A review of the development of a synthetic corneal onlay for refractive correction

A synthetic corneal onlay, or implantable contact lens, could obviate the need for spectacles or conventional contact lenses in patients who seek convenient, reversible correction of refractive error. Several research groups have attempted to develop such a product in the past but much of the data from these studies remains unpublished due to commercial interests. This article reviews relevant papers and patents in the corneal implant field and discusses our efforts to develop a synthetic corneal onlay using a perfluoropolyether-based polymer.     

Genetic susceptibility and mechanisms for refractive error

Refractive errors, myopia and hyperopia, are the most common causes of visual impairment worldwide. Recent advances in genetics have been utilized to identify a wealth of genetic loci believed to contain susceptibility genes for refractive error (RE). The current genetic evidence confirms that RE is influenced by both common and rare variants with a significant environmental component. These studies argue that only by combining genetic and environmental knowledge with in vivo measurements of biological states will it be possible to understand the underlying biology of RE that will lead to novel therapeutic targets and accurate genetic predictions.     

Variation of corneal refractive index with hydration

We report the effect of changes in the corneal hydration on the refractive index of the cornea. Using optical coherence tomography (OCT), the geometrical thickness and the group refractive index of the bovine cornea were derived simultaneously as the corneal hydration was varied. The corneal hydration was then calculated from the corneal thickness. The group refractive index of the cornea increased non-linearly as the cornea dehydrated. In addition, a simple mathematical model was developed, based on the assumption that changes in corneal hydration occur only in the interfibrilar space with constant water content within the collagen fibrils. Good agreement between the experimental results and the mathematical model supports the assumption. The results also demonstrate that the measurement of refractive index is a quantitative indicator of corneal hydration.     

Assessing the contribution of genetic nurture to refractive error

Parents pass on both their genes and environment to offspring, prompting debate about the relative importance of nature versus nurture in the inheritance of complex traits. Advances in molecular genetics now make it possible to quantify an individual’s genetic predisposition to a trait via his or her ‘polygenic score’. However, part of the risk captured by an individual’s polygenic score may actually be attributed to the genotype of their parents. In the most well-studied example of this indirect ‘genetic nurture’ effect, about half the genetic contribution to educational attainment was found to be attributed to parental alleles, even if those alleles were not inherited by the child. Refractive errors, such as myopia, are a common cause of visual impairment and pose high economic and quality-of-life costs. Despite strong evidence that refractive errors are highly heritable, the extent to which genetic risk is conferred directly via transmitted risk alleles or indirectly via the environment that parents create for their children is entirely unknown. Here, an instrumental variable analysis in 1944 pairs of adult siblings from the United Kingdom was used to quantify the proportion of the genetic risk (‘single nucleotide polymorphism (SNP) heritability’) of refractive error contributed by genetic nurture. We found no evidence of a contribution from genetic nurture: non-within-family SNP-heritability estimate = 0.213 (95% confidence interval 0.134–0.310) and within-family SNP-heritability estimate = 0.250 (0.152–0.372). Our findings imply the genetic contribution to refractive error is principally an intrinsic effect from alleles transmitted from parents to offspring.Subject terms: Risk factors, Diseases     

Electrophysiological correlates of error correction

Evidence in the literature for the proposed relationship between the error-related negativity (ERN) and error correction is rather limited and inconsistent. We investigated corrective behavior and the ERN in two groups of participants who performed a flanker task. The correction-instructed group was asked to immediately correct all encountered errors. The noninstructed group was unaware that corrective responses were recorded. We found a negative deflection following corrected errors that peaked at 200-240 ms after the error. We refer to this negativity in the ERP waveform as correction-related negativity (CoRN). We assume that the correction-related negativity reflects evaluative functions of the motor system necessary for error corrections. ERN latency and amplitude were modulated by the occurrence and temporal characteristics of immediate corrections. These results are discussed within the framework of current models of performance monitoring.     

