Healing Of Corneal Epithelial Defects Research Articles

Comparison of the Effect of Autologous Serum on Therapy Resistant Corneal Erosions and Ulcers on the Corneal Graft vs. the Patient's Own Cornea

The aim of this study is to compare the healing of corneal epithelial defects or ulcers on the corneal graft in comparison with the patient's own cornea after treatment with 100%, undiluted autologous serum eye drops. In a retrospective study over 7 years, we analysed 263 treatments with autologous serum eye drops of persistent corneal epithelial defects (erosions [88%] vs. ulcers [12%]). We compared the epithelial healing tendency of patients with defects on their own cornea (51.9%) vs. patients who had previously undergone penetrating keratoplasty (48.1%). Complete epithelial healing during the 28 days of treatment was considered as therapeutic success. In addition, the recurrence rate of the epithelial defects after finishing the therapy was analysed. 88.2% of the epithelial defects healed during 28 days of therapy. The recurrence rate during follow-up was 5.1%. There was no significant difference with respect to success rate between corneal defects on the patient's own cornea (87.8%) and on the graft (88.6%; p = 0.137). There was a significantly lower success rate for corneal ulcers (74.2%) than for erosions (90.3%; p < 0.001). The recurrence rate of erosions was 4.4%, vs. 4.3% in ulcers during follow-up. The results of our study suggest that autologous serum eye drops are a non-invasive and safe alternative treatment for persistent corneal epithelial defects - with no significant difference in patients with a defect on their own cornea vs. defects on the corneal graft. The success rate, but not the recurrence rate, is significantly worse in ulcers than in erosions.

Effect of 2% Hyaluronic Acid on the Rate of Healing of Corneal Epithelial Defect After Pterygium Surgery: A Randomized Controlled Trial.

PurposeThe study aimed to investigate the effects of 2% hyaluronic acid (HA) on corneal epithelial defect after pterygium surgery in comparison with the control group, measured in terms of the healing rate of corneal epithelial defect and pain score after surgery.MethodsIn this double-blind randomized clinical trial, fifty patients with primary pterygium were randomized into 2 groups: a control group or the group treated with a single topical application of 2% HA. Comprehensive ophthalmological examinations included measuring the area of corneal epithelium defect using ImageJ freeware and the pain score assessment after the operation.ResultsThe mean and SD of the area of epithelial defect measured on postoperative Day 0, 1, and 2 were 10.89 ± 1.33 mm2, 5.04 ± 0.87mm2, and 2.44 ± 0.74 mm2 for the HA group, and 11.14 ± 1.11 mm2, 7.74 ± 1.17 mm2, and 5.31 ± 1.15 mm2 for the control group, respectively. While the initial area of the defect on Day 0 was essentially the same for both groups (p = 0.478), the area of the defect in the HA group was significantly smaller on both Day 1 and Day 2 (p < 0.001, p < 0.001), respectively. Similarly, the HA group exhibited a statistically significant higher rate of healing for the cornea epithelial defect over Day 0 and 1 compared to the control group (5.85 ± 0.89 mm2/day vs 3.14 ± 1.28 mm2/day, p < 0.001), respectively. The median (range) pain scores were evaluated at Day 0 was 7 (4–10) in the HA group and 7 (3–10) in the control group (p = 0.953). There was no statistically significant difference between two groups (p > 0.05) for Days 1, 2, and 3.ConclusionA single topical application of 2% HA tended to accelerate the healing process of corneal epithelium defect after pterygium surgery without any observable adverse effects during short-term follow-up.

Experimental evaluation of safety and efficacy of plasma-treated poly-ε-caprolactone membrane as a substitute for human amniotic membrane in treating corneal epithelial defects in rabbit eyes.

Purpose:To evaluate biocompatibility and safety of plasma-treated poly-ε-caprolactone (pPCL) membrane compared to the human amniotic membrane in the healing of corneal epithelial defects in an experimental model.Methods:This is a prospective, randomized animal study including 12 rabbits. Circular epithelial injury measuring 6 mm in diameter was induced over the central cornea of one eye in twelve rabbits. The rabbits were randomized into two groups; in group A, the defect was covered with human amniotic membrane, while in group B, an artificial membrane made of bio-polymer plasma-treated poly-ε-caprolactone was grafted. Six rabbits were euthanized after 1 month and the other six after 3 months and the corneal epithelium was evaluated histopathologically and with immunohistochemistry.Results:Light microscopy of the corneal tissue performed after 1 month and 3 months demonstrated similar findings with no significant complications in either group. Immunohistochemistry with anti-CK-3 antibody showed characteristic corneal phenotype in the healed epithelium. In eyes grafted with pPCL membrane, epithelial healing as estimated by a decrease in size of the defect was significantly better than the group treated with the human amniotic membrane at all time periods monitored (P < 0.05), except day 1 (P = 0.83). The percentage reduction in the size of the epithelial defect was also significantly more in the pPCL membrane group as compared to the human amniotic membrane at all time periods (P < 0.05 at all observations) post-implantation except day 1 (P = 0.73).Conclusion:Plasma-treated poly-ε-caprolactone membrane is safe, biocompatible, and effective in the healing of corneal epithelial defects in rabbits.

