Desarrollo de modelos experimentales de prótesis de córnea humanizada autóloga

La regeneración corneal es una etapa esencial en la restitución de la normalidad anatómica en las patologías debilitantes de la córnea. El objetivo en esta tesis doctoral es el desarrollo de biomateriales transportadores de células autólogas humanas de tipo pluripotencial, con la finalidad de promover la integración de dichos biomateriales y regenerar el estroma en las córneas estructuralmente debilitadas. En una primera fase analizamos las propiedades físicas in vitro de injertos porosos de 90[my]m de espesor de polietilacrilato (PEA) y estroma corneal humano descelularizado, además de analizar la capacidad de proliferación, infiltración y adhesión de células madre derivadas del tejido adiposo humano (ADASC) sobre los mismos. En una segunda fase se estudió el comportamiento in vivo de estos dos tipos de implantes con y sin colonización celular mediante un ensayo controlado y triple enmascarado, usando un modelo experimental de conejo albino neozelandés. Los implantes se introdujeron dentro de bolsillos instraestromales disecados manualmente y se realizó un seguimiento completo de 3 meses, donde se analizaron clínicamente la inyección conjuntival, trasparencia y vascularización corneal. Tras la eutanasia de los conejos se realizó un análisis histológico e histoquímico con el objetivo de evaluar la supervivencia de las ADASC y su diferenciación en queratocitos adultos. La prótesis de PEA con un 10% de hidroxietilacrilato redujo drásticamente su tasa de extrusión, pudiendo ser utilizado como scaffold en futuros modelos de queratoprótesis. Las láminas de córnea humana descelularizada con posterior recelularización demostraron una óptima biointegración en el estroma corneal en ausencia de respuesta inflamatoria alguna, además de permitir una mejor supervivencia y diferenciación de las células madre en comparación con las membranas de PEA. Este modelo de trasplante lamelar mediante descelularización con posterior recelularización con células madre extraoculares permite la obtención de injertos lamelares funcionalizados autólogos a partir de córneas alogénicas

Desarrollo de modelos experimentales de prótesis de córnea humanizada autóloga

La regeneración corneal es una etapa esencial en la restitución de la normalidad anatómica en las patologías debilitantes de la córnea. El objetivo en esta tesis doctoral es el desarrollo de biomateriales transportadores de células autólogas humanas de tipo pluripotencial, con la finalidad de promover la integración de dichos biomateriales y regenerar el estroma en las córneas estructuralmente debilitadas. En una primera fase analizamos las propiedades físicas in vitro de injertos porosos de 90[my]m de espesor de polietilacrilato (PEA) y estroma corneal humano descelularizado, además de analizar la capacidad de proliferación, infiltración y adhesión de células madre derivadas del tejido adiposo humano (ADASC) sobre los mismos. En una segunda fase se estudió el comportamiento in vivo de estos dos tipos de implantes con y sin colonización celular mediante un ensayo controlado y triple enmascarado, usando un modelo experimental de conejo albino neozelandés. Los implantes se introdujeron dentro de bolsillos instraestromales disecados manualmente y se realizó un seguimiento completo de 3 meses, donde se analizaron clínicamente la inyección conjuntival, trasparencia y vascularización corneal. Tras la eutanasia de los conejos se realizó un análisis histológico e histoquímico con el objetivo de evaluar la supervivencia de las ADASC y su diferenciación en queratocitos adultos. La prótesis de PEA con un 10% de hidroxietilacrilato redujo drásticamente su tasa de extrusión, pudiendo ser utilizado como scaffold en futuros modelos de queratoprótesis. Las láminas de córnea humana descelularizada con posterior recelularización demostraron una óptima biointegración en el estroma corneal en ausencia de respuesta inflamatoria alguna, además de permitir una mejor supervivencia y diferenciación de las células madre en comparación con las membranas de PEA. Este modelo de trasplante lamelar mediante descelularización con posterior recelularización con células madre extraoculares permite la obtención de injertos lamelares funcionalizados autólogos a partir de córneas alogénicas

Morphogeometric analysis for characterization of keratoconus considering the spatial localization and projection of apex and minimum corneal thickness point

