Cellular characteristics of model β and α thalassemic RBC [18, 19, 20, 21, 22, 23, 24, 25, 26, 27].
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"71",leadTitle:null,fullTitle:"Image Fusion",title:"Image Fusion",subtitle:null,reviewType:"peer-reviewed",abstract:"Image fusion technology has successfully contributed to various fields such as medical diagnosis and navigation, surveillance systems, remote sensing, digital cameras, military applications, computer vision, etc. Image fusion aims to generate a fused single image which contains more precise reliable visualization of the objects than any source image of them. This book presents various recent advances in research and development in the field of image fusion. It has been created through the diligence and creativity of some of the most accomplished experts in various fields.",isbn:null,printIsbn:"978-953-307-679-9",pdfIsbn:"978-953-51-5512-6",doi:"10.5772/602",price:139,priceEur:155,priceUsd:179,slug:"image-fusion",numberOfPages:440,isOpenForSubmission:!1,isInWos:1,hash:null,bookSignature:"Osamu Ukimura",publishedDate:"January 12th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/71.jpg",numberOfDownloads:45458,numberOfWosCitations:49,numberOfCrossrefCitations:25,numberOfDimensionsCitations:60,hasAltmetrics:1,numberOfTotalCitations:134,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 12th 2010",dateEndSecondStepPublish:"June 9th 2010",dateEndThirdStepPublish:"October 14th 2010",dateEndFourthStepPublish:"November 13th 2010",dateEndFifthStepPublish:"January 12th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"18400",title:"Dr.",name:"Osamu",middleName:null,surname:"Ukimura",slug:"osamu-ukimura",fullName:"Osamu Ukimura",profilePictureURL:"https://mts.intechopen.com/storage/users/18400/images/1600_n.jpg",biography:"Osamu Ukimura, MD, PhD is an internationally recognized expert in image-guided surgery and diagnosis and minimally invasive therapy for prostate and kidney cancer. He is one of the world’s most experienced urologists in transrectal ultrasonography for diagnosis, staging, biopsy and management of prostate cancer. Dr. Ukimura pioneered augmented reality, image-fusion of 3-dimensional ultrasound with CT or MRI and 4-dimensional navigation technologies in the filed of urology. Dr. Ukimura also authored over 100 peer-reviewed publications and book chapters, and was awarded at multiple international medical meetings, and edited book entitled “Contemporary Interventional Ultrasonography in Urology”. Current position and title: Professor of Clinical Urology, Institute of Urology, University of Southern California/Norris Cancer Center, Los Angeles, USA and Dedicated Professor of Urology, Kyoto Prefectural University of Medicine, Kyoto Japan.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"544",title:"Image Processing",slug:"computer-and-information-science-computer-graphics-image-processing"}],chapters:[{id:"12981",title:"F-Transform Based Image Fusion",doi:"10.5772/14504",slug:"f-transform-based-image-fusion",totalDownloads:1609,totalCrossrefCites:7,totalDimensionsCites:13,signatures:"I. Perfilieva, M. Dankova, P. Hodakova and M. Vajgl",downloadPdfUrl:"/chapter/pdf-download/12981",previewPdfUrl:"/chapter/pdf-preview/12981",authors:[{id:"17962",title:"Dr.",name:"Irina",surname:"Perfilieva",slug:"irina-perfilieva",fullName:"Irina Perfilieva"},{id:"20478",title:"Dr.",name:"Martina",surname:"Dankova",slug:"martina-dankova",fullName:"Martina Dankova"},{id:"20479",title:"Ph.D.",name:"Marek",surname:"Vajgl",slug:"marek-vajgl",fullName:"Marek Vajgl"}],corrections:null},{id:"12982",title:"Image Enhancement and Image Hiding Based on Linear Image Fusion",doi:"10.5772/14331",slug:"image-enhancement-and-image-hiding-based-on-linear-image-fusion",totalDownloads:2442,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Cheng-Hsiung Hsieh and Qiangfu Zhao",downloadPdfUrl:"/chapter/pdf-download/12982",previewPdfUrl:"/chapter/pdf-preview/12982",authors:[{id:"17494",title:"Prof.",name:"Cheng-Hsiung",surname:"Hsieh",slug:"cheng-hsiung-hsieh",fullName:"Cheng-Hsiung Hsieh"},{id:"19638",title:"Prof.",name:"Qiangfu",surname:"Zhao",slug:"qiangfu-zhao",fullName:"Qiangfu Zhao"}],corrections:null},{id:"12983",title:"A Multi Views Approach for Remote Sensing Fusion Based on Spectral, Spatial and Temporal Information",doi:"10.5772/14748",slug:"a-multi-views-approach-for-remote-sensing-fusion-based-on-spectral-spatial-and-temporal-information",totalDownloads:2463,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Farah Imed Riadh",downloadPdfUrl:"/chapter/pdf-download/12983",previewPdfUrl:"/chapter/pdf-preview/12983",authors:[{id:"18665",title:"Prof.",name:"Farah",surname:"Imed Riadh",slug:"farah-imed-riadh",fullName:"Farah Imed Riadh"},{id:"20813",title:"Dr.",name:"Hemissi",surname:"Selim",slug:"hemissi-selim",fullName:"Hemissi Selim"}],corrections:null},{id:"12984",title:"Performance Evaluation of Image Fusion Methods",doi:"10.5772/14653",slug:"performance-evaluation-of-image-fusion-methods",totalDownloads:3857,totalCrossrefCites:2,totalDimensionsCites:2,signatures:"Vassilis Tsagaris, Nikos Fragoulis and Christos Theoharatos",downloadPdfUrl:"/chapter/pdf-download/12984",previewPdfUrl:"/chapter/pdf-preview/12984",authors:[{id:"17178",title:"Dr.",name:"Vassilis",surname:"Tsagaris",slug:"vassilis-tsagaris",fullName:"Vassilis Tsagaris"},{id:"24863",title:"Dr.",name:"Nikos",surname:"Fragoulis",slug:"nikos-fragoulis",fullName:"Nikos Fragoulis"},{id:"24864",title:"Dr.",name:"Christos",surname:"Theoharatos",slug:"christos-theoharatos",fullName:"Christos Theoharatos"}],corrections:null},{id:"12985",title:"Estimating 3D Surface Depth Based on Depth-of-Field Image Fusion",doi:"10.5772/14661",slug:"estimating-3d-surface-depth-based-on-depth-of-field-image-fusion",totalDownloads:2692,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Marcin Denkowski, Pawel Mikolajczak and Michal Chlebiej",downloadPdfUrl:"/chapter/pdf-download/12985",previewPdfUrl:"/chapter/pdf-preview/12985",authors:[{id:"18466",title:"Dr.",name:"Marcin",surname:"Denkowski",slug:"marcin-denkowski",fullName:"Marcin Denkowski"},{id:"18470",title:"Dr.",name:"Michal",surname:"Chlebiej",slug:"michal-chlebiej",fullName:"Michal Chlebiej"},{id:"18471",title:"Prof.",name:"Pawel",surname:"Mikolajczak",slug:"pawel-mikolajczak",fullName:"Pawel Mikolajczak"}],corrections:null},{id:"12986",title:"EM-Based Bayesian Fusion of Hyperspectral and Multispectral Images",doi:"10.5772/14662",slug:"em-based-bayesian-fusion-of-hyperspectral-and-multispectral-images",totalDownloads:2108,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Yifan Zhang",downloadPdfUrl:"/chapter/pdf-download/12986",previewPdfUrl:"/chapter/pdf-preview/12986",authors:[{id:"18454",title:"Dr.",name:"Yifan",surname:"Zhang",slug:"yifan-zhang",fullName:"Yifan Zhang"}],corrections:null},{id:"12987",title:"Pansharpening Methods Based on ARSIS Concept",doi:"10.5772/15267",slug:"pansharpening-methods-based-on-arsis-concept",totalDownloads:2553,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Mehran Yazdi and Arash Golibagh Mahyari",downloadPdfUrl:"/chapter/pdf-download/12987",previewPdfUrl:"/chapter/pdf-preview/12987",authors:[{id:"19984",title:"Dr.",name:"Mehran",surname:"Yazdi",slug:"mehran-yazdi",fullName:"Mehran Yazdi"},{id:"20683",title:"MSc.",name:"Arash",surname:"Golibagh Mahyari",slug:"arash-golibagh-mahyari",fullName:"Arash Golibagh Mahyari"}],corrections:null},{id:"12988",title:"Image Fusion Using a Parameterized Logarithmic Image Processing Framework",doi:"10.5772/15306",slug:"image-fusion-using-a-parameterized-logarithmic-image-processing-framework",totalDownloads:2171,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Sos S. Agaian, Karen A. Panetta and Shahan C. Nercessian",downloadPdfUrl:"/chapter/pdf-download/12988",previewPdfUrl:"/chapter/pdf-preview/12988",authors:[{id:"20281",title:"Dr.",name:"Shahan C.",surname:"Nercessian",slug:"shahan-c.-nercessian",fullName:"Shahan C. Nercessian"},{id:"20563",title:"Dr.",name:"Sos S.",surname:"Agaian",slug:"sos-s.-agaian",fullName:"Sos S. Agaian"},{id:"20564",title:"Dr.",name:"Karen A.",surname:"Panetta",slug:"karen-a.-panetta",fullName:"Karen A. Panetta"}],corrections:null},{id:"12989",title:"A Perceptive-Oriented Approach to Image Fusion",doi:"10.5772/15327",slug:"a-perceptive-oriented-approach-to-image-fusion",totalDownloads:2142,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Boris Escalante-Ramírez, Sonia Cruz-Techica, Rodrigo Nava and Gabriel Cristóbal",downloadPdfUrl:"/chapter/pdf-download/12989",previewPdfUrl:"/chapter/pdf-preview/12989",authors:[{id:"20366",title:"Dr.",name:"Boris",surname:"Escalante-Ramírez",slug:"boris-escalante-ramirez",fullName:"Boris Escalante-Ramírez"},{id:"20621",title:"M.Sc.",name:"Rodrigo",surname:"Nava",slug:"rodrigo-nava",fullName:"Rodrigo Nava"},{id:"24158",title:"MSc.",name:"Sonia",surname:"Cruz-Techica",slug:"sonia-cruz-techica",fullName:"Sonia Cruz-Techica"},{id:"24159",title:"Dr.",name:"Gabriel",surname:"Cristóbal",slug:"gabriel-cristobal",fullName:"Gabriel Cristóbal"}],corrections:null},{id:"12990",title:"Image Fusion Based on Multi-Directional Multiscale Analysis and Immune Optimization",doi:"10.5772/15375",slug:"image-fusion-based-on-multi-directional-multiscale-analysis-and-immune-optimization",totalDownloads:1928,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Fang Liu, Jing Bai, Shuang Wang, Biao Hou and Licheng Jiao",downloadPdfUrl:"/chapter/pdf-download/12990",previewPdfUrl:"/chapter/pdf-preview/12990",authors:[{id:"14348",title:"Prof.",name:"Licheng",surname:"Jiao",slug:"licheng-jiao",fullName:"Licheng Jiao"},{id:"20576",title:"Prof.",name:"Fang",surname:"Liu",slug:"fang-liu",fullName:"Fang Liu"},{id:"21379",title:"Prof.",name:"Shuang",surname:"Wang",slug:"shuang-wang",fullName:"Shuang Wang"},{id:"23031",title:"Prof.",name:"Biao",surname:"Hou",slug:"biao-hou",fullName:"Biao Hou"},{id:"24187",title:"Prof.",name:"Jing",surname:"Bai",slug:"jing-bai",fullName:"Jing Bai"}],corrections:null},{id:"12991",title:"Image Fusion Based Enhancement of Nondestructive Evaluation Systems",doi:"10.5772/15462",slug:"image-fusion-based-enhancement-of-nondestructive-evaluation-systems",totalDownloads:1776,totalCrossrefCites:4,totalDimensionsCites:4,signatures:"Ibrahim Elshafiey, Ayed Algarni and Majeed A. Alkanhal",downloadPdfUrl:"/chapter/pdf-download/12991",previewPdfUrl:"/chapter/pdf-preview/12991",authors:[{id:"20905",title:"Dr.",name:"Ibrahim",surname:"Elshafiey",slug:"ibrahim-elshafiey",fullName:"Ibrahim Elshafiey"},{id:"20906",title:"Dr.",name:"Ayed",surname:"Algarni",slug:"ayed-algarni",fullName:"Ayed Algarni"},{id:"20907",title:"Prof.",name:"Majeed",surname:"Alkanhal",slug:"majeed-alkanhal",fullName:"Majeed Alkanhal"}],corrections:null},{id:"12992",title:"Fusion of Infrared and Visible Images for Robust Person Detection",doi:"10.5772/14173",slug:"fusion-of-infrared-and-visible-images-for-robust-person-detection",totalDownloads:4409,totalCrossrefCites:1,totalDimensionsCites:17,signatures:"Thi Thi Zin, Hideya Takahashi, Takashi Toriu and Hiromitsu Hama",downloadPdfUrl:"/chapter/pdf-download/12992",previewPdfUrl:"/chapter/pdf-preview/12992",authors:[{id:"17039",title:"Dr.",name:"Thi Thi",surname:"Zin",slug:"thi-thi-zin",fullName:"Thi Thi Zin"},{id:"20504",title:"Dr.",name:"Hideya",surname:"Takahashi",slug:"hideya-takahashi",fullName:"Hideya Takahashi"},{id:"20505",title:"Prof.",name:"Hiromitsu",surname:"Hama",slug:"hiromitsu-hama",fullName:"Hiromitsu Hama"},{id:"24105",title:"Prof.",name:"Takashi",surname:"Toriu",slug:"takashi-toriu",fullName:"Takashi Toriu"}],corrections:null},{id:"12993",title:"Remote Sensing Image Fusion for Unsupervised Land Cover Classification",doi:"10.5772/14221",slug:"remote-sensing-image-fusion-for-unsupervised-land-cover-classification",totalDownloads:2388,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Chaabane Ferdaous",downloadPdfUrl:"/chapter/pdf-download/12993",previewPdfUrl:"/chapter/pdf-preview/12993",authors:[{id:"17200",title:"Dr.",name:"Ferdaous",surname:"Chaabane",slug:"ferdaous-chaabane",fullName:"Ferdaous Chaabane"}],corrections:null},{id:"12994",title:"Region-Based Fusion for Infrared and LLL Images",doi:"10.5772/14333",slug:"region-based-fusion-for-infrared-and-lll-images",totalDownloads:1868,totalCrossrefCites:2,totalDimensionsCites:5,signatures:"Junju Zhang, Yiyong Han, Benkang Chang and Yihui Yuan",downloadPdfUrl:"/chapter/pdf-download/12994",previewPdfUrl:"/chapter/pdf-preview/12994",authors:[{id:"17496",title:"Dr.",name:"Junju",surname:"Zhang",slug:"junju-zhang",fullName:"Junju Zhang"},{id:"20731",title:"Dr.",name:"Yiyong",surname:"Han",slug:"yiyong-han",fullName:"Yiyong Han"},{id:"20732",title:"Dr.",name:"Yihui",surname:"Yuan",slug:"yihui-yuan",fullName:"Yihui Yuan"},{id:"24150",title:"Dr.",name:"Benkang",surname:"Chang",slug:"benkang-chang",fullName:"Benkang Chang"}],corrections:null},{id:"12995",title:"Cognitive Image Fusion and Assessment",doi:"10.5772/14787",slug:"cognitive-image-fusion-and-assessment",totalDownloads:1428,totalCrossrefCites:4,totalDimensionsCites:6,signatures:"Alexander Toet",downloadPdfUrl:"/chapter/pdf-download/12995",previewPdfUrl:"/chapter/pdf-preview/12995",authors:[{id:"10059",title:"Dr.",name:"Alexander",surname:"Toet",slug:"alexander-toet",fullName:"Alexander Toet"}],corrections:null},{id:"12996",title:"Image Fusion Methods for Confocal Scanning Laser Microscopy Experimented on Images of Photonic Quantum Ring Laser Devices",doi:"10.5772/14495",slug:"image-fusion-methods-for-confocal-scanning-laser-microscopy-experimented-on-images-of-photonic-quant",totalDownloads:1711,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Stefan G. Stanciu",downloadPdfUrl:"/chapter/pdf-download/12996",previewPdfUrl:"/chapter/pdf-preview/12996",authors:[{id:"17941",title:"Dr.",name:"Stefan G.",surname:"Stanciu",slug:"stefan-g.