Accepted Manuscript

Treatment of Acute Ocular Chemical Burns

Namrata Sharma, MD, Manpreet Kaur, MD, Tushar Agarwal, MD, Virender S.Sangwan, MS, Rasik B. Vajpayee, FRCS(Edin), FRANZCO

PII: S0039-6257(16)30201-6

DOI: 10.1016/j.survophthal.2017.09.005

Reference: SOP 6754

To appear in: Survey of Ophthalmology

Received Date: 11 October 2016

Revised Date: 8 September 2017

Accepted Date: 11 September 2017

Please cite this article as: Sharma N, Kaur M, Agarwal T, Sangwan VS, Vajpayee RB, Treatment ofAcute Ocular Chemical Burns, Survey of Ophthalmology (2017), doi: 10.1016/j.survophthal.2017.09.005.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

1

Treatment of Acute Ocular Chemical Burns

Authors

1. Namrata Sharma MD1

2. Manpreet Kaur MD1

3. Tushar Agarwal MD1

4. Virender S Sangwan MS2

5. Rasik B. Vajpayee FRCS(Edin),FRANZCO3

Affiliations

1Dr. Rajendra Prasad Institute for Medical Sciences, AIIMS, New Delhi, India

2L V Prasad Eye Institute, Hyderabad, India

3Vision Eye Institute, Royal Victorian Eye and Ear Hospital, North West Academic Centre,

University of Melbourne, Australia

Conflicts of interest: None

This research did not receive any specific grant from funding agencies in the public, commercial,

or not-for-profit sectors.

Address for correspondence:

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

2

Namrata Sharma, MD, DNB, MNAMS

Professor, Cornea & Refractive Surgery Services

Dr. Rajendra Prasad Centre for Ophthalmic Sciences

All India Institute of Medical Sciences

New Delhi-110029,India

Phone no: +91-011-26593144

Email ID: namrata.sharma@gmail.com, namrata103@hotmail.com

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

3

Abstract

Ocular chemical burns are an ophthalmic emergency and are responsible for 11.5% to

22.1% of ocular injuries. Immediate copious irrigation is universally recommended in acute

ocular burns to remove the offending agent and minimize damage. Conventional medical therapy

consists of the use of agents that promote epithelialization, minimize inflammation, and prevent

cicatricial complications. Biological fluids such as autologous serum, umbilical cord blood

serum, platelet-rich plasma, and amniotic membrane suspension are a rich source of growth

factors and promote healing when used as adjuncts to conventional therapy. Surgical treatment of

acute ocular burns includes the debridement of the necrotic tissue, application of tissue

adhesives, tenoplasty, and tectonic keratoplasty. Amniotic membrane transplantation is a novel

surgical treatment that is increasingly being used as an adjunct to conventional treatment to

promote epithelial healing, minimize pain, and restore visual acuity. Various experimental

treatments that aim to promote wound healing and minimize inflammation are being evaluated

such as human mesenchymal and adipose stem cells, beta-1,3 glucan, angiotensin-converting

enzyme inhibitors, cultivated fibroblasts, zinc desferrioxamine, anti-fibrinolytic agents,

antioxidants, collagen cross-linking, and inhibitors of corneal neovascularization.

Keywords: acute ocular burns, amniotic membrane transplantation in acute ocular burns, ocular

chemical burns, ocular alkali burns, umbilical cord serum in acute ocular burns, autologous

serum in acute ocular burns

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

4

Manuscript

I. Introduction

Acute ocular chemical burns are an ophthalmic emergency and require immediate

diagnosis and prompt management. They are responsible for 11.5% to 22.1% of ocular

injuries.218 A recent epidemiologic survey reported that children aged 1 to 2 years are at a

significantly higher risk of sustaining ocular chemical injuries than other age groups.69

Ocular burns may occur accidentally at the workplace, laboratories, home, or be intentional

as a result of assault or vitriolage.117 A majority of ocular chemical burns occur at residential

locations in the lower socioeconomic groups.69 The various types of chemical agents that

cause ocular burns include alkalis and acids; alkalis are responsible for 60% of ocular

burns.166

The clinical course of an ocular chemical injury may be divided into the immediate,

acute, early reparative, and late reparative phases.124 The immediate phase begins at the

moment of contact of the chemical agent with the ocular surface. The initial 7 days after

chemical eye injury constitute the acute phase of recovery. This is followed by the early

reparative phase, which is the transition period of ocular healing and lasts 8-21 days after the

injury. Herein, we describe the treatment modalities in the initial immediate, acute, and early

reparative phases. For the purpose of this review, the term “acute ocular burns” refers to

burns with duration of less than 3 weeks.

Ocular chemical burns may result in extensive long-term damage to the ocular surface

and limbal stem cells. Limbal stem cell deficiency may lead to severely dry eyes, corneal

neovascularization, and corneal opacity. The potential cicatricial sequelae of ocular chemical

burns include lid margin abnormalities, symblepharon, ankyloblepharon, and trichiasis.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

5

Conventional management of acute ocular burns focuses on the promotion of

epithelialization, reduction of inflammation, and prevention of progressive corneal melt and

cicatricial complications.9,218 The various medical therapies that have been used to treat

ocular burns include ascorbic acid,20,107,144citrate,144 tetracycline,140,156,180 corticosteroids,50

and medroxyprogesterone.218 The surgical treatment of acute ocular burns includes the

debridement of necrotic tissue, application of tissue adhesives,58 tenoplasty,206,165 and

tectonic keratoplasty, if required.158

Growth factors play an important role in corneal epithelial wound healing and repair.116

Amniotic membrane is a rich source of growth factors and is increasingly being used in the

treatment of acute ocular burns.78,87,109,154,187,196,126,202 It has anti-inflammatory and anti-

fibrotic properties that promote the restoration of a stable ocular surface. Other biological

agents that are rich sources of growth factors and have been used topically in acute ocular

burns include autologous serum, umbilical cord serum, and autologous platelet-rich

plasma.108,134,186,187,181

II. Classification

Acute ocular chemical burns may be classified on the basis of limbal, corneal, and

conjunctival involvement at the time of injury. Various classification systems have been

proposed to help prognosticate the outcome of acute ocular burns. The Roper-Hall and Dua

classification systems are commonly used.52,174 The Roper-Hall classification system was

initially proposed by Ballen in 1964 and was subsequently modified by Roper-Hall in

1965.8,174 The extent of tissue damage is assessed by the degree of corneal haze and the

amount of limbal ischemia and is used to determine the prognosis following ocular surface

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

6

injury (Table 1); however, it classifies all cases with 50%-100% limbal ischemia as grade IV

burns, even though not all such cases have a poor prognosis. The Dua classification system is

based on the limbal involvement in clock hours as well as the percentage of bulbar

conjunctival involvement (Table 2).52 It re-classifies Roper Hall grade IV burns into grade

IV, V, or VI burns, and the prognosis is determined by the extent of limbal and conjunctival

involvement. This is based on the fact that the limbal epithelial stem cells and the forniceal

stem cells of the conjunctival epithelium may help in the restoration of an intact ocular

surface and wound healing.52 Intact limbal anatomy of even one clock hour may promote re-

epithelialization and healing after ocular surface injury and an intact conjunctival epithelium

may grow over the denuded cornea and promote the natural repair mechanism while

minimizing stromal melt. Hence, only eyes that have 12 clock hours of limbal involvement

and 100% of conjunctival involvement are classified as grade VI burns, with a very poor

prognosis.

Dua’s classification also incorporates an analogue scale that allows for a continuous score

to be assigned to the limbal and conjunctival involvement in addition to the step-wise

gradation of the severity of ocular injury.52 The analogue scale enhances the flexibility of the

classification system by allowing crossover between the grades of chemical injury in

different clinical scenarios and can accurately reflect the daily progress and healing following

acute burns, even if the grade of injury remains the same. Dua’s classification helps in more

precise definition of the extent of ocular surface injury and a better prediction of injury

outcomes. 52

III. Medical Management

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

7

Medical management aims at the removal of the offending agent, copious irrigation, the

promotion of epithelialization, the minimization of ulceration, and controlling inflammation.

Topical biological fluids are increasingly being used in acute ocular burns as a source of

growth factors in order to promote corneal wound healing and repair. The role of oxygen

therapy is being evaluated in experimental animal as well as in human studies to assist

wound healing.73,183,184

A. Emergency treatment

Prompt institution of emergency treatment in cases of acute ocular chemical burns

is the keystone in management and helps in the prevention of long-term debilitating

cicatricial sequelae. Removal of particulate matter and irrigation are well-established

modalities to minimize further ocular damage. The benefit of paracentesis in cases of

acute ocular chemical injuries is controversial.

1. Irrigation

Immediate copious irrigation of the ocular surface in acute ocular burns is

universally recommended to minimize the potential ocular injury.23,128,25,98,112 In

experimental alkali-burned porcine corneas, minimal changes were observed in the

intraocular pH of eyes that had been rinsed immediately after the induction of an alkali

burn.169 Irrigation should be continued until neutralization of the ocular surface pH is

achieved. A minimum of 30 minutes of irrigation is recommended using 1-3 liters of

fluid. The pH should be checked every 15-20 minutes during irrigation. Continuous

irrigation systems have been developed for the emergency management of acute ocular

burns.223 Irrigating contact lenses such as the Morgan lens (MorTan, Inc., Missoula, MT,

USA) may be used to deliver a continuous stream of the irrigating fluid. Following

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

8

copious irrigation, the lids should be everted and a comprehensive ocular surface

examination should be undertaken to remove any remnant particulate matter and to

document the extent of the injury. Double eversion of the lid should be performed if

needed. The chemical particles are removed from the ocular surface with a moist cotton

tip or fine-tipped forceps.

The rinsing solutions that have been used for irrigation include water, normal saline,

Ringer's lactate, phosphate buffer, Diphoterine® (Prevor, Cologne, Germany), and

Cederroth® eye wash(Cederroth Industrial Products, Upplands Vasby

Sweden).169,77,91,90,95,79 Clean tap water is an effective rinsing solution in emergency

situations when none of the physiological solutions are available. Immediate copious

irrigation with clean tap water may reduce the severity of ocular burns and shorten the

healing time.169,77,91Hypo-osmolarity of the tap water may lead to corneal edema. The

subsequent enlargement of the diffusion barrier and intracorneal dilution inhibits elevated

intracameral pH levels.90 Iso-osmolar saline is less efficacious than tap water as an

irrigating agent for ocular burns.90 Amphoteric solutions that have a non-specific binding

with bases and acids are also useful in emergency situations.95,79 Diphoterine is a

hypertonic, polyvalent, amphoteric substance with buffering capacity comparable to that

of phosphate buffer.99,91 Cederroth eye wash is a borate buffer solution. A comparative

evaluation of different irrigating solutions reported that both Diphoterine and Cederroth

eye wash solutions are superior to tap water in lowering intracameral pH following

experimental alkali burns; however, saline and isotonic phosphate buffer are not effective

in buffering intraocular pH.170 Prompt commencement of irrigation is more important

than the choice of irrigating solution.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

9

2. Paracentesis

The role of paracentesis and anterior chamber irrigation in acute ocular chemical

burns is not well established owing to a paucity of clinical studies.11,25,66,128,137

Paracentesis and anterior chamber irrigation lowered the intracameral pH in experimental

animal studies when instituted within 1-30 minutes of chemical injuries.137,11,66 We do not

recommend the use of paracentesis or anterior chamber irrigation in acute ocular

chemical burns.

B. Promotion of epithelialization

The agents that promote epithelialization following acute ocular burns include artificial

tears, fibronectin, epidermal growth factor, retinoic acid, and sodium hyaluronate. The role of

fibronectin, epidermal growth factor, retinoic acid and sodium hyaluronate is experimental,

with no conclusive studies in human subjects to determine their efficacy in cases of acute

ocular burns.

1. Artificial tears

Artificial tears are the mainstay of treatment in cases of acute ocular chemical injuries

and are routinely administered to promote epithelialization.218 Preservative-free tear

substitutes may ameliorate persistent epitheliopathy, reduce the risk of recurrent erosion,

and accelerate visual rehabilitation.

2. Fibronectin

Fibronectin promotes corneal wound healing following acute ocular burns in

experimental animal studies.7,159,167,165,234,150,195,12 Increased expression of fibronectin and

laminin has been observed in rat corneal alkali burns as early as 7 hours following an

alkali burn.12, It enhances epithelialization and prevents secondary breakdown of the

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

10

regenerating epithelium in alkali burns induced in rabbits167 Fibronectin helps preserve a

stable, intact ocular surface by decreasing the peeling back of the healing epithelium and

promoting re-epithelialization in experimental animal burns;195 however, the role of

fibronectin in acute ocular burns is still experimental, and its usage is not recommended

routinely.

3. Epidermal growth factor

Epidermal growth factor (EGF) plays an essential role in wound healing in tissues

such as the skin, cornea, and gastrointestinal tract.177 It stimulates the proliferation of

keratocytes in the early stages of wound healing and promotes re-epithelialization in

experimental animal alkali burn models.18,191,60,163,178,164,209,159 The safety and efficacy of

EGF in acute ocular chemical burns has not been established in human studies, and its

routine use is not recommended.

4. Retinoic acid

Vitamin A is necessary for normal epithelial growth and differentiation.88 Vitamin A

deficiency leads to the loss of goblet cells, increased epidermal keratinization, and

squamous metaplasia of the mucous membranes, including the cornea and conjunctiva.70

Retinoic acid stimulates the conversion of limbal stem cells to transient amplifying cells,

inhibits the proliferation of corneal and limbal transient amplifying cells, and prevents

abnormal terminal epithelial differentiation in experimental studies.92 It promotes

transdifferentiation of the conjunctival epithelium into the corneal epithelium following

severe chemical injury. Theoretically, it may be useful following severe chemical injury

in promoting goblet cell recovery, tear film stabilization, and improved ocular surface

wetting. Kim et al. demonstrated that 1500 IU/ml of retinyl palmitate eye drops

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

11

administered 4 times a day for 3 days can inhibit vascular endothelial growth factor-A

(VEGF-A), activate thrombospondin 2, and improve conjunctival impression cytologic

findings in experimental corneal alkali burns in rats. 84 Toshida et al. demonstrated

accelerated wound healing in experimental ocular chemical burns in rabbits after

administering 1500 IU/ml of retinol palmitate 6 times a day for 11 days;208 however,

there is a paucity of human studies and retinoic acid is currently not advocated in the

routine management of acute ocular chemical burns.

5. Sodium hyaluronate

Hyaluronic acid (HA) is a high-molecular-weight glycosaminoglycan and

extracellular matrix component that promotes cell proliferation. High-molecular-weight

HA modulates biosynthetic pathways, cell migration, cell outgrowth, and protein

degradation to stimulate wound healing and prevent cell death.222 Histochemical analysis

of animal corneas following acute ocular burns demonstrates the presence of hyaluronic

acid in the healing epithelium, repopulating keratocytes/fibroblasts and the cells forming

the retrocorneal membrane.56Topical HA (1% and 2%) promotes corneal epithelial

wound healing in experimentally induced ocular burns.38,40,7,224 Topical 1% HA may

enhance the formation of hemidesmosomes during the early healing phase in n-heptanol-

induced experimental corneal wounds.41 The routine use of HA is not recommended in

cases of acute burns because of lack of definitive literature in humans.

C. Support repair and minimize ulceration

Ascorbate, tetracyclines, and collagenase inhibitors support repair and minimize

ulceration following acute ocular burns. Both topical and systemic ascorbate, as well as

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

12

tetracycline, exert a beneficial effect in the acute phase of wound healing. The role of

collagenase inhibitors is experimental with no studies on human subjects.

