Historically, by the mid-19th century, the RPE was recognized as a distinct ocular tissue within the eye as a result of advances in histology and microscopy, as well as an appreciation of its embryonic origin.² Notable for its melanin content and resulting deep pigmentation, this property, coupled with the location of the RPE just posterior to the retina, at first suggested a primary function in absorption of stray light that had not been absorbed by the retina, which would otherwise result in degradation of the visual image caused by reflection and scattering within the eye. However, even 19th century clinical observations had already linked detachment of the neural retina from the RPE to loss of visual function, and suggested that the RPE possessed a more active and vital role in visual physiology. Subsequent clinical findings, combined with extensive in vitro cellular and molecular analyses, and in vivo animal model studies, have clearly identified the RPE as a physiologically complex tissue with a variety of functions that support the visual process. Enhanced understanding of the cellular and molecular basis of retinal disorders has identified RPE dysfunction as playing either a direct primary role, or an indirect secondary role through interaction with the NR, in ocular diseases such as age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR), retinitis pigmentosa (RP), Stargardt disease, Leber's congenital amaurosis, and congenital hyperplasia of the RPE (CHRPE), which are discussed further.

TABLE 1. Summary of Structural and Functional Specializations of the RPE

The embryonic origin of the RPE, along with the neural retina, can be traced back to formation of the neural tube during neurulation, with subsequent formation of the optic vesicles as outpouchings of the diencephalic region of the primitive brain. Invagination of the optic vesicles results in formation of a two-layered optic cup, with the RPE derived from the outer layer and the neural retina derived from the inner layer (Fig. 1). Thus, the RPE is a neuroepithelial derivative that becomes highly specialized in structure and function as an epithelial monolayer with unique properties.³ Because of the topological relationship of the nascent RPE and NR tissues during formation of the optic cup and optic vesicle, the RPE comes to lie adjacent and closely apposed to the NR, but with these two layers facing each other in an apical-to-apical fashion with respect to cellular polarity. This topographic relationship thus permits the intimate interaction of the apical microvilli of RPE cells with the apical outer segments of retinal rod and cone photoreceptors found in the mature retina (Figs. 2 and 3). On a gross level, the orientation of the RPE is such that its basal epithelial surface is oriented toward the outside of the eye, whereas the apical surface faces inward toward the vitreous chamber. Although intimately associated, the RPE and NR do not truly fuse to form a single coherent tissue, and although the original lumen of the optic vesicle is greatly reduced, this potential space between their apical surfaces persists as the intraretinal space (or subretinal space if expanded experimentally, surgically, or pathologically). As a consequence of the persistence of this potential space, retinal detachment may result from traumatic injury, with subsequent loss of visual function unless surgical re-attachment is made. However, the RPE and NR nevertheless normally remain intimately associated through RPE microvilli-NR-outer segment interdigitation, as well as by the presence of a specialized extracellular matrix known as the interphotoreceptor matrix.⁴

The focus of this review is the RPE proper, i.e., that portion of the RPE in association with the NR. It should be noted that the optic cup is double-layered throughout its extent to its most anterior margin, and that specializa- tions of this anterior margin give rise, through interaction with surrounding mesenchymal tissues, to the ciliary body and iris. Thus, the RPE also makes a contribution to these structures as the RPE of the ciliary body and its processes, as well as the RPE of the iris, with their own unique secretory and contractile properties.⁵

Proper differentiation of the RPE from the outer layer of the optic cup is dependent on signals received from surrounding tissues, including both the embryonic surface ectoderm as well as the loose extraocular mesenchymal tissue that fills the space between the presumptive RPE and the ectoderm. One of the specific signals that triggers this differentiation is the growth factor activin, a member of the TGFβ family.⁶ Such signals activate specific changes in gene expression, and advances in our understanding of the genetics of ocular development and disease have led to the identification of several genes that are required for normal development of the RPE as well as a number of human mutations that are now known to be associated with congenital anomalies of the RPE. For example, mutations of the gene encoding microphthalmia-associated transcription factor (MITF) result in forms of Waardenburg syndrome and Tietz syndrome, characterized by hypopigmentation and deafness. Although a variety of isoforms of MITF occur in a number of tissue types, MITF-A is particularly associated with the RPE.⁷ Another transcription factor controlling RPE differentiation is Otx2.⁸ MITF and Otx2 both appear to be required for maintenance of several functions of RPE cells, including proliferation, differentiation, and survival. Recent research has also identified several potential regulatory and patterning genes that establish the RPE phenotype, although these also affect additional aspects of ocular development including the NR, lens, and cornea. These include Pax2 and Pax6, in whose absence the external layer of the optic cup tissues develop into neural retina rather than RPE, or when overexpressed can induce neighboring tissues to develop RPE-like properties.⁹ Thus, differentiation of the RPE, as with other specific tissues, results from a complex interplay of genetic regulation and signaling pathways whose correct balance is required for proper embryonic development.