-stanciu",fullName:"Stefan G. Stanciu"}],corrections:null},{id:"12997",title:"Architectures for Image Fusion",doi:"10.5772/14470",slug:"architectures-for-image-fusion",totalDownloads:1585,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Michael Heizmann and Fernando Puente Leon",downloadPdfUrl:"/chapter/pdf-download/12997",previewPdfUrl:"/chapter/pdf-preview/12997",authors:[{id:"10784",title:"Prof.",name:"Fernando",surname:"Puente Leon",slug:"fernando-puente-leon",fullName:"Fernando Puente Leon"},{id:"17878",title:"Dr.",name:"Michael",surname:"Heizmann",slug:"michael-heizmann",fullName:"Michael Heizmann"}],corrections:null},{id:"12998",title:"Image Fusion for Computer Assisted Tumor Surgery (CATS)",doi:"10.5772/14499",slug:"image-fusion-for-computer-assisted-tumor-surgery-cats-",totalDownloads:2051,totalCrossrefCites:3,totalDimensionsCites:5,signatures:"K.C. Wong, S.M. Kumta, L.F. Tse, E.W.K. Ng and K.S. Lee",downloadPdfUrl:"/chapter/pdf-download/12998",previewPdfUrl:"/chapter/pdf-preview/12998",authors:[{id:"17953",title:"Dr.",name:"K.C.",surname:"Wong",slug:"k.c.-wong",fullName:"K.C. Wong"},{id:"20916",title:"Dr.",name:"S.M.",surname:"Kumta",slug:"s.m.-kumta",fullName:"S.M. Kumta"},{id:"20917",title:"Dr.",name:"L. F.",surname:"Tse",slug:"l.-f.-tse",fullName:"L. F. Tse"},{id:"20918",title:"Dr.",name:"E.W.K.",surname:"Ng",slug:"e.w.k.-ng",fullName:"E.W.K. Ng"},{id:"20919",title:"Dr.",name:"K.S.",surname:"Lee",slug:"k.s.-lee",fullName:"K.S. Lee"}],corrections:null},{id:"12999",title:"Multimodal Medical Image Registration and Fusion in 3D Conformal Radiotherapy Treatment Planning",doi:"10.5772/14636",slug:"multimodal-medical-image-registration-and-fusion-in-3d-conformal-radiotherapy-treatment-planning",totalDownloads:2228,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Bin Li",downloadPdfUrl:"/chapter/pdf-download/12999",previewPdfUrl:"/chapter/pdf-preview/12999",authors:[{id:"18404",title:"Dr.",name:"Bin",surname:"Li",slug:"bin-li",fullName:"Bin Li"}],corrections:null},{id:"13000",title:"Image-Fusion for Biopsy, Intervention, and Surgical Navigation in Urology",doi:"10.5772/15125",slug:"image-fusion-for-biopsy-intervention-and-surgical-navigation-in-urology",totalDownloads:2053,totalCrossrefCites:1,totalDimensionsCites:3,signatures:"Osamu Ukimura",downloadPdfUrl:"/chapter/pdf-download/13000",previewPdfUrl:"/chapter/pdf-preview/13000",authors:[{id:"18400",title:"Dr.",name:"Osamu",surname:"Ukimura",slug:"osamu-ukimura",fullName:"Osamu Ukimura"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"99",title:"Image Segmentation",subtitle:null,isOpenForSubmission:!1,hash:"c5a76ae0e1714cc2c4019296ef7f4f08",slug:"image-segmentation",bookSignature:"Pei-Gee Ho",coverURL:"https://cdn.intechopen.com/books/images_new/99.jpg",editedByType:"Edited by",editors:[{id:"21284",title:"Dr.",name:"Pei-Gee",surname:"Ho",slug:"pei-gee-ho",fullName:"Pei-Gee Ho"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"165",title:"Image Fusion and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"782ec4f52d3333c64421f1368ede04bf",slug:"image-fusion-and-its-applications",bookSignature:"Yufeng Zheng",coverURL:"https://cdn.intechopen.com/books/images_new/165.jpg",editedByType:"Edited by",editors:[{id:"24502",title:"Dr.",name:"Yufeng",surname:"Zheng",slug:"yufeng-zheng",fullName:"Yufeng Zheng"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"149",title:"Recent Advances on Video Coding",subtitle:null,isOpenForSubmission:!1,hash:"3e7cf16c546740b7b07ff0b182637f23",slug:"recent-advances-on-video-coding",bookSignature:"Javier Del Ser Lorente",coverURL:"https://cdn.intechopen.com/books/images_new/149.jpg",editedByType:"Edited by",editors:[{id:"49813",title:"Dr.",name:"Javier",surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3767",title:"Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"9f9c08038d039627926e5f110f72aa8e",slug:"image-processing",bookSignature:"Yung-Sheng Chen",coverURL:"https://cdn.intechopen.com/books/images_new/3767.jpg",editedByType:"Edited by",editors:[{id:"2311",title:"Professor",name:"Yung-Sheng",surname:"Chen",slug:"yung-sheng-chen",fullName:"Yung-Sheng Chen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1326",title:"Digital Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"4aabc0c4713da53c9c996abed9fe259a",slug:"digital-image-processing",bookSignature:"Stefan G. Stanciu",coverURL:"https://cdn.intechopen.com/books/images_new/1326.jpg",editedByType:"Edited by",editors:[{id:"17941",title:"Dr.",name:"Stefan G.",surname:"Stanciu",slug:"stefan-g.-stanciu",fullName:"Stefan G. Stanciu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3230",title:"Advanced Video Coding for Next-Generation Multimedia Services",subtitle:null,isOpenForSubmission:!1,hash:"a890bd46555d3cd1652bf69eb6b313df",slug:"advanced-video-coding-for-next-generation-multimedia-services",bookSignature:"Yo-Sung Ho",coverURL:"https://cdn.intechopen.com/books/images_new/3230.jpg",editedByType:"Edited by",editors:[{id:"33840",title:"Prof.",name:"Yo-Sung",surname:"Ho",slug:"yo-sung-ho",fullName:"Yo-Sung Ho"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"112",title:"Effective Video Coding for Multimedia Applications",subtitle:null,isOpenForSubmission:!1,hash:"09a9826a6f8e7d58cf8516c609b4fa05",slug:"effective-video-coding-for-multimedia-applications",bookSignature:"Sudhakar Radhakrishnan",coverURL:"https://cdn.intechopen.com/books/images_new/112.jpg",editedByType:"Edited by",editors:[{id:"26327",title:"Dr.",name:"Sudhakar",surname:"Radhakrishnan",slug:"sudhakar-radhakrishnan",fullName:"Sudhakar Radhakrishnan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1925",title:"Advanced Image Acquisition, Processing Techniques and Applications",subtitle:null,isOpenForSubmission:!1,hash:"877298c5eacd9e7081a4f4d89be5db4c",slug:"advanced-image-acquisition-processing-techniques-and-applications",bookSignature:"Dimitrios Ventzas",coverURL:"https://cdn.intechopen.com/books/images_new/1925.jpg",editedByType:"Edited by",editors:[{id:"109555",title:"Dr.",name:"Dimitrios",surname:"Ventzas",slug:"dimitrios-ventzas",fullName:"Dimitrios Ventzas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3766",title:"Vision Sensors and Edge Detection",subtitle:null,isOpenForSubmission:!1,hash:"991ded9232cebeeb3c6c51def14827d6",slug:"vision-sensors-and-edge-detection",bookSignature:"Francisco Gallegos-Funes",coverURL:"https://cdn.intechopen.com/books/images_new/3766.jpg",editedByType:"Edited by",editors:[{id:"2868",title:"Dr.",name:"Francisco",surname:"Gallegos-Funes",slug:"francisco-gallegos-funes",fullName:"Francisco Gallegos-Funes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3125",title:"Advances in Image Segmentation",subtitle:null,isOpenForSubmission:!1,hash:"94056fc0687fbb81e9d8cc4b1e297312",slug:"advances-in-image-segmentation",bookSignature:"Pei-Gee Peter Ho",coverURL:"https://cdn.intechopen.com/books/images_new/3125.jpg",editedByType:"Edited by",editors:[{id:"21284",title:"Dr.",name:"Pei-Gee",surname:"Ho",slug:"pei-gee-ho",fullName:"Pei-Gee Ho"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"74026",slug:"corrigendum-to-calf-sex-influence-in-bovine-milk-production",title:"Corrigendum to: Calf-Sex Influence in Bovine Milk Production",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/74026.pdf",downloadPdfUrl:"/chapter/pdf-download/74026",previewPdfUrl:"/chapter/pdf-preview/74026",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/74026",risUrl:"/chapter/ris/74026",chapter:{id:"73504",slug:"calf-sex-influence-in-bovine-milk-production",signatures:"Miguel Quaresma and R. Payan-Carreira",dateSubmitted:"April 21st 2020",dateReviewed:"September 10th 2020",datePrePublished:"October 8th 2020",datePublished:"January 20th 2021",book:{id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,fullTitle:"Animal Reproduction in Veterinary Medicine",slug:"animal-reproduction-in-veterinary-medicine",publishedDate:"January 20th 2021",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"38652",title:"Dr.",name:"Rita",middleName:null,surname:"Payan-Carreira",fullName:"Rita Payan-Carreira",slug:"rita-payan-carreira",email:"rtpayan@gmail.com",position:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",fullName:"Miguel Quaresma",slug:"miguel-quaresma",email:"miguelq@utad.pt",position:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}}]}},chapter:{id:"73504",slug:"calf-sex-influence-in-bovine-milk-production",signatures:"Miguel Quaresma and R. Payan-Carreira",dateSubmitted:"April 21st 2020",dateReviewed:"September 10th 2020",datePrePublished:"October 8th 2020",datePublished:"January 20th 2021",book:{id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,fullTitle:"Animal Reproduction in Veterinary Medicine",slug:"animal-reproduction-in-veterinary-medicine",publishedDate:"January 20th 2021",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"38652",title:"Dr.",name:"Rita",middleName:null,surname:"Payan-Carreira",fullName:"Rita Payan-Carreira",slug:"rita-payan-carreira",email:"rtpayan@gmail.com",position:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",fullName:"Miguel Quaresma",slug:"miguel-quaresma",email:"miguelq@utad.pt",position:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}}]},book:{id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,fullTitle:"Animal Reproduction in Veterinary Medicine",slug:"animal-reproduction-in-veterinary-medicine",publishedDate:"January 20th 2021",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"7669",leadTitle:null,title:"Standards, Methods and Solutions of Metrology",subtitle:null,reviewType:"peer-reviewed",abstract:"The goal of acceptable quality, cost, and time is a decisive challenge in every engineering development process. To be familiar with metrology requires choosing the best combination of techniques, standards, and tools to control a project from advanced simulations to final performance measurements and periodic inspections. This book contains a cluster of chapters from international academic authors who provide a meticulous way to discover the impacts of metrology in both theoretical and application fields. The approach is to discuss the key aspects of a selection of untraditional metrological topics, covering the analysis procedures and set of solutions obtained from experimental studies.",isbn:"978-1-78984-463-4",printIsbn:"978-1-78984-462-7",pdfIsbn:"978-1-83962-256-4",doi:"10.5772/intechopen.77475",price:119,priceEur:129,priceUsd:155,slug:"standards-methods-and-solutions-of-metrology",numberOfPages:106,isOpenForSubmission:!1,hash:"29d82c2091fb9ca1c49620000d170f2c",bookSignature:"Luigi Cocco",publishedDate:"October 2nd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7669.jpg",keywords:null,numberOfDownloads:2253,numberOfWosCitations:1,numberOfCrossrefCitations:3,numberOfDimensionsCitations:4,numberOfTotalCitations:8,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 24th 2018",dateEndSecondStepPublish:"December 6th 2018",dateEndThirdStepPublish:"February 4th 2019",dateEndFourthStepPublish:"April 25th 2019",dateEndFifthStepPublish:"June 24th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"112023",title:"Dr.",name:"Luigi",middleName:null,surname:"Cocco",slug:"luigi-cocco",fullName:"Luigi Cocco",profilePictureURL:"https://mts.intechopen.com/storage/users/112023/images/system/112023.jpg",biography:'Dr. Luigi Cocco has received his master\'s degree in Telecommunication Engineering and his Ph.D. in Information Engineering before to join the automotive industry. Since 2005, From the Ferrari F1 Team to Automobili Lamborghini, he has worked on Electrical/Electronics systems; he has expertise in Research & Design, Supply Quality and Product Development. Currently, he is System Responsible for Passive Safety & ADAS of Maserati vehicles. His research interests include electronic measurements and digital signal processing, he has published several papers and three books with InTech: "Modern Metrology Concerns” (2012), "New Trends and Developments in Metrology” (2016) and "Standards, methods, and solutions of Metrology” (2018).',institutionString:"Maserati S.p.A.",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1417",title:"Metrology",slug:"technology-metrology"}],chapters:[{id:"66092",title:"Metrological Traceability at Different Measurement Levels",slug:"metrological-traceability-at-different-measurement-levels",totalDownloads:502,totalCrossrefCites:2,authors:[{id:"94982",title:"Dr.",name:"Tetyana",surname:"Gordiyenko",slug:"tetyana-gordiyenko",fullName:"Tetyana Gordiyenko"},{id:"223340",title:"Prof.",name:"Oleh",surname:"Velychko",slug:"oleh-velychko",fullName:"Oleh Velychko"}]},{id:"66673",title:"Self-Calibration of Precision XYθz Metrology Stages",slug:"self-calibration-of-precision-xy-em-sub-z-sub-em-metrology-stages",totalDownloads:413,totalCrossrefCites:0,authors:[{id:"178057",title:"Prof.",name:"Chuxiong",surname:"Hu",slug:"chuxiong-hu",fullName:"Chuxiong Hu"}]},{id:"65687",title:"Third-Order Nonlinear Optical Properties of Quantum Dots",slug:"third-order-nonlinear-optical-properties-of-quantum-dots",totalDownloads:772,totalCrossrefCites:1,authors:[{id:"36065",title:"Dr.",name:"Khalil",surname:"Jasim",slug:"khalil-jasim",fullName:"Khalil Jasim"}]},{id:"67358",title:"Analysis of Pulsating White Dwarf Star Light Curves",slug:"analysis-of-pulsating-white-dwarf-star-light-curves",totalDownloads:261,totalCrossrefCites:0,authors:[{id:"265224",title:"Dr.",name:"Denis",surname:"Sullivan",slug:"denis-sullivan",fullName:"Denis Sullivan"}]},{id:"67258",title:"Biotoxicological Monitoring of Organic Solvents in the Tunisian Footwear Industry",slug:"biotoxicological-monitoring-of-organic-solvents-in-the-tunisian-footwear-industry",totalDownloads:307,totalCrossrefCites:0,authors:[{id:"186371",title:"Associate Prof.",name:"Imed",surname:"Gargouri",slug:"imed-gargouri",fullName:"Imed Gargouri"},{id:"188100",title:"Dr.",name:"Moncef",surname:"Khadhraoui",slug:"moncef-khadhraoui",fullName:"Moncef Khadhraoui"},{id:"294793",title:"Dr.",name:"Fatma",surname:"Omrane",slug:"fatma-omrane",fullName:"Fatma Omrane"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"278926",firstName:"Ivana",lastName:"Barac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/278926/images/8058_n.jpg",email:"ivana.