A Systematic Review of Emerging Therapeutic Strategies in the Management of Chemical Injuries of the Ocular Surface

To evaluate recent in vivo studies on emerging therapies for managing corneal epithelial injuries. The search was conducted on PubMed for articles published between January 2015 and September 2019 and in English language. Thirty studies were identified for evaluation, including those on mesenchymal stem cells, amniotic membrane-derived therapies, endogenous peptides and their inhibitors, as well as hydrogel therapies. Intermediate to strong levels of evidence are presented regarding the use of these strategies on chemically injured cornea, including their effects on healing of corneal epithelial defect, anti-inflammatory properties, prevention of corneal neovascularization, as well as restoration of anatomy and functions of the anterior eye, although clinical trials are needed to determine the safety and efficacy of these strategies on humans. Recent advances and understanding in various novel therapeutic methods for corneal epithelial chemical injuries should provide potential alternatives to current standard treatment regimens and help reduce risks of complications, hence improve patient outcomes.

Topical Umbilical Cord Serum for Corneal Epithelial Defects after Diabetic Vitrectomy.

PurposeTo evaluate the role of topical umbilical cord serum (TUCS) therapy in treating corneal epithelial defects (CEDs) after diabetic vitrectomy.MethodsIn this double-masked, randomized clinical trial, we included 80 eyes of 80 patients who were candidates for vitrectomy due to proliferative diabetic retinopathy complications. In cases of corneal edema obscuring the fundus view during surgery, the corneal epithelium was removed using a 6-mm trephine and a blade no.15. The day after the surgery, patients were randomly divided into two groups: (1) the TUCS group that received 20% TUCS six times/day in addition to the conventional treatment of CED and (2) the control group, which was prescribed artificial tears as placebo in addition to the conventional treatment of CED. The rate of healing of CEDs was measured via two maximum linear dimensions perpendicular to each other at the start of therapy and on postoperative days 1–5, 7, and 12.ResultsOf 80 eyes, 40 were assigned to each treatment group. The mean times to complete CED healing were 2.4 0.7 and 3.8 2.1 days in the TUCS and control groups, respectively (P 0.001). Persistent CED occurred in two eyes in the control group but in no eyes in the TUCS group.ConclusionTUCS therapy may be safe and effective in healing CEDs after vitrectomy in patients with diabetes.

Hyaluronic Acid Combined with Serum Rich in Growth Factors in Corneal Epithelial Defects.

The aim of this study is to assess if an adhesive biopolymer, sodium hyaluronate (NaHA), has synergistic effects with s-PRGF (a serum derived from plasma rich in growth factors and a blood derivative that has already shown efficacy in corneal epithelial wound healing), to reduce time of healing or posology. In vitro proliferation and migration studies, both in human corneal epithelial (HCE) cells and in rabbit primary corneal epithelial (RPCE) cultures, were carried out. In addition, we performed studies of corneal wound healing in vivo in rabbits treated with s-PRGF, NaHA, or the combination of both. We performed immunohistochemistry techniques (CK3, CK15, Ki67, ß4 integrin, ZO-1, α-SMA) in rabbit corneas 7 and 30 days after a surgically induced epithelial defect. In vitro results show that the combination of NaHA and s-PRGF offers the worst proliferation rates in both HCE and RPCE cells. Addition of NaHA to s-PRGF diminishes the re-epithelializing capability of s-PRGF. In vivo, all treatments, given twice a day, showed equivalent efficacy in corneal epithelial healing. We conclude that the combined use of s-PRGF and HaNA as an adhesive biopolymer does not improve the efficacy of s-PRGF alone in the wound healing of corneal epithelial defects.

In vitro activity of Cacicol® on herpes simplex virus type 1: a promising adjunct therapy of herpetic corneal infections?