Some abnormalities of the RPE, while themselves sometimes relatively benign and not necessarily presenting an immediate threat to visual function, may nevertheless reflect other systemic problems. For example, congenital hyperplasia of the RPE (CHRPE) is recognized on fundus examination as a flat hyperpigmented region of the retina. Although isolated nonmalignant hamartomas of the RPE may occur, with little apparent effect on vision,¹⁰ it is important to distinguish such a finding from a choroidal melanoma. Furthermore, CHRPE has been associated as part of a syndrome including familial adenomatous polyposis (FAP), resulting from a mutation in the adenomatous polyposis coli (APC) gene. Although generally thought to represent a benign RPE hyperplasia with little effect on the adjacent retina, in this case CHRPE is associated with FAP and the extensive formation of colon polyps usually progressing to colon cancer.¹¹ Furthermore, recent studies have indicated that CHRPE itself may progress to adenocarcinoma.^12,13 Given this and the further association of altered RPE pigmentation with a variety of ocular diseases as discussed, the RPE can serve as an accessible sentinel for detection of ocular and systemic diseases, which may be further distinguished after ophthalmoscopic examination with fluorescein angiography and other diagnostic tests.¹⁴

The histological appearance of the mature RPE proper (that associated with the NR) is of a simple cuboidal polarized epithelium.¹⁵ When viewed en face, as seen in an explanted intact sheet of RPE, the cells generally appear as tightly adherent cells with hexagonal packing. RPE cells possess a characteristic cytological appearance and organelle distribution (Fig. 4). In RPE cells, mitochondria are located basally, beneath the nucleus, and close to the basal infoldings of the plasma membrane. The cells contain numerous catalase-containing microperoxisomes that function in the conversion of hydrogen peroxide to water. The RPE cell cytoplasm contains mainly smooth, and relatively little rough, endoplasmic reticulum, a characteristic of cells actively involved in lipid metabolism.¹⁵ RPE cells possess a Golgi complex, an organelle in which newly synthesized molecules are sorted, modified, and targeted to appropriate sites in the cell, a function critical for maintenance of RPE cell polarity. The Golgi complex of RPE cells is small and often scarcely distinguishable from the other tubules and vesicles of the endoplasmic reticulum. Lipid droplets (homogeneous-appearing spheres 0.5 to 1 μm in diameter with no limiting membrane) are seen rarely in primate pigment epithelial cells but are common in amphibian and rat retinas, where they have been shown to be a normal site of vitamin A storage. There are approximately 5 million RPE cells in the human eye, and during development the density of pigment epithelial cells increases steadily in the macular area, gradually reaching a stable level 6 months after birth. In contrast, near the ora serrata, cell density starts at high levels and decreases rapidly through the first postnatal year and more gradually thereafter. Furthermore, there is some concomitant variation in the dimensions of RPE cells depending on the location in the eye, and further variation may occur with aging.^16,17 In the macular region of the adult eye the cells are tall (14–16 μm) and narrow (10–14 μm), whereas toward the periphery they become significantly flatter and wider, such that at the ora serrata RPE cells may be 60-μm-wide (Fig. 5). After age 60, RPE cells throughout most of the retina become shorter, broader, and generally demonstrate a more variable morphology, with macular RPE cells increasing in height with advancing age. However, after age 90, when there has been cell loss, even macular RPE cells become wider and flatter. While these events represent generally slow responses to age-related intrinsic and extrinsic changes, RPE cells both in vitro and in vivo can exhibit rapid and wide-ranging phenotypic variation including epithelial-mesenchymal transformation and transdifferentiation.^18,19 Such a capacity for plasticity may represent a necessary and beneficial ability to respond to disease and injury, and indeed differentiated mammalian RPE cells remain capable of cell division and wound healing.²⁰ However, there is limited capacity for extensive repair, such as after damage of the deeper layers of Bruch's membrane, which often leads to scarring and lack of normal re-pigmentation.²¹ Furthermore, the normal program of RPE wound healing may be subverted by events such as exposure to vitreous and serum after rhegmatogenous retinal detachment, possibly resulting in the aberrant wound healing response and subsequent scarring seen in PVR.^22,23 Thus, further elucidation of the molecular mechanisms underlying the phenotypic variability of RPE cells may provide important insights leading to therapeutic interventions in such circumstances.

