Letter to the editor

[Excerpt] Recently, Alió and co-works published a study [1] comparing the clinical optical image quality of patients following implantation with different intraocular lenses (IOLs), based on the analysis of the wavefront measured with a pyramidal wavefront sensor-based aberrometer. A set of nine groups of patients was evaluated, including patients implanted with two diffractive trifocals. Surprisingly, accordingly to the results reported by the authors, the group implanted with the trifocal diffractive AT Lisa stands out in terms of distance image quality calculated from the captured wavefront, with a monochromatic Strehl ratio above other groups implanted with monofocal designs. Another example of these intriguing result is the similarity in Strehl ratio between the spherical monofocal control group and the group implanted with the PanOptix trifocal. Considering that any residual refraction was accounted in the analysis and that other contributions apart from the IOL design such as patient high-order aberrations, lens decentration or tilt were equally distributed between groups, the results presented in Fig. 1 are likely caused by an erroneous interpretation of the wavefront data. [...](undefined

Analysis of wavefront data obtained with a pyramidal sensor in pseudophakic eyes implanted with diffractive intraocular lenses

Purpose: To investigate the clinical validity of using wavefront measurements obtained with a recently available pyramidal aberrometer to assess the optical quality of eyes implanted with diffractive intraocular lenses (IOLs). Methods: Individual biometric data were used to create models of pseudophakic eyes implanted with two diffractive IOLs. Their synthetic wavefronts were calculated by ray-tracing with near infrared wavelength (0.85 μm). Comparisons of the through-focus visual acuity of 12 pseudophakic eyes were obtained with three different methods: clinical defocus curves; simulated defocus curves calculated from ray-tracing in the customized model eyes; and through-focus simulated defocus curves calculated from the wavefront data measured with a pyramidal aberrometer. Results: Image quality calculated from wavefront data obtained by ray-tracing with 0.85 μm wavelength, without scaling the phase to 0.55 μm, resulted in a significantly different through-focus curve compared to the reference values. Even so, after scaling of the wavefront data to 0.55 μm, the defocus curves calculated from the wavefronts measured with the pyramidal aberrometer did not match the shape and the depth of field of the clinical defocus curves or the theoretical expected values. Conclusions: Correcting for the longitudinal chromatic aberration of the eye when measuring the wavefront of eyes implanted with diffractive IOLs under near infrared light only accounts for the best focus shift due to the longitudinal chromatic aberration, but not for the wavelength dependence of the diffractive element. The pyramidal sensor does not seem to properly sample the slopes of a wavefront measured from a pseudophakic eye implanted with a presbyopia-correcting diffractive IOL to a clinically acceptable level.Acknowledgments: The authors thank CSO for providing the Osiris-T during the study and Pete Kollbaum and Matt Jaskulski from Indiana University for sharing the Matlab code used to parse the Osiris .wfm files

Modeling the effects of eye shape in peripheral refraction and myopia progression