PurposeHerpes simplex keratitis (HSK) remains the leading cause of infectious blindness in developed countries. Cacicol®, a topical eye biopolymer containing a poly‐carboxymethyl sulfate solution is a recent licensed regenerating agent used for matrix repair therapy, intended for wound healing of corneal epithelial defects. According to its chemical composition, we hypothesized that Cacicol® could compete with natural heparan sulfate which initiates cell surface attachment of herpes simplex virus type 1 (HSV‐1) and that Cacicol® could have unexplored antiherpetic activities.MethodsCacicol® was tested in vitro against both cell free HSV‐1 SC16 strain and HSV‐1 PSL‐R, a clinical isolate resistant to both acyclovir and foscarnet due to mutations in both thymidine kinase and DNA polymerase, and compared to the activity of vehicle, equivalent to active drug minus the active component. The reduction of the initial viral inoculum by Cacicol® or vehicle, during 1 h adsorption was determined by plaque reduction assays on Vero cells.ResultsA dose dependent effect was demonstrated when both SC16 and PSL‐R were pre‐treated with Cacicol® during adsorption. Initial inoculums of 1,104 PFU were significantly decreased to 160 PFU (±26.6) and 117 PFU (±22.3) for SC16 and PSL‐R respectively, while vehicle has no effect on viral replication.ConclusionsCacicol® has a significant in vitro antiherpetic activity and seems particularly interesting for the management of HSV‐1 resistant to acyclovir or foscarnet, especially in tissues that can receive Cacicol® by topical application (such as the cornea). Clinical studies are necessary to determine its in vivo activity and its usefulness as a promising adjunct or alternative therapy of recurrent HSK.

Novel implantable composite biomaterial by fibrin glue and amniotic membrane for ocular surface reconstruction.

Amniotic membrane transplantation (AMT) is considered a substantial treatment option in the management of ocular surface disorders. However, several inherent drawbacks still remain. The present study devised a novel implantable composite biomaterial of fibrin glue-double layer Amniotic membrane (AM) and evaluated the biomechanical properties and effects on corneal surface reconstruction in alkali-burned rabbit model. Biomechanic parameters were calculated by an electronic universal testing machine. Corneal alkali burning was done in the right eyes of thirty rabbits, which were randomized into three groups of ten animals each. The eyes in group 1 underwent fibrin glue-double layer AMT, the eyes in group 2 underwent ordinary single layer AMT, and the eyes in group 3 (control group) did not undergo any surgical procedure. Healing of corneal epithelial defect, extent of corneal vascularization and corneal clarity were assessed and compared at two time points. One month after surgery, animals were killed and the eyes were processed for histopathology. The fibrin glue-double layer AM composites had more ideal biomechanical properties. In fibrin glue-double layer AM group, the rate of epithelial healing, vascularization inhibition and corneal clarity was significantly better than the other two groups. Novel fibrin glue-double layer AMT with corneal alkali burns is more effective and useful for ocular surface reconstruction and has great potential applications.

Effects of Hydroxypyridine Derivatives Mexidol and Emoxypin on the Reparative Processes in Rabbit Eye on the Models of Corneal Epithelial Defect and Conjunctival Ischemia

Deepithelialization of the cornea (diameter 7 mm) was performed in rabbits and the rate of defect epithelialization was evaluated. Conjunctival ischemia was modeled by application of graduated alkaline burn. Antioxidant activity and content of nitrates and nitrites was measured in the tear fluid before and after burn by chemiluminescence and Griess methods, respectively. Emoxypin and mexidol promoted healing of corneal epithelial defect at the stage of epitheliocyte migration to the defect area and at the stage of their proliferation, respectively. After treatment with both agents, the area of conjunctival ischemia decreased more rapidly, but the efficiency of mexidol was higher. Antioxidant activity and content of products of NO metabolism in tear fluid decreased after burn. Mexidol, but not emoxypin, increased these parameters. Thus, mexidol and emoxypin have different effects on corneal epithelialization and conjunctival ischemia and effects of mexidol are more pronounced.