As already discussed, the topography of retinal development results in the intimate association of RPE apical microvilli with rod and cone photoreceptor outer segments across the intraretinal space (Figs. 4 and 6). These are bound together by the interphotoreceptor matrix (IPM), a network of proteins and proteoglycans containing a variety of enzymes, growth factors, carrier proteins, and other constituents.⁴ A number of constituents of this matrix have been localized in three distinct patterns, such as those that demonstrate rod- and cone-specific localization, those with an apical-to-basal heterogeneity, and others with a more homogeneous distribution. When there is a neurosensory retinal detachment, the potential interphotoreceptor space expands as fluid accumulates to form what is clinically referred to as the subretinal space, and the photoreceptors, now deprived of their supportive RPE functions, will degenerate if re-attachment is not effective. To maintain normal retinal attachment, RPE cells develop long slender apical microvilli of 5 to 7μm in length, forming sheaths that appear to participate in phagocytosis of outer segments. Villous processes surrounding rods contain smooth endoplasmic reticulum, ribosomes, melanin granules, and actin filaments. Villous processes that surround extrafoveal cones are usually devoid of intracellular organelles except for pigment granules. Despite their intimate relationship, no junctional attachments have been found between the RPE apical processes and the photoreceptor outer segments, although several molecular mechanisms forming the basis of this recognition and adhesion have been proposed, as discussed later.

As previously mentioned, the tight junctions of the RPE contribute to formation of the blood–retinal barrier and also help to establish the compartmentalization required to maintain the unique microenvironment of the IPM. In part this involves control of the ionic milieu required for phototransduction and its component dark current in photoreceptors. The apical membrane contains ion channels and transport molecules involved in fluid movement from the retina to the choroid.³⁰ As already alluded to, unlike most transporting epithelia, which have Na⁺-K⁺ ATPase located in the basolateral plasma membrane near the energy-producing mitochondria, the RPE has this enzyme in the apical membrane. Na⁺-K⁺ ATPase helps regulate extracellular potassium levels and fluid fluxes that contribute to the adhesion of the neurosensory retina. RPE cells make an important contribution to this via regulation of K⁺ transport mediated by the KIR family of inwardly-rectifying K⁺ channel proteins, specific isoforms of which are expressed in the RPE and are localized along the cell surface membranes of the apical microvilli.³¹ Another important apical specialization of RPE cells is the localization of Na⁺K⁺/Cl^- cotransport proteins that, in concert with additional basal Cl^- channels (see later), regulate the chloride flux that appears to be the major determinant of net fluid transport across the RPE.³⁰ This net vectorial transport of fluid from retina to choroid helps to maintain RPE/NR adhesion, and water-conducting aquaphorin membrane channels have been identified on the apical surface of RPE cells that facilitate this process.³² Additionally, apical localization of the monocarboxylate transporter MCT1 isoform may help regulate pH and osmolarity in the intraretinal space (again, see later for a basal membrane counterpart).³³ Finally, another important specialization of the apical membranes of RPE cells is the presence of receptors that mediate binding and phagocytosis of shed photoreceptor outer segment membranes, and transport of vitamin A metabolites in the visual cycle, which is described further.

The epithelial integrity of the RPE, as with all epithelial tissues, is critically dependent on lateral cell-cell interactions mediated by a variety of specialized intercellular junctions. The lateral cell membranes of the RPE have relatively flat surfaces, in contrast to the highly convoluted apical and basal surfaces (Figs. 7 and 8). As in typical epithelial cells, the cell-cell junctions of RPE cells form a classical “junctional complex” along the lateral cell membranes, and are arranged in the apical to basal direction as: (1) tight junctions or zonula occludens; (2) adherens junctions or zonula adherens; and (3) desmosomes or macula adherens^34,35 (Figs. 4 and 9). However, the latter are not observed as prominently as in many other epithelia, and although desmosomes are observed in human RPE, there is some species-specificity of appearance.³⁶ In addition, a fourth type of cell–cell junction, the gap junction or communicating junction, is also found in RPE cells. While originally classified on the basis of their morphologically distinct electron microscopic appearance, the molecular composition of these cell junctions has now been well characterized. Furthermore, these junctions are recognized to function as more than passive intercellular glues that bind RPE cells together, but in addition they function as loci of bi-directional signaling, integrating the cytoskeleton, intracellular metabolism and gene expression with the extracellular milieu (Figs. 9 and 10).