This work evaluates changes in new morphogeometric indices developed considering the position of anterior and posterior corneal apex and minimum corneal thickness (MCT) point in keratoconus. This prospective comparative study included 440 eyes of 440 patients (age, 7–99 years): control (124 eyes) and keratoconus (KC) groups (316 eyes). Tomographic information (Sirius®, Costruzione Strumenti Oftalmici, Italy) was treated with SolidWorks v2013, creating the following morphogeometric parameters: geometric axis–apex line angle (GA–AP), geometric axis–MCT line angle (GA–MCT, apex line–MCT line angle (AP–MCT), and distances between apex and MCT points on the anterior (anterior AP–MCTd) and posterior corneal surface (posterior AP–MCTd). Statistically significant higher values of GA–AP, GA–MCT, AP–MCT and anterior AP–MCTd were found in the keratoconus group (p ≤ 0.001). Moderate significant correlations of corneal aberrations (r ≥ 0.587, p < 0.001) and corneal thickness parameters (r ≤ −0.414, p < 0.001) with GA–AP and AP–MCT were found. Anterior asphericity was found to be significantly correlated with anterior and posterior AP–MCTd (r ≥ 0.430, p < 0.001). Likewise, GA–AP and AP–MCT showed a good diagnostic ability for the detection of keratoconus, with optimal cutoff values of 9.61° (sensitivity 85.5%, specificity 80.3%) and 18.08° (sensitivity 80.5%, specificity 78.7%), respectively. These new morphogeometric indices allow a clinical characterization of the 3-D structural alteration occurring in keratoconus, with less coincidence in the spatial projection of the apex and MCT points of both corneal surfaces. Future studies should confirm the potential impact on the precision of these indices of the variability of posterior corneal surface measurements obtained with Scheimpflug imaging technology.This publication has been carried out in the framework of the Thematic Network for Co-Operative Research in Health (RETICS), reference number RD16/0008/0012, financed by the Carlos III Health Institute–General Subdirection of Networks and Cooperative Investigation Centers (R&D&I National Plan 2013–2016) and the European Regional Development Fund (FEDER). The author David P. Piñero has been supported by the Ministry of Economy, Industry and Competitiveness of Spain within the program Ramón y Cajal, RYC-2016-20471

Safety and visual outcomes following posterior chamber phakic intraocular lens bilensectomy

To evaluate the safety, efficacy, refractive outcomes and causes for bilensectomy (phakic intraocular lens - pIOL - explantation with cataract surgery and pseudophakic intraocular lens implantation) in patients previously implanted with posterior chamber pIOLs. This multi-center retrospective study included 87 eyes of 55 patients who underwent bilensectomy for posterior chamber pIOL with a follow up time of 12 months. The uncorrected and best corrected distance visual acuities (UDVA, CDVA), endothelial cell density before and after bilensectomy were assessed, as well as the cause of bilensectomy and intra or postoperative complications. There was a statistically significant improvement in uncorrected and best corrected visual acuities after bilensectomy (p = 0.00). The main reason for bilensectomy was cataract development (93.1% of the cases), followed by miscalculation of lens size, and corneal edema. The endothelial cell count remained stable without a statistically significant change after surgery (p = 0.67). The refractive efficacy index was 0.8, none of the patients lost lines of CDVA after surgery, 73% of the patients were within ±1 D (spherical equivalent) of the target refraction. Intraoperative complications were one posterior capsule rupture with the intraocular lens (IOL) implanted in the sulcus, and 3 eyes required the use of pupil expanders for adequate pupil dilation. Postoperatively, one eye developed retinal detachment. The three pIOLs models explanted were the Implantable Collamer Lens (ICL), Implantable Phakic Contact Lens (IPCL) and the Phakic Refractive Lens (PRL). Good safety and visual outcomes were observed 1 year after bilensectomy for posterior chamber phakic intraocular lenses (PC pIOLs). There were few intra and postoperative complications and there was no significant endothelial cell loss after the bilensectomy procedure

Corneal regeneration using adipose-derived mesenchymal stem cells

Producción CientíficaAdipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells)

Cellular therapy of the corneal stroma: a new type of corneal surgery for keratoconus and corneal dystrophies

Abstract Cellular therapy of the corneal stroma, with either ocular or extraocular stem cells, has been gaining a lot of interest over the last decade. Multiple publications from different research groups are showing its potential benefits in relation to its capacity to improve or alleviate corneal scars, improve corneal transparency in metabolic diseases by enhancing the catabolism of the accumulated molecules, generate new organized collagen within the host stroma, and its immunosuppressive and immunomodulatory properties. Autologous extraocular stem cells do not require a healthy contralateral eye and they do not involve any ophthalmic procedures for their isolation. Mesenchymal stem cells have been the most widely assayed and have the best potential to differentiate into functional adult keratocytes in vivo and in vitro. While embryonic stem cells have been partially abandoned due to ethical implications, the discovery of the induced pluripotent stem cells (iPSC) has opened a new and very promising field for future research as they are pluripotent cells with the capacity to theoretically differentiate into any cell type, with the special advantage that they are obtained from adult differentiated cells. Cellular delivery into the corneal stroma has been experimentally assayed in vivo in multiple ways: systemic versus local injections with or without a carrier. Encouraging preliminary human clinical data is already available although still very limited, and further research is necessary in order to consolidate the clinical applications of this novel therapeutic line