PhD Thesis in Sciences - Specialty in PhysicsMyopia affects approximately 25% of the World population, being a public health concern due to the socioeconomic impact and to the risk of vision loss related to other co-morbidities. If current trends continue, half the world’s population (almost 5 billion) will be short-sighted in just over three decades, with one-fifth of those expected to have a significantly increased risk of blindness. Clinical evidence from animal models and human clinical trials seems to indicate that the peripheral refraction pattern plays an important role in the regulation of eye growth. Lower progression rates have been reported over the last years in myopic children wearing orthokeratology (ortho-k) or special design contact lenses, when compared with those wearing traditional ophthalmic lenses. To date, the only justification for this effect seems to lie in the significant myopization effect induced by these alternative forms of correction beyond the foveal area, but despite the moderate results obtained researcher’s still lack knowledge of the exact mechanism behind this effect and why does it work better in some subjects than others. In this thesis a frame work was developed to model the possible impact of the eye’s posterior shape and the optical changes produced by ortho-k in myopia progression. Optical modeling and biometric eye length measures were used to calculate the retinal contour in 55 myopic subjects, with an accuracy of tenths of a micron. The results show that there is large inter-subject variability in the shape of the posterior pole, even among subjects with similar refractive errors. An exhaustive characterization of the ortho-k cornea was also conducted to analyze the main morphological, topographical and optical changes induced by these treatments and their possible implications in the peripheral refractive error and accommodative response. The results suggest that the reported effects in the retention of eye growth, supposedly due to the peripheral myopization produced by ortho-k treatments, might be dependent on pupil size. Optical quality analysis revealed that although the increase in positive spherical aberration is the main cause of the loss of retinal image quality in the unaccommodated eye after ortho-k, it also seems to have a positive effect, as it extends the depth of field of the eye and may contribute to a better image quality in subjects with accommodative lag during high contrast near vision tasks.A actual prevalência mundial da Miopia (25%) é já considerada um problema de saúde pública devido ao impacto sócio-económico e ao risco de perda de visão relacionada com outras co-morbidades. Se as tendências actuais se mantiverem, metade da população mundial (quase 5 mil milhões) será míope daqui a pouco mais de três décadas, e cerca de um quinto deverá ter um aumento significativo do risco de cegueira. Evidências clínicas baseadas em modelos animais e ensaios clínicos com pacientes humanos parecem indicar que o padrão da refracção periférica desempenha um papel importante na regulação do crescimento axial do olho. Níveis mais baixos de progressão têm sido reportados ao longo dos últimos anos em grupos de crianças míopes corrigidas com ortoqueratologia (orto-k) ou lentes de contacto com geometrias especiais, em comparação grupos de controle compensados com lentes oftálmicas tradicionais. Até à data, a única justificação plausível para estes resultados parece residir no efeito miopização periférica induzido por essas formas alternativas de correção para além da área foveal, mas apesar dos resultados moderados obtidos ainda falta conhecimento do exacto mecanismo por trás deste efeito e porque o efeito é maior em alguns indivíduos que em outros. Nesta tese foi desenvolvido um quadro de trabalho com o objectivo de modelizar o possível impacto da forma do polo posterior do olho e a das alterações estruturais induzidas pela ortoqueratologia na progressão da miopia. O contorno da retina de 55 indivíduos míopes foi calculado com recurso a modelização óptica e medidas biométricas do comprimento do olho, com uma precisão de décimos de micras. Os resultados demonstram que existe uma grande variabilidade inter-individual na forma do pólo posterior do olho, mesmo entre indivíduos com erros refractivos semelhantes. Foi também realizada uma caracterização exaustiva da córnea pós orto-k, com o objectivo de analisar as principais alterações morfológicas, topográficas e ópticas induzidas por estes tratamentos e as suas possíveis implicações no erro refractivo periférico, assim na resposta acomodativa. Os resultados sugerem que os relatos de uma menor taxa de progressão da miopia em olhos tratados com ortok, supostamente devido à miopização periférica produzida por estes tratamentos, pode ser dependente do tamanho da pupila. A análise da qualidade óptica revelou que, embora o aumento da aberração esférica positiva após orto-k seja a principal causa da diminuição da qualidade da imagem retiniana no olho desacomodado, também aparenta ter um efeito positivo na extensão da profundidade de campo, o que poderá contribui para um aumento da qualidade da imagem retiniana em indivíduos com atraso acomodativo durante tarefas de alto contraste em visão próxima

Avaliação do efeito terapêutico da ação combinada de uma droga e do DNA plasmídico