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1547",title:"Modern Metrology Concerns",subtitle:null,isOpenForSubmission:!1,hash:"27edf8c2b79a9c6ae0c3d87ca8cae49c",slug:"modern-metrology-concerns",bookSignature:"Luigi Cocco",coverURL:"https://cdn.intechopen.com/books/images_new/1547.jpg",editedByType:"Edited by",editors:[{id:"112023",title:"Dr.",name:"Luigi",surname:"Cocco",slug:"luigi-cocco",fullName:"Luigi Cocco"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4622",title:"New Trends and Developments in Metrology",subtitle:null,isOpenForSubmission:!1,hash:"27aa3947c35b65d08f9c1f4a56b7f468",slug:"new-trends-and-developments-in-metrology",bookSignature:"Luigi Cocco",coverURL:"https://cdn.intechopen.com/books/images_new/4622.jpg",editedByType:"Edited by",editors:[{id:"112023",title:"Dr.",name:"Luigi",surname:"Cocco",slug:"luigi-cocco",fullName:"Luigi Cocco"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6760",title:"Scientometrics",subtitle:null,isOpenForSubmission:!1,hash:"f439a48f9b20628b0dd34b804a061967",slug:"scientometrics",bookSignature:"Mari Jibu and Yoshiyuki Osabe",coverURL:"https://cdn.intechopen.com/books/images_new/6760.jpg",editedByType:"Edited by",editors:[{id:"197098",title:"Dr.",name:"Mari",surname:"Jibu",slug:"mari-jibu",fullName:"Mari Jibu"}],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:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],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"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],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. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"16750",title:"Ferroelectric Properties and Polarization Switching Kinetic of Poly (vinylidene fluoride-trifluoroethylene) Copolymer",doi:"10.5772/17147",slug:"ferroelectric-properties-and-polarization-switching-kinetic-of-poly-vinylidene-fluoride-trifluoroeth",body:'\n\t\t
The discovery of the piezoelectric properties of poly(vinylidene fluoride) (PVDF) by Kawai [Kawai, 1969], and the study of its pyroelectric and nonlinear optical properties [Bergman et al., 1971; Glass, 1971] led to the discovery of its ferroelectric properties in the early 1970s. Since that time, considerable development and progress have been made on both materials and devices based on PVDF. This work helped establish the field of ferroelectric polymer science and engineering [Nalwa, 1995a]. There are many novel ferroelectric polymers, such as poly(vinylidene fluoride) (PVDF) copolymers, poly(vinylidene cyanide) copolymers, odd-numbered nylons, polyureas, ferroelectric liquid crystal polymers and polymer composites of organic and inorganic piezoelectric ceramics [Nalwa, 1991 and Kepler & Anderson, 1992 as cited in Nalwa, 1995b; Nalwa, 1995a]. Among them, PVDF, and its copolymers are the most developed and promising ferroelectric polymers because of their high spontaneous polarization and chemical stability.
\n\t\t\tFerroelectricity is caused by the dipoles in crystalline or polycrystalline materials that spontaneously polarize and align with an external electric field. The polarization of the dipoles can be switched to the opposite direction with the reversal of the electric field. Similar to inorganic ferroelectric materials such as PbZr0.5Ti0.5O3 (PZT) and SrBi2Ta2O9 (SBT), organic ferroelectric materials exhibit ferroelectric characteristics such as Curie temperature (the transition temperature from ferroelectrics to paraelectrics), coercive field (the minimum electric field to reverse the spontaneous polarization) and remanent polarization (the restored polarization after removing the electric field). However, the low temperature and low fabrication cost of organic ferroelectric materials enable them to be used in a large number of applications, such as flexible electronics.
\n\t\t\tIn this chapter, the discussion is focused on poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)], one of the most promising PVDF ferroelectric copolymers. The main objective of this chapter is to describe the ferroelectric properties of P(VDF-TrFE) copolymer and review the current research status of ferroelectric devices based on this material. The chapter is divided in six sections. The first section introduces the topic of organic ferroelectrics. The second section describes the material properties of the ferroelectric phase of P(VDF-TrFE) including phase structures, surface morphology, crystallinity and molecule chain orientation. Next, the electrical properties such as polarization, switching current, etc. are discussed. In section four, the fundamental ferroelectric polarization switching mechanisms are introduced and the models for P(VDF-TrFE) thin films are reviewed. The nucleation-limited-switching (NLS) model, based on region-to-region switching kinetics for P(VDF-TrFE) thin film will be emphasized. The fifth section reviews the impact of annealing temperature, film thickness and contact dependence for P(VDF-TrFE) based ferroelectric capacitors. Finally, the most important results from this chapter will be summarized, and one of the P(VDF-TrFE) copolymer’s potential applications as flexible non-volatile ferroelectric random access memory will be briefly discussed.
\n\t\tP(VDF-TrFE) is a random copolymer synthesized using two homopolymers, PVDF and poly(trifluoroethylene) (PTrFE). The chemical formula is shown in Figure 1. PVDF is a crystalline polymer, has a monomer unit of -CH2-CF2-, in between polyethylene (PE) ( -CH2-CH2-) and polytetrafluoroethylene (PTFE) (-CF2-CF2-) monomers. The similarity of PVDF to these two polymers gives rise to its physical strength, flexibility and chemical stability [Tashiro, 1995]. Its ferroelectric properties originate from the large difference in electronegativity between fluorine, carbon and hydrogen, which have Pauling’s values of 4.0, 2.5 and 2.1, respectively [Pauling, 1960]. Most of the electrons are attracted to the fluorine side of the polymer chain and polarization is created [Salimi & Yousefi, 2004; Fujisaki et al., 2007]. The Curie temperature of PVDF is estimated to be above the melting temperature at 195-197 oC [Lovinger, 1986, as cited in Kepler, 1995]. The melting of the ferroelectric phase and recrystallization to the paraelectric phase may happen in the same temperature range. The addition of TrFE (-CF2-CFH-) into the PVDF system plays an important role in the phase transition behavior. TrFE modifies the PVDF crystal structure by increasing the unit cell size and inter-planar distance of the ferroelectric phase, as seen from X-ray diffraction measurements [Tashiro et al., 1984; Lovinger et al.., 1983a, 1983b, as cited in Tashiro, 1995]. The interactions between each unit and between dipole-to-dipole are reduced, resulting in a lower Curie temperature. Therefore, it allows the copolymer to crystallize into the ferroelectric phase at temperatures below the melting point. The copolymer crystal structure, phase transition behavior and ferroelectric properties are affected by the ratio of VDF/TrFE content and the synthesizing conditions [Yamada & Kitayama, 1981]. The experimental data from UT Dallas shown in this chapter are for P(VDF-TrFE) copolymer with 70/30 (VDF/TrFE), synthesized using a suspension polymerization process. The ferroelectric properties are measured and tested at room temperature, except if stated otherwise.
\n\t\t\tThe chemical formula of P(VDF-TrFE) random copolymer [Naber et al., 2005].
When the P(VDF-TrFE) copolymer chains are packed and form a solid material, there are four types of crystalline phases. The phase configurations are very similar to PVDF, including phase I (β), phase II (α), phase III (γ), and phase IV (δ) [Xu et al., 2000]. Among these four phases, only the β phase is the polar phase with a large spontaneous polarization along the b axis which is parallel to the C-F dipole moment, and perpendicular to the polymer chain direction (c axis) [Hu et al., 2009.]
\n\t\t\t\ta)The schematic of the β phase crystal structure for P(VDF-TrFE) copolymer in the ab plane (the c axis is normal to the ab plane), and (b) along the c axis of the all-trans (TTTT) zigzag planar configuration from the top view.
The schematic of the β phase crystal structure is shown in Figure 2. The molecules are in a distorted, all-trans (TTTT) zigzag planar configuration. When the polymer is cooled from its melt state, it crystallizes into the α phase. This crystal is nonpolar with the molecules in a distorted trans-gauche-trans-gauche’ (TGTG’) configuration, which is the state with the lowest energy. In the γ phase, the crystal has polar unit cells with molecules in the T3GT3G’ configuration, and the dipole moment is smaller than phase I (β). For the δ phase, the crystal has the same configuration as the α phase, but with a different orientation of the molecules’ dipole moments in the unit cell [Kepler, 1995]. Different phases can be achieved by using different processing conditions. The material can transition between phases by using annealing, stretching and poling methods [Tashiro et al., 1981, as cited in Tashiro 1995]. In this chapter, the discussion is focused on the polar β phase.
\n\t\t\tThe mechanics and aggregation characteristics of the polymeric chains can be different when forming each crystalline phases, resulting in different surface morphologies. This can be studied using atomic force microscopy (AFM). Figure 3 shows a 3D 1µm×1µm AFM image of a typical P(VDF-TrFE) film. The rod-like shape of the grains is attributed to the β phase crystallites. The size of the grains and the roughness of the surface are related to the annealing conditions and are sensitive to the maximum processing temperature [Park et al., 2006; \n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta]. The sample shown in Figure 3 corresponds to a 210 nm spin coated film annealed at 144 oC for 2 hours in vacuum. The length of the grains is approximately 180 nm with a surface RMS roughness of 14.6 nm [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta].
\n\t\t\t\tAFM tapping mode height image of a 210 nm P(VDF-TrFE) film annealed at 144 oC for 2 hours in vacuum.
X-ray Diffraction (XRD) can be used to study the crystalline characteristics. The diffraction angle corresponds to the inter-planar spacing and orientation of the crystal planes, and the diffraction intensity indicates the quantity of the corresponding crystal planes, which relates to the degree of crystallinity. The crystal structure of P(VDF-TrFE) is normally related to the composition (mole ratio of VDF/TrFE) of the copolymer and the annealing process. In the β crystal phase of P(VDF-TrFE), the unit cell is orthorhombic, with each chain aligned and packed with the CF2 groups parallel to the b axis [Lando et al, 1966; Gal’perin & Kosmynin, 1969; Hasegawa et al, 1972, as cited in Tashiro, 1995], as indicated in Figure 2 (a). Figure 4 shows the XRD results from a 210 nm P(VDF-TrFE) (VDF/TrFE of 70/30) film annealed at 144 oC and measured at room temperature. The diffraction peak at 2θ=19.9o is attributed to the (110) and (200) orientation planes, which are associated with the polar β phase. From the position of this sharp peak, the inter-planar spacing b is determined to be 4.5 Å [\n\t\t\t\t\t\tMao et al, 2010\n\t\t\t\t\ta]. The strong diffraction peak indicates a high degree of crystallinity in the β phase.