1. Ascorbate

Alkali injury to the ciliary epithelial transport processes and the ciliary body

vasculature may result in a decrease in the aqueous humor ascorbate levels to one-third

the normal values.146,171 The scorbutic state results in the failure of the fibroblasts to

synthesize collagen for repair. Immediate treatment with systemic or topical ascorbate to

reverse this deficiency significantly decreases the incidence of subsequent corneal

ulceration and perforation in experimental animal models.146,149,147,221 Topical

administration is more effective than systemic administration, since the latter has

inadequate penetration in the anterior segment of the injured eye as observed in

experimental studies.149 Transmission electron microscopy has demonstrated the presence

of basal lamina under the regenerating epithelium in rabbit eyes with alkali burns

following treatment with 10% sodium ascorbate.175 Topical ascorbate also potentiates the

effect of topical citrate in preventing corneal ulceration.144

A majority of the experimental studies demonstrate a definite benefit of topical and

systemic sodium ascorbate in the management of acute ocular chemical

burns.144,175,146,149,147,221Even in studies that do not show any significant difference in

outcome, a trend toward the beneficial effect of ascorbate is evident as there is a decrease

in the perforation rates, rapid healing, and a shift of the adenosine triphosphate

(ATP)/adenosine diphosphate (ADP) ratio.148,162,20,119

Based on our clinical experience and the available literature, we recommend the

administration of 500 mg of oral ascorbate 4 times a day, along with 10% topical

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

13

ascorbate eye drops every 2 hours, in the initial 4 weeks, followed by tapering the dose

over 1 month in cases of grade III-VI (Dua classification) acute ocular burns.

2. Tetracyclines

Tetracyclines prevent collagenolytic degradation of the cornea after ocular chemical

injury.24 Increased tetracycline levels in the ocular tissues decrease the likelihood of

ulceration in alkali burn-induced rabbit eyes.180 Tetracyclines inhibit matrix

metalloproteinases through multiple mechanisms involving the restriction of gene

expression of neutrophil collagenase and epithelial gelatinase, suppression of alpha-

1antitrypsin degradation, and scavenging of reactive oxygen species.156,215,63,64,140 The

anticollagenolytic mechanism is independent of the anti-microbial mechanism of

tetracyclines.140,63Oral tetracycline, 250 mg 4 times a day; doxycycline, 100 mg twice a

day; or minocycline, 100 mg twice a day may be used alongwith topical tetracycline

preparations (1% suspension or 3% ointment) in cases of acute ocular burns. Both topical

and systemic tetracycline have beneficial effects in cases of acute ocular burns.180,156

Doxycyline is more potent than minocycline or tetracycline in preventing collagen

ulceration, and the effect is not reversible by an excess of cationic calcium.24,141 However,

all the referenced studies are experimental animal studies, and there is an absence of well

controlled human studies showing clinical benefit.

3. Collagenase inhibitors

N-acetyl cysteine (10-20%) and synthetic inhibitors of metalloproteinases (SIMP)

significantly delay or prevent the ulceration of alkali-injured corneas by influencing

collagen degradation.76,179,83,143,22,24,93,127,55 In addition to collagenase inhibition, SIMPs

also cause a significant reduction in the accumulation of polymorphonuclear leukocytes

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

14

(PMNL) in alkali-injured corneas. The dual effect of the inhibition of PMNL chemotaxis

and collagenase activity make SIMP a potential drug for combating ulceration in alkali-

injured corneas.143,22 An experimental study did not observe any beneficial effect of n-

acetyl cysteine in cases of acute alkali burns.145 The role of collagenase inhibitors is not

well established with a paucity of human studies; hence, they are not recommended for

routine clinical use in cases of acute ocular chemical burns.

D. Control of inflammation

The agents that have been used to control inflammation include corticosteroids,

progestational steroids, non-steroidal anti-inflammatory drugs, and citrate.

1. Corticosteroids

Corticosteroids have traditionally been the mainstay of therapy for the reduction of

tissue injury related to acute or chronic inflammatory conditions. They reduce

inflammatory cell infiltration and stabilize PMNL cytoplasmic and lysosomal

membranes.80,106 Corticosteroids can be used intensively during the first week following

an alkali burn without increasing the risk of corneal melting. Topical prednisolone 1%

and topical dexamethasone 0.1% may be used in the acute phase after ocular burns;

however, they should be rapidly tapered in 10-14 days to minimize their deleterious

effects.

The use of topical steroids for more than 6 days after ocular chemical injury

increases the incidence of corneoscleral melting in experimental animal models.50 The

mechanism for enhancement of corneal ulceration is not a direct augmentation of

collagenase activity, but probably involves the inhibition of the repair process.50 Vitamin

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

15

C has been used in conjunction with topical steroids for prolonged periods without an

increase in corneoscleral melting.48

In an experimental animal study, corneas treated with 0.1% dexamethasone alone

for the first week maintained a well-preserved basement membrane for as long as 4

weeks after the initial damage without enhancement of the inflammatory cell

infiltration.39 In another experimental study, topical administration of 0.1%

dexamethasone deterred endothelial healing during the early period and prevented

secondary endothelial breakdown. The total repair process of the endothelium was

accelerated by the dexamethasone treatment and it may have therapeutic potential in the

management of endothelial healing after corneal alkali injury.42

Conjunctival damage in alkali burns results in the loss of goblet cells in the acute

post-injury period. A deficiency in goblet cells and mucin is associated with both short-

and long-term ocular sequelae. Topical steroids in the acute phase of ocular chemical

burns are also beneficial in suppressing goblet cell loss in experimental animal models.19

We recommend the institution of topical prednisolone 1% or topical dexamethasone 0.1%

every 2 hours in the acute phase of ocular burns in conjunction with topical and oral

ascorbate. The topical steroids are tapered in 10-14 days.

2. Progestational steroids

Progestational steroids have less potent anti-inflammatory properties compared to

corticosteroids; however, they have a minimal inhibitory effect on stromal repair and

collagen synthesis.152 The mode of action is related to the suppressive effect of

progestational steroids on the production of tissue collagenase, as indicated by the

considerable reduction in collagenolytic activity by living explants of the treated

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

16

corneas.129,76 They may have the potential to substitute corticosteroids after 10-14 days of

acute ocular chemical burns in inflamed eyes.

The incidence of perforation and deep ulceration in experimental alkali-burned

rabbit corneas is reduced by the topical or parenteral administration of

medroxyprogesterone;129,101,45 however, further clinical studies in humans are required to

definitely establish the clinical role of medroxyprogesterone in acute ocular chemical

burns.

3. Citrate

Sodium citrate significantly inhibits the development of corneal ulcers after alkali

injury. It inhibits collagenase activity as well as PMNL infiltration of the cornea

following alkali burns.24,138,135 Citrate acts by chelating calcium and magnesium. This has

been supported by an experimental study in which the addition of calcium and

magnesium annulled the favorable effect of 10% topical citrate in alkali-injured rabbit

eyes.67 Sodium citrate-induced collagenase inhibition is also reversible by excess calcium

cations.24 Topical citrate 10% was observed to be superior to 10% ascorbate, 20%

acetylcysteine, or Adsorbotear in reducing the incidence of corneal ulceration and

perforation after experimental alkaliburns.145 The combination of citrate and ascorbate is

superior to citrate alone in preventing corneal ulceration.144 A retrospective 11-year

review of ocular burns observed a trend toward rapid healing in grade III burns (Roper-

Hall classification) with the use of topical citrate.20 We recommend the use of topical

10% citrate every 2 hours in the acute phase of ocular chemical burns, followed by

tapering after the initial 4 weeks in grade III-VI (Dua classification) burns.

4. Non-steroidal anti-inflammatory drugs (NSAIDs)

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

17

NSAIDs and experimental lipogenase and leukotriene inhibitors are effective

inhibitors of PMN leukocytes.197 Anti-inflammatory non-steroidal therapy combined with

free radical scavengers may be a potential alternative to corticosteroid treatment in cases

of chemical injuries.100 Pretreatment with aspirin or indomethacin abolishes the increase

in intraocular pressure and the elevation of prostaglandin-like activity in the aqueous

humor following experimentally induced corneal burns;136,198 however, further clinical

studies in humans are required to establish the clinical role of NSAIDs in acute ocular

chemical burns.

E. Adjuvant therapy

The use of prophylactic topical antibiotics is warranted during the initial treatment stages to

prevent the occurrence of secondary infection, especially in the presence of epithelial defect.

Severe ocular chemical burns (Roper-Hall grade III or IV) are more likely to be associated

with glaucoma and require surgical management for the control of intraocular pressure (IOP).

Elevated IOP generally occurs within 1 week in such eyes.111Topical aqueous suppressants are

advocated to reduce IOP secondary to chemical injuries, both as an initial therapy and during the

later recovery phase, if IOP is high (>30 mm Hg). Systemic anti-glaucoma drugs are advocated

to control IOP. This also minimizes epithelial toxicity that may occur due to the use of topical

aqueous suppressants. Glaucoma-filtering surgery and drainage devices may be needed in cases

of severe chemical burns with uncontrolled IOP.

Topical cycloplegic agents are required to manage the ciliary spasm and oral analgesics may

be required in some cases initially to control pain.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

18

Preservative-free topical medications are preferred to prevent exacerbation of the ocular

surface injury and secondary drug-induced toxicity. Oral medications may be considered when

appropriate to further spare the ocular surface.

F. Topical biological fluids

Biological fluids that have been used to promote epithelialization and accelerate wound

healing in cases of acute ocular burns include autologous serum, umbilical cord serum, amniotic

membrane suspension, and autologous platelet-rich plasma (Table 3).108,134,186,187,181,188 They also

find an application in various other ocular surface disorders such as dry

eyes,5,59,155,173,211,228,229,230 persistent epithelial defects,212,216,232 neurotrophic

ulcers,231,3,123recurrent erosion syndrome,227,49and superior limbic keratoconjunctivitis.65

1. Biological properties

The rationale for the use of biological fluids in acute ocular burns stems from the

presence of various growth factors in serum. Autologous serum contains growth factors

such as epidermal growth factor, acidic fibroblast growth factor, basic fibroblast growth

factor, platelet-derived growth factor, hepatocyte growth factor, transforming growth

factor-beta, insulin-like growth factor-1, and nerve growth factor. It also contains vitamin

A, substance P, fibronectin, immunoglobulins, and serum anti-proteases such as alpha-2-

macroglobulin, which promote wound healing and re-epithelialization.113,123,153 The

composition is similar to natural tears, with a higher concentration of vitamin A,

transforming growth factor-beta-1, insulin-like growth factor-1, nerve growth factor,

fibronectin, and lysosyme than tears.123,213Autologous serum eye drops are superior to

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

19

artificial tears in treating dry eyes27 and have the additional advantage of being

preservative free.

The constituents of umbilical cord serum are similar to autologous serum; however,

the concentrations of growth factors are several times higher in umbilical cord serum than

in peripheral blood serum.229,231 Vitamin A and insulin-like growth factor-1

concentrations are higher in autologous serum compared to cord blood serum.229,231

Autologous platelet-rich plasma contains platelets in addition to the growth factors

and cytokines. The platelets contribute to the prolonged release of growth factors and

cytokines.122

Amniotic membrane is a rich source of growth factors, with additional anti-

inflammatory and anti-scarring properties.68,86,89 Topical amniotic membrane suspension

obviates the need for a surgical procedure as required in amniotic membrane

transplantation.108

2. Outcomes

The efficacy of amniotic membrane suspension, autologous serum, and umbilical

cord serum in acute chemical burns has been demonstrated in various experimental

animal studies.35,72,132,176,182 Undiluted autologous serum eyedrops promoted the epithelial

healing process in experimental corneal alkali wounds induced in rabbits.176 Umbilical

cord serum was superior to peripheral blood serum and artificial tears in promoting

wound healing and decreasing the corneal haze in a mouse model of ocular chemical

burns.132 Amniotic membrane suspension promoted faster epithelial healing than

autologous serum in a rabbit model of alkaline corneal injury.182Amniotic membrane

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

20

suspension promotes epithelial healing and decreases corneal haze, neovascularization,

and inflammation in cases of alkali burns.36,72

Only a few human studies exist evaluating the role of different biological fluids in

cases of acute ocular burns. A prospective study assessed the role of 50% autologous

serum in various ocular surface disorders including chemical burns.181 Fifteen eyes with

grade II-III chemical injury (Dua classification) received 50% autologous serum drops 5-

6 times per day in addition to conventional therapy. The autologous serum was

introduced 7 days after the corticosteroid therapy in patients with persistent

inflammation, epithelial defects, or any type of ocular surface instability. The dose was

reduced to 3 times daily after 1 month and continued until the absence of symptoms for at

least 3 more months without supportive therapy. At the end of a mean follow up of

16±5.86 weeks, all patients with chemical injury experienced symptomatic relief and an

average gain of 4 lines of Snellen acuity. Epithelial integrity was achieved in all cases,

with a decrease in inflammation and corneal opacity.

Two randomized control trials compared the efficacy of umbilical cord serum in

acute ocular burns.186,188 The first prospective randomized control trial compared the role

of umbilical cord serum, autologous serum, and artificial tears in acute ocular chemical

burns.186A total of 33 eyes of 32 patients with grade III, IV, or V burns (Dua

classification) were randomized to receive either 20% umbilical cord serum (n=12), 20%

autologous serum (n=11), or artificial tears (n=10) administered 10 times per day. The

patients were followed up for 3 months. Patients receiving umbilical cord serum

experienced significantly more pain relief at day 7 compared to autologous serum and

artificial tears. Umbilical cord serum was superior in terms of epithelial defect healing,

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

21

corneal clarity, decrease in vascularization, and limbal involvement at the end of 3

months. No significant difference was observed between the groups with regard to

symblepharon formation.

Another randomized controlled trial compared the efficacy of topical umbilical

cord serum drops and amniotic membrane transplantation (AMT) in acute ocular

chemicalburns.188A total of 45 eyes with acute chemical burns of grade III, IV, and V

(Dua's classification) presenting within the first week of injury were randomized into 3

groups to receive either 20% umbilical cord serum with medical therapy, AMT with

medical therapy, or conventional medical therapy alone. Umbilical cord serum and AMT

were found to be equally efficacious in terms of time to corneal re-epithelialization and

both were superior to medical therapy alone. Umbilical cord serum achieved faster

improvement in corneal clarity, better pain control, and helped avoid surgery in inflamed

eyes.

A retrospective interventional comparative case series compared umbilical cord

serum (20%, 10 times/day) with AMT and conventional management in 55 eyes with

moderate (grade II-IV Dua classification) acute ocular burns.187 Both umbilical cord

serum and AMT were superior to conventional management in healing the epithelial

defect. Umbilical cord serum was superior to AMT in terms of a healthy ocular surface;

furthermore, there is an additional advantage of avoiding surgery in inflamed eyes.

