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Interconnections between diabetic corneal neuropathy and diabetic retinopathy:diagnostic and therapeutic implications

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Neural Regeneration Research 2025年第8期20卷 2169-2180页

作者： Mingyi Yu Faith Teo En Ning Chang Liu Yu-Chi Liu Tissue Engineering and Stem Cell Group Singapore Eye Research InstituteSingapore Yong Loo Lin School of Medicine National University of SingaporeSingapore Department of Cornea and External Eye Disease Singapore National Eye CenterSingapore Ophthalmology and Visual Sciences Academic Clinical Program Duke-NUS Medical SchoolSingapore

Diabetic corneal neuropathy and diabetic retinopathy are ocular complications occurring in the context of diabetes *** corneal neuropathy refers to the progressive damage of corneal *** retinopathy has traditionally been considered as damage to the retinal ***,growing evidence suggests that diabetic retinopathy is a complex neurovascular disorder resulting from dysfunction of the neurovascular unit,which includes both the retinal vascular structures and neural *** retinopathy is one of the leading causes of blindness and is frequently screened for as part of diabetic ocular ***,diabetic corneal neuropathy is commonly overlooked and underdiagnosed,leading to severe ocular surface *** studies have found that these two conditions tend to occur together,and they share similarities in their pathogenesis pathways,being triggered by a status of chronic *** review aims to discuss the interconnection between diabetic corneal neuropathy and diabetic retinopathy,whether diabetic corneal neuropathy precedes diabetic retinopathy,as well as the relation between the stage of diabetic retinopathy and the severity of corneal *** also endeavor to explore the relevance of a corneal screening in diabetic eyes and the possibility of using corneal nerve measurements to monitor the progression of diabetic retinopathy.

关键词： cornea corneal nerves diabetes diabetic corneal neuropathy diabetic retinopathy retina

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clinical associations of corneal neuromas with ocular surface diseases

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Neural Regeneration Research 2024年第1期19卷 140-147页

作者： Charmaine Jan Li Toh Chang Liu Isabelle Xin Yu Lee Molly Tzu Yu Lin Louis Tong Yu-Chi Liu Lee Kong Chian School of Medicine Nanyang Technological UniversitySingapore Singapore Eye Research Institute Singapore Department of Cornea and External Eye Disease Singapore National Eye CentreSingapore Ophthalmology and Visual Sciences Academic Clinical Program Duke-NUS Medical SchoolSingapore

Corneal neuromas,also termed microneuromas,refer to microscopic,irregula rly-shaped enlargements of terminal subbasal nerve endings at sites of nerve damage or *** formation of corneal neuromas results from damage to corneal nerves,such as following corneal pathology or corneal or intraocular surge ***,denervated areas of sensory nerve fibers become invaded by sprouts of intact sensory nerve fibers,and later injured axons regenerate and new sprouts called neuromas *** recent years,analysis of corneal nerve abnormalities including corneal neuromas which can be identified using in vivo confocal microscopy,a non-invasive imaging technique with microscopic resolution,has been used to evaluate corneal neuropathy and ocular surface *** neuromas have been shown to be associated with clinical symptoms of discomfort and dryness of eyes,and are a promising surrogate biomarker for ocular surface diseases,such as neuropathic corneal pain,dry eye disease,diabetic corneal neuropathy,neurotrophic keratopathy,Sjogren's syndrome,bullous keratopathy,post-refra ctive surgery,and *** this review,we have summarized the current literature on the association between these ocular surface diseases and the presentation of corneal microneuromas,as well as elaborated on their pathogenesis,visualization via in vivo confocal microscopy,and utility in monitoring treatment *** current quantitative analysis on neuromas mainly relies on manual annotation and quantification,which is user-dependent and labor-intensive,future direction includes the development of artificial intelligence software to identify and quantify these potential imaging biomarkers in a more automated and sensitive manner,allowing it to be applied in clinical settings more *** imaging and molecular biomarkers may also help elucidate the associations between corneal neuromas and ocular surface diseases.

