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Aim: To understand the effect of the geometric and material properties of the lens on the age-related decline in accommodative amplitude. Methods: Using a non-linear finite-element model, a parametric assessment was carried out to determine the effect of stiffness of the cortex, nucleus, capsule and zonules, and that of thickness of the capsule and lens, on the change in central optical power (COP) associated with zonular traction. Convergence was required for all solutions. Results: Increasing either capsular stiffness or capsular thickness was associated with an increase in the change in COP for any specific amount of zonular traction. Weakening the attachment between the capsule and its underlying cortex increased the magnitude of the change in COP. When the hardness of the total lens stroma, cortex or nucleus was increased, there was a reduction in the amount of change in COP associated with a fixed amount of zonular traction. Conclusions: Increasing lens hardness reduces accommodative amplitude; however, as hardness of the lens does not occur until after the fourth decade of life, the age-related decline in accommodative amplitude must be due to another mechanism. One explanation is a progressive decline in the magnitude of the maximum force exerted by the zonules with ageing.

Background To evaluate the age-related changes in the stiffness of the human lens nucleus in vivo. Methods A total of 78 volunteers with best-corrected visual acuity of 20/20with a mean ± standard deviation intraocular pressure (IOP) of 16 ± 2.5 mmHg were divided into 3 groups of 26. The mean ages of Groups A, B and C were 81 ± 5.5, 44 ± 3.2 and 21 ± 2.5 years, with mean axial lengths of 23.8 ± 0.5 mm, 23.8 ± 0.4 mm and 23.9 ± 0.3 mm, respectively. Using an elastographer, the ultrasound echolucency and elastic strain rate of the lens nucleus of one eye, selected randomly, of each subject were measured three times. The strain rate of the lens cortex could not be assessed. The qualitative differences in the strain rates across the groups were assessed, and differences in the strain rate ratios of the lens nuclei across groups were analysed by one-way ANOVA. Results The strain rates of the lens nuclei of Group A were much lower than those in Groups B and C, as assessed qualitatively; the elastograph images of the lens nuclei of the older group showed a blue colour.The strain rate ratios of the lens nuclei of Groups A, B and C were 0.02 ± 0.08, 0.69 ± 0.12 and 1.95 ± 0.85, respectively. The differences in the lens nucleus strain rate ratios across the groups were statistically significant, with p -values < 0.05. Conclusions Ultrasound elastography demonstrated in vivo that an older age is associated with a statistically significantly lower lens nucleus strain rate ratio and therefore a markedly higher lens nuclear stiffness.

Cataract is a visible opacity in the lens substance, which, when located on the visual axis, leads to visual loss. Age-related cataract is a cause of blindness on a global scale involving genetic and environmental influences. With ageing, lens proteins undergo non-enzymatic, post-translational modification and the accumulation of fluorescent chromophores, increasing susceptibility to oxidation and cross-linking and increased light-scatter. Because the human lens grows throughout life, the lens core is exposed for a longer period to such influences and the risk of oxidative damage increases in the fourth decade when a barrier to the transport of glutathione forms around the lens nucleus. Consequently, as the lens ages, its transparency falls and the nucleus becomes more rigid, resisting the change in shape necessary for accommodation. This is the basis of presbyopia. In some individuals, the steady accumulation of chromophores and complex, insoluble crystallin aggregates in the lens nucleus leads to the formation of a brown nuclear cataract. The process is homogeneous and the affected lens fibres retain their gross morphology. Cortical opacities are due to changes in membrane permeability and enzyme function and shear-stress damage to lens fibres with continued accommodative effort. Unlike nuclear cataract, progression is intermittent, stepwise and non-uniform.

The purpose of the lens is to project a sharply focused, undistorted image of the visual surround onto the neural retina. The first pre-requisite, therefore, is that the tissue should be transparent. Despite the presence of remarkably high levels of protein, the lens cytosol remains transparent as a result of short-range-order interactions between the proteins. At a cellular level, the programmed elimination of nuclei and other light-scattering organelles from cells located within the pupillary space contributes directly to tissue transparency. Scattering at the cell borders is minimized by the close apposition of lens fibre cells facilitated by a plethora of adhesive proteins, some expressed only in the lens. Similarly, refractive index matching between lens membranes and cytosol is believed to minimize scatter. Refractive index matching between the cytoplasm of adjacent cells is achieved through the formation of cellular fusions that allow the intermingling of proteins. Together, these structural adaptations serve to minimize light scatter and enable this living, cellular structure to function as ‘biological glass’.

