\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"5916",leadTitle:null,fullTitle:"Dermatologic Surgery and Procedures",title:"Dermatologic Surgery and Procedures",subtitle:null,reviewType:"peer-reviewed",abstract:"This book is intended for dermatologists, skin surgeons, and general practitioners who are interested in skin surgery and cosmetic procedures. The topics of broad and current interest in shaping the practice nowadays have been selected by the editor, Dr. Pierre Vereecken, MD, PhD, allowing the reader to expand his/her skills and surgical techniques. This book aims to meet the need for a practical guide to help the clinicians to extend their offer in daily practice in dermatology and corrective and skin cancer surgery.",isbn:"978-953-51-3852-5",printIsbn:"978-953-51-3851-8",pdfIsbn:"978-953-51-3995-9",doi:"10.5772/66008",price:119,priceEur:129,priceUsd:155,slug:"dermatologic-surgery-and-procedures",numberOfPages:234,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"4db72fff153d0878ec21a7e7b71515d8",bookSignature:"Pierre Vereecken",publishedDate:"February 28th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/5916.jpg",numberOfDownloads:16282,numberOfWosCitations:4,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:10,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:20,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 7th 2016",dateEndSecondStepPublish:"December 21st 2016",dateEndThirdStepPublish:"September 16th 2017",dateEndFourthStepPublish:"October 16th 2017",dateEndFifthStepPublish:"December 16th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"157965",title:"Dr.",name:"Pierre",middleName:null,surname:"Vereecken",slug:"pierre-vereecken",fullName:"Pierre Vereecken",profilePictureURL:"https://mts.intechopen.com/storage/users/157965/images/system/157965.jpg",biography:"Dr. Pierre Vereecken, MD, PhD, is a Doctor of Medicine graduate and is certified and specialized in dermatology (general, aesthetic, and corrective) and skin oncology. He studied medicine in Brussels, Belgium (1991, ULB), and obtained his PhD degree from the same university in 2008, with a research work on the topic of cutaneous malignant melanoma biology and progression. After working for the Belgian Army (Belgium, Germany) and the United Nations Protection Force (Central Bosnia), he was the head of the Department of Dermatology in academic hospitals (Brugmann University Public Hospital, Belgium, and Saint-Luc University U.C.L. Hospital, Belgium). He is convinced that knowledge has to be shared with not only colleagues, specialists, or GPs but also nurses for the best care of our patients. He also emphasizes the need for a better communication of medical information with patients. In 2010, he decided to dedicate his own practice to patients and research and to build an international dermatologic network, Cliderm. He also founded the European Institute for Dermatological Practice and Research, a multifaceted organization that aims to promote clinical dermatology and dermatological research in the European Union. He has published more than 100 scientific papers in international medical literature and also edited and authored chapters for more than 20 books.",institutionString:"CLIDERM (Clinics in Dermatology)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1398",title:"Dermatopathology",slug:"dermatopathology"}],chapters:[{id:"58693",title:"Local Anesthesia",doi:"10.5772/intechopen.72930",slug:"local-anesthesia",totalDownloads:1265,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Local anesthesia is a routine procedure in dermatological practice. This chapter deals with the basic principles of pharmacology and pharmacodynamics related to the most commonly used anesthetics in dermatology as well as its side effects, the most common anesthetic solutions, anesthesia techniques, and topical anesthesia.",signatures:"Caio Lamunier de Abreu Camargo",downloadPdfUrl:"/chapter/pdf-download/58693",previewPdfUrl:"/chapter/pdf-preview/58693",authors:[{id:"219137",title:"M.D.",name:"Caio",surname:"Camargo",slug:"caio-camargo",fullName:"Caio Camargo"}],corrections:null},{id:"56603",title:"Cryotherapy for Common Premalignant and Malignant Skin Disorders",doi:"10.5772/intechopen.70286",slug:"cryotherapy-for-common-premalignant-and-malignant-skin-disorders",totalDownloads:1500,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cryotherapy, also known as cryosurgery or cryoablation, is a common dermatological treatment that is an expanded area from benign to malignant lesions. The system has been designed as a localized freezing cold that causes the destruction of cell integrity. The treatment has been also used for all ages, which is not required to have a condition of wellness. It is convenient, fast, and easy to apply in clinics, and there is no need for anesthesia. Additionally, multiple lesions are also cured in the same sessions. After the treatment, recovery period has not taken much longer and also has simple adverse effects, which are tolerable. Lastly, cryotherapy has gained excellent cosmetic results. It is highly effective for actinic keratosis and is the treatment of choice for most old patients who show poor cooperation and recurrent multiple lesions. Additionally, due to increasing premalignant lesions all over the world associated with increasing age, it is a considerable choice for lentigo maligna and Bowen’s disease. In non-melanoma skin cancers, it is also the most important option in patients who do not undergo surgery and when other options are not appropriate. In this chapter, the use of cryotherapy for premalignant and malignant cutaneous disorders has been mainly focused.",signatures:"Sevgi Akarsu and Isil Kamberoglu",downloadPdfUrl:"/chapter/pdf-download/56603",previewPdfUrl:"/chapter/pdf-preview/56603",authors:[{id:"182444",title:"Prof.",name:"Sevgi",surname:"Akarsu",slug:"sevgi-akarsu",fullName:"Sevgi Akarsu"},{id:"194631",title:"Dr.",name:"Işıl",surname:"Kamberoğlu Turan",slug:"isil-kamberoglu-turan",fullName:"Işıl Kamberoğlu Turan"}],corrections:null},{id:"57105",title:"Application of Cryogenic Methods in Skin Diseases of Different Etiology",doi:"10.5772/intechopen.70509",slug:"application-of-cryogenic-methods-in-skin-diseases-of-different-etiology",totalDownloads:1598,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The modern demand for effective treatment options in dermatology was successfully addressed by the invention of cryogenic method. By 2009, Dr. V.I. Kochenov had developed and patented cryogenic set of instruments based on 30 years of his personal clinical experience. The set includes a number of instruments, which could be used independently. It allows implementing a wide range of therapeutic and surgical procedures and has no commercially available alternatives. The main applications of the set include cryogenic revitalization, and treatment for such common dermatological ailments as psoriasis, warts, acne, hypertrophic scars, purulent diseases of the skin and subcutaneous fat, epithelial cysts, skin hemangiomas, precancerous skin lesions, and even malignant melanoma of the skin. A brief overview of etiology, classification and pathogenesis of these maladies is presented alongside with the step-by-step guidelines to cryo-exposure procedures. Not only guidelines but also comprehensive theoretical and practical training is provided to physicians at the center which was established at Nizhny Novgorod State Medical Academy. Physicians at Scientific Clinical Center of Medical Cryology “OnKolor” have been using the set, which proved to be effective even in the most difficult and otherwise costly cases. The procedures that have pronounced cosmetic effect, leaves no scars and dark spots.",signatures:"Tatyana Gennadyevna Kotova, Sergei Nikolaevich Tsybusov,\nVladimir Ivanovich Kochenov and Maksim Igorevich Tcyganov",downloadPdfUrl:"/chapter/pdf-download/57105",previewPdfUrl:"/chapter/pdf-preview/57105",authors:[{id:"203916",title:"Ph.D.",name:"Tatyana",surname:"Kotova",slug:"tatyana-kotova",fullName:"Tatyana Kotova"},{id:"219207",title:"Dr.",name:"Sergei Nikolaevich",surname:"Tsybusov",slug:"sergei-nikolaevich-tsybusov",fullName:"Sergei Nikolaevich Tsybusov"},{id:"219208",title:"Dr.",name:"Vladimir Ivanovich",surname:"Kochenov",slug:"vladimir-ivanovich-kochenov",fullName:"Vladimir Ivanovich Kochenov"}],corrections:null},{id:"58133",title:"Simultaneous Excisions and Extemporary Skin Plastics: New Reconstructive Techniques after Tumor Surgery",doi:"10.5772/intechopen.71691",slug:"simultaneous-excisions-and-extemporary-skin-plastics-new-reconstructive-techniques-after-tumor-surge",totalDownloads:1060,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Occurrence of two or more skin tumors closely situated to each other is not so rare in clinical dermasurgical practice. Excision of multiple contiguous skin lesions can represent a major dermasurgical problem that can be solved in different surgical times. However, in our opinion, the best therapeutic solution is to carry out the removal in a single surgical session; this choice allows saving time, an easier plastic reconstruction, and better esthetic results. Many different reconstructive procedures can be designed and applied, to achieve the best result. The simplest Burow’s triangle flap permits excision of two contiguous lesions with less tension compared to two fusiform cuts, but many other plastic solutions can be chosen to satisfy the needs of different anatomical sites and according to skin features. In the author’s personal experience, of about 8000 patients who have undergone dermatologic surgery over the past 20 years, the presence of multiple contiguous lesions occurred in about 200 cases. In all of these, triangle, rotation, advancement, or transposition flaps allowed simultaneous removals, saving time and money and giving better esthetic results compared to multiple direct excision carried out at successive times. In this chapter, the different techniques are described and illustrated in detail.",signatures:"Paolo Boggio, Benedetta Miglino, Federica Veronese, Rossana\nTiberio and Paola Savoia",downloadPdfUrl:"/chapter/pdf-download/58133",previewPdfUrl:"/chapter/pdf-preview/58133",authors:[{id:"34125",title:"Dr.",name:"Paola",surname:"Savoia",slug:"paola-savoia",fullName:"Paola Savoia"},{id:"219854",title:"Dr.",name:"Paolo",surname:"Boggio",slug:"paolo-boggio",fullName:"Paolo Boggio"},{id:"219855",title:"Dr.",name:"Benedetta",surname:"Miglino",slug:"benedetta-miglino",fullName:"Benedetta Miglino"},{id:"223433",title:"Dr.",name:"Rossana",surname:"Tiberio",slug:"rossana-tiberio",fullName:"Rossana Tiberio"},{id:"223434",title:"Dr.",name:"Federica",surname:"Veronese",slug:"federica-veronese",fullName:"Federica Veronese"}],corrections:null},{id:"56876",title:"Mohs Micrographic Surgery",doi:"10.5772/intechopen.70285",slug:"mohs-micrographic-surgery",totalDownloads:1369,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Mohs micrographic surgery (MMS) is used to obtain clear margins in skin cancer treatment. MMS involves staged excisions and complete margin assessment of the specimen from fresh tissue frozen sectioning. It has been shown to achieve higher cure rates with malignancies, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), lentigo maligna, melanoma in situ and dermatofibrosarcoma protuberans. This technique is especially useful in face, feet and hand regions to avoid cosmetic deformities.",signatures:"Merdan Serin",downloadPdfUrl:"/chapter/pdf-download/56876",previewPdfUrl:"/chapter/pdf-preview/56876",authors:[{id:"199977",title:"Dr.",name:"Merdan",surname:"Serin",slug:"merdan-serin",fullName:"Merdan Serin"}],corrections:null},{id:"58016",title:"CO2 Laser-Assisted Otoplasty: A New Dermatosurgical Procedure",doi:"10.5772/intechopen.71992",slug:"co2-laser-assisted-otoplasty-a-new-dermatosurgical-procedure",totalDownloads:1390,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Otoplasty is the surgical procedure characteristically performed to improve the appearance of unpleasant, protruding auricles. An incision in the back of the ear with or without excision of cartilage is the usual approach. A novel technique performed with CO2 laser is presented. The objective of CO2 laser-assisted otoplasty is to decrease the mastoid-scapha angle up to approximately 30°; also, the conchal-scapha angle should be reduced to its usual of approximately 90°. The aims of this procedure are to restructure the scapha and the antihelix fold, to diminish the size of the concha (hinge effect), and to relocate the reshaped ear closer to the head in esthetically desired angles, not only horizontally (lateral angle), but also (and of extreme importance for most patients) vertically (superior angle).",signatures:"Hector Leal Silva",downloadPdfUrl:"/chapter/pdf-download/58016",previewPdfUrl:"/chapter/pdf-preview/58016",authors:[{id:"204525",title:"Dr.",name:"Hector",surname:"Leal Silva",slug:"hector-leal-silva",fullName:"Hector Leal Silva"}],corrections:null},{id:"57073",title:"Photodynamic Therapy and Skin Cancer",doi:"10.5772/intechopen.70309",slug:"photodynamic-therapy-and-skin-cancer",totalDownloads:1511,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Non-melanoma skin cancer (NMSC) is the most common type of cancer among white skin individuals worldwide with an increasing incidence over the last years. NMSC is mostly treated with surgical or non-invasive methods such as cryotherapy or topical chemotherapeutics. Over the last years, there has been a rapidly growing interest in the use of photodynamic therapy (PDT) which is a well-tolerated, safe and effective alternative treatment option. PDT involves a photosensitizer, a light source and tissue oxygen and is based on a photo-oxidation reaction in the target tissue which results to a selective destruction of the cancer cells. PDT has been approved for treatment of actinic keratosis, Bowen’s disease and basal cell carcinoma in Europe. Off-label uses include treatment of invasive squamous cell carcinoma, cutaneous T-cell lymphoma, Kaposi’s sarcoma, Paget’s disease and prevention of recurrence of squamous cell carcinoma in organ-transplant recipients. Also combination of PDT with other treatment options such as cryotherapy, surgery and topical therapies has been reported with improved efficacy, tolerability and long-term results. Development of novel photosensitizers and light sources together with targeted delivery systems will increase specificity, efficiency and treatment field of PDT in the future. This chapter aims to give the reader an overview of the important applications of PDT, including indications, approved treatments, advantages and disadvantages of this method such as future trends.",signatures:"Eleni Papakonstantinou, Florian Löhr and Ulrike Raap",downloadPdfUrl:"/chapter/pdf-download/57073",previewPdfUrl:"/chapter/pdf-preview/57073",authors:[{id:"203520",title:"Dr.",name:"Eleni",surname:"Papakonstantinou",slug:"eleni-papakonstantinou",fullName:"Eleni Papakonstantinou"},{id:"203630",title:"Dr.",name:"Ulrike",surname:"Raap",slug:"ulrike-raap",fullName:"Ulrike Raap"},{id:"205792",title:"M.D.",name:"Florian",surname:"Löhr",slug:"florian-lohr",fullName:"Florian Löhr"}],corrections:null},{id:"57377",title:"Advanced Technologies in Dermatology",doi:"10.5772/intechopen.70288",slug:"advanced-technologies-in-dermatology",totalDownloads:1534,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cellular therapies are an attractive area of regenerative medicine. For large partial thickness wound, keratinocytes transplant is suggested. The transplantation of cell graft is achieved by obtaining large amounts of cultured cells from a skin biopsy in 3 weeks. Stem cells can be applied before that, but are also efficient in chronic