局部点药是眼部用药最常见的方式，但一般药物通过角膜困难，药物生物利用度低。纳米载体药物于8 0年代开始用于眼部，脂质体和类脂质囊泡(niosomes)与眼表的黏蛋白相互作用，延长药物在眼表的停留时间。纳米乳剂(nanoemulsion)的表面活性剂可以松解角膜上皮细胞紧密连接，形成转运开口，抑制细胞表面糖蛋白酶P(glycoprotein P，Pgp)降解药物活性蛋白。纳米粒子(nanoparticles)通过角膜上皮和结膜上皮而不会引起毒性。纳米胶囊(nanocapsules)更深地内化到角膜上皮(50 μm处)。聚合物胶束(polymeric micelles)自组装成核-壳纳米载体增强药物渗透角膜的能力。阴离子高代聚酰氨基胺(poly-amidoamine，PAMAM)树枝状大分子增强药物通透性，中性和阳离子低代树枝状大分子通过网格蛋白途径介导药物更高的通透性。纳米晶体(nanocrystal)，除增强药物溶解度和溶解速率之外，它的高黏附能力帮助药物保留和渗透到眼组织中。纳米结构材料与干眼关联密切，为干眼的治疗、诊断提供手段。
Topical administration is the most common method of ocular medication, but it is generally difficult for the drug to pass through the cornea, and the bioavailability of the drug is low. Nanocarrier drugs were used in eyes in the 1980s, and liposomes and lipoids vesicles (Niosomes) interacted with ocular surface mucins to prolong the residence time of the drug on the ocular surface. Nanoemulsion surfactants can release the tight junctions of corneal epithelial cells, form transport openings, and inhibit the degradation of pharmaceutically active proteins by cell surface glycoprotein P (Pgp). Nanoparticles pass through the corneal and conjunctival epithelium without causing toxicity. Nanocapsules internalize deeper into the corneal epithelium (at 50 μm). Polymeric micelles self-assemble into core-shell nanocarriers to enhance the ability of drugs to penetrate the cornea. Anionic high-generation poly-amidoamine (PAMAM) dendrimers enhance drug permeability. Neutral and cationic low-generation dendrimers mediate higher drug permeability through clathrin pathway. Nanocrystal, in addition to enhancing drug solubility and dissolution rate, its high adhesion ability helps drug retention and penetration into ocular tissues. Nanostructured materials are closely related to dry eye and provide a choice for the treatment and diagnosis of dry eye.
近视是危害儿童青少年视力最常见的眼部疾病，高度近视对视功能造成极大的威胁。近年来，我国近视发病率逐年升高，对近视筛查与防控的需求也不断增加，随着人工智能理论与技术的不断发展与成熟，可以辅助眼科医生进行近视筛查、诊断与治疗。本文将简要介绍人工智能在近视的筛查、预测、检测、病理性近视以及角膜屈光手术中的应用，浅谈了目前人工智能在研究中存在的可比度较低、影像要求较高、可解释性较低及隐私保护等问题，并展望人工智能在近视相关领域的应用前景。
Myopia is the most common ocular disease that harms the vision of children and adolescents. High myopia poses a great threat to visual function. The incidence of myopia in China has been increasing in recent years, and the demand for myopia screening, prevention and control has also expanded. With the continuous development of artificial intelligence theory and technology, Artificial intelligence can assist ophthalmologists in myopia screening, diagnosis and treatment. This review will briefly introduce artificial intelligence in the screening, prediction, and detection of myopia; also, the application in pathological myopia and corneal refractive surgery. This review will discuss some problems of current artificial intelligence research, such as low comparability, high image requirements, low interpretability, privacy protection, and the application prospects of artificial intelligence in myopia.