关键词： cornea corneal diseases corneal nerve corneal neuropathy in vivo confocal microscopy microneuroma neuroma ocular surface diseases

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Retinal oxygen extraction during systemic hypoxia assessed with laser-speckle flowgraphy and retinal oximetry

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ACTA OPHTHALMOLOGICA 2025年第S284期103卷

作者： Pai, Viktoria Lindner, Theresa Janku, Patrick Schmetterer, Leopold Schmidl, Doreen Garhofer, Gerhard Department of Clinical Pharmacology Medical University of Vienna Vienna Austria Singapore National Eye Centre Singapore Eye Research Institute Singapore Singapore Duke-NUS Medical School Ophthalmology and Visual Sciences Academic Clinical Program Singapore Singapore SERI-NTU Advanced Ocular Engineering (STANCE) Nanyang Technological University Singapore Singapore Center for Medical Physics and Biomedical Engineering Medical University of Vienna Vienna Austria Institute of Molecular and Clinical Ophthalmology Basel Switzerland School of Chemistry Chemical Engineering and Biotechnology Nanyang Technological University Singapore Singapore

Aims/Purpose: Retinal oxygen extraction has been found to be altered in several ocular and systemic diseases, such as diabetic retinopathy, glaucoma or neurodegenerative diseases. However, measurement techniques for the assessment of retinal oxygen extraction are limited because most of them are based on time-consuming and custom-built devices. In the present pilot study, we assessed retinal oxygen extraction during systemic hypoxia with a combination of two commercially available devices: Laser-Speckle Flowgraphy (LSFG) and retinal oximetry. Methods: Retinal blood flow and retinal oxygen saturation were measured in each vessel around the optic nerve head at the same position. Arterial and venous oxygen content was estimated from the measured retinal oxygen saturation parameters and the difference between these two parameters was calculated (cO 2 , DIFF ). By using mean vessel flow rate (MV) for retinal blood flow and cO 2 , DIFF , retinal oxygen extraction was determined. For each healthy study participant, baseline measurement and measurement during inhalation of 88% nitrogen in 12% oxygen were performed. Results: Ten (10) healthy subjects (4 females, 6 males) with a mean age of 27 ± 3 years were included in this study. During systemic hypoxia, a significant decrease in arterial oxygen content occurred ( p = 0.046) while venous oxygen content did not change, leading to a decrease in cO 2 , DIFF . As expected, this was accompanied by a significant increase in MV ( p = 0.014). No change in retinal oxygen extraction was observed (46 ± 8 a.u. at baseline vs. 46 ± 5 a.u. during hypoxia, p = 0.997). Conclusions: Breathing of 88% nitrogen in 12% oxygen caused a significant decrease in retinal arterial oxygen content. This was compensated by an increase in retinal blood flow in order to keep retinal oxygen extraction constant. This was physiologically expected, and these findings are consistent with the literature. Therefore, the presented approach for measurement of reti

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Histone deacetylases facilitate Th17-cell differentiation and pathogenicity in autoimmune uveitis via CDK6/ID2 axis

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Journal of Advanced Research 2024年 72卷 633-652页

作者： Zhang, Chun Liu, Xiuxing Gu, Chenyang Su, Yuhan Lv, Jianjie Liu, Yidan Gao, Yuehan Chen, Hui Xu, Nanwei Xiao, Jing Xu, Zhuping Su, Wenru Department of Ophthalmology West China Hospital Sichuan University Sichuan Chengdu 610041 China Department of Ophthalmology Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 China State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science Guangzhou 510060 China Department of Clinical Medicine Zhongshan School of Medicine Sun Yat-Sen University Guangzhou 510060 China Clinical Medicine (Eight-Year Program) West China School of Medicine Sichuan University Chengdu 610044 China