wound closure. Alternative treatment methods are transplants of allogeneic, biostatic skin and amnion. Amnion can be applied as a skin substitute on shallow facialburn wounds, hand burn wounds, on donor areas and granulating wounds. For medium depth or even deep burns, allogeneic skin is recommended. Thanks to the removing of cells from human allogeneic dermis, collagen scaffolding is obtained. It can be populated de novo by autologous skin cells. Artificial skin substitutes are especially good for hand burns and shallow burns. Even though scarring is a part of normal wound healing, it often leads to a pathological process. When scar treatment methods prove insufficient, surgical intervention becomes necessary. Surgical scar intervention involves removal of the pathological skin tissue fragment and replacing it with healthy skin or application of expanders. Improvement of the visual features can be also achieved by laser therapy.",signatures:"Diana Kitala, Agnieszka Klama-Baryła, Wojciech Łabuś, Marcelina\nMisiuga, Mariusz Nowak and Marek Kawecki",downloadPdfUrl:"/chapter/pdf-download/57377",previewPdfUrl:"/chapter/pdf-preview/57377",authors:[{id:"203598",title:"Ph.D.",name:"Diana",surname:"Kitala",slug:"diana-kitala",fullName:"Diana Kitala"},{id:"204300",title:"Dr.",name:"Agnieszka",surname:"Klama-Baryła",slug:"agnieszka-klama-baryla",fullName:"Agnieszka Klama-Baryła"},{id:"204301",title:"Dr.",name:"Wojciech",surname:"Łabuś",slug:"wojciech-labus",fullName:"Wojciech Łabuś"},{id:"204302",title:"MSc.",name:"Marcelina",surname:"Misiuga",slug:"marcelina-misiuga",fullName:"Marcelina Misiuga"},{id:"204303",title:"Dr.",name:"Mariusz",surname:"Nowak",slug:"mariusz-nowak",fullName:"Mariusz Nowak"},{id:"204304",title:"Prof.",name:"Marek",surname:"Kawecki",slug:"marek-kawecki",fullName:"Marek Kawecki"}],corrections:null},{id:"57503",title:"Treatment of Skin Laxity Using Multisource, Phase-Controlled Radiofrequency",doi:"10.5772/intechopen.71749",slug:"treatment-of-skin-laxity-using-multisource-phase-controlled-radiofrequency",totalDownloads:1497,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Regardless of age, sex and skin type, skin tightening is a common procedure requested by patients seeking cosmetic treatments to improve facial contours and skin laxity. Radiofrequency has been proven to penetrate deeper than optical light sources independent of skin color and to be beneficial for skin tightening. I previously reported on the efficacy of multisource phase-controlled radiofrequency treatment and noninsulated microneedle radiofrequency applicator with fractionated pulse mode. The evaluation process was both subjective and objective; I evaluated objectively using three-dimensional color schematic representation with quantitative volume measurements. These three-dimensional results showed significant improvement after the treatments. The post-treatment volume was drastically reduced as compared to the pretreatment volume. Most of the patients reported satisfaction with the improvement of skin laxity. The advantages of these multisource phase-controlled radiofrequency treatments are their long-lasting high efficacy of tightening effects, and the reduction of discomfort and side effects. These characteristics facilitate repeated treatments as well as provide safe and effective treatment of skin tightening.",signatures:"Yohei Tanaka",downloadPdfUrl:"/chapter/pdf-download/57503",previewPdfUrl:"/chapter/pdf-preview/57503",authors:[{id:"36633",title:"Dr.",name:"Yohei",surname:"Tanaka",slug:"yohei-tanaka",fullName:"Yohei Tanaka"}],corrections:null},{id:"56688",title:"The Wonder Tool Platelet Rich Plasma in Cosmetic Dermatology, Trichology and Hair Transplant",doi:"10.5772/intechopen.70287",slug:"the-wonder-tool-platelet-rich-plasma-in-cosmetic-dermatology-trichology-and-hair-transplant",totalDownloads:2349,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Platelet-rich plasma or PRP therapy is a form of regenerative medicine where body’s own cells, tissues or organs can be utilized by replacing, regenerating or engineering to restore or establish normal function. Various published articles demonstrating the role of PRP therapy in cosmetic procedures like scar revision, facial rejuvenation, stretch mark removal, androgenetic alopecia, alopecia areata and hair transplant were analyzed in depth to understand its efficacy based on facts and figures along with inputs from personal experience. PRP therapy is one of the most upcoming forms of regenerative medicine with the potential to improve the homeostasis of the treated cells and tissues, provided that harvesting standards are maintained.",signatures:"Garg Suruchi, Manchanda Shweta and Garg Chandi",downloadPdfUrl:"/chapter/pdf-download/56688",previewPdfUrl:"/chapter/pdf-preview/56688",authors:[{id:"203666",title:"Dr.",name:"Suruchi",surname:"Garg",slug:"suruchi-garg",fullName:"Suruchi Garg"},{id:"207637",title:"Dr.",name:"Shweta",surname:"Manchanda",slug:"shweta-manchanda",fullName:"Shweta Manchanda"},{id:"207639",title:"Dr.",name:"Chandi",surname:"Garg",slug:"chandi-garg",fullName:"Chandi Garg"}],corrections:null},{id:"57681",title:"Oral Naturally Derived Agents as an Adjuvant Photoprotection after Dermatologic Surgery",doi:"10.5772/intechopen.71750",slug:"oral-naturally-derived-agents-as-an-adjuvant-photoprotection-after-dermatologic-surgery",totalDownloads:1215,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"To be effective in protecting against the harmful effects of ultraviolet radiation (UVR), many photoprotective strategies have been used. Inadequate physical protection, amount of topical application, and allergic reactions to topical agents are limitations associated with current photoprotective strategies. Systemic agents are an emerging alternative, providing promising protection against UVR. This chapter will thoroughly review photoprotective outcomes of oral naturally derived agents from randomized controlled trials using evidence-based method. From total 24 clinical trials with 850 participants, two categories of naturally derived agents were identified. Plant-derived agents include beta-carotene, green tea, golden serpent fern, tomato, cocoa bean, and vitamin E, whereas animal-derived products consist of nicotinamide and omega-3 polyunsaturated fatty acids. In conclusion, systemic plant and animal-derived photoprotective agents may be a promising alternative in addition to conventional photoprotection.",signatures:"Premjit Juntongjin and Chavanatda Chanyasak",downloadPdfUrl:"/chapter/pdf-download/57681",previewPdfUrl:"/chapter/pdf-preview/57681",authors:[{id:"220950",title:"Dr.",name:"Premjit",surname:"Juntongjin",slug:"premjit-juntongjin",fullName:"Premjit Juntongjin"},{id:"221878",title:"Dr.",name:"Chavanatda",surname:"Chanyasak",slug:"chavanatda-chanyasak",fullName:"Chavanatda Chanyasak"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3323",title:"Highlights in Skin Cancer",subtitle:null,isOpenForSubmission:!1,hash:"e02ed90ccd31d7381b24ace99358ff43",slug:"highlights-in-skin-cancer",bookSignature:"Pierre Vereecken",coverURL:"https://cdn.intechopen.com/books/images_new/3323.jpg",editedByType:"Edited by",editors:[{id:"157965",title:"Dr.",name:"Pierre",surname:"Vereecken",slug:"pierre-vereecken",fullName:"Pierre Vereecken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10306",title:"Atopic Dermatitis",subtitle:"Essential Issues",isOpenForSubmission:!1,hash:"2bc6360aa278dad8f3a09289fe68bd73",slug:"atopic-dermatitis-essential-issues",bookSignature:"Celso Pereira",coverURL:"https://cdn.intechopen.com/books/images_new/10306.jpg",editedByType:"Edited by",editors:[{id:"66336",title:"Prof.",name:"Celso",surname:"Pereira",slug:"celso-pereira",fullName:"Celso Pereira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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A cholesterol-rich diet causes postprandial hyperlipaemia with an accumulation of chylomicrons. This accumulation leads to a redistribution of the very-low-density lipoproteins (VLDL), thereby determining the elimination of the coarsest particles, the residual chylomicrons, which promote the onset of atherogenesis [1].
For some years, cholesterol-rich food has been associated with the subsequent development of complications such as the formation of atheromatous plaque and lipid deposits at the ocular level. These findings have been reproduced in an experimental rabbit model [2,3], this animal being particularly sensitive to the induction of atheromatous lesions, which faithfully reproduce those caused in human atherosclerosis [4-6].
One of the main barriers of the eye is Bruch’s membrane, which, for its strategic situation between the choroidal vascular membrane and the outer retina, constitutes a semi-permeable filtration zone, through which the nutrients pass from the choriocapillaris towards the photoreceptors, while the cell-degradation products of the retina pass in the opposite direction. The accumulation of these waste products thickens Bruch’s membrane and the basal layer of the retinal pigment epithelium (RPE) [7]. These changes in the outer retina may be the consequence of metabolic stress associated with the metabolism of fatty acids or of the changes in choroidal perfusion due to atherosclerosis [8]. In any case, the lipids that accumulate in a structurally altered Bruch’s membrane cause a hydrophobic barrier that can hamper the free metabolic exchange between the choriocapillaris and the RPE, on interfering with the passage of nutrients and oxygen to the retina. This situation could contribute to the loss of retinal sensitivity and play a pathogenic role in the development of age-related macular degeneration (AMD) [9], the leading cause of blindness among people over 65 years in developed countries. On the other hand, the deposits that accumulate underneath the RPE, which contains unsaturated fatty acids, are oxidized by the light, strengthening lipid peroxidation [10,11] and negatively influencing retinal function. The changes in the RPE-Bruch’s membrane complex contribute to the death of multiple retinal neurons, this translating as a thinning and disorganization of its layers.
Cholesterol is essential for cell functioning. The main cholesterol source for the photoreceptors and the RPE comes from extracellular lipid metabolism, as has been demonstrated on detecting native low-density lipoprotein (LDL) receptors at the RPE level [12], which could be involved in the local production of apolipoprotein E (apoE). The retina also locally produces lipoprotein particles that contain apoE. These particles are secreted fundamentally by the Müller glia to the extracellular retinal compartment and to the vitreous, from which they are transported to the optic nerve [13]. Also, the retinal astrocytes associated with the axons of the ganglion cells participate in the secretion of apoE. This cholesterol transport is essential to supply the retinal neurons the lipids needed for the maintenance and remodelling of their cell membrane.
Studies in apoE-deficient mice have demonstrated the presence of alterations in Müller glia and in amachrine cells, these generating aberrations in the retinal circuit as a consequence of the local disruption of cholesterol homeostasis [14]. In a hypercholesterolaemic rabbit model, cell loss in the inner nuclear layer and in the ganglion-cell layer of the retina has been demonstrated [15,16]. This cell loss probably results from the deprivation of the neurotrophic support [17] and of the CNTF (ciliary neurotrophic factor) and glial fibrillary acidic protein (GFAP) upregulation secondary to the reactivation of the Müller cells [18,19]. In hypercholesterolaemic rabbits, added to the situation of ischaemia at the level of the outer retina induced by the alterations in Bruch’s membrane and in the choriocapillaris, is the thickening of the basal membranes of the retinal vessels, which by hampering the passage of oxygen and nutrients towards the inner retina would generate a prolonged situation of ischaemia [15,20]. This chronic ischaemia could increase the concentration of extracellular glutamate, conditioning oxidative damage by a neuronal cytotoxic mechanism [21,22]. This situation can be counteracted so long as the astrocytes maintain their capacity to eliminate cytotoxic neurotransmitters and to supply growth factors and cytokines [23].
In summary, in the present chapter, the structural and ultrastructural changes in the retina of an experimental model of hypercholesterolaemia are described, specifically changes in Bruch’s membrane, RPE, and retinal layers as well as the vascular changes responsible for chronic ischaemia. Further on, the effects of the diet-induced normalization of the plasma-cholesterol levels in the retinal structures are discussed. The comparison between the two scenarios suggests that hypercholesterolaemia is a risk factor for the development of chronic ischaemia in the retina and therefore for neuronal survival.
Bruch’s membrane, the innermost layer of the choroid, fuses with RPE as a 5-layered structure consisting of (from outer to inner): a basement membrane of the choriocapillaris, an outer collagenous layer, an elastic layer, an inner collagenous layer, and a basement membrane of the RPE [7,24] (Figure 1, 3A, 4A). Fine filaments from the basement membrane of the RPE merge with the fibrils of the inner collagenous zone, contributing to the tight adhesion between choroid and the RPE. The basement membrane of the choriocapillaris is discontinuous and is absent in the intercapillary spaces [25]. The collagenous layers surround the elastic layer [7]. Some collagen fibres are arranged parallel to the tissue plane, especially at the inner collagenous zone; others cross from one side of the elastic fibre layer to another, interconnecting the two collagenous layers [7]. Collagen fibres pass through the disruption of the basement membrane to join the collagen fibres of the intercapillary septae. This arrangement may help Bruch’s membrane to attach to the choriocapillaris. Vesicles, linear structures, and dense bodies occur in the collagenous and elastic zones but predominantly in the inner collagenous layer [26]. The elastic layer is made up of inter-woven bands of elastic fibres with irregular spaces between them, through which the collagen fibres pass [7,26] (Figure 3A,\n\t\t\t\t4A). The exchange of substances between the choroid and retina (both directions) must traverse Bruch’s membrane [7]. The importance of this process is evident in situations in which this membrane is disrupted. During aging, Bruch’s membrane gradually thickens [27]. The collagenous layers thicken from the accumulation of membranous lipidic debris [28], abnormal extracellular matrix components (collagen fibres "cross-linking") and the advanced glycation end-product [29]. This decreases the porosity of Bruch’s membrane, presumably heightening resistance to the movement of water through it [30]. Also, it has been found that this thickening of Bruch’s membrane is accompanied by lower membrane permeability [31]. Although this thickening with aging is relatively minor, greater increases can appear in specific regions. The accumulation of material in the inner collagenous layer bulging toward the retina, is what is known by the term "drusen" [32]. These drusen will deprive the photoreceptors of their nutrition from the choriocapillaris.
Histological section of the human retina. Retinal layers. Hematoxylin/eosin. 1: retinal pigment epithelium; 2: photoreceptor layer; 3: outer limiting membrane; 4: outer nuclear layer; 5: outer plexiform layer; 6: inner nuclear layer; 7: inner plexiform layer; 8: ganglion-cell layer; 9: nerve-fibre layer; 10: inner limiting membrane. [Bruch’s membrane (BM); choroidal vascular layers (C)].