\n\t\t\t\tXRD results for 210 nm β phase P(VDF-TrFE) (VDF/TrFE of 70/30) film annealed at 144 oC and measured at room temperature
Molecular vibration analysis is a key to understanding the dynamics of a material. Fourier-transform infrared spectroscopy (FT-IR) can be used to detect the vibrational mechanics of a material system by monitoring the absorption of infrared energy. The incident electro-magnetic field from the IR source interacts with the molecular bonding of the P(VDF-TrFE) film, resulting in a large absorption when the molecular vibration and the electric field component of the IR are perpendicular to each other. Each phase of the P(VDF-TrFE) polymer will provide a characteristic FT-IR spectrum. Details of the absorption band assignments can be found in the literature [Kobayashi et al, 1974; Reynolds et al, 1989; Kim et al, 1989]. Here we only discuss the three intense bands, 1288 cm-1, 850 cm-1, and 1400 cm-1 associated with the β phase of P(VDF-TrFE). The 1288 cm-1 and 850 cm-1bands belong to the CF2 symmetric stretching with the dipole moments parallel to the polar b axis [Reynolds et al, 1989]. The 1400 cm-1 band is assigned to the CH2 wagging vibration, with the dipole moment along the c axis. As illustrated in Figure 5 [\n\t\t\t\t\t\tMao et al, 2010\n\t\t\t\t\t], a polarized IR source with the electrical component parallel to the substrate (p-polarized) is used to measure two P(VDF-TrFE) thin film samples. The strong absorption bands at 1288 cm-1 and 850 cm-1 in spectrum A (sample A) indicates that the polar b axis of the P(VDF-TrFE) copolymer chain is perpendicular to the substrate and the planar zigzag chains are aligned parallel to the substrate [Hu et al, 2009]. However, in spectrum B (sample B), week absorption bands observed at 1288 cm-1 and 850 cm-1 indicate that the b axis is tilted away from the direction normal to the substrate. Additionally, the strong absorption band at 1400 cm-1 band indicates the polymer chain (c axis) is tilted, and a significant number of the molecules are aligned normal to the substrate, which is undesirable for vertical polarization [Park et al, 2006; \n\t\t\t\t\t\tMao et al, 2010\n\t\t\t\t\ta].
\n\t\t\t\tFT-IR analysis of the β phase of P(VDF-TrFE) polymer films (A and B) with different polymer chain alignment characteristics. In sample A, the polymer chains are aligned parallel to the substrate, and in sample B, the polymer chains are tilted and some portions are aligned perpendicular to the substrate.
The fabrication of the polymer films into devices and the electrical characterization of the ferroelectric properties are introduced here. The discussion focuses on ferroelectric capacitors (FeCap), which is the fundamental device for studying this material.
\n\t\t\tThere are two common methods to prepare P(VDF-TrFE) thin films. The first one is the melt and press method[Yamada & Kitayama, 1981]. The copolymer crystallizes into α or γ phases when it is slowly cooled to room temperature from the melt. The film has a high degree of crystallinity. Stretching or poling process is required to achieve the β phase crystals. For the melt and press fabrication process, the film thickness is usually > 1 µm. Spin coating from solution is another common fabrication method. By changing the weight percentage of the polymer in solution, spin coating can be used to produce films with thickness ≤100 nm. Different crystal phases can be achieved from polymer dissolved in different solvents. Spin coat from 2-butanone or cyclohexanone solutions allow the film to be crystallized into the β phase directly. Another method of making ultra thin film reported by A.V. Bune et al. [Bune et al., 1998] is Langmuir-Blodgett deposition, which results in films which are a few monolayers thick and can be switched at 1 V. After making the films, thermal annealing is always used to increase the degree of crystallinity. The annealing will be discussed in section 5.
\n\t\t\tThe application of an electric field across the FeCap with an amplitude higher than the coercive field will reverse the polarity of the dipoles, and induce a switching current flow through the external closed loop. The total number of dipoles determines the electric displacements or polarization of the film. By integrating the switching current in the time domain, the total number of the switched dipoles or charges can be calculated. Two types of waveforms are commonly used to measure the polarization, the triangular wave for hysteresis loop characterization and a sequence of pulses for the standard Positive Up Negative Down (PUND) method [Kin et al, 2008; \n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\tb], as shown in figures 6 (a) and (b), respectively.
\n\t\t\t\tThe polarization measurement waveforms for (a) hysteresis loop and (b) PUND characterizations.
In the hysteresis loop measurement, the first triangular wave is used for initialization of the ferroelectric capacitor, followed by the second waveform for polarization measurement in both positive and negative directions. In the PUND measurement, switching polarization (P\n\t\t\t\t\t\n\t\t\t\t\t\tsw\n\t\t\t\t\t) and nonswitching polarization (P\n\t\t\t\t\t\n\t\t\t\t\t\tns\n\t\t\t\t\t) are measured. P\n\t\t\t\t\t\n\t\t\t\t\t\tsw\n\t\t\t\t\t corresponds to the current integration in the polarization switching transient, and P\n\t\t\t\t\t\n\t\t\t\t\t\tns\n\t\t\t\t\t corresponds to the current integration when the polarization has the same direction as the applied electric field. They are defined as [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\tb]
\n\t\t\t\twhere P\n\t\t\t\t\t\n\t\t\t\t\t\ts\n\t\t\t\t\t and P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t represent the spontaneous polarization and remanent polarization, respectively. The five sequential pulses represent initialization, measurement for P\n\t\t\t\t\t\n\t\t\t\t\t\tsw\n\t\t\t\t\t, P\n\t\t\t\t\t\n\t\t\t\t\t\tns\n\t\t\t\t\t in positive and negative directions, respectively.
\n\t\t\tThe hysteresis loop is one of the most important tools to characterize ferroelectrics. A significant amount of information can be extracted from the hysteresis loop. Similar to other ferroelectrics, P(VDF-TrFE) copolymer exhibits remanent polarization. Figure 7 (a) shows the hysteresis loops measured at 1 Hz with different applied voltages for a FeCap with P(VDF-TrFE) film thickness of approximately 154 nm. As the voltage increases to 8 V, the FeCap starts to show hysteresis characteristics, and saturates at above 10 V. P\n\t\t\t\t\t\n\t\t\t\t\t\ts\n\t\t\t\t\t and +/-P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t are plotted as a function of voltage in Figure 7 (b). P\n\t\t\t\t\t\n\t\t\t\t\t\ts\n\t\t\t\t\t and P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t increase rapidly at voltage > 6 V, and saturate at 8.2 µC/cm2 and 6.9 µC/cm2, respectively. The coercive voltage (V\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t) is defined as the voltage when dP/dV reaches maximum, which is approximately 6.7 V, corresponding to a coercive field (E\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t) of 0.44 MV/cm.
\n\t\t\t\ta) Hysteresis loops measured at different voltages for P(VDF-TrFE) FeCap, and (b) P\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\ts\n\t\t\t\t\t\t\t and +/-P\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tr\n\t\t\t\t\t\t\t as a function of applied voltage.
In the PUND method, a circuit is used to measure the currents in polarization switching and nonswitching transients, or measure the displacement and polarization of the FeCaps. In order to measure the polarization switching transient, we use a function generator to bias the FeCap, and measure the voltage across a linear resister using an oscilloscope, as shown in Figure 8. The transient current can be calculated by dividing the voltage with the resistance. P\n\t\t\t\t\t\n\t\t\t\t\t\tsw\n\t\t\t\t\t and P\n\t\t\t\t\t\n\t\t\t\t\t\tns\n\t\t\t\t\t can be calculated by integrating the current in the time domain.
\n\t\t\t\tTypical PUND measurement data from a P(VDF-TrFE) based FeCap (size of 300µm × 300µm) are plotted in Figure 9. V1 and V2 represent the voltages measured from channel 1 and 2 of the oscilloscope, respectively. Rescaling V2 by 1/R (1000 ohms in the measurement) gives the transient current. The 1st, 3rd and 5th pulses induce large responses, representing the polarization switching of the dipoles, while the 2nd, 4th, and 6th pulses correspond to the nonswitching transient with small current responses, because the dipoles have already aligned in the same direction as the applied electric field. The sharp response for polarization switching indicates the fast rotation of the dipoles, and the large difference between the switching and nonswitching responses indicates a large remanent polarization. P\n\t\t\t\t\t\n\t\t\t\t\t\tsw\n\t\t\t\t\t and P\n\t\t\t\t\t\n\t\t\t\t\t\tns\n\t\t\t\t\t are calculated from the transient switching current to be 11.2 µC/cm2 and 1.3 µC/cm2, respectively. The switching current is a function of the applied electric field.
\n\t\t\t\tThe circuit schematic used to measure the currents in the switching and nonswitching transients using the PUND method.
The switching and nonswitching transient measurement of a P(VDF-TrFE) based FeCap using the PUND method.
The nonlinearity of the dielectric response to electric field is also present in P(VDF-TrFE), as shown in Figure 10. An FeCap with P(VDF-TrFE) thickness of 154 nm is measured at 100 KHz. The dielectric permittivity is a function of dP/dV, which corresponds to the slope of the polarization-voltage plot. The dielectric constant is measured to be between 7.8 and 11, depending on the electric field [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta]. The peaks in the capacitance correspond to the polarization reversal of the dipoles, and the electric field for the peak capacitance corresponds to the coercive field [Lohse et al., 2001].
\n\t\t\t\tThe capacitance-voltage response of a 154 nm thick P(VDF-TrFE) based FeCap.
Understanding the kinetics of polarization switching is important to the application of ferroelectric materials. The polarization dipole reversal mechanism of inorganic ferroelectric materials such as lead zirconate titanate (PZT) has been studied for many years. The switching kinetics in a single crystal ferroelectric is found to follow the classical model called the Kolmogorov-Avrami-Ishibashi (KAI) model [Lohse et al., 2001; Tagantsev et al, 2002]. The KAI model was developed by the group of Ishibashi, based on the statistical theory of Kolmogorov and Avrami (KA) [Kolmogorov, 1937; Avrami 1939; Avrami 1940; Avrami 1941, as cited in Lohse et al., 2001], which was originally developed for the modeling of the crystallization process in metals. However, for polycrystalline ferroelectric thin films, the switching kinetics were frequently found to disobey the KAI model [Lohse et al., 2001; Tagantsev et al, 2002]. In this section, the polarization switching mechanism and the KAI model will be briefly discussed, and correlated with a model based on region-by-region switching for P(VDF-TrFE) thin films[Tagantsev et al, 2002]. Some alternative models for P(VDF-TrFE) will also be briefly introduced.
\n\t\t\tFerroelectric polarization is defined as the electric dipole moment, or the displacement of charge density away from the center of the unit cell in the crystal lattice. The polarization direction can be switched by applying an electric field. The polarization switching process is commonly considered to be controlled by two mechanisms; domain nucleation and expansion [Merz, 1956; Kimura & Ohigashi, 1986]. The switching time is a function of the electric field, and for these two mechanisms, the switching time for each mechanism has a different dependence on the electric field. The domain nucleation process has an exponential relationship and can be expressed as [Merz, 1956]
\n\t\t\t\twhere E0 is the activation field, τa is the switching time at E= E0, which corresponds to the fastest switching speed of the material, and n is a constant related to the dimension of the domain growth. For domain expansion, the reciprocal of 1/τ0 has a linear relationship as described in equation (4) [Merz, 1956];
\n\t\t\t\twhere µ is the mobility of the domain expansion and E1 is a limiting electric field similar to a coercive field strength. The polarization switching of the ferroelectric is considered to be a combination of these two processes. Therefore, for a single crystal material, it exhibits a total switching time τ0, which is a function of applied electric field.
\n\t\t\t\tThe KAI model describes the switching polarization phenomenon as initially being a uniform formation of the reversal nucleation centers, followed by the unrestricted expansion and overlapping of the domains throughout the sample. The volume of polarization can be mathematically expressed as [Lohse et al., 2001; Tagantsev et al, 2002];
\n\t\t\t\twhere p(t) is the volume of the ferroelectric that has been switched in time t, τ\n\t\t\t\t\t\t0\n\t\t\t\t\t is the switching time and n is a dimension constant. The electric displacement D can be expressed as [Tajitsu et al., 1987];
\n\t\t\t\twhere ε, E, P and Pr are the linear dielectric permittivity, electric field, polarization and remanent polarization, respectively.
\n\t\t\t\tDue to the nature of polycrystalline ferroelectric thin films, the KAI assumptions are not always met. It was observed in many cases that the switching time increases and the distribution of the switching time broadens as the film thickness decreases [Lohse et al., 2001; Tagantsev et al, 2002]. In the P(VDF-TrFE) system, Tajitsu et al. proposed that the increase of switching time for thinner films correspond to the increase in the activation field, which is caused by the formation of a surface layer [Tajitsu, 1995]. Nakajima et al, found that the increase in the switching time happens for FeCaps with Al contacts, but for Au contact FeCaps, the switching time is independent with film thickness [Nakajima et al., 2005]. The film thickness and contact dependence of polarization switching will be discussed in section 5. To explain the broadening of the switching time distribution for P(VDF-TrFE) thin films, alternate methods have been proposed to model the polarization switching kinetics. They are introduced and discussed below.
