Prevention of Exuberant Granulation Tissue and Neovascularization ...

LABORATORY SCIENCES 

Prevention of Exuberant Granulation Tissue and 

Neovascularization in the Rat Cornea by Naltrexone 

Ian S. Zagon, MS, PhD; Matthew S. Klocek, MS; James W. Griffith, DVM; Joseph W. Sassani, MD, MHA; 

András M. Komáromy, DVM, PhD; Patricia J. McLaughlin, MS, DEd 

Objective: To determine whether topical application of 

naltrexone prevents exuberant granulation tissue formation 

with neovascularization in diabetic rat corneas. 

Methods: Diabetes was induced with streptozotocin. A 

5-mm corneal abrasion at 9 or 11 weeks was treated topically 

for 7 days (4 times daily) with naltrexone or a sterile 

vehicle. 

Results: Within 2 to 5 days after reepithelialization, diabetic 

rats given the sterile vehicle had a 41% incidence 

of corneal lesions represented by exuberant granulation 

tissue with corneal neovascularization extending from the 

limbus. These lesions exhibited edema, cellular and vascular 

inflammation, and disruption of stromal lamella by 

fibrovascular tissue and calcium mineralization, but infection 

was not detected. No corneal lesions were re- 

Author Affiliations: 

Departments of Neural and 

Behavioral Sciences (Drs Zagon 

and McLaughlin and 

Mr Klocek), Comparative 

Medicine (Dr Griffith), and 

Ophthalmology (Dr Sassani), 

The Milton S. Hershey Medical 

Center, Pennsylvania State 

University, Hershey; and the 

Department of Clinical Studies, 

School of Veterinary Medicine, 

University of Pennsylvania, 

Philadelphia (Dr Komáromy). 

CORNEAL NEOVASCULARIZAtion 

has been estimated to 

affect 1.4 million Americans 

annually. 1 Corneal 

neovascularization is associated 

with a wide variety of conditions, 

including contact lens wear, surgical 

and nonsurgical trauma, alkali and 

other chemical burns, and infection. 1-3 Corneal 

neovascularization may be helpful in 

combating infections, assisting in corneal 

healing, and arresting autoimmune 

corneal melting. 3,4 Nevertheless, such vascularization 

can lead to corneal scarring, 

edema, lipid deposition, and inflammation 

that may significantly compromise 

corneal transparency and result in severe 

visual impairment, including blindness. 

1-3 The etiology of corneal neovascularization 

is unclear, though the association 

of stromal edema proximal to the 

limbus has been proposed as necessary to 

allow blood vessels into the usually compact 

stroma. 1-3,5 Treatment modalities 

include surgery, topical corticosteroids, 

angiostatic steroids, nonsteroidal antiinflammatory 

agents, and natural inhibi- 

corded in the diabetic group treated with naltrexone or 

the control group given the sterile vehicle. Diabetic rats 

with corneal lesions given the sterile vehicle reepithelialized 

more slowly than diabetic rats given the sterile vehicle 

without such lesions, but no difference in blood glucose 

levels were noted. 

Conclusions: Using a minimally invasive model in diabetic 

rats, topical naltrexone normalizes corneal wound 

healing and prevents neovascularization. 

Clinical Relevance: Direct application of naltrexone 

may serve as an important strategy for facilitating corneal 

healing and inhibiting corneal neovascularization. 

Arch Ophthalmol. 2008;126(4):501-506 

(REPRINTED) ARCH OPHTHALMOL / VOL 126 (NO. 4), APR 2008 WWW.ARCHOPHTHALMOL.COM 

501 

©2008 American Medical Association. All rights reserved. 

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tors of angiogenesis. 1-3 However, treatments 

of ocular neovascularization may 

have limitations, such as recurrence, adverse 

effects, and patients being ineligible 

for therapy. 1 Thus, models of ocular 

neovascularization, as well as treatment 

regimens for corneal lesions with neovascularization, 

are needed. 