The elastic layer also suffers a disruption with aging, namely, an increase in density and calcification [33]. These aged-related changes could cause cracks and holes in Bruch’s membrane. Major breaks in Bruch’s membrane are associated with oedema, leading to the accumulation of fluid between the RPE and photoreceptors, and hence to a retinal detachment. This association between the discontinuity of Bruch\'s membrane and retinal oedema suggests that, under normal conditions, Bruch’s membrane could play a role in limiting fluid movement to and from the retina [25].
The primary function of the retina is to convert light into nerve impulses which are transferred to the brain via the optic nerve. The retina comprises the retinal pigment epithelium and the neurosensory retina, the latter containing neurons, glial cells and components of the vascular system. Various types of neurons are present, such as: photoreceptors, bipolar cells, ganglion cells, amacrine cells and horizontal cells [34]. The coding function of the retina depends not only on photoreceptors but also on neurons, glial cells and RPE, which amplify the signal [35]. The photoreceptors are the cells that capture light and are situated at the most external side of the neurosensory retina, in the vicinity of the RPE. These cells are of two types: rods (for scotopic vision) and cones (for photopic vision) [34]. The ability of photoreceptors to convert light photons into an electrical signal is due to the presence of a photopigment in their outer segments. These segments consist of a stack of disk membranes that are synthesised in the proximal portion of the outer segment and shed at its apical size [35]. Photoreceptors form contacts with horizontal and bipolar cells in the outer plexiform layer (OPL). Coupling between neighbouring rods and cones in OPL allows the first stage of visual processing. The inner nuclear layer (INL) contains cell bodies of Müller glial, bipolar, amacrine, and horizontal cells. The inner plexiform layer (IPL) consists of a synaptic connection between the axons of bipolar cells and dendrites of ganglion and amacrine cells. The ganglion-cell layer (GCL) contains the cell bodies of retinal ganglion cells, certain displaced amacrine cells, and astrocytes. Inside the eye, ganglion-cell axons run along the retinal surface toward the optic-nerve head forming nerve-fibre layer (NFL) [34,35] (Figure 1).
The neural retina also contains two types of macroglial cells: Müller cells and astrocytes (Figure 2).
Müller cells are long, radially oriented cells which span the width of the neural retina from the outer limiting membrane (OLM), where their apical ends are located, to the inner limiting membrane (INL), where their basal endfeet terminate (Figure 2A). In the nuclear layers, the lamellar processes of the Müller cells can be seen to form basket-like structures which envelope the cell bodies of photoreceptors and neural cells. In plexiform layers, fine processes of these cells are interwoven between the synaptic processes of neural cells. In both the plexiform and nuclear layers, Müller cell processes cover most but not all neural surfaces [36].
Astrocytes are located mainly in the NFL and GCL in most mammals (human, rabbit, rats and mouse, among others) [37-39] (Figure 2B). Astrocyte morphology differs between species. In humans, two types of astrocytes can be distinguished: elongated (located in the NFL) and star-shaped (located in GCL) astrocytes. In mice and rats the astrocytes are stellate (Figure 2B). The greatest variety of retinal astroglial cell morphologies is found in the rabbit, which possesses two large astrocyte groups: astrocytes associated with the nerve-fibre bundles (AANFB) which are aligned parallel to the axonal bundles in the NFL (Figure 10G), and perivascular astrocytes (PVA), associated with the retinal and vitreous blood vessels (Figure 10A,D). PVA can be further subdivided into: i) type I PVA, which have numerous sprouting, hair-like processes, associated with medium-sized epiretinal vessels, and with capillaries located over the inner limiting membrane (ILM) (Figure 10A), and ii) type II star-shaped PVA, which are located on and between larger and medium-sized epiretinal vessels [15,38,40-42] (Figure 10D). The morphology of retinal astrocytes in different animal species is determined by the way their processes adapt to the surrounding structures [43].
Immunohistochemistry anti-GFAP in mouse retinal whole-mount. A: GFAP+ Müller cells after 15 days of laser-induced ocular hypertension. The pressure exerted by the cover glass on the retinal whole-mount, produced a retinal-like section effect in some retinal borders. Müller cells exhibit a radial morphology that creates a columnar matrix that maintains the laminar structure of the retina [Astrocyte (*); inner limiting membrane (ILM)]. B: Confocal microscopy of normal retinal astrocytes. These cells form a homogeneous plexus on the nerve-fibre-RCG layer constituted by stellate cells. (Modified from Gallego et al [
Macroglial cells perform a variety of essential roles for the normal physiology of the retina, maintaining a close and permanent relationship with the neurons [43]. Thus every aspect of the development, homeostasis, and function of the visual system involves a neuron-glia partnership. Glial cells insulate neurons, provide physical support, and supplement them with several metabolites and growth factors. These cells also play important roles in axon guidance and control of synaptogenesis [44]. Under normal conditions, astrocytes and Müller cells maintain the homeostasis of extracellular ions, glucose, and other metabolites, water, pH and neurotransmitters such as glutamate and GABA [45]. These cells also produce a great quantity of growth factors and cytokines, which may contribute both to neurotoxic as well as neuroprotective effects. It has also been demonstrated that macroglial cells are more resistant to oxidative damage than are the neurons, this trait protecting them against such damage. This potential is due to the fact that these cells contain high concentrations of antioxidants such as reduced glutathione and vitamin C. Consequently, a depression of these cellular activities could lead to neuronal dysfunction [46]. Macroglial cells induce the properties of barrier in the endothelial cells of retinal capillaries (the blood-retinal barrier), securing immune privilege to protect neurons from potentially damaging effects of an inflammatory immune response. Finally, glial cells can play fundamental roles in local immune responses and immunosurveillance [44].
Macroglial cells also play a part in pathological processes in central nervous system (CNS). Glial cells in the CNS have been cited as participants in the pathological course of neuronal damage after mechanical, ischaemic, and various other insults. Glial cell activation is a hallmark of CNS injury, characterized by an increase in size and number of glial cells and upregulation of GFAP, with additional cellular changes that may cause or relieve neuronal impairment. These reactive cells also have higher metabolic activity. After injury, reactive glial cells participate in the formation of a glial scar, in which there is an accumulation of enlarged astrocyte bodies and a thick network of processes with increased expression of GFAP and vimentin. Macroglial cells become reactive in response to a wide variety of stimuli, including inflammation and oxidative and mechanical stress [47].
Other components of the retina are the blood vessels. Photoreceptors receive nutrients via the choriocapillaris. The inner retinal layers have their own blood supply coming from the blood vessels entering the retina at the optic-nerve head. For its protection, the retina is physiologically and immunologically segregated from the rest of the body by tight junctions between vascular endothelial cells (inner blood-retinal barrier) and RPE cells (outer blood-retinal barrier). This fact is responsible for intraocular tissue to be an immune privileged site, thus protecting the eye from the innocent-bystander effect of inflammation [34]. In addition, only small molecules can cross these barriers, making it difficult for many drugs to reach ocular tissue.
The outermost retinal layer is the RPE (Figure 1), which is formed by a single layer of pigmented hexagonal cells. These cells provide the supportive role necessary to sustain the high metabolic demands of photoreceptors. RPE cells supply nutrients and oxygen, regenerate phototransduction products, and digest debris shed by the photoreceptors. The basal aspect of RPE cells contains numerous infoldings and is adjacent to Bruch’s membrane. The apical surface is adjacent the neural retina. The RPE cells contain numerous pigment granules (melanosomes), lipofuscin granules, and degradation products of phagocytosis, which grow in number with age (Figure 4A) [7]. The RPE had several intercellular junctions: zonula occludens, zonula adherents, desmosomes, and gap junctions. The latter allow the cell electrical coupling and provide a low-resistance pathway for the passage of ions and metabolites [48]. The RPE fosters the health of the neural retina and choriocapillaris in several ways: the zonula occludens joining the RPE cells are part of the blood-retinal barrier and selectively control movement of nutrients and metabolites from choriocapillaris into the retina and removal of waste products from the retina into the choriocapillaris [49]. RPE cells phagocytose fragments of the photoreceptor outer segment discs, metabolise and store vitamin A, and produce growth factors, helping to maintain choriocapillaris and retinal function. Other, less well-characterized functions of the RPE are the absorption of stray light and the scavenging of free radicals by the melanin pigment in the epithelium and the drug detoxification by the smooth endoplasmic reticulum cytochrome p-450 system [50]. From the several functions displayed by RPE, it can be easily concluded that dysfunction of RPE cells has serious consequences on the health of photoreceptors [34].
Recent studies have demonstrated that fatty acids are fundamental for normal visual function [51]. Humans are unable to synthesise essential fatty acids (EFAs) and must acquire them through the food intake. Dietary EFAs are transformed into the endoplasmic reticulum of hepatic and retinal cells [52] into long-chain polyunsaturated fatty acids (LCPUFAs). LCPUFAs perform various functions, e.g. serving as ligands for gene-transcription factors for cell growth and differentiation, to participate in the metabolism of lipids, carbohydrates, and proteins, and to intervene in the inter- and intracellular signal cascades that influence vascular, neural, and immune functions [51].
In the neural retina, the richest LCPUFA-containing lipids are the phospholipids of the cell membranes [53], and the most abundant LCPUFAs in the retina are docosahexaenoic acid (DHA) and arachidonic acid (AA). DHA is a long-chain polyunsaturated fatty acid from the omega 3 series. It is present at high levels in the neurosensory retina [54]. DHA improves the kinetics of the photocycle by creating specific intermolecular associations with rhodopsin [35]. Brain astrocytes [55] and retinal tissue [34] can produce DHA, but in a limited way [56], given that the synthesis process is slow [57] and restricted to the RPE and the endothelial cells of the retinal vessels [58]. Consequently, retinal requirements of LCPUFAs depend on input from the liver (the main site of LCPUFA biosynthesis) [59] and hence on transportation of LCPUFAs from the choriocapillaris to the outer segments of the RPE-photoreceptor.
Cell-membrane permeability is thought to depend on the balance between LCPUFAs and cholesterol [60,61]. Ocular DHA levels are lower in high-cholesterol diets, a fact that could influence the development of ocular disease [62]. Recently, it has been reported the relationship between lipid intake and AMD in patients with low intake of linoleic acid (a LCPUFA) [63].
Cholesterol is present exclusively as the free form in the neurosensory retina, and distributed in all cell layers [54,64]. Cholesterol in the neuroretina originates from
Similar to the brain [68,69], the neurosensory retina expresses cholesterol-24S-hydroxylase (CYP46A1) [70]. CYP46A1 is a microsomal cytochrome P450 enzyme which catalyses the hydroxylation of cholesterol at position C24. It has been suggested that CYP46A1 represents a mechanism of cholesterol removal from neurons [71] and strongly induces oxidative stress as well the inflammatory response in RPE cells. RGC specifically express CYP46A1 [70], a hydroxylase that might promote apoptosis of RGC in glaucoma. Cholesterol-27-hydroxylase (CYP27A1) shows a property the similar to that of CYP46A1, converting cholesterol into a more polar metabolite [72]).
7-ketocholesterol is a non-enzymatic-oxidation product of cholesterol. The formation of 7-ketocholesterol in the retina has been thoroughly studied in the retina, in connection with oxidative stress, aging and AMD [73].
With age, the diffusion characteristics of the choriocapillaris-Bruch’s membrane-RPE-photoreceptor complex [74,75] change, RPE density decreases [76], and the cytoarchitecture of RPE cells transforms [77]. Such morphological and functional changes lead to AMD in some patients. Additionally, there may be age-related changes in the specific activities of the lysosomal enzymes of the RPE and it has been reported that animals fed a fish-oil-enriched diet presented higher activity of lysosomal acid lipase [78,79]. This could augment the hydrolysis of the intralysosomal lipids of the RPE, thus reducing lipofuscin deposits and oxidative damage of the RPE, this in turn preventing the development of AMD.
Recent studies have demonstrated the relationships between dietary fat and the promotion of vascular disease [51]. Lipoprotein metabolism has also been associated with neurodegenerative disorders in rats [14] but preliminary results showed no marked changes in apo-E knockout mice [80]. Eukaryotic cells require sterols to achieve normal structure and function of their plasma membranes, and deviations from normal sterol composition can perturb these features and compromise cell and organism viability [81]. Given that cholesterol is required by neurons, an intimate relationship could exist between cholesterol homeostasis and the development, maintenance, and repair of these cells [14].
The particular spatial arrangement of retinal macroglial cells (astrocytes and Müller cells) that are intercalated between vasculature and neurons points to their importance in the uptake of nutrients from the circulation, metabolism, and transfer of energy to neurons [37,40,82]. Moreover, apoE lipoprotein, which plays a central role in serum-cholesterol homeostasis through its ability to bind cholesterol with other lipids and to mediate their transport into cells, is produced by glial cells [83]. Müller cells express HMGcoA reductase. Glia is also known to support neurons in the formation and maintenance of synapses in which cholesterol is crucial [84]. Therefore, all together, these data suggest that glial Müller cells may also help deliver cholesterol to neurons [35].
As mentioned above, associations between 24S-hydroxycholesterol in glaucoma and other neurodegenerative diseases are suspected. Glial expression of CYP46A1 has also been reported in the brain of Alzheimer’s patients [85,86]. Glia may compensate for the loss of neurons while expressing CYP46A1. Meanwhile, Müller cells play a key role in the maintenance of RGC bodies in the retina, besides participating in lipid metabolism, including fatty acid oxidation [86].
Reactive gliosis, a general response to injury and inflammation in the adult brain [87,88], is characterized by up-regulation of various kinds of molecules, the best known being GFAP [89]. The
Given the intricate metabolic interdependence between vessels, macroglial cells, and neurons, high cholesterol levels could deregulate a number of cell functions in both macroglial and neuronal cells.
Most of the information available on vascular diseases is based mainly on studies of ischaemic heart disease [97] and cerebrovascular diseases [98]. In both, the underlying phenomenon is artherosclerosis, a general term referring to any vascular degeneration causing the thickening and loss of arterial-wall elasticity and that encompasses atherosclerotic and non-atherosclerotic conditions. Atherosclerosis involves a hardening of the arterial intima due to a lipid build-up in artery, a condition that appears in humans at an early age and develops progressively over the aging process [99].
Schematically, we can point to various types of long-recognized vascular risk factors: i) non-reversible factors, such as age, male gender or family history of early atherosclerosis; ii) reversible factors such as smoking, hypertension, obesity or hypercholesterolaemia; iii) partially reversible factors such as hypertriglyceridaemia and other forms of hyperlipidaemia, hyperglycaemia, and diabetes mellitus; and iv) potential risk factors such as physical inactivity or emotional stress. Some new factors can be added to the aforementioned vascular risk factors, including lipoprotein A, homocysteine, coagulation factors and C-reactive protein [99,100].