目的：运用Lea Symbols视力表、HOTV视力表对2.5~5.0岁正常儿童视力发育情况进行探究，并评价2种视力表的应用效果。方法：以随机顺序先后应用Lea Symbols视力表与HOTV视力表对广州地区2所早教中心及3所幼儿园共461例儿童(922只眼)进行单眼视力检查，所有儿童提前1 d行小瞳下检影验光、眼前节裂隙灯检查、眼底情况、眼球活动、眼位检查，筛选无器质性眼病、屈光度在正常范围的儿童作为研究对象。视力值采用5分记录方法表示。结果：1 )可测率(视力表使用配合程度)。407名儿童完成Lea Symbols视力检查，总体可测率92.08%；402名儿童完成HOTV视力检查，总体可测率90.95%；前者可测率高于后者，差异无统计学意义(χ2 =0.417，P=0.580)。进一步研究发现2种视力的可测率随年龄增长不断提高，儿童3岁之后基本都能完成2种视力的检查。2)2种视力结果及比较(5分记录法表示)。Lea视力值：右眼为4.89±0.05，左眼为4.90±0.05；HOTV视力值：右眼为4.84±0.05，左眼为4.85±0.04；前者视力好于后者，差异有统计学意义(右眼：t=3.171，P=0.003；左眼：t=3.230，P=0.003)。3)视力发育与年龄的相关性。2种视力发育与年龄存在显著正相关(P<0.001)，即随着年龄的增长，视力水平逐渐提高。4)视力发育与眼别、性别的关系。左右眼之间的视力发育差异无统计学意义(P>0.05)；男性儿童的视力发育好于女性，且差异有统计学意义(P<0.05)。结论：Lea Symbols及HOTV视力表建议用于年龄大于3岁儿童的视力检查，且儿童更容易接受Lea Symbols视力表的检查。伴随年龄的增长，儿童的视力发育呈现提高的趋势；Lea视力优于HOTV视力。视力的发育与眼别无关，男性儿童的视力发育快于女性儿童。
Objective: To conduct a preliminary study of the Lea Symbols and HOTV charts to explore the visual development of children aged 2.5 to 5.0 years, and evaluate the application values of the two charts. Methods: A total of 461 children (922 eyes) in 2 early education centers and 3 kindergartens in Guangzhou were examined by using the Lea Symbols visual acuity chart and HOTV visual acuity chart in random order. All the children underwent low-pupil photometry, anterior section slit-lamp examination, retinal condition, eye movement, and eye position examination 1 day in advance. Children with no organic eye disease and normal diopter were selected as subjects. Visual acuity was recorded with 5 points. Results: 1) Measurable rate (visual acuity chart use degree of cooperation). 407 children completed visual examination of Lea Symbols, with an overall detectable rate of 92.08%; 402 children completed HOTV vision examination, with an overall detectable rate of 90.95%. The detectable rate of the former was higher than that of the latter, but the difference was not statistically significant (χ2 =0.417, P=0.580). Further study found that the detectable rate of both visual acuities increased with age, and children were able to complete both visual acuity tests after the age of 3. 2) Results and comparison of two visual acuity (5-point recording method). The visual acuity of Lea was 4.89±0.05 in the right eye and 4.90±0.05 in the left eye. HOTV visual acuity was 4.84±0.05 in the right eye and 4.85±0.04 in the left eye. The visual acuity of the former was better than that of the latter, the difference was statistically significant (right eye: t=3.171, P=0.003; left eye: t=3.230, P=0.003). 3) Correlation between visual development and age. There was a significant positive correlation between the two types of visual development and age (P<0.001), that is, visual acuity gradually improves with age. 4) The relationship between visual development and eye and sex. There was no difference in visual development between the left and right eyes, but male children had better visual development than female, and the difference was statistically significant (P<0.05). Conclusion: Lea Symbols and HOTV visual acuity charts are recommended for visual acuity examination of children over 3 years old, and children are more likely to receive examination of Lea Symbols visual acuity chart. With the growth of age, the visual development of children shows a trend of improvement. Lea vision is superior to HOTV vision. Vision development has nothing to do with the eye, male children’s vision development is faster than female children.
