A Review on Dry Eye Disease Treatment: Recent Progress, Diagnostics, and Future Perspectives
Abstract
:1. Introduction
2. Treatments of Dry Eye Disease
2.1. Weakness of Existing Treatments
2.2. Contact Lenses as an Alternative DED Treatment
Drug Molecules | Contact Lens Type | Drug Loading Method | Duration | References |
---|---|---|---|---|
Cyclosporine A | Hydrogel and silicone hydrogel | Soaking | 1 day (hydrogel) 15 days (silicone hydrogel). Pre-soaking with vit. E increases time release to 30 days | [73] |
Hyaluronic acid | Hydrogel and silicone hydrogel | Soaking | 1 h | [74] |
Phospholipids | Silicone hydrogel | Soaking | 10 h | [75] |
Dexamethasone | Silicone hydrogel | Soaking | 2 weeks–3 months | [76] |
Dexamethasone | Silicone hydrogel | Soaking | 7 days | [77,78] |
Ap4A (Secretagoge) | Hydrogel and silicone hydrogel | Soaking | 5–6 h | [41,79] |
Betaine (Osmoprotectant) | Silicone hydrogel | Soaking | 10 h | [41,80] |
Polyvinilpyrrolidone | Hydrogel | Polymerization | 30 days | [81] |
Hyaluronic acid | Hydrogel and silicone hydrogel | Polymerization | 21 days (hydrogel), 49 days (silicone hydrogel) | [82] |
Polyvinilpyrrolidone | Hydrogel | Polymerization | 30 days | [81] |
Diclofenac | Hydrogel | Copolymerization | 7 days | [83] |
Dexamethasone | Hydrogel | Copolymerization | 50 h | [84] |
Diclofenac | Hydrogel | Copolymerization | 14 days | [85] |
Cyclosporine A | Hydrogel | Nanoparticles (Brij surfactants) | 20–30 days | [86,87,88] |
Dexamethasone | Hydrogel | Nanoparticles/soaking | 50 h | [89] |
Hydroxypropyl methylcellulose | Silicone hydrogel | Molecular imprinting | 60 days | [90] |
Hyaluronic acid | Hydrogel and silicone hydrogel | Molecular imprinting | 24 h | [91] |
Diclofenac | Hydrogel | Molecular imprinting | 6 days | [79] |
2.3. Contact Lens-Based Drug Delivery for DED
2.3.1. Advantages of CsA
2.3.2. In Vitro CsA Release from Contact Lenses
2.3.3. In Vivo Biological Activity of CsA Contact Lenses
3. Challenges of Contact Lenses in Drug Delivery
4. Biosensors Integrated Contact Lens
4.1. Tear Film Biomarkers for DED
4.2. Contact Lens Sensors for Sensing of Tear Fluid Biomarkers in DED
5. The Future Perspective of Biosensor Fused Contact Lens
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Medication | Description | Mechanism of Action | References |
---|---|---|---|
Artificial tears | Polyvinyl alcohol, povidone, hydroxypropyl guar, cellulose derivatives, and hyaluronic acid | Increase tear film stability. Reduce ocular surface stress. Improve contrast sensitivity and the optical quality of the surface. | [28,29,30,31,32,33] |
Topical corticosteroids (loteprednol 0.5%) | Unpreserved corticosteroid eyedrops, instilled over a period of 2 to 4 weeks, improve the symptoms and clinical signs of moderate to severe dry eye disease. | Corticosteroids act by the induction of phospholipase A2 inhibitory proteins and inhibiting the release of arachidonic acid. | [34,35,36] |
Cyclosporin A (CsA) | Topical application of CsA leads to increased production of tear fluid, possibly via local release of parasympathetic neuro transmitters. CsA eyedrops 0.05% (Restasis) were approved for the topical treatment of dry eye by the FDA in 2002. | CsA is an immunosuppressant that inhibits the calcineurin–phosphatase pathway by complex formation with cyclophilin, and thus reduces the transcription of T-cell-activating cytokines such as interleukin-2 (IL-2). | [37,38,39,40,41] |
Tacrolimus/pimecrolimus | Appear to be as effective as CsA and are used in patients who cannot tolerate CsA | Inhibition of interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis. | [5] |
Tetracyclines | Bacteriostatic antibiotics with anti-inflammatory effect. | They reduce the synthesis and activity of matrix metalloproteinases, the production of interleukin-1 (IL-1) and tumor necrosis factor, collagenase activity, and B-cell activation. | [5,42,43] |
Macrolides | Azithromycin 1% has been successfully used to improve meibomian gland function and symptoms, a reduction in bacterial colonization of the eyelid margins, and normalization of the meibomian gland secretion lipid profile. | Inhibition of bacterial protein biosynthesis by preventing peptidyltransferase from adding the growing peptide attached to tRNA to the next amino acid and also inhibiting bacterial ribosomal translation. | [44,45,46] |