It bears noting that the importance of hypercholesterolaemia as a cardiovascular risk factor lies not only in its direct effect on the pathogenesis of coronary or cerebrovascular disease, but also in the influence exerted on the course of other pathologies. For ocular diseases, epidemiological studies have demonstrated that hypercholesterolaemia is a risk factor for several pathologies despite not being considered the primary cause of the process.
In the case of retinal lesions, classical risk factors for atherosclerosis seem to lose influence. The Atherosclerosis Risk in Communities Study (ARIC) has suggested that changes in the retinal vessels (arteriolar narrowing, arteriovenous index, and abnormalities where the arterioles cross or arteriovenous nicking) are closely linked to hypertension but not to other factors [101], although the presence of retinal lesions is associated with a higher prevalence of ischaemic heart disease, myocardial infarction, stroke, or carotid plaques in patients over 65 years [102,103]. It has been suggested that the retinal lesions could reflect the persistence of small-vessel damage due to hypertension and possibly inflammation and endothelial dysfunction, although they have little relation to large-vessel damage [103].
Another work of the ARIC study found that retinal arteriolar narrowing intensifies the risk of ischaemic heart disease in women but not men after adjusting the population for other known risk factors such as blood pressure, diabetes, smoking, and lipids. The authors speculated that the difference between sexes may be due to the fact that microvascular lesions may have a greater role in women than in men. Hormones protect women from macrovascular injury but it is not clear whether small vessels receive the same protection [104].
The examination of the retinal vasculature offers a unique opportunity to investigate cerebral microcirculation [105], which can be of outstanding importance to clarify the role of microcirculation in stroke [106]. The presence of retinal microvascular abnormalities is linked to the incidence of any stroke and also to the presence of high blood pressure, not only at the time of diagnosis, but also beforehand. Furthermore, stroke has been associated with markers of inflammation and endothelial dysfunction, suggesting the possibility of a significant microvascular component in stroke that a retinal examination might reveal [107]. Notably, although the importance of the association between brain and retinal microvascular lesions is still unknown, the prediction of a stroke provided by the white-matter lesions multiply in the presence of retinal lesions [108].
In conclusion, epidemiological studies have shown an association between vascular changes in the retina and elsewhere. This association appears to be related to common factors of microvasculature damage, the role of which, both in ischaemic heart disease and stroke, may be greater than suspected.
Animal models provide a controlled environment in which to study disease mechanisms and to devise technologies for diagnosis and therapeutic intervention for human atherosclerosis. Different species have been used for experimental purposes (cat, pig, dog, rabbit, rat, mouse, zebra fish). The larger animal models more closely resemble human situations of atherosclerosis and transplant atherosclerosis and can also be easily used in (molecular) imaging studies of cardiovascular disease, in which disease development and efficacy of (novel) therapies can be monitored objectively and non-invasively. Imaging might also enable early disease diagnosis or prognosis [109]. On the other hand, the benefits of genetically modified inbred mice remain useful, especially in quantitative trait locus (QTL)-analysis studies (a genetic approach to examine correlations between genotypes and phenotypes and to identify (new) genes underlaying polygenic traits [109].
Wild-type mice are quite resistant to atherosclerosis as a result of high levels of anti-atherosclerotic HDL and low levels of pro-atherogenic LDL and very-low-density-lipoproteins (VLDL). All of the current mouse models of atherosclerosis are therefore based on perturbations of lipoprotein metabolism through dietary or genetic manipulations [110].
In apoliprotein-deficient mice (apoE-/-) the homozygous delection of the apoE gene results in a pronounced rise in the plasma levels of LDL and VLDL attributable to the failure of LDL-receptor (LDLr-) and LDL-related proteins (LRP-) mediated clearance of these lipoproteins. As a consequence, apoE-/- mice develop spontaneous atherosclerosis. Of the genetically engineered models, the apoE-deficient model is the only one that develops extensive atherosclerotic lesions on a low-fat cholesterol-free chow diet (<40g/kg). The development of atherosclerosis lesion can be strongly accelerated by a high-fat, high-cholesterol (HFC) diet [111].
ApoE-knockout mice have played a pivotal role in understanding the inflammatory background of atherosclerosis, a disease previously thought to be mainly degenerative. The apoE-deficient mouse model of atherosclerosis can be used to: i) identify atherosclerosis-susceptibility-modifying genes; ii) define the role of various cell types in atherogenesis; iii) characterize environmental factors affecting atherogenesis; and iv) to assess therapies [112].
Because of the rapid development of atherosclerosis and the resemblance of lesion to human counterparts, the apoE-/- model have been widely used. However, some drawbacks are associated with the complete absence of apoE proteins: i) the model is dominated by high levels of plasma cholesterol; ii) most plasma levels are confined to VLDL and not to LDL particles, as in humans; and iii) apoE protein has additional antiatherogenic properties besides regulating the clearance of lipoproteins such as antioxidant, antiproliferative (smooth-muscle cells, lymphocytes), anti-inflammatory, antiplatelet, and also has NO-generating properties or immunomodulatory effects [113-115]. The study of the above processes and the effects of drugs thereupon is restricted in this model.
In humans, mutations in the gen for the LDLr cause familial hypercholesterolaemia. Mice lacking the gene for LDL receptor (LDLr-/- mice), develops atherosclerosis, especially when fed a lipid-rich diet [116]. The morphology of the lesions in LDLr-/- mice is comparable to that in apoE-/-, while the main plasma lipoprotein in LDLr-/- mice are LDL and high-density-lipoprotein (HDL) [117].
ApoE*3Leiden (E3L) transgenic mice are being generated by introducing a human ApoE*3-Leiden construct into C57B1/6 mice. E3L mice develop atherosclerosis on being fed cholesterol. Because they are highly responsive to diets containing fat, sugar, and cholesterol, plasma lipid levels can easily be adjusted to a desired concentration by titrating the amount of cholesterol and sugar in the diet. E3L mice have a hyperlipidaemic phenotype with a prominent increase in VLDL- and LDL-sized lipoproteins fractions [118] and are more sensitive to lipid-lowering drugs than are apoE-/- and LDLr-/- mice [110].
Because of their well-known physiological and anatomical similarities to humans, swine are considered to be increasingly attractive toxicological and pharmacological models. Pigs develop plasma cholesterol levels and atherosclerotic lesions similar to those of humans, but their maintenance is more difficult and expensive than that of smaller animals [109]. The minipig, smaller than the domestic swine, has served as a model of hypercholesterolaemia for more than two decades now. In 1986, the ref. [119] reported that the Göttingen strain had more susceptibility to alimentary hypercholesterolaemia and experimental atherosclerosis than did domestic swine of the Swedish Landrace. Clawn, Yucatan, Sinclair, and Handford are among other general minipigs used for experimental use [120-122].
Down-sized Rapacz pigs are minipigs with familial hypercholesterolaemia caused by a mutation in the low-density lipoprotein receptor. It is a model of advanced atherosclerosis with human like vulnerable plaque morphology that has been used to test an imaging modality aimed at vulnerable plaque detection [123].
The Microminipig (MMP) is the smallest of the minipigs used for experimental atherosclerosis [124]. One of its advantages is that in 3 months an atherosclerosis very similar in location, pathophysiology and pathology to that in humans can be induced [125]. The easy handling and mild character of the MMP make it possible to draw blood and conduct CT scanning under non-anaesthesized conditions.
Cholesterol-fed zebra fish represent a novel animal model in which to study the early events involved in vascular lipid accumulation and lipoprotein oxidation [126,127]. Feeding zebra fish a high-cholesterol diet results in hypercholesterolaemia, vascular lipid accumulation, myeloid cell recruitment, and other pathological processes characteristic of early atherogenesis in mammals [128]. The advantages of the zebra-fish model include the optical transparency of the larvae, which enables imaging studies.
Investigation has continued on hypercholesterolaemic rabbits since 1913, when Anitschkow demonstrated that, in rabbits fed a hypercholesterolaemic diet underwent atherosclerotic changes at the level of the arterial intima similar to those in atherosclerotic humans. The atheromatose lesions in this animal are similar to those in humans also in sequence, as confirmed in aortic atherosclerosis [3], making this animal a universal model for studying the anti-atherogenic activity of many drugs [129-132].
For the characteristics detailed below, the New Zealand rabbit is an excellent model to reproduce human atheromatosis because: i) it is possible to induce hypercholesterolaemia in a few days after administration of a high-cholesterol diet [2]; ii) it is sensitive to the induction of atheromatose lesions [3]; iii) hypercholesterolaemia results from excess LDL [133]; iv) excess cholesterol is eliminated from the tissues to be incorporated in HDL [134]; vi) it is capable of forming cholesterol-HDL complexes associated with apoE which are transported by the blood to the liver [134]; vii) the lipoprotein profile is similar in size to that of humans in the highest range, with HDL being practically the same [135]; viii) it presents postprandial hyperlipaemia for the existence of chilomicron remnants [136]; ix) the hyperlipaemic diet increases apoE [4]; and x) the sustained alteration of lipids after feeding with a cholesterol-rich diet is reversible when the diet [130] is replaced by a normal one [2].
Studies on hypercholesterolaemic rabbits have improved our knowledge of human atherosclerosis by delving into different aspects of the disease such as lipoproteins, mitogenes, growth factors, adhesion molecules, endothelial function, and different types of receptors. At the vascular level, the importance of endothelial integrity and cell adhesion has been investigated [137]. It has been demonstrated that the high levels of lysosomal iron start the oxidation of the LDL, spurring the formation of lesions [138]. In addition, the expression of VCAM-1 preceding the infiltration of the subendothelial space by macrophages has been studied [139], as have the proteins, including MCP-1. In hypercholesterolaemic rabbits, this protein is over-expressed when the serum-cholesterol levels rise in macrophages and smooth-muscle cells, contributing to the development of fatty streaks [140].
In hypercholesterolaemic rabbits, the expression of Fas-L in cells of the arterial wall help us to understand the progression of the atherosclerotic lesion, as this expression indicates an increase in cell injury, as well as a greater accumulation in the intima of smooth-muscle cells [141]. Also, a hyperlipaemic diet causes a selective alteration of the functioning of certain regulatory proteins that are involved in gene expression, as occurs with the nuclear B factor, which stimulates the proliferation of macrophages and smooth-muscle cells [142].
In this model, a study was also made of the pre-thrombosis state triggered by the platelet aggregation in an altered endothelium and the possibilities of its inhibition [143], as well as the interactions of the LDL with the extracellular matrix to form aggregates that accumulate in the intima of the artery wall [144].
The consequences of hypercholesterolaemia in ischaemic cardiopathy and cerebrovascular pathology are well known. The same does not occur with the functional repercussions of the hypercholesterolaemia at the ocular level, partly because the underlying structural changes are not well known.
The hypercholesterolaemic rabbit constitutes a useful model to explore the repercussions of excess lipids at the ocular level. This is because rabbits are susceptible to both systemic as well as ocular alterations. One of the broadest contributions made to the implications of experimental hypercholesterolaemia at the ocular level was that of ref. [145]. These authors, apart from analysing the changes in the liver, spleen, adrenaline glands, heart, aorta, and supraaortic trunk, described the most significant ocular findings, such as the accumulation of lipids in the choroid, retinal disorganization, and lipid keratopathy. With respect to the retinal macroglia, the synthesis of the apoE by the Müller cells, its subsequent secretion in vitro, and its being taken up by the axons and transported by the optic nerve enabled the detection of apoE in the latter geniculate body and in the superior colliculus [13].
Studies with electron microscopy on hypercholesterolaemic rabbits have revealed hypercellularity and optically empty spaces in the corneal stroma. These optically empty spaces, with an elongated or needle shape, were previously occupied by crystals of cholesterol monohydrate or crystals of cholesterol esters [146]. In other studies, the analysis in the form adopted for the crystallizations of the different types of lipids revealed that the needles corresponded to esterified cholesterol, and the short, thin ones to triglycerides [134]. Both crystallizations appear to be associated with other components such as collagen.
It had been recently reported that hypercholesterolaemic rabbis had a build-up of lipids (foam cells and cholesterol clefts) mainly at the suprachoroidea and to a lesser extent at the choroidal vascular layers. This lipids compressed the choroidal vessels and causes hypertrophy of the vascular endothelial- and vascular smooth-muscle cells. The ultrastructural analysis of these vascular structures demonstrated numerous sings of necrosis and a severe damage of the cytoplasmic organelles and caveolar system [16,147].
Recently, it has been reported that in comparison with normal control animals, hypercholesterolaemic rabbits had a reduction of the amplitudes of the first negative peak of the visually evoked potentials, the density of the RGCs, and the thickness of the INL and photoreceptor-cell layer. Additionally, the immunoreactivity to eNOS was reduced and increased to iNOSs. Enhanced activity of iNOS in hypercholesterolaemic rabbits might be involved in impaired visual function and retinal histology. Downregulation of eNOS activity might be one of the causes for impairment of the autoregulation [148].
The formation of foam cells is a consequence of phagocytes from the macrophage-oxidized LDL [16], with the retention of cholesterol in the vascular wall and the activation of ACAT (acetyl-cholesterol-acyl-transferase) [149], this point being key to the role of macrophages in the progression or regression of the lesions [134].
The Watanabe heritable hyperlipidaemic (WHHL) rabbit is an animal model for hypercholesterolaemia due to genetic defects in LDL receptors [150] and a lipoprotein metabolism very similar to that of humans [150,151]. These features make WHHL rabbits a true model of human familial hypercholesterolaemia. The first paper on the WHHL rabbit was published in 1980 [152]. The original WHHL rabbits had a very low incidence of coronary atherosclerosis and did not develop myocardial infarction. Several years of selective breeding led to the development of coronary atherosclerosis-prone WHHL rabbits, which showed metabolic syndrome-like features, and myocardial infarction-prone WHHLMI rabbits. WHHL rabbits have been used in studies of several compounds with hypocholesterolaemic and/or anti-atherosclerotic effects with special relevance for statins [151]. Recently, WHHLMI rabbits have been used in studies of the imaging of atherosclerotic lesions by MRI [153], PET [154] and intravascular ultrasound [155].