In previous investigations, we have reported 

that topical treatment with the opioid 

antagonist naltrexone facilitates corneal 

reepithelialization in healthy and 

diabetic corneas. 6-9 Subsequent preliminary 

histological examination has revealed 

that a subset of reepithelialized 

poorly controlled diabetic rat corneas exhibit 

exuberant granulation tissue formation 

with stromal neovascularization. 

These observations have led to the present 

study, which examines the hypothesis 

that topical application of the opioid 

antagonist naltrexone prevents granulation 

tissue formation and accompanying 

neovascularization in a unique model of 

delayed wound healing in rats with type 

1 diabetes.

Mean Weight, g 

Mean Glucose Level, mg/dL 

600 

500 

400 

300 

200 

100 

0 

600 

500 

400 

300 

200 

100 

0 

A Control 

Diabetic 

B 

0 

Control 

Diabetic 

0 

∗ 

2 4 6 8 

∗ 

METHODS 

∗ ∗ ∗ 

1 4 8 

Time, wk 

Figure 1. Body weights (A) and glucose levels (B) of rats rendered diabetic 

with streptozotocin (n=65) and untreated animals receiving citrate buffer 

(controls [n=26]). Body weight was recorded at the time of streptozotocin 

injection (week 0) and every 2 weeks thereafter. Blood glucose levels were 

recorded 1, 4, and 8 weeks after administration of streptozotocin. To convert 

glucose to mmol/L, multiply by 0.0555. *Indicates significantly different 

from control rats at P.001; error bars, standard error of the mean. 

ANIMALS AND INDUCTION OF DIABETES 

We obtained male Sprague-Dawley rats (weight, approximately 

175 g) from Charles River Laboratories (Wilmington, 

Massachusetts) and housed them under standard laboratory conditions. 

All investigations conformed to the regulations of the 

Association for Research in Vision and Ophthalmology and the 

National Institutes of Health and the guidelines of the Institutional 

Animal Care and Use Committee of the College of Medicine 

at Pennsylvania State University. 

Type 1 diabetes was induced according to Havel et al 10 and 

Ahrén et al. 11 An intraperitoneal injection of 40 mg of streptozotocin 

(Sigma-Aldrich Corp, St Louis, Missouri) per kilogram 

of body weight in 0.5 mol/L of ice-cold citrate buffer (pH 

4.5) was administered. A second dose of streptozotocin (40 mg/ 

kg) was injected 24 hours later. This regimen produced insulindeficient 

diabetes in 100% of the animals within 48 to 72 hours; 

this group consisted of 65 rats. Animals not receiving streptozotocin 

that were injected with citrate buffer served as the control 

group; this group consisted of 26 rats. 

Blood glucose levels were monitored from the tail vein using 

a True Track Smart System Glucometer (Home Diagnostics Inc, 

Ft Lauderdale, Florida) immediately before administering streptozotocin 

and at 1, 4, and 8 weeks after streptozotocin administration. 

A glucose level of 400 mg/dL [to convert to mmol/L, 

multiply by 0.0555] was considered the minimum level compatible 

with a stable nontoxic diabetic state. 12 

∗ 

∗ 

CORNEAL ABRASIONS 

The procedures for epithelial debridement and observation of 

repair followed those reported earlier. 6-8 In brief, animals were 

anesthetized with a mixture of ketamine (70 mg/kg), xylazine 

(7 mg/kg), and acepromazine (10 mg/kg). Eyes were examined 

under a dissecting microscope. If judged to be disease free, 

a 5 mm–diameter circle was outlined in the center of the cornea 

with a disposable dermatological skin punch (Acuderm, 

Ft Lauderdale, Florida). The encircled corneal epithelium was 

removed with a No. 15 Bard-Parker scalpel blade. Care was taken 

not to injure the underlying basement membrane and subjacent 

corneal tissue. 6 Epithelial defects were created between 7:30 

and 8:30 AM or 4 and 5 PM; we chose these times because previous 

studies showed no differences in the labeling index between 

morning and afternoon. 6 Any animal that experienced 

bleeding in the course of mechanical abrasion was not included 

in the study. Only 1 eye was abraded at a time in each 

animal. The right eye was abraded on the ninth week following 

injection of streptozotocin. Two weeks later, following closure 

of the initial epithelial defect, the left eye was abraded. 