Omega fatty acids | Omega-3 and omega-6 are essential fatty acids for ocular surface homeostasis. | Omega-3 fatty acids work by blocking pro-inflammatory eicosanoids and reducing cytokines through anti-inflammatory activity. | [47] |
Eyelid hygiene | Hot compresses, eyelid warming masks or goggles, infrared heaters, and eyelid massage improve eyelid margin morphology with a reduction in blocked meibomian gland excretory ducts, and an increase in tear film stability and lipid layer thickness of the tear film. | [48,49,50,51] | |
Punctal plugs | Temporary occlusion of the tear ducts by small collagen or silicone plugs (punctal plugs) is effective in patients with severe aqueous-deficient dry eye disease. | [36,52,53] | |
Lifitegrast (Xidra) | The U.S. Food and Drug Administration approved Xiidra (lifitegrast ophthalmic solution) for the treatment of signs and symptoms of dry eye disease, on Monday, 11 July 2016. Xiidra is the first medication in a new class of drugs, called lymphocyte function-associated antigen 1 (LFA-1) antagonist, approved by the FDA for dry eye disease. Xiidra is manufactured by Shire US Inc., of Lexington, Massachusetts. | Lifitegrast blocks the interaction of cell surface proteins LFA-1 and intercellular adhesion molecule-1 (ICAM-1), and is believed to inhibit T-cell-mediated inflammation in DED. | [54,55] |
Vitamin A | Vitamin A is an essential nutrient present naturally in tear film of healthy eyes. Vitamin A plays an important role in production of the mucin layer, the most innermost lubricating layer of tear film that is crucial for a healthy tear film. Vitamin A deficiency leads to loss of mucin layer and goblet cell atrophy. | Vitamin A drops protect the eyes from free radicals, toxins, allergens, and inflammation. | [1,28,56] |
Vitamin E | Vitamin E is a fat-soluble antioxidant that prevents the oxidation of fatty acids by reactive oxygen species. The retina is a lipid-rich environment and is bombarded by ultraviolet radiation. In cell culture, vitamin E has been found to enhance the antioxidant ability of lutein to protect retinal pigment epithelial cells from acrolein-induced oxidation. | [57,58] |
Functions | Drug | Stage |
---|---|---|
A mucin-like glycoprotein | Lacritin | Phase II |
Lubricin | Phase II | |
Anti-inflammatory and/or immunosuppressive | Loteprednol etabonate 0.25% suspension | FDA-approved |
OCS-O2 | Phase II | |
A higher concentration of Cyclosporine | Phase III | |
Tacrolimus (0.03%) eye drops | Phase IV | |
Rapamycin (sirolimus) | Phase I | |
EBI-005 | Phase III | |
Resolvin E1 analogues | Phase II | |
Biological components | Albumin 5% | Phase II |
Estradiol | Phase II | |
N-acetylcysteine | Phase II | |
Thymosin b4 | Phase II | |
Amniotic membrane extract eye drops | Phase I/II | |
Mesenchymal stem cells | Phase I/II | |
Mucin secretagogues | Tavilermide (MIM-D3, 1% or 5%) | Phase II |
Ecabet sodium | Phase III | |
Mycophenolate mofetil | Phase II | |
15(s)-HETE or Icomucret | Phase III/II | |
Other’s products | Visomitin (SkQ1) | Phase II/III |
Tivanisiran (SYL1001) | Phase III |
Dosage Form | Contact Lens Material | Loading Method | Drug Release Duration | References |
---|---|---|---|---|
Contact lens | hydroxyethyl methacrylate (HEMA), cholesterol-hyaluronate (C-HA) micelle | mixing | 12 days | [103] |
Contact lens | poly-hydroxyethyl methacrylate (p-HEMA), Brij 97, Brij 78 and Brij 700 | mixing | Brij 97—20 days, Brij 78—50 days, Brij 700—20 days | [86] |
Silicone contact lenses | ethylene glycol dimethacrylate (EGDMA) | soaking | 2 weeks, with vitamin E—1 month | [73] |
Contact lens | poly-hydroxy ethyl methacrylate (p-HEMA), Brij 98 | mixing | 25 days | [87] |
Contact lens | poly (2-hydroxyethyl methacrylate) (p-HEMA), Brij 97 | mixing | 20 days | [73] |
Contact lens | graphene oxide | soaking | - | [104] |
Analyte | Tear Fluid Concentration [mM] | Blood Concentration [mM] | Diagnostic Application |
---|---|---|---|
Glucose | 0.013–0.051 | 3.3–6.5 | Diabetes management |
Lactate | 2.0–5.0 | 0.36–0.75 | Ischemia, sepsis, liver disease, and cancer |
Na+ | 120–165 | 130–145 | Hyper/hyponatremia |
K+ | 20–40 | 3.5–5.0 | Hyper/hypokalemia and an indicator of ocular disease |
Ca2+ | 0.4–1.1 | 2.0–2.6 | Hyper/hypocalcemia |
Mg2+ | 0.5–0.9 | 0.7–1.1 | Hyper/hypomagnesemia |