To investigate the tilt and decentration of the crystalline lens and the intraocular lens (IOL) relative to the corneal topographic axis using anterior segment ocular coherence tomography (AS-OCT). A sample set of 100 eyes from 49 subjects (41 eyes with crystalline lenses and 59 eyes with IOLs) were imaged using second generation AS-OCT (CASIA2, TOMEY) in June and July 2016 at Okayama University. Both mydriatic and non-mydriatic images were obtained, and the tilt and decentration of the crystalline lens and the IOL were quantified. The effects of pupil dilation on measurements were also assessed. The crystalline lens showed an average tilt of 5.15° towards the inferotemporal direction relative to the corneal topographic axis under non-mydriatic conditions and 5.25° under mydriatic conditions. Additionally, an average decentration of 0.11 mm towards the temporal direction was observed under non-mydriatic conditions and 0.08 mm under mydriatic conditions. The average tilt for the IOL was 4.31° towards the inferotemporal direction relative to the corneal topographic axis under non-mydriatic conditions and 4.65° in the same direction under mydriatic conditions. The average decentration was 0.05 mm towards the temporal direction under non-mydriatic conditions and 0.08 mm in the same direction under mydriatic conditions. A strong correlation was found between the average tilt and decentration values of the crystalline lens and the IOL under both non-mydriatic and mydriatic conditions (all Spearman correlation coefficients, r ≥ 0.800; all P < 0.001). When measured using second generation AS-OCT, both the crystalline lens and the IOL showed an average tilt of 4-6° toward the inferotemporal direction relative to the corneal topographic axis and an average decentration of less than 0.12 mm towards the temporal direction. These results were not influenced by pupil dilation and they showed good repeatability.

The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells. A new procedure for cataract removal that preserves lens epithelial progenitor cells in mammals, which require Pax6 and Bmi1 for their self-renewal, achieves lens regeneration in rabbits, macaques and in infants with cataracts. Sight restoration through cellular regeneration The only current treatment for cataracts, the leading cause of blindness, is to extract the damaged lens surgically and implant an artificial intraocular lens. The technique has its limitations, so there is great interest in the possibility of a regenerative medicine approach. Two papers published in this issue of Nature report advances that could bring that prospect a little closer. Kang Zhang and colleagues isolate mammalian lens epithelial stem/progenitor cells and show that Pax6 and Bmi1 are required for their renewal. They have also developed a removal procedure for cataract-affected tissue that preserves these cells, and achieved lens regeneration in rabbits, macaques and in human infants with cataracts. In the second paper, Kohji Nishida and colleagues describe a protocol for in vitro generation of a self-formed ectodermal autonomous multi-zone (SEAM) from human induced pluripotent stem cells. The SEAM includes distinct cell lineages from the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. Previous experiments had focused mainly on obtaining one cell type. These authors show that cells from the SEAM can be expanded to form a functional corneal epithelium when transplanted to an animal model of blindness.

The ability to focus at near is achieved by dynamic changes in the shape of the lens of the eye. The Helmholtz hypothesis of accommodation proposes that, at distance gaze, all of the lenticular supporting zonules are at maximal tension. To bring a near object into focus, this tension is reduced by action of the ciliary muscle. The resultant release of tension allows the elastic lens capsule to mold the lens into a more rounded shape, increasing both its central thickness and central optical power (COP). Based upon Helmholtz’s hypothesis, complete removal of these zonules should result in a rounded shaped lens of maximal COP. Schachar has offered an alternative mechanism of accommodation based upon the distinct actions of the three different groups of lenticular zonules. Schachar believes that for distant objects, all the zonules are under the minimum tension required to maintain lens stability; however, during lenticular accommodation, equatorial zonular tension increases while, simultaneously, the anterior and posterior zonular tension decreases. The selective increase in equatorial zonular tension results from the unique orientation of the different ciliary muscle fiber groups. With this increase in equatorial zonular tension, the peripheral lens surfaces flatten, central surfaces steepen and central lens thickness and COP increase. Schachar’s hypothesis would anticipate that with zonular removal, the COP of the isolated lens would be minimal and diametrically opposite to the high lens COP expected with the Helmholtz hypothesis. In order to determine the COP of the isolated human lens, we obtained, through the kindness of the authors of an independent research study, the x-y coordinates of the central sagittal lens profiles of 10 freshly isolated human lenses (donors aged 20–30 years). These coordinate data were then mathematically utilized by fitting them into Chien, Forbes, Fourier, and elliptical equations. Additionally, the coordinate data was smoothed and fit to third-degree polynomials (S4W 3rd Poly). Independent of which of these equations was employed, within central optical zone diameters of ≤ 3 mm, the COP was found to be minimal. Since the S4W 3rd Poly provided the best fit, it was used to represent lens surfaces in optically modeled eyes. In all modeled eyes, Zernike spherical aberration (SA) coefficients were positive. These findings are consistent with in vivo measurements of SA obtained from human eyes while viewing distant visual objects. Having thus demonstrated that freshly removed human lenses, free of zonular tension, have their least COP, it is likely that this condition mimics the physiologic status of the human lens in the eye while attending to the most distant visual objects. In an independent, companion paper, we observed, using interferometric measurements of surface radius of curvatures of 12 fresh, isolated human lenses, obtained from donors aged 20–30 years, that the minimal COP was also associated with the unaccommodated state in vivo.