A prospective case series evaluated the use of topical amniotic membrane extract

in 14 eyes of 11 patients with acute chemical burns. Amniotic membrane extract was

instilled hourly for the first 4 weeks, then every 2 hours for 2 weeks and tapered slowly

until the inflammation subsided. Symptomatic relief and epithelial defect healing were

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

22

reported in all cases. Improvement in visual acuity and a reduction of inflammation was

observed, with a greater efficacy in mild to moderately acute cases.108

Panda et al. randomly assigned 20 eyes with grade III-V (Dua classification) acute

chemical injury into2 groups. Group I (10 eyes) received autologous platelet-rich plasma

eye drops 10 times per day along with standard medical treatment, and group II (10 eyes)

received standard medical treatment alone. At the end of 3 months of follow up, the

group receiving the autologous platelet-rich plasma demonstrated faster healing of

epithelial defects and better corneal clarity.134

A single case controlled study evaluated the role of subconjunctival application of

regenerative factor-rich plasma for the treatment of ocular alkali burns in 35 eyes. A

significant reduction in the corneal and conjunctival epithelialization times and healing

times was reported in cases of moderate burns receiving the regenerative factor-rich

plasma.121

We recommend the instillation of topical biological fluids 10-12 times per day for the

initial 4 weeks followed by slowly tapering the dose until the inflammation subsides in all

cases of grade III-VI (Dua classification) ocular burns (Figure 1). Umbilical cord serum

is preferred over autologous serum and topical amniotic membrane suspension.

G. Oxygen therapy

Oxygen therapy has been used to assist wound healing for many years. Multiple mechanisms

have been proposed to explain the beneficial effect of the hyperoxia induced by hyperbaric

oxygen. Hyperbaric oxygen therapy induces vasoconstriction and promotes fibroblast

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

23

proliferation and also increases bacterial killing by the recruitment of leukocytes and facilitates

toxin inhibition and antibiotic synergy.102

Two animal studies have studied the role of oxygen therapy in acute ocular burns. Hirst et al.

did not report any beneficial effect of hyperbaric oxygen in preventing corneal perforation in 24

rabbit eyes with experimental alkali burns;73 however, Sharifipour et al. observed a delay in the

onset of ulceration and a decreased incidence of corneal perforation in 28 rabbit eyes receiving

5L/min oxygen therapy for 1 hour daily.184

A pilot study evaluated the effect of the systemic administration of oxygen in cases with

acute ocular burns in a nonrandomized prospective comparative study.183A total of 24 eyes of 22

patients with grade III-IV burns (Roper-Hall classification) were administered 100% oxygen at

flow rates of 10 L/min for 1 hour twice a day. The eyes receiving oxygen therapy had

significantly faster corneal epithelialization and vascularization of the ischemic areas with a

better mean visual acuity. The use of oxygen may salvage the partially injured ischemic limbal

stem cells, thereby promoting the restoration of an intact transparent ocular surface and

preventing the development of sight-threatening complications. No case receiving oxygen

developed corneoscleral melt or had symblepharon.

Large-scale studies are needed to further elucidate the effects of systemic oxygen therapy

in acute ocular burns so that a therapeutic regimen describing the specific dosage and duration

may be formulated. Currently, we do not recommend the routine use of oxygen therapy in acute

ocular chemical burns.

IV. Surgical Therapy

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

24

The surgical therapy in cases of acute ocular burns consists of debridement of the

necrotic tissues, amniotic membrane transplantation, use of tenoplasty if required, and

keratoplasty.

A. Debridement

Debridement of the necrotic epibulbar tissue removes inflammatory debris from the

ocular surface. Necrotic tissues act as a site for the accumulation of polymorphonuclear

neutrophils and leukocytes that release detrimental proteolytic enzymes, further aggravating

the damage.160,161

B. Amniotic membrane transplantation

1.Biological properties

The amnion is the innermost layer of fetal membranes and consists of the epithelium,

basement membrane, and stroma.47 Bourne described 5 layers in the amnion, namely the

epithelium, basement membrane, compact layer, fibroblast layer, and spongy layer.16 The

epithelium consists of a single layer of cuboidal cells that are attached to the underlying

basement membrane with the help of numerous hemidesmosomes. The basement membrane

consists of collagen IV and VII, fibronectin, and laminin 1 and 5. The laminin isoforms in the

amniotic membrane promote adhesion and the spread of corneal epithelial cells onto the

amniotic membrane.28,97 The stroma contains loose connective tissue that provides tensile

strength to the amniotic membrane. The epithelium and stroma act as sources of growth

factors and cytokines, which serve to maintain the microenvironment of the stem cells of the

corneal epithelium. They help maintain undifferentiated epithelial phenotype when culturing

the limbal stem cells. Epidermal growth factor, transforming growth factor-alpha,

keratinocyte growth factor, hepatocyte growth factor, basic fibroblast growth factor, and

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

25

transforming growth factor beta-1 and beta-2 are some of the growth factors that have been

demonstrated in the amniotic membrane epithelium and stroma.89 The basement membrane

provides the framework for epithelial cell migration and also induces their differentiation. It

strengthens adhesion on the basal cells and prevents apoptosis.14,15 The stromal matrix

inhibits cicatrization through the downregulation of transforming growth factor beta

signalling.210 It suppresses corneal, conjunctival, and limbal fibroblast proliferation and

differentiation and reduces subconjunctival fibrosis. The mRNA of antiangiogenic and anti-

inflammatory proteins has been demonstrated in the amniotic membrane; additionally,

protease inhibitors that reduce stromal inflammation and ulceration are also present.68,86 The

stromal matrix traps and induces apoptosis of the inflammatory cells and reduces

neovascularization.86 Antimicrobial properties have also been demonstrated in amniotic

membrane in a few studies.157,172

2.Preparations of amniotic membrane

Various types of amniotic membrane preparations have been used for acute ocular

burns. The most commonly used preparation is cryopreserved amniotic

membrane,78,87,109,154,187,196,202,203,205,207,126,131,235 followed by fresh amniotic

membrane6,30,214,235 and sutureless amniotic membrane (PROKERA®,Bio-Tissue, Inc.,

Miami, FL, USA).82,201 Dried amniotic membrane (amnioplastin) was historically used in

initial trials of amniotic membrane transplantation in acute ocular surface burns.193,194

a) Fresh amniotic membrane

Before delivery, fresh amniotic membrane is obtained during elective caesarean

section from the placenta of women who are seronegative for hepatitis B, hepatitis C,

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

26

syphilis, and HIV. The amniotic membrane is separated from the placenta under sterile

conditions and irrigated with copious sterile salt solution.214 It is stored in normal saline

solution containing 50,000 IU penicillin and 1g streptomycin per 400 ml saline at 4°C.6

Fresh amniotic membrane should be used within 24 hours of retrieval. Fresh amniotic

membrane, although more biologically active, is not preferred because of the potential

risk of microbiological transmission.125

b) Cryopreserved amniotic membrane

Most surgeons use cryopreserved amniotic membrane in cases of acute ocular

burns.78,87,109,154,187,196,202,203,205,207,126,235 Cryopreserved amniotic membrane is prepared

in accordance with the method described by Kim and Tseng,85 with minor

modifications. Amniotic membrane is harvested from placentas procured through

elective caesarean section of a seronegative donor. The serology of the donor is done to

exclude hepatitis B and C viruses, HIV, and syphilis during pregnancy or at the time of

delivery. The serology is repeated 3 to 6 months after delivery when the membrane is

cryopreserved to account for any infections at the time of initial screening. Meller et al.

additionally tested the donors for human T cell lymphotropic virus (HTLV).126 The

original method described by Kim and Tseng includes washing the membrane under a

lamellar flow hood to remove the blood clots, followed by dissecting the amnion

bluntly from the chorion.85 This amnion is flattened onto nitrocellulose filter paper with

the epithelium/basement membrane side up, and then washed 3 times with buffered

phosphate saline containing 1000U/ml penicillin, 20 mg/ml streptomycin, and 2.5

mcg/ml amphotericin B. The resulting membrane is cut into 1.5 cm diameter disks and

stored at 4°C in 100% glycerine.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

27

Lee and Tseng made minor modifications in the above technique.105 The

placenta is cleaned of the blood clots under a lamellar flow hood using Earle’s balance

salt solution containing 50 µg/ml penicillin, 50 µg/ml streptomycin, 100 µg/ml

neomycin, and 2.5 µg/ml amphotericin B. The amnion is flattened onto nitrocellulose

filter paper (0.45 micron pore size) and cut into small disks of 3×4 cm. It is

cryopreserved at -80°C in a sterile vial containing Dulbecco’s modified Eagle’s

medium and glycerol at a ratio of 1:1 (v/v). A similar method has been described by

Dua and Azuara-Blanco that involves washing the placenta with physiological saline or

0.01 M phosphate buffered saline (PBS) containing 100 mg of dibekacin sulphate.51

Tamhane et al. placed the amnion-chorion complex in sterile solution of normal saline

(540 ml), dexamethasone (8mg), gentamicin (80 mg), and heparin (5000 IU) after

retrieval.202

c) PROKERA

PROKERA (Bio-Tissue, Inc., Miami, FL, USA) contains cryopreserved amniotic

membrane clipped onto a symblepharon ring-like concave polycarbonate dual-ring

structure. The ring has an inner diameter of 15 mm (for pediatric patients) or 16 mm

(for adult patients) and adheres to the corneal and limbal surface like a contact lens. It is

a class II medical device that the FDA approved in 2003 for use as a temporary

amniotic membrane patch that is easy to insert and remove and obviates the need for

sutures. It acts as a biological bandage, with the stromal side of the amniotic membrane

in contact with the ocular surface and the symblepharon ring-like structure fitting

snugly in the fornices holding the amniotic membrane in place.82,201

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

28

3.Surgical techniques

Meller et al. initially performed cryopreserved amniotic membrane transplantation

(AMT) in accordance with the technique described by Brown et al.21,126 The amniotic

membrane was placed on the eye covering the entire ocular surface from the upper lid

margin to the lower lid margin and anchored using interrupted episcleral and lid margin

bites with 9/10-0 vicryl sutures. Fornix formation was done with 6-0 silk sutures passing

through the amniotic membrane and newly formed fornices brought out through the lid

and tied over the skin with bolsters. In a few cases with less extensive damage, the

amniotic membrane was used as a graft to cover only the damaged area. The sticky

stromal side was in contact with the corneo-conjunctival surface; however, in some

studies, the amniotic membrane with the stromal side up was also transplanted.

Variations in the technique of AMT have been described based on the orientation,

size, and layers of the amniotic membrane.6,78,87,109,115,114,154,187,193,194,196,202,203,205,126,214

Various modifications to decrease the dislodgement of the amniotic membrane have been

described, such as the use of a bandage contact lens, symblepharon ring, fibrin glue, and

modification of the suturing technique.6,82,87,109,115,114,187,196,201,202,205,207,126,214

a) Amniotic membrane layers and orientation

Most studies have transplanted a single layer of amniotic membrane onto the

damaged ocular surface, with a few studies using multilayered amniotic membrane with

the epithelial side facing upward.6,78,87,109,115,114,154,187,193,194,196,202,203,205,126,214A few

studies have also placed the amniotic membrane with the sticky stromal side facing

upward, and the epithelial side in contact with the ocular surface.109,126

b) Size of amniotic membrane

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

29

Depending on the severity of injury, the amniotic membrane either covers the

whole ocular surface stretching until the lid margins or may act as a graft covering only

the localized area of damaged corneoconjunctiva.126

c) Permanent versus temporary amniotic membrane transplantation

Amniotic membrane may be allowed to cover the ocular surface post

transplantation until its spontaneous dissolution or it may be removed after a few days,

acting as a temporary patch in that period.82,87,109,193,194,126,203

d) Modification in suturing technique

Kobayashi et al. introduced the technique of using running a nylon suture to

anchor the amniotic membrane to the lid margin and a purse string suture 1-2 mm from

the limbus to anchor the amniotic membrane to the episclera. This reduces redundant

amniotic membrane, decreasing the risk of infection and detachment.87

e) Use of fibrin glue

We routinely use fibrin glue (TISSEEL VH fibrin sealant, Baxter AG, Vienna,

Austria) to anchor the amniotic membrane to the ocular surface. The amniotic

membrane is placed stromal side down on the ocular surface, and 4 8-0 vicryl stay

sutures are placed in the perilimbal area. This is followed by injecting fibrin glue

beneath the amniotic membrane after drying the ocular surface. A symblepharon ring is

then placed, and the redundant amniotic membrane is trimmed.

f) Use of symblepharon ring

Tamhane et al. anchored the amniotic membrane with perilimbal and lid margin

interrupted 8-0 vicryl sutures, and used a symblepharon ring to spread the amniotic

membrane on the ocular surface.202 The symblepharon ring was removed after the

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

30

amniotic membrane was anchored with vicryl sutures along the lid margins, and sutures

applied after removing the ring. A similar technique was used by Sharma et al. in their

recent study.187 Tejwani et al. placed a symblepharon ring after suturing amniotic

membrane graft with interrupted 10-0 nylon perilimbal sutures and interrupted 8-0

vicryl episcleral sutures, which was removed after 1 week after surgery.205

Thanikachalam et al. placed a pediatric scleral shell after AMT.207 Liang et al.

fabricated a modified symblepharon ring made of polymethyl methacrylate (PMMA),

obviating the need for suturing the amniotic membrane.109 The modified symblepharon

ring was made by creating an impression of the anterior ocular surface on PMMA

conformers using an ocular prosthesis. The resultant 1 mm thick PMMA device had a

30-35 mm inner diameter, 35-38 mm outer diameter horizontally, and 35-40 mm outer

diameter vertically, with a gap in the lowest part of the fornix of the device. The

amniotic membrane was placed epithelial side down covering the entire ocular surface,

and the modified symblepharon ring was placed on it, followed by trimming of the

redundant amniotic membrane.

g) Use of bandage contact lens

Arora et al. used a bandage contact lens in addition to the symblepharon ring.6

Bandage contact lenses following AMT have been used by others to ensure the safety

of the transplanted amniotic membrane.114,115,196,126,214 Ucakhan et al. kept the bandage

contact lens in situ until the completion of epithelialization.214 We prefer to keep the

bandage contact lens over the amniotic membrane as this prolongs the duration the

amniotic membrane remains in situ.

h) PROKERA insertion

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

31

PROKERA (Bio-Tissue, Inc., Miami, FL, USA), a device for sutureless AM

delivery, is inserted under topical anesthesia in adult patients on an outpatient basis. The

patient is asked to look down and the PROKERA is inserted in the superior fornix,

followed by the inferior fornix. It is removed after healing.82,201

4.Outcomes

After AMT, the patients were followed up over a 30-960 day period.201 A majority

of patients experienced symptomatic relief after amniotic membrane

transplantation.6,82,87,114,115,126,202,205,188,214Following AMT, an improvement in visual

acuity and faster epithelialization was noted in most studies, with grade II-III burns

(Roper-Hall classification) healing better than grade IV

burns.6,82,87,109,114,115,126,187,193,194,196,202,203,205,214

a)Symptoms

Most patients undergoing amniotic membrane transplantation experienced a

resolution of pain, photophobia, and tearing in the immediate postoperative

period.6,82,87,114,115,126,205,188,214 Tejwani et al. reported symptomatic relief in 100% of

patients with acid injuries compared to 94.44% of patients with alkali injuries.205 There

was immediate reduction in light sensitivity and foreign body sensation, and the

patients were more comfortable.

b) Visual acuity

Following AMT in cases of acute ocular burns, an improvement in visual acuity

has been noted in most studies.6,82,87,109,114,115,126,187,193,194,196,202,205,214,220 Liang et al.

reported a gain in visual acuity in 46.15% of patients undergoing sutureless AMT using

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

32

the modified symblepharon ring compared to 41.67% of patients in the sutured AMT

group.109 Grade II-III (Roper-Hall classification) of ocular burns had more mean

improvement in visual acuity compared to grade IV ocular burns;6,126,202 however, no

improvement in visual acuity was reported in grade IV (Roper-Hall classification)

ocular burns undergoing AMT in few studies, with worsening of visual acuity in some

cases.6,78,202 In a case series by Joseph et al, all four eyes had a visual acuity of no

perception of light at the end of two years.78 In two randomized control trials, there was

no significant difference in the visual outcome amongst patients undergoing AMT or

those receiving conventional medical management.188,203

c) Time to epithelialization

After AMT, the time taken for restoration of stable ocular surface was variable,

ranging from less than one week to more than three months.87,114,115,187,193,194,214 Faster

epithelial defect healing was noted in grade II-III (Roper Hall classification) ocular

surface burns compared to grade IV burns.126,202,214 On histopathological examination,

faster re-epithelialization and better epithelial and stromal regeneration was observed

following AMT compared to conventional medical therapy in moderate alkaline burns.

