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The retinogram is unremarkable in the right eye (A). The left eye shows chorioretinal atrophy with pigment distribution following the inferior temporal arcade and a lamellar hole (B). The autofluorescence image of the right eye is unaltered (C) and the left eye shows a hypoautofluorescent area with defined borders in the area of the lesion (D).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.C. Castaño Silos, I. Sanchez-Guillen, I. Almorín-Fernández-Vigo, M. Jerez Fidalgo, J.I. Fernández-Vigo" "autores" => array:5 [ 0 => array:2 [ "nombre" => "J.C." "apellidos" => "Castaño Silos" ] 1 => array:2 [ "nombre" => "I." "apellidos" => "Sanchez-Guillen" ] 2 => array:2 [ "nombre" => "I." "apellidos" => "Almorín-Fernández-Vigo" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "Jerez Fidalgo" ] 4 => array:2 [ "nombre" => "J.I." "apellidos" => "Fernández-Vigo" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0365669123000011" "doi" => "10.1016/j.oftal.2022.12.006" "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/S0365669123000011?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S217357942300018X?idApp=UINPBA00004N" "url" => "/21735794/0000009800000004/v2_202304071550/S217357942300018X/v2_202304071550/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2173579423000294" "issn" => "21735794" "doi" => "10.1016/j.oftale.2023.03.004" "estado" => "S300" "fechaPublicacion" => "2023-04-01" "aid" => "2079" "copyright" => "The Author(s)" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Arch Soc Esp Oftalmol. 2023;98:213-9" "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">Original article</span>" "titulo" => "IMPULSE Study: Impact of COVID-19 in the present of ophthalmology focusing on ocular surface and future trends" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "213" "paginaFinal" => "219" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estudio IMPULSO: impacto de la COVID-19 en el presente de la oftalmología centrada en superficie ocular y tendencias de futuro" ] ] "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" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1153 "Ancho" => 2925 "Tamanyo" => 287845 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0110" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Impact of lack of presence on ophthalmic patient follow-up and diagnostic accuracy during the pandemic. Percentages of agreement according to an ordinal Likert-type scale from 1 to 9.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.M Benítez del Castillo, N. Alejandre Alba, I. Henares, M.P. Ferraris, M. Águila" "autores" => array:5 [ 0 => array:2 [ "nombre" => "J.M" "apellidos" => "Benítez del Castillo" ] 1 => array:2 [ "nombre" => "N." "apellidos" => "Alejandre Alba" ] 2 => array:2 [ "nombre" => "I." "apellidos" => "Henares" ] 3 => array:2 [ "nombre" => "M.P." "apellidos" => "Ferraris" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "Águila" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579423000294?idApp=UINPBA00004N" "url" => "/21735794/0000009800000004/v2_202304071550/S2173579423000294/v2_202304071550/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Effectiveness of topical insulin for the treatment of surface corneal pathologies" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "220" "paginaFinal" => "232" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M.P. Castro Mora, J. Palacio Varona, B. Perez Riaño, C. Laverde Cubides, D.V. Rey-Rodriguez" "autores" => array:5 [ 0 => array:4 [ "nombre" => "M.P." "apellidos" => "Castro Mora" "email" => array:1 [ 0 => "mpcastro@unbosque.edu.co" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Palacio Varona" ] 2 => array:2 [ "nombre" => "B." "apellidos" => "Perez Riaño" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Laverde Cubides" ] 4 => array:2 [ "nombre" => "D.V." "apellidos" => "Rey-Rodriguez" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Universidad El Bosque, Bogotá, Cundinamarca, Colombia" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectividad de la insulina tópica en el tratamiento de patologías de la superficie corneal" ] ] "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" => 2370 "Ancho" => 2508 "Tamanyo" => 228514 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Flowchart for articles selection.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Epithelial lesions can favor the appearance of infections, ulcers, perforations, and corneal scars that lead to significant loss of vision. Although the incidence of persistent epithelial defects (PED) is unknown, studies based on its etiology estimate an annual incidence of less than 200,000 cases in the United States.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Even so, the approach should be timely due to the possible complications that can lead to functional loss of the eyeball.</p><p id="par0010" class="elsevierStylePara elsevierViewall">There are traditional treatments for the therapeutic approach of ocular surface pathologies, among which are the use of artificial tears, prophylactic antibiotics, anti-inflammatories, therapeutic contact lenses, autologous serum, umbilical cord serum, platelet-rich plasma, immunosuppressants and surgical techniques such as use of amniotic membrane and debridement.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Novel treatments related to topical insulin have been used for pathologies of the ocular surface, where it is believed that insulin, being an anabolic protein, has been associated with the mechanisms of cell growth and differentiation.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Different insulin and IGF receptors are found on the corneal surface (insulin-like growth factors) that aid cell migration and normalize the growth and development of corneal epithelial cells. These receptors are found in keratocytes and in the epithelial cells of the cornea, and are essential in the regeneration activity of the corneal surface.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> Topical insulin in low concentrations has been a promoter of cell migration, stabilizing corneal enzymes and regulating its biological environment.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> Insulin has been shown to be safe for topical ocular use in humans.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Therefore, it is deemed as an optimal therapy in the treatment of ocular surface pathologies.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Although there is limited information to date regarding the efficiency of topical insulin treatment in corneal surface pathologies, satisfactory results have been reported in various studies on the use of this therapy in PED and neurotrophic ulcers. Several of these studies showed that this treatment can accelerate and promote re-epithelialization. Furthermore, this therapy showed excellent tolerance in the participants.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,7,8</span></a> The purpose of this study is to identify, through a systematic literature review, the current evidence regarding the effectiveness of topical insulin treatment in ocular surface pathologies.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">A review of literature was conducted based on worldwide information, in order to identify information related to clinical results on the use of topical insulin as a treatment for ocular surface defects through primary studies.