Accommodative intraocular lenses: where are we and where we are going

Abstract Presbyopia still remains the last frontier of refractive surgery. Its surgical management is under constant evolution due to the limitations that exist today with respect to its management, which is probably in relation with the multifactorial basis in which presbyopia is clinically developed in the human. Until currently, virtually all surgical techniques that have been proposed for its correction are based on the induction of pseudoaccommodation in the presbyopic eye, including multifocality. However, the real restoration of accommodation is more complex, and it has been tried by the use of different, so called, “accommodative” pseudophakic intraocular lenses (AIOL). Overall, the reported results with these lenses by independent authors have been modest in relation with the restoration of the accommodative power of the eye and these modest benefits are usually lost with time due to the long term changes in the capsular bag. This fact made these lenses to be almost abandoned in the last few years, but there are currently other AIOL models being used with innovative mechanisms of action and different anatomical support outside the capsular bag that offer encouraging preliminary results that could bring a new potential of application to these types of lenses. In this article, we will update the modern refractive surgeon about the fundamentals and provide updated information about the outcomes of AIOLs by reviewing the concept of accommodation, the different attempts that have been accomplished in the past, their demonstrated published results in human clinical trials, and the future alternatives that may arrive in the near future

Small incision lenticule extraction (SMILE) in the correction of myopic astigmatism: outcomes and limitations - an update

Abstract Small Incision Lenticule Extraction (SMILE) is a flap-free intrastromal technique for the correction of myopia and myopic astigmatism. To date, this technique lacks automated centration and cyclotorsion control, so several concerns have been raised regarding its capability to correct moderate or high levels of astigmatism. The objective of this paper is to review the reported SMILE outcomes for the correction of myopic astigmatism associated with a cylinder over 0.75 D, and its comparison with the outcomes reported with the excimer laser-based corneal refractive surgery techniques. A total of five studies clearly reporting SMILE astigmatic outcomes were identified. SMILE shows acceptable outcomes for the correction of myopic astigmatism, although a general agreement exists about the superiority of the excimer laser-based techniques for low to moderate levels of astigmatism. Manual correction of the static cyclotorsion should be adopted for any SMILE astigmatic correction over 0.75 D

Comparison of the Cost-Effectiveness of SMILE, FS-LASIK, and PRK for Myopia in a Private Eye Center in Spain

PURPOSE: To describe and compare the cost-effectiveness of small incision lenticule extraction (SMILE), femtosecond laser–assisted in situ keratomileusis (FS-LASIK), and photorefractive keratectomy (PRK) for treating myopia and myopic astigmatism in a private eye center. METHODS: The perspectives for this cost-effectiveness analysis were for the payer and the health care sector. For the payer's perspective, a decision tree model was made, with a time period of 30 years, and the average weighted utility values and quality-adjusted life years (QALY) were computed for each procedure. The average weighted costs were derived for each procedure and divided by the QALY to obtain the incremental cost-effectiveness ratios (ICER). For the health care sector's perspective, the direct and indirect costs of acquiring the equipment and maintaining the facilities—including consumables and personnel salaries—were obtained to compute the minimum number of patients treated per year. RESULTS: The weighted utility values were 0.8 for SMILE and PRK and 0.77 for FS-LASIK. The weighted QALYs were 24 for SMILE and PRK, and 23.1 for FS-LASIK. The average weighted costs were 335.45, 443, and 346.96€, respectively. The resulting incremental cost-effectiveness ratios were 13.98 €/QALY for SMILE, 18.46 €/QALY for PRK, and 15.02 €/QALY for FS-LASIK. There was a negative correlation between the ICER and the time (in years) after the surgery. To achieve a profit, the minimum number of patients treated per year is 155 for SMILE, 136 for PRK, and 155 for FS-LASIK. CONCLUSIONS: Laser corneal refractive surgery is cost-effective for a person desirous of refractive correction for myopia. SMILE had the lowest ICER, followed by FS-LASIK and PRK. This trend was noted at all time periods. The cost of investing in laser refractive surgery facilities is outweighed by the potential income in high-volume eye centers