114,115 On comparison of sutureless AMT with conventional sutured AMT, faster

epithelialization was noted in the sutureless group, with 71.79% of eyes achieving

complete epithelialization compared to 47.22% eyes in the sutured group.109 In a

randomized control trial comparing conventional medical treatment with AMT, faster

epithelial healing with AMT occurred compared to conventional medical treatment in

grade II-III (Roper Hall classification), but not grade IV ocular surface burns.202 In

another randomized control trial comparing the role of umbilical cord serum and amniotic

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

33

membranes as adjuncts in cases of acute ocular burns, faster epithelialization was

observed in both the AMT group and cord serum group when compared to conventional

medical therapy alone.188 Few studies have also reported persistent epithelial defects and

failure of amniotic membrane transplantation to restore stable ocular surface in grade IV

burns.6,78,126,114,115,154,202,205

5.Complications

The most common sequelae occurring after AMT were symblepharon formation,

corneal vascularization, and limbal stem cell deficiency. In a randomized control trial that

compared sutureless AMT using a modified symblepharon ring with sutured AMT,

symblepharon was significantly less in the sutureless group (38.46%) compared to the

sutured group (61.11%).109 Another randomized control trial evaluated AMT vs

conventional medical management and found less tendency toward symblepharon

formation in eyes undergoing AMT compared to conventional medical therapy in

moderate grade II-III burns (Roper-Hall classification); however, the same did not hold

true for severe burns (grade IV Roper Hall classification).203 A few studies did not report

any cicatricial complications.82,87,214 Grade IV (Roper-Hall) injuries usually had persistent

limbal stem cell deficiency despite AMT, with a poorer prognosis than grade II-III

burns.6,168,78,87,126,154,202,205

Additional procedures such as limbal stem cell transplant, keratolimbal allograft, or

conjunctival limbal autograft are often needed to treat limbal stem cell deficiency.126,203

Dislodgement of the graft in the postoperative period necessitating a regraft has been

reported, usually caused by frequent eye rubbing.126,193 Persistent epithelial defects may

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

34

lead to corneal perforation that eventually requires a penetrating

keratoplasty.6,78,126,154202,235 Granuloma pyogenicum, infective keratitis, and recurrent

ulceration were also infrequently observed.6,154,202,201 Corneal scarring, corneal melt, and

lid abnormalities have also been observed in few cases.78,126,154,187,193,194,201,196,203

Contraction of the conjunctival sac and fornices have also been observed in severe grade

V-VI burns (Dua classification).109 Less than 1% of eyes were lost from uncontrolled

inflammation, phthisis bulbi, autoevisceration, or exenteration.78,194 Although

transplantation of fresh amniotic membrane is associated with a theoretical risk of

transmission of infection, no such case has been reported following AMT.

Repeat amniotic membrane transplantation was the most common additional surgical

procedure required post AMT (74.2%) for persistent epithelial defect after dissolution of

the initial amniotic membrane.78,126,154,193,194,201,196,203,205,82,109 Dislodgement of the

previous graft and increased corneal staining were additional reasons for regraft.126,193

Although symblepharon is a common complication, symblepharon release was performed

in only 2.2%.205,201,78,126,154 Additional procedures for limbal stem cell deficiency, such as

limbal stem cell transplant, conjunctival autograft, and large diameter lamellar

keratoplasty and keratolimbal allograft were required in 16.5% cases, where amniotic

membrane alone was not sufficient to restore the limbal anatomy.126,203 Fornix formation

and lid reconstruction were infrequently required.78,205 Tectonic penetrating keratoplasty

was carried out in a few cases of progressive corneal melt and perforation.78,126

Conjunctival flap and tenoplasty have also been carried out in poor prognosis cases with

recalcitrant epithelial defects not amenable to repeat AMT.78,126

6. Conclusion

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

35

A Cochrane systematic review did not find enough evidence to recommend AMT

in acute ocular chemical burns in the first 7 days following injury. It included only 1

randomized control trial and highlighted the lack of high-quality evidence supporting the

use of AMT in acute ocular burns.43 Future well-designed randomized control trials are

needed to conclusively establish the guidelines for the use of AMT in acute ocular

chemical burns. However, a majority of studies have observed a beneficial effect of AMT

in acute ocular chemical burns.

Both umbilical cord serum and AMT are superior to conventional management in

promoting epithelialization. In cases of acute ocular burns, the use of cord serum as an

adjunct has an additional advantage of avoiding surgery in already inflamed eyes.187,188

However, umbilical cord serum is a scarce biological resource and may not be available

at all centers. Therefore, the use of AMT is an effective alternative in cases where

umbilical cord serum is not readily available (Figure 2).

We recommend AMT in all cases of grade III-VI (Dua’s classification) acute

ocular burns. Grade I-II (Dua’s classification) ocular chemical burns are mild and may be

effectively managed with conventional medical therapy alone. Although the role of AMT

in severe ocular chemical burns (grade IV-VI, Dua’s classification/grade IV, and Roper-

Hall classification) is controversial, we recommend AMT based on our clinical

experience. In our experience, AMT provides symptomatic relief and promotes healing in

grade IV-VI (Dua’s classification) ocular chemical burns, although the benefits are not as

pronounced as in grade III burns. The surgical procedure should be undertaken as soon as

possible after providing emergency care. Cryopreserved or fresh amniotic membrane may

be used. PROKERA is preferred in pediatric patients and systemically unstable patients

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

36

due to the ease of insertion of the device even at bedside. The high cost of the device and

the limited availability of PROKERA may limit its widespread usage, especially in

developing countries.

C. Tenoplasty

Tenoplasty is based on the principle of re-establishment of the limbal blood supply in

cases of severe ocular burns to potentially prevent late complications.206,96,165,159 A vital

connective tissue of orbit is used to cover the damaged ocular surface.

The technique of tenoplasty first described by Teping and Reim206 requires initial

debridement of all necrotic tissue from the conjunctiva and sclera. The tenon is then bluntly

separated from the extraocular muscles and the equatorial region of the globe, taking care to

preserve the vascular supply of the tenon tissue. After the preparation of a smooth tenon flap, it

is advanced to the limbus and sutured to the sclera, thus providing a revascularization of the

denuded sclera and the limbus region.

Tenoplasty helps in the resolution of scleral ulceration and prevents anterior segment

necrosis in eyes with severe chemical and thermal burns.206 It shortened the period of intensive

inpatient treatment in a series of 24 eyes with severe chemical burns.165 The conjunctival

epithelium regenerated in 10-50 days, and the corneoscleral ulceration healed in all cases. In 14

of 24 eyes, the denuded corneal stroma was covered with an artificial epithelium. Keratoplasty

was performed in 11 cases. Although some cases developed symblepharon, corneal opacity, and

neovascularization, tenoplasty laid the foundation for further reconstructive surgeries.

Augmentation of the tenoplasty may be needed with glued-on contact lenses, amniotic

membrane, or lamellar corneal patch graft.159,165,206

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

37

Cyanoacrylate tissue adhesive augmented tenoplasty has been successfully tried in a case

of progressive corneolimboscleral ulceration after grade IV chemical burns.185 The cyanoacrylate

tissue adhesive is directly applied to the ulcerated corneoscleral surface to augment the

tenoplasty. It results in fibrous tissue proliferation and the formation of leucomatous corneal

opacity with symblepharon. The ocular integrity was preserved and the final visual acuity was

6/36.

D. Tissue adhesives

Tissue adhesives may be used in the management of impending or actual perforations

following sterile corneal ulcerations in acute ocular burns. They provide tectonic support and

promote re-epithelialization. When used in conjunction with a contact lens, they prevent further

ulceration by inducing fibrovascular scarring and minimizing the stromal infiltration of

polymorphonuclear leukocytes.81

Both fibrin and cyanoacrylate tissue adhesives are effective for the closure of corneal

perforations up to 3 mm in diameter. Fibrin glue is associated with less corneal inflammation and

neovascularization, and there is no need for removal of the glue.217,190,53,13

The direct application of cyanoacrylate tissue adhesive on the ulcer bed followed by the

placement of a bandage lens helps prevent progressive corneal melt.58 The cyanoacrylate glue is

left in situ until it loosens spontaneously with the progress of re-epithelialization. It can be

removed with forceps 6 to 8 weeks after inflammation has subsided and neovascularization has

eliminated the risk of recurrent ulceration.

Tissue adhesives have been used in conjunction with amniotic membrane for small

corneal perforations.53,204,199 They may help to delay penetrating keratoplasty for treating corneal

perforations, especially in acute cases with an increased risk of graft rejection.53 Tissue adhesive

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

38

combined with amniotic membrane transplantation helps the rapid restoration of corneal and

conjunctival surfaces, thus preventing late stage cicatricial sequelae. In severe burns, it arrests

corneoscleral melting and restores the conjunctival surface and anterior segment blood supply,

but does not restore the integrity of the corneal surface.204

E. Keratoplasty

Corneoscleral ulcerations and perforations are severe complications of ocular burns. An

emergency full thickness keratoplasty may be required to provide tectonic support and maintain

the integrity of the globe.

1.Lamellar keratoplasty

The role of deep anterior lamellar keratoplasty (DALK) has been evaluated in acute

ocular chemical burns alone or in conjunction with AMT or a conjunctivo-limbal graft.

DALK alone or combined with AMT helps to restore ocular integrity and has been reported

to result in excellent graft transparency in 86% of cases and improvement in visual acuity in

100% of cases with acute chemical burns.192 Eyes with grade II and grade III ocular burns

experience more improvement than grade IV burns (Roper-Hall classification). DALK leads

to a faster resolution of symptoms and epithelial healing compared to the control group. The

incidence of symblepharon, corneal perforation, and the severity of vascularization decreased

in cases that underwent DALK.192

2.Penetrating keratoplasty

An emergency therapeutic keratoplasty may be needed in acute ocular burns with large

perforations. The prognosis for graft survival is poor because of the co-existent limbal stem

cell dysfunction. A large diameter keratoplasty also provides limbal stem cells along with

tectonic support.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

39

A large keratoplasty 11-12 mm in diameter has been successfully tried in 8 eyes with

widespread progressive corneal ulcerations and deep stromal defects. Six grafts remained

clear with a healthy epithelial layer but an early rejection within 3 months was experienced in

2 cases. Large keratoplasties may help achieve long-lasting healing and rehabilitation in very

severe ocular burns with total corneal melts. Restoration of an intact limbal anatomy is

essential for graft survival.94

A retrospective analysis of keratoplasty with scleral rim undertaken in cases of severe

ocular burns evaluated the putative role of surgery as a globe-salvaging procedure. Twelve

keratoplasties with a scleral rim were undertaken in 9 eyes with severe corneal burns. Three

eyes needed a repeat keratoplasty. Keratoplasty with a scleral rim can potentially save the

eye in cases with extensive corneoscleral ulceration or perforation. Nevertheless, visual

rehabilitation may not be achieved in most cases because of imminent graft failure. Only 2

grafts in the study remained clear, with failed grafts in the remaining 10 cases. Incomplete

eyelid closure, severe vascularization, corneal scarring, and poor epithelial healing may

contribute to graft failure.158

V. Investigational Agents

A. Stem cells

Human adipose-derived stem cells and mesenchymal stem cells inhibited inflammation

and angiogenesis and promoted corneal wound healing in experimental ocular chemical

burns in animal models.

1. Human adipose-derived stem cells

Human adipose-derived stem cells promoted cell renewal and healing in

experimental rabbit models of ocular chemical injury.110,54 Human adipose-derived stem

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

40

cells overlaid on a scleral contact lens (SCL) carrier reduced inflammation and corneal

haziness in severe ocular alkali burns in rabbits.54 Eyes receiving human adipose-derived

stem cells had smaller epithelial defects and less corneal opacities and neovascularization

compared to eyes receiving SCL alone. Untreated corneas melted in 2 weeks and

developed severe symblepharon.

Subconjunctival injection of human adipose-derived stem cell suspension (1.3 ×

105cells/0.2 mL) in rabbits with acute ocular chemical burns resulted in faster wound

healing than in the control group. Transplantation of cultured human adipose tissue-

derived stem cells in acute corneal chemical burns promotes cell renewal and assists in

damage repair.110

2.Mesenchymal stem cells

Subconjunctivally administered mesenchymal stem cells (MSCs) promote corneal

wound healing in the acute stage of alkali burns.

Subconjunctival injection of MSCs significantly enhanced the recovery of the

corneal epithelium and decreased the corneal neovascularization area in experimental

ocular alkali burns in rats. These effects are related to a reduction of infiltrated CD68 (+)

cells and the downregulation of MIP-1α, TNF-α, and VEGF.225

Human MSCs have also been transplanted into rat corneas using the amniotic

membrane as a carrier 7 days after chemical burns. They lead to the successful

reconstruction of the damaged corneal surface. The therapeutic effect of transplantation

may be associated with the inhibition of inflammation and angiogenesis rather than

epithelial differentiation from MSCs.118

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

41

B. Beta 1,3 glucan

Beta1,3 glucan promotes invitro epithelial wound healing and suppresses the acute

inflammatory reaction in experimental corneal alkali burns in rats. Laminarin and beta

1,3glucan increased the in vitro epithelial cell migration of immortalized human corneal

epithelial cells (HCECs) and hyaluronic acid (HA) conjugated beta 1,3glucandemonstrates

enhanced the migration rate more than beta 1,3glucan alone.37

Forty rats with experimentally induced alkali burns were divided into 4 groups receiving

200 µg/mL topical laminarin (n = 10), beta 1,3glucan (n = 10),beta 1,3glucan HA (n = 10), or

no treatment (n=10). The highest wound healing ratio and the lowest opacity score were

observed in the beta 1,3 glucan-HA group. Tissue sections revealed relatively fewer

polymorphonuclear leukocyte infiltrates in the corneal stroma in the beta 1,3 glucan and beta

1,3glucan-HA groups compared to the injury-only group.37

C. Anti-fibrinolytic agents

Anti-fibrinolytic agents such as epsilon-aminocaproic acid (EACA) and

tranexamic acid (TXA) competitively inhibit plasmin through binding at the serine site,

blocking the catabolic function of plasmin. They inhibit plasmin-mediated catabolism of

fibronectin on the basilar membrane surface attachment of the epithelial cells. These

agents also promote the activation of plasmin from plasminogen, thereby depleting the

pool of available plasminogen.130 Fibronectin establishes a supportive base for the

migrating epithelium by anchoring the regenerating epithelial cells to the underlying

stroma. The anti-fibrinolytic agents inhibit fibronectin catabolism and are hypothesized to

increase the rate of initial re-epithelialization of the corneal epithelium immediately

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

42

following the induction of epithelial defects by alkali burn. They have shown a

significant improvement in the treatment of persistent epithelial defect in rabbits.

