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Review Article

Surgical Management of Limbal Stem Cell Deficiency

Iyer, Geetha FRCS, FRCOphth; Srinivasan, Bhaskar MD; Agarwal, Shweta MD; Agarwal, Manokamna MD; Matai, Hiren MD

Author Information
Asia-Pacific Journal of Ophthalmology: November-December 2020 - Volume 9 - Issue 6 - p 512-523
doi: 10.1097/APO.0000000000000326
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Abstract

INTRODUCTION

The role of limbal stem cells (LSCs) in maintaining the integrity and regeneration of the corneal epithelium was established way back in 1964 and was clinically demonstrated by Kenyon and Tseng in 1989.1 The location of these stem cells at the limbus was established by means of proliferation and differentiation studies. This paved the way for limbal stem cell transplantation as a means of surgically addressing limbal stem cell deficiency (LSCD). LSCD is an ocular surface disease caused by a decrease in the population and/or function of corneal epithelial stem/progenitor cells. Depending upon the extent of disease, LSCD is described as partial and complete. Partial LSCD is characterized by incomplete conjunctivalization of the corneal surface and the presence of residual limbal and corneal epithelial cells. Total LSCD is characterized by conjunctivalization of the entire corneal surface due to a complete loss of corneal epithelial stem/progenitor cells.2 Various causes for LSCD have been listed in Table 1.

TABLE 1 - Etiology of LSCD
Hereditary LSCD
 Aniridia
 Multiple endocrine deficiency
 Epidermal dysplasia
 Dyskeratosis congenita
 Epidermolysis bullosa
 Xeroderma pigmentosa
 Levy-Hollister syndrome
 Keratitis-ichthyosis-deafness syndrome
Acquired LSCD
 Chemical/thermal injuries
Stevens-Johnson syndrome
 Ocular cicatricial pemphigoid
 Cicatrizing conjunctival disorders, eg, trachoma
 Graft-versus-host disease
 Chronic allergic conjunctivitis
 Contact lens wear
 Bullous keratopathy
 Neurotrophic keratitis
 Radiation
 Infectious keratitis extending to limbus
 Chronic lid disease like severe meibomitis, rosacea
 Surgeries involving the limbus
 Tumors of the ocular surface
 Drug-induced: mitomycin C, 5-fluorouracil
 Idiopathic
LSCD indicates limbal stem cell deficiency.

With the advent of refined techniques of stem cell transplant and the revolution in the field of keratoprosthesis, significant evolution in the management of LSCD has been witnessed in the past 2 decades. Both techniques simultaneously established their presence in the domains of unilateral and bilateral LSCD respectively and have undergone several refinements to improve outcomes and ease of utilization.3,4

The International LSCD Working Group's Global Consensus has recently published their comprehensive guidelines on the clinical presentation, classification, diagnosis, staging, and management of LSCD. This comprehensive framework has simplified the understanding of LSCD, which is a challenging disease condition, and has provided an algorithmic approach to the management of LSCD.2,5 The global consensus iterated the need for optimization of the ocular surface with the aim of improving outcomes of the technique chosen to address the LSCD.

Is There a Role for Preventive Measures That Help Salvage the Limbal Stem Cells?

In vivo evidence has demonstrated that a certain number of LSCs are essential to maintain a stable corneal epithelium. There is a need to optimize the ocular surface in the acute and semiacute stages of acquired disorders that cause LSCD. This can be accomplished by reduction of surface inflammation, dryness, and neurotrophic issues, in addition to disease-specific therapy such as antiallergics or immunomodulators. A customized comprehensive therapy is the best approach to management of the condition.1,6 An additional factor that contributes to inflammation further compromising the residual LSCs if any, and to corneal complications is a large nonhealing epithelial defect along with the primary limbal insult that occurs in the acute stage of the disease. The 2 most common causes of acquired LSCD with epithelial defects are ocular chemical injuries and Stevens-Johnson syndrome (SJS).

The role of amniotic membrane grafting (AMG) in the acute stage of SJS in ameliorating inflammation has been highlighted in earlier reports. AMG assists in quick healing of the corneal and bulbar conjunctival epithelial defects and specifically the tarsal conjunctival defects by virtue of which it prevents the occurrence of lid margin keratinization when performed in the appropriate window of opportunity in the acute stage of the disease. This helps avoid lid margin keratinization–induced LSCD in the chronic stage of the disease.7,8

Similarly, the persistence of the epithelial defect in acute chemical injuries not only prevents the possible survival of residual LSCs due to inflammation but also augments the risk of corneal complications, mainly stromal melt and scarring and/or infection involving especially the central cornea. In the acute stage, allogenic simple limbal epithelial transplantation (alloSLET) offers several advantages that include resolution of inflammation, faster epithelization, lesser occurrence of more severe grades of symblepharon, lesser need for tectonic procedures or subsequent optical keratoplasties, and in rare instances, lesser need for a subsequent LSC transplantation if adequate residual LSCs were enabled to survive.9

Nonhealing epithelial defects in the acute or exacerbatory stage of other disorders that lead to acquired LSCD, such as mucous membrane pemphigoid (MMP) or graft-versus-host disease, can be addressed using similar broad guidelines, in addition to the use of appropriate immunomodulators.10,11

Management in the chronic stage includes procedures for visual rehabilitation after remedial measures for associated comorbidities. These measures help in stabilizing or optimizing the ocular surface.12

The aim of this review is to provide a brief of the surgical options in the management of LSCD of commonly occurring ocular surface disorders, both in the acute and chronic stages as outlined in Table 2. We share an overview of the common indications, the surgical techniques, perioperative care, and complications of the procedures. Important pearls related to the procedures are highlighted alongside.