TOPICAL ADMINISTRATION OF NALTREXONE 

Naltrexone (Sigma-Aldrich) was prepared at concentrations of 

10 −4 or 10 −5 M in a moxifloxacin hydrochloride ophthalmic 

solution (Vigamox; Alcon Inc, Ft Worth, Texas). Compounds 

were given as a single drop using the commercial applicator 

bottle to the central cornea of the injured eye, with the lower 

eyelid held away from the eye to avoid overflow. Eye drops were 

administered to unanesthetized animals at 7:30 AM, 10:30 AM, 

1:30 PM, and 4:30 PM for 7 consecutive days. Diabetic rats were 

randomly assigned to receive either naltrexone or a vehicle, 

whereas control animals received only the vehicle. 

SLITLAMP OBSERVATIONS OF THE CORNEA 

All animals were examined with a handheld slitlamp microscope 

to document overall corneal morphology and pathology, 

particularly the progression of corneal lesions. Corneas 

were observed with the slitlamp every day after debridement 

for the first 7 days and every other day for 3 weeks. Rats were 

placed in an isoflurane chamber for 60 seconds, and evaluation 

with the slitlamp was conducted before and after dilation 

of each eye. Corneal lesions were graded subjectively as grade 

1, 2, or 3 depending on whether they covered no more than 

25%, 50%, or 75%, respectively, of the corneal surface area. 

PHOTOGRAPHY 

Animals were anesthetized in a Plexiglas chamber attached to 

an isoflurane vaporizer, and the residual epithelial defect was 

stained with topical fluorescein. Rat eyes were viewed using a 

dissecting microscope with a tungsten light source and a gelatin 

Wratten No. 47 filter and photographed with a chargecoupled 

device camera at 1.5 magnification. Photographs were 

taken immediately after epithelial debridement (0 hours) and 

16, 24, 32, and 40 hours later. No animal was photographed at 

intervals shorter than 12 hours to prevent disruption of the healing 

process. The area of defect was determined using Optimas 

software (Meyer Instruments Inc, Houston, Texas) and was calculated 

as the percentage of the original epithelial defect. 

HISTOLOGY 

Animals were euthanized at 2, 3, 4, or 21 days following debridement 

by a lethal intraperitoneal injection of 100 mg/kg sodium 


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A B C D 

Figure 2. Photographs of corneas from control (A) and diabetic (B-D) rats treated topically with a sterile vehicle. Corneal lesions were divided into grades 1, 2, and 

3, indicating lesions that covered no more than 25% (B), 50% (C), or 75% (D), respectively, of the corneal surface area. 

pentobarbital; eyes were enucleated and placed in formalin for 

24 hours and prepared for paraffin embedding. Vertical sections 

(8 µm) that included the corneal surface, limbus, and conjunctiva 

were processed using hematoxylin-eosin, Masson trichrome, 

Brown-Hopps, or von Kossa staining protocols. 

STATISTICAL ANALYSIS 

Body weights and glucose measurements were analyzed using 

the 2-tailed t test. The area of residual defect was analyzed each 

time using 1-way analysis of variance, with subsequent analysis 

by the Newman-Keuls test. The incidence of corneal lesions 

was analyzed using the 2 test. 

RESULTS 

INDUCTION OF DIABETES 

All rats weighed a mean (SE) of 174 (2) g at the time of 

streptozotocin injections (Figure 1A). Control rats gained 

approximately 301 g during the 8 weeks. Rats in the diabetic 

group were comparable in body weight with control 

animals until 2 weeks after injection of streptozotocin. 