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Literature search</span><p id="par0030" class="elsevierStylePara elsevierViewall">The search strategy was prepared from the identification of keywords such as "insulin" and "cornea" or "corneal" or "dry eye" and the search lines were combined with the Boolean operators AND, OR and NOT.</p><p id="par0035" class="elsevierStylePara elsevierViewall">A literature search was implemented in Medline (Pubmed), Embase and Web Of Science medical indexing databases in December 2022 through the search strategy for Medline (Pubmed): (topical [All Fields] AND ("insulin "[MeSH Terms] OR" insulin "[All Fields])) AND (" cornea "[MeSH Terms] OR" cornea "[All Fields] OR" corneal "[All Fields]) NOT (" animals "[MeSH Terms: noexp] OR animals [All Fields])) AND ("2011/03/28" [PubDate]: "2022/12/26" [PubDate]) and ("dry eye syndromes" [MeSH Terms] OR ("dry" [All Fields] AND "eye" [All Fields] AND "syndromes" [All Fields]) OR "dry eye syndromes" [All Fields] OR ("dry" [All Fields] AND "eye" [All Fields]) OR "dry eye" [All Fields]) AND ("insulin" [MeSH Terms] OR "insulin" [All Fields]) NOT ("animals" [MeSH Terms: noexp] OR animals [All Fields]) AND ("2011/03/28 "[PDat]:" 2022/12/26 "[PDat]), for Embase: insulin AND cornea * AND eye * NOT animal AND [2011−2022] / py and finally for Web of Science; topical AND insulin 'AND corneal OR cornea NOT animals AND dry eye along with selection of filters from “main collection of Web of Science”, customization of year ranges from 2011−2022 and selection of SCI-EXPANDED.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Likewise, the references of the selected papers and grey literature were consulted in OpenGrey, The Electronic Theses Online Service (EThOS), Doctoral theses on the network (TDR in Spanish). The inclusion criteria in this review were observational and experimental studies reporting on topical insulin treatment of epithelial defects, dry eye, or other ocular surface pathologies treated in humans.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The systematic literature review was registered on PROSPERO with the code CRD42021254692.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Study selection</span><p id="par0050" class="elsevierStylePara elsevierViewall">The initial selection included the individual reading of titles and abstracts (MC, JP, and BP) and disagreements were resolved by consensus. Out of 100 documents subjected to review of the abstracts, 11 were chosen for a complete review of the text. The content of each paper was checked regarding the availability of information on topical insulin as a treatment for ocular surface pathologies; since they were non-duplicate articles, that included the inclusion criteria (Presence of "insulin" AND "cornea" or "corneal" or "dry eye" in the title or abstract and topical insulin treatment), and two were excluded, since it referred to minutes of a presentation in a congress with patients that were used in a later study and the second one wasn't found the full text article. In addition, a systematic review protocol was developed based on the PRISMA statement (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">The studies included 180 participants, ranging in age from 2 to 95 years. The studies were carried out in 7 countries: the United States, Spain, Ireland, Canada, Portugal and Malaysia. The following data was found: 1 randomized, controlled, double-blind clinical trial, 1 prospective non-randomized clinical trial, 4 retrospective studies, and 3 case reports. These were performed between 2013 and 2021, including patients with refractory persistent epithelial defects and induced during vitreoretinal surgery. Within the information obtained from the different studies, the ophthalmological history and management provided prior to topical insulin therapy were considered. Differences in the extent of the lesions (3,75<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> to 65.47<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span>) and healing time (from 2.5 days to 60.9 days) were documented.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Within the case reports, Fobelo, et al. 2020 in Spain refer to a 41-year-old female patient with an ocular burn secondary to caustics caused by a splash of car battery content. With medical management since 2015 and different treatments including: debridement, therapeutic contact lenses, tobramycin, dexamethasone, atropine, autologous serum, and artificial tears. At the end of that year, she had a corneal perforation with prolapse of the iris for which management with penetrating keratoplasty was indicated, in addition to covering with amniotic membrane, and use of corticosteroids for a postoperative remaining lesion requiring corneal trepanation in 2017. In 2019, after 4 years of persistence of the corneal ulcer, management of the lesion was started with topical insulin (50 IU/mL, no type or brand of insulin or the vehicle was reported) applying 1 drop every 4<span class="elsevierStyleHsp" style=""></span>h with complete resolution of the defect to within two months of starting topical insulin therapy.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> This case was the one in which the longest healing time of the corneal lesion was documented in the review performed.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In 2020, in Canada, Tong, et al. describes another case report of a 55-year-old patient with poorly controlled diabetes mellitus, severe hypoesthesia, and bilateral neurotrophic keratitis. In addition, epithelial defects with extensions of 7.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4.5<span class="elsevierStyleHsp" style=""></span>mm in the right eye (OD) and 5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>mm in the left eye (OS), both with raised borders and corneal neovascularization that extended from the lower limbus to the borders of both ulcers, presenting visual acuity of OD 20/150 and OS 20/200, without evidence of diabetic retinopathy. He was initially managed with topical lubricants without preservatives, topical moxifloxacin 3 times a day, oral valacyclovir 500<span class="elsevierStyleHsp" style=""></span>mg twice a day, topical prednisolone 1% (for suspected herpetic keratitis), therapeutic contact lenses, and bilateral temporal tarsorrhaphy without improvement of the ulcers. Subsequently, treatment with topical insulin was established at a concentration of 25 IU/mL (type or brand of insulin or the vehicle used was not reported) and a dose of 1 drop 6 times a day in both eyes. One week after starting treatment with topical insulin, epithelialization of the ulcers, improvement in ocular comfort and visual acuity of OD 20/70 and OS 20/200 were evidenced. Central corneal <span class="elsevierStyleItalic">haze</span> was greater in the OS.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The last case report found was described in 2019 by Bourke, et al., in Ireland, in which an 8-year-old patient with a history of type 2 neurofibromatosis and meningioma of the left optic nerve with ipsilateral corneal denervation is presented. This patient developed a neurotrophic corneal ulcer that was being treated with dexamethasone drops and eye lubricants. In a follow-up after a swimming pool immersion, hypopyon with a lower corneal infiltrate of 5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm was identified, for which in-hospital management was provided with vancomycin and topical ceftazidime and oral ciprofloxacin. The hypopyon was slowly reduced with this treatment. She received 7 days of topical antibiotics and a lateral tarsorrhaphy was performed. She was discharged with topical prednisolone, ophthalmic ointment with vitamin A, sodium hyaluronate and chloramphenicol ointment. One week later, management was started with topical insulin (Actrapid insulin in polyethylene glycol and propylene glycol -Systane- at a concentration of 1 IU/ml) 3 times a day in OS. After this, the decrease in the size of the corneal ulcer is described. However, it is not mentioned whether the re-epithelialization was complete or the time of it.