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array:24 [ "pii" => "S2173579421001626" "issn" => "21735794" "doi" => "10.1016/j.oftale.2021.04.003" "estado" => "S300" "fechaPublicacion" => "2021-11-01" "aid" => "1936" "copyright" => "Sociedad Española de Oftalmología" "copyrightAnyo" => "2021" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Arch Soc Esp Oftalmol. 2021;96 Supl 1:15-37" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S036566912100188X" "issn" => "03656691" "doi" => "10.1016/j.oftal.2021.04.003" "estado" => "S300" "fechaPublicacion" => "2021-11-01" "aid" => "1936" "copyright" => "Sociedad Española de Oftalmología" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Arch Soc Esp Oftalmol. 2021;96 Supl 1:15-37" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Revisión</span>" "titulo" => "Aniridia y superficie ocular: problemas y soluciones médicas y quirúrgicas" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "15" "paginaFinal" => "37" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Aniridia and the ocular surface: medical and surgical problems and solutions" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figura 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2552 "Ancho" => 2167 "Tamanyo" => 782132 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> LC escleral vista por OCT-SA. Se aprecia la distancia de respeto sobre el epitelio corneal. <span class="elsevierStyleBold">B.</span> La lente se apoya sobre la conjuntiva bulbar.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Álvarez de Toledo Elizalde, S. López García, J.M. Benítez del Castillo, J. Durán de la Colina, O. Gris Castejón, J. Celis Sánchez, J.M. Herreras Cantalapiedra" "autores" => array:7 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Álvarez de Toledo Elizalde" ] 1 => array:2 [ "nombre" => "S." "apellidos" => "López García" ] 2 => array:2 [ "nombre" => "J.M." "apellidos" => "Benítez del Castillo" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Durán de la Colina" ] 4 => array:2 [ "nombre" => "O." "apellidos" => "Gris Castejón" ] 5 => array:2 [ "nombre" => "J." "apellidos" => "Celis Sánchez" ] 6 => array:2 [ "nombre" => "J.M." "apellidos" => "Herreras Cantalapiedra" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173579421001626" "doi" => "10.1016/j.oftale.2021.04.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579421001626?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S036566912100188X?idApp=UINPBA00004N" "url" => "/03656691/00000096000000S1/v1_202111190822/S036566912100188X/v1_202111190822/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2173579421000773" "issn" => "21735794" "doi" => "10.1016/j.oftale.2020.12.008" "estado" => "S300" "fechaPublicacion" => "2021-11-01" "aid" => "1912" "copyright" => "Sociedad Española de Oftalmología" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Arch Soc Esp Oftalmol. 2021;96 Supl 1:38-51" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Crystalline lens alterations in congenital aniridia" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "38" "paginaFinal" => "51" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Alteraciones del cristalino en la aniridia congénita" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0070" "etiqueta" => "Fig. 14" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr14.jpeg" "Alto" => 2086 "Ancho" => 3333 "Tamanyo" => 524176 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0070" "detalle" => "Fig. 1" "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Evolution of the patient in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> with development of opacities, while the subluxation does not seem to increase significantly. Top: BE appearance at the age of 21 years; cortical opacities have appeared in the inferior sectors. Middle row: the LE at age 27, with progression of cortical opacities and development of opalescent nuclear cataract. Bottom: the RE at age 35, with cortical cataract, more diffuse but nucleus still transparent; the densest opacity coincides with the area of greatest subluxation, as revealed by retroillumination. Bottom right: the LE with diaphragm IOL implantation.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "F. D’Oria, R. Barraquer, J.L. Alio" "autores" => array:3 [ 0 => array:2 [ "nombre" => "F." "apellidos" => "D’Oria" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Barraquer" ] 2 => array:2 [ "nombre" => "J.L." "apellidos" => "Alio" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0365669121000289" "doi" => "10.1016/j.oftal.2020.12.016" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365669121000289?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579421000773?idApp=UINPBA00004N" "url" => "/21735794/00000096000000S1/v1_202111240624/S2173579421000773/v1_202111240624/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2173579421001559" "issn" => "21735794" "doi" => "10.1016/j.oftale.2021.02.002" "estado" => "S300" "fechaPublicacion" => "2021-11-01" "aid" => "1929" "copyright" => "The Author(s)" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Arch Soc Esp Oftalmol. 2021;96 Supl 1:4-14" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Genetics and epidemiology of aniridia: Updated guidelines for genetic study" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "4" "paginaFinal" => "14" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Genética y epidemiología de la aniridia congénita: actualización de buenas prácticas para el diagnóstico genético" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2116 "Ancho" => 2925 "Tamanyo" => 301731 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Representation of the <span class="elsevierStyleItalic">PAX6</span> locus on chromosomal region 11p13, <span class="elsevierStyleItalic">PAX6</span> gene and its regulatory elements. A) The downstream regulatory region (DDR), located in the introns of the neighboring gene <span class="elsevierStyleItalic">ELP4,</span> is represented with the main regulatory elements that have been involved in aniridia, SIMO and E180B (in red). In addition, the breakpoints of the previously detected 11p13 deletions that have allowed us to determine the critical region for the transcriptional regulation of <span class="elsevierStyleItalic">PAX6</span> are represented. Dashed blue and red lines indicate the 244 Kb region, defined by Ansari et al. and then narrowed to 18 Kb by Plaisancié et al. B) The <span class="elsevierStyleItalic">PAX6</span> gene and protein are depicted. In the upper part, the exon structure is depicted with the 14 exons of the <span class="elsevierStyleItalic">PAX6</span> gene, including non-coding regions (in gray) and the different coding regions, where the colors indicate the encoded protein domain, and the promoters (P0, P1 and P α). In the lower part of the image, the structure and the different functional domains of the 2 main protein isoforms, the canonical form and the isoform 5a of 422 and 436 amino acids, respectively, are represented. HD: homeodomain; PD: paired domain; PST: proline/serine/threonine-rich region.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "F. Blanco-Kelly, M. Tarilonte, M. Villamar, A. Damián, A. Tamayo, M.A. Moreno-Pelayo, C. Ayuso, M. Cortón" "autores" => array:8 [ 0 => array:2 [ "nombre" => "F." "apellidos" => "Blanco-Kelly" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Tarilonte" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Villamar" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Damián" ] 4 => array:2 [ "nombre" => "A." "apellidos" => "Tamayo" ] 5 => array:2 [ "nombre" => "M.A." "apellidos" => "Moreno-Pelayo" ] 6 => array:2 [ "nombre" => "C." "apellidos" => "Ayuso" ] 7 => array:2 [ "nombre" => "M." "apellidos" => "Cortón" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0365669121001246" "doi" => "10.1016/j.oftal.2021.02.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365669121001246?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579421001559?idApp=UINPBA00004N" "url" => "/21735794/00000096000000S1/v1_202111240624/S2173579421001559/v1_202111240624/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Aniridia and the ocular surface: Medical and surgical problems and solutions" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "15" "paginaFinal" => "37" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J. Álvarez de Toledo Elizalde, S. López García, J.M. Benítez del Castillo, J. Durán de la Colina, O. Gris Castejón, J. Celis Sánchez, J.M. Herreras Cantalapiedra" "autores" => array:7 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Álvarez de Toledo Elizalde" "email" => array:1 [ 0 => "jae24565@telefonica.net" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "S." "apellidos" => "López García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J.M." "apellidos" => "Benítez del Castillo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "J." "apellidos" => "Durán de la Colina" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "O." "apellidos" => "Gris Castejón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 5 => array:3 [ "nombre" => "J." "apellidos" => "Celis Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 6 => array:3 [ "nombre" => "J.M." "apellidos" => "Herreras Cantalapiedra" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "aff0035" ] ] ] ] "afiliaciones" => array:7 [ 0 => array:3 [ "entidad" => "Departamento de Segmento Anterior, Centro de Oftalmología Barraquer, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Cátedra de Oftalmología, Hospital Clínico San Carlos, Universidad Complutense, Clínica Rementería, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Cátedra de Oftalmología, Universidad del País Vasco, Instituto Clínico-Quirúrgico de Oftalmología, Bilbao, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Departamento de Córnea y Superficie Ocular, Instituto de Microcirugía Ocular de Barcelona (IMO), Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Unidad de Córnea y Superficie ocular, Hospital La Mancha-Centro, Alcázar de San Juan, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Instituto Universitario de Oftalmobiología Aplicada (IOBA) de la Universidad de Valladolid, Servicio de Oftalmología del Hospital Clínico Universitario de Valladolid, Valladolid, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Aniridia y superficie ocular: problemas y soluciones médicas y quirúrgicas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 598 "Ancho" => 900 "Tamanyo" => 77317 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Patient with congenital aniridia and complete limbic insufficiency of long evolution. Extensive conjunctivalization of the cornea is observed.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The ocular surface is one of the anatomo-functional ocular structures most affected in patients with congenital aniridia. The mutation in the <span class="elsevierStyleItalic">PAX6</span> gene causes a number of progressive cellular changes that affect the tear film and limbal homeostasis, with serious medium-term consequences on corneal transparency, developing in a significant percentage of cases the so-called keratopathy in congenital aniridia. This article describes the alterations that occur, their pathophysiological bases, the medical and surgical treatments that can be performed depending on the severity of each case, as well as the new fields that are opening up with the development and breakthroughs in regenerative medicine of the ocular surface.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Ocular surface alterations in congenital aniridia</span><p id="par0010" class="elsevierStylePara elsevierViewall">Aniridia-associated keratopathy (AAK) may affect up to 90% of patients. Clinical expressions are progressive, with irregular thickening of the peripheral corneal epithelium, superficial neovascularization, subepithelial fibrosis and stromal centripetally-progressing scarring. Patients suffer recurrent erosions, ulcers, tearing, chronic pain and decreased vision.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a> Along with glaucoma and cataract, AAK causes progressive loss of visual acuity and is the main source of non-visual symptoms, ranging in intensity from no or minimal occasional problems to continuous and disabling discomfort.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenic basis of keratopathy associated with aniridia</span><p id="par0015" class="elsevierStylePara elsevierViewall">AAK is considered a primary dysfunction of limbal epithelial stem cells (LSC), secondary to an alteration of the limbal microenvironment caused by <span class="elsevierStyleItalic">PAX6</span><a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a> mutation. The normal expression of <span class="elsevierStyleItalic">PAX6</span> is necessary for the correct development of the eye; controlling the processes of cell proliferation,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> differentiation, migration and apoptosis, and also playing an important role in the development of corneal innervation and in the contribution of neurotrophic factors.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">PAX6</span> regulates the expression of corneal cytokeratins (CK) such as CK-12 and CK-3, cytoskeleton proteins that form the intermediate filaments of epithelial cells. It is also essential for the expression of adhesion molecules such as desmoglein and α-β catenin, responsible for the maintenance of the cytoskeleton, the organization of microtubules and the capacity for cell adhesion and migration. In experimental models of congenital aniridia, a reduction in the levels of these proteins is observed which, together with CK-12 and CK-3 deficiency, causes fragility of the corneal epithelium.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,9–11</span></a> On the other hand, <span class="elsevierStyleItalic">PAX6</span> also regulates the expression of the MMP-9 metalloproteinase. The extracellular matrix undergoes a slow but continuous remodeling in which there is a balance between collagen production by keratocytes and its degradation by these metalloproteinases (MMP). In experimental models, MMP-9 deficiency produces fibrin accumulation and cellular infiltration that stimulates vascular proliferation and loss of corneal transparency. In summary, <span class="elsevierStyleItalic">PAX6</span> alteration generates a “chronic state of active scarring”, that accounts for the clinical manifestations<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Recently,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> the mutational status of the <span class="elsevierStyleItalic">PAX6</span> gene has been related to the severity of the clinical (phenotypic) manifestations. In cases of aniridia in which there is no detectable mutation in the <span class="elsevierStyleItalic">PAX6</span> gene or there is heterozygosity in the deletions of genes flanking the <span class="elsevierStyleItalic">PAX6</span> region (<span class="elsevierStyleItalic">DCDC1, DNAJC24, IMMP1L, and ELP4</span>), the degree of severity is lower (clear cornea, better visual acuity, almost normal subbasal nerve plexus density, discrete reduction of sensitivity and less increased corneal thickness. On the other hand, in those cases with demonstrable mutations of the <span class="elsevierStyleItalic">PAX6</span> gene correlated with a higher degree of keratopathy with visual impairment, advanced stages of keratopathy, marked reduction of the subbasal plexus and increased corneal dendritic cells. This study demonstrates a genotype/phenotype correlation.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical manifestations of aniridia keratopathy</span><p id="par0025" class="elsevierStylePara elsevierViewall">The natural course of AAK has several stages of progression. Signs usually begin after the first decade of life, although irregular thickening of the peripheral corneal epithelium can be observed from the age of three years.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> From the second decade onwards, peripheral epithelial changes that capture fluorescein appear, with the development of thin superficial neovessels that advance centripetally over the years (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), in some cases affecting the entire cornea. Corneal abnormalities become more pronounced with age. The most unfavourable cases develop subepithelial fibrosis and stromal scarring with a significant decrease in visual acuity. Clinically, pain, photophobia, red eye and the presence of corneal erosions are common.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">It is important to classify AAK in order to plan therapeutic management. Although there are different classifications,<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,16</span></a> we propose one based on signs or lesions, symptoms and severity of squamous metaplasia determined by impression cytology. According to this classification (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) four levels of severity can be distinguished: grade 0 or subclinical keratopathy, in which patients do not express corneal alterations or symptoms, but do express cytological alterations. Grade 1 or mild keratopathy, characterized by a peripheral <span class="elsevierStyleItalic">pannus of</span> less than 1 mm and alterations in fluorescein uptake, with occasional clinical signs of epiphora and epithelial defects. Grade 2 or moderate keratopathy, in which the vascular pannus, with or without subepithelial fibrosis, affects more than half of the cornea, but leaving the corneal center free. Lacrimal instability, photophobia and epiphora are relatively common and patients report two or more episodes of epithelial defects in the last six months. Finally, grade 3 or severe keratopathy, when <span class="elsevierStyleItalic">pannus</span> or stromal opacity affects the corneal center. In these patients, epiphora, red eye, lacrimal alterations and epithelial defects are common (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">In all patients with congenital aniridia, generalized corneal thickening can be documented and demonstrated with OCT or ultrasonic pachymetry. The average corneal thickness usually varies according to the series studied between 632 and 692 ± 75 μm.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> It is not known whether this is due to the presence of a high number of keratocytes or to an overproduction of corneal collagen.