Few experimental studies examine the effects of hypercholesterolaemia on the posterior segment of the eye [14,15,145,156-158]. Hypercholesterolaemic rabbits constitute a useful model to delve into the repercussions of excess lipids at the ocular level. Rabbits fed a 0.5% cholesterol-enriched diet for 8 months showed a statistical increase in total serum cholesterol [15,16,147,158,159]. In these animals, the hypercholesterolaemia caused numerous changes in the Bruch’s membrane-retinal complex. Bruch’s membrane was thicker than in normal animals (Figure 3A,B) due to the build-up of electrodense and electrolucent particles (Figure 3B) in the inner and outer collagenous layers [15]. As in hypercholesterolaemic animals, thickening and lipid accumulation in Bruch’s membrane has been described in human AMD [160,161]. These deposits of lipids or lipid-rich material could add resistance to the flow of solutes and water through the Bruch’s membrane-RPE complex, as demonstrated by the studies that have measured the hydraulic conductivity of isolated Bruch’s membranes [162,163]. The local metabolism and transport of cholesterol, impaired in hypercholesterolaemic rabbits as a result of a thickened Bruch’s membrane with changes in its collagenous layers, could play an important role in the contribution of lipids required for retinal neurons to maintain and remodel their membranes.
The cholesterol source for RPE and photoreceptors are the plasma lipids. Given that there is no direct contact between the photoreceptors and the choroidal circulation, adjacent cell types (RPE cells and Müller cells) must facilitate the transfer of lipids to the photoreceptors. In fact, the expression of native receptors for LDL on RPE cells has been reported [12,164]; this could be related to local production of apoE by RPE cells. An abnormal metabolism of lipids secondary to a cholesterol-enriched diet and/or apoE deficiencies could upset the cholesterol balance in RPE and photoreceptors. This could be the situation in hypercholesterolaemic rabbits in which ERP changes have been reported [15]. In this experimental model, RPE showed numerous hypertrophic cells and some nuclei were absent. The cytoplasm of these cells showed numerous dense bodies, debris from cell membranes, and numerous clumps of lipids (Figure 4B) filling the cytoplasm and replacing the nucleus and organelles that could be contributing to the hypertrophy and degeneration of the RPE [15]. Additionally, the basal zone of some RPE cells revealed autophagic vesicles, vacuoles, electrodense deposits, and debris from cell membranes [15] that could correspond to the laminar deposits described by [165] (Figure 4B). As in human AMD, changes of RPE could contribute to the degeneration of the photoreceptors [164] whose metabolism depends on normal RPE function and integrity [15,166].
Transmission electron microscopy of Bruch’s membrane and choriocapillaris. A: Control rabbit. B: Hypercholesterolaemic rabbit. Electrodense (black arrowhead) and electroluminescent (white arrowhead) particles at the inner collagenous layer Modified from Triviño et al. [
Transmission electron microscopy of Bruch’s membrane and retinal pigment epithelium cells (RPE). A: Choriocapillaris - Bruch’s membrane - RPE complex from control rabbit. Detail of Bruch’s membrane (insert) showing the outer collagenous layer, elastic layer and inner collagenous layer. B: The cytoplasm of RPE cell in hypercholesterolaemic rabbit shows dense bodies (white arrows), debris from cell membranes (*) and droplets of lipids. The apical microvilli have disappeared and the basal infolding forms lamellar structures (black arrow). C: RPE cells in reverted rabbit. Few lipids, dense bodies (white arrows) and some lamellar structures are visible in the cytoplasm. [Choriocapillaris (CC); retinal pigment epithelium (RPE); Bruch’s membrane (BM); inner collagenous layer (ICL); elastic layer (E); outer collagenous layer (OCL); lipids (L)]. (Modified from Ramírez et al. [
Retinal semi-thin sections (light microscopy). Retinal-layer changes. A: Control rabbit. B: Hypercholesterolaemic rabbit. C: Reverted rabbit. The figure illustrates the overall thinning of the retinal layers in hypercholesterolaemic and reverted animals with respect to control. The empty spaces (arrows) secondary to cell loss and degeneration observed in hypercholesterolaemic (B) are less evident in reverted rabbit (C). [Ganglion-cell layer (GCL); inner nuclear layer (INL); inner plexiform layer (IPL); inner limiting membrane (ILM); nerve-fibre layer (NFL); outer nuclear layer (ONL); outer plexiform layer (OPL); photoreceptor layer (RL)]. (Modified from Ramírez et al. [
The nutrition of the outer retina depends on the integrity of the choriocapillaris vessels and on the diffusion of plasma through the Bruch’s membrane-RPE complex. The alterations in the endothelium of the choriocapillaris and the build-up of lipids (hydrophobic barrier) detected in the Bruch’s membrane-RPE complex of hypercholesterolaemic rabbits [15] could interfere with oxygen and nutrient transportation, leading to an ischaemic state [30].
The conditions of hypoxia-ischaemia lead to higher glutamate levels in the extracellular fluid, and thereby could cause oxidative damage by excitotoxic mechanisms in the neurons [21,22]. In hypercholesterolaemic rabbits, neurosensory retinal changes were detected (Figure 5A,B) [15].
These changes were not uniformly distributed throughout the retina, being more intense in the retinal areas overlying the most altered RPE cells. In these areas, the photoreceptor discs were mostly absent. The thickness of the retinal layers (ONL, OPL, INL, IPL, GCL and NFL) were reduced (Figure 5B) and empty spaces were visible at different retinal levels that consisted of different stages of cell degeneration due to necrosis and apoptosis (Figure 6A,7A,B). In necrotic cells, the nucleoplasm, cytoplasm, and cytoplasmic organelles underwent progressive hydropic degeneration (swelling, vacuolization, and disappearance of specific ultrastructural features) (Figure 6A). The nuclear and cytoplasm membranes ruptured and released their contents into the intercellular space (Figure 6A). The remains were taken up and absorbed by neighbouring cells –essentially Müller cells (Figure 6A,7A) and astrocytes -, the latter only in the NFL. The apoptotic cells showed progressive condensation and shrinkage of the nucleoplasm and cytoplasm (Figure 7A,B). Cells in more advanced stages of apoptosis shed part of their substance, which was observed as dense inclusion bodies in neighbouring cells (Figure 6A,7A). The compact bodies appeared surrounded by or engulfed in Müller cells and astrocytes [15,158].
Changes found in the nuclear layers of the retina of hypercholesterolaemic rabbits resemble those described in human AMD [74]. As in human AMD, hypercholesterolaemic rabbits exhibited a loss of ganglion cells and had cell features of apoptosis and necrosis as well as electrodense inclusions (probably lipofuscin) in the cytoplasm of this cell type (Figure 7B). This ganglion-cell loss could be caused, at least partly, by a local disruption of cholesterol homeostasis [14]. A reduced population of ganglion cells could secondarily impair the neurotrophic support of the retinal neurons as a consequence of reduced secretion of brain-derived neurotrophic factor (BDNF) by ganglion cells. This scenario is feasible, given that amacrine cells express the TrkB receptor for BDNF [17] and that BDNF improves the survival of bipolar cells upon activation of the p75 receptor, which then induces the secretion of fibroblast growth factor b (bFGF) [167]. The situations described could contribute to the axon loss observed in hypercholesterolaemic rabbits [158]; this loss parallels human AMD, in which a considerable axonal degeneration has been reported [74].
In hypercholesterolaemic rabbits, the capillaries in the NFL and in the vitreous humour had a thickening of the basal membrane, dense bodies, and cytoplasm vacuoles (Figure 8A,B). These alterations have also been reported in hypercholesterolaemic rats [156].
In summary, the thickening of the basal membrane together with the alterations of the endothelial cells of the intraretinal and epiretinal capillaries, combined with the changes in Bruch’s membrane and the build-up of lipids in the outer retina, could contribute to a situation of chronic ischaemia observed in the retina of hypercholesterolaemic rabbits.
Ultrastructural retinal changes in outer nuclear layer and outer plexiform layer. A: Hypercholesterolaemic rabbit. Numerous dense bodies (black arrows) and empty spaces (*) are visible in these layers. The processes of Müller cells fill the empty spaces left by degenerated cells. Insert: at greater magnification the empty spaces consist of degenerated cytoplasm with numerous dense bodies (black arrow) and cell debris (black arrowhead). B: Reverted rabbit. Apoptosis (white arrows) and necrosis (black arrows) of photoreceptors are visible in the ONL. [Müller cells (M); inner nuclear layer (INL); inner plexiform layer (IPL); outer nuclear layer (ONL); outer plexiform layer (OPL)]. (Modified from Ramírez et al. [
Ultrastructural retinal changes in inner nuclear layer and ganglion-cell layer. A-B: Hypercholesterolaemic rabbit. A: Cells in apoptosis (white arrows) in the inner nuclear layer. Dense bodies (black arrows) inside the Müller cell processes. B: Apoptosis (white arrow) in the ganglion-cell layer. Cell debris (black arrowheads) and dense bodies (black arrow). [Müller cell (M); axon (ax); ganglion cell (GC)]. C-D: Reverted rabbit. C: Cell necrosis (black arrow) in the inner nuclear layer. D: Ganglion cell in advanced stage of necrosis. (Modified from Ramírez et al. [
Transmission electron microscopy of capillaries in the vitreous humour. A: Control rabbit. B: Hypercholesterolaemic rabbit. The basal membrane is thickened with respect the control. C: Reverted rabbit. The basal membrane is thicker than control and cholesterol animals. Necrotic features (arrowhead) are visible in some endothelial cells. [Basal membrane (bm); capillary (cap); endothelial cell (E); glial tuft (GT); pericyte (P); vitreous humour (V); dense bodies (black arrows); retina (R); vascular lumen (L); astrocyte (A)]. (Modified from Ramírez et al. [
An abnormal metabolism of lipids secondary to a cholesterol-enriched diet and/or apoE deficiencies could upset the cholesterol balance in the retinal layers, as mentioned above. However, it appears that other retinal components can produce heterogeneous particles locally containing apoE [13]. These particles are synthesised mainly by Müller cells, although astrocytes associated with ganglion cells axons could be involved in their production [13]. Müller cells are radially oriented cells that along their course, extend branches that interdigitate with every type of retinal neuron, with other types of glia (Figure 2A), and with the blood vessels of vascularized retinas [168]. Its participation in the cholesterol metabolism (supplying heterogeneous lipoprotein particles and apoE) and transport (due to its anatomical position in the retina) determines its importance as a source of the lipids needed by neurons for maintaining and restructuring their cell membranes [13,168].
Transmission electron microscopy of retinal astrocytes and Müller cells. A: Hypercholesterolaemic rabbit. Three nuclei of Müller cells displaced to the nerve-fibre layer. One of the Müller cells participates in the formation of the inner limiting membrane (white asterisk). Astrocytes in advanced stage of necrosis (black asterisk). B: Reverted rabbit. The empty spaces left by degenerated axons in the medullated nerve-fibre region are occupied only by the Müller cells in the retinal periphery. [Axon (ax); basal membrane of the ILM (bm); Müller cell (M); vitreous humour (V)]. (Modified from Ramírez et al. [
In situations of sustained hypercholesterolaemia, alterations of lipid metabolism could take place, potentially influencing the glial response. In fact, in hypercholesterolaemic rabbits Müller cells were reactive, exhibiting large amounts of rough endoplasmic reticulum and abundant glial filaments in their cytoplasm (Figure 9A), manifested by a more intense immunoreaction to GFAP (Figure 10H) [158]. Normally, GFAP is expressed at a low level or is not detectable in mammalian Müller cells (Figure 10G). In pathological situations, the major intermediate filament expressed by reactive Müller cells appears to be GFAP. The loss of retinal integrity as a result of mechanical injury, detachment, photoreceptor degeneration or glaucoma (Figure 2A) provokes intense GFAP immunoreactivity in Müller cells and increases the GFAP content of the retina [39,91,169-171]. This over-expression of GFAP is due to the activation of the transcriptional gene for GFAP in Müller cells [168]. Additionally, Müller cell reactivity transduces an increase in cell metabolism [168].
Another consequence of the reactivity of Müller cells is their capacity to form glial scars, most probably in an attempt to restore the blood-retinal barrier [172]. These scars, formed by hypertrophic cells in which the nuclei were displaced to the NFL, were detected in hypercholesterolaemic rabbits (Figure 9A). In addition, hypertrophic Müller cells occupied some of the empty spaces left by degenerated neurons in the INL, ONL, IPL, and NFL (Figure 6A) [15,158,173]. This type of cell response, which has also been described in human AMD [74] resembles that following photoceptor degeneration, which induces the processes of Müller cells to extend into and fill the empty spaces [168]. Another similarity between human AMD and experimental hypercholesterolaemia are the ultrastructural changes affecting the outer and inner retina. In both instances, the bodies of Müller cells are displaced from the INL to the vitreous in the case of human AMD [74] and to the NFL and ILM in hypercholesterolaemic rabbits [15,158]. It is possible that in both situations Müller cells migrate in an attempt to reach the metabolic reserve in the vitreous. This could be an adaptive system for transporting nutrients and energy substrates to those areas of the retina exposed to the chronic ischaemic insult.
Like Müller cells, astrocytes are related to apoE secretion [174,175], making these cells susceptible to alteration in long-term hypercholesterolaemia. Müller cells and astrocytes are intermediate between neurons and vessels; they are located on the basal membrane of capillaries separating them from neurons [37,82,95,168]. The thickening of the basal membrane and the presence of dense bodies and vacuoles in the endothelial cytoplasm of the retinal blood vessel in hypercholesterolaemic rabbits (Figure 8A) [15] could indicate impaired transport of oxygen and nutrients to the retinal tissue as well as the removal of cellular debris, thus contributing to a situation of chronic ischaemia [20] in the inner retina. It is known that astrocytes protect neurons from ischaemia by different mechanisms: they remove excitotoxic neurotransmitters and ions from the perineural space, doing so partly by glutamine synthetase, which also provides glutamine to neurons ([176,177]. In addition, astrocytes store glycogen, have the potential to provide lactate, and produce growth factors as well as cytokines [23]. Moreover, it has been shown that astrocytes are more resistant to oxidative damage because they possess antioxidant mechanisms such as high concentrations of reduced glutathione and vitamin C [21]. Therefore, a reduction in the protective function of astrocytes could contribute to neural dysfunction.
Differences between rabbit and human retinas and astrocytes must be taken into account when comparing the two species [38,41,42,82]. The rabbit retina has epiretinal vascularization and possesses perivascular astrocytes which are absent in humans. However, in both species, astrocytes are located at the NFL and GCL. The rabbit retina had two main groups of astrocytes: astrocytes associated with the nerve-fibre bundles (Figure 10A) and perivascular astrocytes (type I and type II) (Figure 10A,D), associated with the vitreous blood vessels [40].