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A non-randomized prospective clinical trial was found, which was carried out in Spain and published in 2020 by Diaz, et al. This trial included 21 participants with a diagnosis of persistent epithelial defects that were refractory to conventional treatment. Hence, management was provided with topical insulin 4 times a day (regular insulin based on polyethylene glycol and propylene glycol) at a concentration of 1 IU / ml. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the treatment prior to the use of insulin, finding that 100% (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>21) of the participants received artificial tears, 86% (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>18) received antibiotics and 62% (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>13) used therapeutic contact lenses. Regarding the re-epithelialization of the PED, this was complete in 17 participants (average of days 34.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>29.9) and incomplete in 4 (average reduction of the area of ​​91.5%). Therefore, it was considered that topical insulin can accelerate this re-epithelialization, with excellent tolerance, since only a single adverse event was reported (crystalline keratopathy), which is believed to be secondary to the chronic use of topical steroids.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Regarding the retrospective studies, 4 were documented. The first of them in 2017 by Wang, et al. in the United States provides 6 cases of patients with neurotrophic ulcers or epithelial defects refractory to standard medical and surgical treatment (therapeutic contact lenses, amniotic membrane graft and permanent tarsorrhaphy), for which the use of regular insulin drops in artificial tears (polyethylene glycol and propylene glycol base) was indicated at a concentration of 1 IU/ml 2–3<span class="elsevierStyleHsp" style=""></span>g times a day. The patients included, with age ranges from 2 to 73 years, presented complete corneal re-epithelialization within 7–25 days.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In the second retrospective study published in 2013 by Bastion, et al., in Malaysia, the use of topical insulin was analyzed in 15 diabetic patients who required corneal debridement during vitrectomy. The patients were classified into three groups (DTI: diabetic patients who received 1 IU / drop of Actrapid insulin (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5); DTC: diabetic patients treated with conventional management (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5); and NDTC: non-diabetic patients with postoperative conventional management (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5). The topical insulin preparation was 250 IU in 2.5<span class="elsevierStyleHsp" style=""></span>ml (50 IU/ml) of normal saline with application 4 times a day and the postoperative conventional management was with dexamethasone and topical ciprofloxacin. It was identified that patients treated with topical insulin re-epithelialized in an average time of 60<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>h, while diabetic and non-diabetic patients treated with conventional therapy re-epithelialized in an average time of 78<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>h and 65<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>31<span class="elsevierStyleHsp" style=""></span>h, respectively.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The third retrospective, observational single center study by Soares, et al. in 2021 included 20 patients from Espinho; Portugal. Each one of those had a diagnosis of Neurotrophic keratopathy stage 2 (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11 eyes) o stage 3 (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>20 eyes) who reported therapeutic failure to standard medical or surgical treatment. Topical insulin drops were applied 4 times per day at a concentration 1IU fast-acting insulin / 1<span class="elsevierStyleHsp" style=""></span>ml propylene glycol, preserved at 2<span class="elsevierStyleHsp" style=""></span>°Celsus and a contact lens was placed; brand of insulin used were not reported. 19 of the 21 eyes (90%) had complete re-epithelialization being shorter for stage 2 (18<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>9 days) than for stage 3 (29<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11 days) presenting a statistically significant difference (P<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,025). The 2 cases with partial closure, contact lenses could not be placed, one had paralytic lagophthalmos (after temporary tarsorrhaphy the re-epithelialization was complete) and for the second one, the reason was not reported. The differences in time between stage 2 and 3 were expected because stage 3 has more severe wounds.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The fourth and last retrospective, consecutive case–control series study in 2021 by Diaz, et al. in Spain. This trial included 61 participants with a diagnosis of persistent epithelial defects treated with topical insulin (case group) and 23 treated with autologous serum (control group). The insulin eye drops were prepared at a concentration of 1 IU/mL, using fast-acting insulin (Actarapid) diluted in a polyethylene glycol and polypropylene glycol base. All insulin patients were prescribed insulin eye drops every 6<span class="elsevierStyleHsp" style=""></span>h (four times a day). Epithelization was achieved in 51 patients (84%) on insulin and 11 patients (48%) on autologous serum. In patients where PED closure was achieved, the mean time until reepithelization was 32.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>28.3 days (range 4–124) in the insulin group and 82.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>82.4 days (range 13–231) in the autologous serum group. PED recurrence was higher in patients treated on autologous serum (10 patients; 43%) compared with insulin (7 patients; 11%). Topical insulin was well tolerated, and no adverse events were reported with the treatment.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Finally, in a controlled, randomized, double-blind clinical study, Fai, et al. in 2017 in Malaysia, the effect of topical insulin was determined in 3 different concentrations in diabetic patients with induced epithelial defects (debridement) during vitrectomy. 