At this time, the diabetic group had a 15% reduction 

(P.001) in body weight relative to the control animals. 

Diabetic rats weighed significantly less (approximately 

25%-35%) than control rats beginning week 4 and 

throughout the study. 

Mean (SE) baseline glucose readings were 139 (8) 

mg/dL for all rats, and these values were consistent in 

the control group throughout the study (Figure 1B). Rats 

receiving streptozotocin became hyperglycemic within 

5 days and had glucose levels greater than 450 mg/dL 

throughout the duration of experimentation. 

SLITLAMP OBSERVATIONS OF THE CORNEA 

Within 2 to 5 days after reepithelialization, 41% of the 

29 diabetic animals receiving the sterile vehicle exhibited 

corneas with exuberant granulation tissue and blood 

vessels extending from the limbus to the corneal lesion 

(Figure 2). No additional diabetic animals receiving the 

sterile vehicle exhibited corneal lesions after this period. 

However, those animals with corneal lesions often 

had changes in severity of this complication (Table). 

None of the animals in the control group receiving the 

sterile vehicle or in the diabetic group receiving either 

10 −4 or 10 −5 M of naltrexone presented with corneal lesions 

during the study. The incidence of corneal lesions 

in the diabetic rats receiving the sterile vehicle differed 

significantly (P.001) from those recorded for the control 

group receiving the sterile vehicle and diabetic group 

receiving naltrexone. 

HISTOLOGY 

2 mm 

Table. Severity of Corneal Lesions With Neovascularization 

in Diabetic Rats Given a Sterile Vehicle 

Corneal Lesion 

Severitya No. of Rats 

Week 1 Week 2 Week 3 

Grade 1 7 2 2 

Grade 2 5 4 4 

Grade 3 0 6 6 

a Corneal lesions were graded as 1, 2, and 3, depending on whether the 

lesion covered no more than 25%, 50%, or 75% of the corneal surface area, 

respectively. 

Examination of the corneas of rats in all groups revealed 

a complete epithelial layer by 2 to 3 days after debridement. 

However, within 4 to 7 days after mechanical abrasion, 

animals in the diabetic group receiving the sterile vehicle 

were identified with corneal lesions, segmented 

leukocytes in clefts in some areas of the stroma, and numerous 

spindle cell nuclei and melanin pigment. Edema 

in the stroma was observed in these animals. Rats in the 

diabetic group receiving the sterile vehicle that had corneal 

lesions exhibited capillaries containing red blood cells 

in the stroma, particularly at the margins of the cornea. 

Moreover, in some of these specimens, the epithelial layer 

appeared to be detached from the corneal surface. 

Histological examination of sections of corneas collected 

3 weeks after debridement from diabetic rats receiving 

the sterile vehicle were characterized by cellular 

and vascular indications of inflammation and edema 

(Figure 3). Focal necrosis and loss of surface epithelium 

with segmented leukocytes and macrophages were 

visible within the subjacent stroma. The inflammatory 

cells and capillary proliferation disrupted the normally 

transparent lamellar pattern of collagen within the stroma 

(Figure 3F). There was focal degeneration and mineralization 

of the subepithelial basement membrane that was 

confirmed positive for calcium with the von Kossa stain 

(data not shown). Examination of sections stained with 

the Brown-Hopps tissue gram stain revealed an absence 


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Ep 

St 

En 

A B 

50 µm 

C D 

E F 

Ep 

BV 

Figure 3. Photomicrographs of sections of the central cornea taken 21 days 

after wounding from rats in the control group receiving a sterile vehicle 

(A and B), in the diabetic group receiving naltrexone (C and D), and in the 

diabetic group receiving a sterile vehicle that had corneal lesions (E and F). 