\n\t\t\tThe polarization switching process in a ferroelectric is affected by many factors, especially the nucleation rate of reversal domains, domain dimension, and the mobility of the domain wall [Tagantsev et al, 2002]. Different from single crystal materials, AFM and TEM studies suggest that the switching process in thin films occur region-by-region [Colla et al., 1998; Ganpule et al. 2000; Kim et al., 2010]. The polarization switching process in one region does not necessarily expand through the neighboring regions and switch the whole film. Therefore, the switching of each region is independently determined by its own characteristics, such as nucleation rate and domain dimension. Based on this analysis, Tagantsev et al proposed a model called nucleation-limited-switching (NLS) for the polarization switching of a ferroelectric thin film [Tagantsev et al, 2002]. In this model, the assumption is that each region switches independently, and in each region, the switching process is dominated by the nucleation time of the first reversal domain. The switching of the whole system is controlled by the statistics of domain nucleation, instead of domain expansion in the KAI model.
\n\t\t\t\tFor the P(VDF-TrFE) copolymer, polarization reversal originates from the rotation of the carbon-fluorine and carbon-hydrogen covalent bonding around the central chain of the polymer [Furukawa et al., 2006]. In thin film P(VDF-TrFE), the activation field for domain expansion is small (approximately 0.87 MV/cm) [Kim et al., 2010] compared to domain nucleation (approximately 7.8-12 MV/cm) [Tajitsu, 1995; Nakajima et al., 2005; Kusuma et al., 2010]. Therefore, the polarization switching dynamics are dominated by domain nucleation. Because of polycrystalline nature of thin films, they consist of many grains separated by grain boundaries. The NLS model better describes the switching process of this system. Therefore, it can be used to model the switching polarization as a function of time [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\tb].
\n\t\t\t\tIn Figure 11, P\n\t\t\t\t\t\n\t\t\t\t\t\ts\n\t\t\t\t\t is shown as a function of time for a FeCap with a P(VDF-TrFE) film thickness of 100 nm using the PUND method. The experimental data and the calculated response using the NLS model are plotted as symbols and solid lines, respectively. The polarization dispersion at a pulse width equal to 1 s (corresponding to log (t) = 0) is due to the high dc conductance of the devices caused by the increased dielectric leakage at high voltage and low frequencies [Nakajima et al., 2005]. These points are not included in the model calculation. The agreement between the experimental data and the model suggests the region-by-region polarization switching process in P(VDF-TrFE) system is a reasonable description.
\n\t\t\t\tThe relationship of the normalized switching polarization and applied voltage pulse width in positive region. The symbols are experimental data and the lines are the calculated response using the NLS model. Reprinted from [\n\t\t\t\t\t\t\t\tMao et al, 2010\n\t\t\t\t\t\t\tb] with permission.
Since the nucleation limited switching dynamic of P(VDF-TrFE) thin film dominate this switching polarization, the polarization switching time (τ) can be described as the delay time for domain nucleation, while the time for domain expansion can be neglected. The difference in domain dimensions, region sizes and especially the distribution of the nucleation centers and the nucleation rate of the reversal polarization among each region leads to a distribution of switching times throughout the film. For each region, τ is a function of applied voltage, characterized by an individual activation voltage (V0). The dispersion of τ, characterized by τmax and τmin, corresponding to the maximum and minimum V0 among all regions in the film can be extracted from the model and plotted as a function of applied voltage (symbols), as shown in Figure 12. The exponential relationship of τ and applied voltage follows equation (3). τmax is used to fit equation (3) (plotted as the solid line in Figure 12), τ0 and E0 can be extracted as 5 ns and 9.6 MV/cm.
\n\t\t\t\tExperimental τmax and τmin data from Figure 11 plotted as a function of applied voltage, and the fitting for τmax in positive polarization region. Reprinted from [\n\t\t\t\t\t\t\t\tMao et al, 2010\n\t\t\t\t\t\t\tb] with permission.
\n\t\t\t\t\tFigure 11 shows the switching dynamics (+/-P\n\t\t\t\t\t\n\t\t\t\t\t\tsw\n\t\t\t\t\t versus time) for P(VDF-TrFE) with a distribution as long as three decades, compared to eight decades for the 135 nm Pb(Zr,Ti)O3 system reported in the literature[Tagantsev et al, 2002]. The reduced range of switching dynamics in P(VDF-TrFE) films indicates a more uniform distribution of switching time, or activation field among the regions. One of the reasons could be the more uniform size of the regions and distribution of nucleation centers within the regions. Additionally, P(VDF-TrFE) has a much higher activation field of 9.6 MV/cm compared to Pb(Zr,Ti)O3, 0.77 MV/cm, therefore, the reversal polarization domain nucleation kinetics at room temperature for P(VDF-TrFE) are less dependent on thermal activation [Stolichnov et al., 2003; \n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\tb]
\n\t\t\tAs the film thickness decreases, the surface roughness becomes significant, resulting in a non-uniform electric field distribution. For the broadening of the switching time distribution, Nakajima et al proposed a model based on surface roughness [Nakajima et al., 2005]. The non-uniform distribution of electric field on the ferroelectric thin film leads to different values of switching time on different regions, and causes the broadening of the switching time.
\n\t\t\t\tUsing this method, the authors plotted the thickness distribution vs. average film thickness of four P(VDF-TrFE) samples (symbol) and fit the data with the Gaussian distribution function (line); as shown in Figure 13 (a). The electric field distribution across the film surface can be determined, which is correlated to the switching time using equation (3). The electric displacement D and polarization P can be calculated using equation (6). The calculated switching time distributions for different film thicknesses are plotted in Figure 13 (b) [Nakajima et al., 2005]. As seen for the 50 nm P(VDF-TrFE) films, the maximum amplitude of the surface roughness is approximately 20 nm, which causes a significant broadening of the switching time distribution, based on the model calculation shown in Figure 13 (b). Compared to the experimental results in Figure 19 (a) by the authors, the model predicts the correct trend, but the predicted distribution is slightly broader.
\n\t\t\t\tThe surface roughness for (a) The thickness distribution vs. the average film thickness of four P(VDF-TrFE) (75/25) copolymer thin films from 50-330 nm, and (b) the calculated differential switching time distribution at electric field of 120 MV/m. Reprinted from [Nakajima et al., 2005] with permission.
The switching kinetics of P(VDF-TrFE) thin films were also studied by Kimura et al [Kimura & Ohigashi, 1986], who proposed a model based on the defects in the crystalline phase. The defects can modulate the local electric field in the surrounding material and prevent domain growth. The effect of defects can be described as a dipole moment ∆µ, therefore, the C-F dipole moment can be affected by the defects and deviated from its intrinsic value. The ∆µ is non-uniformly distributed, which can broaden the distribution of switching time in the film [Kimura & Ohigashi, 1986].
\n\t\t\tThe fabrication process and device structure are significant factors that need to be understood to optimize device performance. Thermal annealing, P(VDF-TrFE) film thickness and contacts are discussed in this section.
\n\t\t\tThe main purpose for annealing P(VDF-TrFE) films is to increase the degree of crystallinity of the β phase and remove the residual solvent in the film [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta]. The microstructure and electrical performance of the polymer are related to the annealing temperature, time and temperature ramp up and cool down rate. The two phase transition temperatures, the Curie temperature (T\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t) and the melting temperature (T\n\t\t\t\t\t\n\t\t\t\t\t\tm\n\t\t\t\t\t) are critical in the annealing process [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta]. When heating above Tc, the ferroelectric materials loses spontaneous polarization and becomes paraelectrics. It is necessary to anneal the sample in the paraelectric phase, since the thermal energy allows the polymer chains to rearrange their orientation and position to form a more crystalline structure after cooling [Furukawa et al, 2006]. For P(VDF-TrFE) copolymer, if the films are annealed at temperatures above Tm, the β phase decreases and recrystallizes into the α or γ phase when slowly cooled down. Therefore, to achieve high β phase crystallinity films of P(VDF-TrFE), T\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t< T\n\t\t\t\t\t\n\t\t\t\t\t\tanneal< T\n\t\t\t\t\t\n\t\t\t\t\t\tm\n\t\t\t\t\t is required for annealing.
\n\t\t\t\tThe annealing effects on the microstructure of the P(VDF-TrFE) film can be studied from the point of view of surface morphology, degree of crystallinity and molecular chain orientation. The characteristics of the β phase P(VDF-TrFE) have been discussed in section 2. For 70/30 P(VDF-TrFE) films (T\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t=118 oC, T\n\t\t\t\t\t\n\t\t\t\t\t\tm\n\t\t\t\t\t =144 oC) annealed at temperatures below T\n\t\t\t\t\t\n\t\t\t\t\t\tm\n\t\t\t\t\t, increasing the annealing temperature causes a dramatic increase in grain size, as shown in the AFM height images in Figure 14 (a)-(d). The increase in the crystallinity of β phase is reflected in the XRD results, as the diffraction intensity increased for the (110), (200) diffraction peaks at 2θ=19.9o, which is shown in Figure 15. When annealed above Tm, the β phase grains disappeared and the characteristics of the surface morphology change significantly (Figure 14 (e)). The melting and recrystallization process are also recognized as a decrease of the crystallinity of β phase in XRD data (Figure 15). The surface roughness increases dramatically as the annealing temperature increase above T\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta].
\n\t\t\t\tThe effects of annealing on molecular bond and polymer chain orientation can be clearly detected using polarized FT-IR, as discussed in section 2. Figure 16 [\n\t\t\t\t\t\tMao et al. 2010\n\t\t\t\t\ta] shows the p-polarized FT-IR results for the P(VDF-TrFE) film annealed at different temperatures. When annealed below Tc (at 65 oC), the molecular and polymer chains do not have sufficient energy to align, therefore, they have a random orientation, as shown by the low IR absorption at 850 and 1288 cm-1. When annealed above T\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t but below T\n\t\t\t\t\t\n\t\t\t\t\t\tm\n\t\t\t\t\t, the higher thermal energy allows the polymer chains to start to reorient and align parallel to the substrate, as indicated by the increase of the IR absorption at 850 and 1288 cm-1 (118-144 oC). Annealing above T\n\t\t\t\t\t\n\t\t\t\t\t\tm\n\t\t\t\t\t, the polymer chains start to rotate and partially align normal to the substrate, and the β phase decreases, observed by the increase of the IR absorption at 1400 cm-1 and the decrease of the 850 and 1288 cm-1 bands.
\n\t\t\t\tFor the electrical properties of P(VDF-TrFE) FeCaps, P\n\t\t\t\t\t\n\t\t\t\t\t\ts\n\t\t\t\t\t, P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t and E\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t of the FeCap depend mainly on the molecular and polymer chain orientation of the β phase crystals, as shown in Figure 17. The FeCaps were annealed at different temperature before the deposition of the top contacts. In Figure 17, FeCaps annealed below T\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t or above T\n\t\t\t\t\t\n\t\t\t\t\t\tm\n\t\t\t\t\t show low P\n\t\t\t\t\t\n\t\t\t\t\t\ts\n\t\t\t\t\t, P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t and large E\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t. When annealed between Tc and Tm, high P\n\t\t\t\t\t\n\t\t\t\t\t\ts\n\t\t\t\t\t, P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t and low E\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t are achieved, with negligible difference as a function of temperature.
\n\t\t\t\tAFM 1µm×1µm height images of P(VDF-TrFE) film annealed at different temperatures. (a) 65 oC, (b) 118 oC, (c) 133 oC, (d) 144 oC, and (e) 154 oC. The height scales are 30 nm for (b), (c), (d), 10 nm for (a), and 100 nm for (e). All of the images were collected at room temperature.
XRD intensity of (110), (200) orientations after different annealing temperatures. The (110), (200) diffraction peaks at 2θ=19.9o are attributed to the β phase of P(VDF-TrFE).
Polarized FT-IR results for P(VDF-TrFE) films annealed at different temperatures. The different absorption at 850, 1288 and 1400 cm-1 bands represent the annealing temperature affects on polymer chain alignment. Reprinted from [\n\t\t\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\t\t\ta] with permission.
The hysteresis loops of P(VDF-TrFE) FeCaps annealed at different temperatures. Reprinted from [\n\t\t\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\t\t\ta] with permission.
For P(VDF-TrFE) copolymers, E\n\t\t\t\t\t\n\t\t\t\t\t\tc\n\t\t\t\t\t is large, approximately 0.5 MV/cm, and depends on the VDF/TrFE ratio. For low voltage applications, it is necessary to reduce the film thickness, while maintaining good ferroelectric properties. It has been shown that as the film thickness decreases, the grain size decreases, along with a decrease in the degree of crystallinity [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta]. The x-ray diffraction angle (2θ) for the (110) (200) orientation of the β phase remains constant, indicating that the inter-planar spacing, b, in the crystal lattice does not change for thinner films [\n\t\t\t\t\t\tMao et al., 2010\n\t\t\t\t\ta].
\n\t\t\t\tMerz studied the film thickness dependence of switching kinetics for BaTiO3 crystals and found the activation field increases as the film thickness decreases, which is attributed to the formation of an interfacial layer between the ferroelectric crystal and the contacts [Merz, 1956]. Based on Merz’s approach, Tajitsu [Tajitsu, 1995] and Xia et al [Xia et al., 2001] studied the switching kinetics of P(VDF-TrFE) FeCaps with Al contacts for different ferroelectric film thicknesses. Their experimental data suggest that the increase in polarization switching time as the P(VDF-TrFE) film thickness decreases can possibly be explained by the formation of an interfacial layer.
\n\t\t\t\tIn Merz’s approach, the thickness dependence of E0 for thin films can be expressed as [Merz, 1956]
\n\t\t\t\twhere E\n\t\t\t\t\t\n\t\t\t\t\t\t01\n\t\t\t\t\t is the activation field for thick films, β is an experimental fitting parameter and d is the film thickness.