32 patients were included, who were randomized into 4 different groups, each with 8 patients: Control group (DNS) with instillation of drops of normal saline solution; Group DTI 0.5: with instillation of topical insulin at a concentration of 0.5 IU / drop (25 IU / ml); Group DTI 1: with instillation of topical insulin at a concentration of 1 IU/drop (50 IU/ml) and Group DTI 2: with instillation of topical insulin at a concentration of 2 IU/drop (100 IU/ml). For patients in all groups, the dosage was 4 times a day. It was found that the patients in the group with insulin use at a concentration of 0.5 IU/drop was superior to the other groups with 100% of the patients having re-epithelialization at 72<span class="elsevierStyleHsp" style=""></span>h of treatment, compared to 62.5% and 72% in the DTI 1 and DTI 2 groups respectively: and 62.5% in the control group (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">This study aims to identify the current scientific evidence regarding the effectiveness of topical insulin treatment in ocular surface pathologies. Despite the limited information currently available on this topic, the studies included in this paper detail promising results regarding the use of topical insulin promoting corneal re-epithelialization. The cases included show groups of participants from different countries, with wide age ranges (2–95 years), with previous ocular pathologies and various treatments received before the use of topical insulin (artificial tears, antibiotics, antivirals, anti-inflammatories, glasses of therapeutic contact, autologous serum, immunosuppressants and surgical techniques such as use of amniotic membrane) or after corneal debridement in surgical procedures.</p><p id="par0105" class="elsevierStylePara elsevierViewall">A de-epithelialized cornea shows a great inflammatory response and the absence of keratocytes, characterized by an apoptosis process possibly mediated by interleukin 1 (IL-1), oxygen free radicals and the presence of polymorphonuclear cells (PMN).<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> This reaction can lead to osmotic changes and metabolic diseases of the stroma that make re-epithelialization of the lesion even more difficult, leading to possible persistent ulcers or corneal melting.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> New treatments aimed at healing these ocular surface defects must be aimed at the molecular processes of re-epithelialization to obtain optimal results in healing time and quality, avoiding epithelial hyperplasia processes or uncontrolled proliferation of stromal keratocytes that could end in leucomas or corneal haze in late stages.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Although there is currently no clearly established management for the treatment of PED, there are multiple therapeutic options such as the aforementioned conventional therapies. At present, great interest has arisen in the research of re-emerging therapies such as the effect of topical insulin. The use of this as a treatment for ocular surface defects was first described in 1945 by Aynsley T.R, who reported improvements in corneal ulcer healing times.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,16</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Likewise, there is no established protocol for the preparation and dosage of the insulin mixture with the concentrations used in these studies (from 1 IU/ml to 100 IU/ml) and using different types of insulin (regular insulin -Humalog-, human insulin -Actrapid- and all prepared with different types of lubricants).</p><p id="par0120" class="elsevierStylePara elsevierViewall">In the reviewed studies, the authors report good results in the healing of corneal epithelial defects. In one of the studies included in this review an incomplete closure of the PED was documented in 4 participants, with a mean reduction of the area of 91.5%, which indicates a high effectiveness of this therapy, in addition to the fact that no cases of recurrence were reported.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Soares, et al., reported 90% of complete re-epithelialization, in the remaining 10% it was not possible to adapt a contact lenses because of paralytic lagophthalmos, ectropion and incomplete blinking.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Patients with Actrapid insulin (fast-acting recombinant DNA brand of human insulin) in the studies by, Bastion, et al., and Fai, et al., had shorter recovery times compared to those documented by regular insulin (Wang, et al. and Diaz, et al.), and in relation to reports that do not document the type of insulin was used (Fobelo, et al. and Tonng, et al.). A possible explanation for this is that Actrapid insulin is an insulin with an onset of action after 30<span class="elsevierStyleHsp" style=""></span>min. Its maximum effect is reached in 1.5–3.5<span class="elsevierStyleHsp" style=""></span>hours with an effect lasting approximately 7 or 8<span class="elsevierStyleHsp" style=""></span>h.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> On the other hand, regular insulin is an intermediate-acting recombinant DNA human insulin with an onset at 30<span class="elsevierStyleHsp" style=""></span>min and a maximum effect 2–3<span class="elsevierStyleHsp" style=""></span>h after application, being effective for approximately 3–6<span class="elsevierStyleHsp" style=""></span>.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> This information suggests that the duration of insulin could be a determining factor in its therapeutic effect, since insulin has a low conformational stability, which can be easily degraded by enzymes present in the biological environment.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However, further research is required to verify this hypothesis.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The selection of the insulin vehicle, being in most cases polyethylene glycol and propylene glycol, may or may not be a contributing factor in the re-epithelialization process. This vehicle was used in the studies that presented a higher healing speed as well as in those that required a longer treatment time. Polyethylene glycol and propylene glycol are ocular lubricants that provide moisture and complementary lipids to the ocular surface, indicated as symptomatic treatment of dry eye. They improve the ocular surface as they increase the stability of the tear film, which promotes an environment conducive to the healing and renewal of both epithelial cells and goblet cells, in addition to the decrease in the expression of inflammatory markers such as the human leukocyte antigen DR present in dry eye pathologies; thus, achieving optimization of the homeostasis of the ocular surface.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Regarding the insulin concentration, a direct relationship with the healing time was identified according to the works of Fai, et al. and Bastion, et al., who showed that insulin is better than normal saline. Also, in the study by Diaz, et al. 2021, it was documented that topical insulin presented better epithelization outcomes than autologous serum.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> However, among the different insulin concentrations, the low concentrations (1 IU/ml) were more effective, which could be related to the toxic effects of the frequent introduction of topical insulin on a previously injured ocular surface.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However, it is believed that this difference in healing times has a greater relationship with the type of insulin and the etiology causing the epithelial defect than with its concentration.