Tight junctions form a nearly impermeable seal between RPE cells, preventing unregulated intercellular diffusion between RPE cells, and forming the basis for the blood–retinal barrier between the retina and choroidal circulation. Tight junctions are composed of transmembrane proteins called occludins, in association with submembranous intracellular proteins such as ZO-1. A number of isoforms of occludins occur in RPE cells, which are subject to developmental and physiological regulation, and their properties establish the extent of transepithelial electrical resistance of the RPE and selectivity of diffusion between the cel1s.^27,37 Adherens junctions form very strong intercellular linkages between adjacent cells and are composed of transmembrane proteins of the cadherin family.^19,38–41 The cadherins in turn are bound to submembrane intracellular proteins called catenins, which through a variety of other proteins are ultimately linked to the actin microfilament cytoskeleton. Desmosomes are rivet-like attachments between cells that consist of transmembrane proteins that are also members of the cadherin family, although these are distinct from the “classical” cadherins that form adherens junctions, and they preferentially associate with cytoskeletal elements of the intermediate filament family such as cytokeratins and vimentin. Finally, gap junctions function to provide limited cytoplasmic continuity between adjacent cells, and are composed of hexameric arrays of proteins called connexins, with each individual hexamer called a connexon. Large plaques of multiple connexons link together across adjacent cell surfaces, forming the gap junctions that provide physiologically regulated channels between cells that provide electrical coupling of the cells, as well as allow passage of calcium, hydrogen ions, cyclic adenosine monophosphate, and other small molecules of less than 1000 daltons in size from one cell to another.⁴²

A hallmark of epithelial cells is the location at their basal surface of a supporting structure composed of organized extracellular matrix called a basement membrane, whose molecular constituents include collagen, laminin, entactin, and heparan sulfate proteoglycan^15,35 (Figs. 3, 5, and 6). The RPE is indeed separated from the underlying choriocapillaris by a thick extracellular matrix called Bruch's membrane, although the latter is more complex than a simple basement membrane. Bruch's membrane contains five distinct layers, of which the outermost is the true basement membrane of the RPE cells.⁴³ Adhesion between the basal surface of the RPE and its basement membrane is stronger than that between the apical membrane and the outer segments of the photoreceptors, hence the resultant detachments that preferentially occur at the RPE/NR interface after traumatic injury. The molecular basis of RPE adhesion to its underlying matrix has been the subject of investigation indicating that cell-matrix adhesion proteins called integrins mediate this process both in vitro⁴⁴ and on Bruch's membrane.⁴⁵ Integrins are heterodimeric transmembrane proteins that form a bridge linking vinculin, talin and fodrin and other components to the actin cytoskeleton intracellularly, and to matrix proteins such as collagen, laminin, and fibronectin outside the cell.³⁵ Together, these components form junctional structures called focal adhesions that are visible at the basal surface of RPE cells^35,46 (Figs. 9 and 11). The adhesive interactions between the RPE and the underlying connective tissue constitute a major conduit for regulation of cell function and maintenance of phenotype.^18,19

Similar to the outermost layer, the innermost layer of Bruch's membrane is also a true basement membrane, in this case associated with the endothelial cells of the choriocapillaris. Between these layers is a tripartite structure composed of a central layer rich in elastic fibers, surrounded on either side by a thick collagenous layer. It is within the outer collagenous layer, underneath the RPE basement membrane, where drusen form. Drusen are lipid-rich deposits whose accumulation is associated with the aging process and that may presage AMD. Additional age-related changes in Bruch's membrane have also been described that may deleteriously affect exchange of materials between the choroid and the retina and that thus may lead to retinal malfunction.⁴⁷ The surface of the basal membrane of RPE cells is characterized by numerous invaginations resulting in a greatly increased surface area that is indicative of active absorption and secretion, and which is involved in regulation of transport and exchange across Bruch's membrane and with the underlying choriocapillaris (Figs. 7 and 12). A variety of channels and receptor molecules for passage and uptake of essential nutrients have been localized here in the basal RPE membrane, including the lactate transport protein MCT3³³ and a selective chloride channel.³⁰