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Ocular dryness is also frequent in patients with aniridia. There is a marked relationship between the severity of the keratopathy and the lacrimal alteration. The instability of the ocular surface determines the appearance of an epitheliopathic dry eye that hinders a correct tear anchorage. The presence of a dysfunction of the Meibomian glands that produces an alteration of the lipid component is also relatively common. In these patients, at least initially, the aqueous component is not affected, as shown by the fact that the Schirmer's test is often normal. A decrease in <span class="elsevierStyleItalic">break up time</span> (BUT) and an increase in tear osmolarity are observed as keratopathy progresses, which induces an increase in inflammatory stress by increasing the levels of inflammatory cytokines TNF-7α, IL-1, IL-6 or matrix metalloproteases. The secondary alterations produced in the ocular surface will cause a series of changes in the epithelium (squamous metaplasia) that leads to an alteration in the goblet cell population, responsible for the damage of the mucous component of the tear that these patients often end up presenting.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,18–21</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis</span><p id="par0045" class="elsevierStylePara elsevierViewall">The diagnosis of AAK is fundamentally clinical and consists of evidencing the findings of the disease or of the instability of the tear film. Slit lamp examination is usually sufficient to reveal these changes at the corneal level.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Morphological or histochemical diagnostic techniques can also be of great help, especially in early stages of the disease or to assess the response to treatment. Impression cytology is used to evaluate the degree of corneal and conjunctival squamous metaplasia. This metaplasia is characterized by a continuous process of abnormal epithelial differentiation, common to various diseases affecting the ocular surface. Cytology allows the study of the most superficial epithelial cell layers in a minimally invasive way, respecting the morphology and spatial arrangement of the cells in the epithelium.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21–23</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Immunohistochemistry can also be used to study the epithelial phenotype. These techniques are rarely used in routine clinical practice and are generally limited to research studies. Corneal and conjunctival epithelium express different markers. Conjunctival epithelium expresses CK19, while corneal epithelial cells express CK3 and CK12. The “conjunctivalization” of the corneal epithelium is determined by the presence of goblet cells and/or epithelial cells expressing markers of conjunctival lineage. Along the same lines, goblet cell markers such as MUC5AC can be used to assess conjunctivalization of the cornea.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Medical treatment of keratopathy associated with aniridia</span><p id="par0060" class="elsevierStylePara elsevierViewall">Affection of the LSCs or the microenvironment surrounding them reduces or eliminates the proliferative capacity of the corneal epithelium. The LSCs are the only source of epithelial cells with a corneal phenotype, both for the physiological renewal of the cornea and for the repair of any defects on its surface. The inability to maintain a stable corneal epithelium promotes the presence of conjunctival epithelial cells in the cornea, which is the most characteristic finding of limbar insufficiency. As in other cases of limbal insufficiency, treatment requires the provision of progenitor cells or improvement of the surrounding microenvironment. Although considerable progress has been made in recent years in the understanding of the pathophysiological mechanisms of AAK, we still do not have an effective treatment as most therapeutic options provide only a symptomatic and temporary improvement.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The management of these patients will depend on the severity of the ocular involvement. General measures such as sun protection with glasses, avoiding drafts or measures aimed at humidifying the environment are important. In cases with corneal erosions or epithelial defects, they will be treated in the usual way depending on the case.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In asymptomatic or mildly affected patients (grades 0 and 1), treatment with preservative-free artificial tears is usually sufficient. Early treatment with tear substitutes can delay the corneal changes that occur in the development of this disease, improving clinical symptoms and slowing the process of squamous metaplasia. In these patients, in whom there is a dry eye with a marked epitheliopathic component, sodium hyaluronate artificial tears are particularly indicated. These, in addition to providing excellent moisturizing and lubricating properties, have a proven regenerative effect. It is also important to treat meibomian gland dysfunction by means of regular therapy, thermoexpression and intense pulsed light (IPL).</p><p id="par0075" class="elsevierStylePara elsevierViewall">In patients with moderate corneal involvement (grade 2), treatment with artificial tears is usually not sufficient. In these cases, therapy with autologous serum or other blood derivatives can be a useful therapeutic measure to improve the survival and expansion of LSCs. Autologous serum provides growth factors that improve proliferation, differentiation and migration of epithelial cells, having also a direct effect on mucin expression.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18,25</span></a> In patients with mild keratopathy, treatment with 20% autologous serum cycles has shown an objective and subjective clinical improvement, delaying the progression of the disease and reducing the frequency of corneal erosions.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Although it will be discussed in detail in another section, the use of scleral lenses is useful in many of these cases. Another option in these patients is to decrease neovascularization with topical bevacizumab.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In patients with more severe forms of keratopathy it will be necessary to resort to therapies such as amniotic membrane transplantation or the contribution of LSC by different techniques that will be discussed in other sections.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Investigational medical therapies</span><p id="par0080" class="elsevierStylePara elsevierViewall">Normally, people with aniridia have only one functional copy of the <span class="elsevierStyleItalic">PAX6</span> gene in each cell and not two as would be normal. The mutant cells cannot produce the amount of PAX6 protein as would be desirable for the eye. Recently a drug, Ataluren, used for Duchenne muscular dystrophy, is being tested to rescue the mutant cells and make them produce more protein. This drug is only useful in “mild” mutations, not when the whole gene is missing. Its mechanism of action allows the ribosomes to produce the PAX6 protein, ignoring the genetic mutation. It has been successfully tested in mice<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> and should be applied topically for the treatment of AAK, as its effect on the ocular surface is minimal by injection. There is currently a clinical trial underway in humans.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Contact lenses and congenital aniridia</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Contact lenses and limbic insufficiency</span><p id="par0085" class="elsevierStylePara elsevierViewall">In a detailed review, Rossen et al. concluded that, in a normal eye, contact lens (CL) damage to the limbus is multifactorial.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> These include preservative toxicity, mechanical trauma, dry eye, hypoxia and ocular surface inflammation.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">mechanical trauma</span> of the CL is due to the fact that, even with a well-fitted lens, friction of the lens on the limbus is unavoidable. A displacement of 0.1 to 0.4 mm is well tolerated and considered normal. Blinking causes these movements, in addition to pressure on the upper limbus which removes the tear lubrication under the lens and increases direct damage. Some types of CL can increase this effect: silicone LS, with curved profile, poor fit, etc. For the same reason, in the context of a <span class="elsevierStyleItalic">dry eye, the</span> effect of friction and pressure is increased, as well as poor oxygenation.</p><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Maintenance solutions</span> have been a matter of debate because of their toxic effects on the corneal surface. In addition to the toxic effect, they give rise to an <span class="elsevierStyleItalic">inflammatory response</span> that adds to the damage process, as well as the accompanying lacrimal changes, such as hyperosmolarity.</p><p id="par0100" class="elsevierStylePara elsevierViewall">As for <span class="elsevierStyleItalic">hypoxia</span>, its effects are greater in the limbus covered by the upper eyelid. This, together with the mechanical effect, explains why this area is the one that most tends to show limbic alterations in patients with CL. Predisposing factors have been suggested that would increase the risk of limbic insufficiency, including free-border disease, time of use of LCs, being female, type of eyelid (tension, racial, etc.).</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Potential contact lens applications</span><p id="par0105" class="elsevierStylePara elsevierViewall">In a recent long-term retrospective study, said authors found that treatment of keratopathy in association with congenital aniridia includes the use of artificial tears, autologous serum and scleral LCs.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> They also found that cases requiring advanced corneal surgeries are at higher risk of glaucoma progression.</p><p id="par0110" class="elsevierStylePara elsevierViewall">In addition, and leaving aside the limbus problem, the potential advantages of the use of LCs would include: regularization of the corneal surface, treatment of the dioptric defect, stabilization of the epithelium and the possibility of tinted LCs to improve photophobia and aesthetics.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Hydrogel or fluorosilicone LCs would be contraindicated for routine use. However, if the parameters are favourable, i.e., incipient epithelial lesion, good adaptation, absence of dry eye or free edge disease, their use limited to a few hours a day could be considered. In addition, preservation liquids should avoid toxicity as much as possible, and the use of peroxide is advisable. The state of the corneal epithelium should be closely monitored for any signs of limbal worsening. New CL can provide mechanisms to protect the cells of the niche, such as those that block the passage of UV rays.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Follow-up should include biomicroscopic study and impression cytology. In these cases, and in order to make an early detection, the criterion of finding goblet cells is not useful. This finding is observed in advanced cases and possibly difficult to reverse. The use of specific cytokeratin biomarkers would be more appropriate. Despite the simplicity and safety of this test, confocal microscopy is less invasive, although less sensitive.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Congenital aniridia can coexist with high refractive errors, which would always benefit from the use of CL. One of the potential benefits of the use of CL would be the reduction of the amplitude of the nystagmus.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> In cases of nystagmus due to other causes, different types of LCs have been used, with rigid gas permeable LCs being the most effective. Galileo systems have also been used to improve visual capacity (in glasses +25/+28 dioptres; in the CL −15/−20 dioptres). This could be a proposal if the nystagmus is well controlled and macular hypoplasia coexists.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Photophobia is another clinical feature of congenital aniridia. Tinted CL may improve this bothersome and often disabling symptom. The impact of photophobia on the quality of life of patients is often underestimated. It may be a bigger problem than low vision. When fitting tinted LCs, a tighter curve than usual is sought in order to reduce movement. This, however, would be inadvisable in these patients due to the greater aggression on the limbus.</p><p id="par0130" class="elsevierStylePara elsevierViewall">At present, and hopefully even more so in the near future, a tinted scleral lens can be customized.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> This would open up more possibilities for the indication of tinted LCs in these cases. Scleral LCs (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) may have applications in the treatment of patients with congenital aniridia. Their advantages comprise high visual quality, respect for the corneal surface and limbus, and the possibility of applying therapeutic substances. The first of these would facilitate a maximum degree of vision and reduction of nystagmus. Due to the design of these lenses and the way they adapt to the eye, the modifications on the corneal surface and limbus would be minimal. This makes them more suitable for use in cases with a compromised limbus. It is possible that future medical treatments may improve the evolution of epithelial damage. Applying them through scleral LCs would be a seemingly ideal route. Some therapies currently in use (autologous serum, plasma rich in growth factors [PRGF], etc.) could be applied with this method.</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Cases of advanced keratopathy deserve another consideration. In this stage, visual impairment, pain and photophobia coexist. In addition to the diffuse opacity located in the epithelium, there is an accompanying irregularity that contributes to reduced vision and worsening photophobia due to light scattering. Once again, it is necessary to insist on the serious deterioration that can be caused by this photophobia. The use of contact lenses could be a solution to this problem. In the case of patients who are going to undergo surgery (limbal cell transplant or keratoprosthesis), they could temporarily improve their condition before surgery, or even improve to levels that would allow them to delay surgery. Another advantage of these LCs would be the reduction of pain due to epithelial fragility. In short, by reducing pain and photophobia, the patient could experience a subjective improvement that compensates for the possible iatrogenic effect of wearing the CL.</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Surgical ocular surface treatment options in congenital aniridia</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">1. Allogeneic limbal transplantation</span><p id="par0140" class="elsevierStylePara elsevierViewall">In patients with congenital aniridia, limbal involvement is always bilateral and, therefore, it is not possible to use autotransplantation. With allogeneic keratolimbal transplantation, a fragment of donor tissue is provided that includes the stem cells in their natural environment. Although the donor can be a direct relative of the non-aniridia patient, we prefer to use tissue (if possible fresh) from a cadaver donor for two reasons. First, complete immunological compatibility is exceptional and, therefore, even if the tissue comes from a direct relative, the risk of rejection exists and systemic immunosuppression is also necessary. Secondly, using a cadaver donor allows us to transplant the limbus in the 360 of ° the recipient cornea (unlike living donor transplantation, which significantly limits the amount of tissue, and therefore stem cells, to be transplanted).</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Surgical technique</span><p id="par0145" class="elsevierStylePara elsevierViewall">The surgical technique and postoperative management of patients with this procedure has been previously described by the authors.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> To obtain donor tissue, a 360° lamellar dissection of ° the sclerocorneal limbus must be performed, including 1–2 mm of peripheral cornea and 4–5 mm of conjunctiva. Tissue can be obtained from a fresh whole eyeball kept at 4 °C in a humid chamber or from a sclerocorneal button kept in the usual preservation medium for corneas. Ideally, the tissue used for transplantation should preferably come from a young donor (less than 40–50 years old), should include preserved corneal epithelium and be obtained as soon as possible after death.</p><p id="par0150" class="elsevierStylePara elsevierViewall">The procedure can be performed under local or general anesthesia. In complete limbal insufficiency with conjunctivalization of the entire cornea, a 360° peritomy with conjunctival recession is performed. The important bleeding points are cauterized using bipolar diathermy with the minimum necessary power. The dissection plane is sought just under the fibrovascular conjunctival layer over the cornea and dissection is carefully performed in this plane, from the limbus towards the center of the cornea. In areas where blunt dissection with a dissector or corneal scissors is possible, this is preferable so as not to lose the dissection plane and avoid deepening the corneal stroma. Once the fibrovascular layer has been completely removed, the bleeding sites are cauterized again, so that the bed is prepared to receive the graft.</p><p id="par0155" class="elsevierStylePara elsevierViewall">If we have one donor eye we will transplant the complete sclerocorneal ring, including the limbus in the 360°. If we have two donor eyes we can transplant a complete limbus plus ¼ of the second one, in order to provide a greater number of stem cells. First, we cut the ring with the donor sclerocorneal limbus at any point to open it, and then place it along the circumference of the recipient limbal area, slightly posterior to the anatomical limbus. This leaves a space of uncovered circumference, which is covered with an appropriately sized graft taken from the quadrant of limbal tissue obtained from the second donor eye. The inner circumference of the graft is sutured with loose stitches of 10/0 monofilament nylon, taking care to bury the knots in the recipient cornea outside the graft. Next, the corresponding sutures are placed along the outer circumference of the graft to fix the donor sclera to the recipient sclera, using 8 or 9/0 resorbable suture, depending on surgeon preference. Finally, the donor conjunctiva is sutured to the recipient conjunctiva, also with resorbable suture. Finally, to promote epithelialization in the immediate postoperative period, a suture can be used joining the upper and lower palpebral margin on the outside, so as to reduce the trauma of blinking on the cornea during the first few days.