目的：获取眼表图像的综合信息，建立眼表疾病综合诊断和评估。方法：将超高分辨率光学相干断层成像仪(ultra-high resolution optical coherence tomography，UHR-OCT)与基于裂隙灯生物显微镜的微血管成像系统相结合，开发了一种多模态、非接触式的眼科光学成像平台。结果：UHR-OCT模块在组织中实现轴向分辨率约为2 μm 。眼表微血管成像模块在最大放大倍率下横向分辨率约为3.5 μm。通过集成在裂隙灯显微镜成像光学路径的不同模块，多模态成像平台能够执行实时前段OCT结构成像、结膜微血管成像和传统裂隙灯成像功能。利用自主开发的软件，进一步分析结膜血管网络图像和血流图像，获取血管分形维数、血流速度、血管直径等定量形态学和血流动力学参数。结论：通过在健康受试者和角膜炎患者的在体成像测试，表明多模态眼前段成像设备可为眼科临床应用及人工智能提供结构和功能信息数据。
Objective: To obtain the comprehensive information of the anterior eye image, establish complementary information for the diagnosis and evaluation of ocular diseases. Methods: We developed a multi-modal, non-invasive optical imaging platform by combining ultra-high resolution optical coherence tomography (UHR-OCT) with a microvascular imaging system based on slit-lamp biomicroscopy. Results: The uHR-OCT module achieved an axial resolution of approximately 2 μm in tissues. The lateral resolution of the ocular surface microvascular imaging module under maximum magnification was approximately 3.5 μm. By combining the imaging optical paths of different modules, the customized multi-modal eye imaging platform was capable of performing real-time cross-sectional UHR-OCT imaging of the anterior eye, conjunctival vessel network imaging, high-resolution conjunctival blood flow videography, and traditional slit-lamp imaging on a single device. With self-developed software, a conjunctival vessel network image and blood flow videography were further analyzed to acquire quantitative morphological and hemodynamics parameters, including vessel fractal dimensions, blood flow velocity and vessel diameters. Conclusion: The ability of the multi-modal anterior eye imager to provide both structural and functional information for ophthalmic clinical applications can be demonstrated in a healthy human subject and a keratitis patient.
视网膜退行性疾病的种类繁多、患病人口基数大，该病特征为终末期严重的视网膜细胞丢失。视网膜类器官(retinal organoid，RO)可通过3D干细胞体外分化培养技术大量获取，并拥有完整的各亚型视网膜细胞和经典的视网膜分层结构。因此，RO可作为最佳的视网膜退行性疾病建模方法之一，以便于发现潜在致病机制。目前，RO衍生物已被广泛用于视网膜细胞替代治疗的动物实验和临床研究，具体的成效参差不齐，可能的影响因素包括移植细胞数量、移植时间窗、移植工具等。随着RO相关研究的快速发展，视网膜退行性疾病在分子和个体上的诊断和治疗将进一步完善。
Retinal degenerative diseases, characterized by severe retinal cell loss at the end stage, are of various kinds and haunt vast amounts of patients. Retinal organoid (RO) with complete retinal cell subtypes and classic retinal stratification structures can be obtained in large quantities through stem cells in vitro 3D differentiation and culture method. Therefore, RO can serve as one of the best ways for retinal degenerative disease modeling to facilitate the decipherment of underlying pathogenic mechanisms. At present, RO derivatives have been widely used in animal experiments and clinical studies of retinal cell replacement therapy with varying results possibly affected by cell quantity, time window, or tools in terms of transplantation. With the booming progress of RO-related research, the diagnosis and treatment on molecular and individual level for retinal degenerative diseases will be further improved.