Nature and nurture: the complex genetics of myopia and refractive error

The refractive errors, myopia and hyperopia, are optical defects of the visual system that can cause blurred vision. Uncorrected refractive errors are the most common causes of visual impairment worldwide. It is estimated that 2.5 billion people will be affected by myopia alone within the next decade. Experimental, epidemiological and clinical research has shown that refractive development is influenced by both environmental and genetic factors. Animal models have showed that eye growth and refractive maturation during infancy are tightly regulated by visually guided mechanisms. Observational data in human populations provide compelling evidence that environmental influences and individual behavioral factors play crucial roles in myopia susceptibility. Nevertheless, the majority of the variance of refractive error within populations is thought to be because of hereditary factors. Genetic linkage studies have mapped two dozen loci, while association studies have implicated more than 25 different genes in refractive variation. Many of these genes are involved in common biological pathways known to mediate extracellular matrix (ECM) composition and regulate connective tissue remodeling. Other associated genomic regions suggest novel mechanisms in the etiology of human myopia, such as mitochondrial-mediated cell death or photoreceptor-mediated visual signal transmission. Taken together, observational and experimental studies have revealed the complex nature of human refractive variation, which likely involves variants in several genes and functional pathways. Multiway interactions between genes and/or environmental factors may also be important in determining individual risks of myopia, and may help explain the complex pattern of refractive error in human populations.     

The influence of surface topography of a porous perfluoropolyether polymer on corneal epithelial tissue growth and adhesion

Design principles for corneal implants are challenging and include permeability which inherently involves pore openings on the polymer surface. These topographical cues can be significant to a successful clinical outcome where a stratified epithelium is needed over the device surface, such as with a corneal onlay or corneal repair material. The impact of polymer surface topography on the growth and adhesion of corneal epithelial tissue was assessed using porous perfluoropolyether membranes with a range of surface topography. Surfaces were characterised by AFM and XPS, and the permeability and water content of membranes was measured. Biological testing of membranes involved a 21-day in vitro tissue assay to evaluate migration, stratification and adhesion of corneal epithelium. Similar parameters were monitored in vivo by surgically implanting membranes into feline corneas for up to 5 months. Data showed optimal growth and adhesion of epithelial tissue in vitro when polymer surface features were below a 150 nm RMS value. Normal processes of tissue growth and adhesion were disrupted when RMS values approached 300 nm. Data from the in vivo study confirmed these findings. Together, outcomes demonstrated the importance of surface topography in the design of implantable devices that depend on functional epithelial cover.     

Pencil kernel correction and residual error estimation for quality-index-based dose calculations

Experimental data from 593 photon beams were used to quantify the errors in dose calculations using a previously published pencil kernel model. A correction of the kernel was derived in order to remove the observed systematic errors. The remaining residual error for individual beams was modelled through uncertainty associated with the kernel model. The methods were tested against an independent set of measurements. No significant systematic error was observed in the calculations using the derived correction of the kernel and the remaining random errors were found to be adequately predicted by the proposed method.     

Effect of the first day correction on systematic setup error reduction

Treatment simulation is usually performed with a conventional simulator using kV X-rays or with a computed tomography (CT) simulator before the treatment course begins. The purpose is to verify patient setup under the same conditions as for treatment planning. Systematic (preparation) setup errors can be introduced by this process. The purpose of this study is to characterize the setup errors using electronic portal image (EPI) analyses and to propose a method to reduce the systematic component by performing simulation and patient preparation on the treatment machine. In this study, the first four or five days EPIs were analyzed from a total of 533 prostate cancer patients who were simulated on conventional simulators. We characterized setup errors using four parameters: {M(microi), Sigma (microi), RMS(microi), sigma (sigmai)}, where microi and sigmai are individual patient mean and standard deviation, M, Sigma, and RMS are the mean, standard deviation, and root-mean-square of underlying variables (microi and sigmai). We have performed a simulation of removing systematic components by correcting the first day setup error. As a comparison, we also carried out a similar analyses for patients simulated on a CT simulator and patients treated on a linac with an on-board kV CT imaging system, although a limited number of patients were available in these two samples. We found that Sigma (/ui)=(2.6,3.4,2.4) mm, and RMS(sigmai)=(1.5,1.9,1.0) mm in lateral, anterior/posterior, and cranial/caudal directions, indicating that systematic errors are much larger than random errors. Strong correlations were found between measurement on the first day and microi, implying the first day's measurement is a good predictor for microi. The same parameters were also computed for days 2-4, with and without the first day correction. Without correction, M(microi)2-4=(0.7,1.6,-1.0) mm, and Sigma(microi)2-4=(2.6,3.5,2.4) mm. With correction, M(microi)2-4=(0.0,0.4,0.4) mm, much closer to zero, and Sigma(microi)2-4=(1.8,2.2, 1.2) mm, also much smaller. While the use of a CT simulator can reduce the systematic errors, the benefits of first day correction can still be observed, although at a smaller magnitude. Therefore, the systematic setup error can be significantly reduced if the patient is marked and fields are verified on the treatment machine on the first fraction, preferably with an on-board kV imaging system.     