Na última década, vários investigadores têm realizado diversos estudos com o intuito de projetar e desenvolver sistemas de entrega de material genético que pudessem ser biocompatíveis e competentes para internalizar em células alvo. Este enorme contributo para o sucesso das terapias génicas foi complementado com a aplicação de sistemas de co-entrega que permitem entregar simultaneamente genes e drogas anticancerígenas. O efeito sinergético demonstrado por estes agentes trouxe um enorme progresso na eficácia terapêutica para o tratamento de diversos cancros. O cancro do colo do útero é um dos cancros com maior incidência nas mulheres em todo o mundo, especialmente em mulheres jovens. O aparecimento desta doença advém da infeção pelo vírus do papiloma humano (HPV), sendo os genótipos de elevado risco responsáveis por 99,7% dos casos. Em particular, os genótipos do tipo 16 e 18 são responsáveis por mais de 70% das ocorrências. A infeção por HPV é responsável pela integração do genoma viral nas células do colo do útero levando à interrupção da sequência da proteína E2 que é repressora das oncoproteínas E6 e E7. A oncoproteína E6 induz a degradação do supressor de tumor p53, responsável por regular a apoptose das células. No caso da proteína E7, inibe a atuação da proteína do retinoblastoma (pRb) levando a uma desregulação do ciclo celular e consequente crescimento descontrolado das células. O objetivo deste trabalho prende-se por repor os níveis da p53 no interior das células cancerígenas do colo do útero através da entrega de um plasmídeo (pDNA) que codifica para este supressor de tumor, e em simultâneo entregar também um fármaco anticancerígeno com o objetivo final de induzir a apoptose destas células de forma mais eficiente. Para este fim, foi desenvolvido um sistema de co-entrega baseado no polímero catiónico polietilenimina (PEI) que permitiu encapsular o DNA plasmídico que contém o gene da p53. Adicionalmente, o fármaco anticancerígeno metotrexato (MTX) foi também encapsulado nestes vetores poliméricos. A utilização da droga MTX na formulação destes sistemas deve-se, não só ao seu efeito terapêutico já comprovado em diversos tipos de cancro, mas também ao facto de ser reconhecido pelos recetores do ácido fólico, abundantemente presentes nas células tumorais, conferindo assim um direcionamento dos sistemas para as células alvo. Os resultados obtidos neste trabalho revelam que os dois sistemas formulados (PEI/pDNA e PEI/pDNA/MTX) produziram nanotransportadores com características apropriadas em termos de morfologia, tamanho e carga à superfície para a captação e internalização celular dos dois agentes terapêuticos. As células HeLa foram transfetadas com sucesso pelos sistemas que contêm o gene responsável pela produção da proteína supressora de tumor p53. O efeito terapêutico dos dois sistemas foi avaliado, comprovando-se que os poliplexos que continham os dois bioativos inibiram com maior eficácia o crescimento das células tumorais em comparação com o sistema PEI/pDNA. O efeito sinergético evidenciado nas células cancerígenas com a utilização desta co-entrega de um agente genético e de um fármaco anticancerígeno é promissor para estudos adicionais in vivo e futura aplicação terapêutica. Além disso, a utilização combinada de quimioterapia e terapia génica nas células alvo representa um avanço incrível no desenvolvimento de intervenções terapêuticas inovadoras, podendo assim contribuir grandemente para a evolução do tratamento de vários tipos de cancro.In the last decade, several researchers have conducted diverse studies with the aim of designing and developing delivery systems for genetic material that could be biocompatible and competent to internalize in target cells. This enormous contribution to the success of gene therapies was been complemented by the application of co-delivery systems, which allow to simultaneously deliver genes and anticancer drugs. The synergistic effect demonstrated by these agents has brought tremendous progress in therapeutic efficacy for the treatment of various cancers. Cervical cancer is one of the cancers with the highest incidence in women worldwide, especially in young women. The cause of this disease is due to infection by the human papillomavirus (HPV), with high risk genotypes accounting for 99.7% of the cases. Specifically, genotypes of type 16 and 18 are responsible for more than 70% of occurrences. HPV infection is responsible for integrating the viral genome into the cells of the cervix, leading to the disruption of the E2 protein sequence – repressor of E6 and E7 oncoproteins. The E6 oncoprotein induces degradation of the p53 tumor suppressor, responsible for regulating cell apoptosis while E7 protein inhibits the action of the retinoblastoma protein (pRb), leading to a dysregulation of the cell cycle and consequent uncontrolled growth of cells. The aim of this work is to restore the p53 levels within cervical cancer cells by delivering a plasmid encoding this tumor suppressor gene and, simultaneously, delivering an anticancer drug with the ultimate goal of inducing apoptosis of these cells more efficiently. To this end, a co-delivery system based on the cationic polymer polyethyleneimine (PEI) was developed, which allowed to encapsulate the plasmid DNA containing the p53 gene. In addition, the anticancer drug methotrexate (MTX) was also encapsulated into these polymeric vectors. The use of the MTX drug in the formulation of these systems is due not only to its already proven therapeutic effect in several types of cancer but also to the fact that it’s recognized by folic acid receptors, abundantly present in tumor cells, thus conferring cancer cells targeting effect. The results obtained in this work show that the two formulated systems (PEI/pDNA and PEI/pDNA/MTX) produced nanotransporters with appropriate characteristics in terms of morphology, size and surface charge, gene and drug loading/encapsulation efficiencies suitable for both the cellular uptake and internalization of the two therapeutic agents. HeLa cells were successfully transfected by systems containing the gene responsible for the production of p53 tumor suppressor protein. The therapeutic effect of the two systems was evaluated, proving that the polypeptides containing the two therapeutic agents were more effective to inhibit tumor cell growth, when compared to the PEI/pDNA system. The synergistic effect evidenced in cancer cells with the use of this co-delivery of a gene agent and an anticancer drug is promising for additional in vivo studies and future therapeutic application. In addition, the combined use of chemotherapy and gene therapy in target cells represents an incredible advance in the development of innovative therapeutic interventions and can thus greatly contribute to the evolution of the treatment of various types of cancer