TABLE 2 - Guidelines to Surgical Management of LSCD in the Various Stages of Common OSD
OSD Within 2 wk Semiacute (2 wk to Resolution of Acute Signs) Chronic (After Resolution of Acute Signs)
SJS AMG Repeat AMG Procedures to stabilize/optimize ocular surface1. Punctal cautery2. MMG for LMK3. Fornix reconstruction (AMG ± COMET)Procedures for visual rehabilitation1. Type 2 KproMOOKPOsteo-KproBoston Type 2 KproLux Kpro(Type 1 Kpro is generally not recommended)In moist eyes only with immunosuppression, can consider:2. AlloSLET (unpublished data, Fig. 6)3. AlloSCT (guarded prognosis)
Chemical injury Address I'S and E'S1. Inciting agent (surgical removal of lime plaque, when indicated)2. Inflammation3. Epithelial defectAMGAlloSLET4. IschemiaTenonplasty5. IOP6. ExposureTarsorrhaphy Address I's and E's (till healing of epithelial defect) Simultaneous/sequential approach1. Fornix reconstruction2. AMG/SSCE3. AutoSCT (unilateral disease)AlloSCT (bilateral disease) with immunosuppression4. LK/PK5. Type 1 or 2 Kpro for bilateral disease(refer to Figs. 3–5) for an algorithmic approach
MMP AMG (for conjunctival ulceration not healing with immunosuppression) 1. Fornix reconstruction (AMG ± MMG ± COMET)2. AlloSLET (unpublished data, Fig. 6)3. Type 2 Kpro(Type 1 Kpro is generally not recommended)
AlloSCT indicates allogenic stem cell transplant; alloSLET, allogenic simple limbal epithelial transplantation; AMG, amniotic membrane grafting; autoSCT, autologous stem cell transplant; COMET, cultivated oral mucosal epithelial transplantation; IOP, intraocular pressure; Kpro, keratoprosthesis; LK, lamellar keratoplasty; LMK, lid margin keratinization; LSCD, limbal stem cell deficiency; MMG, mucous membrane grafting; MMP, mucous membrane pemphigoid; MOOKP, modified osteo-odonto-keratoprosthesis; OSD, ocular surface disorders; Osteo-Kpro, osteo-keratoprosthesis; PK, penetrating keratoplasty; SJS, Stevens-Johnson syndrome; SSCE, sequential sectoral conjunctival epitheliectomy.Tectonic procedures may be required during any stage of any disease, as warranted.
To facilitate scleral lens fitting or stabilize the tear film or along with MMG for LMK.
Any procedure in MMP that involves conjunctival handling should be performed under immunosuppressive cover.
Primarily medical management, but contributes to the outcome of surgical intervention for the other parameters.

SURGICAL PROCEDURES IN THE ACUTE STAGE

Amniotic Membrane Grafting

Amniotic membrane acts as a biological bandage providing a basement membrane for epithelial cells to grow, promotes proliferation of epithelial cells, and suppresses inflammation and scarring. Amniotic membrane grafting (AMG) is used in conditions like SJS, chemical and thermal injuries, and other ocular surface disorders presenting with nonhealing epithelial defects or exacerbations with inflammation.

The primary aim of treatment in the acute stage is to remove all inflammatory debris and necrotic material from the ocular surface and drape it with amniotic membrane. Choice of anaesthesia depends on the age and systemic status of the patient. With the use of fibrin glue, the procedure can be done at the bedside and it also helps reduce the surgical time, in the presence of an epithelial defect. The amniotic membrane is secured over the entire denuded area. When the defect extends onto or is independently present on the tarsal surface, the membrane is secured in the fornix with fornix-forming sutures or using a conformer, and the lid is everted to drape the membrane over the palpebral conjunctiva and secured to the lid margin using 8-0 polyglactin 910 sutures.

In a bedside setting in patients of SJS, alternative options are to insert a self-retaining device (eg, PROKERA; Bio-Tissue, Inc., Miami, FL)13 or drape the amniotic membrane over the entire ocular surface and secure it over the raw eyelid skin with cyanoacrylate glue14 if suturing is not possible due to the general condition of the patient.7,8 A large-diameter bandage contact lens (BCL) is placed at the end of the surgery.

Postoperative care includes topical steroids, antibiotics, and lubricants. Any need for systemic medication is based on the indication for AMG. The amniotic membrane usually disintegrates in 2 to 3 weeks and may be repeated depending upon surface healing.

AMG is a safe procedure without any major complications. Hematoma formation under the membrane in the immediate postoperative period, early disintegration, or residual subepithelial membrane have been reported with AMG. The incidence of microbial infection is as low as 1.6%.15,16

Allogenic Simple Limbal Epithelial Transplantation

Allogenic simple limbal epithelial transplantation (AlloSLET) is performed in eyes with severe (grades 5 and 6 Dua classification, grade 4 Roper-Hall classification) chemical injury and nonhealing epithelial defect in lesser grade injuries (Fig. 1A, B).17,18 There is limited experience in other ocular surface disorders.

FIGURE 1
FIGURE 1:
Nonhealing epithelial defect (A) in a 2-year-old child at 1 month post–alkali chemical injury, almost healed ocular surface at 3 weeks (B) post-alloSLET in semiacute stage of chemical injury. Features of total LSCD with symblepharon superiorly (C) with central corneal opacity and diffuse subpannus corneal thinning noted on ASOCT. Simultaneous large lamellar corneo-scleral graft with conjunctival-limbal autograft (D) improved vision to 20/60 (amblyopic age—6 years) at 2 years of follow-up. Chronic stage of LSCD after unilateral alkali chemical injury in a 7-year-old child (E). Underwent ex vivo limbal stem cell transplantation followed by lamellar keratoplasty (F) with vision improving to 20/80, maintained at 3 years of follow-up. Chronic stage of LSCD after unilateral alkali chemical injury in a 10-year-old child (I). Underwent SLET with vision improving to 20/30 with corneal clarity (J) maintained at 2-year follow-up. Features of total LSCD (K) in the eye of a 30-year-old patient with bilateral chemical injury, who underwent a living-related conjunctival-limbal allograft with penetrating keratoplasty (L) with systemic immunosuppression, continued to maintain the achieved BCVA of 20/30 for 5 years postoperation. Tectonic cyanoacrylate glue application for a central small perforation in a 1-eyed 40-year-old male after chemical injury with total LSCD (M), underwent simultaneous keratolimbal allograft with penetrating keratoplasty with systemic immunosuppression, achieved and maintained vision of 20/80 in a clear graft (N) with associated glaucoma. The graft subsequently failed after a period of 2 years. Features of LSCD in an eye (O) of a patient with bilateral chemical injury, post-COMET improvement in clarity of cornea (P) at 6 months postoperation with improvement in vision to 20/30. Recurrence of peripheral vascularization was noted at 1-year postprocedure. Diffuse symblepharon post–unilateral alkali chemical injury (Q). Symblepharon release combined with alloSLET to aid faster epithelization and reduce the risk of recurrence of symblepharon (R), after confirmation of which autoSLET was performed with an improvement in features of LSCD (S) after which a penetrating keratoplasty was performed (T). BCVA improved to 20/40 and was maintained at follow-up of 18 months. Final appearance of the eye after type 1 Boston Kpro (U) in a patient with chemical injury, BCVA of 20/20 at 6 years of follow-up. Modified osteo-odonto-keratoprosthesis in a patient with SJS (V) maintaining 20/20 at 15-year follow-up. Boston type 2 Kpro in a SJS patient (W) maintaining 6/9 at 4-year follow-up. Lux Kpro in a patent of SJS (X) maintaining 20/30 at 2-year follow-up. Optical coherence tomography image (Y) showing a hyperreflective thick irregular pannus with underlying reduced corneal thickness. AlloSLET indicates allogenic simple limbal epithelial transplantation; ASOCT, anterior segment optical coherence tomography; autoSLET, autologous simple limbal epithelial transplantation; BCVA, best-corrected visual acuity; COMET, cultivated oral mucosal epithelial transplantation; Kpro, keratoprosthesis; LSCD, limbal stem cell deficiency; SJS, Stevens-Johnson syndrome.

