A variety of cycloplegic, anti-inflammatory agents, and off-label use oral drugs are used in the treatment of noninfectious corneal injuries. |
Various mechanical barrier therapies, amniotic membrane therapies (AMTs), and blood-based therapies have gained significant attention recently for their usefulness in facilitating corneal wound healing. |
A number of novel agents with good preclinical profiles remain an area of future investigation and interest as effective adjunctive and solo therapies. |
Currently, there lacks a compendium-style article on current and recently developed corneal agents. This article is intended to concisely summarize each diagnostic and therapeutic agent to assist clinicians encountering this challenging patient population. |
1 Introduction
2 Diagnostic Agents
2.1 Diagnostic Analgesic Agents
2.1.1 Proparacaine 0.5%
Diagnostic agent | Purpose | Onset | Duration | Other notes |
---|---|---|---|---|
Proparacaine 0.5% | TOA | 30 s | 15 min | Recommend to be used exclusively for diagnostic purposes |
Use of dilute or physician-dispensed proparacaine is controversial | ||||
Tetracaine 0.5% | TOA | 30 s | 10–20 min | Cold tetracaine causes less burning sensation |
Lidocaine | TOA | 30 s to 1 min | 5–30 min | Available in 1–4% solution or 2% gel formulation |
More useful agent when longer duration of anesthetic effect is desired |
2.1.2 Tetracaine 0.5%
2.1.3 Lidocaine
2.2 Diagnostic Staining Agents
2.2.1 Fluorescein
Diagnostic agent | Purpose | Other notes |
---|---|---|
Fluorescein | Dye | Available in paper strips or solution with anesthetic ± preservatives |
Recommend strips due to less risk of contamination | ||
Various punctate staining patterns suggest different diagnoses | ||
Non-toxic and water-soluble | ||
Lissamine Green | Dye | Available as strips or 1% solution |
Stains epithelial cells when mucin coating of cornea is disrupted | ||
Not shown to stain healthy cells | ||
No toxicity | ||
Recommend in red eyes due to green contrast | ||
More effective | ||
Rose Bengal | Dye | Available as strips or 1% solution |
Derivative of fluorescein | ||
Stains damaged and healthy cells | ||
May cause patient discomfort upon instillation | ||
Toxic to corneal epithelium |
2.2.2 Lissamine Green
2.2.3 Rose Bengal
3 Cycloplegic/Pain Control Agents
Cycloplegic agent | Onset | Duration | Other notes |
---|---|---|---|
Atropine | 10–15 min, maximal effect in 30–40 minutes | 3–7 days | Not recommended for children < 3 months |
Homatropine | 15 min, maximal effect in 30–40 min | 1–2 days | Not recommended for children < 3 months |
Cyclopentolate | 20–30 min, maximal effect in 60 min | 8 h | Not recommended for children < 3 months |
Tropicamide | 15–20 min | 4–10 h | 0.5% tropicamide with 5% epinephrine is a safe and effective agent for infant patients |
Scopolamine | Rapid, maximal effect within 8 min | 3–7 days | Not recommended for children < 3 months |
3.1 Atropine Sulfate
3.2 Homatropine
3.3 Cyclopentolate
3.4 Tropicamide
3.5 Scopolamine
4 Anti-Inflammatory Agents
4.1 Anti-Inflammatory Agents: Steroid Medications
Steroidal agent | Formulation | In vivo relative anti- inflammatory activity | Other notes | |
---|---|---|---|---|
Prednisolone acetate | 0.125%, 1% suspension | 600 | 4 | Requires 16–20 shakes prior to instillation |
Prednisolone phosphate | 1% solution | 600 | 4 | Solution does not require shaking |
Loteprednol | 0.2%, 0.25%, 0.5%, 1% suspension 0.38% gel 0.5% ointment | 550 | 25 | Shorter duration of effect, with fewer adverse reactions |
Difluprednate | 0.05% emulsion | 1,800 | 60 | High propensity to elevated IOP 2nd line agent for recalcitrant ocular inflammation |
Fluorometholone | 0.1%, 0.25% suspension | 350 | 40 | Acetate base offers greater penetration than alcohol formulation |
Rimexolone | 1% suspension | 300 | 25 | Requires IOP monitoring in pediatric patients |
Dexamethasone | 0.1% solution | 400 | 25 | Poor ocular penetration |