As mentioned above, astrocytes are essential for the maintenance of neural homeostasis, and their susceptibility to alteration in long-term hypercholesterolaemia has been reported [15]. Thus, in hypercholesterolaemic rabbits, all retinal types of astrocytes were reactive, having large amounts of rough endoplasmic reticulum and upregulation of GFAP immunoreactivity (Figure 10B,E,H). The altered lipid homeostasis, in conjunction with increased astrocyte activity, could explain the build-up of electrodense particles, probably lipofuscin and lipids, found in their cytoplasm. The exposure of these electrodense particles to light and high oxygen concentrations provide ideal conditions for the formation of reactive oxygen species that damage cellular proteins and lipid membranes [178], a situation that could impair the mechanism of protection from ischaemia. If we add to this the higher concentrations of extracellular toxic substances (e.g. glutamate) which could damage the neurons by cytotoxic mechanisms [21,22], the possibilities of keeping the cellular machinery intact against ischaemia diminish in favour of neuronal death. All the above-mentioned conditions could contribute to macroglial swelling and subsequent breakdown of intermediate filaments (loss of GFAP staining) and ultimately macroglial death [23]. In fact, hypercholesterolaemic rabbits showed apoptosis and necrosis affecting Müller cells and astrocytes (Figure 7B,9A), resulting in a statistically significant loss of all types of astrocytes in comparison with control animals (Figure 10A,B,\n\t\t\t\t11) [15].
In summary, long-term hypercholesterolaemia lowers the astrocyte number and their antioxidant activity as well as the capability to remove glutamate from the extracellular space; it may also contribute to neuronal dysfunction [15,158]. The reactivation and migration of retinal Müller cells may be reflecting an adaptive system to supply nutrients to those areas of the retina exposed to the chronic ischaemia generated by the hyperlipidaemia.
It has been established that the atherosclerotic lesions can undergo regression in experimental animals such as rabbits, dogs, and non-human primates [179]; and the lack of progression or even regression can occur in humans, especially with the introduction of new therapeutic options [180].
Animal models are useful for studying lesion regression after the normalization of cholesterol serum values. When high levels of cholesterol are withdrawn from the diet, rabbits recover some of the biochemical and histological parameters altered in cholesterol-fed animals [16,181]. Serum concentration of total cholesterol, triglycerides, phospholipids, VLDL, HDL, LDL, and intermediate-density lipoprotein (IDL) have reported to increase in rabbits fed with a 0.5% cholesterol-enriched diet for eight months. When the same animals are then fed a standard diet for another 6 months, (reverted rabbits), lipid values returned to normal [158]. Notably, the normalization of serum values was not followed by a complete recovery of the thoracic aorta, choroid [16], or histology of the retina (Figure 5C) [158]. Specifically, in reverted rabbits, Bruch’s membrane (Figure 3C) and RPE alterations (Figure 4C) were still present although to a lesser extent than in hypercholesterolaemic animals (Figure 3B,\n\t\t\t\t4B). Bruch’s membrane was thicker in some areas due to collagenous and electrodense material in the outer collagenous layer (Figure 3C). This contrasted with the observations in hypercholesterolaemic rabbits in which the thicker Bruch’s membrane resulted from the build-up of electrodense and electrolucent particles, mainly at the inner collagenous layer (Figure 3B) [15]. The cytoplasm of RPE cells contained a considerably lower quantity of lipids in reverted animals (Figure 4C), although in some instances the lamellar structures (the plasma membrane of basal infolding back on itself) described in hypercholesterolaemic rabbits were also seen. This partial structural recovery could improve the diffusion of nutrients from the choriocapillaris and removal of cell debris from RPE, thus exerting a possible effect on the retina. However, reverted rabbits retained features observed in hypercholesterolaemic animals, such as an apparent decrease in retinal thickening (Figure 5C), intense cell degeneration due to necrosis and apoptosis in the ONL, INL, and GCL and axonal degeneration at the NFL (Figure 6B, 7CD). The empty spaces following neuronal death observed in hypercholesterolaemic animals were occupied by Müller cells (in OPL, IPL, NFL) and by astrocytes (in NFL) in reverted rabbits (Figure 6A) [158].
It bears mentioning that the retinal vessel in reverted rabbits showed greater damage than in hypercholesterolaemic animals such as: thickening of the basal membrane with numerous dense bodies, necrosis of endothelial cells, hypertrophy of the muscle layer, and increase in the collagen tissue of the adventitia (Figure 8C) [158]. The maintenance of retinal damage observed in reverted animals could be at least partly due to the greater alterations of retinal vessels and the persistence of the choriocapillaris alterations [16]. The vascular retinal alterations, which extended from the endothelium to the adventitia, could contribute to sustain an ischaemic situation despite the diet-induced normalization of lipid levels. Another factor that could contribute to the maintenance of retinal damage would be the role of Müller cells in neuronal swelling and apoptosis. During ischaemia, over-excitation of ionotropic glutamate receptors not only leads to neuron depolarization, which causes excess Ca2+ influx into the cells, but also activates the apoptosis machinery. The ion fluxes in the retinal neurons, associated with water movements that are mediated by aquaporin-4 water channels expressed by Müller cells, can result in neuronal swelling [182]. Thus, during ischaemic episodes in the rabbit retina, the plexiform layers and the cytoplasm of neurons become oedematous.
In summary, normalization of the lipid level is not followed by a complete normalization of the retinal histology. The remaining changes in the retina are due mainly to the sustained chronic ischaemia caused by the alterations in the retinal vessel, Bruch’s membrane, and RPE. Such ischaemic situations exert a detrimental impact on the neurons of the different layers of the retina.
As described for the Bruch’s membrane-retinal complex, the normalization of the blood-lipid levels by the substitution of 8 months of a hypercholesterolaemic diet by 6 months of a standard one, do not reverse the changes in the retinal macroglial population of hypercholesterolaemic rabbits [158].
In reverted animals, Müller cells were hypertrophic and filled up the empty spaces left by degenerated neurons and axons (Figure 9B). This hypertrophy could be due to the osmotic swelling of Müller cells. A significant correlation between Müller cell hypertrophy and the extent of osmotic Müller cell swelling has been reported in rat retina during retinal inflammation, suggesting that the alterations of swelling properties is characteristic of Müller cell gliosis [183]. It has also been proposed that Müller cell swelling in the post-ischaemic retina is caused by inflammatory mediators, due to the activation of phospholipase A2 by osmotic stress [182]. In both hypercholesterolaemic and reverted rabbits, the hyperlipaemic diet could have caused an imbalance in long-chain polyunsaturated fatty acids (in the neural retina, these are present mainly in the phospholipids of the cell membranes [53]) which could prompt an increase in inflammatory elements such as reactive oxygen species from macrophages, TNF-α, IL-1β, IL-6, Natural Killer, cytotoxic T lymphocyte activation, and lymphocyte proliferation [51]. Therefore, ischaemic and inflammatory processes could trigger Müller cell hypereactivity in hypercholesterolaemic animals and reverted rabbits and provoke the hypertrophy and swelling of this cell type.
The astrocytes of reverted rabbits displayed changes with respect to hypercholesterolaemic animals. The area occupied by the astrocytes associated with the nerve-fibre bundles was significantly lower than in the hypercholesterolaemic group (Figure 10H,I,11). With respect PVA (perivascular astrocytes), a striking feature was the absence of type I PVA, thus the intense GFAP immunoreactivity found in the retinal blood vessels was due mainly to type II PVA (Figure 10C,F). The processes of these cells formed a network similar to that exhibited by the type I PVA of the normal rabbits [158]. The maintenance of the area occupied by the PVA in reverted animals (Figure 11) could be due to the hyperplasia of type II PVA as an attempt to compensate for the loss of type I PVA (Figure 10C,F). This cell proliferation is presumably a response to the sustained retinal ischaemia undergone by reverted rabbits despite of normalization of cholesterol levels. Type II PVA of reverted animals were reactive, hypertrophic, and had an enlargement of their cell bodies and processes (Figure 10F) [158]. These features plus the above-mentioned hyperplasia are typical changes of glial cells in response to nerve damage [184].
The specific function of reactive gliosis is unknown. It has been reported that glial cells undergoing reactive gliosis up-regulate the production of cytokines and neurotrophic factors which may be crucial for the viability of injured neurons [168]. Additionally, it is presumed that reactive gliosis is involved in phagocytosis of debris and in restoring breaches in the blood-brain barrier by scar formation [185]. Müller cells and astrocytes from hypercholesterolaemic and reverted rabbits had cell debris in their cytoplasm [158]. It has been reported that astrocytes [186] as well as Müller cells [187] can exert phagocytic functions and that the microglia (the main phagocytic cell of the nervous system) intervene only when the build-up of debris in the nervous tissue is abundant [188]. Phagocytosis of exogenous particles, cell debris, and hemorrhagic products may be an important scavenging function of Müller cells [168]. It has been suggested that the phagocytic process of these cells is similar to that associated with macrophages and that in addition they can function as antigen-presenting cells [39,168].
From the above, it can be concluded that the substitution of a hyperlipaemic diet by a standard one in an experimental rabbit model normalizes the blood-lipid levels. However, the progressive and irreversible chronic retinal ischaemia secondary to cholesterol-induced changes in the choroid [16,147] as well as the retinal blood vessels trigger a sustained reactive gliosis that could be exerting neurotrophic, phagocytic or immune-related functions among others.
Immunohistochemistry anti-GFAP in rabbit retinal whole-mount. A-C: Type I perivascular astrocytes (PVA). D-F: Type II PVA. G-I: Astrocytes associated with the nerve-fibre bundles (AANFB). A, D, G: Control rabbits. B, E, H: Hypercholesterolaemic rabbits. C, F, I: Reverted rabbits. A-C: In hypercholesterolaemic animals Type I PVA have a higher GFAP+ immunoreactivity than in control animals; these cells are absent from many retinal vessels. In reverted animals a striking feature is the absence of type I PVA. D-F: In hypercholesterolaemic animals Type II PVA have higher GFAP immunoreactivity, robust cell bodies and thicker processes than in control. In reverted animals the intense GFAP+ cells are morphologically similar to the reactive type II PVA of hypercholesterolaemic animals. G-I: In hypercholesterolaemic and reverted animals the AANFB show high GFAP+ immunoreactivity, robust cell bodies, and thick processes. [Astrocytes cell bodies (arrow); vessel free of type I PVA ( arrowhead); GFAP immunorectivity of Müller cells (empty arrow)]. (Modified from Ramírez et al. [
Area occupied by astrocytes per zone measured (0.1899mm2) in Control, hypercholesterolaemic, and reverted animals. (Modified from Ramírez et al. [
Hypercholesterolaemia is a risk factor for the development of chronic ischaemia in the retina and therefore for neuronal survival [15,158]. It is now recognized that lipids play a key role as structural and signalling molecules. Given that lipid intake is most dependent on food composition, the dietary regimen could contribute to induction or prevention of retinal diseases. In relation to this, a pertinent question would be whether or not the normalization of the plasma-cholesterol levels could restore the retinal changes that take place during hypercholesterolaemia and reverse the chronic ischaemia process generated by this situation. The answer to this question seems to be no, since, although it is true that the lipid accumulations in the choroid and Bruchs’ membrane are reduced with the normalization of the blood-lipid level, some structural changes do not reverse [16,158], implying an irreversibly chronic situation and very probably progressive ischaemia in retina.
The authors would like to thank David Nesbitt for correcting the English version of this work. This work was supported by RETICs Patología Ocular del Envejecimiento, Calidad Visual y Calidad de Vida (Grant ISCIII RD07/0062/0000, Spanish Ministry of Science and Innovation); Fundación Mutua Madrileña (Grant 4131173); BSCH-UCM GR35/10-A Programa de Grupos de Investigación Santander-UCM. Beatriz Gallego is currently supported by a predoctoral fellowship from the Universidad Complutense de Madrid.
Vision-based SLAM systems are much appreciated nowadays in a broad spectrum of applications in robotics, autonomous navigation, and guidance systems, in airborne, underwater, and terrestrial environments [1, 2, 3, 4]. A global comparison shows that SLAM applications underwater are less abundant (see some state-of-the-art works) [5, 6, 7, 8, 9, 10].
In particular, underwater navigation generally excludes any form of global positioning system such as in other environments, so vision is a sound alternative, provided visibility is good enough. On the other hand, in turbid waters it is possible, to some extent, to navigate at low altitude on the seabed. However, in these extreme cases, the texture of the seabed may appear voluminous, which implies visual occlusions and collision probabilities. Conversely, shallow waters, rapid changes in the natural illumination, for example, due to the sunlight caustic on the floor, shadows, and flashes, can seriously damage the photometric properties of the images. In such extreme cases, the estimation of the vehicle position can be so impaired with the possibility of vehicle loss.
These characteristics of the underwater environment pose major challenges to the success of navigation, especially if it takes place in unknown regions. These challenges relate not only to robust estimations of the vehicle position and surrounding cartography [11] but also to the ability of the guidance system to avoid possible collisions at low altitudes.
In this work we will present an approach for the autonomous exploration of unknown regions of the seabed by means of a navigating system connected to a decision-making process hosted in the submarine. This vision-based approach is called Corridor SLAM (C-SLAM), because it combines SLAM techniques with a strategy to build a corridor over the seabed. The original concept was described in [12]. This document presents a generalization of previous work centered on a robust network of corridors. A variant of the basic concept uses active SLAM for exploring and building a grid map (see recent works [13, 14, 15]), but they do not enclose in any way the concept of path optimality as here, which proposes continuous paths with viewpoints associated.
A relatively close idea to the concept of corridor can be found in the “teach and repeat” method, [16], to follow a path in unfamiliar outdoor environment, such as in the exploration on the surface of Mars by a rover. However, the basic method does not include an autonomous exploration, as the first path construction is given remotely by a human operator with the aid of a camera at the rover front. Once an a priori feasible path has been defined, the vehicle can “repeat” the path that was previously “learned.”
The main objective of our approach is to make the right decisions to build robust pathways to explore and configure them in a network. At the same time, the system is able to bring the vehicle back to the starting point from any position in the explored area. The robustness properties of the network are conceived in the sense that there are preferential directions to explore and are such that one allows a successful return.
Figure 1 illustrates the complete structure of the proposal for an autonomous vision-based system. It consists of three nested feedback loops, called adaptive control loop, reference adjustment loop, and dense mapping loop. They are described in details below.
C-SLAM structure. Three-loop-based approach to underwater exploration.
The adaptive control loop generates the control actions
In the adaptive control loop feedback, there is the vision system that basically takes images of the seabed with the vehicle in motion to estimate the position
The reference adjustment loop has the function of reformulating the references
The outer loop of the C-SLAM, namely, the dense mapping loop, is dedicated to the construction of the corridor network, providing alternatives for bifurcating the path during the exploration. The feedback consists of the navigation system, a block for estimating a dense mapping
A typical navigation route consists in part of stretches between relevant points or landmarks. For example, a stretch that links a starting point with a bifurcation point, or one that covers an entire branch, or one between a bifurcation point and a point of no return. During the exploration, the path is created step by step, in which the vehicle direction is regularly changed towards preferential points that should ensure the continuity of the future path.