Introduction: Autoimmune uveitis (AU) is a prevalent ocular autoimmune disease leading to significant visual impairment. However, underlying pathogenesis of AU required to develop more efficient therapy remain unclear. Methods: We isolated peripheral blood mononuclear cells (PBMCs) from AU patients and performed single-cell RNA sequencing (scRNA-seq). Besides, experimental autoimmune uveitis (EAU) model was established and treated with histone deacetylase inhibitor (HDACi) Belinostat or vehicle. We extracted immune cells from Blank, EAU, and HDACi-treated EAU mice and used scRNA-seq, flow cytometry, siRNA, specific inhibitors, and adoptive transfer experiments to explore the role of HDACs and its downstream potential molecular mechanisms in the immune response of EAU and AU. Results: We found highly expressed histone deacetylases (HDACs) family in AU patients and identified it as a key factor related to CD4⁺ effector T cell differentiation in the pathogenesis of AU. Our further studies showed that targeted inhibition of HDACs effectively alleviated EAU, restored its Th17/Treg balance, and reduced inflammatory gene expression, especially in CD4⁺ T cells. Post-HDACs inhibition, Treg proportions increased with enhanced immunomodulatory effects. Importantly, HDACs exhibited a positive promoting role on Th17 cells. Based on scRNA-seq screening and application of knock-down siRNAs and specific inhibitors in vitro and vivo, we identified CDK6 as a key downstream molecule regulated by HDAC1/3/6 through acetyl-histone H3/p53/p21 axis, which is involved in Th17 pathogenicity and EAU development. Additionally, HDACs-regulated CDK6 formed a positive loop with ID2, inducing PIM1 upregulation, promoting Th17 cell differentiation and pathogenicity, and correlates with AU progression. Conclusion: Based on the screening of clinical samples and downstream molecular functional validation experiments, we revealed a driving role for HDACs and the HDACs-regulated CD

关键词： Autoimmune uveitis CDK6 Histone deacetylase ID2 Single-cell RNA sequencing Th17 cells

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Diabetic corneal neuropathy as a surrogate marker for diabetic peripheral neuropathy

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Neural Regeneration Research 2022年第10期17卷 2172-2178页

作者： Wei Zheng So Natalie Shi Qi Wong Hong Chang Tan Molly Tzu Yu Lin Isabelle Xin Yu Lee Jodhbir S.Mehta Yu-Chi Liu Yong Loo Lin School of Medicine National University of SingaporeSingaporeSingapore Singapore Eye Research Institute SingaporeSingapore Department of Endocrinology Singapore General HospitalSingaporeSingapore Department of Cornea and External Eye Disease Singapore National Eye CentreSingaporeSingapore Ophthalmology and Visual Sciences Academic Clinical Program Duke-NUS Medical SchoolSingaporeSingapore

Diabetic neuropathy is a prevalent microvascular complication of diabetes mellitus,affecting nerves in all parts of the body including corneal nerves and peripheral nervous system,leading to diabetic corneal neuropathy and diabetic peripheral neuropathy,*** peripheral neuropathy is diagnosed in clinical practice using electrophysiological nerve conduction studies,clinical scoring,and skin ***,these diagnostic methods have limited sensitivity in detecting small-fiber disease,hence they do not accurately reflect the status of diabetic *** recently,analysis of alterations in the corneal nerves has emerged as a promising surrogate marker for diabetic peripheral *** this review,we will discuss the relationship between diabetic corneal neuropathy and diabetic peripheral neuropathy,elaborating on the foundational aspects of each:pathogenesis,clinical presentation,evaluation,and *** will further discuss the relevance of diabetic corneal neuropathy in detecting the presence of diabetic peripheral neuropathy,particularly early diabetic peripheral neuropathy;the correlation between the severity of diabetic corneal neuropathy and that of diabetic peripheral neuropathy;and the role of diabetic corneal neuropathy in the stratification of complications of diabetic peripheral neuropathy.

