Retinal Prosthesis： A Potential Benefit for the Blind

Retinal degenerative diseases may induce the degeneration of outer retina and in turn, blindness. Nevertheless, due to the maintenance of inner retina, the coding and processing of visual neurons responses are still able to be executed naturally. Therefore, an effective retinal prosthesis device may be developed by mimicking the function of outer retina： transferring the visual light into artificial stimulus and delivering the stimulus to the retina aiming to evoke the neural responses. As two main developing directions for current retinal prosthesis,epiretinal （ER） and subretinal （SR） prosthesis are both undergoing experimental stage and possessing advantages and limitations. Further investigations in power supply, biocompatibility, etc. are still required. Additionally, suprachoroidal transretinal stimulation （STS） and neurotransmitter-induced stimulation as some other alternatives in retinal prosthesis are also considered as promising research directions, although they are not mature enough to be applied commercially, either.     

Droplet Tailoring Using Evaporative Inkjet Printing

An experimental study into the in‐flight evaporation and impact of equally sized inkjet printed droplets that consist of a systematically varied polystyrene concentration in either toluene or butyl acetate is presented. At low polymer concentrations, a linear relationship that decreased was observed between dried droplet diameter and printing height. However, increased concentrations revealed an initial exponential decay in the dried droplet diameter, which stabilized at greater heights. At higher concentration and height, the polymer forms a skin on the surface of the inkjet printed droplet, which causes inhibition of the in‐flight evaporation of the solvent.

     

视网膜假体专用集成电路研究进展

近些年来,人工视网膜假体的研究成为视觉修复领域的一个热点。文中根据不同的视网膜假体实现方案,概括介绍了视网膜假体专用集成电路的主要种类及实现方法;分析比较了视网膜上假体和视网膜下假体两种实现方式的优缺点。重点论述了视网膜假体专用集成电路中能量和数据收发、全局数字控制器以及神经驱动阵列等模块的基本原理及研究进展。最后讨论了视网膜假体专用集成电路设计上所面临的一些挑战及关注问题的展望。     

Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium

Adhesion between epithelial cells mediates apical–basal polarization, cell proliferation, and survival, and defects in adhesion junctions are associated with abnormalities from degeneration to cancer. We found that the maintenance of specialized adhesions between cells of the retinal pigment epithelium (RPE) requires the phosphatase PTEN. RPE-specific deletion of the mouse pten gene results in RPE cells that fail to maintain basolateral adhesions, undergo an epithelial-to-mesenchymal transition (EMT), and subsequently migrate out of the retina entirely. These events in turn lead to the progressive death of photoreceptors. The C-terminal PSD-95/Dlg/ZO-1 (PDZ)-binding domain of PTEN is essential for the maintenance of RPE cell junctional integrity. Inactivation of PTEN, and loss of its interaction with junctional proteins, are also evident in RPE cells isolated from ccr2^−/− mice and from mice subjected to oxidative damage, both of which display age-related macular degeneration (AMD). Together, these results highlight an essential role for PTEN in normal RPE cell function and in the response of these cells to oxidative stress.     

年龄相关性黄斑变性与单核甘酸多态性相关性的研究进展

年龄相关性黄斑变性(AMD)是发达国家老年人致盲的首要疾病.遗传因素在AMD的发生、发展中起重要作用.近几年研究发现,一些单核甘酸多态性(SNP)与AMD的发病明显相关.因而对补体因子H(CFH)基因,补体因子B(CFB)基因,补体因子2(C2)基因,补体因子3(C3)基因,CX3C趋化因子受体1(CX3CR1)基因,三磷酸腺苷结合盒转运体基因亚家族A第4成员(ABCA4)在AMD形成过程中的研究具有重要意义.     