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Concerning the etiology, it was observed in the reviewed studies that the fastest healing was in lesions of neurotrophic origin of lower stage (epithelial defect without stromal defect),<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and those secondary to vitrectomy. In contrast, infectious or chemical burns took longer to resolve. This could be explained because the epithelium influences the processes of cellular and metabolic activation of the stroma during tissue healing, Thus, in pathologies where the epithelial damage is more extensive and deeper, the regenerative capacity of the stroma may be more compromised.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In addition, chemical burns have greater risk of presenting damage to the stem cells of the limbus, which hinders the epithelialization processes.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Among the limitations, the variability in the methodologies used in the analyzed studies and the different pathologies or lesions in which the use of topical insulin was evaluated should be noted.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Further research is required on the effects of topical insulin on epithelial defects, due to the limited literature, this is the main limitation of this work. It is essential to compare it with placebos and other innovative therapies such as substance P (due to its cytogenetic effect on epithelial cells and its ability to stimulate DNA synthesis and cell growth), type 1 insulin-like growth factor (IGF-1) (due to their ability to stimulate the migration of epithelial cells to the corneal stroma) or together due to their possible synergistic effect.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Likewise, its action in comparison with other emerging therapies should be analyzed, such as; recombinant human nerve growth factor (Cenegermin), which is important in the maintenance and differentiation of nerve cells, its receptors being expressed in structures of the anterior segment; matrix therapies (Regeneration Agent, RGTA®), since they are polysaccharides that replace the destroyed heparan sulfate with two main functions: the first is the restoration of the structure of the extracellular matrix (ECM), by allowing the binding of different proteins of the ECM, and the second as a protective role by regulating the process of proteolysis of ECM proteins; GAP-type cell junction modulators (CODA001) decreasing the expression of connexins (connexin 43), which are elevated in epithelial defects, thus limiting the extent of the lesion, inflammation, edema and increasing epithelial recovery; and metalloproteinase modulators (Thymosin β4), leading to increased cell migration of the corneal epithelium, acting as a regulator of actin filament polymerization.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16,20,21</span></a> It is suggested that the comparison of the behavior of topical insulin vs insulin administered in release systems be studied, such as silk fibroin (SF) due to its biocompatibility, biodegradation, high mechanical strength and permeability to water vapor.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> SF is a protein present in the cocoons of silkworms, which has been studied as a possible tissue regeneration agent due to the previously mentioned properties and as a delivery system, since it is an enzymatic stabilizer (used in live vaccines).<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,22–24</span></a> Finally, it is considered as an immunomodulatory molecule due to its action in the activation of NF-kβ pathway that stimulates the secretion of growth factors, such as the endothelial growth factor, and reduces the expression of interleukins, such as l to IL-6, IL-10 and TNF-α (tumor necrosis factor α), thus controlling inflammation and contributing to the healing process.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,25</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Additionally, it is suggested that research be carried out on dry eye, which is one of the main causes of persistent epithelial defects in the cornea, since it could have a favorable therapeutic effect given the mechanism of action of insulin. Today, research for the treatment of dry eye is migrating from a therapy based on symptom control, to one that treats the basic biological and molecular factors that cause the disease. In this regard, insulin could play an important role due to its anabolic and potentially anti-inflammatory properties. Similarly, there is a need for studies on the appropriate vehicle for the preparation of the insulin mixture, taking into account different components such as: polyethylene glycol, propylene glycol, polyacrylic acid, carbomer 940, carboxymethylcellulose, hyaluronic acid or sodium hyaluronate, hydroxyethylmethylcellulose, polyvinyl alcohol and povidone.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0165" class="elsevierStylePara elsevierViewall">Topical insulin as a reemergent therapy for the treatment of persistent ulcers is a therapeutic possibility that should be considered, provided the pathology, the type of insulin and the concentration; highlighting greater effectiveness in low concentrations (1 IU / ml - 25 IU / ml), with intermediate-acting insulins, in neurotrophic ulcers and induced during vitreoretinal surgery, probably extrapolated to various types of persistent corneal epithelial defects of non-infectious origin.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Although topical insulin appears to be a simple and effective treatment for PEDs, it is necessary to carry out prospective studies, in which the most appropriate type and concentration for its use is identified, and thus achieve an optimization of the therapy and determine its effectiveness, in addition to its comparison with innovative therapies.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Funding</span><p id="par0180" class="elsevierStylePara elsevierViewall">The author(s) received no financial support for the research, authorship, and/or publication of this article.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1876905" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1628164" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1876906" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1628163" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Literature search" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study selection" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Funding" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-11-01" "fechaAceptado" => "2023-01-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1628164" "palabras" => array:6 [ 0 => "Epithelial defect" 1 => "Corneal epithelium" 2 => "Topical insulin" 3 => "Corneal ulcer" 4 => "Keratopathy" 5 => "Neurotrophic corneal ulcer" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1628163" "palabras" => array:6 [ 0 => "Defecto epitelial" 1 => "Epitelio corneal" 2 => "Insulina tópica" 3 => "Úlcera corneal" 4 => "Queratopatía" 5 => "Úlcera corneal neurotrófica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The Purpose is to identify, through a systematic literature review, the current evidence regarding the effectiveness of topical insulin treatment in ocular surface pathologies. A literature search was implemented in Medline (Pubmed), Embase and Web Of Science medical indexing databases by using keywords such as “insulin” AND “cornea” OR “corneal” OR “dry eye” in published papers in English or Spanish within the last eleven years (2011-2022). Nine papers were identified with 180 participants from the United States, Spain, Ireland, Canada, Portugal and Malaysia, with persistent refractory epithelial defects and secondary to vitrectomy, whose extension of the lesion was from 3,75<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> to 65.47<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span>. The preparation was dissolved with artificial tears and the insulin concentration ranged from 1 IU/ml to 100 IU/ml. In all cases, the resolution of the clinical picture was complete with a healing time from 2.5 days to 60.9 days, the latter being a secondary case to a difficult-to-control caustic burn. Topical insulin has been effective for the treatment of persistent epithelial defects. The intermediate action and low concentrations showed a shorter resolution time in neurotrophic ulcers and induced during vitreoretinal surgery.