Control of predictive error correction during a saccadic double-step task

We explored the nature of control during error correction using a modified saccadic double-step task in which subjects cancelled the initial saccade to the first target and redirected gaze to a second target. Failure to inhibit was associated with a quick corrective saccade, suggesting that errors and corrections may be planned concurrently. However, because saccade programming constitutes a visual and a motor stage of preparation, the extent to which parallel processing occurs in anticipation of the error is not known. To estimate the time course of error correction, a triple-step condition was introduced that displaced the second target during the error. In these trials, corrective saccades directed at the location of the target prior to the third step suggest motor preparation of the corrective saccade in parallel with the error. To estimate the time course of motor preparation of the corrective saccade, further, we used an accumulator model (LATER) to fit the reaction times to the triple-step stimuli; the best-fit data revealed that the onset of correction could occur even before the start of the error. The estimated start of motor correction was also observed to be delayed as target step delay decreased, suggesting a form of interference between concurrent motor programs. Taken together we interpret these results to indicate that predictive error correction may occur concurrently while the oculomotor system is trying to inhibit an unwanted movement and suggest how inhibitory control and error correction may interact to enable goal-directed behaviors.     

Tibial inlay for posterior cruciate ligament reconstruction: A systematic review

Although no consensus has been reached regarding the management of PCL deficiency, in vitro and in vivo studies have investigated whether the tibial inlay technique restores the anatomical site of insertion of the PCL, prevents elongation, stretching, graft failure, and improves long-term PCL stability. A systematic search using PubMed, Ovid, the Cochrane Reviews, and Google Scholar databases using ‘posterior cruciate ligament tear’, ‘Tibial inlay technique’ and ‘posterior cruciate ligament reconstruction’ as keywords identified 71 publications, of which 10 were relevant to the topic, and included a total of 255 patients. The tibial inlay technique restores the anatomic insertion site of the PCL, eliminates the killer turn effect, and places the graft at lower potential risk for abrasion and subsequent rupture. It has the disadvantages of increased operating time and risk to the posterior neurovascular structures. There was no evidence of an association between outcome results and Coleman methodology score, but the Coleman methodology scores correlated positively with the level-of-evidence rating. The methodological quality of the studies included has not improved over the years. Given the few reported published findings, we cannot ascertain whether this procedure may provide a consistent alternative to commonly used PCL surgical strategies. The lack of published randomized clinical trials and few reported findings did not allow to ascertain whether the tibial inlay for posterior cruciate ligament reconstruction may provide a consistent alternative to commonly used PCL surgical strategies and to demonstrate procedure efficacy.     

Inferior olive oscillation as the temporal basis for motricity and oscillatory reset as the basis for motor error correction

The cerebellum can be viewed as supporting two distinct aspects of motor execution related to a) motor coordination and the sequence that imparts such movement temporal coherence and b) the reorganization of ongoing movement when a motor execution error occurs. The former has been referred to as “motor time binding” as it requires that the large numbers of motoneurons involved be precisely activated from a temporal perspective. By contrast, motor error correction requires the abrupt reorganization of ongoing motor sequences, on occasion sufficiently important to rescue the animal or person from potentially lethal situations. The olivo-cerebellar system plays an important role in both categories of motor control. In particular, the morphology and electrophysiology of inferior olivary neurons have been selected by evolution to execute a rather unique oscillatory pace-making function, one required for temporal sequencing and a unique oscillatory phase resetting dynamic for error correction. Thus, inferior olivary (IO) neurons are electrically coupled through gap junctions, generating synchronous subthreshold oscillations of their membrane potential at a frequency of 1–10 Hz and are capable of fast and reliable phase resetting. Here I propose to address the role of the olivocerebellar system in the context of motor timing and reset.     

Mixed control for perception and action: timing and error correction in rhythmic ball-bouncing

The task of bouncing a ball on a racket was adopted as a model system for investigating the behavioral dynamics of rhythmic movement, specifically how perceptual information modulates the dynamics of action. Two experiments, with sixteen participants each, were carried out to definitively answer the following questions: How are passive stability and active stabilization combined to produce stable behavior? What informational quantities are used to actively regulate the two main components of the action—the timing of racket oscillation and the correction of errors in bounce height? We used a virtual ball-bouncing setup to simultaneously perturb gravity (g) and ball launch velocity (v _b) at impact. In Experiment 1, we tested the control of racket timing by varying the ball’s upward half-period t _up while holding its peak height h _p constant. Conversely, in Experiment 2, we tested error correction by varying h _p while holding t _up constant. Participants adopted a mixed control mode in which information in the ball’s trajectory is used to actively stabilize behavior on a cycle-by-cycle basis, in order to keep the system within or near the passively stable region. The results reveal how these adjustments are visually controlled: the period of racket oscillation is modulated by the half-period of the ball’s upward flight, and the change in racket velocity from the previous impact (via a change in racket amplitude) is governed by the error to the target.     