The procedure is performed preferably under general anaesthesia using LSCs from relatively fresh cadaveric tissue (within 24 to 72 hours) with donor age younger than 60 years. The amniotic membrane is draped over the entire denuded recipient ocular surface and secured using fibrin glue. Up to 4 to 6 clock hours of limbal tissue (1 mm × 1 mm) is harvested from donor cornea, and the alloSLET bits are placed in 2 to 3 concentric rows not extending up to the limbus, sparing the central cornea and secured using fibrin glue. A large-diameter BCL (up to 18 mm) is placed at the end of surgery.9

Topical steroids in tapering doses along with antibiotics and lubricants are initiated in the immediate postoperative period.

The BCL can be removed once a week to assess the status of epithelial healing and can be discontinued after complete healing. After removal of the BCL, tacrolimus ointment (0.03%) can be applied twice a day for 4 to 6 months based on the limbal recovery status.

In spite of being allogenic, there is no need for systemic immunosuppression in unilateral injuries, wherein the role of the alloSLET is only to facilitate quick epithelization and therefore abate the defect-induced inflammation. In case of subsequent failure of the allocells, an autologous SLET (autoSLET) can be planned at the appropriate time frame. In bilateral cases, the need for appropriate immunosuppression can be decided after the procedure.9

Loss of alloSLET bits and persistence of defects may occur in the postoperative period and may need a repeat procedure.

Tenonplasty

Tenonplasty is done for scleral ischemia involving more than 3 to 4 clock hours of limbus.19 Care should be exercised to prevent forniceal shortening by using adequate relaxing incisions.20,21

Temporary Tarsorrhaphy

Temporary tarsorrhaphy could serve as an alternative to tenonplasty in chemical injuries with limited bulbar ischemia and healthy tarsal conjunctiva. It is also a temporizing measure before definitive intervention for nonhealing corneal epithelial defects, and as an adjunct to procedures in the acute stage to reduce exposure. Epithelial defects could heal beneath a tarsorrhapy without associated stromal melt.

This simple procedure ameliorates exposure-related complications like severe dryness, persistence of epithelial defects, and corneal perforation and infection, reduces hypoxic damage, and reduces blink-related microtrauma.22

Without the need for lid margin debridement, temporary tarsorrhaphy is done using a 5-0 silk or polypropylene suture in U-shaped manner from the gray line of the lower and then the upper lid. Suture-related granuloma or early loosening of the tarsorrhaphy has been reported in a few cases. This can be managed by early removal of the suture and selecting an alternative site.

SURGICAL PROCEDURES IN THE CHRONIC STAGE TO OPTIMIZE/STABILIZE THE OCULAR SURFACE

Punctal Cautery

Lacrimal punctal occlusion helps retain tears on the ocular surface and reduces dry eye–induced inflammation and corneal staining.23

The procedure is commonly performed in patients with moderate to severe dry eye associated with significant corneal fluorescein staining and in those with LSCD, or awaiting LSC transplantation or other ocular surface reconstructive procedures.24

Punctal cautery can be performed by a battery-operated thermal cautery unit/unipolar cautery.25

With the patient in reclined or supine position, the looped tip of the thermal cautery unit is inserted deep into the punctum to the full depth of the ampulla and vertical canaliculus before the cautery unit is activated. The tip should be rocked and rotated inside the punctum. Blanching of the surrounding tissues indicates sufficient treatment. The tip should be removed while still hot and activated to enable removal of any adherent epithelium ensuring that the canalicular mucosal epithelium does not heal to recannulate the punctum.26

Complications include recanalization, epiphora, localized punctal cellulitis, localized entropion with trichiasis, punctal dilation, conjunctivitis, canaliculitis, pyogenic granuloma, or dacryocystitis.27

Conjunctival Reconstruction

In LSCD, the abnormalities of eyelids and conjunctiva include symblepharon, ankyloblepharon, shortening or loss of fornices, lid margin and surface keratinization, scarring of tarsal conjunctival plate, lagophthalmos, ectropion, entropion, distichiasis, and trichiasis. For better outcomes, it is imperative to address these abnormalities before any LSC transplantation. In milder grades, fornix reconstruction can be performed along with stem cell transplant procedures. However, in severe grades, a sequential approach is preferred (Fig. 2A, B). More often than not, this requires a multidisciplinary approach.5,28 However, oculoplastic procedures to correct adnexal disorders are beyond the scope of this review.

FIGURE 2
FIGURE 2:
Fornix reconstruction in moderate to severe grade symblepharon (A) with amniotic membrane grafting and anchoring suture in an eye post–chemical injury with a moist surface with well-formed fornices (B) at 4 months postsurgery, awaiting autoSLET. Fornix reconstruction in moderate to severe (C) grade symblepharon with amniotic membrane and mucous membrane grafting to the lower palpebral surface in an eye (BCVA [email protected] m) with mucous membrane pemphigoid on systemic mycophenolate with a short course of perioperative systemic steroids, with well-formed fornix and improvement in dryness and corneal clarity (D) secondary to reduced blink-induced microtrauma. The vision improved to 20/60 with PROSE lens, which could not be introduced earlier due to the shortened fornix. Inflamed surface (E) in an eye due to lid margin keratinization of upper (G) and lower lid (I) in a patient with Stevens-Johnson syndrome. Significant reduction in surface inflammation post–mucous membrane grafting and a decrease in corneal vascularization (F) without postoperative topical steroids. Smooth contour of the thin mucosal graft along the lower (H) and upper (J) lids noted. AutoSLET indicates autologous simple limbal epithelial transplantation; BCVA, best-corrected visual acuity; CF, counting fingers; PROSE, Prosthetic Replacement of the Ocular Surface Ecosystem.