关键词： corneal nerve quantification corneal nerves diabetic cornea diabetic corneal neuropathy diabetic microvascular complications diabetic peripheral neuropathy in vivo confocal microscopy neurotrophic keratopathy ocular surface

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Analysis of corneal nerve plexus in corneal confocal microscopy images

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Neural Regeneration Research 2021年第4期16卷 690-691页

作者： Yu-Chi Liu Molly Tzu-Yu Lin Jodhbir S.Mehta Tissue Engineering and Cell Therapy Group Singapore Eye Research InstituteSingapore Department of Cornea and External Eye Disease Singapore National Eye CentreOphthalmology and Visual Sciences Academic Clinical ProgramDuke-NUS Medical SchoolSingapore

Small Aδand C nerve fibers of the sensory and autonomic nervous systems constitute 70–90%of peripheral nerve fibers including corneal nerves(Muller et al.,2003).Corneal nerves originate from the ophthalmic branch of the trigeminal nerve and enter the cornea at the limbus radially from all directions toward the central cornea at the level of anterior and middle *** subepithelial nerve plexus lies at the interface between the Bowman layer and anterior *** then divide into smaller branches and turn 90°toward Bowman’s layer(Muller et al.,2003),travelling between Bowman’s layer and the basal epithelial layer and forming the sub-basal nerve plexus(Muller et al.,2003).

关键词： Bowman layer travelling

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A deep learning system for predicting time to progression of diabetic retinopathy

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NATURE MEDICINE 2024年第2期30卷 358-359页

作者： [Anonymous] Shanghai Belt and Road International Joint Laboratory for Intelligent Prevention and Treatment of Metabolic Disorders Department of Computer Science and Engineering School of Electronic Information and Electrical Engineering Shanghai Jiao Tong University Department of Endocrinology and Metabolism Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai Diabetes Institute Shanghai Clinical Center for Diabetes Shanghai China MOE Key Laboratory of AI School of Electronic Information and Electrical Engineering Shanghai Jiao Tong University Shanghai China Department of Ophthalmology Huadong Sanatorium Wuxi China Department of Ophthalmology Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China Department of Ophthalmology and Visual Sciences The Chinese University of Hong Kong Hong Kong China Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore Department of Computer Science and Engineering The Hong Kong University of Science and Technology Hong Kong China Department of Chemical and Biological Engineering The Hong Kong University of Science and Technology Hong Kong China State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science Guangzhou China Department of Ophthalmology Peking Union Medical College Hospital Peking Union Medical College Chinese Academy of Medical Sciences Beijing China Medical Records and Statistics Office Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China Department of Geriatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China National Engineering Research Center for Big Data Technology and System Services Computing Technology and System Lab Cluster and Grid Computing Lab School of Computer Science and Tech

We developed and validated a deep learning system (termed DeepDR Plus) in a diverse, multiethnic, multi-country dataset to predict personalized risk and time to progression of diabetic retinopathy. We show that DeepDR Plus can be integrated into the clinical workflow to promote individualized intervention strategies for the management of diabetic retinopathy.

关键词： Diabetes complications Machine learning Predictive markers

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Electrospun Aligned PCL/Gelatin Scaffolds Mimicking the Skin ECM for Effective Antimicrobial Wound Dressings

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Advanced Fiber Materials 2023年第1期5卷 235-251页

作者： Erfan Rezvani Ghomi Rajamani Lakshminarayanan Vijila Chellappan Navin Kumar Verma Amutha Chinnappan Rasoul Esmaeely Neisiany Kottaiswamy Amuthavalli Zhi Sheng Poh Brandon Han Siang Wong Nileshkumar Dubey Roger Narayan Seeram Ramakrishna Department of Mechanical Engineering Center for Nanotechnology and SustainabilityNational University of SingaporeSingapore 117581Singapore Ocular Infections and Antimicrobials Research Group Singapore Eye Research InstituteThe Academia20 College RoadDiscovery TowerSingapore 169856Singapore Institute of Materials Research and Engineering(IMRE) Agency for Science Technology and Research(A*STAR)#08‑032 Fusionopolis WayInnovisSingapore 138634Singapore Lee Kong Chian School of Medicine Nanyang Technological University SingaporeClinical Sciences Building11 Mandalay RoadSingapore 308232Singapore Department of Pharmacy National University of Singapore18 Science Drive 4Singapore 117543Singapore Academic Clinical Program in Ophthalmology and Visual Sciences Academic Clinical Program Duke-NUS Medical SchoolSingapore 169857Singapore National Skin Centre 1 Mandalay RoadSingapore 308205Singapore Department of Materials and Polymer Engineering Faculty of EngineeringHakim Sabzevari UniversitySabzevar ***Iran Faculty of Dentistry National University of SingaporeSingapore 119085Singapore ORCHIDS:Oral Care Health Innovations and Designs Singapore National University of SingaporeSingaporeSingapore 119085Singapore Department of Biomedical Engineering University of North Carolina at Chapel HillChapel HillNC 27514USA