Haplotypes of RHO polymorphisms and susceptibility to age-related macular degeneration

Objective: To investigate whether haplotypes of rhodopsin (RHO) polymorphisms including rs7984, rs2855552, rs2855557 and rs2410 were associated with age-related macular degeneration (AMD) risk in Chinese Han population. Methods: Genotypes of rs7984, rs2855552, rs2855557 and rs2410 were detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 186 cases and 196 healthy controls. Then, the haplotypes were established with Haploview 4.2 software. And the effects of clinical charactersitics on the frequency of GTTG haplotype were also analyzed. Odds ratios (ORs) with 95% confidence interval (95% CI) were utilized to assess the relationship of haplotypes and genotypes of RHO polymorphisms with susceptibility to AMD. Results: Genotype distribution of all polymorphisms in control group were all in agreement with Hardy-Weinberg equilibrium (HWE) (P>0.05). In the analysis, we found that mutant alleles of rs7984 and rs2855557 were both associated with increased risk of AMD. For genotype analysis, rs7984 AA and rs2855557AA, rs2410GG genotypes all could increase the risk for AMD (OR=1.905, 95% CI=1.143-3.174; OR=2.226, 95% CI=1.261-3.932; OR=2.073, 95% CI=1.105-3.888). However, rs2855552 showed no effects on the onset of AMD. Compared with GTTA, the haplotypes of GGTG, ATAA and GTTG were all related with AMD susceptibility. Further analysis suggested that age, hypertension and hyperlipidemia history play important roles in the frequency alteration of GTTG haplotype. Conclusion: RHO polymorphisms (rs7984, rs2855557 and rs2410) and haplotypes may confer remarkable susceptibility to AMD. Further investigation showed that gene and environmental factors may work together in the pathogenesis of AMD.     

年龄相关性黄斑变性的分子遗传流行病学研究进展

年龄相关性黄斑变性是发达国家老年人致盲的主要原因,它是一种具有高度遗传异质性的疾病.随着分子生物学和分子遗传学的发展,已经发现多个潜在的致病基因.现就年龄相关性黄斑变性的易感基因和遗传流行病学的研究进展进行综述.     

Identification of a Suppressor of Retinal Degeneration in Drosophila Photoreceptors

During sensory transduction, Drosophila photoreceptors experience substantial increases in intracellular Ca²⁺ levels ([Ca²⁺]_i). Nevertheless in a number of mutants associated with excessive Ca²⁺ influx through transient receptor potential (TRP) channels, Drosophila photoreceptors undergo loss of normal cellular structure manifest as a retinal degeneration. However, the molecular mechanisms that underpin this degeneration process remain unclear. The authors previously isolated a mutant, su(40), that is able to suppress the retinal degeneration seen in photoreceptors from loss-of-function alleles of rdgA that are known to have constitutively active TRP channels. Here the authors report the genetic mapping of su(40) as well the isolation of additional alleles of su(40). Studies of su(40) as well as these new alleles should facilitate the understanding of the mechanisms by which excessive Ca²⁺ influx results in retinal degeneration.     

Age-related macular degeneration: A disease of extracellular complement amplification

Age-related macular degeneration (AMD) is a major cause of vision impairment in the Western World, and with the aging world population, its incidence is increasing. As of today, for the majority of patients, no treatment exists. Multiple genetic and biochemical studies have shown a strong association with components in the complement system and AMD, and evidence suggests a major role of remodeling of the extracellular matrix underlying the outer blood/retinal barrier. As part of the innate immune system, the complement cascade acts as a first-line defense against pathogens, and upon activation, its amplification loop ensures a strong, rapid, and sustained response. Excessive activation, however, can lead to host tissue damage and cause complement-associated diseases like AMD. AMD patients present with aberrant activation of the alternative pathway, especially in ocular tissues but also on a systemic level. Here, we review the latest findings of complement activation in AMD, and we will discuss in vivo observations made in human tissue, cellular models, the potential synergy of different AMD-associated pathways, and conclude on current clinical trials and the future outlook.     

Multilocus analysis of age-related macular degeneration

Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case–control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4–4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5–4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway''s involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD.     