Fornix Reconstruction

The surgical procedure to correct symblepharon involves cicatricial lysis followed by reconstruction with tissue substitutes like conjunctiva, oral or nasal mucosa, or amniotic membrane.28,29 These may be combined with insertion of a conformer, symblepharon ring, silicone sheet implant, or intraoperative or postoperative application of mitomycin C to prevent re-adhesion. In ocular MMP (Fig. 2C, D), severe SJS, and graft-versus-host disease, systemic immunosuppression should be adopted to prevent or control exacerbation of conjunctival cicatrization.5,8,11

In mild cases of symblepharon, a circumlinear incision of the conjunctiva at the perilimbal region is followed by relaxing incisions toward the fornix along the borders of the symblepharon. Subconjunctival fibrovascular cicatrix is then dissected and amputated at the base using scissors without removing the overlying conjunctival epithelium. Sponges soaked in 0.04% of mitomycin C solution may be applied into the deep fornix for 3 to 5 minutes depending on the severity of inflammation. The bare ocular surface is draped with amniotic membrane securing it with either fibrin glue or sutures.28

In cases of moderate symblepharon, an additional anchoring suture is placed in the fornix to anchor the edge of the recessed conjunctiva through full thickness of the lid. In eyes with severe symblepharon or ankyloblepharon, a free oral mucosal graft harvested from the labial area or a free conjunctival autograft can be attached to the recessed conjunctiva and secured to the palpebral surface using an anchoring suture, which is removed within 1 to 2 weeks after surgery. Complications include failure or scar formation, recurrence of symblepharon, conjunctival inflammation around the surgical site, and conjunctival pyogenic granuloma.28

Mucous Membrane Grafting for Lid Margin Keratinization

Lid margin keratinization, affecting the tarsal conjunctiva, is an important cause of chronic blink-related microtrauma and LSCD, and hence should be addressed to stabilize the ocular surface (Fig. 2E–J).8,12 Mucous membrane grafting (MMG) is done for keratinization of grade 2 and above, especially when associated with corresponding corneal epitheliopathy or vascularization.2

It is preferably done in both eyes under general anesthesia. After lid eversion with 4-0 silk sutures, up to 15 to 20 mm of the central, keratinized lid margin is dissected with the tarsal conjunctiva as a flap to a width of 5 mm for each lid. A lower lip mucosal graft (30–40 mm× 10 mm) is then harvested and washed in antibiotic solution. An edge of the adequately sized mucosal graft is then sutured to the lid margin using 8-0 polyglactin 910 continuous suture with exteriorization of the knots. Fibrin glue is used to secure the graft over the tarsal conjunctiva. Postoperative care includes the use of a topical antibiotic eyedrop 4 times daily for a week along with frequent application of lubricants. No topical steroids are used. Chlorhexidine mouthwash, started 5 days preoperatively, is continued for a week after surgery.30 Buttonholing of the graft, graft retraction, graft detachment, graft necrosis, breakthrough trichiasis, and recurrence of keratinization may potentially complicate MMG.31

SURGICAL PROCEDURES FOR PARTIAL LSCD

Sequential Sectoral Conjunctival Epitheliectomy

The conjunctival epithelium encroaching into a sector of the cornea is removed once or more often in sequence to prevent it from invading the visual axis. This allows the denuded surface to be covered by corneal epithelium from the remaining healthy LSCs. Since the efficacy of this procedure is not predictable, it can be attempted in eyes with minimal LSCD and is not regularly recommended for extensive conjunctivalization due to the postprocedural risk of delayed re-epithelialization.32

Amniotic Membrane Grafting

In the presence of localized pannus over the corneal surface, amniotic membrane may be transplanted after pannus removal to aid in re-epithelization by virtue of its properties to stimulate the LSC niche. The efficacy of this procedure should be further evaluated in randomized controlled clinical trials for LSCD.

SURGICAL PROCEDURES FOR TOTAL LSCD

Corneal status with regard to thickness and clarity (determined pre–, intra–, or post–LSC transplantation) helps in further planning for initial, simultaneous (Fig. 1C, D), or subsequent lamellar (Fig. 1E, F) or penetrating keratoplasty (Fig. 1G, H) for tectonic and/or optical purposes. This essential step in the algorithmic management of unilateral and bilateral LSCD (Figs. 3, 4) has not been highlighted in earlier reports and forms an important aspect of the authors’ preoperative planning.

FIGURE 3
FIGURE 3:
Algorithmic approach to assist in decision making for cell therapy in patients with unilateral total LSCD. ASOCT indicates anterior segment optical coherence tomography; autoLSCT, autologous limbal stem cell transplantation; CLAU, conjunctival-limbal autograft; LK, lamellar keratoplasty; LSCD, limbal stem cell deficiency; PK, penetrating keratoplasty; SLE, slit lamp examination; SLET, simple limbal epithelial transplantation.
FIGURE 4
FIGURE 4:
Algorithmic approach to assist in decision making for stem cell therapy in patients with bilateral total LSCD. The decision between stem cell therapy vs primary keratoprosthesis depends on various patient- and surgeon-related factors, and the few mandatory ones that aid in decision making for primary keratoprosthesis are highlighted in bold. AlloSCT indicates allogenic stem cell transplant; alloSLET, allogenic simple limbal epithelial transplantation; ASOCT, anterior segment optical coherence tomography; COMET, cultivated oral mucosal epithelial transplantation; KLAL, keratolimbal allograft; LK, lamellar keratoplasty; lr-CLAL, living-related conjunctival-limbal allograft; LSCD, limbal stem cell deficiency; LSCT, limbal stem cell transplantation; PK, penetrating keratoplasty; SLE, slit lamp examination.

UNILATERAL LSCD

In unilateral total LSCD, where the other eye is healthy, autologous LSC transplantation is preferred over allogenic limbal cells due to better graft survival rates and avoidance of systemic immunosuppression. In cases where the other eye is not suitable for retrieval of limbal cells, allografts can be considered with systemic immunosuppression.

Limbal Autografts

First described in 1964 and modified in 1977, conjunctival-limbal autograft (CLAU) has a success rate of 35% to 88% depending upon the amount of transplanted tissue.33–35

In this technique, 2 limbal grafts (2 to 3 clock hours each, separated at 180 degrees) are harvested from the normal eye and transplanted to the affected eye. As the niche of LSCs is located deep in the limbus, the harvesting should be at an appropriate depth is superficial subepithelial on the corneal side.36 As this procedure allows transplantation of one's own limbal cells, there is no risk of rejection and the long-term results of this procedure are good.37 Eslani et al38 reported about 78% of long-term success with this procedure in a series of 27 eyes with unilateral LSCD. Concerns have been raised regarding the risk of iatrogenic partial LSCD in the donor eye, yet long-term results have been favorable.39–41

Autologous Ex Vivo Cultivated Limbal Epithelial Transplantation

Irradiated 3T3 fibroblasts were an initial substrate for LSC cultivation after various substrates like amniotic membrane, fibrin or collagen sheet, and contact lens have been used to successfully expand the stem cells. These substrates act as a scaffold for the stem cells to multiply over a period of 2 to 3 weeks, which are then transferred to the affected eye as a confluent epithelial sheet.42–44

Explant culture on amniotic membrane is commonly used to grow LSCs without the need for feeder cells.43 The long-term success rates of transplantation of ex vivo–cultivated LSCs range from 50% to 86% and are thus similar to those achieved by CLAU. An advantage of cultivated limbal epithelial transplantation (CLET) over CLAU is the decreased risk of iatrogenic LSCD, but the technique requires a qualified laboratory for culture process and is expensive.