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Post-operative treatment</span><p id="par0160" class="elsevierStylePara elsevierViewall">Standard postoperative treatment includes topical prophylactic steroids and antibiotics, as well as systemic immunosuppression. Topical treatment should not contain preservatives and may be supplemented with artificial tears and/or hematological derivative eyedrops. Since the sclerocorneal limbus is a vascularized tissue and has a high antigenic load, when an allogeneic limbal transplant is performed (either from a cadaver donor or a close relative), systemic immunosuppression should always be associated with the recipient. It is considered that the levels of immunosuppression required in limbal transplantation are similar to those used for renal transplantation. Various drugs have been used successfully to achieve this immunosuppression, including cyclosporine A, tacrolimus (FK506), azathioprine and mycophenolate mofetil, in addition to oral steroids that may be associated during the first weeks after transplantation. These immunosuppressants can be used alone or in combination, which allows the doses of each of them to be reduced. Different immunosuppression protocols have been shown to be effective<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35,36</span></a> and, in our opinion, the best approach is to involve an internist or rheumatologist with special interest in post-transplant immunosuppression. How long immunosuppressive treatment should be maintained after transplantation is still a matter of debate although, from a theoretical point of view, it should be indefinite or until side effects dictate otherwise.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Corneal epithelialization and intraocular pressure should be monitored regularly. An episode of graft rejection should be suspected when increased ocular congestion, vascular thickening around the transplant site, graft oedema, loss of epithelium and persistent epithelial defect over the corneal area corresponding to the rejection site are observed. Early diagnosis and vigorous treatment of a rejection episode are two basic factors for graft survival. Treatment consists of topical steroids and systemic steroids at high doses (either oral or intravenous methylprednisolone pulses). The dose of systemic immunosuppression should also be reviewed and increased if appropriate.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0170" class="elsevierStylePara elsevierViewall">Allogeneic limbal transplantation has good postoperative results in most patients when the kerato-limbic graft encompasses all 360° of the cornea. In our experience, sectorial grafts have worse outcomes and are currently only performed in other cases of limbal insufficiency where autografting from the healthy eye is possible. There are few studies published in the international literature on limbal transplantation in patients with aniridia. In the published results,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> which coincide with ours, as long as adequate systemic immunosuppression is used, a stable ocular surface is obtained in approximately 75% of cases with a keratolimbal transplant of 360° and with an average follow-up period of two to three years. The results during the first year are better, while extending the follow-up to more than three or four years shows that a significant proportion of limbal transplants fail and need to be retransplanted.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> It is believed that this new failure of the transplanted germ cells occurs as a consequence of a chronic inflammatory process, subclinical rejection episodes, or a combination of both.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Limbal transplant considerations</span><p id="par0175" class="elsevierStylePara elsevierViewall">As mentioned above, stem cell transplantation is the only treatment that can halt the progression of keratopathy (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>) in these patients, and the results with limbal transplantation are good in the short term when systemic immunosuppression is performed (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>). However, it should not be forgotten that systemic immunosuppression has potential side effects and that surgery can cause iatrogenesis in the patient. For these reasons we believe that the ophthalmologist should always consider the following three points before indicating limbal transplantation in a patient with aniridia: <ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0180" class="elsevierStylePara elsevierViewall">Confirm the diagnosis of complete limbic insufficiency. To transplant a donor limbus, the recipient limbus must be completely removed. If a limbal transplant is performed on a patient whose limbus was functioning (even partially) and the transplant fails, the final result will be worse than the preoperative state.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0185" class="elsevierStylePara elsevierViewall">To assess the improvement that the patient may experience with the surgery. Limbal transplantation aims to stabilize the corneal surface and this translates into an improvement in the patient's vision and discomfort. However, in patients with congenital aniridia, both the decrease in vision and the chronic discomfort they present have a multifactorial origin, so it is sometimes very difficult to predict what degree of visual improvement or clinical improvement can be achieved with limbal transplantation. If this point is not carefully assessed together with the patient before surgery, the postoperative outcome can be disappointing for both the patient and the ophthalmologist.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0190" class="elsevierStylePara elsevierViewall">Assess risk-benefit on an individual basis. In elderly patients or those with systemic pathology, immunosuppression may represent too high a risk. In these cases, the possibility of using other surgical techniques such as keratoprosthesis should be considered. In young patients, the risk of long-term immunosuppression and the high chance of late failure should be considered.</p></li></ul></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">However, once a decision has been made to perform a limbal transplant, surgery should not be delayed excessively. In the initial stages, in which the stroma remains transparent, limbal transplantation is sufficient to stabilize the corneal surface and improve vision. If surgery is delayed and stromal opacities appear, keratoplasty should be associated with limbal transplantation, which not only complicates the treatment but also worsens the end result.</p><p id="par0200" class="elsevierStylePara elsevierViewall">There is little literature evaluating the long-term outcomes of allogeneic limbal transplantation in congenital aniridia. Published studies regarding the survival of allogeneic limbal transplants with oral immunosuppression in longer series are listed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. In the study by Ang et al.,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> in which a majority of cases were in patients with congenital aniridia, it is concluded that the prognosis for recovery of the ocular surface is poor in the long term, with late failure in most patients, despite prolonged immunosuppressive treatment and repeated transplants. For a better prognosis, said authors consider critical a very strict control of patients to make an early diagnosis of the immunological reaction, which was observed in 39% of cases, and to ensure compliance with the immunosuppressive protocol.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">2. Keratoplasty in congenital aniridia</span><p id="par0205" class="elsevierStylePara elsevierViewall">Aniridia can be divided in a practical way into two groups: the classic form that is associated with mutations in the <span class="elsevierStyleItalic">PAX6</span> gene and the so-called “<span class="elsevierStyleItalic">aniridia-like</span>”, which is associated with mutations in other different genes. Ocular manifestations in the classic form include partial or total absence of the iris, lens subluxation, cataract, cameral angle anomalies, glaucoma, foveal hypoplasia, optic nerve hypoplasia and OAH (<a class="elsevierStyleCrossRef" href="#fig0035">Fig. 7</a>). Keratopathy occurs in 20% of cases, but ocular surface abnormalities occur in more than 90% of patients.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> As <span class="elsevierStyleItalic">PAX6</span> is involved in embryonic and postnatal corneal development, changes in the cornea can be found from birth. Initially, irregular thickening of the peripheral corneal epithelium appears, followed by the growth of neovessels or peripheral <span class="elsevierStyleItalic">pannus</span>, although the cornea is clear in the first years of life. Studies with confocal microscopy reveal different epithelial alterations that vary according to the degree of disease, with focal opacities appearing at the level of the basal epithelium, alteration of the subbasal nerve plexus, infiltration of the epithelium by dendritic cells, lack of stability in the tear film, increased stromal thickness and degradation of Vogt's palisades that eventually converge in a severe limbal insufficiency with the presence of goblet cells in the corneal epithelium.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> To this a severe dysfunction of the Meibomian glands is added, which alters the lacrimal lipid layer and involves the appearance of an evaporative dry eye that worsens the situation at the ocular surface.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0210" class="elsevierStylePara elsevierViewall">The treatment of AAK will depend on the stage of the disease and, above all, on the degree of signs and symptoms that the patient exhibits. When the maximum medical treatment is not enough, a surgical approach should be considered. This medical treatment will include measures to improve the tear film such as tear substitutes (without preservatives), hematic derivatives (autologous serum, PRGF, platelet-rich plasma), scleral support lenses, as well as ocular inflammation suppressors such as corticosteroids and immunomodulators (cyclosporine, tacrolimus). Simple surgical procedures such as tarsorrhaphy or amniotic membrane grafting may be sufficient in stages I and II to improve patient signs and symptoms.</p><p id="par0215" class="elsevierStylePara elsevierViewall">However, due to the fact that the fundamental problem derives from total or partial limbal epithelial stem cell failure, no corneal surgical approach, whether penetrating or lamellar keratoplasty, will be effective without first addressing limbal failure. Corneal transplantation as the only surgical technique will only produce a temporary visual improvement and the long-term outcome of AAK will not be influenced by keratoplasty.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48,49</span></a> Accordingly, before considering any surgery on the ocular surface we should determine the degree of limbal insufficiency. This can be studied by examination with vital slit lamp stains such as fluorescein and lissamine green or, more precisely, by impression cytology or detection of MUC5AC in the corneal epithelium (Limbo-Kit®).</p><p id="par0220" class="elsevierStylePara elsevierViewall">Keratoplasty techniques should be reserved for cases of AAK with significant visual compromise due to corneal opacification and mild limbal insufficiency, or in patients who have been previously treated with simple limbal epithelial transplantation (SLET), cultured limbal epithelial transplantation (CLET), cultured oral mucosal epithelial transplantation (COMET) or kerato-limbal allograft (KLAL), as detailed elsewhere in this publication.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50–52</span></a> In some milder cases of aniridia with few iridian defects, minimal foveal hypoplasia and no nystagmus, limbal surgery alone may be effective in improving clinical and visual acuity. However, even if surgery to improve limbal insufficiency has been successful, there is still a high risk of failure with subsequent keratoplasty.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Since aniridia affects the corneal epithelium and stroma, but does not appear to involve the Descemet or endothelium, these patients may benefit from deep anterior lamellar keratoplasty (DALK)<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> techniques. This type of keratoplasty is less aggressive than penetrating keratoplasty as it reduces the antigenic load and, therefore, considerably reduces the possibility of rejection, which is limited to stromal forms, since the endothelium of the recipient is preserved. Another advantage is that, in the event of an eventual need for retransplantation, this will be technically simpler and will cause less aggression to the ocular surface. Moreover, this corneal graft modality can be performed even with acellular corneas, which would also reduce the possibility of stromal and epithelial rejection.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Among the different types of DALK, we recommend predescemetic techniques in which we access the deep stroma by manual dissection until a plane close to the Descemet is reached, ideally leaving a thickness of less than 80 μm. This type of manual approach ensures that we obtain a deep lamellar keratoplasty compared to descemetric techniques (<span class="elsevierStyleItalic">big-bubble</span>, visco-DALK) and a lower risk of having to convert to a penetrating keratoplasty, which would cloud the prognosis in these patients. With a descemetic technique we would achieve a faster visual recovery and greater sensitivity to contrast, but the rate of achieving the result is lower, so in a risk-benefit balance we opt for predescemetic techniques (<a class="elsevierStyleCrossRef" href="#fig0040">Fig. 8</a>).</p><elsevierMultimedia ident="fig0040"></elsevierMultimedia><p id="par0235" class="elsevierStylePara elsevierViewall">Another possibility would be to perform a corneal transplant that also includes limbus or limbokeratoplasty, to simultaneously solve the problems of limbal insufficiency and corneal opacification.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> These techniques are surgically more complicated, require systemic immunosuppression and suffer a depletion of limbal stem cells over time, so their diffusion is currently moderate.</p><p id="par0240" class="elsevierStylePara elsevierViewall">The medium-term evolution of keratoplasty in aniridia (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>) will be influenced by the possible appearance of complications related to limbal insufficiency. These include persistent epithelial defects and conjunctivalization of the graft. Epithelial defects can lead to corneal ulceration and even perforation. These ulcerations can also loosen the sutures, leading to irregular astigmatism. Another frequent complication is infectious keratitis. For all the above reasons, these patients will need frequent check-ups and continuous treatment with artificial tears, antibiotics, hypotensives and corticoids which, whenever possible, should be preservative-free so as not to add further damage to the fragile epithelium in these patients.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0245" class="elsevierStylePara elsevierViewall">We advise accompanying any lamellar surgery with an amniotic membrane (AM) graft because of its properties on the corneal surface, which facilitate epithelialization by restoring or providing an intact basement membrane (<a class="elsevierStyleCrossRef" href="#fig0045">Fig. 9</a>). This basement membrane is an ideal substrate that facilitates the growth of epithelial progenitors by prolonging their lifespan and maintaining their clonogenicity. This may prevent a persistent epithelial defect and subsequent corneal ulceration. In addition, the stromal side of AM contains matrix components that have an antifibrotic effect and reduce the inflammatory response. AM helps to reduce the risk of rejection by reducing fibrotic changes, scar formation and immunomodulation with reduced inflammatory response. AM will also be very useful in case an epithelial defect appears after keratoplasty.</p><elsevierMultimedia ident="fig0045"></elsevierMultimedia><p id="par0250" class="elsevierStylePara elsevierViewall">For some years now, the therapeutic arsenal has included corneal prostheses, among which the Boston keratoprosthesis (Kpro), which will be explained in another section of this publication, has become popular. Although for some authors it has become the technique of choice over keratoplasty, it must be taken into account that, in advanced stages, KLAL associated with DALK may be an option over keratoprosthesis in patients without previous transplants or valve drainage devices for glaucoma due to the high endothelial failure in patients with valves.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Keratoprosthesis in congenital aniridia</span><p id="par0255" class="elsevierStylePara elsevierViewall">In certain cases of congenital aniridia with advanced keratopathy, or that have been previously treated with failed limbal or mesenchymal stem cell allografts, or after multiple keratoplasty surgeries that have failed to maintain acceptable corneal transparency, the use of a keratoprosthesis may be considered as a last surgical option for visual rehabilitation (<a class="elsevierStyleCrossRef" href="#fig0050">Fig. 10</a>). Many of these patients present previous cataract surgeries with diaphragm intraocular lens implantation or glaucoma surgeries with valve tubes and, in addition to corneal opacity, they exhibit the progressive anterior segment fibrosis syndrome, very characteristic of this pathology.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> These factors add complexity to the definitive treatment of these patients and constitute a significant surgical challenge. In addition, in some cases of congenital aniridia it is not possible to consider prolonged immunosuppression due to systemic or tolerance problems. In all these cases, the option of surgical intervention with the use of keratoprosthesis is a viable option with acceptably good results.</p><elsevierMultimedia ident="fig0050"></elsevierMultimedia><p id="par0260" class="elsevierStylePara elsevierViewall">The preoperative examination should assess the tension status, which is difficult to perform due to the irregular opacity and corneal thickening that occurs in these cases, the poor visibility to assess the state of the optic nerve and the unreliability of campimetry due to the low vision of these patients, Therefore, digital tonometry, the use of Goldmann campimetry and an electrophysiological study with electroretinogram and visual evoked potentials can provide information on the visual potential and assist in making a surgical decision. The state of the eyelids, the associated presence of blepharitis, its functionality and correct occlusion capacity, the state of the tear, the conjunctival sacs, the presence of neovascularization and inflammation of the perikeratotic conjunctiva, the peripheral corneal thickness and the anatomy of the anterior segment should be explored, in which an optical coherence tomography of the anterior segment (OCT-SA) may be useful, the presence and location of valvular drainage devices, and if there are previous keratoplasty surgeries or limbal allografts, intraocular lens (IOL) implants and type of implanted IOL, etc.