楔形野剂量计算中的误差分析和修正

目的研究楔形野剂量计算中的误差,并探讨解决方法.材料与方法在10MV和6MVX线条件下,用NEFarmer25710.6cc指形电离室和三维水箱在水模中测出平野和楔形野的各种参数,并用二种方法计算剂量,结果与实侧值比较.结果实测数据显示Pdd和Scp在平野和楔形野情况下存在差异.楔形因子因此随深度而变化,变化程度受射线能量、楔形板规格影响.与实测值比较,用传统方法计算楔形野剂量的结果存在误差,误差大小与能量、野面积、深度有关.6MVX线、15×15野、20cm深度处的计算误差可达11%.而用改进的方法进行计算,可将误差控制在1%以内.结论由于忽略了Pdd等物理参数在楔形野条件下的变化,用传统方法计算楔形野剂量存在误差.为保证临床剂量计算的准确性,应在计算公式中加入修正因子.     

Beside the point: motor adaptation without feedback-based error correction in task-irrelevant conditions

Adaptation of movement may be driven by the difference between planned and actual motor performance, or the difference between expected and actual sensory consequences of movement. To identify how the nervous system differentially uses these signals, we asked: does motor adaptation occur when movement errors are irrelevant to the task goal? Participants reached on a digitizing tablet from a fixed start location to one of three targets: a point, an arc, or a ray. For the arc, reaches could be in any direction, but to a specific extent. For the ray, reaches could be to any distance, but in a targeted direction. After baseline reaching to the point, the direction or extent of continuous visual feedback was perturbed during training with either a cursor rotation or gain, respectively, while reaching to either the ray (goal = direction) or the arc (goal = extent). The perturbation, therefore, was either relevant or irrelevant to the task goal, depending on target type. During interspersed catch trials, the perturbation was removed and the target switched back to the point, identical to baseline. Although the goal of baseline and catch trials was the same, significant aftereffects in catch trials indicated behavioral adaptation in response to the perturbation. Adaptation occurred regardless of whether the perturbation was relevant to the task, and it was independent of feedback control. The presence of adaptation orthogonal to task demands supports the hypothesis that the nervous system can rely on sensory prediction to drive motor learning that can generalize across tasks.     

Analytic evaluation of diffuse fluence error in multilayer scattering media with discontinuous refractive index

A simple analytic method of estimating the error involved in using an approximate boundary condition for diffuse radiation in two adjoining scattering media with differing refractive indices is presented. The method is based on asymptotic planar fluences and enables the relative error to be readily evaluated without recourse to Monte Carlo simulation. Three examples of its application are considered: (1) evaluating the error in calculating the diffuse fluences at a boundary between two media with differing refractive index and dissimilar scattering properties, (2) the dependence of the relative error in a multilayer medium with discontinuous refractive index on the ratio of the reduced scattering coefficient to the absorption coefficient μ(s)'/μ(a), and (3) the parametric dependence of the error in the radiant flux J(s) at the surface of a three-layer medium. The error is significant for strongly forward-biased scattering media with non-negligible absorption and is cumulative in multilayered media with refractive index increments between layers.     

A novel method for incorporating respiratory-matched attenuation correction in the motion correction of cardiac PET-CT studies

Mismatches between PET and CT datasets due to respiratory effects can lead to artefactual perfusion defects. To overcome this, we have proposed a method of aligning a single CT with each frame of a gated PET study in a semi-automatic manner, incorporating a statistical shape model of the diaphragm and a rigid registration of the heart. This ensures that the structures that could influence the appearance of the reconstructed cardiac activity are correctly matched between emission and transmission datasets. When tested on two patient studies, it was found in both cases that attenuation correction using the proposed technique resulted in PET images that were closer to the gold standard of attenuation correction with a gated CT, compared with scenarios where only heart matching was considered (and not the diaphragm) or where no transformation was performed (i.e. where a single CT frame was used to attenuation-correct all PET frames). These preliminary results suggest that diaphragm matching between PET and CT improves the quantitative accuracy of reconstructed PET images and that the proposed method of using a statistical shape model to describe the diaphragm shape and motion, in combination with a rigid registration to determine respiratory-induced heart motion, is a feasible method of achieving this.