Insofar as the phototransduction process, by which light energy is converted into neuronal signaling, occurs in the neural retina, the details of that process are covered elsewhere in this series. However, there is a critical role for the RPE in maintenance of this process that bears discussion here. The light absorbing property of photoreceptor pigments such as rhodopsin is dependent on the presence of the vitamin A-derived ligand 11-cis-retinal. After light absorption, photoisomerization of 11-cis-retinal to all-trans-retinol occurs, however, the enzymes required for the re-conversion of all-trans-retinol to 11-cis-retinal are localized in the RPE, so that this transformation requires shuttling of these products between photoreceptors and the RPE in a process known as the visual cycle.^48,49 RPE cells also concentrate retinoids from the circulation through specific transport properties (Fig. 13). Transportation of retinoids from photoreceptors to RPE is mediated by interphotoreceptor retinoid binding protein (IRBP), a major protein of the interphotorecptor space.^50,51 Once endocytosed by the RPE, re-isomerization occurs before transport back to the neural retina. There still remains much to be learned regarding details of the mechanisms underlying aspects of the RPE cell's role in the visual cycle of retinoid accumulation and processing. Recently, however, additional important insights into the role of the RPE in the visual cycle process have been gained by elucidation of the role of the RPE65 protein. RPE65 was first identified as an RPE-specific protein following screening with libraries of anti-RPE monoclonal antibodies.⁵² RPE65 was subsequently identified as the product of the human gene causing Leber's congenital amaurosis (LCA), which is characterized by retinal degeneration in childhood.⁵³ This was the first human genetic defect to be clearly associated with retinal degeneration as a result of a primary RPE defect. A mechanistic explanation for this connection, underscoring the critical role of the RPE in the visual cycle, was the identification of RPE65 as a specific binding protein for all-trans-retinyl esters.⁵⁴

RPE cells play a critical role in the process of turnover and renewal of shed photoreceptor outer segments (Figs. 14 and 15). The amount of material processed by the RPE is quite prodigious, and classic experiments identified both the diurnal nature of the process, and estimated that the total amount of photoreceptor membrane material processed per day may be as much as four times the surface area of the RPE cell membrane itself.^55–57 The phagocytic process occurs through engulfment by the apical membrane of the RPE, and although the RPE is capable of slow, nonspecific phagocytosis of a diversity of large and small particles, it is the daily, specific phagocytosis of photoreceptor outer segment disks that constitutes one of the most important functions of RPE cells.⁵⁸ If the phagocytic capacity of the RPE is impaired, the photoreceptor cells are unable to renew the outer segments, and as a consequence the photoreceptors degenerate and die. Once a phagosome has formed following internalization, fusion occurs with lysosomes, and if lysosomal proteases are inhibited, the RPE rapidly becomes engorged with undegraded phagosomes.⁵⁹ The phagocytic load, that is, the number of photoreceptor disks shed per day per RPE cell, was calculated by Young to be 2000 disks per day in the parafovea, 3500 in the perifovea, and nearly 4000 in the periphery of the monkey eye. Phagocytosis by the RPE results in the complete turnover of the photoreceptor outer segments once every 8 to 13 days.⁶⁰ Although the specific receptors of the apical RPE membrane involved in this process remain to be definitively identified, a variety of cell-surface proteins have been experimentally implicated in recognition, binding, and endocytosis of photoreceptor outer segments by RPE cells, including receptors for glycoproteins containing high levels of the sugar mannose,⁶¹ and cell surface receptors such as CD36 and the specific integrin alpha(v)beta5.^62,63

RPE cells are brown in color because of the aforementioned melanosomes that are concentrated in the apical portion of the cell. Although the number of melanin granules per cell is the same in macular RPE cells as in equatorial RPE cells, the macular cells are taller and narrower, and the layer of melanin is therefore denser in this region of the fundus. This produces the darker color of the macula, which is further accentuated by the presence of macular pigment in the NR. Although pigmentation of RPE cells was originally considered to function in absorption of stray light, more recent analyses have indicated several additional functions. These include protection against oxidative stress and bindingand/or inactivation of toxic substances.⁶⁴ Indeed, evidence suggests that melanosomes may play an active role in aspects of RPE metabolism, and may interact with lysosomes in the clearance of bound compounds⁶⁵ (Figs. 16 and 17). Melanogenesis of RPE cells occurs early in development, and RPE cells are the first cells of the body to become pigmented. The aging RPE gradually assumes a more golden hue because of the accumulation of lipofuscin pigment granules in the perinuclear and basal cytoplasm (see later). Lipofuchsin has long been thought to accumulate in RPE cells as a by-product of processing in lysosomes, membrane-bound organelles whose basic function is the intracellular degradation via acid hydrolases of high-molecular-weight compounds to low-molecular-weight products.³⁵ RPE lysosomes vary considerably in size, from small primary lysosomes to bodies as large as the nucleus, such as secondary lysosomes containing many melanosomes. RPE lysosomes contain enzymes capable of degrading most types of complex biological macromolecules, including nucleic acids, proteins, complex carbohydrates, and lipids.⁶⁶