Both EACA and TXA increased the rate of re-epithelialization compared to an

untreated control in the cultured corneas of rat alkali burn models. EACA was up to 35%

more efficacious than TXA.46

D. Angiotensin converting enzyme inhibitors

The local renin-angiotensin system activity determines the microcirculation in the

eye, and an increase in the activity of angiotensin-converting enzyme (ACE) has been

found in conjunctival ischemia. Instillation of the ACE inhibitor in rabbit eyes within 2

weeks of experimental alkali burns resulted in a reduction in ACE activity and an earlier

recovery of microcirculation in the area of conjunctival ischemia. ACE inhibitor

facilitates the maintenance of a high level of tear antioxidant potential and may have a

positive effect on the course of reparative processes after ocularburns.34

E. Allogenic fibroblasts cultivated in collagen gel

Transplantation of allogenic fibroblasts cultivated in collagen gel promoted

wound healing and corneal regeneration in an experimental model of acute alkali corneal

burns in rabbits.120

F. Zinc desferrioxamine

Topical zinc desferrioxamine (220 microM 7 times a day for 4 weeks) was

effective in decreasing the severity of ulceration in acute corneal alkali burns in rabbits. It

may be an adjunctive treatment in protecting the cornea against alkali injury.189

G. Hydroxypyridine derivatives

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

43

Emoxypine promoted healing of the corneal epithelial defect at the stage of

epitheliocyte migration to the defect area in experimental alkali burns in rabbits. Mexidol

also promoted epithelialization at the stage of epitheliocyte proliferation was is more

effective than emoxypine in decreasing the area of conjunctival ischemia. Antioxidant

activity and the content of products of nitric oxide metabolism in tear fluid decreased

after chemical burns, which may be restored by Mexidol.33

H. Antioxidant therapy

Antioxidant therapy may be considered as a complementary treatment in the

pharmacological modulation of acute corneal inflammation. Topical treatment with

antioxidants such as 0.2% superoxide dismutase and 0.5% dimethylthiourea (DMTU)

reduced inflammation, improved corneal transparency, and promoted healing in

experimental studies.4

I. Collagen cross-linking

Collagen cross-linking allows covalent bonds to be formed between the collagen

fibrils, thus promoting thickening of the collagen fibrils through the deposition of

structural molecules such as proteoglycans.2

The effect of riboflavin-ultraviolet-A-induced cross-linking (CXL) was evaluated

in 10 eyes with experimentally induced corneal alkali burns in rabbits. CXL-treated eyes

demonstrated significant decrease in the size of epithelial defect with a smaller extent of

corneal opacity compared to the control group. Histopathological evaluation of the CXL-

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

44

treated eyes showed the presence of collagen bridges linking the collagen fibers. CXL

may have the potential to improve the prognosis of acute corneal alkali burns.44

J. Inhibitors of corneal neovascularization

Corneal neovascularization (CNV) results from an imbalance between the angiogenic

and antiangiogenic factors and can lead to corneal scarring, edema, lipid deposition, and

inflammation.226,29 One of the most common causes of visual impairment, CNV leads to a

loss of the immunologic privilege of the cornea and is a high-risk factor for rejection after

allograft corneal transplantation.10,71,104,233,142 The role of various inhibitors of CNV in

preventing the debilitating long-term sequelae of ocular burns is being evaluated.

1. Endostatin

The antiangiogenic activities of lipid-mediated subconjunctival injection of endostatin

have been evaluated in a rabbit model of neovascularization. Both native endostatin and a

modified human endostatin gene containing a RGDRGD (arginine-glycin-aspartic-

arginine-glycin-aspartic) motif significantly inhibit CNV by suppressing the expression

of vascular endothelial growth factor (VEGF). Modified endostatin with an RGDRGD

motif is a more effective inhibitor of angiogenesis than native endostatin.62

2. Canstatin

Recombinant canstatin protein administered intraperitoneally (5-10mg/kg body

weight once a day for up to 14 days) suppresses corneal neovascularization in an alkaline

burn-induced mice model. Expression of VEGF and TNF-α significantly decreased in

canstatin-treated corneas. It may be used as an inhibitor of angiogenesis to treat

neovascularization-related corneal diseases.219

3. Subconjunctival angiostatin

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

45

Subconjunctival injection of recombinant adeno-associated virus (rAAV)-angiostatin

in alkali burn-induced rats reduced corneal angiogenesis. Ocular gene therapy involving

the subconjunctival injection of adenovirus-associated gene transfer of angiogenesis

inhibitors may be a simple and safe treatment modality that can achieve therapeutic levels

and long-lasting effects in the treatment of corneal neovascularization induced by ocular

surface disorders.32

4. AMD3100

AMD3100 is a CXCR4 antagonist and rapid stem cell-mobilizing agent.26 Locally

administrated AMD3100 reduced the number of alkali burn induced corneal

neovascularization in mice. The expression of endothelial progenitor cells marker

proteins VEGFR2 and CD34 is decreased by the subconjunctival administration of

AMD3100.139

5. Chondrocyte-derived extracellular matrix

Chondrocyte-derived extracellular matrix (CDECM) suppresses corneal

neovascularization by inhibiting nuclear factor-kappa B (NF-κB) activation by blocking

the PKC- and Akt-signaling pathways. CDECM markedly decreased corneal thickness,

neovascularization, and opacity when transplanted onto the corneal surface in

experimental alkali-burned rabbit corneas. It improved corneal healing by disrupting

corneal epithelial proliferation and reducing fibrotic changes of the stroma.103

6. Anti-angiogenic multigene therapy

Angiogenesis is a complex process, and therapy targeting a single anti-angiogenic

gene cannot block corneal neovascularization completely.17 Anti-angiogenic activity of

multiple genes targeting endostatin (mEndo), murine-soluble vascular endothelial growth

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

46

factor receptor-2 (msFlk-1), or murine-soluble Tie2 (msTie2) have been evaluated to

inhibit alkaline burn-induced corneal neovascularization in mice. Overexpression of these

putative anti-angiogenic proteins inhibits the in vitro proliferation and migration of

human umbilical vein endothelial cells. The subconjunctival injection of retroviral

particles of mEndo and msFlk-1 resulted in the most significant inhibition of CNV in a

murine corneal neovascularization model. The combination of multiple anti-angiogenic

genes might be necessary for effective therapy of corneal neovascularization.31

7. Bevacizumab

VEGF stimulates corneal neovascularization, and both VEGF and its receptors are

present in higher concentrations in human corneas with neovascularization.61,151

Bevacizumab (Avastin) is a recombinant humanized murine monoclonal antibody that

binds to and inhibits the biological activity of all human VEGF-A

isoforms.57Subconjunctival bevacizumab (2.5-5mg/ml) reduced corneal

neovascularization as well as VEGF levels in animal rabbit models of alkaline burns.75,1 It

significantly decreased the total neovascularization area, the circumference involved, and

the longest neovascular pedicle length.75 Bevacizumab (1.25 mg/0.05 ml) also decreased

inflammatory cell infiltration in chemically burned rat corneas.133 The levels of

inflammatory cytokines such as IL-2, IFN-gamma, and IL-6 were also decreased in rats

receiving bevacizumab injections.133

Subconjunctival bevacizumab(5mg/day) associated with dexamethasone

(4mg/day) may have an advantage over monotherapy with bevacizumab alone in causing

the involution of corneal neovascularization after corneal alkali burn.74

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

47

Combination therapy of topical doxycycline temperature-sensitive hydrogel

(DTSH) and bevacizumab is more effective in inhibiting corneal neovascularization than

topical bevacizumab or DTSH alone. DTSH combined with bevacizumab significantly

accelerates corneal wound healing by inhibiting the expression and activity of MMPs,

VEGF, phosphorylated VEGFR1, VEGFR2, and the production of iNOS and IL-1β.200

Conclusions

The principle of treatment of acute ocular burns is to prevent further damage, promote

wound healing, and hinder visually debilitating cicatricial sequelae. The management of

acute ocular chemical burns is summarized in Figure 3. Emergency management constitutes

copious irrigation and conventional medical agents--including ascorbic acid, citrate,

tetracycline, and corticosteroids.

Growth factors have been shown to play an important role in wound healing. Topical

biological fluids that are a rich source of growth factors include umbilical cord serum,

autologous serum, platelet-rich plasma, and amniotic membrane suspension. Amniotic

membrane is also a rich source of growth factors, with inherent anti-inflammatory, anti-

angiogenic, and anti-fibroblastic properties. Topical biological fluids and amniotic membrane

are increasingly being used in acute ocular burns, where timely intervention is the key to

preventing future cicatricial complications and preserving visual function. AMT has been

shown to provide immediate symptomatic relief, promote epithelial healing, and improve

visual acuity in cases of acute ocular burns; however, its efficacy is limited to moderate burns

and the results have not been encouraging in severe grade IV (Roper-Hall classification),

possibly because the associated severe limbal ischemia negates the regenerative effects of

AMT. Topical biological fluids are convenient methods of delivering growth factors to the

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

48

eye without the need for surgical intervention. They have been shown to effectively relieve

symptoms and promote healing, although limited evidence is available.

Various experimental treatments that promote wound healing and inhibit corneal

neovascularization are being evaluated, such as beta 1,3 glucan, angiotensin converting

enzyme inhibitors, cultivated fibroblasts, zinc desferrioxamine, anti-fibrinolytic agents,

antioxidants, collagen cross–linking, and inhibitors of angiogenesis. They may play an

important role in the future in preventing cicatricial complications in cases of acute ocular

burns.

Method of Literature Search

The literature search was performed in Medline using the following keywords: acute

ocular burns, amniotic membrane transplantation in acute ocular burns, ocular chemical

burns, ocular alkali burns, umbilical cord serum in acute ocular burns, and autologous serum

in acute ocular burns. The relevant references cited in those articles were also searched.

Abstracts of relevant non-English articles were used. All articles that described the use of

biological fluids (autologous serum, umbilical cord serum, platelet-rich plasma, and amniotic

membrane suspension) were reviewed. Regarding amniotic membrane transplantation in

acute ocular burns, all articles were reviewed since the first use of amniotic membrane in

ocular burns in 1986. For statements that are frequently mentioned in the literature, we chose

the earliest publication and other important articles.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

49

References

1. Ahmed A, Berati H, Nalan A, Aylin S. Effect of bevacizumab on corneal neovascularization in experimental rabbit model. Clinical & experimental ophthalmology. 2009;37(7):730-6. 2. Al-Sabai N, Koppen C, Tassignon MJ. UVA/riboflavin crosslinking as treatment for corneal melting. Bulletin de la Societe belge d'ophtalmologie. 2010(315):13-7. 3. Alio JL, Abad M, Artola A, Rodriguez-Prats JL, Pastor S, Ruiz-Colecha J. Use of autologous platelet-rich plasma in the treatment of dormant corneal ulcers. Ophthalmology. 2007;114(7):1286-93 e1. 4. Alio JL, Ayala MJ, Mulet ME, Artola A, Ruiz JM, Bellot J. Antioxidant therapy in the treatment of experimental acute corneal inflammation. Ophthalmic research. 1995;27(3):136-43. 5. Alio JL, Colecha JR, Pastor S, Rodriguez A, Artola A. Symptomatic dry eye treatment with autologous platelet-rich plasma. Ophthalmic research. 2007;39(3):124-9. 6. Arora R, Mehta D, Jain V. Amniotic membrane transplantation in acute chemical burns. Eye. 2005;19(3):273-8. 7. Asari A, Morita M, Sekiguchi T, Okamura K, Horie K, Miyauchi S. Hyaluronan, CD44 and fibronectin in rabbit corneal epithelial wound healing. Japanese journal of ophthalmology. 1996;40(1):18-25. 8. Ballen PH. Treatment of Chemical Burns of the Eye. Eye, ear, nose & throat monthly. 1964;43:57-61. 9. Baradaran-Rafii A, Eslani M, Haq Z, Shirzadeh E, Huvard MJ, Djalilian AR. Current and Upcoming Therapies for Ocular Surface Chemical Injuries. The ocular surface. 2017;15(1):48-64. 10. Benelli U, Ross JR, Nardi M, Klintworth GK. Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A. Investigative ophthalmology & visual science. 1997;38(2):274-82. 11. Bennett TO, Peyman GA, Rutgard J. Intracameral phosphate buffer in alkali burns. Canadian journal of ophthalmology Journal canadien d'ophtalmologie. 1978;13(2):93-5. 12. Berman M, Manseau E, Law M, Aiken D. Ulceration is correlated with degradation of fibrin and fibronectin at the corneal surface. Investigative ophthalmology & visual science. 1983;24(10):1358-66. 13. Bernauer W, Ficker LA, Watson PG, Dart JK. The management of corneal perforations associated with rheumatoid arthritis. An analysis of 32 eyes. Ophthalmology. 1995;102(9):1325-37. 14. Boudreau N, Sympson CJ, Werb Z, Bissell MJ. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science. 1995;267(5199):891-3. 15. Boudreau N, Werb Z, Bissell MJ. Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(8):3509-13. 16. Bourne GL. The microscopic anatomy of the human amnion and chorion. American journal of obstetrics and gynecology. 1960;79:1070-3. 17. Bradley J, Ju M, Robinson GS. Combination therapy for the treatment of ocular neovascularization. Angiogenesis. 2007;10(2):141-8. 18. Brazzell RK, Stern ME, Aquavella JV, Beuerman RW, Baird L. Human recombinant epidermal growth factor in experimental corneal wound healing. Investigative ophthalmology & visual science. 1991;32(2):336-40. 19. Brent BD, Karcioglu ZA. Effect of topical corticosteroids on goblet-cell density in an alkali-burn model. Annals of ophthalmology. 1991;23(6):221-3. 20. Brodovsky SC, McCarty CA, Snibson G, Loughnan M, Sullivan L, Daniell M, et al. Management of alkali burns : an 11-year retrospective review. Ophthalmology. 2000;107(10):1829-35. 21. BROWN AL. Lime burns of the eye: use of rabbit peritoneum to prevent severe delayed effects: experimental studies and report of cases. Archives of ophthalmology. 1941;26(5):754-69. 22. Burns FR, Gray RD, Paterson CA. Inhibition of alkali-induced corneal ulceration and perforation by a thiol peptide. Investigative ophthalmology & visual science. 1990;31(1):107-14.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