Sections were stained with hematoxylin-eosin (A, C, and E) or Masson 

trichrome (B, D, and F). Note the detached epithelium (Ep), calcified 

basement membrane (*), loss of lamella, and granulation tissue with the 

inclusion of small caliber blood vessels (BV) in the diabetic animals given a 

sterile vehicle (E and F). En indicates endothelium; St, stroma. 

of bacteria associated with the corneal lesions. Animals 

in the control group receiving the sterile vehicle, as well 

as rats in the diabetic group receiving naltrexone at concentrations 

of 10 −4 and 10 −5 M, did not exhibit any histological 

abnormalities. 

CORNEAL REEPITHELIALIZATION 

The 5-mm trephine demarcated the entire corneal region 

of the rat eye but did not encroach on the limbus 

or conjunctiva (Figure 4A). Wound healing occurred 

in a manner consistent with previous studies in healthy 

rats, rabbits, and humans as well as in diabetic rats. 9,13,14 

The initial area of the abrasion ranged from 19.3 mm 2 to 

25.6 mm 2 and corresponded to corneal injuries of 4.9 to 

5.7 mm in diameter. No differences in the size of the initial 

abrasions were noted between groups. 

Diabetic animals (with or without corneal lesions) receiving 

the sterile vehicle had corneal epithelial defect 

measurements that indicated a significant retardation from 

the control group receiving the sterile vehicle at 32 

(P.05) and 40 (P.001) hours and from the diabetic 

groups given 10 −4 Mor10 −5 M naltrexone treatment at 

A 

Mean Epithelial Defect, % 

16 h 

24 h 

32 h 

40 h 

B 

100 

75 

50 

25 

0 

DB SV (CL) 

∗ 

† 

∗ 

Initial Wound 

DB SV (No CL) DB NTX Control SV 

16 (P.05), 24 (P.001), 32 (P.01), and 40 (P.001) 

hours (data not shown). The diabetic animals receiving 

the sterile vehicle that had corneal lesions had greater 

epithelial defects than diabetic rats receiving the sterile 

vehicle without corneal lesions at 16 and 40 hours 

(Figure 4). Diabetic animals receiving naltrexone at concentrations 

of either 10 −4 Mor10 −5 M did not differ from 

each other in corneal reepithelialization at any time (data 

were collapsed for comparison). However, the diabetic 

‡ 

§ 

II 

0 16 24 32 40 

Time, h 

 

DB SV (CL) 

DB SV (No CL) 

DB NTX 

Control SV 

‡ 

‡ ‡ 

# # 

Figure 4. A, Representative photographs of rat eyes stained with fluorescein 

immediately (0 hours) and at 16, 24, 32, or 40 hours following a 5-mm 

corneal abrasion. Diabetic (DB) animals were topically treated with a sterile 

vehicle (SV) and the photographs are subdivided into animals that exhibited 

corneal lesions (CL) and those that did not (No CL) as well as DB corneas 

treated topically with 10 −4 M of naltrexone (NTX). Photographs of corneas 

from control rats receiving an SV are included. Corneal abrasions were 

created 9 weeks after injection of streptozotocin. Original magnification 

1.5. B, Residual epithelial defects after formation of a 5-mm mechanical 

abrasion. Significantly different from the DB SV (CL) group at P.05 (*), 

P.01 (†), or P.001 (‡). Significantly different from the DB SV (No CL) 

group at P.05 (), P.01 (§), or P.001 (#). Significantly different from 

control SV group at P.001 ( ). Error bars indicate standard error of the 

mean. 


504 



animals receiving naltrexone had smaller defects than control 

animals receiving the sterile vehicle at 24 hours but 

were comparable at 16, 32, and 40 hours. 

BLOOD GLUCOSE LEVELS 

In the diabetic group receiving the sterile vehicle, blood 

glucose levels in animals exhibiting corneal lesions did 

not differ from glucose levels in rats without corneal lesions 

at 1, 4, and 8 weeks. Specifically, mean (SE) blood 

glucose levels were 564 (18) mg/dL for 12 diabetic rats 

receiving the sterile vehicle that exhibited corneal lesions 

and 524 (19) mg/dL for 17 diabetic rats receiving 

the sterile vehicle that had no corneal lesions. 