Lipofuscin granules are a subset of secondary lysosomes (or residual bodies), defined by their emission of a yellow fluorescence in response to ultraviolet stimulation. In unstained RPE tissues lipofuchsin granules can be distinguished by their lighter hue from melanin granules that accumulate throughout life. In adult RPE the category of lysosomes occupying the greatest area in the cells is the complement of lipofuscin granules, and these gradually accumulate, beginning at the basal aspect of the cells and gradually accumulating to mingle among melanosomes more apically.^66,67 Evidence suggests that RPE lipofuscin granules represent residual bodies of the lysosomal system, containing material derived primarily from phagocytosed photoreceptor outer segments. Until recently, the process by which RPE cells form lipofuchsin has been poorly understood, but the underlying biochemical process has now become clearer. It appears that two all-trans retinals combine with phosphatidylethanolamine in photoreceptor outer segments, and this adduct is then taken up by the RPE, and converted to a stable form called A2E (pyridinium bisretinoid), which accumulates in and is toxic to RPE.^68,69 While lipofuchsin is found in a variety of cell types, the lipofuchsin pathway is best understood in RPE, and caution must be exercised in extrapolating this process to other tissues.⁷⁰

Age-related macular degeneration (AMD) is the leading cause of blindness among adults. Although the specific causes of AMD remain unknown, these include a combination of intrinsic (i.e., genetic predisposition) and extrinsic (i.e., environmental insult such as toxic and/or photooxidative damage) factors that have their primary impact on the RPE.⁷¹ AMD is associated in its early phases with the buildup of incompletely metabolized waste products in association with the RPE, both intracellularly (i.e., lipofuchsin) (Fig. 17) and extracellularly (i.e., drusen) (Figs. 18 and 19). Subsequent malfunction of the RPE proper, and/or Bruch's membrane, lead to the progression of AMD from its “dry” state with damage to the RPE and neural retina, wherein the focus of the lesion remains at the RPE/neural retina interface, to the “wet” state wherein signals that possibly originate with the RPE result in abnormal responses in surrounding tissues resulting in neovascularization in the choriocapillaris.⁷² Evidence to support the “toxic accumulation” hypothesis has come from studies of Stargardt's disease, a form of juvenile macular degeneration, whereby a primary defect of lipid metabolism in the neural retina leads to accumulation of toxic products following their uptake by the RPE, whose failure then subsequently leads to photoreceptor loss.⁷³

Proliferative vitreoretinopathy (PVR) is another significant ocular disorder of unknown etiology wherein the RPE is implicated. PVR is the major complication resulting from retinal detachment that limits the success of surgery to re-attach the neural retina and RPE, and may occur in up to 10% of all rhegmatogenous retinal detachments.²³ PVR is characterized by aberrant wound healing, after retinal tearing, as cells, including RPE cells and possible astrocytes and fibroblasts as well, proliferate at the vitreal-retinal interface (and sometimes in the subretinal space) leading to scarring and generation of tractional forces that may re-detach the retina. Among the risk factors associated with onset of PVR are the presence of retinal tears, a prolonged period of detachment, vitreal damage, and damage to the RPE with subsequent compromise of the blood–ocular barrier and displacement of RPE cells into the vitreous cavity.⁷⁴ Although specific mechanisms remain to be elucidated, it is likely that PVR results in part from alterations of RPE phenotype in response to growth factors and extracellular matrix components of the vitreous and/or serum encountered as a result of the breakdown of normal tissue compartments of the eye.^22,23

In addition to tissue engineering from the standpoint of cellular replacement, because the underlying matrix has been implicated in RPE function and disease, additional approaches have targeted the substrate as a means to influence behavior of endogenous cells or to encourage success of cell transplants. Artificial biodegradable polymers such as poly-L-lactic acid (PLLA) and poly-dl-lactic-co-glycolic acid (PLGA) have been tested as suitable substrates that could later be resorbed.^80,81 It should be kept in mind that the RPE epithelium is continuous over the anterior specializations of the eye, including the ciliary body and the iris, as well as the intervening pars caeca. These more anterior specializations of the RPE have been discussed as a potential source of autologous cells available for transplantation.⁵

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