According to the main objectives of the exploration, C-SLAM should allow a successful return of the vehicle to the starting point from any distant point of the network. The farthest points are called no-return points. In this case, it is assumed that when the vehicle reaches a point of no return, it possesses at least half of its energy autonomy [25, 26, 27]. It is therefore that C-SLAM must permanently estimate points of no return and also ensure that there exists at least one way for the comeback before losing the energy autonomy.
The network of submarine corridors is the composition of interconnected strips on the seabed, which covers a certain explored region and allows navigation between different points of it. Topographically the strips are sequences of recognizable sites on
A node is characterized by a cluster of seabed characteristics. It has a position and a viewpoint associated with the local characteristics. These characteristics are represented by keypoints of the local scene. The position of the cluster is determined by its centroid.
In the exploration, C-SLAM has to decide at each moment the next step of movement that starts from the current node. Each step consists of the identification of the next node, the direction of its centroid, and the speed of navigation to bridge the gap between nodes. The detection and identification of a node is a process that can involve many steps, during which a node is tracked and classified among other nodes in a merit order list.
In order to choose a suitable node among many possible ones, the vision system evaluates the most outstanding characteristics of the scene and then decides the optimal direction towards the corresponding node. The optimization of this direction results from the maximization of a cost function of the quantifiable requirements. Similarly, the rate is properly determined based on a previously specified vehicle cruising speed. Thus, the speed can be regulated to go up and down according to the curvature of the path. This construction procedure is repeated in the next step permanently during the exploration.
Cluster tracking involves localization on both a scattered local map and a dense map. The estimation of distances between nodes of any network branch is decisive for the planning of revisits according to the available margins of autonomy of the vehicle.
It is worth noting that estimated distances on the maps are simply evaluated on the particular scale of the monocular SLAM method, which does not necessarily coincide with the actual scale. This would not represent an obstacle to C-SLAM as long as the estimated distance between the starting point and any point of no return on the network is exactly related to half the energy autonomy of the vehicle. Some approaches define another type of scaled topology, achieved by means of stereo vision or scanner [8, 10, 27].
Bifurcation points are commonly distributed along each branch. There are two different sets of bifurcation points. The first set includes divergent points at which the paths physically bifurcate. The second set covers the so-called open bifurcation points, which were identified and ranked in a list of suitable landmarks for a future deviation of the path. The ranking position is issued in accordance to a criterion of robustness.
While each new corridor is simply added to the network as a new branch, existing corridors are updated in each new revisiting. Each round trip implies that the vehicle starts with plenty of energy autonomy. This indicates the dimensions of the explored region. Clearly, with the deployment of multi-robots, the scan will be faster [28, 29] but will not necessarily cover a larger region than with this proposal.
Since the camera is monocular, safe return is practically implemented by guiding the vehicle in reverse. This is because the system might not identify all the nodes in the 3D landscape in the way back, i.e., when navigating from the opposite direction. However, with the camera in reverse, the system is able to recognize the seabed features on the path straightforwardly. In reverse motion, all nodes are revisited but from back to front.
Before starting a round trip in the network of corridors, C-SLAM must make the decision to advance the exploration or revisit explored branches of the network. Commonly, both decisions are involved with the intent to expand the explored region. In addition, the system defines a suitable ground altitude for navigation with the end of achieving good visibility conditions.
For the next discussion, Figure 2 is taken as support.
Round trip during exploration (left). Corridor network topology (right).
The first corridor and each new section of the corridor network are constructed according to an optimum criterion. This criterion takes into account the most outstanding characteristics of the seabed in the form of keypoints (shortened KP), which can be categorically recognized over time and preferably from different points of view.
Autonomous navigation begins with a commissioning phase (CP) to adjust the controller and initialize SLAM techniques for scattered and dense mapping. To achieve these objectives, the vehicle is forced to travel fast short distances, zigzagging over the bottom with a rather erratic course. In this way, images can reflect the changes in texture and parallax that are necessary for a visual odometry. This, in turn, produces a stable estimation of the vehicle localization at the beginning of the exploration.
Once odometric data
Figure 2 (left) illustrates the construction of a corridor path from SP up to an end point (shortened EP), for instance, the estimated no-return point. The system analyzes the texture characteristics in the image sequence in order to detect robust clusters (C). Once they are recognized, the system tracks them as they pass in front of the camera. With a set of robust clusters, the system is able to triangulate frame by frame the pose of the camera.
Usually, raw information for robust cluster detection is provided by the feature-based SLAM method employed in the vision system. Certainly, for self-localization, the SLAM method constantly defines keyframes (KF) with the most stable keypoints in the image, i.e., with those that have been followed up so far. Thus, C-SLAM has to group the robust keypoints in clusters and finally perform an evaluation of cluster set. In this way, C-SLAM can define nodes (N) and eventually bifurcation points (BP).
The topology of the corridor network usually contains a diversity of elements that are described in Figure 2 (right), shortened SP, EP, KP, KF, C, N, LM, and BP. Additionally there are trifurcation points (TF) which are created from BPs: confluence points (CO) that occur between two paths that meet at a point; outer points (OP) which are detected landmarks or nodes but due to energy reasons are unreachable; dead-end points (DP) at which the vehicle must turn by force due to the absence of Ns or LMs in the horizon; and, finally, crosspoints (CR) at which a path crosses another path and these can or cannot be detected by the vision system.
It can frequently happen that, due to the existence of COs and CRs, many possible path alternatives are established to return from any point or to join two distant points in the network. Loops can also be generated during the expansion (see Figure 2, right).
As mentioned previously, the topological space is subject to an unknown and variable cartographic scale that produces accumulative odometric errors. This means that corridors can cross others without this being reflected in the global map. However, this does not invalidate the objective of C-SLAM, to return safely to SP.
It is expected that after reiterated revisits along different corridors, the number of loop closures carried out by the basic SLAM method will increase and the network will progressively take on a more real form. Simultaneously, the scale of the map will become more uniform, and the used metric will increasingly gain in accuracy.
The construction of the network is mainly based on a criterion to define a metric in the topological space. This is discussed below.
C-SLAM sets up a node to accurately synchronize future movement steps. For example, the direction to which the vehicle is to be driven in the short term in order to reach the next node is precisely defined at the current node. In addition, the speed of the vehicle on this direction is also defined here. All this gives the reference position
When C-SLAM decides to expand the network with a new branch, it searches for a landmark in the current corridor and then deflects the path in the indicated direction.
Nodes and landmarks are gestated in a common optimization process. Optimization involves maximization of a cost function with one optimum and many suboptimal results. The optimum outcome defines the first place in a ranking list, followed orderly by the suboptimal outcomes. Nodes and landmarks are selected from this ranking list.
The direction that defines
Unlike a node whose next direction is defined in each step, a landmark can demand many steps. A landmark is a node whose high position on the merit list ranks it for a successful future branching. Therefore, not all the nodes become landmarks.
Finally, there is a subtle difference between a node and a keyframe generated from any SLAM technique. A node is the most robust cluster in the current keyframe, and in general its appearance frequency is generally lower than the frequency of a keyframe.
During exploration, keyframes are the basis for selecting nodes. For every few keyframes of the sequence generated by the active SLAM algorithm, C-SLAM chooses the current keyframe and defines a node. The frequency of the node appearance depends physically on the visibility conditions and is commonly fixed in the commissioning phase.
On the other side, the selection of a path direction from the current node to navigate to the next (yet not defined) node follows a particular criterion. Also the selection of a promissory landmark for a future bifurcation is subject to the same criterion.
It is assumed that many keypoint clusters are faced at the same time in the ranking process in order to establish an order of merit. When the score of a particular cluster exceeds a threshold value, it is then considered as a potential landmark. Clearly, many clusters remain in the vision field for a time, so that they may continuously be tracked during their latency periods. Some of them will become landmarks.
After a landmark is lost in the field of vision, it will remain inactive with its last score and its location on the map. While in the exploration phase landmarks are generated, in a revisiting period they are consolidated, or even separated. Eventually, a landmark becomes a bifurcation point when C-SLAM decides to branch out to explore new regions.
The proposed criterion is based on a cost that is defined as a linear combination of quantifiable requirements to be met by each cluster in its latency period. Thus
where
High density of keypoints in a cluster: factor
Continuous traceability of a cluster: period
Robustness against the change of points of view: span angle Δ
Alignment of a cluster on the heading direction: factor
The cost weights will be defined previously according to the emphasis placed on some particular aspects of robust navigation. Since all requirement variables will be normalized to their expected highest values, a trivial choice
Since some detected landmarks are far away from the vehicle position, one should check whether these will be attainable with the current autonomy range of the vehicle. If they are unreachable, they will be removed from the ranking list or marked as OPs. To this goal a metric is required for the topological space of the corridor network.
The key assumption to calculate the first parameter
where
Since the set of selected robust keypoints in the SLAM algorithm is generally sparse, clustering operation should not be excessively time-consuming.
Statistically, the maximum expected number of
The second parameter is related to the traceability of
where
Finally, the maximum number of consecutive keyframes depends to some extent on vehicle speed, altitude, camera tilt, and field of vision, among other factors. As a reference for
The third parameter
where the symbol span
A large value of
The maximal span of
The fourth parameter
Therefore, in the case of nodes,
Since the cost (Eq. (1)) contains terms that must be maximized,
Hence, it results in geometric mean
where
The inclusion of a cluster
where
If
When a new node is created, C-SLAM immediately evaluates the next most promising direction to lead the vehicle into the unknown environment with the goal of exploration. Therefore, the highest score refers to the cluster with which the reference path
In addition, C-SLAM checks whether the second highest score corresponds to an active cluster and in which case decides to set a landmark. Another more cautious strategy is to set a landmark when the second highest cluster just disappears from the list.
Landmarks can be also consolidated in the return and in every passage on any explored corridor. On the other side, the landmark cost may decrease so much that it is to be removed from the list. In this way, landmarks are permanently evaluated up to the moment they are employed to bifurcate into the corridor. At this moment, they change their status from LM to BP and disappear from the list forever.
In a changing environment, the adaptation of Ns, LMs, and BPs after a long period is necessary. This allows a renewal of the corridor network as needed (cf. [7, 30]).
During assiduous navigation, the topology of the network is outlined like a tree of branches. Each branch contains its identification in the tree, the sequence of nodes arranged in one direction, the landmarks, the bifurcation points, and any other particular element that should be important for decision-making.
Extending the boundaries of the corridor network requires C-SLAM to implement certain policy-makings, which goes beyond the corridor network building.
A first policy implies the definition of an appropriate metric to extend the lengths of the corridor network as much as possible according to the available energy autonomy.
A second policy supports the decision-making to choose bifurcations in order to multiply the number of branches. In this case, revisitings are of secondary importance as they take place only when they are needed as bridges to create new branches.
A third and final policy concerns the optimal scheduling of paths between two points of the network. In a situation with many alternatives to get a connection between sites, the system will search for the one with the best energy efficiency.
The metric space represented by the corridor network depends on an unknown scale which also changes over time due to cumulative odometric errors. This will affect, above all, the global map, which is the composition of many local maps with their own scale. As scale variations are generally small from map to map, the metrics are similar.
In order to maximize the length of a corridor without compromising the safety of the way back, it is essential to have a reliable metric. Since safety and energy autonomy are closely related, the metric must express the energy margin that the vehicle possesses at any time and position in the network (cf. [24, 25]).
It is clear that due to the challenging environment, the energy used to connect two points is often not the same in both directions. This will undoubtedly depend on sea currents, vehicle speed changes, travel breaks, and zigzagging on the reference route. Thus, for example, real-time detection of the no-return points based on the battery state of charge may not be reliable enough in unforeseeable circumstances. For this reason, a more powerful detection of no-return points is developed here on an empirical basis.
To this end, a function for the estimation of the energy margin is proposed. It adds up the energy consumption until the full autonomy is completed. The function can be evaluated at any time, especially in the decision to return.
The idea behind the proposal is that almost all the energy available in navigation is intended to move the vehicle. Therefore, an approach that is based solely on the energy of motion along the travelled path seems to be quite rational.
The first one defines the consumption of energy as a set of possible cases:
where
Energy margin to reach total energy consumption. Numerical identification of no-return points on different paths.
It should be noted that all routes cover each shape, both straight and curved ones.
Figure 3 shows numerical simulation results wherein the distance travelled by a vehicle over different paths is computed after accomplishing full autonomy. In the experiments the vehicle acquires a cruise velocity, but this is slightly changed around this value at random. The resulting ground truth statistics must be available before applying C-SLAM but are updated during the construction of the corridor network.
In order for C-SLAM to decide the time point for the comeback on a new corridor, a norm based on the average on the sets in Eqs. (8) and (9) is applied. The Euclidean norm can be used to obtain the energy limits called
subject to the conditions for safe navigating on the path
where the equality of either of the two equations will mean the identification of the end point EPi for this path.
and so the conditions for the detection of a no-return point are as follows:
where again the equality of either of the two equations will mean the identification of the end point EPi for this path
In order to continuously adapt the norm to the environment, the set (Eqs. (8) and (9)) must be updated on each round trip. It can be noticed that the update can be applied both in a new corridor and in a revisiting case as well, regardless of the path chosen.
The way in which C-SLAM progressively explores and increases branches can be supported by different criteria.
The first method is based on the criterion that for fast expansion of new branches, occurrences of revisitings of old branches should be reduced as much as possible. To this end, the number of revisited stretches in old branches and their distances to SP should be minimized during the sequence of round trips. Here, the rectification of the path
Figure 4, right and middle, illustrates a case study of an expanded network in two different forms.
Generation of BPs according to different criteria: the fastest branch expansion (left) and the slowest branch expansion (middle). Number of revisited stretches during network expansion: optimal expansion (red) and a suboptimal expansion (blue).
Once the trunk corridor is created, the proposed method starts from SP and searches for the closest LM and splits into a new branch until it culminates in an EP. At this stage, this LM becomes a BP. In doing so, the approach minimizes the length of all revisited stretches. Any other branch generation is suboptimal. The worst suboptimal generation, on the contrary, expands the network by starting each round trip from SP to the most distant LM. In fact, this option produces a maximization of the revisited stretches.
Even when the optimal branch generation expands the network faster than other options, all methods end up with the same number of revisited stretches. This fact is reflected in Figure 4 (right). Therefore, from the point of view of the total energy consumed, the difference is short and medium term only.