To see near objects clearly, the ciliary muscle shapes the human eye’s crystalline lens to adjust its refractive power, a process known as accommodation. This contraction of the ciliary muscle also results in an electrical potential change. Previous work from the 1950s and 1960s reported electrical voltages in the microvolt range that were attributed to the accommodating ciliary muscle, however without clarifying the interaction between lens and muscle. Here, we present data of 12 emmetropic participants using a custom-developed scleral contact lens electrode which enables to record accommodation-dependent biopotentials of the ciliary muscle with an accuracy up to the millivolt range. Therefore, participants alternately shifted their focus from far to various near targets while the biopotentials of the ciliary muscle and the actual refractive change of the crystalline lens were recorded by a contact lens electrode and an eccentric infrared Photorefractor. In addition, the impact of confounding biopotentials such as squinting and eye movements was investigated. Our research points to a potentially new objective method of measuring accommodative change. Understanding these biopotentials could lead to the development of self-focusing visual aids as an alternative way of vision correction in presbyopes.

The magnitude of zonular forces required to change the shape of the human lens while focusing at near; i.e., accommodating, is still under investigation. During accommodation, ciliary muscle contraction induces a large increase in lens central optical power (COP). Here we used finite element (FE) analysis to evaluate the correlation between zonular forces and lens surface curvatures, central thickness, COP, overall lens shape and longitudinal spherical aberration (LSA). Fresh isolated lenses from donors aged 20, 24, 26, and 30 years were the basis for the analyses. Lens nucleus elastic moduli were specified as equal to, 2, 3, 10, 20 and 30 times greater than its cortex. When equatorial zonular (Ez) force was increased in 3.125 x 10 -6 N steps while the anterior zonular (Az) and posterior zonular (Pz) forces were decreased in 3.125 x 10 -6 N steps, COP was evaluated. Independent of the increase in lens nuclear modulus, less than 0.02 N of Ez force was required to increase COP 10 diopters while Az and Pz forces were decreased. The lens peripheral surfaces flattened, central surfaces steepened, central lens thickness increased, COP increased and LSA shifted in the negative direction consistent with published in vivo accommodation studies. The minimal Ez force required to obtain 10 diopters of COP increase supports that increasing Ez force with decreasing Az and Pz force is the basis for the change in lens shape during accommodation. Since the COP increase was independent of increasing elastic modulus of the nucleus, stiffening of the lens nucleus is not the etiology of the universal age-related decline in accommodative amplitude that results in presbyopia in the fifth decade of life. Increased Ez zonular tension during accommodation has implications for the development and potential treatments of myopia, glaucoma, presbyopia, cortical cataracts and accommodative intraocular lens design.

The extent to which adult newts retain regenerative capability remains one of the greatest unanswered questions in the regeneration field. Here we report a long-term lens regeneration project spanning 16 years that was undertaken to address this question. Over that time, the lens was removed 18 times from the same animals, and by the time of the last tissue collection, specimens were at least 30 years old. Regenerated lens tissues number 18 and number 17, from the last and the second to the last extraction, respectively, were analysed structurally and in terms of gene expression. Both exhibited structural properties identical to lenses from younger animals that had never experienced lens regeneration. Expression of mRNAs encoding key lens structural proteins or transcription factors was very similar to that of controls. Thus, contrary to the belief that regeneration becomes less efficient with time or repetition, repeated regeneration, even at old age, does not alter newt regenerative capacity. Tissue regeneration is of great interest; however the number of times a given tissue can regenerate is unknown. Now, Eguchi et al . demonstrate that the lens of the Japanese newt—Cynops pyrrhogaster—can regenerate 18 times over a 16-year period, and that the new lenses are similar to those of control adult animals.