Bacterial infections and multidrug-resistant bacteria are major health burdens in wound *** antimicrobial agents,e.g.,ε-polylysine(ε-PL),provide a broad spectrum of antibacterial properties and support dermal cell ***,ε-PL was incorporated into polycaprolactone(PCL)/gelatin electrospun scaffolds collected at varying rotation ***,the samples were crosslinked using dopamine hydrochloride to provide highly proliferative dressings with broad antimicrobial *** morphological study showed that the electrospun wound dressings were smooth,continuous,and bead-free,with a mean diameter ranging from 267±7 to 331±8 nm for all random and aligned *** fiber alignment of the electrospun PCL/gelatin scaffolds improved their tensile strength and ***,nanofiber mats are highly hydro-philic,which is crucial for an efficient wound *** samples also demonstrated high antimicrobial properties against common wound bacterial strains,including methicillin-resistant Staphylococcus aureus(MRSA),Staphylococcus aureus(SA),Escherichia coli(EC),Acinetobacter baumannii(AB),and Pseudomonas aeruginosa(PA).Mammalian cell prolifera-tion and morphology assays involving primary human dermal fibroblasts(hDFs)and immortalized keratinocytes(HaCaT)showed excellent biocompatibility of the electrospun mats and remarkably aligned ***,aligned mats showed more cell migration than randomly oriented mats,which is desirable for more efficient wound ***,it can be concluded that aligned PCL/gelatin mats containingε-PL are promising for potential use in wound dressings.

关键词： Electrospinning Wound healing Fiber alignment Biomaterials Nanofiber dressing Bacterial infections

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Large language models for diabetes training:a prospective study

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science Bulletin 2025年第6期70卷 934-942页

作者： Haoxuan Li Zehua Jiang Zhouyu Guan Yuqian Bao Yuexing Liu Tingting Hu Jiajia Li Ruhan Liu Liang Wu Di Cheng Hongwei Ji Yong Wang Ya-Xing Wang Carol Y.Cheung Yingfeng Zheng Jihong Wang Zhen Li Weibing Wu Cynthia Ciwei Lim Yong Mong Bee Hong Chang Tan Elif I.Ekinci David C.Klonoff Justin B.Echouffo-Tcheugui Nestoras Mathioudakis Leonor Corsino Rafael Simó Charumathi Sabanayagam Gavin Siew Wei Tan Ching-Yu Cheng Tien Yin Wong Huating Li Chun Cai Lijuan Mao Lee-Ling Lim Yih-Chung Tham Bin Sheng Weiping Jia Shanghai University of Sport Shanghai 200438China School of Clinical Medicine Beijing Tsinghua Changgung HospitalTsinghua MedicineTsinghua UniversityBeijing 100084China Beijing Visual Science and Translational Eye Research Institute(BERI) Tsinghua MedicineTsinghua UniversityBeijing 100084China Shanghai Belt and Road International Joint Laboratory of Intelligent Prevention and Treatment for Metabolic Diseases Department of Computer Science and EngineeringSchool of ElectronicInformationand Electrical EngineeringShanghai Jiao Tong UniversityDepartment of Endocrinology and MetabolismShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes InstituteShanghai Clinical Center for DiabetesShanghai 200240China MoE Key Lab of Artificial Intelligence Artificial Intelligence InstituteShanghai Jiao Tong UniversityShanghai 200240China Department of Cardiology the Affiliated Hospital of Qingdao UniversityQingdao 266011China CEMS NCMISHCMSMADISAcademy of Mathematics and Systems ScienceChinese Academy of SciencesBeijing 100190China School of Mathematics University of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100049China Key Laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Beijing Institute of Ophthalmology Beijing Tongren HospitalCapital Medical UniversityBeijing Ophthalmology and Visual Sciences Key LaboratoryBeijing 100730China k.Department of Ophthalmology and Visual Sciences The Chinese University of Hong KongHong Kong 999077China State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceGuangdong Provincial Clinical Research Center for Ocular DiseasesGuangzhou 510060China Department of Renal Medicine Singapore General HospitalSingHealth-Duke Academic Medical CentreSingapore169