Simple Limbal Epithelial Transplantation

Simple limbal epithelial transplantation (SLET) was introduced by Sangwan et al45 in 2012 as an alternative to CLET. This technique describes in vivo expansion of autologous LSCs that can be harvested from the contralateral healthy eye. A 2 mm× 2 mm small limbal graft is taken from the donor eye, divided into smaller pieces, and expanded in vivo on a fresh amniotic membrane (Fig. 1I, J). Fibrin glue is used to place the small bits over the de-epithelized amniotic membrane. Amescua et al46 have described a modification to this technique where they used double-layered cryopreserved AMG for management of unilateral LSCD.

An advantage of SLET is smaller donor tissue without the need of ex vivo culture techniques, which makes it cost-effective and reduces the risk of iatrogenic LSCD. Basu et al47 reported successful results of this technique in unilateral chronic ocular surface burns. In a multicenter study, clinical success of SLET for unilateral LCSD was equal or better than techniques reported earlier.48 In a systematic review of 404 cases of SLET, the results of SLET were comparable with CLAU and CLET.49

BILATERAL LSCD

The choice of treatment between stem cell transplant options and keratoprostheses (Fig. 5) for bilateral LSCD is influenced by several factors. These include severity of dryness, shortening of fornix, presence of an underlying immunological disorder, anticipated visual potential of the eye, eligibility for systemic immunosuppression, experience and expertise of the surgeon, and patient factors like compliance and expectations.

FIGURE 5
FIGURE 5:
Algorithmic approach to assist in decision making for keratoprosthesis in patients with bilateral total LSCD. AlloSCT indicates allogenic stem cell transplant; BKP, Boston keratoprosthesis; Kpro, keratoprosthesis; LSCD, limbal stem cell deficiency; MOOKP, modified osteo-odonto- keratoprosthesis; OCP, ocular cicatricial pemphigoid; osteo-Kpro, osteo-keratoprosthesis; SJS, Stevens-Johnson syndrome.

STEM CELL THERAPIES

Limbal Cell Options

In bilateral total LSCD, stem cell reconstruction is performed using allogenic sources, which could be conjunctival-limbal allograft from a living-related donor (lr-CLAL) (Fig. 1K, L) in keratolimbal allograft (KLAL) (Fig. 1M, N) from a cadaveric donor, in combination with systemic immunosuppressive therapy to prevent rejection and maintain ocular surface integrity. To avoid immunosuppression, cultivated oral mucosal epithelial transplantation (COMET) can be considered as an alternative option.

Graft rejection is a major risk after allogenic cell transplantation. A living-related blood donor or HLA-matched donor might have better outcomes and would reduce the dependency on systemic immunosuppression for survival; however, no published reports confirm the same. Systemic immunosuppression is advisable and possibly necessary even with HLA-matched tissues as transplanted stem cell failure may occur over long term due to inadequate stem cell transfer or immune-mediated stem cell damage.50 Allografts from cadaveric tissue have the advantage of providing a larger quantity of LSCs, easy availability of tissue, and the ease of repeating the procedure if required. However, the success rate of KLAL, despite immunosuppression, declines from 75% to 80% in first year to 50% at 3 years.51 The Cincinnati procedure was developed to combine the advantages of lr-CLAL and KLAL.52 Cyclosporine is the most commonly prescribed immunosuppressive drug along with systemic steroids. A steroid minimizing systemic immunosuppression protocol with mycophenolate mofetil and tacrolimus after stem cell transplant has helped achieve a stable ocular surface in 77.2% of cases over a mean follow-up of 42.1 months.53

One of the risk factors for rejection of allogenic cells is the burden of allogenic antigens in the tissues. To address this and limit the possible complications of excising larger limbal/conjunctival tissues from the donor eye, Pelligrini et al42 proposed cultivation of limbal cells for restoring the corneal epithelial surface. The long-term outcomes of ex vivo cultivated allogenic LSCs may be similar to those of KLAL and CLAL.54,55

The same rationale can be extrapolated to the procedure of alloSLET for visual rehabilitation wherein the systemic immunosuppression could be reduced in view of the lower burden of allogenic cells and the placement of cells over the avascular cornea rather than on the vascularized limbus. The authors’ experience of alloSLET in a limited number of eyes with ocular MMP and SJS has been encouraging (unpublished data). A case of ocular cicatricial pemphigoid in a moist eye with a 6-year follow-up is illustrated in Figure 6A and B. Experience with alloSLET in moist eyes with cicatricial conditions has revealed encouraging outcomes (unpublished data). Similarly, alloSLET in a child of SJS with bilateral total LSCD and moist eyes revealed encouraging outcomes at 1 year (unpublished data, Fig. 6C, D). However, patient selection, close follow-up, judicious use of systemic immunosuppression, and the readiness for a tectonic procedure or keratoprosthesis at the earliest sign of a stromal melt should be planned and executed.

FIGURE 6
FIGURE 6:
A, Diffuse corneal vascularization and haze with moist surface in a case of mucous membrane pemphigoid on systemic mycophenolate mofetil 1 g/d with BCVA of CFCF at 1 month. B, Post-alloSLET for visual rehabilitation with additional perioperative systemic steroids and topical steroids and topical tacrolimus (0.03%) ointment with BCVA improving to 20/80 maintained for 2 years postprocedure. C, Total conjunctivalization with moist surface (in the better of the 2 eyes) in an 8-year-old child of Stevens-Johnson syndrome. D, Maintenance of corneal phenotype at 1 year of follow-up with an improvement in BCVA to 20/30 on systemic mycophenolate 500 mg along with topical steroids and topical tacrolimus (0.03%) ointment. AlloSLET indicates allogenic simple limbal epithelial transplantation; BCVA, best-corrected visual acuity; CF, counting fingers.

Rarely, the authors have used alloSLET along with fornix reconstruction in severe grades of symblepharon to facilitate early epithelization, followed by autoSLET and/or optical keratoplasty (Fig. 1Q–T).

Partial epithelial healing, persistent defects, infection, corneal perforation, and rejection have been reported with allogenic LSC transplantation. Rarely side effects due to systemic immunosuppression like altered liver/renal function, myocardial infarction, infection, and anemia can occur.42,50,51,53

CULTIVATED ORAL MUCOSAL EPITHELIAL TRANSPLANTATION

Cultivated oral mucosal epithelial transplantation (COMET) uses autologous tissue that provides an epithelized surface and eliminate the need for systemic immunosuppression. COMET offers advantages of a small amount of donor tissue, ease of the procedure, and little oral discomfort and pain to the patient.56 Multiple studies have reported good long-term outcomes with COMET in total LSCD; however, gradual fibrovascular invasion of the cornea and the cost of the procedure are common limitations.57

Technique

For visual rehabilitation in total LSCD (Fig. 1O, P), the surgical steps are similar to CLET. The only difference is that the cells on the amniotic membrane are cultivated oral mucosal epithelial cells.54

For fornix reconstruction, the procedure is very similar to that described for symblepharon lysis. In place of amniotic membrane, the cultivated oral mucosal epithelial sheets on the amniotic membrane are grafted onto the bare area and fixed with fibrin glue.58

Persistence of epithelial defects, failure of the surface to epithelize, and corneal melt, perforation, and infection have been reported with COMET.57,58

Keratoprosthesis

Keratoprosthesis (Kpro) is the last resort for visual rehabilitation in patients with bilateral end-stage ocular surface disorders. Based on key indications, Kpro is categorized into type 1 and 2 Kpros.