Towards a Retina Prosthesis Model: Neurons on Microphotodiode Arrays In Vitro

Various neurodegenerative diseases of the retina lead to blindness. Since no pharmacological or gene therapy is available, the alternative concept of neuroprostheses has stimulated the development of micromachined photovoltaic devices. One strategy aims to replace degenerated photoreceptors by microphotodiode arrays (MPDA). MPDAs in the subretinal space shall transform light stimuli into electrical current for the stimulation of still unhampered retinal neurons. MPDAs were fabricated as silicon based multilayered PIN microstructures comprising titanium nitride stimulation electrodes of an area of 8 × 8 m². In an effort to develop meaningful tools to evaluate functional MPDA biocompatibility, a novel in vitro system was designed. Retinal cells were cultured on MPDAs, while current generation in MPDAs as in the eye was imitated by light emitting diodes (LED) operating at different wavelengths. For analysis epifluorescence and scannning electron microscopy was employed. MPDAs displayed increasing current delivery with increasing illumination. Surface modification of MPDAs including oxygen plasma treatment and adsorption of polyanions together with laminin were found to render the MPDA surface permissive for cell adhesion. Cell vitality tests using fluorescence markers revealed no adverse effects of optoelectric stimulation via LED/MPDAs. In addition, neurite formation and the expression of differentiation antigen 2A10 were unaffected after stimulation. Optoelectric stimulation allowed regular differentiation of various retinal cell types. In summary, the data provide the first evidence that optoelectric stimulation via MPDAs does not hamper cellular integrity under the experimental conditions chosen. The results support the concept of microphotodiodes as a retinal prosthesis.     

Ocular cytomegalovirus latency exacerbates the development of choroidal neovascularization

Age-related macular degeneration (AMD) is a complex, multifactorial, progressive disease which represents a leading cause of irreversible visual impairment and blindness in older individuals. Human cytomegalovirus (HCMV), which infects 50–80% of humans, is usually acquired during early life and persists in a latent state for the life of the individual. In view of its previously described pro-angiogenic properties, we hypothesized that cytomegalovirus might be a novel risk factor for progression to an advanced form, neovascular AMD, which is characterized by choroidal neovascularization (CNV). The purpose of this study was to investigate if latent ocular murine cytomegalovirus (MCMV) infection exacerbated the development of CNV in vascular endothelial growth factor (VEGF)-overexpressing VEGF-A^hyper mice. Here we show that neonatal infection with MCMV resulted in dissemination of virus to various organs throughout the body including the eye, where it localized principally to the choroid in both VEGF-overexpressingVEGF-A^hyper and wild-type(WT) 129 mice. By 6 months post-infection, no replicating virus was detected in eyes and extraocular tissues, although virus DNA was still present in all eyes and extraocular tissues of both VEGF-A^hyper and WT mice. Expression of MCMV immediate early (IE) 1 mRNA was detected only in latently infected eyes of VEGF-A^hyper mice, but not in eyes of WT mice. Significantly increased CNV was observed in eyes of MCMV-infected VEGF-A^hyper mice compared to eyes of uninfected VEGF-A^hyper mice, while no CNV lesions were observed in eyes of either infected or uninfected WT mice. Protein levels of several inflammatory/angiogenic factors, particularly VEGF and IL-6, were significantly higher in eyes of MCMV-infected VEGF-A^hyper mice, compared to uninfected controls. Initial studies of ocular tissue from human cadavers revealed that HCMV DNA was present in four choroid/retinal pigment epithelium samples from 24 cadavers. Taken together, our data suggest that ocular HCMV latency could be a significant risk factor for the development of AMD. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Translational mini-review series on complement factor H: structural and functional correlations for factor H

The 155-kDa glycoprotein, complement factor H (CFH), is a regulator of complement activation that is abundant in human plasma. Three-dimensional structures of over half the 20 complement control protein (CCP) modules in CFH have been solved in the context of single-, double- and triple-module segments. Proven binding sites for C3b occupy the N and C termini of this elongated molecule and may be brought together by a bend in CFH mediated by its central CCP modules. The C-terminal CCP 20 is key to the ability of the molecule to adhere to polyanionic markers on self-surfaces where CFH acts to regulate amplification of the alternative pathway of complement. The surface patch on CCP 20 that binds to model glycosaminoglycans has been mapped using nuclear magnetic resonance (NMR), as has a second glycosaminoglycan-binding patch on CCP 7. These patches include many of the residue positions at which sequence variations have been linked to three complement-mediated disorders: dense deposit disease, age-related macular degeneration and atypical haemolytic uraemic syndrome. In one plausible model, CCP 20 anchors CFH to self-surfaces via a C3b/polyanion composite binding site, CCP 7 acts as a 'proof-reader' to help discriminate self- from non-self patterns of sulphation, and CCPs 1-4 disrupt C3/C5 convertase formation and stability.     