Diabetes poses a considerable global health challenge,with varying levels of diabetes knowledge among healthcare professionals,highlighting the importance of diabetes *** Language Models(LLMs)provide new insights into diabetes training,but their performance in diabetes-related queries remains uncertain,especially outside the English language like *** first evaluated the performance of ten LLMs:ChatGPT-3.5,ChatGPT-4.0,Google Bard,LlaMA-7B,LlaMA2-7B,Baidu ERNIE Bot,Ali Tongyi Qianwen,MedGPT,HuatuoGPT,and Chinese LlaMA2-7B on diabetes-related queries,based on the Chinese National Certificate Examination for Primary Diabetes Care in China(NCE-CPDC)and the English Specialty Certificate Examination in Endocrinology and Diabetes of Membership of the Royal College of Physicians of the United ***,we assessed the training of primary care physicians(PCPs)without and with the assistance of ChatGPT-4.0 in the NCE-CPDC examination to ascertain the reliability of LLMs as medical *** found that ChatGPT-4.0 outperformed other LLMs in the English examination,achieving a passing accuracy of 62.50%,which was significantly higher than that of Google Bard,LlaMA-7B,and *** the NCE-CPFC examination,ChatGPT-4.0,Ali Tongyi Qianwen,Baidu ERNIE Bot,Google Bard,MedGPT,and ChatGPT-3.5 successfully passed,whereas LlaMA2-7B,HuatuoGPT,Chinese LLaMA2-7B,and LlaMA-7B ***-4.0(84.82%)surpassed all PCPs and assisted most PCPs in the NCE-CPDC examination(improving by 1%–6.13%).In summary,LLMs demonstrated outstanding competence for diabetes-related questions in both the Chinese and English language,and hold great potential to assist future diabetes training for physicians globally.

关键词： Diabetes Diabetestraining Largelanguagemodels Primarydiabetescare Prospectivestudy

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Corneal neuromediator profiles following laser refractive surgery

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Neural Regeneration Research 2021年第11期16卷 2177-2183页

作者： Lily Wei Yun Yang Jodhbir S.Mehta Yu-Chi Liu Yong Loo Lin School of Medicine National University of SingaporeSingapore Tissue Engineering and Cell Therapy Group Singapore Eye Research InstituteSingapore Department of Cornea and External Eye Disease Singapore National Eye CentreSingapore Ophthalmology and Visual Sciences Academic Clinical Program Duke-NUS Medical SchoolSingapore

Laser refractive surgery is one of the most commonly performed procedures *** laser refractive surgery,Femtosecond Laser in Situ Keratomileusis and Refractive Lenticule Extraction have emerged as promising alternatives to microkeratome Laser in Situ Keratomileusis and Photorefractive *** laser refractive surgery,the corneal nerves,epithelial and stromal cells release neuromediators,including neurotrophins,neuropeptides and ***,nerve growth factor,substance P,calcitonin gene-related peptide and various cytokines are important mediators of neurogenic inflammation and corneal nerve *** in neuromediator profiles and ocular surface parameters following laser refractive surgery are attributed to the surgical techniques and the severity of tissue insult *** this review,we will discuss the(1)Functions of neuromediators and their physiological and clinical significance;(2)Changes in the neuromediators following various laser refractive surgeries;(3)Correlation between neuromediators,ocular surface health and corneal nerve status;and(4)Future directions,including the use of neuromediators as potential biomarkers for ocular surface health following laser refractive surgery,and as adjuncts to aid in corneal regeneration after laser refractive surgery.

关键词： cornea corneal nerves dry eye femtosecond laser laser in situ keratomileusis neuromediator refractive surgery small incision lenticule extraction

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