The choice of Kpro is based on several factors as indicated in the algorithm (Fig. 5).

Type 1 Kpro

Type 1 Kpro is preferred in conditions with moist eyes and well-formed fornices like aniridia and chemical injury (Fig. 1U).59,60 Type 1 Kpro is generally not recommended for SJS due to the high risk of carrier graft melt.

The postoperative care and regimen to be followed for the type 1 Kpro is strict and includes long-term use of topical antibiotics (a combination of the fourth-generation fluoroquinolone and vancomycin), tapering doses of topical steroid continued indefinitely along with lubricants, and antiglaucoma medication as required. The BCL is replaced every 3 months when topical povidone-iodine 5% can be used to sterilize the ocular surface. Alternatively, the authors practice advocating the patient to instill a few drops of povidone-iodine fortnightly along with prophylactic use of topical voriconazole 1% monthly for a duration of 5 days.

Glaucoma, the most common comorbidity, should be treated aggressively as it can lead to optic atrophy.61

The Auro Kpro, an indigenous replication of the Boston Kpro, has shown outcomes to be on par with the Boston type 1 Kpro.62

Type 2 Kpros

The modified osteo-odonto-keratoprosthesis (MOOKP), osteo-keratoprosthesis, Boston keratoprosthesis type 2, and the Lux keratoprosthesis are grouped here as type 2 Kpros. These type 2 Kpros are indicated for eyes with severe dryness, severe forniceal shortening or ankyloblepharon, and/or in the presence of underlying immunological disorders such as chemical injury (with severe forniceal shortening and keratinization), SJS, and MMP.

In eyes with end-stage ocular surface disorders eligible for the type 2 Kpro,63–67 functional outcomes at 10 years postsurgery have been reported to be 49% for MOOKP and 25% for the osteo-Kpro.68

The specific type 2 Kpro is chosen based on surgeon, patient, and Kpro-related factors (Fig. 5).

Among the type 2 Kpro, MOOKP is the preferred procedure followed by the Boston type 2 Kpro or the osteo-Kpro. The procedures are not directly comparable in terms of the ease of performance and need for multidisciplinary approach, with the MOOKP being a multistaged and more demanding procedure. Although cosmesis is often cited to be a disadvantage of the MOOKP, the long-term outcome, both anatomical and functional, far surpasses that of the alternative options for similar indications.68,69

Boston Type 2 Kpro

The Boston type 2 Kpro follows similar principles pertaining to the assembly and suturing as the type 1 Kpro. However, the key differences include complete removal of the conjunctiva from the bulbar and palpebral surface, combining the procedure with pars plana vitrectomy and implantation of the Ahmed glaucoma valve (termed the "kitchen sink procedure"), and most importantly, excision of the lid margins and meticulous approximation of the upper and lower lids around the protruding stem of the type 2 Kpro (Fig. 1V).63

Modified Osteo-Odonto-Keratoprosthesis

Modified osteo-odonto-keratoprosthesis (MOOKP) is a 3-staged surgery done over a period of 4 to 6 months as described by the Rome-Vienna protocol.70

It is essential to ensure eligibility of the patient for the MOOKP procedure in terms of availability of a suitable canine tooth.

In the first stage, the eye is prepared by removing the iris, lens, and limited anterior vitrectomy. If required, a tectonic penetrating keratoplasty can be performed at this stage. Importantly, the fundus is examined intraoperatively to gauge the visual potential of the eye before planning the more demanding further stages of the surgery.

A month later, stage IB+C is performed that mainly involves harvesting the canine tooth and fashioning it into a lamina with an optic cylinder fixed in the center. This lamina is then placed in the subcutaneous pouch under the opposite eyelid for a fibrovascular cover. Simultaneously, 3 cm of buccal mucosa is harvested from the cheek and anchored over the ocular surface to the 4 recti muscles and the episclera.

Three months later, the final stage is performed wherein the lamina is removed from the subcutaneous pouch and trimmed of excess fibrovascular tissue. The mucosa is reflected with an inferior hinge and anchoring sutures are placed on the cornea and sclera. The cornea is trephined based on the posterior diameter of the cylinder and then the Kpro is implanted in the eye. The reflected mucosa is sutured back and a central opening over the cylinder is made (Fig. 1W).

Osteo-Kpro

In the osteo-Kpro procedure the tibial bone is harvested and fashioned, instead of the tooth to form the haptic for the optical cylinder.68 Other surgical steps are similar to the MOOKP procedure. The osteolamina is not as resistant as the dentine in the MOOKP lamina to laminar resorption accounting for the reduced long-term outcomes compared with the MOOKP.

The postoperative regimen for the type 2 Kpros does not include significant medications except for the use of antibiotic ointment at bedtime. Antibiotic drops up to 4 times a day are continued indefinitely for the Boston type 2 Kpro. Though the follow-up for the Boston type 2 Kpro is once in 3 months, for the MOOKP and osteo-Kpro, the follow-up period can be safely extended to once in 6 months.

Lux Kpro

The Lux Kpro, a recent addition to the Kpro armamentarium, was developed for patients with severe cicatricial keratoconjunctivitis who are otherwise not candidates for existing Kpro designs. Short-term outcomes with Lux Kpro are encouraging (Fig. 1X).67

Kpro-related complications include periprosthetic tissue melt, laminar resorption and extrusion, retroprosthetic membrane formation and complications related to the covering tissue, viz skin, or mucosa in the type 2 Kpros. Ocular complications include retinal detachment, glaucoma, and endophthalmitis.5

SUMMARY

Expected visual potential based on ocular comorbidities and amblyopia is a crucial factor in determining the need for intervention and the type of intervention in LSCD. Realistic expectations of patients and their families are another important prerequisite. The need for patient compliance with medications and postoperative restrictions and regular follow-ups cannot be overemphasized. The economics of travel for lifelong follow-up and long-term systemic and topical medications is an important aspect to be discussed before initiating any of the procedures for visual rehabilitation in the chronic stage. The acute stage of these disorders must be aggressively managed with the aim to protect LSCs to the extent possible and to avoid corneal perforation at all costs. The windows of opportunity provided at each stage of the disease, especially with respect to performing ocular surface stabilizing procedures, must be capitalized upon to prevent the eye from going to a stage that would require a LSC transplantation or Kpro, especially in bilateral cases. Crucial game changers include alloSLET in the acute stage of severe grade chemical injuries, AMG within 2 weeks of onset of SJS, and MMG for lid margin keratinization in SJS, with reported good outcomes. Any delay in decision making for visual rehabilitation should not deter the aggressive management of glaucoma, the most common comorbidity in these eyes. Kpro in unilateral LSCD and bilateral Kpros are discouraged globally, and the second eye is preferred to be reserved as a spare eye for the future if the need arises. In summary, it is essential to comprehend all the surgeon-patient factors in totality to provide customized care to the affected eye.

