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Conceptual Framework

MethodMain Finding/ Suggestion/ Future

Research

1. Amniotic Membrane Transplantation In Acute Toxic Epidermal Necrolysis: Histopathologic Changes And Ocular Surface Features After 1-Year Follow-Up (Jose Santiago et. al 2014)

Early recognition of ocular involvement andtreatment during the acute phase are important to minimizeocular surface injury.

Dry eye, scars on the tarsal and bulbar conjunctiva, symblepharon, eyelid margin malposition,trichiasis, severe corneal lesions, and blindness are common complications during follow-up.

Amniotic membranetransplantation (AMT) used as a temporary patch has been successful for treating ocular surface diseases (11, 12), including the acute stage of TEN (13-15).

Recent works have shown the beneficial

Prospective observational:

ocular features (Ocular manifestation and slit-lamp)

and histopathologic changes (impression cytology)

Clinical Trial n=5AMT on TEN (toxic epidermal necrolitis)1 year follow up

Amniotic membrane was placed with the epithelium surfaceuppermost and sutured to cover the entire ocular surface.

AM partially disintegrated between 7 and 10 days and sutures and AMT were removedbetween 10 and 12 days after surgery.

Ophthalmic examinations including visual acuity (VA) and biomicroscopy.

tear film evaluation and corneal andconjunctival impression cytology

After 7 to 8 days, the grafts gradually thinned and partially disintegrated.

After AM and suture removal, the underlying conjunctiva was mildly inflamed with mild or moderateconjunctival retraction. The ocular surface reepithelialized in all patients, and the ulcers on eyelid skin and eyelid margin healed without scars after the second week.

Conjunctival cytology showed a significant decrease in goblet cells density in patients with TEN before and afterAMT. Goblet cells density improved after AMT and these differences were statistically significant

Toxic epidermal necrolysis is considered one of the most devastating ocular surface disorders.

If this condition is not controlled quickly, the ensuing wound healing usuallyresults in scarring and damage to the corneal epithelial stem cells (4).

Recently, transplantation of cryopreserved AM to the ocular surface

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effect of the earlyuse of AMT in the management of patients with moderate or severe ocular and eyelid involvement in the acute phase of TEN preventing late cicatricial complications anddecreasing the risk of severe ocular sequelae

during the acute phase has shown great promise in preventing chronic ocular sequelae

Amniotic membrane transplantation improved the ocular surface environment and facilitated the mechanisms involvedin epithelial cell renewal and stromal regeneration by modulating the levels of cytokines and growth factors

Amniotic membrane facilitates migration of epithelial cells and adhesion of basal cells, promotes epithelial differentiation, and plays an important role in preventing epithelial apoptosis and providing anti-inflammatory and antiscarring effects

AMT decreased the ocular symptomatology

Recently, Shammas et al (21) and Gregory (22) described in 2 case series (6 and 10 patients, respectively) the beneficial effects associated with the use of AMT in the early stage of SJS and TEN.

Hsu et al (23), in a retrospective review from 1998 to 2011, presented the first case-control study of the use of AM in the management of acute SJS and TEM, andconcluded that the early use of AMT prevents severe vision loss in patients

with moderate or severe ocular inflammation in the acute phase.

Inflammation and conjunctival necrosis inthe acute phase promotes goblet cells destruction and closing of the lacrimal excretory ducts on conjunctivaand meibomian gland orifices that may result in mucous, aqueous, and lipid tear deficiencies.

Corneal and conjunctival epithelial cell squamous metaplasia improved significantly after AMT

significantly improved the goblet cells density after 1 year follow-up

AMT placed over the entire ocular surface during the acute stage of TEN reduced inflammation and scarring of the ocular surface, improved dry eye and epithelial ocular surface squamous metaplasia, and diminished the late sight-threatening cicatricial complications.

2 Amniotic MembraneTransplantation Elicits Goblet CellRepopulation After ConjunctivalReconstruction In A Case Of SevereOcular Cicatricial

The use of human amniotic membraneto repair conjunctival defects was first reported by De Rotth (1940).Recently,its use has been re-evaluated

The surgical procedures used until now to rebuild the conjunctiva inpatients affected by ocular cicatricial pemphigoid (OCP) have not

This study reports the postoperativeclinical and cytological outcomes of a human amniotic membrane

amniotic membrane was then secured with the epithelium up to the conjunctival edge at the mucocutaneousjunction with interrupted 8–0

Amniotic membrane transplantation was successful as a first step procedure to reduce inflammation and to rebuild a physiological conjunctival epithelium in late stage OCP

Four months after the transplantation,the amniotic membrane had completely

Pemphigoid(Stefano & Maurizio 2003)

because of the demonstration of important properties of use in ocular surface reconstruction,s uch as anti-adhesive,anti-angiogenic and anti-inflammatoryeffects,i ts capacity to stimulatere-epithelialization and its lack of immunogenicity

Laboratory and clinical evidence showthat inflammation is a major factorresponsible for stem cell transplantationfailure (Tsai & Tseng 1995).