Alternative pathway activation: Ever ancient and ever new

Primitive underpinnings of the alternative pathway (AP), namely, a C3-like protein, likely arose more than a billion years ago. The development of an AP amplification loop, while greatly enhancing speed and potency, also presents a double-edged sword. Although critical to combat an infectious disease, it is also potentially destructive, particularly in a chronic disease process involving vital organs where scarring and reduction of regulatory function can occur. Furthermore, new knowledge is pointing to genetic factors involved in an increasing number of complement-related diseases such as age-related macular degeneration. However, even a normal functioning repertoire of complement components can drive cellular damage as a result of low-level complement activation over time. Thus, the modern human AP now faces a new challenge: cumulatively-driven tissue damage from chronic inflammatory processes that mediate cellular injury. The impact of ongoing low-level AP-enhanced complement activation in disease processes is just beginning to be appreciated and studied. However, the sheer numbers of individuals affected by chronic diseases emphasize the need for novel therapeutic agents capable of modulating the AP. The more we learn about this ancient system, the greater is the likelihood of developing fresh perspectives that could contribute to improved human health.     

Retinal function and CFH-ARMS2 polymorphisms analysis: a pilot study in Italian AMD patients

Two major susceptibility genes, complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), have been implicated in age-related macular degeneration (AMD) pathogenesis. We analyzed the association between CFH rs1061170 and/or ARMS2 rs10490924 polymorphisms with central retinal function properties, as evaluated by focal electroretinogram (fERG). Forty early AMD patients, with preserved visual acuity and typical macular lesions, underwent fERG recording (in response to 41 Hz flicker stimuli presented to the central 18 degrees) and CFH/ARMS2 genotyping. Mean fERG amplitude and sensitivity decreased in patients carrying CFH rs1061170 polymorphism (p < 0.01), compared with wild type ones, although visual acuity and funduscopic features were similar across the 2 groups. No significant fERG phase changes were observed. No association was detected between ARMS2 (rs10490924) polymorphism and fERG parameters. Our findings indicate that CFH (rs1061170) polymorphism impacts significantly on retinal function in early AMD patients, and support the hypothesis that dysfunctional CFH might result in early retinal function loss due to a reduction in the immune antioxidant defense mechanism.     

COL8A1 rs13095226 polymorphism shows no association with neovascular age-related macular degeneration or polypoidal choroidal vasculopathy in Chinese subjects

Purpose: Age-related macular degeneration (AMD) is the main cause of visual impairment and legal blindness in older individuals. COL8A1 rs13095226 variants have recently been implicated associated with neovascular age-related macular degeneration (nAMD) and Polypoidal Choroidal Vasculopathy (PCV) in American studies. The aim of this study was to investigate the association between the COL8A1 rs13095226 Polymorphism and neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in Chinese people. Methods: 900 Chinese subjects-300 cases with nAMD, 300 cases with PCV and 300 controls, were enrolled in a cross-sectional observational study. The diagnoses of nAMD and PCV were confirmed by Fundus photography, Fluorescence Fundus Angiography (FFA) and Indocyanine Green Angiography (ICGA). Genomic DNA was extracted from venous blood leukocytes and genotypes of rs13095226 were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Differences in allele distribution between cases and controls were tested by chi-square tests, with age and gender adjusted by logistic regression analysis. Result: The COL8A1 rs13095226 polymorphism was not statistically significantly different from the nAMD or PCV to the normal controls (P>0.05) in Chinese Population. The association remained insignificant after adjustmentfor age and gender differences (P>0.05). Conclusions: This case-control study indicated that the COL8A1 rs13095226 polymorphism is not associated with nAMD or PCV, which suggesting this gene maybe not a susceptibility gene locus for nAMD or PCV in Chinese subjects.     