Hydrocortisone | 1%, 2.5% ointment | n/a | n/a | |
Methylprednisolone | Requires compounding pharmacy | n/a | n/a |
4.1.1 Prednisolone Acetate (0.125% and 1%) and Prednisolone Phosphate 1%
4.1.2 Loteprednol
4.1.3 Difluprednate
4.1.4 Fluorometholone 0.1%
4.1.5 Rimexolone
4.1.6 Dexamethasone
4.1.7 Hydrocortisone
4.1.8 Preservative-Free Methylprednisolone
4.2 Anti-Inflammatory Agents: Non-Steroidal Medications
NSAID | Bottle size | Dosing | Other notes |
---|---|---|---|
Ketorolac Tromethamine 0.4–0.5% | 5 ml | QID | Pediatric use at 3 years |
Available in preservative-free formulation (Acuvail, 0.45%) | |||
Associated with corneal ulceration when used on compromised and neurotrophic ocular surface | |||
Diclofenac sodium 0.1% | 2.5 ml, 5 ml | QID | Compared to Ketorolac, may have more pronounced and longer lasting effects in regards to corneal sensitivity |
Nepafenac 0.1% | 3 ml | TID | Pediatric use at 10 years |
Must be shaken before instillation | |||
Prodrug which is converted to amfenac by corneal esterases | |||
Nepafenac 0.3% | 1.7 ml | QD | Pediatric use at 10 years |
Must be shaken before instillation | |||
Bromfenac 0.075% | 5 ml | n/a | Do not use in sulfite allergy |
Not a prodrug |
4.2.1 Ketorolac Tromethamine 0.4–0.5%
4.2.2 Diclofenac Sodium 0.1%
4.2.3 Nepafenac
4.2.4 Bromfenac
4.3 Immunomodulating Agents
4.3.1 Cyclosporine
4.3.2 Lifitegrast
5 Oral Agents
5.1 Antibiotics (Off-Label Use)
5.1.1 Tetracyclines
5.1.2 Macrolides
5.2 Vitamins
5.2.1 Vitamin C
6 Amniotic Membrane Therapies
AMT | Advantages | Disadvantages | Examples |
---|---|---|---|
Amniotic membrane extract (AME) | Can be used to formulate eyedrops ± umbilical cord blood | Not approved by US Food and Drug Administration | Regenesol® |
Avoids mechanical placement of amniotic membrane (AM) tissue | Genesis ACE® | ||
Amniotic fluid eyedrops (AF) | Contains variety of electrolytes, growth factors and cytokines that help promote ocular surface healing | Regener-Eyes® | |
Avoids mechanical placement of AM tissue | |||
Cryopreserved AMT | Cryopreservation better preserves fetal tissues’ structural and biological signaling molecules | Requires in-office or surgical placement | Prokera® |
Reduces pain, haze, and inflammation | |||
Can treat moderate dry eye diseases | |||
Dehydrated AMT | Air or heat is used to remove moisture from AM | Requires in-office or surgical placement and requires additional placement of bandage contact lens with use of topical antibiotic drops | AmbioDisk® |
Aril® | |||
Sursight® | |||
Absence of a symblepharon ring increases tolerability | Eclipse® |
6.1 Amniotic Membrane Extract (AME) and Amniotic Fluid (AF) Eyedrops
6.2 Cryopreserved Amniotic Membrane Transplantation (Cryopreserved AMT)
6.3 Dehydrated Amniotic Membrane Transplantation (Dehydrated AMT)
7 Blood-Based Therapies
Blood-based therapies | Advantages | Disadvantages |
---|---|---|
Autologous serum tears (ASTs) | Similar composition tears Effective in treating persistent epithelial defects and severe dry eye Concentrations ranging from 20–90% can be used depending on severity of ocular surface disease | Requires patient blood drawn Patient’s blood may contain unwanted autoantibodies or cytokines precluding effective use |
Allogenic peripheral blood serum tears (APBSTs) | Works around the disadvantages of ASTs | Requires ABO antigen matching between donors and recipients |
Requires infection surveillance | ||
Allogenic umbilical cord blood serum tears (AUCBSTs) | Higher concentration of multiple growth factors compared to other blood derived products | Needs to be obtained from umbilical cord serum at time of delivery |
Platelet-derived tears (PDTs) | Includes platelet-rich plasma (PRP) tears and plasma-enriched growth factors (PRGF) tears | |
Both allogenic and autologous sources can be used | ||
Compared to ASTs, PRGF eyedrops exert better wound healing | ||