REFERENCES

1. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 1989; 96:709–722.
2. Deng SX, Borderie V, Chan CC, et al. Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency. Cornea 2019; 38:364–375.
3. Fernandez-Buenaga R, Aiello F, Zaher SS, et al. Twenty years of limbal epithelial therapy: an update on managing limbal stem cell deficiency. BMJ Open Ophthalmol 2018; 3:e000164.
4. Iyer G, Srinivasan B, Agarwal S, et al. Keratoprosthesis: current global scenario and a broad Indian perspective. Indian J Ophthalmol 2018; 66:620–629.
5. Deng SX, Kruse F, Gomes JAP, et al. Global consensus on the management of limbal stem cell deficiency. Cornea 2020; 39:1291–1302.
6. Liang L, Sheha H, Li J, Tseng SC. Limbal stem cell transplantation: new progresses and challenges. Eye 2009; 23:1946–1953.
7. Gregory DG. The ophthalmologic management of acute Stevens-Johnson syndrome. Ocul Surf 2008; 6:87–95.
8. Kohanim S, Palioura S, Saeed HN, et al. Acute and chronic ophthalmic involvement in Stevens-Johnson syndrome/toxic epidermal necrolysis—a comprehensive review and guide to therapy. II. Ophthalmic Disease. Ocul Surf 2016; 14:168–188.
9. Iyer G, Srinivasan B, Agarwal S, et al. Outcome of allo simple limbal epithelial transplantation (alloSLET) in the early stage of ocular chemical injury. Br J Ophthalmol 2017; 101:828–833.
10. Giannaccare G, Pellegrini M, Bernabei F, et al. Ocular surface system alterations in ocular graft-versus-host disease: all the pieces of the complex puzzle. Graefes Arch Clin Exp Ophthalmol 2019; 257:1341–1351.
11. Dart JK. The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on. Eye 2017; 31:301–332.
12. Iyer G, Srinivasan B, Agarwal S, et al. Treatment modalities and clinical outcomes in ocular sequelae of Stevens-Johnson syndrome over 25 years—a paradigm shift. Cornea 2016; 35:46–50.
13. Kolomeyer AM, Do BK, Tu Y, Chu DS. Placement of PROKERA in the management of ocular manifestations of acute Stevens-Johnson syndrome in an outpatient. Eye Contact Lens 2013; 39:e7–e11.
14. Shanbhag SS, Chodosh J, Saeed HN. Sutureless amniotic membrane transplantation with cyanoacrylate glue for acute Stevens-Johnson syndrome/toxic epidermal necrolysis. Ocul Surf 2019; 17:560–564.
15. Dua HS, Gomes JA, King AJ, Maharajan VS. The amniotic membrane in ophthalmology. Surv Ophthalmol 2004; 49:51–77.
16. Marangon FB, Alfonso EC, Miller D, et al. Incidence of microbial infection after amniotic membrane transplantation. Cornea 2004; 23:264–269.
17. Roper-Hall MJ. Thermal and chemical burns. Trans Ophthalmol Soc U K 1965; 85:631–653.
18. Dua HS, King AJ, Joseph A. A new classification of ocular surface burns. Br J Ophthalmol 2001; 85:1379–1383.
19. Teping C, Reim M. Tenonplasty as a new surgical principle in the early treatment of the most severe chemical eye burns. Klin Monbl Augenheilkd 1989; 194:1–5.
20. Iyer G, Srinivasan B, Agarwal S, Barbhaya R. Visual rehabilitation with keratoprosthesis after tenonplasty as the primary globe-saving procedure for severe ocular chemical injuries. Graefes Arch Clin Exp Ophthalmol 2012; 250:1787–1793.
21. Gupta N, Singh A, Mathur U. Scleral ischemia in acute ocular chemical injury: long-term impact on rehabilitation with limbal stem cell therapy. Cornea 2019; 38:198–202.
22. Iyer G, Srinivasan B, Agarwal S. Algorithmic approach to management of acute ocular chemical injuries—I's and E's of Management. Ocul Surf 2019; 17:179–185.
23. Murube J, Murube E. Treatment of dry eye by blocking the lacrimal canaliculi. Surv Ophthalmol 1996; 40:463–480.
24. Kaido M, Goto E, Dogru M, et al. Punctal occlusion in the management of chronic Stevens-Johnson syndrome. Ophthalmology 2004; 111:895–900.
25. Law RWK, Li RTH, Lam DSC, et al. Efficacy of pressure topical anaesthesia in punctal occlusion by diathermy. Br J Ophthalmol 2005; 89:1449–1452.
26. Brightbill FS. Mostby, Corneal surgery. Theory, technique, and tissue. St. Louis:1999.
27. Quiroz BB, Affeldt JC. Complications associated with deep thermal punctal occlusion. Invest Ophthalmol Vis Sci 2002; 43:67.
28. Kheirkhah A, Blanco G, Casas V, et al. Surgical strategies for Fornix reconstruction based on symblepharon severity. Am J Ophthalmol 2008; 146:266–275.
29. Wenkel H, Rummelt V, Naumann GO. Long-term results after autologous nasal mucosal transplantation in severe mucous deficiency syndromes. Br J Ophthalmol 2000; 84:279–284.
30. Iyer G, Pillai VS, Srinivasan B, et al. Mucous membrane grafting for lid margin keratinization in Stevens-Johnson syndrome: results. Cornea 2010; 29:146–151.
31. Weisenthal RW, Daly MK, Freitas D, et al. American Academy of Ophthalmology, External Disease and Cornea. San Francisco:2018.
32. Dua HS. Sequential sectoral conjunctival epitheliectomy (SSCE). Ocular Surface Disease Medical and Surgical Management. New York, NY: Springer; 2002.
33. Holland EJ. Management of limbal stem cell deficiency: a historical perspective, past, present, and future. Cornea 2015; 34:S9–S15.
34. Borderie VM, Ghoubay D, Georgeon C, et al. Long-term results of cultured limbal stem cell versus limbal tissue transplantation in stage III limbal deficiency. Stem Cells Transl Med 2019; 8:1230–1241.
35. Cauchi PA, Ang GS, Azuara-Blanco A, et al. A systematic literature review of surgical interventions for limbal stem cell deficiency in humans. Am J Ophthalmol 2008; 146:251–259.
36. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 1989; 96:709–723.
37. Daya SM. Conjunctival-limbal autograft. Curr Opin Ophthalmol 2017; 28:370–376.
38. Eslani M, Cheung AY, Kurji K, et al. Long-term outcomes of conjunctival-limbal autograft in patients with unilateral total limbal stem cell deficiency. Ocular Surf 2019; 17:670–674.
39. Cheung AY, Sarnicola E, Holland EJ. Long-term ocular surface stability in conjunctival-limbal autograft donor eyes. Cornea 2017; 36:1031–1035.