50

23. Burns FR, Paterson CA. Prompt irrigation of chemical eye injuries may avert severe damage. Occupational health & safety. 1989;58(4):33-6. 24. Burns FR, Stack MS, Gray RD, Paterson CA. Inhibition of purified collagenase from alkali-burned rabbit corneas. Investigative ophthalmology & visual science. 1989;30(7):1569-75. 25. Burns RP, Hikes CE. Irrigation of the anterior chamber for the treatment of alkali burns. American journal of ophthalmology. 1979;88(1):119-20. 26. Cashen AF, Nervi B, DiPersio J. AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent. Future oncology. 2007;3(1):19-27. 27. Celebi AR, Ulusoy C, Mirza GE. The efficacy of autologous serum eye drops for severe dry eye syndrome: a randomized double-blind crossover study. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2014;252(4):619-26. 28. Champliaud MF, Lunstrum GP, Rousselle P, Nishiyama T, Keene DR, Burgeson RE. Human amnion contains a novel laminin variant, laminin 7, which like laminin 6, covalently associates with laminin 5 to promote stable epithelial-stromal attachment. The Journal of cell biology. 1996;132(6):1189-98. 29. Chang JH, Gabison EE, Kato T, Azar DT. Corneal neovascularization. Current opinion in ophthalmology. 2001;12(4):242-9. 30. Chen J, Zhou S, Huang T, Liu Z, Chen L, Lin Y. [A clinical study on fresh amniotic membrane transplantation for treatment of severe ocular surface disorders at acute inflammatory and cicatricial stage]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology. 2000;36(1):13-7, 1. 31. Chen P, Yin H, Wang Y, Mi J, He W, Xie L, et al. Multi-gene targeted antiangiogenic therapies for experimental corneal neovascularization. Molecular vision. 2010;16:310-9. 32. Cheng HC, Yeh SI, Tsao YP, Kuo PC. Subconjunctival injection of recombinant AAV-angiostatin ameliorates alkali burn induced corneal angiogenesis. Molecular vision. 2007;13:2344-52. 33. Chesnokova NB, Beznos OV, Pavlenko TA, Zabozlaev AA, Pavlova MV. Effects of hydroxypyridine derivatives mexidol and emoxypin on the reparative processes in rabbit eye on the models of corneal epithelial defect and conjunctival ischemia. Bulletin of experimental biology and medicine. 2015;158(3):346-8. 34. Chesnokova NB, Kost OA, Nikol'skaia, II, Beznos OV, Binevskii PV, Makarov PV, et al. [Experimental rationale for local use of angiotensin-converting enzyme inhibitors for the treatment of ocular tissue ischemia on a model of postburn conjunctival ischemia]. Vestnik oftalmologii. 2008;124(4):28-31. 35. Choi JA, Choi JS, Joo CK. Effects of amniotic membrane suspension in the rat alkali burn model. Molecular vision. 2011;17:404-12. 36. Choi JA, Jin HJ, Jung S, Yang E, Choi JS, Chung SH, et al. Effects of amniotic membrane suspension in human corneal wound healing in vitro. Molecular vision. 2009;15:2230-8. 37. Choi JA, Oh TH, Choi JS, Chang DJ, Joo CK. Impact of beta-1,3-glucan isolated from Euglena gracilis on corneal epithelial cell migration and on wound healing in a rat alkali burn model. Current eye research. 2013;38(12):1207-13. 38. Chung JH, Fagerholm P, Lindstrom B. Hyaluronate in healing of corneal alkali wound in the rabbit. Experimental eye research. 1989;48(4):569-76. 39. Chung JH, Kang YG, Kim HJ. Effect of 0.1% dexamethasone on epithelial healing in experimental corneal alkali wounds: morphological changes during the repair process. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 1998;236(7):537-45. 40. Chung JH, Kim HJ, Fagerholmb P, Cho BC. Effect of topically applied Na-hyaluronan on experimental corneal alkali wound healing. Korean journal of ophthalmology : KJO. 1996;10(2):68-75. 41. Chung JH, Kim WK, Lee JS, Pae YS, Kim HJ. Effect of topical Na-hyaluronan on hemidesmosome formation in n-heptanol-induced corneal injury. Ophthalmic research. 1998;30(2):96-100.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

51

42. Chung JH, Paek SM, Choi JJ, Park YK, Lee JS, Kim WK. Effect of topically applied 0.1% dexamethasone on endothelial healing and aqueous composition during the repair process of rabbit corneal alkali wounds. Current eye research. 1999;18(2):110-6. 43. Clare G, Suleman H, Bunce C, Dua H. Amniotic membrane transplantation for acute ocular burns. The Cochrane database of systematic reviews. 2012;9:CD009379. 44. Colombo-Barboza M, Colombo-Barboza G, Felberg S, Dantas PE, Sato EH. Induction of corneal collagen cross-linking in experimental corneal alkali burns in rabbits. Arquivos brasileiros de oftalmologia. 2014;77(5):310-4. 45. Crabb CV. Endocrine influences on ulceration and regeneration in the alkali-burned cornea. Archives of ophthalmology. 1977;95(10):1866-70. 46. Crouch ER, 3rd, Crouch ER, Jr., Williams PB. Aminocaproic acid and tranexamic acid increase the rate of acute corneal reepithelialization in Sprague Dawley rats. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. 1998;14(2):109-18. 47. Danforth D, Hull RW. The microscopic anatomy of the fetal membranes with particular reference to the detailed structure of the amnion. American journal of obstetrics and gynecology. 1958;75(3):536-47; discussion 48-50. 48. Davis AR, Ali QK, Aclimandos WA, Hunter PA. Topical steroid use in the treatment of ocular alkali burns. The British journal of ophthalmology. 1997;81(9):732-4. 49. del Castillo JM, de la Casa JM, Sardina RC, Fernandez RM, Feijoo JG, Gomez AC, et al. Treatment of recurrent corneal erosions using autologous serum. Cornea. 2002;21(8):781-3. 50. Donshik PC, Berman MB, Dohlman CH, Gage J, Rose J. Effect of topical corticosteroids on ulceration in alkali-burned corneas. Archives of ophthalmology. 1978;96(11):2117-20. 51. Dua HS, Azuara-Blanco A. Amniotic membrane transplantation. The British journal of ophthalmology. 1999;83(6):748-52. 52. Dua HS, King AJ, Joseph A. A new classification of ocular surface burns. The British journal of ophthalmology. 2001;85(11):1379-83. 53. Duchesne B, Tahi H, Galand A. Use of human fibrin glue and amniotic membrane transplant in corneal perforation. Cornea. 2001;20(2):230-2. 54. Espandar L, Caldwell D, Watson R, Blanco-Mezquita T, Zhang S, Bunnell B. Application of adipose-derived stem cells on scleral contact lens carrier in an animal model of severe acute alkaline burn. Eye & contact lens. 2014;40(4):243-7. 55. Evans RM, Mc Crary JA, 3rd, Christensen G. Mucomyst (acetylcysteine) in the treatment of corneal alkali burns. Annals of ophthalmology. 1972;4(4):320-8. 56. Fagerholm P, Fitzsimmons T, Harfstrand A, Schenholm M. Reactive formation of hyaluronic acid in the rabbit corneal alkali burn. Acta ophthalmologica Supplement. 1992(202):67-72. 57. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochemical and biophysical research communications. 2005;333(2):328-35. 58. Fogle JA, Kenyon KR, Foster CS. Tissue adhesive arrests stromal melting in the human cornea. American journal of ophthalmology. 1980;89(6):795-802. 59. Fox RI, Chan R, Michelson JB, Belmont JB, Michelson PE. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis and rheumatism. 1984;27(4):459-61. 60. Fujisawa K, Katakami C, Yamamoto M. [Keratocyte activity during wound healing of alkali-burned cornea]. Nippon Ganka Gakkai zasshi. 1991;95(1):59-66. 61. Gan L, Fagerholm P, Palmblad J. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in the regulation of corneal neovascularization and wound healing. Acta ophthalmologica Scandinavica. 2004;82(5):557-63. 62. Ge HY, Xiao N, Yin XL, Fu SB, Ge JY, Shi Y, et al. Comparison of the antiangiogenic activity of modified RGDRGD-endostatin to endostatin delivered by gene transfer in vivo rabbit neovascularization model. Molecular vision. 2011;17:1918-28.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

52

63. Golub LM, Lee HM, Lehrer G, Nemiroff A, McNamara TF, Kaplan R, et al. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. Journal of periodontal research. 1983;18(5):516-26. 64. Golub LM, Wolff M, Lee HM, McNamara TF, Ramamurthy NS, Zambon J, et al. Further evidence that tetracyclines inhibit collagenase activity in human crevicular fluid and from other mammalian sources. Journal of periodontal research. 1985;20(1):12-23. 65. Goto E, Shimmura S, Shimazaki J, Tsubota K. Treatment of superior limbic keratoconjunctivitis by application of autologous serum. Cornea. 2001;20(8):807-10. 66. Grant WM. Experimental investigation of paracentesis in the treatment of ocular ammonia burns. AMA archives of ophthalmology. 1950;44(3):399-404. 67. Haddox JL, Pfister RR, Slaughter SE. An excess of topical calcium and magnesium reverses the therapeutic effect of citrate on the development of corneal ulcers after alkali injury. Cornea. 1996;15(2):191-5. 68. Hao Y, Ma DH, Hwang DG, Kim WS, Zhang F. Identification of antiangiogenic and antiinflammatory proteins in human amniotic membrane. Cornea. 2000;19(3):348-52. 69. Haring RS, Sheffield ID, Channa R, Canner JK, Schneider EB. Epidemiologic Trends of Chemical Ocular Burns in the United States. JAMA ophthalmology. 2016;134(10):1119-24. 70. Hatchell DL, Sommer A. Detection of ocular surface abnormalities in experimental vitamin A deficiency. Archives of ophthalmology. 1984;102(9):1389-93. 71. Hayashi A, Popovich KS, Kim HC, de Juan E, Jr. Role of protein tyrosine phosphorylation in rat corneal neovascularization. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 1997;235(7):460-7. 72. Herretes S, Suwan-Apichon O, Pirouzmanesh A, Reyes JM, Broman AT, Cano M, et al. Use of topical human amniotic fluid in the treatment of acute ocular alkali injuries in mice. American journal of ophthalmology. 2006;142(2):271-8. 73. Hirst LW, Summers PM, Griffiths D, Bancroft J, Lillicrap GR. Controlled trial of hyperbaric oxygen treatment for alkali corneal burn in the rabbit. Clinical & experimental ophthalmology. 2004;32(1):67-70. 74. Hoffart L, Matonti F, Conrath J, Daniel L, Ridings B, Masson GS, et al. Inhibition of corneal neovascularization after alkali burn: comparison of different doses of bevacizumab in monotherapy or associated with dexamethasone. Clinical & experimental ophthalmology. 2010;38(4):346-52. 75. Hosseini H, Nejabat M, Mehryar M, Yazdchi T, Sedaghat A, Noori F. Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis. Clinical & experimental ophthalmology. 2007;35(8):745-8. 76. Huang Y, Meek KM, Ho MW, Paterson CA. Anaylsis of birefringence during wound healing and remodeling following alkali burns in rabbit cornea. Experimental eye research. 2001;73(4):521-32. 77. Ikeda N, Hayasaka S, Hayasaka Y, Watanabe K. Alkali burns of the eye: effect of immediate copious irrigation with tap water on their severity. Ophthalmologica Journal international d'ophtalmologie International journal of ophthalmology Zeitschrift fur Augenheilkunde. 2006;220(4):225-8. 78. Joseph A, Dua HS, King AJ. Failure of amniotic membrane transplantation in the treatment of acute ocular burns. The British journal of ophthalmology. 2001;85(9):1065-9. 79. Josset P, Pelosse B, Blomet J, Saraux H. [Value of an amphoteric isotonic solution in the early treatment of corneoconjunctival alkali chemical burns: experimental and histological study]. Bulletin des societes d'ophtalmologie de France. 1986;86(6-7):765-9. 80. Kenyon KR. Inflammatory mechanisms in corneal ulceration. Transactions of the American Ophthalmological Society. 1985;83:610-63. 81. Kenyon KR, Berman M, Rose J, Gage J. Prevention of stromal ulceration in the alkali-burned rabbit cornea by glued-on contact lens. Evidence for the role of polymorphonuclear leukocytes in collagen degradation. Investigative ophthalmology & visual science. 1979;18(6):570-87. 82. Kheirkhah A, Johnson DA, Paranjpe DR, Raju VK, Casas V, Tseng SC. Temporary sutureless amniotic membrane patch for acute alkaline burns. Archives of ophthalmology. 2008;126(8):1059-66.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

53

83. Kigasawa K, Murata H, Morita Y, Odake S, Suda E, Shimizu I, et al. Inhibition of corneal ulceration by tetrapeptidyl hydroxamic acid. Japanese journal of ophthalmology. 1995;39(1):35-42. 84. Kim EC, Kim TK, Park SH, Kim MS. The wound healing effects of vitamin A eye drops after a corneal alkali burn in rats. Acta ophthalmologica. 2012;90(7):e540-6. 85. Kim JC, Tseng SC. Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit corneas. Cornea. 1995;14(5):473-84. 86. Kim JS, Kim JC, Na BK, Jeong JM, Song CY. Amniotic membrane patching promotes healing and inhibits proteinase activity on wound healing following acute corneal alkali burn. Experimental eye research. 2000;70(3):329-37. 87. Kobayashi A, Shirao Y, Yoshita T, Yagami K, Segawa Y, Kawasaki K, et al. Temporary amniotic membrane patching for acute chemical burns. Eye. 2003;17(2):149-58. 88. Kobayashi TK, Tsubota K, Takamura E, Sawa M, Ohashi Y, Usui M. Effect of retinol palmitate as a treatment for dry eye: a cytological evaluation. Ophthalmologica Journal international d'ophtalmologie International journal of ophthalmology Zeitschrift fur Augenheilkunde. 1997;211(6):358-61. 89. Koizumi NJ, Inatomi TJ, Sotozono CJ, Fullwood NJ, Quantock AJ, Kinoshita S. Growth factor mRNA and protein in preserved human amniotic membrane. Current eye research. 2000;20(3):173-7. 90. Kompa S, Redbrake C, Hilgers C, Wustemeyer H, Schrage N, Remky A. Effect of different irrigating solutions on aqueous humour pH changes, intraocular pressure and histological findings after induced alkali burns. Acta ophthalmologica Scandinavica. 2005;83(4):467-70. 91. Kompa S, Schareck B, Tympner J, Wustemeyer H, Schrage NF. Comparison of emergency eye-wash products in burned porcine eyes. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2002;240(4):308-13. 92. Kruse FE, Tseng SC. Retinoic acid regulates clonal growth and differentiation of cultured limbal and peripheral corneal epithelium. Investigative ophthalmology & visual science. 1994;35(5):2405-20. 93. Kubota M, Shimmura S, Kubota S, Miyashita H, Kato N, Noda K, et al. Hydrogen and N-acetyl-L-cysteine rescue oxidative stress-induced angiogenesis in a mouse corneal alkali-burn model. Investigative ophthalmology & visual science. 2011;52(1):427-33. 94. Kuckelkorn R, Redbrake C, Schrage NF, Reim M. [Keratoplasty with 11-12 mm diameter for management of severely chemical-burned eyes]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 1993;90(6):683-7. 95. Kuckelkorn R, Schrage N, Keller G, Redbrake C. Emergency treatment of chemical and thermal eye burns. Acta ophthalmologica Scandinavica. 2002;80(1):4-10. 96. Kuckelkorn R, Schrage N, Reim M. Treatment of severe eye burns by tenonplasty. Lancet. 1995;345(8950):657-8. 97. Kurpakus MA, Daneshvar C, Davenport J, Kim A. Human corneal epithelial cell adhesion to laminins. Current eye research. 1999;19(2):106-14. 98. La Lau C. Continuous lavage in (chemical) corneal lesions. Documenta ophthalmologica Advances in ophthalmology. 1979;46(2):215-8. 99. Langefeld S, Press UP, Frentz M, Kompa S, Schrage N. [Use of lavage fluid containing diphoterine for irrigation of eyes in first aid emergency treatment]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 2003;100(9):727-31. 100. Laria C, Alio JL, Ruiz-Moreno JM. Combined non-steroidal therapy in experimental corneal injury. Ophthalmic research. 1997;29(3):145-53. 101. Lass JH, Campbell RC, Rose J, Foster CS, Dohlman CH. Medroxyprogesterone on corneal ulceration. Its effects after alkali burns on rabbits. Archives of ophthalmology. 1981;99(4):673-6. 102. Leach RM, Rees PJ, Wilmshurst P. Hyperbaric oxygen therapy. Bmj. 1998;317(7166):1140-3. 103. Lee HS, Lee JH, Kim CE, Yang JW. Anti-neovascular effect of chondrocyte-derived extracellular matrix on corneal alkaline burns in rabbits. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2014;252(6):951-61.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