Protection of Human Corneal Epithelial Cells From TNF-α–Induced Disruption of Barrier Function by Rebamipide

TNF-α disrupts the barrier function of cultured human corneal epithelial (HCE) cells. We investigated the effects of the cytoprotective drug rebamipide on this barrier disruption by TNF-α as well as on corneal epithelial damage in a rat model of dry eye. The barrier function of HCE cells was evaluated by measurement of transepithelial electrical resistance. The distribution of tight-junction (ZO-1, occludin) and adherens-junction (E-cadherin, β-catenin) proteins, and the p65 subunit of nuclear factor-κB (NF-κB) was determined by immunofluorescence microscopy. Expression of junctional proteins as well as phosphorylation of the NF-κB inhibitor IκB-α and myosin light chain (MLC) were examined by immunoblot analysis. A rat model of dry eye was developed by surgical removal of exorbital lacrimal glands. Rebamipide inhibited the disruption of barrier function as well as the downregulation of ZO-1 expression, and the disappearance of ZO-1 from the interfaces of neighboring HCE cells induced by TNF-α. It also inhibited the phosphorylation and downregulation of IκB-α, the translocation of p65 to the nucleus, the formation of actin stress fibers, and the phosphorylation of MLC induced by TNF-α in HCE cells. Treatment with rebamipide eyedrops promoted the healing of corneal epithelial defects as well as attenuated the loss of ZO-1 from the surface of corneal epithelial cells in rats. Rebamipide protects corneal epithelial cells from the TNF-α-induced disruption of barrier function by maintaining the distribution and expression of ZO-1 as well as the organization of the actin cytoskeleton. Rebamipide is, thus, a potential drug for preventing or ameliorating the loss of corneal epithelial barrier function associated with ocular inflammation.

Effect of Erythropoietin on Healing of Corneal Epithelial Defects in Rabbits

Background/Aim: Corneal epithelial defects may heal slowly in patients with diabetes, limbal stem cell deficiency, extensive chemical burns or anesthetized corneas. Studies have shown that erythropoietin, a glycoprotein hormone that promotes red blood cell proliferation and inhibits apoptosis of erythroid progenitors, may also exert a cytoprotective, antiapoptotic effect on nonhematopoietic cells. The aim of the study was to examine the effect of erythropoietin on the healing process of corneal epithelial erosions in rabbit eyes. Methods: Fifteen New Zealand albino rabbits were divided into 3 groups following induction of unilateral uniform corneal epithelial erosions. The first group received local treatment with erythropoietin-containing cellulose-based gel 4 times daily; the second group received treatment with cellulose-based gel without erythropoietin 4 times daily, and the third group received no treatment. The healing process was monitored twice daily using cobalt-blue-filtered slit lamp photography and digital images of fluorescein-stained corneas until complete re-epithelization was achieved. Following re-epithelization, corneas were removed for histologic processing. One-way analysis of variance and Mann-Whitney tests were used for statistical analysis. Results: Mean ± SD time to complete re-epithelization was 55 ± 2.19 h in the group treated with erythropoietin-containing cellulose-based gel, 66.5 ± 14.25 h in the group treated with gel only and 62.2 ± 9.09 h in the untreated group (p = 0.16, not significant). There was no significant difference among the groups in the time to complete re-epithelization or the rate of epithelial healing. Histologic corneal evaluation revealed stromal vascularization in 2 of the 6 erythropoietin-treated rabbits and in neither of the control groups. Conclusion: Erythropoietin has no beneficial effect on the rate of healing of corneal epithelial erosions in rabbit eyes, and corneal stroma neovascularization seems to be a significant adverse effect.

Amniotic membrane transplantation as an adjunct to medical therapy in acute ocular burns

AimsTo evaluate the role of amniotic membrane transplantation in patients with acute ocular burns.MethodsIn a prospective, randomised, controlled clinical trial, 100 patients with grade II to IV acute ocular burns...

Preliminary Results of Subconjunctival Bevacizumab in Primary Pterygium Excision

Purpose: To evaluate the efficacy of subconjunctival bevacizumab as an adjunctive therapy for primary pterygium surgery. Material and Methods: This randomized prospective clinical study was conducted on 30 eyes of 30 patients. After pterygium excision and accomplishing a rotational conjunctival flap, 15 patients (case group) received 1.25 mg (0.1 ml) bevacizumab, and 15 other patients (control group) received 0.1 ml balanced salt solution subconjunctivally. The main outcome measures were recurrence of pterygia, horizontal length of the corneal epithelial defect, conjunctival erythema, lacrimation and photophobia during the first postoperative week. Results: There were no statistically significant differences regarding age, sex or recurrence risk factors between the two groups (p > 0.05). The pterygia resolved in 13 (86.6%) of 15 eyes in both groups, with a recurrence rate of 13.4% during a mean follow-up period of 8 ± 1.4 months in the case group and 7.4 ± 1.5 months in the control group (p = 0.2). There were no statistically significant differences regarding reduction in refractive astigmatism, improvement in visual acuity, corneal epithelial defects, conjunctival erythema, lacrimation or photophobia between the case and control groups (p > 0.05). Conclusions: A single intraoperative subconjunctival bevacizumab injection had no effect on recurrence rate or early postoperative conjunctival erythema, lacrimation, photophobia or healing of corneal epithelial defects following pterygium excision.

