):41-46.
89. Dell SJ. Intense pulsed light for evaporative dry eye disease. Clin Ophthalmol. 2017;11:1167-1173.
90. Karu T. Primary and secondary mechanisms of action of visible to near IR radiation on cells. J Photochem Photobiol B. 1999;49(1):1-17.
91. Kirn T. Intense pulsed light eradicates Demodex mites. Skin Allergy News. 2002;33:37.
92. Byun J, Choi H, Myung K, Choi Y. Expression of IL-10, TGF-β1 and TNF-α in cultured keratinocytes (HaCaT cells) after IPL treatment or ALA-IPL photodynamic treatment. Ann Dermatol. 2009;21(1):12-17.
93. Taylor M, Porter R, Gonzalez M. Intense pulsed light may improve inflammatory acne through TNF-α down-regulation. J Cosmet Laser Ther. 2014;16(2):96-103.
94. Kim H, Kim HB, Seo JH, et al. Effect of 808-nm laser photobiomodulation treatment in blepharitis rat model. Cornea. 2021;40:358-363.
95. Gonnelli FA, et al. Low-level laser therapy for the prevention of low salivary flow rate after radiotherapy and chemotherapy in patients with head and neck cancer. Radiol Bras. 2016;49:86-91.
96. Stonecipher K, Abell TG, Chotiner B, et al. Combined low level light therapy and intense pulsed light therapy for the treatment of meibomian gland dysfunction. Clin Ophthalmol. 2019;13:993-999.
97. Di Marino M, et al. Combined low-level light therapy and intense pulsed light therapy for the treatment of dry eye in patients with Sjögren’s syndrome.
98. Chelnis J, Garcia CN, Hamza H. Multi-frequency RF combined with intense pulsed light improves signs and symptoms of dry eye disease due to meibomian gland dysfunction. Clin Ophthalmol. 2023;17:3089-3102.
99. Zhao Y, Veerappan A, Yeo S, et al. Clinical trial of thermal pulsation (LipiFlow) in meibomian gland dysfunction with pretreatment meibography. Eye Contact Lens. 2016;42(6):339-346.
100. Lane SS, DuBiner HB, Epstein RJ, et al. A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. Cornea. 2012;31(4):396-404.
101. Tauber J, Owen J, Bloomenstein M, et al. Comparison of the iLUX and the LipiFlow for the treatment of meibomian gland dysfunction and symptoms: a randomized clinical trial. Clin Ophthalmol. 2020;14:405-418.
102. Ayres BD, Bloomenstein MR, Loh J, et al. A randomized, controlled trial comparing TearCare and cyclosporine ophthalmic emulsion for the treatment of dry eye disease (SAHARA). Clin Ophthalmol. 2023;17:3925-3940.
103. Tseng SC. HC-HA/PTX3 purified from amniotic membrane as novel regenerative matrix: insight into relationship between inflammation and regeneration. Invest Ophthalmol Vis Sci. 2016;57:ORSFh1-ORSFh8.
104. Tseng SC, Espana EM, Kawakita T, et al. How does amniotic membrane work? Ocul Surf. 2004;2:177-187.
105. Tighe S, Mead OG, Lee A, Tseng SCG. Basic science review of birth tissue uses in ophthalmology. Taiwan J Ophthalmol. 2020;10:3-12.
106. Cheng AM, Zhao D, Chen R, et al. Accelerated restoration of ocular surface health in dry eye disease by self-retained cryopreserved amniotic membrane. Ocul Surf. 2016;14:56-63.
107. Chugh JP, Jain P, Sen R. Comparative analysis of fresh and dry preserved amniotic membrane transplantation in partial limbal stem cell deficiency. Int Ophthalmol. 2015;35(3):347-355.
108. John T, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. J Ophthalmol. 2017;2017:6404918.
109. Travé-Huarte S, Wolffsohn JS. Sutureless dehydrated amniotic membrane (Omnigen) application using a specialised bandage contact lens (OmniLenz) for the treatment of dry eye disease: a 6-month randomised control trial. Medicina (Kaunas). 2024;60(6):985.
110. Gupta A, Heigle T, Pflugfelder SC. Nasolacrimal stimulation of aqueous tear production. Cornea. 1997;16(6):645-648.
111. Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol. 2006;70(3):801-805.
112. Wirta DL, Torkildsen GL, Boehmer B, et al. ONSET-1 phase 2b randomized trial to evaluate the safety and efficacy of OC-01 (varenicline solution) nasal spray on signs and symptoms of dry eye disease. Cornea. 2022;41(10):1207-1216.
113. Deeks ED, Lamb YN. Cenegermin: a review in neurotrophic keratitis. Drugs. 2020;80(5):489-494.
114. Balbuena-Pareja A, Bogen CS, Cox SM, Hamrah P. Effect of recombinant human nerve growth factor treatment on corneal nerve regeneration in patients with neurotrophic keratopathy. Front Neurosci. 2023;17:1210179.
115. Stuard WL, Titone R, Robertson DM. The IGF/insulin-IGFBP axis in corneal development, wound healing and disease. Front Endocrinol (Lausanne). 2020;11:1-15.
116. Hatou S, Yamada M, Akune Y, et al. Role of insulin in regulation of Na+-/K+-dependent ATPase activity and pump function in corneal endothelial cells. Investig Ophthalmol Vis Sci. 2010;51:3935.
117. Burgos-Blasco B, Diaz-Valle D, Rego-Lorca D, et al. Topical insulin, a novel corneal epithelial regeneration agent in dry eye disease. Eur J Ophthalmol. 2024;34(3):719-725.