COMMENT 

Our study reveals that more than 40% of rats with poorly 

controlled diabetes and corneal abrasions exhibit exuberant 

granulation tissue formation with neovascularization 

as determined by slitlamp microscopy and confirmed 

with histopathology. This abnormality following 

reepithelialization of the cornea, with indications at the 

histological level, was recorded as early as 2 days after 

debridement. These complications involved inflammation, 

edema, mineralization, and neovascularization but 

did not appear to include an infectious process. 

Our data show that these complications following corneal 

epithelial repair can be completely prevented by topical 

treatment with either 10 −4 or 10 −5 M of naltrexone. 

Interestingly, diabetic animals with corneal lesions were 

found to be correlated with significantly slower rates of 

reepithelialization than those detected in diabetic rats 

without corneal lesions. These results would suggest that 

the appearance of granulation tissue with neovascularization 

may be related to an increased susceptibility for 

damage in these diabetic corneas brought on by delays 

in repair of injury. In this regard, it is well known that 

there is an irregular thickening and multilamination of 

the epithelial basement membrane in diabetic humans 

and animals. 13,15 It may be conjectured that the subset of 

diabetic animals displaying more exaggerated delays in 

reepithelialization than others have a problem with the 

integrity of the basement membrane. However, we did 

find that the blood glucose levels in both groups were 

similar; so it can be concluded that the magnitude of hyperglycemia 

was not an issue in this regard. Presumably, 

the exuberant granulation tissue disrupts the repaired 

corneal epithelium as the excessive granulation 

tissue protrudes above the level of the surrounding epithelium. 

Given the edema in the stroma and the appearance 

of new blood vessels from the limbus, our observations 

support the hypothesis of Cogan, 5 that stromal 

edema occurring near the limbus may be necessary to allow 

blood vessels into the corneal stroma. Thus, for the 

first time, we have defined a model for a pathologic response 

to complications in reepithelialization that involve 

exuberant granulation tissue formation and neovascularization. 

Moreover, we have demonstrated a 

treatment modality using naltrexone that aborts this 

process. 

The mechanism(s) concerning naltrexone’s capacity 

to attenuate neovascularization in the repair of the abraded 

cornea of diabetic rats is unclear. One possibility is that 

naltrexone directly diminishes the proliferation of these 

blood vessels. However, it is known that 5 µg of naltrexone 

placed on a methylcellulose disc stimulates angiogenesis 

(blood vessel number and length) compared with 

controls given vehicles in a chick chorioallantoic membrane 

preparation. 16,17 Moreover, naltrexone at a dosage 

that induced a continuous opioid receptor blockade (ie, 

30 mg/kg daily) has been reported to elevate DNA synthesis 

in the intima and media and to increase intimal 

thickness and reduce luminal area in the carotid artery 

that was denuded with balloon catheterization in comparison 

with vehicle-exposed control rats. 18 These data 

are consistent with findings that sustained opioid receptor 

blockade with naltrexone or other opioid antagonists 

results in enhanced DNA synthesis in tissues undergoing 

development, cellular renewal, or repair as well 

as in neoplasia. 19 Thus, the evidence does not appear to 

support the hypothesis that naltrexone has a direct inhibitory 

effect on neovascularization. Another possible 

mechanism regarding naltrexone treatment and diminished 

neovascularization is based on the observation that 

the cornea of the diabetic rats receiving the sterile vehicle 

heals slower than that in the control group receiving 

the sterile vehicle. 6,7 In the current study, when the 

diabetic group receiving the sterile vehicle is subdivided 

into those with and without corneal lesions, those 

with corneal lesions exhibited even more retarded reepithelialization 

than those without corneal lesions. This finding 

suggests that the pace of repair of corneal defects is 

more highly associated with the appearance of neovascularization, 

with a greater risk of neovascularization in 

animals with the slowest rates of reepithelization. This 

hypothesis is consonant with the observation that diabetic 

animals exposed to topical naltrexone have an accelerated 

rate of corneal wound healing comparable with 

that of the control animals receiving sterile vehicles, and 

these diabetic rats receiving naltrexone did not display 

neovascularization. Thus, it could be conjectured that the 

mechanisms for the promotion of neovascularization in 

the cornea of diabetic animals may be factors and events 

occurring in the extended period of reepithelialization. 