Temporary Eyelid Closure Appliqué

Tarsorrhaphy is used for the treatment of severe ocular surface disorders and for damage from ocular exposure. The temporary tarsorrhaphy has been shown to aid in the healing of corneal epithelial defects. A variety of temporary techniques have been suggested that allow eyelid closure not only to enable epithelial healing but also to allow access to the eye. We describe a temporary eyelid closure appliqué, similar to the Stamler eyelid splint, that provides nearly complete closure of the eyelid that will last for days. The technique is inexpensive, can be applied by a family member with minimal training, and can be used in almost any setting.

TGF-beta signal transduction in corneal wound healing as a therapeutic target.

This article reviews recent progress in research on the role of Smad signaling in corneal wound healing. Smad2 and Smad3 are key signaling molecules downstream of the cell surface receptor of transforming growth factor-beta (TGF-beta) or activin. On ligand binding to the receptor, Smads2/3 undergo phosphorylation, form complexes with Smad4, and thence convey signaling. TGF-beta isoforms have been detected in corneal epithelium and are also deposited in wounded stroma, suggesting their participation in the wound-healing process in corneal tissue. Human or mouse uninjured healthy corneal epithelium shows nuclear accumulation of Smads3/4, indicating active Smad signaling in this tissue. Migrating corneal epithelium lacks nuclear Smad accumulation with up-regulation of Smad7, but p38MAPK is activated. Organ-culture experiments show that p38MAPK activation depends on endogenous TGF-beta and that activation of p38MAPK results in cell proliferation cessation with a reduction of Erk activation and acceleration of cell migration in healing corneal epithelium. These findings indicate that during healing of corneal epithelial defects, endogenous TGF-beta activates p38MAPK for cell migration and suppression of cell proliferation and up-regulates Smad7 for inhibition of Smad2 and Smad3 signaling, resulting in rapid initial resurfacing of the epithelium. Such involvement of p38MAPK in cell migration has been reported in many cell types and observed in keratocyte culture. Possible benefits of preserving non-Smad cascades in treating problems in corneal wound healing by manipulating TGF-beta signals have been suggested.

Effect of topical administration of epidermal growth factor on healing of corneal epithelial defects in horses

OBJECTIVE-To characterize healing of corneal epithelial defects in horses and to evaluate the ability of epidermal growth factor (EGF) to modulate rate of corneal epithelial healing in horses. 20 eyes in 12 adult horses. Corneal epithelial wounds were created by mechanically debriding the limbus. Corneal healing was recorded for 3 treatment groups: 50 microg of EGF/ml (n = 5 eyes), 5 microg of EGF/ml (7), and PBS solution (8). Corneal healing was recorded once daily after instillation of fluorescein stain by use of photography and calculating the area of the wound, using imaging software. After corneal debridement, re-epithelialization was rapid and progressed in a linear fashion for the first 5 to 7 days after surgery in all groups. After that period, rates of healing decreased. A profound increase in the degree of inflammation, neovascularization, melanosis, and scarring was observed in eyes treated with the high dose of EGF (50 microg/ml), but there was not a statistical difference in mean healing time or in mean decrease in radius during the linear phase between the control and either EGF treatment groups. However, for all 8 horses in which both eyes were debrided, the first eye healed significantly faster than the second eye, regardless of treatment. Beneficial effects of topical administration of a high dose of EGF for acceleration of healing of corneal defects in eyes of horses are outweighed by the intensity of the associated inflammatory response.

Growth factor mRNA expression in epiretinal membranes

Long-term reattachment of the retina following the development of proliferative vitreoretinopathy is often prevented by the occurence of cellular reproliferation. 5-fluorouracil, a synthetic pyrimidine analog, is a potent inhibitor of fibroblast proliferation in cell culture and an animal model of tractional retinal detachment. Doses of up to 1.0 mg, when administered intravitreally to rabbits, result in no demonstrable retinal toxicity by microscopic and electrophysiologic criteria. The first 22 consecutive patients with advanced forms of proliferative vitreoretinopathy were treated with a combination of periocular and intraocular 5-fluorouracil, in addition to scleral buckling and vitrectomy. Retinal reattachment was achieved in 60% of patients at 6 months postoperatively. No serious systemic or ocular complications were observed although delayed healing of corneal epithelial defects occurred in 18% of cases and subtle subepithelial scarring in 31.8%. In combination with standard vitrectomy techniques, postoperative fluid gas exchange, and photocoagulation, periocular and subconjunctival 5-fluorouracil appears to improve the prognosis for longterm retinal reattachment following the development of proliferative vitreoretinopathy.