Cl− | 118–135 | 95–125 | Hyper/hypochloremia |
HCO3− | 20–26 | 24–30 | Respiratory quotient indicator |
Urea | 3.0–6.0 | 3.3–6.5 | Renal function |
Pyruvate | 0.05–0.35 | 0.1–0.2 | Genetic disorders of mitochondrial energy metabolism |
Ascorbate | 0.22–1.31 | 0.04–0.06 | Diabetes |
Total Protein | ≈7 g/L | ≈70 g/L | Dry eye conditions, ocular insult, and inflammation |
Dopamine | 0.37 | 475 × 10−9 | Glaucoma |
Types of Biomarker Molecule | Biomarkers | References |
---|---|---|
Proteins | Lysozyme, lactoferrin, lysozyme proline-rich protein 4 (LPRR4), calgranulin A/S100 A8, lysozyme proline-rich protein 3 (LPRR3), nasopharyngeal carcinoma-associated PRP 4, α-1 antitrypsin α-enolase, α-1 acid glycoprotein 1, S100 A4, S100 A11 (calgizzarin), S100 A9/calgranulin B, lipocalin-1 (LCN-1), mammaglobin B, lipophilin A, beta-2 microglobulin (B2M), S100A6, annexin A1 annexin A11, cystatin S (CST4), phospholipase A2-activating protein (PLAA), transferrin, defensin-1, clusterin, lactotransferrin, cathepsin S, anti-SS-A, anti-SS-B, anti-α-fodrin antibodies, malate dehydrogenase (MDH) 2, palate lung nasal clone-PLUNC | [115,121] |
Mucins | (MUC)5AC | [122] |
Neuromediators | Nerve growth factor (NGF), calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), vasointestinal peptide (VIP), serotonin, substance P | [119] |
Cytokines/chemokines | Interleukin-1(IL-1), interleukin-2 (IL-2), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin 8 (IL-8) or chemokine (C-X-C motif) ligand 8 (CXCL8), interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-16 (IL-16), interleukin-33 (IL-33), GCSF, monocyte chemoattractant protein 1 (MCP1)/chemokine (C-C motif) ligand 2 (CCL2), MIP5/chemokine (C-C motif) ligand 15 (CCL15), C-X-C motif chemokine 5 (CXCL5 or ENA78), soluble interleukin-1 receptor Type I (sIL-1RI), soluble interleukin-6 receptor (sIL-6R), soluble gp130 (sgp130), soluble vascular endothelial growth factor receptor 1 (sVEGFR1), soluble epidermal growth factor receptor (sEGFR), soluble tumor necrosis factor receptor I (sTNFR I), interleukin-17A (IL-17A), interleukin-21 (IL-21), interleukin-22 (IL-22), interleukin-1 receptor antagonist (IL-1RA), chemokine (C-X-C motif) ligand 9 (CXCL9)/monokine induced by gamma interferon (MIG), interferon-inducible T-cell alpha chemoattractant (I-TAC)/C-X-C motif chemokine 11 (CXCL11), C–X–C motif chemokine 10 (CXCL10)/interferon γ-induced protein 10 kDa (IP-10), ligand 4 (CCL4)/macrophage inflammatory protein-1β (MIP-1β), chemokine (C-C motif) ligand 5 (also CCL5)/regulated on activation, normal T cell expressed and secreted (RANTES), epidermal growth factor (EGF), tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), matrix metallopeptidase 9 (MMP-9), macrophage inflammatory protein-1 alpha (MIP-1α/CCL3), vascular endothelial growth factor (VEGF), fractalkine | [115,123,124] |
Lipids | (O-acyl) ω-hydroxy fatty acids (OAHFAs), lysophospholipids, PUFA-containing diacylglyceride species, hexanoyl-lysine (HEL), 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA) | [125] |
Metabolites | Cholesterol, N-acetylglucosamine, glutamate, creatine, amino-n-butyrate, choline, acetylcholine, arginine, phosphoethanolamine, glucose, phenylalanine | [126] |
Tear solutes | Osmolarity | [127] |
Biomarkers | Sensor Type |
---|---|
Glucose | Enzymatic biosensor; amperometric |
Osmolarity | Impedimetric |
MMP-9 | Electrochemical immunosensors |
Urea | Voltammetric |
Serum | Electrochemical immunosensors |
TNF-α | Electrochemical aptamer sensor |
Mucins | Electrochemical immunosensors |
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Mondal, H.; Kim, H.-J.; Mohanto, N.; Jee, J.-P. A Review on Dry Eye Disease Treatment: Recent Progress, Diagnostics, and Future Perspectives. Pharmaceutics 2023, 15, 990. https://doi.org/10.3390/pharmaceutics15030990
Mondal H, Kim H-J, Mohanto N, Jee J-P. A Review on Dry Eye Disease Treatment: Recent Progress, Diagnostics, and Future Perspectives. Pharmaceutics. 2023; 15(3):990. https://doi.org/10.3390/pharmaceutics15030990
Chicago/Turabian StyleMondal, Himangsu, Ho-Joong Kim, Nijaya Mohanto, and Jun-Pil Jee. 2023. "A Review on Dry Eye Disease Treatment: Recent Progress, Diagnostics, and Future Perspectives" Pharmaceutics 15, no. 3: 990. https://doi.org/10.3390/pharmaceutics15030990