Refração e comprimento axiais e fora-de-eixo na miopia estável e progressiva

Dissertação de mestrado em Optometria AvançadaObjetivo: O objetivo deste estudo foi comparar o comprimento axial e a refração periférica relativa, decomposta nas suas focais astigmáticas (tangencial e sagital), entre um grupo de míopes progressivos e outro com a refração estável há mais de dois anos. Métodos: Avaliaram-se 62 olhos com miopia entre -0.50 e -7.00 D de equivalente esférico (média -2.83±1.46 D) e com uma média de idades de 22.02±1.75 anos. Destes, 32 eram pacientes com miopia estável há pelo menos 2 anos e 30 com miopia ainda em progressão. Não se verificaram diferenças estatisticamente significativas entre a idade e o erro refrativo de ambos os grupos. Após o exame preliminar foi determinada a refração central e periférica ao longo do meridiano horizontal até aos 35º de excentricidade, nasal e temporal, em passos de 5º. O comprimento axial foi medido até aos 30º de excentricidade, nasal e temporal, em passos de 10º. Resultados: Foram encontradas diferenças estatisticamente significativas (p <0.001) entre as componentes astigmáticas da refração periférica dos dois grupos na parte nasal da retina. O grupo de míopes progressivos tem uma focal sagital relativa mais hipermetrópica (média 35ºN = +1,00±0,83 D) que o grupo dos não progressivos (média 35ºN = -0,10±0,98 D). Relativamente às diferenças morfológicas entre o pólo posterior dos olhos de ambos os grupos, os resultados mostram uma forma mais prolata na região nasal (Test-T; p=0.03) no grupo progressivo, apesar do comprimento axial médio entre ambos os grupos não apresentar diferenças estatisticamente significativas (24,58±0,83 mm nos não progressivos contra 24,63±0,87 mm nos progressivos, p=0.821). A morfologia do pólo posterior nasal (ΔCA_N) apresenta uma forte correlação com a refração periférica (r2=0.523 nos progressivos e r2=0.646 nos não progressivos), o que sugere que os olhos mais prolatos apresentam uma refração periférica relativa mais hipermetrópica. Conclusões: Estes resultados são consistentes com os trabalhos anteriores que sugerem que uma refração periférica hipermetrópica pode atuar, no olho, como um mecanismo de regulação do comprimento axial, estimulando o seu crescimento. A refração periférica relativa depende essencialmente da morfologia da retina e do astigmatismo oblíquo. A sua avaliação não deve ser realizada com base nos valores dos componentes M, J0 e J45 de uma forma isolada, pois desse modo perde-se parte da informação que aqui manifestamos. Se de facto existe um mecanismo retiniano de regulação do comprimento axial visualmente guiado, o seu feedback poderá estar baseado na posição das focais, tangencial e sagital, da imagem astigmática periférica.Purpose: The purpose of this study was to compare the axial length and relative peripheral refraction, decomposed in both astigmatic focal (tangential and sagittal), between one group with progressive myopic refraction and another one stable for more than two years. Methods: We evaluated 62 eyes with myopia central myopia between -0.50 and -7.00 D of spherical equivalent (mean -2.83 ± 1.46 D) and with an average age of 22.02 ± 1.75 years. Of these, 32 patients were stable for at least 2 years and 30 still in progress. There were no statistically significant differences between age and refractive error in both groups. After the preliminary examination, central and peripheral refraction was determined, along the horizontal meridian to 35 ° of eccentricity nasal and temporal, in steps of 5º. Axial length was measured up to 30 ° eccentricity, nasal and temporal, in steps of 10º. Results: We found statistically significant differences (p <0.001) in the peripheral astigmatic refractive components, between both groups, on the nasal retina. The myopic progressive