\n\t\t\t\tThe interfacial layer can be treated as a dielectric layer electrically connected in series with the ferroelectric film; therefore, from [Merz, 1956]
\n\t\t\t\twhere V\n\t\t\t\t\t\n\t\t\t\t\t\ttotal\n\t\t\t\t\t\n\t\t\t\t\t, V\n\t\t\t\t\t\n\t\t\t\t\t\tf\n\t\t\t\t\t and V\n\t\t\t\t\t\n\t\t\t\t\t\tit\n\t\t\t\t\t are the total applied voltage, voltage drop across the ferroelectric film and the interfacial dielectric layer, respectively. The charge continuity at the boundary of the two interfaces can be expressed as [Merz, 1956]
\n\t\t\t\twhere ε\n\t\t\t\t\t\n\t\t\t\t\t\tf\n\t\t\t\t\t and ε\n\t\t\t\t\t\n\t\t\t\t\t\tit\n\t\t\t\t\t are the dielectric permittivity of the ferroelectric and interfacial layers, d\n\t\t\t\t\t\n\t\t\t\t\t\tf\n\t\t\t\t\t and d\n\t\t\t\t\t\n\t\t\t\t\t\tit\n\t\t\t\t\t are the thickness of the ferroelectric and interfacial layers, respectively. Due to d\n\t\t\t\t\t\n\t\t\t\t\t\tf\n\t\t\t\t\t>> d\n\t\t\t\t\t\n\t\t\t\t\t\tit\n\t\t\t\t\t and ε\n\t\t\t\t\t\n\t\t\t\t\t\tf\n\t\t\t\t\t\n\t\t\t\t\t/d\n\t\t\t\t\t\n\t\t\t\t\t\tf\n\t\t\t\t\t<< ε\n\t\t\t\t\t\n\t\t\t\t\t\tit\n\t\t\t\t\t\n\t\t\t\t\t/d\n\t\t\t\t\t\n\t\t\t\t\t\tit\n\t\t\t\t\t [Xia et al., 2001], (9) can be rewritten as [Xia et al., 2001]
\n\t\t\t\twhere E\n\t\t\t\t\t\n\t\t\t\t\t\tf\n\t\t\t\t\t and E\n\t\t\t\t\t\n\t\t\t\t\t\ttotal\n\t\t\t\t\t are the electric field across the ferroelectric material and the applied electric field.
\n\t\t\t\tXia et al characterized P(VDF-TrFE) FeCaps with the film thickness ranged from 600 to 120 nm, and used this approach to analyze the switching time dependence. If the interfacial model is not incorporated, a clear thickness dependence of switching time can be found (Figure 18 (a)), as the switching time increases for thinner films. When the interfacial layers are taken into account, switching time is much less dependent on film thickness, as shown in Figure 18 (b).
\n\t\t\t\ta) Switching time as a function of 1/E with different film thicknesses for (from right to left) 600, 370, 200, 150, 120 nm films and (b) switching time as a function of E\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tf\n\t\t\t\t\t\t\t using the interfacial layer model. Reprinted from [Xia et al., 2001] with permission.
Metal is the most commonly used material for FeCap contacts. For organic electronic systems, the physical and chemical processes on the interface need to be considered when metal is deposited on the organic materials. Reactive metals such as Ti, Ni and Al can react with the organic materials and form an interfacial layer, which can degrade the electrical properties [Xu et al., 2009]. For P(VDF-TrFE) copolymer, Ti and Ni can react with the fluorine atom in the –CF2- components and create TiFx and NiFx at the interface, respectively [Xu et al., 2009; Chen & Mukhopadhyay, M., 1995]. For chemically inert metals, such as Au, less chemical reaction occurs between the metal atom and P(VDF-TrFE). However, it is easy for the metal to diffuse into the low density polymer film, creating a large leakage current for thinner films.
\n\t\t\t\tNakajima et al studied the P(VDF-TrFE) FeCaps using different contact metals as Al and Au. The switching time distribution broadens as the film thickness decreases for FeCap with both contacts. However, the authors found that the switching time increase with decreasing film thickness only for the FeCaps with Al contact, not for Au contact FeCaps. The authors suggest that the increase of the switching time is attributed to an interfacial dielectric layer formed when Al is deposited on P(VDF-TrFE), which is in agreement with the above discussion. This interfacial layer helps reduce the leakage current, while degrading the polarization switching speed. No interfacial layer is formed between P(VDF-TrFE) and Au. Therefore, the switching time does not increase with decreasing film thickness.
\n\t\t\t\tIt has also been demonstrated that by using polymeric electrodes, device performance and reliability can be improved. The improvement can be attributed to better adhesion, wetting and similar chemical properties of the surface, compared to metal contacts. Naber et al found that adding a conducting polymer poly(3,4-ethylenedioxythiophene): poly(styrenesulfonicacid) (PEDOT: PSS) on top of Al or indium-tin-oxide (ITO) for bottom contact improves both the P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t and switching time for films as thin as 65 nm of P(VDF-TrFE) [Naber et al., 2004]. Xu et al demonstrated that both polypyrrole-poly(styrene sulfonate) and PEDOT-PSSH can be used as buffer conducting polymer layers for P(VDF-TrFE) top and bottom contacts. Improved device performance with higher P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t and faster switching speeds were achieved. A P\n\t\t\t\t\t\n\t\t\t\t\t\tr\n\t\t\t\t\t of more than 70% of its initial value can be achieved after 1×107 cycles of switching for 50 nm thick P(VDF-TrFE) film devices, as shown in Figure 20 [Xu et al., 2007, 2009]. Xu et al also found that the conducting polymer buffer layers improve the degree of crystallinity of the thin films [Xu et al., 2009].
\n\t\t\t\tThe polarization switching behaviors for (a) Au contact FeCap, and (b) Al contact FeCaps. Reprinted from [Nakajima et al., 2005] with permission.
Hysteresis loops for 50 nm of P(VDF-TrFE) film with Ti as the top and bottom contacts; (a) with two PEDOT-PSSH buffer layers between P(VDF-TrFE) and Ti for top and bottom contacts, (b) without buffer layers. Solid lines and dashed lines are the measurement before and after 1×107 cycles of switching, respectively. Reprinted from [Xu et al., 2009] with permission.
In this chapter, the material and electrical properties, and the ferroelectric polarization switching kinetics of P(VDF-TrFE) copolymer have been reviewed. The ferroelectric properties originate from the large difference in the electronegativity between the fluorine, carbon and hydrogen atoms. The polymer phase structure, surface morphology, crystallinity, and molecular chain orientation associated with the ferroelectric β phase have been discussed. The P(VDF-TrFE) copolymer exhibits a high spontaneous polarization > 8 µC/cm2 (depending on fabrication process and mole ratio of VDF/TrFE) and a square like hysteresis loop. The sharp peak in the switching current indicates the fast rotation of the dipole around the polymer chain.
\n\t\t\tTo illustrate the switching kinetics of P(VDF-TrFE) thin films, two basic polarization switching mechanisms, reversal polarization nucleation and domain wall expansion were reviewed. A commonly accepted statistical model (KAI) for single crystal polarization switching was discussed and extended to models to explain the switching time broadening for P(VDF-TrFE) thin films, including the nucleation-limited-switching (NLS) model based on region-to-region switching kinetics, surface roughness based model, etc. The NLS model can be successfully used to fit P(VDF-TrFE) switching data and τ0 and E0 can be extracted as 5 ns and 9.6 MV/cm.
\n\t\t\tThe annealing temperature, film thickness and contacts were then discussed. For annealing above Tc but below Tm, the grain size and the crystallinity of the (110) (200) orientation of the β phase increases, the polymer chains align parallel to the substrate with the polarization dipole moment perpendicular to the substrate. At annealing above Tm, the surface morphology changes significantly, the degree of crystallinity in the β phase decreases dramatically, and the polymer chains tend to align normal to the substrate. As the film thickness decreases, the grain size and degree of crystallinity decrease. The increase switching time as film thickness decreases can possibly be explained by the formation of an interfacial layer. For the contact, reactive metals induce an interfacial layer, which causes an increase in the switching time. P(VDF-TrFE) FeCaps with Au contacts do not have this film thickness effect, but as the film becomes thinner than 100 nm, the diffusion of Au atoms increases the leakage current. Therefore, thin films with high quality are required. Using conducting polymers, such as PEDOT: PSS and polypyrrole-poly(styrene sulfonate) as a buffer layer for the contacts show improved electrical performance in remanent polarization, switching time and reliability for thin film P(VDF-TrFE) based FeCaps.
\n\t\t\tOne of the most important applications of P(VDF-TrFE) copolymer is ferroelectric nonvolatile memory (FeRAM). The two stable states of the ferroelectric material in positive and negative directions can be used as digital data “1” and “0”, and the remanent polarization leads to data storage with the power off (nonvolatile). Due to the low temperature, solution process of P(VDF-TrFE) films, it is compatible with large area and flexible electronic applications. Even though the polarization switching speed of P(VDF-TrFE) is slow (~1 µs) compared to PZT (~ 10 ns), it is much faster than the conventional flash memory(100 µs) in writing and programming. Moreover, it is reliable with more than 1×107 cycles of switch [\n\t\t\t\t\tMao et al., 2011\n\t\t\t\ta], and can be used in low voltage applications [Fujisaki et al., 2007]. The memory cell can be constructed by combining access transistors with the ferroelectric capacitors. The circuit structure depends on the number of access transistors and ferroelectric capacitors [Arimoto & Ishiwara, 2004]. One transistor-one capacitor (1T1C) FeRAM elements based on P(VDF-TrFE) were recently demonstrated by the authors [\n\t\t\t\t\tMao, et al., 2011\n\t\t\t\tb]. Ferroelectric transistors can also be fabricated using P(VDF-TrFE) for each bit in FeRAM [Naber et al., 2005; Lee et al., 2009], however, the reliability still needs to be improved for future applications.
\n\t\tThe thalassemias are a major cause of morbidity and mortality throughout much of the world [1, 2, 3, 4, 5, 6, 7, 8, 9]. Thalassemias are characterized by the disruption of the synthesis of normal adult hemoglobin (HbA; an α2β2 tetramer; Figure 1) consequent to a diverse array of genetic mutations/deletions to either the β or α-hemoglobin chain genes (Chromosomes 11 and 16, respectively). As a consequence of reduced/absent production of β-chains, β thalassemia is characterized by the presence of highly unstable monomeric α-chains as these chains cannot self-associate and indeed require a chaperone protein to prevent precipitation [10]. In contrast, α thalassemia is characterized by the presence of relatively stable tetrameric β chains. Interestingly, as schematically shown in Figure 1, unlike most genes, there are four copies of the α-globin genes; this is in contrast to the expected two copies of the β-globin genes. The evolutionary duplication of the human α-chain genes may have been favored consequent to the inherent instability of monomeric α-chains. Indeed, the instability of the α-chains is the key factor underlying the pathophysiology of the β thalassemic red blood cell (RBC). Moreover, the pathophysiology of β thalassemia can be further complicated by the geographical prevalence, and high frequency, of a number of mutated β hemoglobin genes (e.g., sickle hemoglobin, hemoglobin E and hemoglobin C). If a mutated β-chain is the only functional β-chain present, the resultant disease will be more severe than that observed in β thalassemia Intermedia (a single normal β-globin gene). Loss of both β-chain genes gives rise to severe β Thalassemia Major which is fatal in the absence of transfusion therapy. The α thalassemias are characterized by a broader range of disease states due to the presence of 4 α genes. The loss of expression from a single gene (α Thalassemia1 Trait) is often asymptomatic and undiagnosed; though the individual is a carrier for α Thalassemia and, in high frequency geographic areas may be at elevated risk for symptomatic disease transmission to an offspring. Deletion of two or three α-genes results in severe disease as a single active α-gene cannot, due to the instability of the chain, produce sufficient mature α-chains to form sufficient HbA. Loss of all four α-genes is fatal (resulting in Hydrops fetalis) due to the crucial role that α-chains play in embryonic and fetal hemoglobin. In contrast to β thalassemia, stable mutated α-chains are rare so typically these do not pose a significant complication in the pathophysiology of α thalassemia.
\nMolecular basis and clinical diagnosis of the α and β thalassemias [1, 2, 3, 4, 5, 6, 7, 8, 9]. β* denotes abnormal β hemoglobin gene such as HbS or HbE.
In this chapter we will further explore the pathophysiology of the β thalassemic RBC. Surprisingly, while significant injury to the thalassemic erythrocyte arises from the excess α-chains, the underlying mechanisms by which these chains damage and subsequently destroy the thalassemic RBC in the bone marrow and peripheral blood have not been clearly delineated. Our lack of understanding of the mechanisms of α-chain mediated damage is due, in part, to three major factors: (1) studies of RBC from β thalassemic individuals are difficult to do since these cells, upon collection, already exhibit significant injury and represent a survivorship bias since up to 80% of erythroid precursors are destroyed within the bone; (2) β thalassemic patients are typically transfused to both correct the severe anemia accompanying the disease and to prevent endogenous erythropoiesis of defective RBC; and (3) the lack of a good experimental model by which the pathophysiology of excess globin chains on human RBC can be examined.
\nWhile little can be done to change the first two problems, researchers have attempted to tackle the third issue using murine models of thalassemia [11, 12, 13, 14, 15, 16, 17]. Original murine studies examining the knockout of the murine β-chains were not productive as the murine α-chains behave significantly different from their human counterpart. To overcome this problem, human α-chain genes were inserted into the mouse genome in place of the murine genes. Again, these studies failed to give rise to as severe a phenotype as is seen in the human disease. Subsequent studies utilized additional mutations to produce symptomatic disease in the murine context—albeit with still substantial differences from the pathophysiology seen in the human β thalassemic RBC. Hence, an alternative approach for studying the pathophysiology of unpaired α-chains on the human RBC was needed.