</p><p id="par0265" class="elsevierStylePara elsevierViewall">In general, in patients with congenital aniridia, the conditions of the eyelids and ocular surface are usually favourable for the implantation of keratoprostheses, unlike other more compromised and higher risk situations such as caustications or autoimmune diseases of the ocular surface, in which the degree of chronic inflammation of the ocular surface is greater.</p><p id="par0270" class="elsevierStylePara elsevierViewall">Once a full complete examination has been carried out, the advantages of this surgery should be discussed with the patient, such as the good vision and visual field that can be obtained depending on the state of the retina and optic nerve, the absence of astigmatism and immunological reaction. The disadvantages of surgery with a non-biological keratoprosthesis should also be discussed, including above all the need for strict postoperative care, the use of antibiotics and topical anti-inflammatory drugs on a continuous basis, the obligation to wear a large diameter contact lens with monthly replacement, strict blood pressure control due to the increased risk of worsening of pre-existing glaucoma or its <span class="elsevierStyleItalic">de novo</span> appearance, the possibility of infections even in the long term, the foreseeable formation of retroprosthetic membranes, given the relatively frequent presence of progressive fibrosis syndrome of the anterior segment in this pathology, the extrusion of the prosthetic piece, retinal detachment and sterile vitritis.</p><p id="par0275" class="elsevierStylePara elsevierViewall">If the patient chooses the intervention option, it is carried out. In general, we proceed in the usual way, making a trepanation of 8–9 mm and placing the Boston type 1 keratoprosthesis included in a graft of good endothelial and epithelial quality of a diameter 0.25−0.5 mm larger than the trepanation in the recipient and sutured with 16 independent stitches of 10-0 nylon or 11-0 mersilene, burying the knot. If the patient has a crystalline lens, an intracapsular extraction and anterior vitrectomy is performed and a keratoprosthesis is implanted with the appropriate dioptric power for the axial length measured preoperatively by ultrasonic biometry. If the patient has had previous cataract surgery with an IOL implantation, the patient age should be taken into account when deciding on the explantation because the presence of an IOL in young patients greatly increases a fibrosis reaction of the anterior segment and the formation of retroprosthetic membranes. A study, not yet concluded, is being carried out on the influence of age and presence of IOL on the development of this complication. In young patients, it would therefore be advisable to explant the IOL and use a keratoprosthesis for aphakia, which already incorporates all the dioptric power necessary for the approximate focus on the macula.</p><p id="par0280" class="elsevierStylePara elsevierViewall">If the patient has previous glaucoma that requires oral medication, a valve implant can be performed in the same surgery, preferably Baerveldt type through the <span class="elsevierStyleItalic">pars plana</span>, performed by a surgeon who can also perform a vitrectomy as complete as possible of the vitreous base to avoid its obstruction. In this situation, once the trepanation has been performed, a Landers-type temporary keratoprosthesis is placed through which the vitreoretinal surgeon can perform a complete peripheral vitrectomy and place the drainage implant, with the selected Boston type 1 keratoprosthesis being placed in a third surgical stage. If the patient already has a valvular tube, it is advisable to reposition it posterior to the IOL or reimplant it in the vitreous chamber to avoid occlusion, if fibrotic tissue develops in the anterior segment.</p><p id="par0285" class="elsevierStylePara elsevierViewall">Once the surgery has been performed, the patient should be monitored regularly to avoid or detect all the possible complications mentioned above. In general, once the first phase of the immediate postoperative period has passed, the patient is monitored every two months and is evaluated at each visit by means of a slit lamp examination with fluorescein, assessing the presence or absence of periprosthetic epithelial defects, which can be a gateway to bacterial or fungal infection. In addition, OCT-SA is performed to assess the periprosthetic corneal thickness and the presence of fibrosis or retroprosthetic membrane and angular status, as well as Goldmann campimetry, retinography and OCT of the optic nerve, digital tonometry, washing of the fornices with 5% povidone iodine for three minutes and replacement of the 16 mm therapeutic contact lens (TCL) with a new one.</p><p id="par0290" class="elsevierStylePara elsevierViewall">In the experience of the authors (Barraquer Ophthalmology Center), eight cases of congenital aniridia have been operated on using Boston type 1 keratoprosthesis with anatomical retention of the piece in all cases. Two pediatric cases developed endophthalmitis and, after multiple procedures, lost their vision. Three cases required sectoral tectonic procedures due to thinning of the periprosthetic corneal graft, and all patients developed retroprosthetic membrane (<a class="elsevierStyleCrossRef" href="#fig0055">Fig. 11</a>), which was treated with YAG laser or surgical membranotomy. All patients had or developed glaucoma postoperatively, but were controlled with adjunctive medical treatment. The two older patients had a lower complication rate, so patient age seems to be a decisive factor in the development of complications.</p><elsevierMultimedia ident="fig0055"></elsevierMultimedia><p id="par0295" class="elsevierStylePara elsevierViewall">Despite being a surgery of last resort in the treatment of severe keratopathy associated with this disease, the visual results (taking into account the associated macular hypoplasia) of the Boston keratoprosthesis are similar in terms of results to other pathologies, although the prevalence of preoperative associated glaucoma (76.2%) or previous glaucoma surgeries (57.1%) was higher than in other pathologies in which this surgical technique was performed.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Other authors also confirmed the usefulness of keratoprosthesis in advanced stages of keratopathy.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> In another short series of seven patients, percentages similar to ours were found, with 100% anatomical retention of the prosthesis, high incidence of retroprosthetic membrane formation and one case that required secondary tectonic surgery.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> In another series, the presence of congenital aniridia was associated with a higher incidence of final visual loss, probably due to the high incidence of glaucoma in these patients.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> Other authors also highlighted the role of angular anomalies associated in aniridia as a negative factor in the development of glaucoma, and the importance of avoiding chronic anterior segment inflammation, which could induce ganglion cell damage, producing visual impairment even in the presence of normal intraocular pressures, proposing the use of systemic anti-inflammatory drugs such as infliximab to minimize such cell damage mediated by inflammatory cytokines and the early use of valvular drainage devices in patients with congenital aniridia.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">Postoperative infection is also a devastating complication after keratoprosthesis if not diagnosed and treated in time. Its incidence is around 8% in long series<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> and can progress to endophthalmitis and irreversible loss of visual function. Prevention is essential through proper personal hygiene, the use of prophylactic antibiotics on a continuous basis, periodic washing with povidone iodine and the replacement of therapeutic contact lenses. Even so, infections can be observed in areas with epithelial defect and periprosthetic corneal melting (<a class="elsevierStyleCrossRef" href="#fig0060">Fig. 12</a>). Rapid intervention with sampling and culture is essential as the germs involved are usually rare bacteria or fungi, generally yeasts, although endophthalmitis due to actinomyces has also been observed. If despite intensive topical and systemic medical treatment, the infection is not controlled quickly, it is necessary to act promptly and replace the piece with a graft, preferably with a larger diameter than the previous one to avoid leaving areas of infected tissue.</p><elsevierMultimedia ident="fig0060"></elsevierMultimedia><p id="par0305" class="elsevierStylePara elsevierViewall">In summary, when more conservative surgical treatments such as limbal allografts have failed, either in their macroscopic form or in the form of <span class="elsevierStyleItalic">ex vivo</span> expanded cell transplantation, the Boston keratoprosthesis offers good functional results, although a rate of glaucoma and retroprosthetic fibrosis formation is observed due to the particular characteristics of this disease. It is necessary for this type of patients to be operated and monitored by specialized units familiar with this surgical procedure to ensure adequate follow-up of these patients, which is usually lifelong.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">4. Regenerative medicine in ocular surface pathology in congenital aniridia</span><p id="par0310" class="elsevierStylePara elsevierViewall">Advanced therapy medicinal products are defined as medicinal products for human use based on the use of genes, known as gene therapy, or based on the use of cells, then defined as cell therapy, or based on the use of tissues, which constitutes tissue engineering, or combined medicinal products, when they have the characteristics of all three of the above. It includes products whose origin may be autologous, allogeneic or xenogeneic (Regulation of the European Parliament and the Council [EC] N °1394/2007. This article, among others, addresses cell therapy and tissue engineering).</p><p id="par0315" class="elsevierStylePara elsevierViewall">Cell therapy is understood as the use of medicinal products containing or consisting of cells or tissues that have undergone substantial manipulation such that their biological characteristics, physiological functions or structural properties relevant to the intended clinical use have been modified. It is important to understand that non-substantial manipulations include cutting, crushing, moulding, centrifugation, imbibition in antimicrobial solutions, sterilisation, irradiation, cell separation, concentration or purification, filtration, lyophilisation, freezing, preservation and vitrification. Therefore, a cell culture, which is of interest in this section, does have substantial manipulations. Also of interest in this chapter are tissue engineered products, i.e., containing cells or tissues and in addition biomolecules, biomaterials, supports or matrices.</p><p id="par0320" class="elsevierStylePara elsevierViewall">Regenerative therapy or medicine aims to restore the function of diseased tissues and organs by stimulating the body's own repair mechanisms.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> It differs, therefore, from replacement or reconstructive therapy, such as organ or complex tissue transplants, including corneal or limbal transplants, or the use of prostheses, as is done in lens surgery. In the current regenerative therapy for the treatment of corneal diseases, cells can be used in the form of cell therapy, either stem cells or differentiated cells in culture,<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> or tissue engineering, such as artificial corneas,<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> or cellular products can be used, such as enriched eyedrops, which act by chemical or biological induction mechanisms<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> and, in most cases, an aggregation of all of them.</p><p id="par0325" class="elsevierStylePara elsevierViewall">This section will address regenerative therapy or medicine in congenital aniridia. Although it is not intended to be recognized as the perfect alternative to more classical reconstructive therapies, such as limbal transplantation, certain advantages are clear, such as the contribution of more stem cells, more profitability of the donor in allogeneic cases, and less traumatic than autologous, simpler surgical procedure of the graft, and with the ability to be repeated easily, and very few complications, almost only its failure.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> It is understood that the fundamental disadvantage with respect to limbal transplantation is the technological complexity required for the preparation of the product, so the intention is to offer it not so much as an alternative, but as a complementary aid to other therapies.</p><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Types of regenerative therapy in aniridia</span><p id="par0330" class="elsevierStylePara elsevierViewall">The very low prevalence of congenital aniridia, estimated at one case per 40,000–100,000 people,<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> and taking into account that not all patients are candidates for these therapies, makes the experience with these treatments very limited, with low scientific evidence, and therefore with a poor recommendation level. In short, the therapeutic proposals are based on the extrapolation of the application of regenerative therapy to other cases of limbic insufficiency, or on isolated and small experiences of some research groups.</p><p id="par0335" class="elsevierStylePara elsevierViewall">Regenerative medicine in cases of limbic insufficiency, and specifically in congenital aniridia, aims to restore as far as possible the corneal epithelial phenotype of the corneal epithelium which, due to the destruction of the limbus and the absence of limbal stem cells, presents a conjunctival phenotype which causes, to varying degrees, epithelial defects, inflammation of the ocular surface, and worsening of the already limited visual function. Two tools are currently available: eyedrops enriched with hematic derivatives and cell transplants. It is necessary to take into account that acceptable results can be achieved with the condition of performing an exhaustive evaluation of the ocular surface, which facilitates the staging of the severity of the situation, and thus be able to apply personalized treatments for each patient.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Eyedrops enriched with hematic derivatives</span><p id="par0340" class="elsevierStylePara elsevierViewall">Although it seems that the application on the ocular surface of hematic derivatives is new, it is interesting to remember that already in the Ebers papyrus its use is described in the year 1500 BC.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> Hippocrates (5th–4th century B.C.) recommended to provoke bleeding in the eyes of patients with ocular surface diseases,<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> and Pliny in the 1st century proposed the instillation of menstrual blood in the conjunctiva.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> These products contain substances with trophic effect that act on the proliferation, migration and differentiation of epithelial cells. The aim is to apply growth factors involved in the healing processes of the ocular surface, as they interact and coordinate the biological processes that lead to tissue regeneration. Some of these are transforming growth factor beta (TGF-1β), epithelial growth factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF-1), substance P, neuronal growth factor (NGF), albumin, α2-macroglobulin, immunoglobulins, lysozyme, complement factors, among others. All these elements generate or facilitate actions such as migration, proliferation and differentiation of epithelial cells and fibroblasts, increase the synthesis of fibronectin, decrease apoptosis, inhibit the effect of metalloproteinases, stimulate angiogenesis, favor the synthesis and contraction of the extracellular matrix, inhibit microbial proliferation, etc.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">The effects can be specified in facilitating epithelial turnover,<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> regulating an adequate production of mucins on the ocular surface,<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> improving the stability of the tear film, and improving staining with rose Bengal and fluorescein, and corneal transparency, particularly in patients with congenital aniridia,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> even increasing corneal sensitivity.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> In any case, it is important to keep in mind that the effect can take up to four weeks to be noticed.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a></p><p id="par0350" class="elsevierStylePara elsevierViewall">A very important aspect of this therapy is the scarcity of adverse effects, excluding the lack of efficacy. Thus, the appearance of peripheral corneal infiltrates due to the deposition of immune material has been described.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a> It also seems reasonable not to prescribe these treatments in the context of active infections of the ocular surface. Terminological confusion exists, both at the technical and administrative level. For example, fibrin and albumin derivatives, autologous and allogeneic serum, umbilical cord blood, cryoprecipitates, platelets or platelet derivatives, plasmin, or even fresh frozen plasma<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> have been used. At the administrative level the confusion is even greater and thus, the Spanish Agency of Medicines and Health Products in its Report/V1/23052013, published on 23 May 2013, summarized the definition of platelet-rich plasma and its modalities (PRP) as a volume of autologous plasma containing a concentration of platelets above the basal level (150,000–350,000/μL). Depending on the system used for its preparation, the concentrations of platelets, leukocytes, erythrocytes and growth factors may vary. Using different methods, different fractions are obtained, including preparation rich in growth factors (PRGF), plasma rich in platelets and growth factors (PRPGF), platelet-rich plasma (PRP), platelet-poor plasma (PPP), platelet-rich and leukocyte-rich plasma (LR-PRP), and platelet-rich and leukocyte-poor plasma (LP-PRP).