Anatomically, the ocular surface encompasses the entire mucosal epithelial lining bordered by the skin at the superior and inferior eyelid margins. Histologically, this epithelial surface covers two major territories (i.e., the cornea and the conjunctiva). The primary function of the ocular surface is to provide clear vision during an open-eye state. To achieve this goal while maintaining comfort and preventing microbial invasion, the ocular surface has to be covered by a stable tear film. Therefore, the mechanism by which the ocular surface health is ensured is inherently built into the relationship between ocular surface epithelia and the preocular tear film. As recently summarized,¹ compositional factors including the ocular surface epithelia, meibomian glands, and lacrimal glands and hydrodynamic factors such as eyelid blinking and closure are essential to constitute ocular surface defense that governs how preocular tear film stability is maintained (Fig. 1). These two major factors are integrated via two neuronal reflex arcs, triggered by the sensory drive of the first branch of trigeminal nerve (V₁), and mediated by the parasympathetic branch and the motor branch of the facial nerve (VII) as the efferent output, respectively (Fig. 2). Such a neuroanatomic integration of ocular surface defense explains how external adnexal glands and eyelids can be integrated with ocular surface epithelia as a unit to maintain a stable tear film.

Based on this concept, one predicts that deficiency or alteration of any of these elements involved in such neuroanatomic integration can lead to an unstable tear film, a hallmark of various forms of dry eye.² Therefore, investigation into dysfunction of this neuroanatomic integration is the first step toward better understanding of the pathogenesis of various ocular surface disorders, and is a prerequisite before any ocular surface reconstruction.

According to the resultant epithelial phenotype defined by impression cytology ³, all severe ocular surface diseases can be classified to express one of the two major types of ocular surface failure. The first type is squamous metaplasia (Fig. 3) in which a normal nonkeratinized ocular surface epithelium transforms into a skin-like keratinized epithelium.³ Because of skin-like epithelial differentiation (skin-like), the ocular surface with squamous metaplasia becomes nonwettable, a hallmark of various dry eye disorders.² If the underlying insults are primarily derived from poor ocular surface defense, such squamous metaplasia can be reversed to a normal state when ocular surface defense is restored, indicating that epithelial progenitor cells (i.e., stem cells) of the ocular surface are not intrinsically altered. Squamous metaplasia can be caused by insults not originating from ocular surface defense. In xerophthalmia caused by systemic vitamin A deficiency,^4,5 squamous metaplasia can also be reversed by replacement of vitamin A. Nevertheless, squamous metaplasia can also be caused by various insults damaging epithelial progenitor cells, the basement membrane, and the underlying stroma leading to chronic inflammation and scarring as seen in various forms of cicatricial keratoconjunctivitis such as chemical burns, Stevens-Johnson syndrome, ocular pemphigoid, etc.^6,7 Except for early active ocular cicatricial pemphigoid, in which systemic immunosuppression can reverse squamous metaplasia, the rest cannot be reversed by conventional medical treatments. The irreversibility of such abnormal epithelial differentiation strongly implies that epithelial progenitor cells (i.e., stem cells [SC]), may have been intrinsically altered.

Before reconstruction, one should realize that keratinization in squamous metaplasia and vascularization in LSCD are two important pathologic mechanisms to prevent such corneal complications as epithelial defects, ulcers, or melt in eyes without an unstable tear film. Therefore, one should avoid performing conventional corneal transplantation to correct these two types of corneal failures if the ocular surface defense cannot first be restored. Because ocular surface reconstruction aims to restore a clear avascular cornea, which will require a stable tear film to maintain its health (see “Basic Concepts” section), it is of utmost important to restore a sound ocular surface defense. If not restored or unable to be restored, poor ocular surface defense in these eyes represent a contraindication for corneal surface reconstruction with epithelial SC transplantation.

Deficiencies in ocular surface defense can be recognized by history taking, and external and biomicroscopic examinations, and by the use of special tests such as dynamic tear function test, dye staining and impression cytology. Measures taken to correct severe aqueous tear deficiency dry eye include punctal occlusion and frequent application of autologous serum drops for mechanical microtrauma caused by lid margin and lash abnormalities such as trichiasis, entropion, or meibomian gland orifice metaplasia, which can be corrected by high oxygen permeability (Dk) contact lens, scleral contact lens, or appropriate plastic surgeries including mucous membrane graft. Symblepharon that causes obliteration of tear meniscus, misdirected lashes, inability of adequate blinking and closure, and motility restriction should also be corrected by fornix reconstruction before corneal surface reconstruction. Exposure problems may be corrected by Botox-induced ptosis, high DK contact lens, scleral lens, or tarsorrhaphy.

The state and severity of LSCD can be graded as partial or total. In partial LSCD, a portion of the limbal SC remains intact. In partial or total LSCD, if the central cornea still preserves a normal corneal epithelial phenotype and satisfactory vision, treatments should be directed to maintaining the remaining corneal epithelium and to activating the remaining limbal SC. Besides bandage contact lens or scleral lens to shield against continuous attrition, one new way of expanding remaining limbal or conjunctival epithelial SC in vivo is to transplant preserved amniotic membrane to restore stromal environment that has been destroyed in diseases mentioned in Table 1.

Amniotic membrane (i.e., the innermost layer of the placental membrane) consists of a simple epithelium, a thick basement membrane, and an avascular stroma. When appropriately procured and processed, cryopreserved amniotic membrane can be used as a surgical graft for substrate replacement and does not elicit immunologic reactions.¹⁹ A number of studies have shown that amniotic basement membrane facilitates epithelialization and maintains epithelial phenotype, while amniotic avascular stroma exerts anti-inflammatory, antiangiogenic and antiscarring effects [for reviews see Dua and Azuara-Blanco,²⁰ Kruse et al.,²¹ Sippel et al.,²² and Tseng and Tsubota²³), properties important for reconstruction of epithelium-lining tissues. For partial LSCD, debridement of conjunctivalized epithelium from the corneal surface²⁴ with or without additional amniotic membrane transplantation²⁵ is effective to restore the corneal surface. Because of its anti-inflammatory effect, amniotic membrane transplantation as a temporary patch (bandage) is also effective in restoring ocular surfaces during the acute attack of chemical burns²⁶ and Stevens-Johnson syndrome²⁷.