目的：建立能驱动GFP在视网膜神经节细胞(retinal ganglion cell，RGC)中特异性表达的小鼠胚胎干细胞系。方法：通过同源重组的方式建立Brn3b-GFP敲入的小鼠胚胎干细胞系(Brn3b-GFP ESC)，利用3D培养将其诱导成视网膜类器官检测GFP表达的细胞特异性，再用流式细胞分选富集GFP阳性RGC，采用玻璃体腔注射的方式将GFP阳性RGC移植到健康小鼠和NMDA损伤模型小鼠眼中探索该细胞的应用价值。结果：Brn3b-GFP ESC经3D视网膜诱导培养后在RGC中特异性表达GFP，将这些GFP阳性RGC移植到两种小鼠中2周后能在所有视网膜内观察到GFP阳性细胞存活，且均能观察到有供体RGC整合到宿主视网膜RGC层。结论：本研究建立了RGC特异的报告基因干细胞系Brn3b-GFP ESC，通过将该细胞系诱导成视网膜类器官进而获得的GFP阳性RGC移植后能够整合进宿主视网膜。该细胞系的建立将为青光眼及相关疾病提供重要的研究手段和工具。
Objective: This study was designed to establish a mouse embryonic stem cell line that can drive GFP expression specifically in retinal ganglion cells (RGCs). Methods: In this study, we established a Brn3b-GFP knock-in embryonic stem cell line (Brn3b-GFP ESC) by homologous recombination. By 3D culture, we induced these cells into retinal organoids to investigate the cell-specificity of GFP expression. GFP-positive RGCs were then enriched by flow cytometry and transplanted by intravitreal injection into the eyes of healthy mice and NMDA injury model mice to explore the feasibility of a potential clinical application. Results: GFP was specifically expressed in RGCs following induction of Brn3b-GFP ESCs into 3D retinal organoids. Two weeks after these GFP-positive RGCs were transplanted into the control and injured mice, GFP-positive cells were observed in all transplanted retinas, and donor RGCs were seen to integrate into the RGC layer of the host retina. Conclusion: This study has established a retinal ganglion cell-specific reporter stem cell line Brn3b-GFP ESC. The GFP-positive RGCs obtained by inducing the cell line into retinal organoids can be integrated into the host retina after transplantation. The establishment of such a cell line will provide an important research tool for glaucoma and related diseases.
视网膜疾病大多以周边视网膜病变为首要表现，后者的早期诊断、监测对于视网膜疾病的治疗及预防起着至关重要的作用。以往传统眼底成像技术仅能提供20°视网膜的可视范围，即便使用蒙太奇拍摄技术，也只能采集部分眼底范围。目前眼底成像技术已步入最新的超广角时代，其所提供的眼底视野至少可达200°，并且基于该技术的超广角眼底彩色照相、荧光素血管造影、光学相干断层扫描及其血管造影等已广泛应用于临床实践中，对于诊断及评估视网膜疾病发挥重要作用，如糖尿病性视网膜病变、视网膜静脉阻塞、早产儿视网膜病变、视网膜色素变性及视网膜脱离等。本文将从超广角成像技术的产生、发展及其国内外的临床应用现状作一综述，旨在为临床工作及研究提供指导意义。
Retinal diseases primarily feature with peripheral retinopathy, and its early diagnosis as well as the later following up both play a vital role in the treatment and prevention of retinal diseases. In the past, traditional fundus imaging technology can only provide the visual range of 20 degrees. Even if montage photography technology is used, it can only partially reveal the fundus field. At present, fundus imaging technology has entered the latest era of ultra-wide-field, which provides at least 200-degree fundus field of vision. Ultra-wide-field fundus photochromy, fluorescein angiography, optical coherence tomography and angiography based on this technology have been widely used in clinical practice, and play an important role in the diagnosis and evaluation of retinal diseases, such as diabetes retinopathy, retinal vein occlusion, retinopathy of prematurity, retinitis pigmentosa and retinal detachment. This article aims to review the occurrence and development of ultra-wide-field fundus imaging technology and its clinical applications up to now to provide a relative guideline for clinic and research.