May benefit patients suffering from autoimmune diseases | ||
Clinicians are able to make tears in office | ||
Finger-prick autologous blood (FAB) | Cheaper and more convenient |
7.1 Autologous Serum Tears
7.2 Allogenic Peripheral Blood Serum Tears
7.3 Allogenic Umbilical Cord Blood Serum Tears
7.4 Platelet-Derived Tears
7.5 Finger-Prick Autologous Blood
8 Mechanical Barrier Therapies
8.1 Bandage Contact Lenses
8.2 Nonbiologic Glue: Cyanoacrylate
8.3 Biologic Glue: Fibrin Glue
8.4 Tarsorrhaphy
9 Novel Agents
Novel agent | Key points | Notable studies and tested species |
---|---|---|
Cenegermin 0.002% | First FDA-approved medication to treat persistent epithelial effects due to neurotrophic keratitis | |
Clinical trials found agent to be safe and effective | ||
Formulation is not highly stable requiring refrigeration and weekly trays being sent to patients | ||
Topical insulin | Effective and simple adjuvant therapy | Safe for human use for neurotrophic ulcers that do not respond to standard therapy [140] |
Randomized controlled trial concluded topical insulin is safe for human ocular usage [141] | ||
Case report concludes effectiveness of insulin drop and absence of toxicity in a nondiabetic patient with a post-caustic corneal ulcer [159] | ||
Substance P (FGLM-NH2 derived) | Studies noted successful resurfacing of corneal epithelial defects | Promotion of corneal epithelial wound healing in diabetic rats [160] |
Topical administration promoted corneal epithelial wound healing in mice [161] | ||
16-month-old boy treated with this agent resulted in resurfacing of corneal epithelial defect [142] | ||
Insulin-like growth factor (SSSR derived) | Local administration of SSSR tetrapeptide alone or in combination with FGLM amide can treat persistent epithelial defects | Safe for human use; eyedrops containing SSSR induced rapid resurfacing of persistent epithelial defects in stem cell-positive individuals with neurotrophic keratopathy [143] |
Metalloproteinase modulators (thymosin B4, RGN-259) | Reduces ocular irritation and promotes healing without significant neovascularization | Tbeta4 treatment decreases corneal inflammation and promotes corneal wound repair and clarity after alkali injury in mice [162] |
Results of nine human patients found thatTbeta4 may provide a novel, topical approach to wound healing in chronic nonhealing neurotrophic corneal ulcers [146] | ||
A phase 3, multicenter, randomized, double-masked, placebo-controlled clinical study to assess the safety and efficacy of RGN-259 ophthalmic solution for the treatment of neurotrophic keratopathy completed in 2020 (NCT02600429) | ||
RGN-259 found to improve dry eye, corneal integrity, and reduce inflammation in a dry eye mouse model [163] | ||
Gap junction hemichannel modulators/CODA001 (antisense nucleotide) | Can aid in healing persistent epithelial defects due to ocular burn or chemical injury | Five human eyes with nonhealing ocular burn wounds treated with connexin modulation experienced reduction in inflammation and stable corneal reepithelialization [149] |
Matrix therapy agent (ReGenerating Agent or RGTA) | Promotes tissue regeneration and epithelial wound closure while reducing pain reduction Combining RFTAs with other therapies could be potential options for treating persistent epithelial defects | In preclinical studies on rabbit corneal alkali burn models, RGTA acted as tissue protector, promoting the healing process and reducing corneal inflammation [166] A pilot study showed that RGTA was well-tolerated and led to significant pain reduction in humans and treated chronic and severe corneal dystrophies as well as corneal ulcers resistant to usual treatments [152] RGTA was effective in 14 human eyes with persistent corneal ulcer after cessation of fortified antibiotics [167] 25 human eyes with neurotrophic keratopathy treated with RGTA had complete corneal healing [168] |