54

104. Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review. Survey of ophthalmology. 1998;43(3):245-69. 105. Lee SH, Tseng SC. Amniotic membrane transplantation for persistent epithelial defects with ulceration. American journal of ophthalmology. 1997;123(3):303-12. 106. Leibowitz HM. Management of inflammation in the cornea and conjunctiva. Ophthalmology. 1980;87(8):753-8. 107. Levinson RA, Paterson CA, Pfister RR. Ascorbic acid prevents corneal ulceration and perforation following experimental alkali burns. Investigative ophthalmology. 1976;15(12):986-93. 108. Liang L, Li W, Ling S, Sheha H, Qiu W, Li C, et al. Amniotic membrane extraction solution for ocular chemical burns. Clinical & experimental ophthalmology. 2009;37(9):855-63. 109. Liang X, Liu Z, Lin Y, Li N, Huang M, Wang Z. A modified symblepharon ring for sutureless amniotic membrane patch to treat acute ocular surface burns. Journal of burn care & research : official publication of the American Burn Association. 2012;33(2):e32-8. 110. Lin HF, Lai YC, Tai CF, Tsai JL, Hsu HC, Hsu RF, et al. Effects of cultured human adipose-derived stem cells transplantation on rabbit cornea regeneration after alkaline chemical burn. The Kaohsiung journal of medical sciences. 2013;29(1):14-8. 111. Lin MP, Eksioglu U, Mudumbai RC, Slabaugh MA, Chen PP. Glaucoma in patients with ocular chemical burns. American journal of ophthalmology. 2012;154(3):481-5 e1. 112. Lippas J. Continuous Irrigation in the Treatment of External Ocular Diseases. American journal of ophthalmology. 1964;57:298-305. 113. Liu L, Hartwig D, Harloff S, Herminghaus P, Wedel T, Geerling G. An optimised protocol for the production of autologous serum eyedrops. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2005;243(7):706-14. 114. Lopez-Garcia JS, Rivas Jara L, Garcia-Lozano I, Murube J. Histopathologic limbus evolution after alkaline burns. Cornea. 2007;26(9):1043-8. 115. Lopez-Garcia JS, Rivas L, Garcia-Lozano I, Murube J. Analysis of corneal surface evolution after moderate alkaline burns by using impression cytology. Cornea. 2006;25(8):908-13. 116. Lu L, Reinach PS, Kao WW. Corneal epithelial wound healing. Experimental biology and medicine. 2001;226(7):653-64. 117. Lusk PG. Chemical eye injuries in the workplace. Prevention and management. AAOHN journal : official journal of the American Association of Occupational Health Nurses. 1999;47(2):80-7; quiz 8-9. 118. Ma Y, Xu Y, Xiao Z, Yang W, Zhang C, Song E, et al. Reconstruction of chemically burned rat corneal surface by bone marrow-derived human mesenchymal stem cells. Stem cells. 2006;24(2):315-21. 119. Mackway-Jones K, Marsden J. Ascorbate for alkali burns to the eye. Emergency medicine journal : EMJ. 2003;20(5):465-6. 120. Makarov PV, Gundarova RA, Terskikh VV, Vasil'ev AV, Khodzhabekian GV, Ivanov AA, et al. [An efficiency study of transplantation of allogenic fibroblasts cultivated in collagen gel for the treatment of corneal burn defects in experiment]. Vestnik oftalmologii. 2004;120(4):27-9. 121. Marquez De Aracena Del Cid R, Montero De Espinosa Escoriaza I. Subconjunctival application of regenerative factor-rich plasma for the treatment of ocular alkali burns. European journal of ophthalmology. 2009;19(6):909-15. 122. Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant dentistry. 2001;10(4):225-8. 123. Matsumoto Y, Dogru M, Goto E, Ohashi Y, Kojima T, Ishida R, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology. 2004;111(6):1115-20. 124. McCulley JP. Ocular hydrofluoric acid burns: animal model, mechanism of injury and therapy. Transactions of the American Ophthalmological Society. 1990;88:649-84. 125. Mejia LF, Acosta C, Santamaria JP. Use of nonpreserved human amniotic membrane for the reconstruction of the ocular surface. Cornea. 2000;19(3):288-91. 126. Meller D, Pires RT, Mack RJ, Figueiredo F, Heiligenhaus A, Park WC, et al. Amniotic membrane transplantation for acute chemical or thermal burns. Ophthalmology. 2000;107(5):980-9; discussion 90.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

55

127. Menna F, Antonucci R, Ippolito S, Maronne V, Matrisciano F. [The use of cysteine and acetylcysteine collyria in chemical burns of the cornea. Experimental studies]. Bulletins et memoires de la Societe francaise d'ophtalmologie. 1982;94:425-8. 128. Nelson JD, Kopietz LA. Chemical injuries to the eyes. Emergency, intermediate, and long-term care. Postgraduate medicine. 1987;81(4):62-6, 9-71, 5. 129. Newsome NA, Gross J. Prevention by medroxyprogesterone of perforation in the alkali-burned rabbit cornea: inhibition of collagenolytic activity. Investigative ophthalmology & visual science. 1977;16(1):21-31. 130. Nishida T, Nakamura M, Mishima H, Otori T. Differential modes of action of fibronectin and epidermal growth factor on rabbit corneal epithelial migration. Journal of cellular physiology. 1990;145(3):549-54. 131. Nubile M, Dua HS, Lanzini TE, Carpineto P, Ciancaglini M, Toto L, et al. Amniotic membrane transplantation for the management of corneal epithelial defects: an in vivo confocal microscopic study. The British journal of ophthalmology. 2008;92(1):54-60. 132. Oh HJ, Jang JY, Li Z, Park SH, Yoon KC. Effects of umbilical cord serum eye drops in a mouse model of ocular chemical burn. Current eye research. 2012;37(12):1084-90. 133. Oh JY, Kim MK, Shin MS, Lee HJ, Lee JH, Wee WR. The anti-inflammatory effect of subconjunctival bevacizumab on chemically burned rat corneas. Current eye research. 2009;34(2):85-91. 134. Panda A, Jain M, Vanathi M, Velpandian T, Khokhar S, Dada T. Topical autologous platelet-rich plasma eyedrops for acute corneal chemical injury. Cornea. 2012;31(9):989-93. 135. Parker AV, Williams RN, Paterson CA. The effect of sodium citrate on the stimulation of polymorphonuclear leukocytes. Investigative ophthalmology & visual science. 1985;26(9):1257-61. 136. Paterson CA, Pfister RR. Prostaglandin-like activity in the aqueous humor following alkali burns. Investigative ophthalmology. 1975;14(3):177-83. 137. Paterson CA, Pfister RR, Levinson RA. Aqueous humor pH changes after experimental alkali burns. American journal of ophthalmology. 1975;79(3):414-9. 138. Paterson CA, Williams RN, Parker AV. Characteristics of polymorphonuclear leukocyte infiltration into the alkali burned eye and the influence of sodium citrate. Experimental eye research. 1984;39(6):701-8. 139. Peng LH, Shen W, Yong W, Lu L, Liu L. Effects of AMD3100 subconjunctival injection on alkali burn induced corneal neovascularization in mice. International journal of ophthalmology. 2011;4(1):44-8. 140. Perry HD, Golub LM. Systemic tetracyclines in the treatment of noninfected corneal ulcers: a case report and proposed new mechanism of action. Annals of ophthalmology. 1985;17(12):742-4. 141. Perry HD, Hodes LW, Seedor JA, Donnenfeld ED, McNamara TF, Golub LM. Effect of doxycycline hyclate on corneal epithelial wound healing in the rabbit alkali-burn model. Preliminary observations. Cornea. 1993;12(5):379-82. 142. Peyman GA, Kivilcim M, Morales AM, DellaCroce JT, Conway MD. Inhibition of corneal angiogenesis by ascorbic acid in the rat model. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2007;245(10):1461-7. 143. Pfister RR, Haddox JL, Sommers CI. Effect of synthetic metalloproteinase inhibitor or citrate on neutrophil chemotaxis and the respiratory burst. Investigative ophthalmology & visual science. 1997;38(7):1340-9. 144. Pfister RR, Haddox JL, Yuille-Barr D. The combined effect of citrate/ascorbate treatment in alkali-injured rabbit eyes. Cornea. 1991;10(2):100-4. 145. Pfister RR, Nicolaro ML, Paterson CA. Sodium citrate reduces the incidence of corneal ulcerations and perforations in extreme alkali-burned eyes--acetylcysteine and ascorbate have no favorable effect. Investigative ophthalmology & visual science. 1981;21(3):486-90. 146. Pfister RR, Paterson CA. Ascorbic acid in the treatment of alkali burns of the eye. Ophthalmology. 1980;87(10):1050-7.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

56

147. Pfister RR, Paterson CA, Hayes SA. Topical ascorbate decreases the incidence of corneal ulceration after experimental alkali burns. Investigative ophthalmology & visual science. 1978;17(10):1019-24. 148. Pfister RR, Paterson CA, Hayes SA. Effects of topical 10% ascorbate solution on established corneal ulcers after severe alkali burns. Investigative ophthalmology & visual science. 1982;22(3):382-5. 149. Pfister RR, Paterson CA, Spiers JW, Hayes SA. The efficacy of ascorbate treatment after severe experimental alkali burns depends upon the route of administration. Investigative ophthalmology & visual science. 1980;19(12):1526-9. 150. Phan TM, Foster CS, Shaw CD, Zagachin LM, Colvin RB. Topical fibronectin in an alkali burn model of corneal ulceration in rabbits. Archives of ophthalmology. 1991;109(3):414-9. 151. Philipp W, Speicher L, Humpel C. Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas. Investigative ophthalmology & visual science. 2000;41(9):2514-22. 152. Phillips K, Arffa R, Cintron C, Rose J, Miller D, Kublin CL, et al. Effects of prednisolone and medroxyprogesterone on corneal wound healing, ulceration, and neovascularization. Archives of ophthalmology. 1983;101(4):640-3. 153. Poon AC, Geerling G, Dart JK, Fraenkel GE, Daniels JT. Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. The British journal of ophthalmology. 2001;85(10):1188-97. 154. Prabhasawat P, Tesavibul N, Prakairungthong N, Booranapong W. Efficacy of amniotic membrane patching for acute chemical and thermal ocular burns. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2007;90(2):319-26. 155. Quinto GG, Camacho W, Castro-Combs J, Li L, Martins SA, Wittmann P, et al. Effects of topical human amniotic fluid and human serum in a mouse model of keratoconjunctivitis sicca. Cornea. 2012;31(4):424-30. 156. Ralph RA. Tetracyclines and the treatment of corneal stromal ulceration: a review. Cornea. 2000;19(3):274-7. 157. Rao TV, Chandrasekharam V. Use of dry human and bovine amnion as a biological dressing. Archives of surgery. 1981;116(7):891-6. 158. Redbrake C, Buchal V. [Keratoplasty with scleral rim after the most severe chemical eye burns of the anterior eye segment]. Klinische Monatsblatter fur Augenheilkunde. 1996;208(3):145-51. 159. Reim M. [A new treatment concept in severe caustic injuries and burns of the eye]. Fortschritte der Ophthalmologie : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 1989;86(6):722-6. 160. Reim M. [A new treatment concept for severe caustic and thermal burns of the eyes]. Klinische Monatsblatter fur Augenheilkunde. 1990;196(1):1-5. 161. Reim M. The results of ischaemia in chemical injuries. Eye. 1992;6 ( Pt 4):376-80. 162. Reim M, Beil KH, Kammerer G, Krehwinkel S. Influence of systemic ascorbic acid treatment on metabolite levels after regeneration of the corneal epithelium following mild alkali burns. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 1982;218(2):99-102. 163. Reim M, Busse S, Leber M, Schulz C. Effect of epidermal growth factor in severe experimental alkali burns. Ophthalmic research. 1988;20(5):327-31. 164. Reim M, Kehrer T, Lund M. Clinical application of epiderm growth factor in patients with most severe eye burns. Ophthalmologica Journal international d'ophtalmologie International journal of ophthalmology Zeitschrift fur Augenheilkunde. 1988;197(4):179-84. 165. Reim M, Overkamping B, Kuckelkorn R. [2 years experiences with Tenon-plasty]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 1992;89(6):524-30. 166. Reim M, Redbrake C, Schrage N. Chemical and thermal injuries of the eyes. Surgical and medical treatment based on clinical and pathophysiological findings. Archivos de la Sociedad Espanola de Oftalmologia. 2001;76(2):79-124.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

57

167. Ren G, Song C, Liang P, Zhang Z. The effect of fibronectin on re-epithelialization of rabbits cornea after alkali burn. Yan ke xue bao = Eye science / "Yan ke xue bao" bian ji bu. 1994;10(3):138-43. 168. Ricardo JR, Barros SL, Santos MS, Souza LB, Gomes JA. [Amniotic membrane transplantation for severe acute cases of chemical ocular burn and Stevens-Johnson syndrome]. Arquivos brasileiros de oftalmologia. 2009;72(2):215-20. 169. Rihawi S, Frentz M, Becker J, Reim M, Schrage NF. The consequences of delayed intervention when treating chemical eye burns. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2007;245(10):1507-13. 170. Rihawi S, Frentz M, Schrage NF. Emergency treatment of eye burns: which rinsing solution should we choose? Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2006;244(7):845-54. 171. Risa O, Saether O, Midelfart A, Krane J, Cejkova J. Analysis of immediate changes of water-soluble metabolites in alkali-burned rabbit cornea, aqueous humor and lens by high-resolution 1H-NMR spectroscopy. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2002;240(1):49-55. 172. Robson MC, Krizek TJ. The effect of human amniotic membranes on the bacteria population of infected rat burns. Annals of surgery. 1973;177(2):144-9. 173. Rocha EM, Pelegrino FS, de Paiva CS, Vigorito AC, de Souza CA. GVHD dry eyes treated with autologous serum tears. Bone marrow transplantation. 2000;25(10):1101-3. 174. Roper-Hall MJ. Thermal and chemical burns. Transactions of the ophthalmological societies of the United Kingdom. 1965;85:631-53. 175. Saika S, Uenoyama K, Hiroi K, Tanioka H, Takase K, Hikita M. Ascorbic acid phosphate ester and wound healing in rabbit corneal alkali burns: epithelial basement membrane and stroma. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 1993;231(4):221-7. 176. Salman IA, Gundogdu C. Epithelial healing in experimental corneal alkali wounds with nondiluted autologous serum eye drops. Cutaneous and ocular toxicology. 2010;29(2):116-21. 177. Schultz G, Rotatori DS, Clark W. EGF and TGF-alpha in wound healing and repair. Journal of cellular biochemistry. 1991;45(4):346-52. 178. Schultz GS, Davis JB, Eiferman RA. Growth factors and corneal epithelium. Cornea. 1988;7(2):96-101. 179. Schultz GS, Strelow S, Stern GA, Chegini N, Grant MB, Galardy RE, et al. Treatment of alkali-injured rabbit corneas with a synthetic inhibitor of matrix metalloproteinases. Investigative ophthalmology & visual science. 1992;33(12):3325-31. 180. Seedor JA, Perry HD, McNamara TF, Golub LM, Buxton DF, Guthrie DS. Systemic tetracycline treatment of alkali-induced corneal ulceration in rabbits. Archives of ophthalmology. 1987;105(2):268-71. 181. Semeraro F, Forbice E, Braga O, Bova A, Di Salvatore A, Azzolini C. Evaluation of the efficacy of 50% autologous serum eye drops in different ocular surface pathologies. BioMed research international. 2014;2014:826970. 182. Shahriari HA, Tokhmehchi F, Reza M, Hashemi NF. Comparison of the effect of amniotic membrane suspension and autologous serum on alkaline corneal epithelial wound healing in the rabbit model. Cornea. 2008;27(10):1148-50. 183. Sharifipour F, Baradaran-Rafii A, Idani E, Zamani M, Jabbarpoor Bonyadi MH. Oxygen therapy for acute ocular chemical or thermal burns: a pilot study. American journal of ophthalmology. 2011;151(5):823-8. 184. Sharifipour F, Zamani M, Idani E, Hemmati AA. Oxygen therapy for severe corneal alkali burn in rabbits. Cornea. 2007;26(9):1107-10. 185. Sharma A, Pandey S, Sharma R, Mohan K, Gupta A. Cyanoacrylate tissue adhesive augmented tenoplasty: a new surgical procedure for bilateral severe chemical eye burns. Cornea. 1999;18(3):366-9.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