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El propósito es identificar a través de una revisión sistemática de la literatura, la evidencia actual frente a la eficacia del tratamiento de la insulina tópica en patologías de la superficie ocular. Se implementó una búsqueda de literatura en bases de datos de indexación médica Medline (Pubmed), Embase y Web Of Science a través de palabras claves como “insulin” AND “córnea” OR “corneal” OR “dry eye” artículos publicados en inglés o español en los últimos once años (2011−2022). Se identificaron nueve artículos con 180 participantes provenientes de Estados Unidos, España, Irlanda, Canadá, Portugal y Malasia, con defectos epiteliales persistentes refractarios y secundarios a vitrectomía, cuya extensión de la lesión fue de 3,75<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> hasta 65.47<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span>. La preparación fue disuelta con lágrimas artificiales y la concentración de insulina fue desde 1 UI/mL hasta 100 UI/mL. En todos los casos la resolución del cuadro clínico fue completa con un tiempo de curación desde 2,5 días hasta 60.9 días siendo este último un caso secundario a una quemadura por cáusticos de difícil control. La insulina tópica ha sido efectiva para el tratamiento de defectos epiteliales persistentes; la de acción intermedia y en bajas concentraciones demostró menor tiempo de resolución, en úlceras neurotróficas y secundarias a vitrectomías.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2370 "Ancho" => 2508 "Tamanyo" => 228514 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Flowchart for articles selection.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">OD: Oculus dexter. OS: Oculus sinister. AU: Oculus uterque. IU: International Unit. DNS: Control group, DTI 0,5: Group treated with topical insulin 0,5 units. DTI 1: Group treated with topical insulin 1 unit. DTI 2: Group treated with topical insulin 2 units. DTI: Diabetic group treated with topical insulin 1 unit. DCT: Diabetic group treated with conventional post-operative medications. NDCT: Nondiabetic group treated with conventional post-operative therapy. NSAID: nonsteroidal anti-inflammatory drugs.</p>" "tablatextoimagen" => array:1 [ 0 => array:1 [ "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, 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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case number \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Region \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age (Years) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of study \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pathology (Indication to use insulin) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Systemic diseases \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Previous eye history \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Management prior to insulin use \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Insulin solution \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Insulin dosage \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Extension \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Re-epithelialization time (Average, days) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug comparison \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adverse events \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">Bastion, et al. 2013<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</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">14 \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">Kuala Lumpur (Malaysia) \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">31−69 \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 \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">Postoperative corneal epithelial wound healing after vitrectomy \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">Diabetes mellitus \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">Rhegmatogenous retinal detachment (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3), total retinal detachment (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), vitreous haemorrhage (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3), vitreous haemorrhage and tractional retinal detachment (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), rhegmatogenous retinal detachment and tractional retinal detachment (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), epiretinal membrane (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), secondary glaucoma (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), vitreous haemorrhage and tractional retinal detachment and rhegmatogenous retinal detachment (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), rhegmatogenous retinal detachment and vitreous hemorrhage and subluxated lens (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), full thickness macular hole (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), post dislocated lens and giant retinal tear (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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">– \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">2.5<span class="elsevierStyleHsp" style=""></span>ml of insulin (Actrapid HM insulin 1000 IU) contains 250 IU +2.5<span class="elsevierStyleHsp" style=""></span>ml of normal saline, total of 5<span class="elsevierStyleHsp" style=""></span>ml (50 IU/mL). DTI: 1 IU of topical insulin \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">DTI: 4 times per day (QID) \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">DTI: 63.92 mm<span class="elsevierStyleSup">2</span> ± 12.63 mm<span class="elsevierStyleSup">2</span>; DCT: 63.14 mm<span class="elsevierStyleSup">2</span> ± 12.40 mm<span class="elsevierStyleSup">2</span>; NDCT: 65.47 mm<span class="elsevierStyleSup">2</span> ± 11.39 mm<span class="elsevierStyleSup">2</span> \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">DTI: 2,5; DCT: 5; NDCT: 2,5 \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">DCT y NDCT: postoperative conventional treatment (Dexamethasone and ciprofloxacin) \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">Not reported \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">Bourke, et al. 2019<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</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">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">Dublin (Ireland) \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">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">Case report \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">Neurotrophic