The optimal solution described above has a theoretical rather than a practical value. The disadvantage of method I is that the way BPs are used has no connection with the merit order list. For that reason, vehicle safety might be compromised. When making decisions about where to branch, trust in the list is the only support for secure expansion.
Therefore, the main focus of the second method is to build up a solid network in which the path from every EPi to SP maximizes the trust on the BPs on the pathway. This means that the LMs chosen for bifurcation have the maximal score on this pathway. The number of revisited stretches over time is described by a curve that lies between the two extreme curves in Figure 4 (right). This means that in the long term, the new curve will also converge to the same extreme value.
Many other strategies can be applied besides the other two methods. For instance, one could be specifically interested in developing the branches to the left (or to the right) of the trunk line or in creating a solid statistic for the newly explored branch before continuing with the exploration.
Starting from the conception of a fully interconnected corridor network, multiple alternatives can be considered to obtain a connection between two distant points of the network (see, for example, in Figure 3, right, the bypass shaped by the points BP-CO and BP-TP-CO). In such situations, C-SLAM should be able to seek that path that involves the best energy efficiency. For that purpose C-SLAM must count with odometric information of each stretch and the energy consumption cost per unit of length.
Once the network has converged in its expansion and especially after a large number of revisits, it is common to count with the presence of bypasses and loops. Thereupon these elements will become part of the topology of the network.
In the case of one-way corridors, the existence of a bypass can only occur in the presence of COs or CRs (see Figure 5, left). On the other hand, the generation of a loop needs indefectibly at least one CR (see Figure 5, right). It is worth noticing that a loop represents a dummy alternative to connect a point with oneself through the loop as illustrated in Figure 5 (right).
Bypass (left) and loop (right) in the network topology.
As topological elements of the network, loops are marked to avoid unnecessary energy consumption. For example, in Figure 5 (right) when a loop is encountered, the path entering the loop is avoided unless the destination is a BP allowing exit from the loop. For the optimization of paths, the criterion consists in searching for the shortest path between two points or for the path that minimizes the energy consumption, or a combination of both. If safety aspects are emphasized, the energy approach is the most suitable for C-SLAM. This option is described in the following.
To find the optimal path, the following cost functional is minimized for a path starting at node
where
To assist Eq. (16), the A* search algorithm has been chosen in this work over other tree search algorithms because of its optimal efficiency [31]. Therefore, the cost is
where
The heuristic function
This section shows some experimental results which are selected to illustrate the viability of the proposal for autonomous navigation based on the proposal. Many of the functions of the approach are tested together according to the C-SLAM structure in Figure 1. It is important to note that the case studies are carried out in limited spaces with simulation of light effects and seabed textures. However, the staged environment
In order to provide a ground truth for testing and to achieve acceptable reproducibility of results, many scenarios were set up in a basin with a staged underwater landscape that closely resembled the natural seabed. In this scenario, rocks, gravel, sandbanks, and benthos, among others, predominated wherein a variety of underwater visual effects could be obtained [19, 23] (see Figure 6).
Stage installations for tests underwater. Diversity of scenarios.
The bioactivity of microorganisms was cyclically changing the characteristics of soil texture and water transparency. The scenarios were illuminated by direct and indirect sunlight. However, light disturbances and turbidity were controlled for the range of tests. For instance, strong or weak sunlight flickers on the ground were generated by agitating the water in two orthogonal directions. In addition, visibility was reduced by discharging silt particles onto the surface that remained suspended for a period of time.
Therefore, a wide variety of case studies could be faithfully reproduced, such as rapid changes in luminance, transition from dark to bright scenarios, blurriness, lens flares, motion blur, self-similarities, glare, and bubbles (see Figure 6).
An ROV (model OpenROV v2.8) was used as the platform for the experiments, although this was hydrodynamically reformed with side fins to reduce the motion blur.
Two independent cameras were installed on board, a high-resolution, wide-angle vehicle camera (Genius f100) and a high-performance camera (GoPro Session H4). Both cameras are rolling shutter and operate at different frame rates. To attenuate undesired effects of the rolling shutter mechanism, especially in photometric-based algorithms, a high speed of 120 fps with an image size of 848 × 480 pixels was used for dense mapping, albeit off-line at the end of every round trip.
The vehicle was completely steered by C-SLAM that was programmed and installed in a notebook with GPGPU technology. The bi-directional flow of video and control signals was implemented via cable. The altitude was conveniently fixed in advance to adapt to the visibility of the environment. Altitude control was carried out independently of the adaptive controller by a PI controller. An adaptive speed-gradient controller [17] was used to self-adjust the controller coefficients for the main dynamics of the ROV.
Among other functions, C-SLAM uses state-of-the-art free software to localization and mapping. As shown in Figure 1, the block for feature-based SLAM was implemented with the algorithm ORB-SLAM [32]. On the other hand, the block for dense mapping was implemented with the photometric-based DSO-SLAM [33] and sometimes with LSD-SLAM [34, 35]. However, there was a significant modification in the implementation, namely, DSO (or LSD-SLAM) was supported with the estimated camera position provided by ORB. This was necessary in general for improving the stability of the mapping in very harsh environments, especially due to the presence of strong sunlight caustics or/and poor visibility [23]. The deflickering filter in this work is based on estimations of sunlight caustic fringes using a feedback of predicted images [20], which employs very high accuracy velocity estimation [36]. Software for guidance, control, and corridor construction was developed specially for C-SLAM.
One begins with Figure 7 which illustrates the role deflickering filter plays in the improvement of dense mapping in environments with strong sunlight caustics. Generally, spatiotemporal light changes affect the performance of photometric-based methods seriously. As seen in the heat maps, the camera depths are coherent with the physical environment. Thus, the photometric consistence is preserved after image deflickering.
Dense mapping in two cases after image deflickering. Images with sunlight caustics (left), deflickered images (center) [
The situation is totally different in the case of ORB-SLAM, where light disturbances do not affect ORB to the same degree as DSO (or LSD-SLAM) (see Figure 8). However, from several experiments, it was concluded that in turbid waters, robust texture features decrease substantially, although the overall performance of ORB does not degrade as much as in the case of DSO (see [8]). Therefore, the filtering of caustic sunlight waves can be omitted in the case of ORB, but not in the case of DSO (or LSD-SLAM). For this reason, the deflickering filter in the C-SLAM structure in Figure 1 is necessary only for dense mapping ends. Another conclusion was drawn from navigation in self-similar terrains staged in the basin like in the third picture to the right in Figure 8.
Selection of robust keypoints in three harsh environments: with strong sunlight caustics (left), low visibility (center), and self-similarities (right).
These terrains provide commonly numerous features in a similar cluster pattern, but ORB-SLAM often losses the track as it is unable to deal with nearby similarities.
An important instance at the beginning of C-SLAM navigation is the start-up phase for initializing SLAM algorithms and adaptive controller parameters. To this end, in the study, the vehicle movements were performed manually providing a zigzag path of the camera. Figure 9 illustrates the initial process of constituting a dense mapping of the environment with an adequate camera trajectory. From there, the start of the exploration was supplied with good estimates of vehicle position and speed, which in turn, allow the adaptive controller to adjust its coefficients.
Commissioning phase to initialize photometric dense mappings. Camera path on dense map (left), camera depth (top-right), and original frame (bottom-right).
Dense methods suffer, more than any other class, from odometric errors [8], which are minimized in the particular case of DSO through a very cumbersome and thorough camera calibration process. In these trials, the combination of direct methods for mapping with ORB-SLAM for tracking increases the accuracy of the global map of the corridor network, even in the case of normal rolling shutter cameras as used here. Figure 10 illustrates these results in one experiment with good textured floor.
Estimated camera path and dense map. Map and path (left), heat map of camera depth (top-right), and original frame (bottom-right).
The limited space and relatively short time span for the experiments prevented the use of an energy autonomy metric beyond the context of numerical computer simulations. In this sense, end points located sideways must be at a certain limited distance from the trunk corridor. The frequency of occurrence of nodes was synchronized with the keyframe generation according to the simple strategy, namely, “one keyframe, one node.” The direction to the next node was optimized primarily by the maximizing the density of cluster keypoints near the front line of vision to avoid zigzagging of the vehicle. In this way, branches could be extended to a relatively significant length.
An important feature of the monocular C-SLAM is the vehicle return through the corridor in reverse motion as seen in the display provided by ORB-SLAM by means of the symbol “
Corridor network construction with three branches (top). Camera-taken scenes at the corresponding SP, BPs, and EPs (bottom).
Construction of a corridor network. Path graph with localization of BPs, EPs, COs, and CRs (left). Node sequence in a sparse map (right).
Reverse movements often caused motion blur due to pulling and cable drag on the floor [37]. Besides, the drag of the ROV backside is much more pronounced than in the forward displacement. All this made it necessary to reduce the cruise velocity to minimize large heading perturbations that would cause track loss. In the following, two case studies illustrate the C-SLAM performance under these circumstances.
Figure 11 shows a corridor network that was constructed under the criterion of fast expansion of new branches, i.e., minimizing of revisits in short and medium terms. Here, three bifurcation points were implemented in four steps. First, the system creates the trunk corridor and returns to SP. Accordingly, in the next round trip, the vehicle is led to the nearest BP and forced to bifurcate to create the first branch, and thereafter it returns to SP again. This routine was repeated for the second and third BP.
It is notorious that the way back through the trunk corridor from the BP3 to the SP does not completely agree with the way out. However the position track was never lost, which demonstrates the robustness of the system against changes of points of views. The differences in trajectories were due to many causes, including control tracking errors, cable tugs, and drag disturbances [37].
The diversity of terrain texture shown in Figure 11 (bottom) and their impact in the performance and robustness of C-SLAM are noticeable. For instance, at BP1, the terrain is bulky, so the contrast is high and the keypoints are robust. On the other hand, in BP2 and BP3, the terrain was acquiring an increasingly self-similar appearance, and the keypoint clusters were becoming increasingly volatile. In some trips in reverse through this self-similar zone, the vehicle briefly lost its tracked position.
Figure 12 illustrates a more sophisticated experiment in which branches were allowed to occur on both sides of the trunk corridor. Over time, in addition to the formation of branches, confluence of paths and way crossings were also appearing. The picture on the left shows the network from above and the interconnection of nodes. On the other side, the picture on the right displays the network nodes and keypoints produced during the multiple round trips. It is observed that the density of keypoints is significantly higher in the right zone than in the left zone of the explored area. This is due to the marked self-similarity of the terrain that dispersed the keypoints over the terrain, while in the left zone, the bulky elements concentrate the keypoints around their peripheries.
The trunk corridor was long enough to encompass areas of different textures. Light disturbances were moderate; most of them transitions from dim to shining scenarios.
The sequence of the round trips can be followed by the order of occurrence of EPs and BPs. The strategy of expanding the network is the same as in the case before, i.e., create the trunk corridor, return to SP, annex a new branch, and begin a new round trip.
The most remarkable instance in this experiment occurred on a stretch in front of EP1, in the self-similar zone, where the C-SLAM briefly loses the vehicle location. Afterwards the vehicle was led in the direction of EP1 up to cross the trunk corridor. This CR was recognized by the system and aggregated to the network. From this point, the vehicle could return in reverse to a point that was also recognized by the system as a CO. Finally, after the sixth branch, C-SLAM completed the exploration by providing a global map of the corridor network.
This work deals with the autonomous navigation of underwater vehicles with the aim of achieving a broad exploration of the seabed. Unlike autonomous navigation systems in aerial, terrestrial, and space applications, for which the main source for localization is a GPS system, this approach basically uses only a monocular camera as sensor.
To establish the position of the vehicle, the proposed vision system takes advantage of the characteristics of texture of the seabed. Since underwater scenarios are generally very diverse and harsh due to water turbidity and light disturbances, vision-supported navigation poses a huge challenge for safe autonomous exploration. In particular, the lack of transparency in water forces the control system to lower the altitude to the seabed, which in turns demands a high degree of maneuverability to avoid collisions.
This work describes a vision-based system named C-SLAM that provides a nested loop structure to integrate control, guidance, navigation, and route planning systems into one. To explore the seabed, C-SLAM implements a strategy based on active SLAM. In contrast to many methods in the literature that employs topological models of the environment like feature graphs [13], Bayes tree [14], or grid maps [15], C-SLAM presents the environment as a network of interconnected corridors made up nodes and bifurcation points. It is claimed in this work that this simple topology is highly adequate and robust for harsh underwater environments with self-similarities, strong spatiotemporal light perturbations, and lack of water transparency [23].
Compared to other optimization techniques proposed for underwater applications such as random trees [38], particle swarming [36], octo-trees [39], level setting [40], and genetic background [41], among others, this proposal has a significant level of novelty. It radially searches in the field of vision for the optimal direction to explore. This direction is subject to satisfy quantifiable requirements for the navigation. The requirements are integrated in a weighted linear combination that is maximized step by step. This produces an active scoring list of promising points for selection of nodes and future bifurcation points providing adaptation to the environment and robustness of the node sequence.
The heuristic of the proposal have similitudes with the visual teach and repeat method for long-range autonomy [16]. Therein a pathway is created in an unfamiliar outdoor environment, at first by teleoperation and then followed by a rover. However, C-SLAM is essentially designed for autonomous exploration underwater and deals with a dense exploration in 2D. Besides, the submarine navigates basically on a plane over the seabed contemplating topographic features from above, not over the terrain. So, comparatively, C-SLAM has the advantage to choose the optimal route in order to be able to safely return to the start point. Another difference is that the C-SLAM can cope with the lack of map scale and odometric errors and even so ensure the vehicle return.
In order to expand the explored region as far as possible, a suitable metric in the non-scaled topological space is defined in relation to the vehicle energy autonomy. The key idea is to lead the vehicle by a corridor just up to the no-return point in order to make the return trip safe. In contrast to other approaches that solve the problem in a rather complex form, for instance, employing dynamic programming onto bathymetric and sea current maps [26, 27], C-SLAM proposes a statistic-based connection of odometric information and energy consumption.
The approach was experimentally tested in reduced-scale in a basin, wherein subaquatic environments with a good resemblance to a real seabed were staged. Experimental trials have demonstrated the feasibility of the approach in future applications where an autonomous underwater vehicle can host the C-SLAM vision system for large-scale underwater exploration. With the exception of extremely turbid environments, practically in all other cases, C-SLAM was able to make correct decisions to create and expand the underwater corridor network in a stable manner.
I thank E. Trabes for the valuable assistance in implementing the concepts and ideas elaborated in this work. I also thank J.L. Bustamante, J.L. Bonitatibus, G.D. Van Waarde, and L. Nuciari for their support in the experiments carried out at IADO. This work was financially supported by CONICET, CCT-Bahía Blanca, Argentine.
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",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
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\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
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\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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