\nTo this end, our laboratory developed an in vitro model of the HUMAN β thalassemic erythrocyte [18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. In this model, purified human α-chains are entrapped within normal human RBC (or, if desired, mouse RBC) by osmotic lysis and resealing (Figure 2) [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. As previously shown, osmotic lysis and resealing results in RBC exhibiting normal hemoglobin concentration and volume (Table 1) as well as normal ATP concentration, oxidant sensitivity, morphology and deformability while allowing for the efficient entrapment of exogenous compounds [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. Indeed, studies with resealed human RBC demonstrate that this methodology can be used to correct enzyme deficiencies, enhance antioxidant levels, and be used in vitro to study malarial growth and maturation. Moreover, murine studies demonstrated that osmotically resealed murine RBC exhibited normal in vivo survival. To manufacture the model β thalassemic RBC from normal human donor cells, purified, heme-containing, α-hemoglobin chains were prepared by dissociation of CO-treated HbA in the presence of parahydroxymercuribenzoate, followed by ion exchange chromatography, to isolate the purified CO-α-chains as previously described [1, 18, 20, 21, 22, 35, 36]. Analysis of the purified α-chains by mass spectroscopy demonstrated the expected mass values for the α-globin chain. The purified α-chains can be stored at −80°C as carbon monoxide stabilized chains (CO-α-chains) and then thawed immediately prior to use.
\nGeneration of model β thalassemic RBC from normal human donor cells via osmotic lysis and resealing [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. Osmotically lysed and resealed RBC have normal morphology and metabolism and exhibit normal in vivo survival.
Parameter | \nN | \nNormal | \nResealed*\n | \nModel β thal*\n | \nModel α thal*,**\n | \n
---|---|---|---|---|---|
Mean cell volume (μm3) | \n7 | \n88.9 ± 1.5 | \n85.8 ± 4.5 | \n78.6 ± 0.8 | \n76.0 ± 4.0 | \n
Mean cell hemoglobin (pg) | \n7 | \n30.5 ± 0.8 | \n28.5 ± 2.7 | \n23.4 ± 0.6 | \n26.9 ± 2.1 | \n
Mean cell Hb conc. (g/dl) | \n7 | \n34.2 ± 0.7 | \n33.2 ± 1.7 | \n29.6 ± 0.6 | \n35.5 ± 1.3 | \n
Red cell distribution width (RDW) | \n7 | \n12.9 ± 0.2 | \n17.5 ± 4.5 | \n29.2 ± 0.5 | \n21.3 ± 3.8 | \n
Entrapment of the purified α-chains within normal erythrocytes is done by osmotic lysis and resealing as previously described [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. Briefly, washed, packed erythrocytes (80–85% hematocrit) are mixed with the purified CO-α-chains (10 mg/ml packed red cells) and then placed as a thin film within 11.5 mm diameter dialysis tubing (MW cutoff of 3500). The samples are dialyzed against a hypotonic lysis buffer (5 mM potassium phosphate buffer and 2 mM EDTA; pH 7.4) at 4°C for 60 min. The dialysis tubing is then transferred to an isotonic resealing buffer (5 mM potassium phosphate, 160 mM NaCl, and 5 mM glucose; pH 7.4) with gentle agitation for 30 min at 37°C. Following resealing, cells are washed with saline until the supernatant is clear. Using this procedure, approximately 70–80% of the initial packed erythrocyte volume is recovered. Radiolabeled α-chains can be utilized to quantitate the intracellular entrapment [18, 20].
\nTo determine whether the model β thalassemic erythrocytes exhibit the cellular abnormalities characteristic of true β thalassemic cells, a number of cellular parameters have been examined. The results of these studies demonstrate that the α-chain loaded erythrocytes exhibit structural and functional changes very similar to those seen in β thalassemic erythrocytes (Table 2). Consequently, this model allowed for the systematic examination of the mechanisms underlying the α-chain mediated damage within the β thalassemic RBC and to directly determine the ontogeny of the pathologic events underlying the RBC injury and to experimentally test potential therapeutic approaches.
\nCharacteristic | \nβ thalassemic RBC | \nModel β thalassemic RBC | \n
---|---|---|
Microcytic RBC (MCV <80 fl) | \n+ | \n+ (progressive) | \n
K+ Loss | \n+ | \n+ | \n
Unpaired α-chains | \n1–3% of total hemoglobin in peripheral blood reticulocytes | \n3–4% of total hemoglobin | \n
Membrane Bound Globin | \nIncreased | \nIncreased; correlated with α-chain autoxidation & heme release. | \n
Membrane proteins/thiols | \nLoss of spectrin and ankyrin. Oxidation of membrane thiol (-SH) groups. | \nLoss of spectrin and ankyrin correlated with membrane thiol (-SH) oxidation, α-chain autoxidation, and heme release. | \n
Cellular deformability | \nDecreased cellular and membrane deformability | \nDecreased; correlated with iron/heme deposition in membrane. | \n
Intracellular oxidant stress | \nEvidence supporting increased oxidative damage | \nIncreased H2O2; correlated with α-chain autoxidation & heme release. | \n
Oxidant susceptibility | \nIncreased | \nIncreased; correlated with membrane bound iron/heme. | \n
Membrane bound iron/heme | \nIncreased membrane associated hemoglobin & Heinz body formation | \nIncreased membrane heme; correlated with α-chain autoxidation. | \n
Short in vivo survival | \n+ | \n+ (murine model β Thal RBC) | \n
Containing approximately 20 mM iron, the RBC is the most ferruginous somatic cell in mammals. Under normal conditions, most of this iron is complexed within hemoglobin (as heme) with virtually none present as free metal (i.e., non-heme). This near perfect compartmentalization of iron may, however, break down in certain pathologic states such as β thalassemia and sickle cell disease resulting in the autoxidation of hemoglobin (i.e., formation of methemoglobin and hemichromes). Of physiologic importance, the monomeric α-chains spontaneously autoxidize to methemoglobin, simultaneously generating superoxide (O2\n−), at a rate 8-times that of normal hemoglobin (Figure 3) [18, 20, 22, 23, 24, 25, 26, 27, 37, 38, 39]. Moreover, consequent to the formation of methemoglobin, the non-covalently bound heme is more likely to escape the heme pocket of the globin chain giving rise to elevated levels of free, redox-active, intraerythrocytic iron. The O2\n− produced via the autoxidation of hemoglobin can reduce ferric (Fe+3) to ferrous (Fe+2) iron or form hydrogen peroxide (H2O2; either spontaneously or enzymatically via superoxide dismutase). Importantly, the iron, O2\n−, and H2O2 can, via the Haber-Weiss Reaction, give rise to the formation of the ‘dreaded’ hydroxyl radical (•OH) which rapidly reacts with virtually all biological constituents converting pristine materials into biological garbage (Figure 3). However, despite the general concept that free iron and the formation of free radicals are bad, the actual iron-dependent pathophysiology of the β thalassemic RBC has been poorly understood.
\nFree radical basis of α-hemoglobin autoxidation and free radical injury. Consequent to the formation of methemoglobin, the non-covalently bound heme is 8-times more likely to escape the globin chain. Release of the heme initiates iron-dependent free radical reactions. References: [18, 19, 20, 21, 22, 23, 24, 25, 26, 27].
Mechanistically, studies using the model β thalassemic RBC have demonstrated that the initial autoxidation of the unpaired α-chains initiates an iron and reduced glutathione (GSH) dependent, self-amplifying and self-propagating reaction with the subsequent release of even more heme and, eventually, free iron. Schematically, this self-amplifying, self-propagating injury pathway is shown in Figure 4. As noted, the reaction process is initiated by the autoxidation of the unpaired α-chains which gives rise to the release of free heme and the generation of O2\n−. Interestingly, at this point, a key component of this pathway is GSH; an ‘anti-oxidant’ present at high intracellular (~2.3 mM) concentrations within the RBC [41, 42]. GSH readily reacts with free heme resulting in the cleavage of the heme ring, the release of free iron, and the formation of a thiol radical (GS•). This reaction leads to the rapid amplification of the oxidative damage to the RBC [18, 20, 22, 23, 24, 25, 26, 27]. .The importance of the released iron and GSH was documented experimentally. As shown in Figure 5A, addition of Fe+3 to hemolysates from normal RBC results in the rapid oxidation of oxyhemoglobin in an iron-dose dependent manner. The oxidation of hemoglobin can be inhibited by the inclusion of an iron chelator (shown is deferoxamine; DFO) or by chemical depletion of GSH (not shown) [23, 27]. Moreover, in the intact model β thalassemic RBC, chemical depletion of GSH inhibited iron-driven hemoglobin oxidation (Figure 5B) [23, 27]. In contrast, as shown in Figure 5C, increasing the amount of intracellular GSH (via osmotic lysis and resealing; see Figure 2) in the model β thalassemic RBC significantly exacerbated injury to the cell. This enhanced injury is readily seen by the significantly reduced deformability (i.e., increased mean cell transit time) of the GSH-loaded model β thalassemic cells relative to the control model β thalassemic RBC. Importantly, as shown, GSH supplementation of normal RBC in the absence of iron had no detrimental effects on cellular deformability.
\nDamage to multiple components of the β thalassemic RBC is mediated by an Fe-GSH dependent mechanism. As thalassemic RBC circulate, α-hemoglobin chains autoxidize (A) giving rise to superoxide (O2\n−) and methemoglobin [MetHb]. The heme moiety of the α metHb chains are released yielding free heme and globin (B). Free heme reacts with reduced glutathione [GSH; reaction (C)] resulting in cleavage of the heme group and the formation of a glutathione radical (GS•) and the release of free Fe+2 (D). The free iron (E) reacts with hemoglobin derived reactive oxygen species (ROS: O2\n− and H2O2) to generate •OH – A highly reactive radical capable of damaging all cellular components including cellular metabolism and cation/anion balance. The ferric iron (Fe+3), in the presence of additional GSH or O2\n− regenerates Fe+2 which then oxidizes additional hemoglobin (F). Reactions (G) and (H) represent subsequent oxidative and non-oxidative injury to the cell. Oxidative pathway generated from references: [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 40].
Role of iron and GSH in the destruction of the β thalassemic RBC. (A) Fe+3 is a potent accelerator of hemoglobin oxidation. Shown is the oxyhemoglobin concentration following the addition of 100, 175 and 250 μM Fe+3 to a fresh RBC hemolysate. In contrast to the Fe+3-treated samples, no oxidation was observed in the absence of added Fe+3 or in the presence of an iron chelator [DFO (deferoxamine) or, not shown, the tripeptide Gly-His-Lys]. Also shown are sequential, hemoglobin scans of the hemolysates treated with Fe+3. The time, in minutes, of the individual scan line following addition of Fe+3 are indicated [23, 27]. (B) Depletion of GSH in model β thalassemic RBC inhibits hemoglobin oxidation. Shown is the percent oxyhemoglobin in control-resealed and model β thalassemic cells RBC over 27 h at 37°C. GSH was depleted by treatment with 1-chloro-2.4-dinitrobenzene (CDNB) as previously described [18, 20, 31, 32]. (C) Elevated intracellular GSH levels in model β thalassemic RBC adversely affects cellular deformability as demonstrated by the cell transit analyzer. Less deformable cells take much longer to transit through a pore of known diameter and length. The results shown are the mean ± S.D. of a minimum of four experiments with >2000 RBC measured at each time point. From references: [23, 27].
The enhanced oxidative stress, and consumption of GSH, was further noted by the time dependent decrease in GSH noted in the model β thalassemic RBC (Table 3) [27]. Moreover, a decrease in the NADPH/NADPtotal ratio was noted. NADPH is utilized to regenerate reduced GSH from oxidized (GSSG) glutathione via glutathione reductase. This decrease in the NADPH/NADPtotal ratio is likely reflective of both the high GSH-GSSG-GSH cycling but also of metabolic abnormalities arising consequent to iron and free radical mediated inhibition of normal glucose metabolism (Figure 4). Also of physiological importance, was the finding that the model β thalassemic RBC exhibited significantly (p < 0.001) decreased catalase activity (Table 3). Catalase is the pre-eminent defense against H2O2 within the RBC, making β thalassemic cell particularly increasingly sensitive to H2O2 generated via the pathway described in Figure 4 [31, 32, 33, 34, 43]. Following 20 h incubation at 37°C, only 61.5 ± 2.9% of the initial catalase activity remained in the α-hemoglobin chain loaded cells versus 104.6 ± 4.5% in the control RBC. The loss of catalase arose due to the decrease in the NADPH/NADPtotal ratio as studies have demonstrated that NADPH is essential for maintaining catalase in an enzymatically active state [31, 32, 33, 34, 43, 44, 45, 46, 47]. Indeed, as noted in Table 3, the model β thalassemic erythrocytes exhibit a significant decrease in the NADPH/NADPtotal ratio similar to that seen in severe G6PD deficiency. Hence, consequent to the oxidation of hemoglobin and the formation of free radicals in the thalassemic RBC, significant metabolic and functional changes are noted in the model β thalassemic RBC that mirror those seen in patient derived samples (Figure 4 and Table 2). It is also important to note that non-oxidative driven damage also occurs. As shown in Figure 4, precipitated globin proteins, as well as iron and heme, can alter the intracellular viscosity of the cytoplasm and interact with the cytoskeleton and membrane lipids resulting in mechanical dysfunction. These oxidative and non-oxidative injuries can dramatically affect the function of the RBC.
\nPopulation | \nHours (37°C) | \nGSH (μmol/g Hb) | \nNADPH/NADPtotal (1.0 = Normal) | \nCat. activity (IU/g Hb) | \n
---|---|---|---|---|
Control RBC | \n0 | \n5.6 ± 0.4 | \n0.870 | \n147,300 ± 17,000 | \n
\n | 20 | \n6.0 ± 0.6 | \n1.063 | \n154,100 ± 14,800 | \n
Model β Thal | \n0 | \n5.2 ± 0.3 | \n0.898 | \n145,600 ± 12,300 | \n
\n | 20 | \n2.1 ± 0.0* | \n0.478* | \n89,540 ± 8200* | \n
Association between NADPH, GSH and catalase.
p < 0.001 from time-matched Control RBC.
Modified from [27].