corneal ulcer \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">Neurofibromatosis type 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">Hypopyon, left optic nerve meningioma and left corneal denervation \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">Vancomycin and ceftazidime drops, oral ciprofloxacin. VitA Pos (ointment with vitamin A) and chloramphenicol ointment. Prednisolone drops and HYLO-FORTE (hyaluronate 0.2%), tarsorrhaphy. \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">Actrapid insulin in Systane (polyethylene glycol and propylene glycol) at a concentration of 1 IU/mL1 \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 times per day \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">10 mm<span class="elsevierStyleSup">2</span> \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">Not reported \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">Diaz, et al. 2020<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</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">21 \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">Madrid (Spain) \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">20−92 (mean age 72.2 years) \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">Prospective non-randomized study \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">Persistent epithelial defects \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">PED etiology: Infectious keratitis (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7), calcium keratopathy (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5), previous ocular surgery(n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3), lagophthalmos (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3), bullous keratopathy (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2), herpetic eye disease (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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">Vancomycin, ceftazidime, erythromycin, ganciclovir, fluorometholone, artificial tears, contact lens, moxifloxacin, dexamethasone, platelet-rich plasma, netilmicin, autologous serum, moxifloxacin, tobramycin, voriconazole, amniotic membrane transplantation, cyclosporine. \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">Regular insulin in artificial tears with a polyethylene glycol and propylene glycol base at a concentration of 1 IU/mL \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">4 times per day \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">17.6 mm<span class="elsevierStyleSup">2</span> (mean) \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">34.8 \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">– \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">Not reported \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">Diaz, et al.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> 2021 \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">84 \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">Madrid (Spain) \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">10−95 \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 consecutive case–control series \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">Persistent epithelial defects \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">Diabetes mellitus (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15) \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">Glaucoma (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>21), retinal disorders (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11), corneal alterations (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>30), uveitis (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9), other (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2), none (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>27). PED etiology: Infectious (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>26), neurotrophic (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>30), chronic alterations of the ocular surface (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>24), immune-mediated (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4) \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">Intensive lubrication (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>84), bandage contact lenses (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>52), occlusion (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>19), antibiotics (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>77), antivirals (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15), doxycycline (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>35), corticosteroids (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>25), autologous serum (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>32), cyclosporine (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4), amniotic membrane transplantation (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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">Fast-acting insulin (Actrapid) diluted in a polyethylene glycol and polypropylene glycol base at a concentration of 1 IU/mL \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">4 times per day \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">Case group (treated with topical insulin): 14.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>16.2 mm<span class="elsevierStyleSup">2</span> (mean)Control group (treated with autologous serum): 18.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15.0 mm<span class="elsevierStyleSup">2</span> (mean) \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">Case group: 32.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>28.3Control group: 82.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>82.4 \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">Autologous serum \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">Not reported \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">Fai, et al. 2017<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</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">32 \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">Kuala Lumpur (Malaysia) \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">40−75 \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">A double blind randomized controlled study \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">Postoperative corneal epithelial wound healing after vitrectomy \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">Diabetes mellitus \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">Advanced diabetic eye disease (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>23), retinal detachment (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2), macular repair (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6), dislocated intraocular lens (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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">– \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">Control Group (DNS): 0.9% normal saline; DTI 0.5: Topical insulin 0.5 IU; 1.25<span class="elsevierStyleHsp" style=""></span>ml (125 IU) of Actrapid HM insulin +3.75<span class="elsevierStyleHsp" style=""></span>ml of 0.9% normal saline, total of 5<span class="elsevierStyleHsp" style=""></span>ml (25 IU/mL); DTI 1: Topical insulin 1 IU; 2.5<span class="elsevierStyleHsp" style=""></span>ml (250 IU) of Actrapid HM +2.5<span class="elsevierStyleHsp" style=""></span>ml of 0.9% normal saline, total of 5<span class="elsevierStyleHsp" style=""></span>ml (50 IU/mL), and DTI 2: Topical insulin 2 IU; 5<span class="elsevierStyleHsp" style=""></span>ml (500 IU) of Actrapid HM insulin without 0.9% normal saline, total of 5<span class="elsevierStyleHsp" style=""></span>ml (100 IU/mL) \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">Control Group (DNS): 4 times per day (QID); DTI 0,5: 4 times per day (QID); DTI 1: 4 times per day (QID); DTI 2: 4 times per day (QID). \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">Control group (DNS): 60.32 mm<span class="elsevierStyleSup">2</span> ± 12.92 mm<span class="elsevierStyleSup">2</span>; DTI 0.5: 62.52 mm<span class="elsevierStyleSup">2</span> ± 57.16 mm<span class="elsevierStyleSup">2</span>; DTI 1: 57.16 mm<span class="elsevierStyleSup">2</span> ± 26.43 mm<span class="elsevierStyleSup">2</span>; DTI 2: 59.50 mm<span class="elsevierStyleSup">2</span> ± 10.04 mm<span class="elsevierStyleSup">2</span> \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">DTI 0,5: 3; DTI 1 and DTI 2: 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">0.9% normal saline \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">Not reported \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">Fobelo, et al. 2020<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</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">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">Sevilla (Spain) \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">41 \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">Case report \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">Persistent corneal ulcer \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">Caustic ocular surface 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">Bandage contact lenses, topical tobramycin, topical diclofenac, topical autologous serum, topical artificial tears, penetrating keratoplasty, amniotic membrane coating \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">Insulin drops 50 IU/mL (1 IU/drop) (Type or brand of insulin and vehicle used were not reported) \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">1−2 drops 4 times per day \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">56 \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">Not reported \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">Soares et al. 2021<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</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">20 \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">Espinho (Portugal) \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">13−92 \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, observational single center study \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">Neurotrophic keratopathy stage 2 or 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">Diabetes mellitus, central nervous system causes (acoustic neuroma, trauma and post neurosurgical procedures) \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">Herpes simplex keratitis, postpenetrating keratoplasty, chronic trauma and topical NSAID abuse \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">Lubrication with artificial tears, topical or oral antibiotics, topical and/or oral steroids, antiviral drugs, punctual plugs, therapeutic contact lenses, amniotic membrane surgery and temporary tarsorrhaphy \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">Fast-acting insulin in artificial tears with a polyethylene glycol base at a concentration of 1 IU/mL. a therapeutic corneal contact lens was applied, and fluoroquinolone drops were applied \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 drops 4 times per day \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">Neurotrophic keratopathy stage 2: 18Neurotrophic keratopathy stage 3: 29 \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">Not reported \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">Wang, et al. 2017<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</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">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">Wisconsin (United States) \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">2−73 \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 \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">Neurotrophic corneal ulcers or epithelial defects refractory \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">Diabetes mellitus (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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">Teratoma, proptosis and lagophthalmos (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), aniridia and bilateral congenital glaucoma (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), herpes zoster keratoconjunctivitis (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1) and neurotrophic keratopathy (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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">Artificial tears, antibiotic ointment, amniotic membrane graft, bandage contact lens, tarsorrhaphy, chronic topical steroid therapy \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">Regular insulin in artificial tears with a polyethylene glycol and propylene glycol base at a concentration of 1 IU/mL \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">2 to 3 times per day \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">14,33<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> (mean) \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">13.5 \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">Crystalline keratopathy (likely secondary to chronic topical steroid use) \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">Tong, et al. 2020<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</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">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">Vancouver (Canada) \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 \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">Case report \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">Persistent corneal ulcer \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">Diabetes mellitus \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">Neurotrophic keratitis \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">Topical non -preserved artificial tears, moxifloxacin, oral valacyclovir, topical prednisolone 1%, bandage contact lenses and temporary tarsorrhaphy \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">Insulin drops (25 IU/mL) (Type or brand of insulin and vehicle used were not reported) \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 drop 6 times per day in each eye \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">33,75<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> (OD) y 15<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> (OS) \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">7 \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">Not reported \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Features patients with corneal defect treated with topical insulin.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel therapy to treat corneal epithelial defects: a hypothesis with growth hormone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "B. 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