Amniotic epithelial cells contain many growth factors suchas EGF,KGF, HGF and bFGF which may stimulate epithelial growth (Koizumi et al. 1999),anti-angiogenic and

demonstratedappreciable anatomical and functional success.

transplantation(AMT) to rebuild the conjunctiva in a case of late stage OCP.

vicryl sutures and to the bulbar surfacewith episcleral bites. It was also anchored to the palpebral side deep in the fornices by passing two doublearmed6–0 silk sutures through the fullthickness of the lid. The corneal surfaceof the membrane was then covered bya therapeutic contact lens in order toprevent excessive mobilization.

dissolved. The conjunctival foreshortening was reduced from 75%to 10% and the symblepharon andentropion had disappeared

the globe reacquired its mobility

After 4months, the epithelial cells covering the bulbar conjunctiva were seen to be small and compact,an d the presence of numerous goblet cells was noted

Moreover,we obtained a significant increase in fornix depth.

anti-inflammatory proteins (Hao et al.2000).

Moreover,(Fukuda et al. 1999) demonstrated that the distribution of alfa subchains of type IV collagens and laminin 1 and 5 of the basement membrane in such membranes is the same as that of the conjunctiva

3 Coculture Of Autologous Limbal And Conjunctival Epithelial Cells To Treat SevereOcular Surface Disorders: Long-Term Survival Analysis(Sandhya et. al 2012)

In severe cases with near-total LSCD and extensive conjunctival scarring (with or without symblepharon),additional conjunctival transplantation may also be required inaddition to CLET.

In recent years, thein vivo cultivation of conjunctival cells and transplantation ofcultivated conjunctival

we describe the long-term survival of a novel method of cocultivatingautologous limbal and conjunctival epithelium on a single substrate

Forty eyes of39 patients with severe limbal stem cell deficiency and conjunctival scarring or symblepharon underwenttransplantation of autologous cocultivated epithelium on human amniotic membrane.

Synchronous use of cultured limbal and conjunctival epithelium offers a feasible alternativeand a simpler one-step surgical approach to treat severe ocular surface disorders involving limbus andconjunctiva.

Simulating thenatural ocular surface of conjunctiva at the periphery andlimbal in the center, we placed the explants in the same manner.

Thecultivated conjunctival epithelium on

epithelium for conjunctival disordershave been demonstrated.[9-11]

Of these, 47 eyes of 46 patients whowould have otherwise required additional conjunctivaltransplantation in addition to auto-CLET, for severe ocularsurface damage extensively involving the conjunctiva, suchas scarring or symblepharon, underwent cocultivated limbaland conjunctival epithelium transplantation.

HAM, unlike amnioticmembrane transplantation (AMT) alone, offered a conjunctivalsurface for conjunctival reconstruction in these cases.[17]

However, the risksoutweigh the potential benefits as doing staged surgeries wouldincrease cost and time to recovery for the patient

The alternate possibilityis that early surgery minimizes the degree of complicationssuch as fibrovascular pannus and scarring.[22]

novel alternate approach to CLET with additionalconjunctival transplantation for patients with severe ocularsurface disorders.

demonstrating the feasibility ofcultivation and transplantation of two phenotypically differentbut contiguous epithelia.

4 Conjunctival Reconstruction With Progenitor Cell-Derived Autologous Epidermal Sheets In

The conjunctival epithelium is well vascularized and consistsof loosely organized

This article describes an attempt to overcome the problems ofallogeneic

This study was to explore the possibility ofprogenitor cell-derived

We isolated epidermalprogenitor cells of rhesus monkey by type IV collagen

At 2 weeks after transplantation, ultrastructural examinationrevealed an architecture of well-structured, compact, multilayeredcell sheets with the expected

Rhesus Monkey(Rong Lu et. al 2011)

cell layers. As an important component of theocular surface, the conjunctiva plays a critical role in supportingthe niche of the ocular surface and ensuring continued clarity andsurvival of the corneal epithelium and stroma [3,4]. Severe ocularsurface diseases and injuries – such as Stevens-Johnson syndrome,ocular cicatricial pemphigoid, severe microbial infection, andchemical or thermal burn – can damage conjunctival epithelium[5–7].

All the researches suggest epidermal progenitor cellshave the properties to differentiate the daughter cells of non

transplantation by using epidermal progenitor cells as asubstitute for conjunctival epithelial cells.

epidermal sheets on denuded amniotic membrane to reconstruct ocular surface of conjunctivadamaged monkeys.

adhesion,then expanded epidermal progenitor cells on AM ex vivo. We thentransplanted the autologous cultivated progenitor cell-derivedepidermal sheets onto the ocular surfaces of conjunctiva damagedmonkeys and evaluated the survival of the tissue.

microstructures of the native cells,including microvilli, tight junctions, desmosomes, and hemidesmosomes.Such morphologic characteristics are similar to those ofconjunctival epithelium in vivo.

As shown in Figure 3F,cultured epidermal progenitor cells were able to form gapjunctions and desmosomes with each other. Moreover, hemidesmosomes,the junctions between basal epithelial cells and theamniotic membrane, were clearly visible in culture sheets (

SEM examination of the cultivated epidermal progenitor cellsrevealed a continuous layer of flat, polygonal epithelial cells(Fig. 3G). These cells appeared healthy and well formed withdistinct cell boundaries.

SEM and TEM resultsindicate that our epidermal progenitor cells, after transplanted onocular surface to replace conjunctiva, resembled normal conjunctivalepithelial cells more closely.

Keratin 4 reportedly, is a reliable marker

skinorigin

for conjunctivalepithelial cells [52].

In conclusion, our present study successfully reconstructedconjunctiva with autologous transplantation of progenitor cellderivedepidermal sheets on denuded AM