40. Barros Jde N, Santos MS, Barreiro TR, et al. Cytological features of live limbal tissue donor eyes for autograft or allograft limbal stem cell transplantation. Arq Bras Oftalmol 2011; 74:248–250.
41. Kreimei M, Sorkin N, Einan-Lifshitz A, et al. Long-term outcomes of donor eyes after conjunctival-limbal autograft and allograft harvesting. Can J Ophthalmol 2019; 54:565–569.
42. Pellegrini G, Traverso CE, Franzi AT, et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 1997; 349:990–993.
43. Tsai RJ, Li LM, Chen JK. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med 2000; 343:86–93.
44. Rama P, Bonini S, Lambiase A, et al. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation 2001; 72:1478–1485.
45. Sangwan VS, Basu S, MacNeil S, Balasubramanian D. Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol 2012; 96:931–934.
46. Amescua G, Atallah M, Nikpoor N, et al. Modified simple limbal epithelial transplantation using cryopreserved amniotic membrane for unilateral limbal stem cell deficiency. Am J Ophthalmol 2014; 158:469–475.
47. Basu S, Sureka SP, Shanbhag SS, et al. Simple limbal epithelial transplantation: long-term clinical outcomes in 125 cases of unilateral chronic ocular surface burns. Ophthalmology 2016; 123:1000–1010.
48. Vazirani J, Ali MH, Sharma N, et al. Autologous simple limbal epithelial transplantation for unilateral limbal stem cell deficiency: multicenter results. Br J Ophthalmol 2016; 100:1416–1420.
49. Jackson CJ, Myklebust Ernø IT, et al. Simple limbal epithelial transplantation: current status and future perspectives. Stem Cells Transl Med 2020; 9:316–327.
50. Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal allografting from related live donors for corneal surface reconstruction. Ophthalmology 1999; 106:822–828.
51. Solomon A, Ellies P, Anderson DF, et al. Long-term outcome of keratolimbal allograft with or without penetrating keratoplasty for total limbal stem cell deficiency. Ophthalmology 2002; 109:1159–1166.
52. Biber JM, Skeens HM, Neff KD, Holland EJ. The Cincinnati procedure: technique and outcomes of combined living-related conjunctival-limbal allografts and keratolimbal allografts in severe ocular surface failure. Cornea 2011; 30:765–771.
53. Holland EJ, Mogilishetty G, Skeens HM, et al. Systemic immunosuppression in ocular surface stem cell transplantation: results of a 10-year experience. Cornea 2012; 31:655–661.
54. Cheung AY, Eslani M, Kurji KH, et al. Long-term outcomes of living-related conjunctival-limbal allograft compared with keratolimbal allograft in patients with limbal stem cell deficiency. Cornea 2020; 39:980–985.
55. Shortt AJ, Bunce C, Levis HJ, et al. Three-year outcomes of cultured limbal epithelial allografts in aniridia and Stevens-Johnson syndrome evaluated using the clinical outcome assessment in surgical trials assessment tool. Stem Cells Transl Med 2014; 3:265–275.
56. Nakamura T, Inatomi T, Sotozono C, et al. Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders. Br J Ophthalmol 2004; 88:1280–1284.
57. Cabral JV, Jackson CJ, Utheim TP, et al. Ex vivo cultivated oral mucosal epithelial cell transplantation for limbal stem cell deficiency: a review. Stem Cell Res Ther 2020; 11:301.
58. Gopakumar V, Agarwal S, Srinivasan B, et al. Clinical outcome of autologous cultivated oral mucosal epithelial transplantation in ocular surface reconstruction. Cornea 2019; 38:1273–1279.
59. Harissi-Dagher M, Dohlman CH. The Boston keratoprosthesis in severe ocular trauma. Can J Ophthalmol 2008; 43:165–169.
60. Shanbhag SS, Saeed HN, Paschalis EI, Chodosh J. Boston keratoprosthesis type 1 for limbal stem cell deficiency after severe chemical corneal injury: a systematic review. Ocul Surf 2018; 16:272–281.
61. Wang JC, Rudnisky CJ, Belin MW, Ciolino JB. Boston Type 1 Keratoprosthesis Study Group. Outcomes of Boston keratoprosthesis type 1 reimplantation: multicenter study results. Can J Ophthalmol 2018; 53:284–290.
62. Venugopal A, Rathi H, Rengappa R, et al. Outcomes after Auro keratoprosthesis implantation: a low-cost design based on the Boston keratoprosthesis. Cornea 2016; 35:1285–1288.
63. Lee R, Khoueir Z, Tsikata E, et al. Long-term visual outcomes and complications of Boston keratoprosthesis type 2 implantation. Ophthalmology 2017; 124:27–35.
64. Falcinelli G, Falsini B, Taloni M, et al. Modified osteo-odonto-keratoprosthesis for treatment of corneal blindness: long-term anatomical and functional outcomes in 181 cases. Arch Ophthalmol 2005; 123:1319–1329.
65. Avadhanam VS, Zarei-Ghanavati M, Bardan AS, et al. When there is no tooth—looking beyond the Falcinelli MOOKP. Ocul Surf 2019; 17:4–8.
66. Iyer G, Pillai VS, Srinivasan B, et al. Modified osteo-odonto- keratoprosthesis—the Indian experience—results of the first 50 cases. Cornea 2010; 29:771–776.
67. Bakshi SK, Graney J, Paschalis EI, et al. Design and outcomes of a novel keratoprosthesis: addressing unmet needs in end-stage cicatricial corneal blindness. Cornea 2020; 39:484–490.
68. Charoenrook V, Michael R, de la Paz MF, et al. Comparison of long-term results between osteo-odonto-keratoprosthesis and tibial bone keratoprosthesis. Ocul Surf 2018; 16:259–264.
69. de la Paz MF, Salvador-Culla B, Charoenrook V, et al. Osteo-odonto-, tibial bone, and Boston keratoprosthesis in clinically comparable cases of chemical injury and autoimmune disease. Ocul Surf 2019; 17:476–483.
70. Hille K, Grabner G, Liu C, et al. Standards for modified osteo-odonto-keratoprosthesis (OOKP) surgery according to Strampelli and Falcinelli: the Rome-Vienna Protocol. Cornea 2005; 24:895–908.
Keywords:

keratoprosthesis; limbus; LSCD; ocular chemical injury; SLET; Stevens-Johnson syndrome

Copyright © 2020 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.