group has a more hypermetropic relative sagittal focal (average 35 º N = +1.00 ± 0.83 D) when compared to the non-progressive (group of average 35 º N = -0.10 ± 0.98 D). For the morphological differences in the posterior pole between the eyes of both groups, the results show a more prolate shape in the nasal region (T-Test, p = 0.03) in the progressive group although the mean axial length, between the two groups, did not had a statistically significant difference (24.58 ± 0.83 mm in non-progressive from 24.63 ± 0.87 mm in the progressive, p = 0,821). The morphology of the nasal posterior pole (ΔCA_N) shows a strong correlation with the peripheral refraction (r2=0,523 in the progressive and r2=0,646 in the non-progressive), which suggests that eyes with a more prolate shape have a more hypermetropic relative peripheral refraction. Conclusions: These results are consistent with previous work suggesting that a peripheral hyperopic refraction can act in the eye as a mechanism for regulating axial length, stimulating growth. The relative peripheral refraction depends on the morphology of the retina and the oblique astigmatism. The assessment of the peripheral refraction should not be performed based on the isolated values of the components M, J0 and J45, or it will result in the loss of part the information that shown here. If in fact a visually guided mechanism, for the regulation of axial length, thoroughly exists, its feedback may be based on the position of the tangential and sagittal focal of peripheral astigmatic image

Effect of pupil size on wavefront refraction during orthokeratology

Purpose. It has been hypothesized that central and peripheral refraction, in eyes treated with myopic overnight orthokeratology, might vary with changes in pupil diameter. The aim of this work was to evaluate the axial and peripheral refraction and optical quality after orthokeratology, using ray tracing software for different pupil sizes. Methods. Zemax-EE was used to generate a series of 29 semi-customized model eyes based on the corneal topography changes from 29 patients who had undergone myopic orthokeratology. Wavefront refraction in the central 80 degrees of the visual field was calculated using three different quality metrics criteria: Paraxial curvature matching, minimum root mean square error (minRMS), and the Through Focus Visual Strehl of the Modulation Transfer Function (VSMTF), for 3- and 6-mm pupil diameters. Results. The three metrics predicted significantly different values for foveal and peripheral refractions. Compared with the Paraxial criteria, the other two metrics predicted more myopic refractions on- and off-axis. Interestingly, the VSMTF predicts only a marginal myopic shift in the axial refraction as the pupil changes from 3 to 6 mm. For peripheral refraction, minRMS and VSMTF metric criteria predicted a higher exposure to peripheral defocus as the pupil increases from 3 to 6 mm. Conclusions. The results suggest that the supposed effect of myopic control produced by ortho-k treatments might be dependent on pupil size. Although the foveal refractive error does not seem to change appreciably with the increase in pupil diameter (VSMTF criteria), the high levels of positive spherical aberration will lead to a degradation of lower spatial frequencies, that is more significant under low illumination levels.This study has been funded by FEDER through the COMPETE Program and by the Portuguese Foundation for Science and Technology (FCT) in the framework of projects PTDC/SAU-BEB/098391/2008, PTDC/SAU-BEB/ 098392/2008, and the Strategic Project PEST-C/FIS/UI607/2011. Dr. Navarro acknowledges funding by the Spanish Ministery of Economy and Competivity, grant FIS2014-58303-P. The authors have no proprietary interests in the methods and devices described in this manuscript