If this is the case, then a test of this hypothesis would be 

an examination of the repercussions of a drug- or mechanical-induced 

retardation in corneal repair in diabetic 

rats, which would be predicted to increase the incidence 

of neovascularization. Finally, it is known that 

naltrexone treatment restores corneal sensitivity in diabetic 

rats. 7 In this manner, it may optimize the homeostatic 

milieu and thereby facilitate healing by reestablishing 

the blink reflex and tear production. 

The complications following corneal reepithelialization 

in rats we documented has not been reported in humans. 

One factor that may contribute to the development 

of the corneal lesions we observed is the severity in degree 

and duration of hyperglycemia (blood glucose levels in these 

rats were routinely 450 mg/dL for 8 weeks). Moreover, 

humans have a Bowman membrane that is absent in 

rats. If a corneal abrasion in a rat can be equated to a superficial 

corneal ulcer in humans, the lack of this ana- 


505 



tomic barrier (ie, the Bowman membrane) in the rat could 

make their corneas more susceptible to inflammatory mediators 

accompanying reepithelialization. Further contributing 

to the complications following corneal epithelial repair 

in these poorly controlled diabetic animals may be the 

presence of decreased corneal sensitivity that we have previously 

reported, which can be remedied by topical treatment 

with naltrexone. 14 Decreased corneal sensitivity would 

be expected to decrease tear production and/or blink reflex, 

thereby subjecting the newly repaired cornea to an adverse 

environment. 

The healthy human cornea is free from blood vessels, 

but neovascularization is a common clinical problem 

seen as a response to chronic hypoxia or various inflammatory 

stimuli, such as bacterial keratitis, alkali burns, 

and graft rejection. 1-3 The severity of clinical disorders 

involving corneal neovascularization, which, untreated, 

may lead to pronounced visual impairment, emphasizes 

the importance of broadening our base of knowledge 

in this field. That the model we describe is occurring 

on the ocular surface makes these lesions very accessible 

for defining related structural, biochemical, and 

physiological events, particularly neovascularization. Additionally, 

such a model provides the unique opportunity 

to delineate the effect of various treatment regimens. 

Therefore, for the first time, we have characterized 

a unique model of exuberant granulation tissue with neovascularization 

that accompanies complications of corneal 

reepithelialization that can be tested for toxicity and 

efficacy of therapeutic modalities. 

Submitted for Publication: May 22, 2007; final revision 

received July 17, 2007; accepted July 18, 2007. 

Correspondence: Ian S. Zagon, MS, PhD, Department of 

Neural and Behavioral Sciences, Mail Code H109, The 

M. S. Hershey Medical Center, 500 University Dr, Room 

C3729, Hershey, PA 17033 (isz1@psu.edu). 

Financial Disclosure: None reported. 

Funding/Support: This study was supported in part by 

grants EY16666 and K12 EY015398 from the National 

Institutes of Health. 

From the Archives of the Archives 

Now World War II has thrust on the United States leadership 

in ophthalmology, as in all other branches of medicine. 

At present this is a stimulus to the progress of ophthalmology 

here. It is to be hoped that, in spite of political 

obstacles which many of us fear we foresee in the near 

future, this accelerated progress will continue without 

interruption. 

Reference: Verhoeff FH. American ophthalmology 

during the past century. Arch Ophthalmol. 1948;39:464. 

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