个性化3D打印钛合金短柄股骨假体的生物力学评价

目的 评估个性化3D钛合金打印短柄股骨假体的生物力学性能。方法 采用4种不同的短柄股骨假体：3D打印1组(假体A)、3D打印2组(假体B)、BE组(假体C)、SMF组(假体D),分别对12根成人尸体股骨标本实行人工股骨头置换。在万能材料力学试验机上通过初始稳定性测试和静力压缩测试,对比分析4组假体模型变形量、最大压缩载荷、最大压缩位移和抗压缩刚度。结果 初始稳定性测试结果显示,3D打印2组假体变形量略低于3D打印1组,而明显低于SMF组和BE组,但差异无统计学意义(P>0.05)。3D打印2组假体最大压缩载荷、抗压缩刚度均大于其余3组,最大压缩位移小于其余3组,差异仍无统计学意义(P>0.05)。结论 个性化3D打印钛合金短柄股骨假体力学性能与目前临床常用的股骨SMF、BE 1假体相当,力学稳定性较好。     

新型运动模式铰链膝关节假体磨损有限元分析

目的 对新型球轴运动模式铰链膝关节假体进行有限元分析,研究假体磨损仿真的方法及运动方式对假体磨损的影响。方法 基于球轴假体接触力学有限元模型,根据Archard磨损理论,建立磨损有限元模型,以各种运动数据为加载条件,模拟生理活动下膝关节的力学环境,研究球轴假体磨损情况。结果 对于胫骨衬垫,上下楼时平均和最大接触应力均高于步行,上楼时累积磨损体积大于下楼和步行,且磨损均主要发生在衬垫下表面。对于球轴衬套,仅步行时存在短时间接触和磨损,累积磨损体积为0.19 mm³。结论 铰链膝关节假体的球轴运动模式可改善置换后膝关节力学环境,降低衬套磨损,延长假体生存期。有限元仿真可有效预测铰链假体的磨损,为其设计及改进提供理论支持。     

C3b and factor H: key components of the complement system

In all three complement pathways, the central molecule is C3, which, upon activation cleavage, forms the major opsonin C3b – the key component of complement. C3b is also essential for propagation of the complement cascade to the stage of the lytic terminal complement complexes. In order to prevent damage to self cells and tissues and restrict overconsumption of the complement components, C3b molecules need to be controlled by factor H. Defect in C3 functions leads to compromised microbial defence and increased susceptibility to certain autoimmune diseases. Deficiency of factor H, or a functional defect in its N terminus, often leads to membranoproliferative glomerulonephritis and complement depletion, owing to continuous overconsumption of C3. Defect in the factor H C terminus leads to a dramatically increased risk of atypical hemolytic uremic syndrome. In addition, recently, a polymorphism in the middle part of factor H (Y402H) has been shown to be the major risk factor for the most common cause of blindness in the industrialized world: age-related macular degeneration. In future, analysis of patient samples for defects in these key complement components may prove useful in diagnosis of these diseases and new therapeutic targets will certainly be the aim for use in the recently recognized factor H-related diseases.     

Systematic Investigation of a Novel Low‐Bandgap Terpolymer Library via Inkjet Printing: Influence of Ink Properties and Processing Conditions

The thin‐film properties of a polymer library consisting of novel conjugated low‐bandgap poly(diketopyrrolopyrrole‐co‐benzothiadiazole‐co‐fluorene) (poly(DPP‐co‐BTD‐co‐F)) polymers are investigated. The content of the monomer units in the copolymers is systematically varied. Structure–property relationships are obtained for the ink characteristics, the film formation qualities, and their optical properties. Toluene/o‐DCB in a ratio 90/10 and a concentration of 5 mg mL^?1 is found to be a suitable solvent system for all polymers. The polymer compositions and the choice of solvent have a significant influence on the film properties. Inkjet printing is shown to be a suitable technique for the preparation of thin‐film libraries that subsequently can be characterized by combinatorial screening tools.