白内障作为一种常见的眼科疾病，是全球第一位致盲眼病，目前尚无药物能够治疗，手术是唯一有效的办法。随着现代眼科手术技术的发展以及人工晶状体(intraocular lens，IOL)设计和功能的更新升级，人们对视觉质量的要求越来越高，白内障超声乳化联合IOL植入术已经从单纯的复明手术转变为个性化的屈光手术。为满足不同需求的患者术后获得较好的视觉质量，IOL经历了从单焦点到多焦点、球面到非球面的发展，还有散光型IOL和各类功能性IOL的临床应用，也为患者提供了更多的选择。充分了解不同类型IOL的优势和特点，根据患者自身眼部情况、日常用眼习惯以及需求，个性化地选择IOL植入对视觉质量的恢复和满意度起着至关重要的作用。因此本文将针对不同类型的IOL，从设计与分类、术后临床效果及适应人群进行综述，为IOL的选择提供指导建议。
As a common eye disease, cataract is the first-leading cause of blindness in the world. Currently, there is no drug to treat it, and surgery is the only effective way. With the development of modern ophthalmic surgical technology and the updating and upgrading of the design and function of intraocular lens (IOL), people have higher and higher requirements for visual quality. Cataract phacoemulsification combined with IOL implantation has transformed from a simple vision restoration to personalized refractive surgery. In order to meet the needs of patients with different needs to obtain better visual quality after surgery, IOL has experienced the development from monofocal to multifocal, spherical to aspherical, as well as the clinical application of astigmatic IOL and various functional IOLs, which also provides more choices for patients. Fully understanding the advantages and characteristics of different types of IOLs, according to the patient’s own eye conditions, daily eye habits and needs, individualized selection of IOL implantation plays a crucial role in the recovery and satisfaction of visual quality. Therefore, this article will review different types of IOLs from the aspects of design and classification, postoperative clinical effects and adaptation to the population, and provide guidance for the selection of IOLs.
本文根据上海鹰瞳医疗科技有限公司的创新产品《糖尿病视网膜病变眼底图像辅助诊断软件》在国家药品监督管理局(NMPA，原CFDA)历时两年半的上市前创新申报与注册申报经历，介绍了人工智能类医疗器械产品的产品研发、注册申报流程及相关重点难点，并且列明了在整个过程中需要遵循和参考的法律法规，为此类产品的上市前注册工作提供参考。
Based on the NMPA premarket application through two and a half years for the computer aided diagnosis software using fundus images of diabetic retinopathy, which is an innovative medical device of Shanghai EagleVision Medical Technology Co., Ltd. (Airdoc), this article introduced the development process, the premarket application, and the key points in the application of this artificial intelligence device, also lists the related regulations and guidelines as references to provide some ideas for the follow-up premarketing application of such kind of products.
眼睛是人体最重要的感觉器官之一，主要由角膜和晶状体构成的屈光系统和视网膜构成的视觉神经系统2个部分构成。眼睛各组织的发育和功能异常都可影响视功能，甚至致盲。现有的致盲眼病的治疗方式均存在各自瓶颈问题，新的诊治方法亟待开发。近年来，得益于干细胞和组织工程学的发展，结合现有眼各组织的发育理论知识，研究者们利用多种来源的干细胞在体外成功诱导出具有组织特异结构和功能的眼类器官。眼类器官研究为利用干细胞研究眼组织发育和眼病发病机制、药物筛选以及替代治疗创造了新机遇，将干细胞治疗眼病的转化研究推向了一个更高平台。本文将对现有眼类器官的技术发展及应用进行综述。
Being one of the most important sensory organs, the eye is composed of the cornea, the lens, which are responsible for refraction, and the retina, which is the neural sensory part of the eye. Various kinds of developmental abnormalities and functional defects could lead to visual dysfunctions, and even blindness. Current treatments for blindness-causing eye diseases all have their own limitations, awaiting new efficient diagnostic and treating methods. Thanks to the development in stem cell biology and bioengineering, taking advantage of the rich knowledge accumulated on the mechanisms governing eye development, researchers have successfully generated various ocular organoids using multiple sources of stem cells in vitro, which resemble their counterparts in vivo on both the structural level and functional level. Ocular organoids provide valuable material and models for studying eye development, pathology, drug screening, and cell replacement therapy, pushing translational studies of ocular stem cell to a new era. Here, the paper reviews the development and application of ocular organoid technologies.