</p><p id="par0355" class="elsevierStylePara elsevierViewall">In this text, for ease of understanding, the term autologous serum eyedrops (ASE) will be used when the preparation is serum without platelets or without their content obtained by forced activation, and eyedrops derived from platelets, PRP or PRGF when the content is platelets or their products, without serum. López García studied the effect of 20% autologous serum eyedrops in 13 patients with congenital aniridia keratopathy (26 eyes), and found that subjective symptoms improved in all cases, as well as re-epithelialization criteria, corneal epithelial metaplasia and tear film stability. A slight improvement in visual acuity, conjunctivalization and subepithelial fibrosis was also observed.</p><p id="par0360" class="elsevierStylePara elsevierViewall">Unfortunately, there is no agreement on the method of preparation, and thus there are discrepancies in the literature related to the revolutions per minute and centrifugation time, and even in the concentration of the preparation.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> ASE may be harmful in patients with systemic immune disease, as a concentrate of inflammatory elements is instilled.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a> This applies to patients with congenital aniridia who also have systemic diseases of an inflammatory nature. Platelet derivatives can limit the release of proinflammatory cytokines and thus minimize the processes that hinder tissue regeneration.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a> Experimentally, PRGF has been shown to be much more effective than ASE in stimulating ocular surface fibroblast proliferation in culture<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> and is also more effective in animal models of corneal ulcers.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> Therefore, the absence of proinflammatory elements and the possibly higher concentration of trophic factors make platelet derivatives a better choice than ASE.</p><p id="par0365" class="elsevierStylePara elsevierViewall">There are situations that prevent or limit the use of autologous blood derivatives, such as infection by human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), lupus, difficulties in venipuncture, as occurs in children, or in polymalformative syndromes, which require the use of central lines, or the concomitant use of drugs that alter platelets, such as vitamin B antagonists or vitamin C antagonists, as occurs in children, or in polymalformation syndromes, which require the use of central lines, or the concomitant use of drugs that alter platelets, such as vitamin K antagonists, antiplatelet agents (including NSAIDs), or heparin. In these situations, other alternatives could be considered, such as allogeneic serum, a procedure already implemented in Denmark, Norway, and the Netherlands, using male donors who are not using any medication and have not received any type of transfusion. It is not necessary for them to have the same ABO blood group, and logically they must have ruled out HIV, HBV, HCV and syphilis infections.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> Other alternatives can be umbilical cord serum eyedrops<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> and amniotic membrane eyedrops.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Cell transplants</span><p id="par0370" class="elsevierStylePara elsevierViewall">Although it is not a transplant of corneal epithelial cells, it is worth making a brief comment on amniotic membrane transplantation. Its effect is mainly due to the release of growth factors and anti-inflammatory cytokines, and its ability to act as a temporary reservoir for other treatments that may be applied, in addition to a certain mechanical effect acting as a bandage lens. It has been tested in aniridia, as a previous step to more complex treatments, with acceptable results, although not very long lasting.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> Unfortunately, amniotic membrane transplantation, although useful in mild or partial cases of limbic insufficiency, is not enough in more severe cases, making necessary the contribution of cells in the form of limbal tissue or limbal epithelial cells, or epithelial cells from other mucous membranes. It seems to be demonstrated that these procedures are effective, and that they improve the survival of a subsequent corneal transplant.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a></p><p id="par0375" class="elsevierStylePara elsevierViewall">The following is a summary of cell therapy for these situations. They will be named in English, as this is the terminology with which they are known.</p></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">A. Cultivated limbal epithelial transplantation (CLET)</span><p id="par0380" class="elsevierStylePara elsevierViewall">First described by Pellegrini in 1997, this procedure is based on culturing a 1−2 × 1–2 mm limbal fragment. This procedure can be performed autologously, although in congenital aniridia this is very unlikely given the symmetry of the condition, so it would have to be allogeneic. The authors’ group performed a prospective clinical study, in which 20 eyes were included, 11 of which received an autologous limbic epithelial stem cell transplant and nine allogeneic. This work showed that there was no difference in survival between the two groups, and two of the cases using cadaver donors, which were considered successes, were congenital aniridia (<a class="elsevierStyleCrossRefs" href="#fig0065">Figs. 13 and 14</a>).<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a></p><elsevierMultimedia ident="fig0065"></elsevierMultimedia><elsevierMultimedia ident="fig0070"></elsevierMultimedia><p id="par0385" class="elsevierStylePara elsevierViewall">In this study, the cells were cultured on amniotic membrane, which is easily accessible, inexpensive and, as previously mentioned, has regenerative properties of its own. Since this is an allogeneic cell transplant, rejection may occur, so patients were subjected to immunomodulatory prophylaxis against rejection which, depending on the case, could be mycophenolate mofeltil, 1.5–2 g/day, or cyclosporine A, 3–5 mg/kg/day, during the first 12 months postoperatively. The culture technique is described in more detail in the referenced work, but, in summary, it consisted of placing a 2 × 2 cm fragment of cadaver donor limbus (2 × 2 mm) on a 2 × 2 cm amniotic membrane. In the appropriate culture medium, and in a cell processing unit with accreditation of good handling practices, cell confluence was achieved in approximately two weeks, implanting the membrane with approximately 250,000 cells. Other papers describe in detail the different methodologies for isolating limbic stem cells,<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> with cell suspensions being more cost-effective than explants, and also demonstrate that up to three consecutive cultures can be made from a single sample.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall">The surgical technique, in the case of congenital aniridia, consists of removing the corneal epithelium with a conjunctival phenotype appearance, and fixing the amniotic membrane with the cultured cells down with a continuous 10-zero nylon suture as far away from the limbus as possible, and protecting the graft with a large diameter therapeutic contact lens (18–22 mm). Postoperatively, steroids and topical antibiotics without preservatives were applied, and after approximately two weeks the suture and the remains of the amniotic membrane were removed. The authors’ group places great value on <span class="elsevierStyleItalic">in vivo</span> confocal microscopy in pre- and postoperative assessment, as shown in the figures, as it is simpler, faster and safer than conjunctival impression cytology.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> Based on the same philosophy of transplanting <span class="elsevierStyleItalic">ex vivo</span> cultured corneal epithelial stem cells, other authors used other matrices such as those derived from fibrin, and other culture techniques.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> In fact, the only product approved by the European Medicines Agency (EMA) is based on this technology, although it uses autologous tissue and can only be used in unilateral caustications, (Holoclar™, Chiesi, Italy) so it is not applicable to congenital aniridia.</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">B. Mesenchymal stem cell (MSCs) transplantation</span><p id="par0395" class="elsevierStylePara elsevierViewall">An alternative to the use of limbic epithelial stem cells may be the <span class="elsevierStyleItalic">ex vivo</span> expansion of mesenchymal stem cells. In recent years, their use in cell therapy has gained extraordinary interest,<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">95,96</span></a> because they are relatively easy to obtain from different tissues such as bone marrow, adipose tissue, umbilical cord, etc. In addition, they have the ability to differentiate into mesodermal or non-mesodermal cell lineages<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> and have immunomodulatory properties and are not immunogenic so they cannot be rejected, thus avoiding the need for immunosuppressive<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a> prophylaxis. The working group of the authors began its study on experimental models of limbic insufficiency in the rabbit, in which very encouraging results were obtained.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> It has even been demonstrated that both MSCs from bone marrow and adipose tissue improve corneal opacification, although the former are more effective in reducing corneal neovascularization, and the latter in preventing conjunctivalization (Herreras JM, Galindo S, López-Paniagua M, García-Vázquez C, Calonge M, Nieto-Miguel T. Efficacy of bone marrow-versus adipose tissue-derived mesenchymal stem cells in a rabbit model of limbal stem cell deficiency. ARVO Meeting. 2019 Vancouver. Canada).</p><p id="par0400" class="elsevierStylePara elsevierViewall">Once the experimental work <span class="elsevierStyleItalic">in vitro</span> and in animals was completed, the IOBA group conducted a pilot clinical trial in humans, randomized, double-blind, testing allogeneic bone marrow mesenchymal cells in 17 patients, versus cultured allogeneic limbic epithelial stem cells in 11 cases, The former proved to be as safe and effective as the latter, with the advantages previously described,<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a> so that, from our point of view, the use of mesenchymal stem cells becomes the option of choice for regenerative therapy of limbic insufficiency syndromes, including, of course, congenital aniridia.</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">C. Simple limbal transplant</span><p id="par0405" class="elsevierStylePara elsevierViewall">Other techniques have been described, such as <span class="elsevierStyleItalic">simple limbal epithelial transplantation</span> (SLET),<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> which essentially consists of taking a 2 × 2 limbal fragment from the eye, fragmenting it, and placing it protected by an amniotic membrane over the diseased eye. It requires, therefore, a healthy donor eye, so its application in congenital aniridia is very limited.</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">D. Transplantation of cultured oral mucosa</span><p id="par0410" class="elsevierStylePara elsevierViewall">In order to avoid using autologous or allogeneic limbus as donor tissue, the <span class="elsevierStyleItalic">cultivated oral mucosal epithelial transplant</span> (COMET)<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> has been proposed. The main indication would be in those bilateral situations, such as congenital aniridia, in which prophylactic immunosuppression of rejection is contraindicated, and in which mesenchymal cells are not available.</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">E. Induced pluripotent stem cell transplantation (IPSC)</span><p id="par0415" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Induced pluripotent stem cell transplantation (IPSC)</span> is also proposed, which consists of reprogramming mature cells, such as skin keratinocytes or fibroblasts, into pluripotent cells.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a> The theoretical concept is very similar to the use of mesenchymal cells, although the procedure is significantly more complex. It is very important to be clear that cell transplantation must be accompanied by other therapies, regenerative or not, since in these patients it is especially important to treat dry eye, control inflammation, improve the condition of the eyelids, inhibit the activation of metalloproteinases, etc.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">F. Transplantation of adipose tissue cells</span><p id="par0420" class="elsevierStylePara elsevierViewall">Not only the corneal epithelium is affected in advanced stages of keratopathy in congenital aniridia, but the stromal involvement contributes definitively to the appearance of corneal opacity with disorganization of the corneal collagen structure, formation of stromal scarring and secondary deep neovascularization, which increases the chances of immunological reaction to any type of transplantation. Interest in studying the possibilities of stromal regeneration using mesenchymal cells has significantly increased in recent years.</p><p id="par0425" class="elsevierStylePara elsevierViewall">Among the various sources of mesenchymal cells are human stem cells from autologous adult adipose tissue (h-ADASCs), which meet many requirements including easy accessibility to this tissue, high efficiency in obtaining them and the ability of these cells to differentiate into multiple cell lines (keratocytes, osteoblasts, chondroblasts, myoblasts, hepatocytes and neurons).<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a> The differentiation of these h-ADASCs has been demonstrated <span class="elsevierStyleItalic">in vivo</span> in a study performed in rabbits and, once implanted inside the stroma, they express not only collagen types I and VI (main components of the corneal extracellular matrix), but also keratocyte-specific markers such as keratocan and aldehyde dehydrogenase (ALDH) without inducing any immune response.</p><p id="par0430" class="elsevierStylePara elsevierViewall">The application of these cells can be in the form of topical application,<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> described in some isolated cases without scientific evidence of its usefulness in long series, by direct injection into the stroma, or by injection into a lamellar pocket created with femtosecond laser.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> Intrastromal implantation of an acellular lamellar matrix repopulated with h-ADASCs can also be performed,<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">108</span></a> in which the differentiation of these into functional keratocytes is demonstrated. This implantation has been performed in other pathologies such as advanced keratoconus,<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a> in which good stromal transparency was obtained three months after implantation and an improvement in topographic, aberrometric and refractive parameters.</p><p id="par0435" class="elsevierStylePara elsevierViewall">The use of these autologous adipose stem cells as a source of corneal stroma regeneration paves the way to their application in the future for the treatment of all those hereditary (stromal dystrophies or keratoconus) or acquired pathologies that require an autologous cell source to achieve an improvement or restoration of the transparency of the corneal stroma.<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a></p></span></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conclusions</span><p id="par0440" class="elsevierStylePara elsevierViewall">Aniridia keratopathy is caused by the presence of a state of chronic active scarring due to abnormalities in corneal homeostasis caused by alteration of the <span class="elsevierStyleItalic">PAX6</span> gene.</p><p id="par0445" class="elsevierStylePara elsevierViewall">The alteration of the tear film is based on an epitheliopathic dry eye, due to poor adherence of the tear to the pathological epithelium. The use of artificial tears based on hyaluronic acid and blood-derived eyedrops can be useful in the initial and intermediate stages of keratopathy.</p><p id="par0450" class="elsevierStylePara elsevierViewall">Contact lenses could improve the symptoms of photophobia, visual impairment and pain, which cause a significant deterioration of quality of life. At present, custom scleral lenses could be effective in improving all three of these conditions. It is likely that the development of new materials and designs will allow patients with congenital aniridia to be treated more effectively and safely.</p><p id="par0455" class="elsevierStylePara elsevierViewall">Allogeneic limbal transplants, with potent and prolonged systemic immunosuppression, offer good short-term results, but there is a high possibility of rejection and late failure with ocular surface instability. In young patients they could be considered as an intermediate step towards keratoprosthesis.</p><p id="par0460" class="elsevierStylePara elsevierViewall">Manually performed deep anterior lamellar lamellar keratoplasty appears to be a safer option in those cases with a functioning limbal transplant and dense stromal corneal opacity, although long-term outcomes are often compromised by the late chronic limbal failure associated with allogeneic limbal transplants.</p><p id="par0465" class="elsevierStylePara elsevierViewall">Non-biologic keratoprostheses such as the Boston keratoprosthesis offer a surgical alternative with good visual and campimetric results, but their potential risks and complications must be taken into account, which require very strict and continuous follow-up by the patient and experienced medical team.</p><p id="par0470" class="elsevierStylePara elsevierViewall">New advances in regenerative medicine are enabling less aggressive and more hopeful surgical treatments, and have generated great expectations in patients with limbic insufficiency, although their diffusion is not yet widespread, being carried out only in multidisciplinary teams with extensive experience in obtaining, processing and implanting cell cultures. Numerous cell types are being investigated by multidisciplinary working groups to achieve the regeneration of the various cell layers that form the human corneal tissue.