Depth-of-field after orthokeratology: a theoretical study

Trabajo presentado al 8th European Meeting on Visual and Physiological Optics, celebrado en Antwerp (Bélgica) del 22 al 24 de agosto de 2016.We evaluated the possible effect of orthokeratology on accommodative response. Using optical modelling we computed the negative half of the depth-of-field (DoFi) for the range of target vengeances from –1.00 D to –3.00 D, of two eye models designed to mimic the levels of primary and secondary spherical aberration found in 24 patients before and after undergoing orthokeratology (ortho-k). Five trained observers were subjected to a resolution task to identify the negative threshold of the depth-of-field of these model eyes by viewing a set of computed images representative of the model eyes trough focus retinal image quality for five target vengeances (TV), from –1.00 to – 3.00 D. The differences in the DoFi estimated by the five observers were maximum for a –3.00 D TV (0.21 D), with the post ortho-k model presenting a higher DoFi compared to the pre ortho-k model. Differences were consistent for all five observers and all TV’s. In conclusion, the increase in spherical aberration after ortho-k seems to contribute to a small increase in the DoFi. Although small, the benefits might be sufficient to improve retinal image quality in eyes with high accommodative lag.Peer reviewe

Morphology, topography, and optics of the orthokeratology cornea

The goal of this work was to objectively characterize the external morphology, topography, and optics of the cornea after orthokeratology (ortho-k). A number of 24 patients between the ages of 17 and 30 years (median ¼ 24 years) were fitted with Corneal Refractive Therapy® contact lenses to correct myopia between −2.00 and −5.00 diopters (D) (median ¼ −3.41 D). A classification algorithm was applied to conduct an automatic segmentation based on the mean local curvature. As a result, three zones (optical zone, transition zone, and peripheral zone) were delimited. Topographical analysis was provided through global and zonal fit to a general ellipsoid. Ray trace on partially customized eye models provided wave aberrations and retinal image quality. Monozone topographic description of the ortho-k cornea loses accuracy when compared with zonal description. Primary (C0 4) and secondary (C0 6) spherical aberration (SA) coefficients for a 5-mm pupil increased 3.68 and 19 times, respectively, after the treatments. The OZ area showed a strong correlation with C0 4 (r ¼ −0.49, p < 0.05) and a very strong correlation with C0 6 (r ¼ 0.78, p < 0.01). The OZ, as well as the TZ, areas did not correlate with baseline refraction. The increase in the eye’s positive SA after ortho-k is the major factor responsible for the decreased retinal optical quality of the unaccommodated eyeThis work was funded in part by European Fund for Regional Development (FEDER) through the COMPETE Program and by the Portuguese Foundation for Science and Technology (FCT). FCT provided financial support in the framework of projects PTDC/SAU-BEB/098391/2008, PTDC/SAU-BEB/ 098392/2008 and the Strategic Project PEST-C/FIS/UI607/ 2011. The authors have no proprietary interest in the methods and devices described in this manuscript