58

186. Sharma N, Goel M, Velpandian T, Titiyal JS, Tandon R, Vajpayee RB. Evaluation of umbilical cord serum therapy in acute ocular chemical burns. Investigative ophthalmology & visual science. 2011;52(2):1087-92. 187. Sharma N, Lathi SS, Sehra SV, Agarwal T, Sinha R, Titiyal JS, et al. Comparison of umbilical cord serum and amniotic membrane transplantation in acute ocular chemical burns. The British journal of ophthalmology. 2015;99(5):669-73. 188. Sharma N, Singh D, Maharana PK, Kriplani A, Velpandian T, Pandey RM, et al. Comparison of Amniotic Membrane Transplantation and Umbilical Cord Serum in Acute Ocular Chemical Burns: A Randomized Controlled Trial. American journal of ophthalmology. 2016;168:157-63. 189. Siganos CS, Frucht-Pery J, Muallem MS, Berenshtein E, Naoumidi I, Ever-Hadani P, et al. Topical use of zinc desferrioxamine for corneal alkali injury in a rabbit model. Cornea. 1998;17(2):191-5. 190. Sii F, Lee GA. Fibrin glue in the management of corneal melt. Clinical & experimental ophthalmology. 2005;33(5):532-4. 191. Singh G, Foster CS. Epidermal growth factor in alkali-burned corneal epithelial wound healing. American journal of ophthalmology. 1987;103(6):802-7. 192. Singh G, Singh Bhinder H. Evaluation of therapeutic deep anterior lamellar keratoplasty in acute ocular chemical burns. European journal of ophthalmology. 2008;18(4):517-28. 193. Sorsby A, Haythorne J, Reed H. Further Experience with Amniotic Membrane Grafts in Caustic Burns of the Eye. The British journal of ophthalmology. 1947;31(7):409-18. 194. Sorsby A, Symons HM. Amniotic membrane grafts in caustic burns of the eye (burns of the second degree). The British journal of ophthalmology. 1946;30:337-45. 195. Spigelman AV, Vernot JA, Deutsch TA, Peyman GA, Molnar J. Fibronectin in alkali burns of the rabbit cornea. Cornea. 1985;4(3):169-72. 196. Sridhar MS, Bansal AK, Sangwan VS, Rao GN. Amniotic membrane transplantation in acute chemical and thermal injury. American journal of ophthalmology. 2000;130(1):134-7. 197. Srinivasan BD, Kulkarni PS. Polymorphonuclear leukocyte response. Inhibition following corneal epithelial denudation by steroidal and nonsteroidal anti-inflammatory agents. Archives of ophthalmology. 1981;99(6):1085-9. 198. Struck HG, Giessler S, Giessler C. [Effect of non-steroidal anti-inflammatory drugs on inflammatory reaction. An animal experiment study]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 1995;92(6):849-53. 199. Su CY, Lin CP. Combined use of an amniotic membrane and tissue adhesive in treating corneal perforation: a case report. Ophthalmic surgery and lasers. 2000;31(2):151-4. 200. Su W, Li Z, Li Y, Lin M, Yao L, Liu Y, et al. Doxycycline enhances the inhibitory effects of bevacizumab on corneal neovascularization and prevents its side effects. Investigative ophthalmology & visual science. 2011;52(12):9108-15. 201. Suri K, Kosker M, Raber IM, Hammersmith KM, Nagra PK, Ayres BD, et al. Sutureless amniotic membrane ProKera for ocular surface disorders: short-term results. Eye & contact lens. 2013;39(5):341-7. 202. Tamhane A, Vajpayee RB, Biswas NR, Pandey RM, Sharma N, Titiyal JS, et al. Evaluation of amniotic membrane transplantation as an adjunct to medical therapy as compared with medical therapy alone in acute ocular burns. Ophthalmology. 2005;112(11):1963-9. 203. Tandon R, Gupta N, Kalaivani M, Sharma N, Titiyal JS, Vajpayee RB. Amniotic membrane transplantation as an adjunct to medical therapy in acute ocular burns. The British journal of ophthalmology. 2011;95(2):199-204. 204. Tang X, Wang Z, Dong N. [Tissue adhesive combined with amniotic membrane adhering in the treatment of ocular burns]. Yan ke xue bao = Eye science / "Yan ke xue bao" bian ji bu. 2005;21(2):74-8. 205. Tejwani S, Kolari RS, Sangwan VS, Rao GN. Role of amniotic membrane graft for ocular chemical and thermal injuries. Cornea. 2007;26(1):21-6. 206. Teping C, Reim M. [Tenonplasty as a new surgical principle in the early treatment of the most severe chemical eye burns]. Klinische Monatsblatter fur Augenheilkunde. 1989;194(1):1-5.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

59

207. Thanikachalam S, Kaliaperumal S, Srinivasan R, Sahu PK. Amniotic membrane transplantation for acute ocular chemical burns in a child. Journal of the Indian Medical Association. 2011;109(8):586-7. 208. Toshida H, Odaka A, Koike D, Murakami A. Effect of retinol palmitate eye drops on experimental keratoconjunctival epithelial damage induced by n-heptanol in rabbit. Current eye research. 2008;33(1):13-8. 209. Tripathi BJ, Kwait PS, Tripathi RC. Corneal growth factors: a new generation of ophthalmic pharmaceuticals. Cornea. 1990;9(1):2-9. 210. Tseng SC, Li DQ, Ma X. Suppression of transforming growth factor-beta isoforms, TGF-beta receptor type II, and myofibroblast differentiation in cultured human corneal and limbal fibroblasts by amniotic membrane matrix. Journal of cellular physiology. 1999;179(3):325-35. 211. Tsubota K, Goto E, Fujita H, Ono M, Inoue H, Saito I, et al. Treatment of dry eye by autologous serum application in Sjogren's syndrome. The British journal of ophthalmology. 1999;83(4):390-5. 212. Tsubota K, Goto E, Shimmura S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology. 1999;106(10):1984-9. 213. Tsubota K, Higuchi A. Serum application for the treatment of ocular surface disorders. International ophthalmology clinics. 2000;40(4):113-22. 214. Ucakhan OO, Koklu G, Firat E. Nonpreserved human amniotic membrane transplantation in acute and chronic chemical eye injuries. Cornea. 2002;21(2):169-72. 215. Uitto VJ, Firth JD, Nip L, Golub LM. Doxycycline and chemically modified tetracyclines inhibit gelatinase A (MMP-2) gene expression in human skin keratinocytes. Annals of the New York Academy of Sciences. 1994;732:140-51. 216. Vajpayee RB, Mukerji N, Tandon R, Sharma N, Pandey RM, Biswas NR, et al. Evaluation of umbilical cord serum therapy for persistent corneal epithelial defects. The British journal of ophthalmology. 2003;87(11):1312-6. 217. Vrabec MP, Jordan JJ. A surgical technique for the treatment of central corneal perforations. Journal of refractive and corneal surgery. 1994;10(3):365-7. 218. Wagoner MD. Chemical injuries of the eye: current concepts in pathophysiology and therapy. Survey of ophthalmology. 1997;41(4):275-313. 219. Wang Y, Yin H, Chen P, Xie L, Wang Y. Inhibitory effect of canstatin in alkali burn-induced corneal neovascularization. Ophthalmic research. 2011;46(2):66-72. 220. Westekemper H, Figueiredo FC, Siah WF, Wagner N, Steuhl KP, Meller D. Clinical outcomes of amniotic membrane transplantation in the management of acute ocular chemical injury. The British journal of ophthalmology. 2016. 221. Wishard P, Paterson CA. The effect of ascorbic acid on experimental acid burns of the rabbit cornea. Investigative ophthalmology & visual science. 1980;19(5):564-6. 222. Wu CL, Chou HC, Li JM, Chen YW, Chen JH, Chen YH, et al. Hyaluronic acid-dependent protection against alkali-burned human corneal cells. Electrophoresis. 2013;34(3):388-96. 223. Yamabayashi S, Furuya T, Gohd T, Makino F, Tsukahara S. Newly designed continuous corneal irrigation system for chemical burns. Ophthalmologica Journal international d'ophtalmologie International journal of ophthalmology Zeitschrift fur Augenheilkunde. 1990;201(4):174-9. 224. Yang G, Espandar L, Mamalis N, Prestwich GD. A cross-linked hyaluronan gel accelerates healing of corneal epithelial abrasion and alkali burn injuries in rabbits. Veterinary ophthalmology. 2010;13(3):144-50. 225. Yao L, Li ZR, Su WR, Li YP, Lin ML, Zhang WX, et al. Role of mesenchymal stem cells on cornea wound healing induced by acute alkali burn. PloS one. 2012;7(2):e30842. 226. Yoon KC, Ahn KY, Lee JH, Chun BJ, Park SW, Seo MS, et al. Lipid-mediated delivery of brain-specific angiogenesis inhibitor 1 gene reduces corneal neovascularization in an in vivo rabbit model. Gene therapy. 2005;12(7):617-24. 227. Yoon KC, Choi W, You IC, Choi J. Application of umbilical cord serum eyedrops for recurrent corneal erosions. Cornea. 2011;30(7):744-8.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

60

228. Yoon KC, Heo H, Im SK, You IC, Kim YH, Park YG. Comparison of autologous serum and umbilical cord serum eye drops for dry eye syndrome. American journal of ophthalmology. 2007;144(1):86-92. 229. Yoon KC, Im SK, Park YG, Jung YD, Yang SY, Choi J. Application of umbilical cord serum eyedrops for the treatment of dry eye syndrome. Cornea. 2006;25(3):268-72. 230. Yoon KC, Jeong IY, Im SK, Park YG, Kim HJ, Choi J. Therapeutic effect of umbilical cord serum eyedrops for the treatment of dry eye associated with graft-versus-host disease. Bone marrow transplantation. 2007;39(4):231-5. 231. Yoon KC, You IC, Im SK, Jeong TS, Park YG, Choi J. Application of umbilical cord serum eyedrops for the treatment of neurotrophic keratitis. Ophthalmology. 2007;114(9):1637-42. 232. Young AL, Cheng AC, Ng HK, Cheng LL, Leung GY, Lam DS. The use of autologous serum tears in persistent corneal epithelial defects. Eye. 2004;18(6):609-14. 233. Zhang P, Wu D, Ge J, Zhu Z, Feng G, Yue T, et al. Experimental inhibition of corneal neovascularization by endostatin gene transfection in vivo. Chinese medical journal. 2003;116(12):1869-74. 234. Zhao GQ, Ma YQ, Liang T, Jiang T, Wang CF, Zhang YX. Animal study on expression of laminin and fibronectin in cornea during wound healing following alkali burn. Chinese journal of traumatology = Zhonghua chuang shang za zhi / Chinese Medical Association. 2003;6(1):37-40. 235. Zhou SY, Chen JQ, Liu ZG, Huang T, Chen LS. [A clinical study of amniotic membrane transplantation for severe eye burns at the acute stage]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology. 2004;40(2):97-100.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

61

Abbreviations

Epidermal growth factor (EGF)

Hyaluronic acid (HA)

Synthetic inhibitors of metalloproteinases (SIMP)

Polymorphonuclear leukocytes (PMNL)

Non-steroidal anti-inflammatory drugs (NSAIDs)

Human Immunodeficiency Virus (HIV)

Amniotic membrane transplantation (AMT)

Phosphate buffered saline (PBS)

Dimethylsulfoxide (DMSO)

Deep anterior lamellar keratoplasty (DALK)

Conjunctival limbal autograft (CLAU)

Scleral contact lens (SCL)

Mesenchymal stem cells (MSCs)

Human corneal epithelial cells (HCECs)

Dulbecco's modified Eagle's medium (DMEM)

Epsilon-aminocaproic acid (EACA)

Tranexamic acid (TXA)

Angiotensin-converting enzyme (ACE)

Collagen cross linking (CXL)

Vascular endothelial growth factor (VEGF)

Chondrocyte-derived extracellular matrix (CDECM)

Doxycycline temperature-sensitive hydrogel (DTSH)

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

62

Figure legends:

Figure 1: Grade V (Dua’s classification) acute ocular chemical burn receiving topical umbilical

cord serum in addition to conventional treatment (a) at presentation (b) one month after receiving

topical umbilical cord serum

Figure 2: Grade IV (Dua’s classification) acute ocular chemical burn undergoing AMT (a)

preoperative (b) one month postoperative

Figure 3: Management of acute ocular chemical burns

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Table 1: Roper-Hall classification for the severity of ocular surface burns188

Grade Clinical Findings Prognosis

Cornea Conjunctiva/Limbus

I Corneal epithelial damage No limbal ischemia Good

II Corneal haze, iris details

visible

<1/3 limbal ischemia Good

III Total epithelial loss, stromal

haze and iris details obscured

1/3-1/2 limbal ischemia Guarded

IV Cornea opaque, iris and pupil

obscured

>1/2 limbal ischemia Poor

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Table 2: Dua classification for severity of ocular surface burns51

Grade Clinical Findings Conjunctival Involvement

Analogue Scale (Clock hours of limbal involvement/ % bulbar

conjunctival involvement)

Prognosis

I 0 clock hours limbal involvement

0% 0/0% Very good

II ≤3 clock hours limbal involvement

≤30% 0.1-3/ 1-29.9% Good

III >3-6 clock hours limbal involvement

>30-50% 3.1-6/ 31-50% Good

IV >6-9 clock hours limbal involvement

>50-75% 6.1-9/ 51-75% Good to guarded

V >9-<12 clock hours limbal involvement

>75-<100% 9.1-11.9/ 75.1-99.9% Guarded to poor

VI Total (12 clock hours) limbal involvement

100% (Total) 12/ 100% Very poor

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Table 3: Biological Properties and Dose of Topical Biological Fluids used in Treatment of Acute Ocular Chemical Burns

Biological Fluid Constituents Source Concentration Dose

Autologous Serum

Growth factors

Vitamin A, Substance P, Fibronectin, Immunoglobulins Serum anti-proteases

Patient’s whole blood

20%*, 50%, 100%

10 times/day for 4 weeks. Slow taper till inflammation subsides

Umbilical Cord Serum

Similar to Autologous serum

More growth factors, less Vitamin A and IGF-1

Umbilical cord blood

20% 10 times/day for 4 weeks. Slow taper till inflammation subsides

Platelet Rich Plasma

Platelets

Growth factors

Cytokines

Patient’s whole blood

- 10 times/day for 4 weeks. Slow taper till inflammation subsides

Amniotic Membrane Suspension

Growth factors

Cytokines

Additional anti-scarring, anti-inflammatory properties

Amniotic Membrane

30%, 50% Hourly for first 4 weeks, then 2 hourly for 2 weeks and taper slowly till inflammation subsides

*Most commonly used concentration of autolgous serum

Abbreviations: IGF-1: Insulin like growth factor-1

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具