</p><p id="par0475" class="elsevierStylePara elsevierViewall">In the light of all the scientific work presented, it seems clear that patients with congenital aniridia can receive treatments to improve their quality of life, by reducing the discomfort derived from limbic insufficiency, and increase visual function, or even improve the prognosis of a subsequent corneal transplant or keratoprosthesis in those cases in which it is necessary. Unfortunately, as it is a disease of very low prevalence, there is no strong scientific evidence to decide which therapeutic alternative is the best among the various options, so the therapeutic plan is still based on the experience and skills of the professional teams dedicated to the treatment of this disease.</p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Funding</span><p id="par0480" class="elsevierStylePara elsevierViewall">This study has been funded in part by the <span class="elsevierStyleGrantSponsor" id="gs0005">Thematic Network of Cooperative Health Research “OFTARED”</span> - Reference: <span class="elsevierStyleGrantNumber" refid="gs0005">RD16/0008/0012</span>. Funded by the <span class="elsevierStyleGrantSponsor" id="gs0010">Instituto de Salud Carlos III/Agencia Estatal de Investigación</span> and by the <span class="elsevierStyleGrantSponsor" id="gs0015">European Regional Development Fund (ERDF) “A way of doing Europe”</span>.</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Conflict of interest</span><p id="par0485" class="elsevierStylePara elsevierViewall">Juan Durán de la Colina is consultant for Laboratorios Thea and Ophtec. José Manuel Benitez del Castillo is consultant for Laboratorios Abbvie, Angelini, Brill Pharma, Fidia, GSK, L'Acuité, Esteve, Santen and Sifi. The rest of the authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1614988" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1443664" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1614987" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1443663" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Ocular surface alterations in congenital aniridia" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Pathogenic basis of keratopathy associated with aniridia" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical manifestations of aniridia keratopathy" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Diagnosis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Medical treatment of keratopathy associated with aniridia" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Investigational medical therapies" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Contact lenses and congenital aniridia" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Contact lenses and limbic insufficiency" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Potential contact lens applications" ] ] ] 7 => array:3 [ "identificador" => "sec0055" "titulo" => "Surgical ocular surface treatment options in congenital aniridia" "secciones" => array:10 [ 0 => array:3 [ "identificador" => "sec0060" "titulo" => "1. Allogeneic limbal transplantation" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Surgical technique" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Post-operative treatment" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "Limbal transplant considerations" ] ] ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "2. Keratoplasty in congenital aniridia" ] 2 => array:2 [ "identificador" => "sec0090" "titulo" => "Keratoprosthesis in congenital aniridia" ] 3 => array:3 [ "identificador" => "sec0095" "titulo" => "4. Regenerative medicine in ocular surface pathology in congenital aniridia" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0100" "titulo" => "Types of regenerative therapy in aniridia" ] 1 => array:2 [ "identificador" => "sec0105" "titulo" => "Eyedrops enriched with hematic derivatives" ] 2 => array:2 [ "identificador" => "sec0110" "titulo" => "Cell transplants" ] ] ] 4 => array:2 [ "identificador" => "sec0115" "titulo" => "A. Cultivated limbal epithelial transplantation (CLET)" ] 5 => array:2 [ "identificador" => "sec0120" "titulo" => "B. Mesenchymal stem cell (MSCs) transplantation" ] 6 => array:2 [ "identificador" => "sec0125" "titulo" => "C. Simple limbal transplant" ] 7 => array:2 [ "identificador" => "sec0130" "titulo" => "D. Transplantation of cultured oral mucosa" ] 8 => array:2 [ "identificador" => "sec0135" "titulo" => "E. Induced pluripotent stem cell transplantation (IPSC)" ] 9 => array:2 [ "identificador" => "sec0140" "titulo" => "F. Transplantation of adipose tissue cells" ] ] ] 8 => array:2 [ "identificador" => "sec0145" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0150" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0155" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-12-09" "fechaAceptado" => "2021-04-12" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1443664" "palabras" => array:7 [ 0 => "Congenital aniridia" 1 => "Keratopathy" 2 => "Limbal stem cell transplantation" 3 => "Keratoplasty" 4 => "Keratoprostheses" 5 => "Limbal stem cell culture" 6 => "Mesenchymal cell culture" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1443663" "palabras" => array:7 [ 0 => "Aniridia congénita" 1 => "Queratopatía" 2 => "Trasplante de células madre limbares" 3 => "Queratoplastia" 4 => "Queratoprótesis" 5 => "Cultivo de células madre epiteliales" 6 => "Cultivo de células mesenquimales" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Congenital aniridia is a multisystemic genetic disease due to a mutation in PAX6 gene which severely affects the development and functionality of the human eyes. In patients affected by the mutation, aside from the absence or defects of iris tissue formation, abnormalities in position or opacities of the crystalline lens, macular hypoplasia, ocular surface disease is the main cause of visual loss and the deterioration of the quality of life of most patients. Limbal stem cell deficiency combined with tear film instability and secondary dry eye cause aniridic keratopathy which, in advanced stages, ends up in corneal opacification.</p><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">In this paper, the actual knowledge about congenital aniridia keratopathy physiopathology and medical and surgical treatment options and their efficacy are discussed. Indications and results of topical treatments with artificial tears and blood-derivatives in its initial stages, and different surgical techniques as limbal stem cell transplantation, keratoplasty and keratoprostheses are reviewed. Finally, recent advances and results in regenerative medicine techniques with <span class="elsevierStyleItalic">ex vivo</span> stem cell cultivation or other types of cultivated cells are presented.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">La aniridia congénita es una patología multisistémica derivada de una mutación en el gen PAX6 que afecta severamente al desarrollo y a la función de los globos oculares. En los pacientes afectados por esta enfermedad, además de la ausencia o defectos en la formación del iris, anomalías y opacidades del cristalino e hipoplasia de la mácula, la patología de la superficie ocular es la responsable del deterioro visual y de la calidad de vida en un porcentaje muy importante de casos. La insuficiencia límbica producida por la enfermedad junto a la inestabilidad y deterioro de la película lagrimal desarrollan la llamada queratopatía que, en estadios avanzados, conlleva la opacificación final de la córnea.</p><p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">En este artículo se repasan los conocimientos actuales que se disponen tanto de la fisiopatología de la queratopatía como los posibles tratamientos médicos y quirúrgicos disponibles en la actualidad y las evidencias existentes al respecto de su eficacia en esta patología ocular. Se describen las indicaciones y resultados de los tratamientos tópicos con lágrimas artificiales y colirios hemoderivados en las fases iniciales, y de las diferentes técnicas quirúrgicas como los trasplantes alogénicos de limbo corneal, las queratoplastias, las queratoprótesis y, finalmente, se expondrán los avances y resultados actuales de la medicina regenerativa basada en el trasplante de células obtenidas, expandidas y modificadas <span class="elsevierStyleItalic">ex vivo</span> en el laboratorio.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Álvarez de Toledo Elizalde J, López García S, Benítez del Castillo JM, Durán de la Colina J, Gris Castejón O, Celis Sánchez J, et al. Aniridia y superficie ocular: problemas y soluciones médicas y quirúrgicas. Arch Soc Esp Oftalmol. 2021;96(S1):15–37.</p>" ] ] "multimedia" => array:17 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1253 "Ancho" => 2167 "Tamanyo" => 264718 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Physiopathogenesis of aniridia-associated keratopathy. Alterations in PAX6 cause corneal changes that produce a chronic state of scarring.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 487 "Ancho" => 1300 "Tamanyo" => 64642 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Early stages of aniridia keratopathy. <span class="elsevierStyleBold">A.</span> Peripheral epithelial changes. <span class="elsevierStyleBold">B.</span> Onset of peripheral vascular pannus.</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1134 "Ancho" => 1500 "Tamanyo" => 187190 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Classification of aniridia keratopathy. <span class="elsevierStyleBold">A.</span> Grade 0. Absence of involvement. <span class="elsevierStyleBold">B.</span> Discontinuous areas of peripheral neovascularization. <span class="elsevierStyleBold">C.</span> Grade 2. Areas of vascular pannus that affect the entire periphery and extend centripetally, but do not affect the center of the cornea. <span class="elsevierStyleBold">D.</span> Grade 3. Vascular pannus and corneal opacity affect the center of the cornea.</p>" ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2552 "Ancho" => 2167 "Tamanyo" => 720043 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> Scleral CL seen by OCT-SA. The distance of respect over the corneal epithelium can be seen. <span class="elsevierStyleBold">B.</span> The lens rests on the bulbar conjunctiva.</p>" ] ] 4 => array:8 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 598 "Ancho" => 900 "Tamanyo" => 77317 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Patient with congenital aniridia and complete limbic insufficiency of long evolution. Extensive conjunctivalization of the cornea is observed.</p>" ] ] 5 => array:8 [ "identificador" => "fig0030" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 600 "Ancho" => 900 "Tamanyo" => 76935 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">The same eye as in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> three years after allogeneic keratolimbal transplantation. The cornea is clear and, although conjunctival epithelium is beginning to grow in the nasal-inferior zone, the patient still maintains good vision.</p>" ] ] 6 => array:8 [ "identificador" => "fig0035" "etiqueta" => "Fig. 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 675 "Ancho" => 900 "Tamanyo" => 63247 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Aniridia-associated keratopathy with peripheral pannus and subepithelial fibrosis extending into central positions of the cornea.</p>" ] ] 7 => array:8 [ "identificador" => "fig0040" "etiqueta" => "Fig. 8" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr8.jpeg" "Alto" => 1313 "Ancho" => 1750 "Tamanyo" => 248730 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0040" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> Stage III AAK in the RE of a 45-year-old male patient. <span class="elsevierStyleBold">B.</span> Result after a predescemetic DALK <span class="elsevierStyleBold">C.</span> Anterior pole OCT image showing a DALK graft with small deep stromal remnant. <span class="elsevierStyleBold">D.</span> Same patient after placement of an Ahmed valve.</p>" ] ] 8 => array:8 [ "identificador" => "fig0045" "etiqueta" => "Fig. 9" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr9.jpeg" "Alto" => 1114 "Ancho" => 900 "Tamanyo" => 133600 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0045" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> Case of aniridia treated with DALK + amniotic membrane graft. <span class="elsevierStyleBold">B.</span> Anterior pole OCT showing the predescemetic technique with residual stromal bed and amniotic membrane graft applied on the epithelial surface.</p>" ] ] 9 => array:8 [ "identificador" => "fig0050" "etiqueta" => "Fig. 10" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr10.jpeg" "Alto" => 1642 "Ancho" => 2917 "Tamanyo" => 588909 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Fig. 1" "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> 45-year-old patient with congenital aniridia, severe keratopathy and cataract. <span class="elsevierStyleBold">B.</span> After a limbal allograft followed by keratoplasty and cataract extraction, patient exhibited late rejection with opacity of the central graft. Keratoplasty was repeated, but failed again. <span class="elsevierStyleBold">C.</span> Boston type 1 keratoprosthesis was performed with good postoperative results. <span class="elsevierStyleBold">D.</span> OCT-SA shows the good thickness of the graft around the optic cylinder of the keratoprosthesis and the absence of retrocorneal fibrosis or retroprosthetic membrane, as well as the intraocular lens.</p>" ] ] 10 => array:8 [ "identificador" => "fig0055" "etiqueta" => "Fig. 11" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr11.jpeg" "Alto" => 601 "Ancho" => 900 "Tamanyo" => 101758 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0055" "detalle" => "Fig. 1" "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Very dense retrocorneal membrane and opacification of the posterior titanium base holes of the keratoprosthesis due to anterior segment fibrosis syndrome in a 12-year-old girl with congenital aniridia.</p>" ] ] 11 => array:8 [ "identificador" => "fig0060" "etiqueta" => "Fig. 12" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr12.jpeg" "Alto" => 1407 "Ancho" => 2500 "Tamanyo" => 416053 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0060" "detalle" => "Fig. 1" "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> Marked thinning of the corneal graft around the optic cylinder as evidenced by the presence of a circular air bubble in the space below the contact lens. <span class="elsevierStyleBold">B.</span> OCT-SA of the same case showing extreme thinning of the cornea around the optic cylinder of the keratoprosthesis. <span class="elsevierStyleBold">C.</span><span class="elsevierStyleItalic">Candida albicans</span> infection in a Boston keratoprosthesis that required replacement of the piece and complete vitrectomy with intravitreal antifungals. <span class="elsevierStyleBold">D.</span> Patient who did not attend check-ups for one year and presents without contact lens, calcification in the lower area of the prosthesis and two interposed eyelashes.</p>" ] ] 12 => array:8 [ "identificador" => "fig0065" "etiqueta" => "Fig. 13" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr13.jpeg" "Alto" => 1738 "Ancho" => 3000 "Tamanyo" => 582639 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0065" "detalle" => "Fig. 1" "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> Preoperative: central cornea: mixed phenotype. Confocal photo microscopy 1: Area of fibrosis (blue star), neovessel (orange arrow), very poorly defined corneal epithelium (red arrow). Confocal photo microscopy 2: Neovessel (orange arrow) and area of fibrosis (blue star) (x150). <span class="elsevierStyleBold">B.</span> At 12 months postoperative. Central cornea: Corneal phenotype. Photos 1 and 2: Corneal epithelium (red arrow). Photo 2: Langherans cells (blue star) (x150).</p>" ] ] 13 => array:8 [ "identificador" => "fig0070" "etiqueta" => "Fig. 14" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr14.jpeg" "Alto" => 2388 "Ancho" => 2919 "Tamanyo" => 772205 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0070" "detalle" => "Fig. 1" "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A.</span> Central cornea: conjunctival phenotype. Confocal microscopy photos 1 and 2 Goblet cell (purple arrow) (x150). <span class="elsevierStyleBold">B.</span> Postoperative central cornea: corneal phenotype. Confocal microscopy photos 1: Corneal epithelium (red arrow) (x150).</p>" ] ] 14 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0075" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Lopez-Garcia et al.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Stadium \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical signs and symptoms \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Grade 0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absence of signs and symptoms, but cytologic changes. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Grade 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pannus less than 1 mm. Fine epithelial staining with fluorescein-epiphora. Occasional epithelial defects. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Grade 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Circumferential pannus with free visual axis. Photophobia, epiphora, lacrimal instability and epithelial defects (two or more episodes in the last six months). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Grade 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stromal opacity with deposits and fibrosis affecting the corneal center. Chronic inflammation, marked neovascularization and chronic epithelial defects. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2753641.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Clinical classification of congenital congenital aniridia keratopathy.</p>" ] ] 15 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0080" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ALKT, allogeneic limbal keratoplasty; AMT, amniotic membrane transplantation; ILT, total limbar insufficiency; Fe-TCLA, related relative conjunctival-limbbar transplantation; OS, ocular surface; TCMC, cultured stem cell transplantation.</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Taken from: Serna-Ojeda et al.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Surgical technique \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Immunosuppressive protocol \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Etiology of limbic insufficiency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Eyes; n \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medium follow-up \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tsubota et al. <a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1999 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stem cell ring graft, multiple surgeries \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral cyclosporine 5−10 mg/kg and gradual tapering \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe OS disorders, Stevens Johnson (SJS) and pemphigoid, the most frequent. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1163 days average \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelialization in 51% with 35% with clear cornea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Solomon et al. <a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TQLA and TM; in 58.9% simultaneous QPP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral cyclosporine 5 mg/kg and tapered tapering \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective study in patients with ILT, most frequent chemical burn. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 months (12/117.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Survival of ALWT: 76.9%. 1<span class="elsevierStyleSup">er</span> year, 477.4% at 3 years, 23.7% at 5 years. Survival of QPP: 47.8% at 1<span class="elsevierStyleSup">er</span>year. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Maruyama-Hosoi et al. <a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TQLA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclosporine ev. 3 mg/kg starting 1 day preoperatively and daily for 1 week, followed by oral cyclosporine 5 mg/kg. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective study of the characteristics of immunological reactions; SJS and pemphigoid as the most frequent etiologies. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46.6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55.3% had a clear cornea at last exam \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Javadi et al. <a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fe-TCLA and TQLA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclosporine oral 5 mg/kg and reduced to 3 mg/kg after 6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective study of patients with tardive mustard gas keratitis with simultaneous or sequential PPK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">After faith-TCLA 65.6 months (30/102) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25% of the fe-TCLA required ALRT. The rejection-free rate was 52.2% in the fe-TCLA group and 80.7% in the ASET group at 10 months. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">After ALWT, 19.6 months (13/61) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Holland et al. <a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TQLA by 83.8%. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tacrolimus, mycophenolate mofetil and prednisolone (75%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective study of patients with ILT. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">225 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53.9 months (3.6/147.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77.2% had a stable ocular surface \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ang et al. <a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TQLA by 80.6%. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tacrolimus, mycophenolate mofetil and prednisolone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective study of patients with ILT. Congenital aniridia was the most frequent indication. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">222 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62.7 months (12/158.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Immune reaction in 31.3% of eyes; severe reaction in 19.4% and low grade in 11.7%. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baradaran-Rafii et al. <a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TQLA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mycophenolate mofetil 1 g oral and 4 mg tacrolimus oral/12 h starting one week preoperatively and tapering from month 12. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective study of complications after ALTE in different etiologies, the most frequent being chemical caustication. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.1 months (6/48) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.4% had stable SO at last visit \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Parihar et al. <a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2017 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TCMC <span class="elsevierStyleItalic">ex vivo</span> (25 eyes) vs. TQLA (25 eyes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral cyclosporine 5−10 mg/kg and gradual tapering \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chemical/thermal caustication most common in both groups \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 year \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absence of conjunctival revascularization (TCMC: 60%; TQLA: 54.54%) comparable in both groups. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2753640.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Published studies on limbal allograft and allogeneic limbal stem cell transplantation with systemic immunosuppressive regimen (n > 35 patients).</p>" ] ] 16 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0085" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">DALK: deep anterior lamellar keratoplasty; KP: keratoplasty.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">n (keratoplasties) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comparative \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tiller et al. <a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 (26 DALK and 16 KP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Initial visual improvement in the operated group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 non-operated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Similar final visual acuity in both groups \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Greater total visual loss in the non-operated group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">De la Paz et al. <a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">88 (10 limbal transplants and 13 KP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No significant differences between limbar transplantation and KP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 non-operated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Late failure of limbal grafts \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No long-term difference between performing any type of surgery or not. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kremer et al. <a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 KP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- – \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73% improved one line of sight \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64% immune reactions and 27% re-engraftments \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lang et al. <a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 keratolimbic grafts \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ (with other pathologies) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median survival of 3.2 years in aniridia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lower immune response in the congenital aniridia group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gomes et al. <a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 KP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- – \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recurrence of aniridia keratopathy in all cases \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2753639.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Results of keratoplasty in congenital aniridia.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:110 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ocular surface abnormalities in aniridia" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0002-9394(14)72167-1" "Revista" => array:6 [ "tituloSerie" => "Am J Ophthalmol." "fecha" => "1995" "volumen" => "120" "paginaInicial" => "368" "paginaFinal" => "375" "link" => array:1 [ …1] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of aniridic keratopathy with keratolimbal allograft: a limbal stem cell transplantation technique" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0161-6420(02)01451-3" "Revista" => array:6 [ "tituloSerie" => "Ophthalmology." "fecha" => "2003" "volumen" => "110" "paginaInicial" => "125" "paginaFinal" => "130" "link" => array:1 [ …1] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Analysis of corneal morhhological and pathologic changes in early-stage congenital aniridic keratopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.18240/ijo.2017.03.09" "Revista" => array:6 [ "tituloSerie" => "Int J Ophthalmol." "fecha" => "2017" "volumen" => "10" "paginaInicial" => "378" "paginaFinal" => "384" "link" => array:1 [ …1] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Corneal abnormalities in Pax6+/- small eye mice mimic human aniridia-related keratopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1167/iovs.02-0576" "Revista" => array:6 [ "tituloSerie" => "Invest Ophthalmol Vis Sci." "fecha" => "2003" "volumen" => "44" "paginaInicial" => "1871" "paginaFinal" => "1878" "link" => array:1 [ …1] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congenital aniridia: etiology, manifestations and management" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1586/17469899.2016.1152182" "Revista" => array:6 [ "tituloSerie" => "Expert Rev Ophthalmol." "fecha" => "2016" "volumen" => "11" "paginaInicial" => "135" "paginaFinal" => "144" "link" => array:1 [ …1] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evolving concepts on the pathogenic mechanisms of aniridia related keratopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.biocel.2004.09.002" "Revista" => array:6 [ "tituloSerie" => "Int J Biochem Cell Biol." "fecha" => "2005" "volumen" => "37" "paginaInicial" => "547" "paginaFinal" => "557" "link" => array:1 [ …1] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Primary defects in the lens underlies complex anterior segment abnormalities of the Pas6 heterozygous eye" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.161144098" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci USA." "fecha" => "2001" "volumen" => "98" "paginaInicial" => "9688" "paginaFinal" => "9693" "link" => array:1 [ …1] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Control of patterns of corneal innervation by PAX6" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Inves Ophthalmol Vis Sci." "fecha" => "2009" "volumen" => "50" "paginaInicial" => "1122" "paginaFinal" => "1128" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pax6; a pleiotropic player in development" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/bies.10174" "Revista" => array:6 [ "tituloSerie" => "Bioessays." "fecha" => "2002" "volumen" => "24" "paginaInicial" => "1041" "paginaFinal" => "1051" "link" => array:1 [ …1] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of corneal keratin-12 gene expression by the human Kruppel-like transcription factor 6" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Invest Ophthalmol Vis Sci." "fecha" => "2002" "volumen" => "43" "paginaInicial" => "3422" "paginaFinal" => "3429" "link" => array:1 [ …1] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Requirement for Pax6 in corneal morphogenesis: a role in adhesion" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1242/jcs.00441" "Revista" => array:6 [ "tituloSerie" => "J Cell Sci." "fecha" => "2003" "volumen" => "116" "paginaInicial" => "2157" "paginaFinal" => "2167" "link" => array:1 [ …1] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s1350-9462(01)00015-5" "Revista" => array:6 [ "tituloSerie" => "Prog Retin Eye Res." "fecha" => "2002" "volumen" => "21" "paginaInicial" => "1" "paginaFinal" => "14" "link" => array:1 [ …1] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pax-6 expression and activity are induced in the reepithelializing cornea and control activity of the transcriptional promoter for matrix metalloproteinase gelatinase B" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1006/dbio.2000.9694" "Revista" => array:6 [ "tituloSerie" => "Dev Biol." "fecha" => "2000" "volumen" => "222" "paginaInicial" => "41" "paginaFinal" => "54" "link" => array:1 [ …1] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early phenotypic features of aniridia-associated keratopathy and association with PAX6 coding mutations" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jtos.2019.11.002" "Revista" => array:6 [ "tituloSerie" => "The Ocular Surface." "fecha" => "2020" "volumen" => "18" "paginaInicial" => "130" "paginaFinal" => "140" "link" => array:1 [ …1] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congenital aniridia keratopathy treatment" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4321/s0365-66912006000800004" "Revista" => array:6 [ "tituloSerie" => "Arch Soc Esp Oftalmol." "fecha" => "2006" "volumen" => "81" "paginaInicial" => "435" "paginaFinal" => "444" "link" => array:1 [ …1] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Corneal changes in aniridia" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0002-9394(79)90238-1" "Revista" => array:6 [ "tituloSerie" => "Am J Ophthalmol." "fecha" => "1979" "volumen" => "87" "paginaInicial" => "497" "paginaFinal" => "502" "link" => array:1 [ …1] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathologic epithelial and anterior corneal nerve morphology in early-stage congenital aniridic keratopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ophtha.2012.02.043" "Revista" => array:6 [ "tituloSerie" => "Ophthalmology." "fecha" => "2012" "volumen" => "119" "paginaInicial" => "1803" "paginaFinal" => "1810" "link" => array:1 [ …1] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asociation of aniridia and dry eyes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Opthalmology." "fecha" => "2005" "volumen" => "112" "paginaInicial" => "1535" "paginaFinal" => "1540" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autologous serum eyedrops in the treatment of aniridic keratopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ophtha.2007.03.087" "Revista" => array:6 [ "tituloSerie" => "Ophthalmology." "fecha" => "2008" "volumen" => "115" "paginaInicial" => "262" "paginaFinal" => "267" "link" => array:1 [ …1] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Keratopathy, cataract, and dry eye in a survey of aniridia subjects" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2147/OPTH.S74648" "Revista" => array:6 [ "tituloSerie" => "Clin Ophthalmol." "fecha" => "2015" "volumen" => "9" "paginaInicial" => "291" "paginaFinal" => "295" "link" => array:1 [ …1] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estudio del ojo seco en pacientes con aniridia congénita mediante citología de impresión" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Soc Esp Oftalmol." "fecha" => "2003" "volumen" => "78" "paginaInicial" => "615" "paginaFinal" => "622" "link" => array:1 [ …1] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Topographical distribution of ocular surface cells by the use of impression cytology" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1755-3768.1991.tb04830.x" "Revista" => array:6 [ "tituloSerie" => "Acta Ophthalmol (Copenh)." "fecha" => "1991" "volumen" => "69" "paginaInicial" => "371" "paginaFinal" => "376" "link" => array:1 [ …1] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impression cytology on conjunctiva and cornea in dry eye patients establishes a correlation between squamous metaplasia and dry eye clinical severity" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/112067210301300201" "Revista" => array:6 [ "tituloSerie" => "Eur J Ophthalmol." "fecha" => "2003" "volumen" => "13" "paginaInicial" => "115" "paginaFinal" => "127" "link" => array:1 [ …1] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Changes in corneal expression of MUC5AC after autologous serum eyedrop treatment in patients with limbal stem cell deficiency" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/02713683.2019.1607394" "Revista" => array:6 [ "tituloSerie" => "Curr Eye Res." "fecha" => "2019" "volumen" => "44" …3 ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Use of autologous serum in ophthalmic practice" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4321/s0365-66912007000100004" "Revista" => array:6 [ …6] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Topical bevacizumab treatment in aniridia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10792-017-0605-4" "Revista" => array:6 [ …6] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI70462" "Revista" => array:6 [ …6] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Contact lens-induced limbal stem cell deficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jtos.2016.06.003" "Revista" => array:6 [ …6] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of congenital aniridia-associated keratopathy: long-term outcomes from a tertiary referral center" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ajo.2019.11.003" "Revista" => array:6 [ …6] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "UV lighr-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41598-018-36161-1" "Revista" => array:4 [ …4] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment options for nystagmus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The use of contact lenses for visual rehabilitation: optical and therapeutic applications" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/cxo.12562" "Revista" => array:6 [ …6] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EyePrintPRO therapeutic scleral contact lens: indications and outcomes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jcjo.2017.07.026" "Revista" => array:6 [ …6] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Trasplante de limbo alogénico" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ …5] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systemic immunosuppression for limbal allograft and allogenic limbal epithelial cell transplantation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Manegement of aniridic keratopathy with keratolimbal allograft: a limbal stem cell transplantation technique" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0161-6420(02)01451-3" "Revista" => array:6 [ …6] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Limbal stem cell transplantation: new progresses and challenges" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/eye.2008.379" "Revista" => array:6 [ …6] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ocular surface stem cell transplantation rejection: incidence, characteristics, and outcomes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0b013e318255eac4" "Revista" => array:6 [ …6] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0161-6420(95)30841-x" "Revista" => array:6 [ …6] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term outcome of keratolimbal allograft with or without penetrating keratoplasty for total limbal stem cell deficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0161-6420(02)00960-0" "Revista" => array:6 [ …6] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Changes observed