118. Moreker MR, Thakre N, Gogoi A, et al. Insulin eye drops for neurotrophic keratitis. Indian J Ophthalmol. 2023;71(7):2911-2912.
119. Liu L, Hartwig D, Harloff S, et al. Corneal epitheliotrophic capacity of three different blood-derived preparations. Invest Ophthalmol Vis Sci. 2006;47(6):2438-2444.
120. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol. 1999;83(4):390-395.
121. Sanchez-Avila RM, Merayo-Lloves J, Riestra AC, et al. Treatment of patients with neurotrophic keratitis stages 2 and 3 with plasma rich in growth factors (PRGF-Endoret) eye-drops. Int Ophthalmol. 2018;38(3):1193-1204.
122. Alio JL, Rodriguez AE, Ferreira-Oliveira R, et al. Treatment of dry eye disease with autologous platelet-rich plasma: a prospective, interventional, non-randomized study. Ophthalmol Ther. 2017;6(2):285-293.
123. Avila MY. Restoration of human lacrimal function following platelet-rich plasma injection. Cornea. 2014;33(1):18-21.
124. Alio JL, Colecha JR, Pastor S, et al. Symptomatic dry eye treatment with autologous platelet-rich plasma. Ophthalmic Res. 2007;39:124-129.
125. Hussain M, Shtein RM, Sugar A, et al. Long-term use of autologous serum 50% eye drops for the treatment of dry eye disease. Cornea. 2014;33(12):1245-1251.
126. Albietz J, Sanfilippo P, Troutbeck R, Lenton LM. Management of filamentary keratitis associated with aqueous-deficient dry eye. Optom Vis Sci. 2003;80(6):420-430.
127. Pentapati M, Shah S. Filamentary keratitis: a case series. Int J Scientific Res Pub. 2015;5(3):1-7.
128. Jones L. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628.
129. Akyol-Salman I, Azizi S, Mumcu U, Baykal O. Efficacy of topical N-acetylcysteine in the treatment of meibomian gland dysfunction. J Ocul Pharmacol Ther. 2010;26(4):329-333.
130. Magno M, Moschowits E, Arita R, et al. Intraductal meibomian gland probing and its efficacy in the treatment of meibomian gland dysfunction. Surv Ophthalmol. 2021;66(4):612-622.
131. Solomon A, Touhami A, Sandoval H, et al. Neurotrophic keratopathy: basic concepts and therapeutic strategies. Comp Ophthalmol Update. 2000;3:165-174.
132. Pakarinen M, Tervo T, Tarkkanen A. Tarsorraphy in the treatment of persistent corneal lesions. Acta Ophthalmol. 1987;182:69-73.
133. Donnenfeld ED, Perry HD, Nelson DB. Cyanoacrylate temporary tarsorrhaphy in the management of corneal epithelial defects. Ophthalmic Surg. 1991;22:591-593.
134. Sahlin S, Linderoth R. Eyelid botulinum toxin injections for the dry eye. Dev Ophthalmol. 2008;41:187-192.
135. Ho RW, Fang PC, Chang CH, et al. A review of periocular botulinum neurotoxin on the tear film homeostasis and the ocular surface change. Toxins (Basel). 2019;11:66.
136. Chen KY, Chan HC, Chan CM. Is botulinum toxin A effective in treating dry eye disease? A systematic review and meta-analysis. Eye (Lond). 2025;34(4):1-10.
137. Viana F. Chemosensory properties of the trigeminal system. ACS Chem Neurosci. 2011;2:38-50.
138. Abelson MB, Gamache D. Cool opportunities to modulate nociception. Rev Ophthalmol. 2013;20:48-50.
139. Wirta DL, Senchyna M, Lewis AE, et al. A randomized, vehicle-controlled, phase 2b study of two concentrations of the TRPM8 receptor agonist AR-15512 in the treatment of dry eye disease (COMET-1). Ocul Surf. 2022;26:166-173.
140. Higdon A, Diers AR, Oh JY, et al. Cell signaling by reactive lipid species: new concepts and molecular mechanisms. Biochem J. 2012;442:453-464.
141. Cejkova J, Ardan T, Jirsova K, et al. The role of conjunctival epithelial cell xanthine oxidoreductase/xanthine oxidase in oxidative reactions on the ocular surface of dry eye patients with Sjögren’s syndrome. Histol Histopathol. 2007;22:997-1003.
142. Turk A, Aykut M, Akyol N, et al. Serum anti-carbonic anhydrase antibodies and oxidant-antioxidant balance in patients with acute anterior uveitis. Ocul Immunol Inflamm. 2014;22:127-132.
143. Wakamatsu TH, Dogru M, Ayako I, et al. Evaluation of lipid oxidative stress status and inflammation in atopic ocular surface disease. Mol Vis. 2010;16:2465-2475.
144. Choi W, Lian C, Ying L, et al. Expression of lipid peroxidation markers in the tear film and ocular surface of patients with non-Sjögren syndrome: potential biomarkers for dry eye disease. Curr Eye Res. 2016;41:1143-1149.
145. Aldeyra therapeutics achieves primary endpoint in phase 3 dry eye disease chamber trial of reproxalap and plans NDA pesubmission. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-achieves-primary-endpoint-phase-3-dry-eye-0. Accessed May 8, 2025.
146. Lawrence BD, Karpecki PM, Infanger DW, et al. Silk-derived protein-4 versus vehicle control in treating patients with moderate to severe dry eye disease: a randomized clinical trial. Am J Ophthalmol. 2025;269:315-326.