The Effect of Tarsorrhaphy on Normal Healing of Corneal Epithelial Defects in a Rabbit Model

The presumed benefits of occlusive patching are patient comfort and enhancement of corneal healing. However, there is little experimental evidence to document a beneficial effect of eyelid occlusion on corneal healing. We produced corneal abrasions by mechanical debridement within a 4 mm trephine-marked area on 1 eye each of 23 New Zealand albino rabbits. Homatropine 5% solution and erythromycin ointment were instilled. Then we divided the animals into three groups. The abraded eyes of the first group (7 rabbits) were sutured shut by a temporary tarsorrhaphy. The eyes of the second group (7 rabbits) were left open until 12 h postinjury, when they were sutured shut in a similar fashion. The abraded eyes of the control group (9 rabbits) were left open for the entire observation period. We monitored fluorescein staining patterns of the epithelial defects photographically at a set focal length at 12-h intervals. By 48 h, corneal staining had resolved in 87% of eyes. We performed computerized planimetry on the photographs of wound size for each time point. There was no statistically significant difference in the rate of healing of corneal abrasions in the occluded versus of the unoccluded eyes.

Toxicity of ingredients in artificial tears and ophthalmic drugs in a cell attachment and spreading test†

AbstractDuring re-epithelialization of corneal erosions, the epithelial cells are attached and migrate on a fibronectin-containing substratum. In earlier studies we found that topical application of the plasmin inhibitor aprotinin promoted healing of corneal epithelial defects, presumably inhibiting proteolytic degradation of fibronectin and related adhesive proteins. The present study investigated, using an in vitro cell culture test, the action of various ophthalmic preparations on cell attachment and spreading on a fibronectin-coated substratum. The cell culture test was designed to simulate the situation in the wounded corneal epithelium in vivo. Analysis of 16 different ophthalmic preparations indicated that the toxicity of some of them in the test could be assigned to specific ingredients (benzalkonium chloride, thimerosal sodium, Tween 80) used as additives. In contrast, chlorobutanol, used widely as a preservative, was nontoxic in the test, in concentrations used in ophthalmic preparations. It sho...

The Effect of Sodium Hyaluronate on the Migration of Rabbit Corneal Epithelium. II. The Effect of Topical Administration

The effect of topically administered sodium hyaluronate (Na-HA) on the healing of corneal epithelial defect was investigated using rabbit eyes. The corneal epithelium was removed surgically or with iodine vapor or n-heptanol, and saline was administered to one eye as the control, and 0.1% or 0.25% Na-HA with a molecular weight of 87.3 x 10(4) to the other eye once daily. The area of epithelial defect was measured once daily before a topical administration, and the healing rate of epithelial defect was calculated. When the corneal epithelium was removed with iodine vapor, a topical administration of 0.1% or 0.25% Na-HA did not significantly accelerate the epithelial healing. But when removed surgically or with n-heptanol, the healing rates of the corneas treated with 0.25% Na-HA significantly exceeded those of the control eyes. When the epithelium was removed surgically, treatment with 0.1% Na-HA also significantly accelerated the healing. To determine why the effect of Na-HA differed in these three models with the epithelial defect, the amount of fibronectin (FN) produced by the cornea were investigated. The amount of FN produced was determined from the concentration of FN in the medium obtained after incubation of the corneo-scleral section with corneal epithelial defect, and the amount of Na-HA retained on that cornea was estimated from radioactivity detected in tears and cornea after a topical administration of 14C-labeled Na-HA (14C-Na-HA). The corneo-scleral section whose corneal epithelium had been removed surgically, or with n-heptanol, produced a significantly larger amount of FN than that whose corneal epithelium had been removed with iodine vapor. In addition, the amount of 14C-Na-HA retained on the cornea of the first or second model also significantly exceeded that on the cornea of the third model. The topical administration of Na-HA would thus appear to accelerate the healing of the epithelial defect producing a larger amount of FN or retaining a larger amount of Na-HA.