in keratolimbal allograft" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.ico.0000176608.65708.27" "Revista" => array:6 [ …6] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of mustard gas-induced limbal stem cell deficiency and keratitis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ophtha.2010.11.012" "Revista" => array:6 [ …6] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systemic immunosuppression in ocular surface stem cell transplantation: results of a 10-year experience" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0b013e31823f8b0c" "Revista" => array:6 [ …6] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Complications of keratolimbal allograft surgery" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0b013e31826215eb" "Revista" => array:6 [ …6] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Allogenic cultivated limbal stem cell transplantation versus cadaveric keratolimbal allograft in ocular surface disorder: 1-year outcome" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10792-016-0415-0" "Revista" => array:6 [ …6] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathologic epithelial and anterior corneal nerve morphology in early-stage congenital aniridic keratopathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ophtha.2012.02.043" "Revista" => array:6 [ …6] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of aniridia and dry eyes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ophtha.2005.04.014" "Revista" => array:6 [ …6] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The influence of keratoplasty on visual prognosis in aniridia: a historical review of one large family" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/00003226-200303000-00004" "Revista" => array:6 [ …6] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term visual prognosis of corneal and ocular surface surgery in patients with congenital aniridia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1755-3768.2008.01293.x" "Revista" => array:6 [ …6] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cultivated oral mucosa epithelium in ocular surface reconstruction in aniridia patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2015/150603" "Revista" => array:4 [ …4] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical outcomes from cultivated allogenic stem cells vs. oral mucosa epithelial transplants in total bilateral stem cells deficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fmed.2020.00043" "Revista" => array:5 [ …5] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "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" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5966/sctm.2013-0025" "Revista" => array:6 [ …6] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term outcomes of allogeneic ocular surface reconstruction: keratolimbal allograft (KLAL) followed by penetrating keratoplasty (PK)" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ …3] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Histopathology findings of corneal buttons in congenital aniridia patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000444930" "Revista" => array:6 [ …6] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deep anterior lamellar keratoplasty using irradiated acellular cornea with amniotic membrane transplantation for intractable ocular surface diseases" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3341/kjo.2015.29.2.79" "Revista" => array:6 [ …6] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0280" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homologous lamellar central limbokeratoplasty in severe limbal stem cell deficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2008-1034984" "Revista" => array:6 [ …6] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0285" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Results of penetrating keratoplasty in aniridia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0002-9394(14)73581-0" "Revista" => array:6 [ …6] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0290" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term results of allogenic penetrating limbo-keratoplasty: 20 years of experience" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/eye.2016.217" "Revista" => array:6 [ …6] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0295" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recurrent keratopathy after penetrating keratoplasty for aniridia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0300" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Surgical and visual outcomes of the type I Boston Keratoprosthesis for the management of aniridic fibrosis syndrome in congenital aniridia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ajo.2011.10.027" "Revista" => array:6 [ …6] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0305" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glaucoma management in patients with aniridia and Boston type 1 keratoprostheses" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ajo.2019.06.018" "Revista" => array:6 [ …6] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0310" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of aniridia with Boston type I keratoprostheses" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0b013e318281724a" "Revista" => array:6 [ …6] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0315" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "No light perception outcomes following Boston keratoprosthesis type 1 surgery" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ajo.2017.06.012" "Revista" => array:6 [ …6] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0320" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glaucoma progression and role of glaucoma surgery in patients with Boston keratoprostheses" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0000000000000067" "Revista" => array:6 [ …6] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0325" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Infectious keratitis after Boston type 1 keratoprostheses implantation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0b013e318245c02a" "Revista" => array:6 [ …6] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0330" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stem cells application in regenerative medicine and disease therapeutics»" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ …3] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0335" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stem cell therapy for corneal epithelium regeneration following good manufacturing and clinical procedures" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2015/150603" "Revista" => array:4 [ …4] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0340" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Artificial human corneas. Scaffolds for transplantation and host regeneration" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0345" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic modulation of growth factors and cytokines in regenerative medicine" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2174/138161206777699007" "Revista" => array:6 [ …6] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0350" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(96)11188-0" "Revista" => array:6 [ …6] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0355" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Limbal stem cell transplantation: an evidence-based analysis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0360" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The History of Ophthalmology" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:5 [ …5] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0365" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:1 [ "host" => array:1 [ 0 => array:1 [ "Libro" => array:5 [ …5] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0370" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Plinio el Viejo, Cayo. Historia Naturalis (Siglo I). Traducción de G. Huerta. Madrid: Impr. L. Sánchez, 1624. Lib. 28, cap 7, y Lib. 36, caps 20 y 21." ] ] ] 74 => array:3 [ "identificador" => "bib0375" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.exer.2004.07.008" "Revista" => array:6 [ …6] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0380" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The elaboration, use and evaluation of eye-drops with autologous serum in corneal lesions" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0385" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activations in the mouse mammary gland" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.M011248200" "Revista" => array:6 [ …6] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0390" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autologous serum application in the treatment of neurotrophic keratopathy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ophtha.2003.10.019" "Revista" => array:6 [ …6] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0395" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in vitro toxicity studies" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bjo.85.10.1188" "Revista" => array:6 [ …6] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib0400" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Opthalmic use of blood-derived products" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.survophthal.2015.03.003" "Revista" => array:6 [ …6] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib0405" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autologous serum eyedrops for ocular surface disorders" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bjo.2004.044347" "Revista" => array:6 [ …6] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib0410" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of clinical efficacies of autologous serum eye drops in patients with primary and secondary Sjögren syndrome" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0000000000000147" "Revista" => array:6 [ …6] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib0415" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Platelet-rich plasma: growth factors and pro-inflammatory properties" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1902/jop.2007.060302" "Revista" => array:6 [ …6] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib0420" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PRGF exerts more potent proliferative and antinflammatory effects than autologous serum on a cell culture inflammatory model" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.exer.2016.08.012" "Revista" => array:6 [ …6] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib0425" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Corneal wound healing promoted by 3 blood derivates: an in vitro and in vivo comparative study" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib0430" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Implementation of standardized method for the production of allogenic serum eye drops from regular blood donors in a Norwegian University Hospital: some methodological aspects and clinical considerations" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.transci.2015.05.014" "Revista" => array:6 [ …6] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib0435" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Umbilicalcord blood serum therapy for the management of persistant epithelial defects" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3980/j.issn.2222-3959.2014.05.12" "Revista" => array:6 [ …6] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib0440" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of amniotic membrane suspension in human corneal wound healing in vitro" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 88 => array:3 [ "identificador" => "bib0445" "etiqueta" => "89" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Trasplante de membrana amniótica en el tratamiento de la insuficiencia limbal moderada de pacientes con aniridia congénita" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4321/s0365-66912005000900005" "Revista" => array:6 [ …6] ] ] ] ] ] 89 => array:3 [ "identificador" => "bib0450" "etiqueta" => "90" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "In sickness and in health: corneal epithelial stem cell biology, pathology and therapy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.exer.2009.09.023" "Revista" => array:6 [ …6] ] ] ] ] ] 90 => array:3 [ "identificador" => "bib0455" "etiqueta" => "91" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of functional limbal epithelial stem cell isolation methods" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.exer.2015.12.002" "Revista" => array:6 [ …6] ] ] ] ] ] 91 => array:3 [ "identificador" => "bib0460" "etiqueta" => "92" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful consecutive expansion of limbal explants using a biosafe culture medium under feeder layer-free conditions" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/02713683.2016.1250278" "Revista" => array:6 [ …6] ] ] ] ] ] 92 => array:3 [ "identificador" => "bib0465" "etiqueta" => "93" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "In vivo confocal microscopy assessment of the corneoscleral limbal stem cell niche before and after biopsy for cultivated limbal epithelial transplantation to restore corneal epithelium" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.14670/HH-30.183" "Revista" => array:6 [ …6] ] ] ] ] ] 93 => array:3 [ "identificador" => "bib0470" "etiqueta" => "94" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Limbal stem-cell therapy and long-term corneal regeneration" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0905955" "Revista" => array:6 [ …6] ] ] ] ] ] 94 => array:3 [ "identificador" => "bib0475" "etiqueta" => "95" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Concise review: mesenchymal stem cells and translational medicine: emerging issues" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 95 => array:3 [ "identificador" => "bib0480" "etiqueta" => "96" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mesenchymal stem cells for treating ocular surface diseases" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12886-015-0138-4" "Revista" => array:5 [ …5] ] ] ] ] ] 96 => array:3 [ "identificador" => "bib0485" "etiqueta" => "97" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adult mesenchymal stem cells: Differentiation potential and therapeutic applications" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4103/0022-3859.32215" "Revista" => array:6 [ …6] ] ] ] ] ] 97 => array:3 [ "identificador" => "bib0490" "etiqueta" => "98" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human mesenchymal stem cells modulate allogenic immune cell responses" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2004-04-1559" "Revista" => array:6 [ …6] ] ] ] ] ] 98 => array:3 [ "identificador" => "bib0495" "etiqueta" => "99" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic effect of human adipose tissue-derived mesenchymal stem cells in experimental corneal failure due to limbal stem cell niche damage" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/stem.2672" "Revista" => array:6 [ …6] ] ] ] ] ] 99 => array:3 [ "identificador" => "bib0500" "etiqueta" => "100" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A proof-of-concept clinical trial using mesenchymal stem cells for the treatment of corneal epithelial stem cell deficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.trsl.2018.11.003" "Revista" => array:6 [ …6] ] ] ] ] ] 100 => array:3 [ "identificador" => "bib0505" "etiqueta" => "101" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bjophthalmol-2011-301164" "Revista" => array:6 [ …6] ] ] ] ] ] 101 => array:3 [ "identificador" => "bib0510" "etiqueta" => "102" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The successful culture and autologous transplantation of rabbit oral mucosal epithelial cells on amniotic membrane" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 102 => array:3 [ "identificador" => "bib0515" "etiqueta" => "103" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Induced pluripotent stem cells: past, present and future" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.stem.2012.05.005" "Revista" => array:6 [ …6] ] ] ] ] ] 103 => array:3 [ "identificador" => "bib0520" "etiqueta" => "104" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congenital aniridia: etiology, manifestations and management" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1586/17469899.2016.1152182" "Revista" => array:6 [ …6] ] ] ] ] ] 104 => array:3 [ "identificador" => "bib0525" "etiqueta" => "105" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adipose-derived stem cells are a source for cell therapy of the corneal stroma" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1634/stemcells.2007-0653" "Revista" => array:6 [ …6] ] ] ] ] ] 105 => array:3 [ "identificador" => "bib0530" "etiqueta" => "106" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Topical application of autologous adipose-derived mesenchymal stem cells (MSCs) for persistent sterile corneal epithelial defect" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00417-011-1841-3" "Revista" => array:6 [ …6] ] ] ] ] ] 106 => array:3 [ "identificador" => "bib0535" "etiqueta" => "107" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cellular therapy with human autologous adipose-derived adult stem cells for advanced keratoconus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ICO.0000000000001228" "Revista" => array:6 [ …6] ] ] ] ] ] 107 => array:3 [ "identificador" => "bib0540" "etiqueta" => "108" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acellular human corneal matrix sheets seeded with human adipose-derived mesenchymal stem cells integrate functionally in an experimental animal model" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.exer.2015.01.020" "Revista" => array:6 [ …6] ] ] ] ] ] 108 => array:3 [ "identificador" => "bib0545" "etiqueta" => "109" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Corneal stroma enhancement with decellularized stromal laminas with or without stem cell recellularization for advanced keratoconus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ajo.2017.10.026" "Revista" => array:6 [ …6] ] ] ] ] ] 109 => array:3 [ "identificador" => "bib0550" "etiqueta" => "110" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cellular therapy of the corneal stroma: a new type of corneal surgery for keratoconus and corneal dystrophies" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s40662-018-0122-1" "Revista" => array:5 [ …5] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735794/00000096000000S1/v1_202111240624/S2173579421001626/v1_202111240624/en/main.assets" "Apartado" => array:4 [ "identificador" => "58824" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => 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