From a functional standpoint, perhaps the most important consequence of the oxidative changes to the β thalassemic RBC, as well as other RBC abnormalities, is the loss of cellular deformability [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 48, 49, 50, 51, 52]. The physiology, fluidics and vascular bed of the circulatory system impart unique rheological stresses on circulating RBC (Figure 6A) [53]. These include extreme variations in shear stress and viscosity as well as biomechanical obstacles (e.g., capillaries and splenic filtration). With an average resting cardiac output of approximately 5 L/min, blood flow varies from approximately 40 cm/s in the aorta to 0.03 cm/s in the smallest capillaries [53, 54]. Moreover, blood viscosity (affecting shear stress) is also variable. At high RBC counts and high flow rates, blood is highly viscous while at low RBC counts and low flow rates (capillaries), blood viscosity is greatly reduced. Rheological stress is further exacerbated by the biomechanical stresses induced by the extreme disparity in the size of RBC (~8 μm) to the minimum diameter of the vascular capillary beds (4–5 μm) and splenic interendothelial clefts (0.5–1.0 μm) [55, 56]. Hence, consequent to the shear forces, viscosity and biomechanical stresses placed on blood cells, a key biologic/physiologic requirement of the RBC within the vascular space is rheological deformability. Biomechanically, the intracellular viscosity and membrane rigidity of the RBC are the key factors in imparting their vascular rheological deformability; both of which can be dramatically altered consequent to hemoglobin oxidation, heme release and/or redox-damage to cytoplasmic, cytoskeletal, or membrane components (Figure 4) [57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68]. Indeed, as shown in Figure 6B, ektacytometric analysis of the model β thalassemic RBC shows a significant loss of cellular deformability induced by shear stress (e.g., large vessels). Moreover, cell transit analysis of these cells (analogous to capillary deformation) showed a very significant loss of deformability in the model β thalassemic cells as reflected by the very large and significant increase in transit time (Figure 6C).
\nVascular deformability of model β thalassemic RBC. (A) The vascular bed is composed of blood vessels of various sizes which create significant disparity in blood (fluid and cellular) velocity consequent to vessel diameter. The fluid flow induces rheological sheer stress while the vessel size creates biomechanical deformation of cellular elements. Shown is an RBC undergoing deformation in a microfluidic channel. (B) Ektacytometric analysis of α-chain loaded RBC demonstrate that these chains dramatically reduce the sheer-induced shape change of the cell [24]. Ektacytometry bests approximates high flow rates. (C) The mean cell transit time (in ms) of model β thalassemic cells was significantly increased, similarly to that observed in patient samples [20]. This microfluidic flow best approximates capillary flow.
Consequent to the loss of deformability and immune recognition (e.g., Kupffer cells of the liver and, potentially, antibodies), the circulatory survival of β thalassemic RBC is impacted. As demonstrated in Figure 7A, model β thalassemic RBC (Blood group A) exhibited enhanced immune recognition and phagocytosis by autologous monocytes when compared to control cells from the same donor. Indeed, the level of phagocytosis was similar to that of the anti-A opsonized positive control RBC. The loss of deformability and enhanced immune recognition both contribute to decreased in vivo survival. This was demonstrated using mice transfused with model β thalassemic murine cells (mouse RBC + human α-chains) in which the transfused RBC exhibited a dramatic reduction in the circulatory lifespan (Figure 7B). The role of α-chain mediated oxidation was supported by the finding that lightly oxidized (phenazine methosulphate treated; 50 μM) murine cells showed similar circulatory dynamics. These results are comparable to that observed in humans where, consequent to the α-chain driven oxidation, β thalassemic RBC have a very short circulatory lifespan (7–14 days depending on spleen status) compared to the 120 days of a normal RBC.
\nModel β thalassemic RBC are immunologically recognized and cleared rapidly from the peripheral circulation in vivo. (A) Blood group A RBC that were loaded with purified α-chains were phagocytosed by human monocytes. Shown for comparison are control cells from the same donor that were either unopsonized or opsonized with an anti-A blood typing antibody. (B) Model β thalassemic mouse RBC were made by the entrapment of purified human α-hemoglobin chains within Normal murine RBC. Oxidatively damaged RBC were made by treating mouse RBC with 50 μM phenazine methosulfate (PMS) for 2.5 h then washing. Both PMS-treatment and the entrapment of α-hemoglobin chains lead to membrane iron deposition and extensive RBC oxidation. The model β thalassemic and PMS-treated RBC have half-lives of 4 and 7 days, respectively in the peripheral circulation versus 26 days for normal murine RBC. Shown is the percent total RBC mass that is PKH-26 labeled. Inset: The peripheral blood lifespan of the human β thalassemic RBC are approximately 6–10 days in a patient with a functioning spleen and 12–16 days in a splenectomized individual. Normal RBC circulates approximately 120 days, data modified from Blendis et al. [69].
Interestingly, thalassemias have been clinically associated with an increased risk of recurrent bacterial infections [70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87]. This is most evident in under-developed nations where sanitary and medical facilities are most lacking. Despite the clinical evidence of recurrent bacterial infections in thalassemic patients, the biological events underlying this finding are unclear. This confusion arises as a natural consequence of the heterogeneity of the microbial disease itself, the patients age, the state of splenic function, the frequency of transfusion, the degree of similarity between the patient and the blood donor pool, the nutritional status of the patient (e.g., United States versus Thailand) and whether one is looking at humoral or cell-mediated immunity [70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87].
\nIn general, studies on the humoral (i.e., immunoglobulin-based) immunity of thalassemic patients suggest that this arm of the immune system is ‘relatively’ normal. These studies have indicated normal to elevated levels of IgG, IgA, and IgM but decreased levels of Factor B, C3, and C4 (perhaps due to consumption via oxidatively damaged β thalassemic cells). Reflective of this normality, and consequent to the extensive oxidant injury to the thalassemic cells, circulating immune complexes and an elevated risk of autoimmune hemolytic anemia have been described in β thalassemia intermedia and major patients. Serum fractions from these patients also exhibited increased amounts of C1q-precipitable immune complexes. In contrast, as suggested by the clinically described recurrent bacterial infections, cell-mediated immunity is highly suspect in the thalassemic patient (and sickle cell patients). The few direct studies on cell-mediated immunity in thalassemic patients were, typically, enumeration of the mononuclear cell populations (T cells, B cells, NK cells and monocytes). In general, these studies suggest normal cell numbers but a skewed distribution of the CD4+ to CD8+ T cell ratio. The altered ratio was characterized by a relative depression in CD4+ T cells (i.e., helper T cells) and NK (Natural Killer) cells and a relative rise in CD8+ (cytotoxic and suppressor) T cells that increased linearly with the number of units transfused. However, very few functional studies have been done in thalassemic patients to answer the question: Why are β thalassemic patients at risk of recurrent bacterial infections?\n
\nPrevious studies have suggested that increased bioavailable iron in transfused patients might facilitate the growth of organisms in which iron is a limiting nutrient (i.e., most bacteria). Other studies have implicated the loss of splenic function. While both of these factors may indeed play important roles in recurrent bacterial infections, they may not offer a complete explanation. In addition to thalassemia, a number of other diseases and trauma scenarios are characterized by recurrent bacterial infections (e.g., malaria and burn injury) suggestive of impaired cell-mediated immunity. Interestingly, a common characteristic of all these conditions is erythrophagocytosis. Previous studies have demonstrated that phagocytic uptake of IgG-coated and oxidatively stressed RBC resulted in a transient depression of further macrophage phagocytosis, decreased respiratory burst (i.e., NADPH-oxidase activity; O2\n− production), and impaired killing of bacteria [88, 89, 90, 91, 92, 93]. Interestingly, in the case of Plasmodium falciparum-infected RBC, only phagocytosis of mature (trophozoite), but not immature (ring stage), stages had an inhibitory effect on monocyte function. Importantly, a major difference between the mature and immature malarial infected RBC is the presence of malarial pigment (hemozoin), an iron/heme rich degradation product of parasite hemoglobin catabolism. Τhe heme- and iron-rich membranes of the β thalassemic RBC, which we have previously documented [22], may function in a manner analogous to malarial pigment or iron salts and impair cell-mediated immunity—primarily at the level of the APC but potentially extending to the T cell level. Some data from thalassemic patients support the hypothesis for impairment of the T cell response. For example, patients with thalassemia intermedia have been reported to have diminished T cell mitogen responses when their serum iron and ferritin were higher than 200 and 600 μg/dl, respectively [94].
\nHence, injury arising from the iron-GSH pathway can result in (any combination of) RBC opsonization by endogenous antibodies, phosphatidylserine (PS) exposure, protein clustering, sublytic levels of complement binding, and/or loss of cellular deformability (Figure 7) that leads to the removal of the damaged β thalassemic cells from the circulatory system by components of the mononuclear phagocytic system (MPS). Erythrophagocytosis can occur within the spleen (if present and functioning), liver (Kupffer cells) or the microvasculature itself when non-deformable RBC are trapped and then cleared by circulating macrophages. Regardless of the location of removal, erythrophagocytosis results in impaired MPS function. As shown in Figure 8A, antigen presentation of purified tetanus toxoid (TT; a peptide) or fixed, intact, S. mutans (SM; an intact bacteria) by normal human antigen presenting cells (APC; blood monocytes) was dramatically, and differentially, affected by the presence of either control (unoxidized) or oxidized (50 μM PMS as per Figure 7) human RBC. As shown, oxidized RBC prevented successful antigen presentation to human T cells while normal RBC showed no detrimental effects. Further experimentation demonstrated that the inhibitory effect was due to heme/iron. As shown in Figure 8B,C, direct addition of hemin to the APC impaired successful antigen presentation of both tetanus toxoid and Strep. mutans in a dose dependent manner.
\nAntigen processing and presentation is inhibited by oxidized RBC and hemin. (A) Antigen presentation of TT and SM was inhibited by the erythrophagocytosis of oxidized RBC. Normal RBC had no inhibitory effect. The efficacy of antigen processing and/or presentation was assessed by 3H-thymidine incorporation in proliferating T cells. PBMC were resuspended in Aim V media at a final concentration of 2.5 × 105 PBMC per 200 μl. Final RBC concentration was 8 × 106 per 200 μl. Antigens were diluted in Aim V and added at the indicated concentrations. Results shown are of a representative experiment with quadruplicate samples. (B, C) Heme pretreatment of PBMC (2 h at 37°C) dramatically inhibits the proliferative response to tetanus toxoid (B) and S. mutans (C). Interestingly, the ability of PBMC to respond to intact bacteria is more significantly blunted than is the response to tetanus toxoid at intermediate hemin concentrations (50 μM). Results shown are of a representative experiment with quadruplicate samples.
β thalassemias arise from a number of underlying genetic defects that interfere with the synthesis of the β hemoglobin chain and the subsequent production of the normal α2β2 hemoglobin tetramer. As a consequence of this decreased/absent β-chain synthesis, unpaired, monomeric, α-hemoglobin chains are produced. While the presence of the highly unstable α-chains mediate the pathophysiology of the RBC, it has been difficult to fully elucidate the mechanisms underlying their destructive processes in human cells. This lack of understanding of the mechanisms of α-chain mediated damage is due, in large part, to the fact that peripheral RBC isolated from β thalassemic individuals are already severely damaged cells (with most being destroyed within the bone marrow). Moreover, severe β thalassemia patients are typically transfused to both correct the severe anemia accompanying the disease and to prevent endogenous erythropoiesis of defective RBC. Hence, murine models of β thalassemia have been developed and extensively studied. However, problems exist with these models (e.g., mouse vs. human α-chains; interaction of human globins with mouse cytoskeletal proteins) and these mice, as in human patients, still suffer from the heterogeneity of RBC changes arising from the different ages of the peripheral blood RBC [11, 12, 13, 14, 15, 16, 17].
\nTo better study the fate of unpaired α-chains in human RBC, the model β thalassemic cell was developed [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. The entrapment of purified α-hemoglobin chains within normal erythrocytes via osmotic lysis and resealing provides an excellent and reproducible human model for studying the pathologic effects of the unpaired α-chains on the structural and functional characteristics of the RBC. Indeed, as noted in Table 2, the α-chain induced structural and functional RBC changes are very similar to those observed in human donor derived β thalassemic RBC. Schematically the pathophysiology of the β thalassemic RBC, and its downstream consequences, as elucidated by the model human β thalassemic RBC, are summarized in Figure 9. Importantly, these studies have demonstrated that the unpaired α-chains initiate an iron, GSH-dependent, self-amplifying and self-propagating reaction with the subsequent release of even more heme and, eventually, free iron (Figure 4). Membrane proteins and reactive thiol groups (not shown) were rapidly decreased in a pattern similar to that observed in vivo in β thalassemia [18, 20, 21, 22, 23, 25, 26, 27]. These oxidative events also result in membrane vesiculation of the thalassemic RBC. One consequence of membrane vesiculation is the preferential loss of phosphatidylinositol (PI) anchored proteins from the RBC. Among these PI-anchored proteins are decay accelerating factor (DAF; CD55) and the membrane inhibitor of reactive lysis (MIRL; CD59) both of which play important roles in preventing complement-mediated binding and lysis. The effects of the vesiculation-mediated loss of CD55 and CD59 can range from sublytic levels of bound complement enhancing phagocytosis to overt hemolysis. Indeed, a common endpoint for all the α-chain mediated injury is enhanced erythrophagocytosis. As shown, oxidized RBC or the heme from these cells (Figure 8) significantly inhibits antigen processing, presentation and T cell proliferation. The systemic importance of this on cell-mediated immunity has not be fully appreciated and may potentially explain the predisposition of thalassemic patients to recurrent bacterial infections.
\nSchematic representation of the pathophysiology of the β thalassemic RBC and its immunological consequences.
In sum, these findings show the utility of the model β thalassemic human RBC for investigating the pathophysiology of the unpaired α-chains. Moreover, these cells are easily ‘manufactured’ from normal donor RBC and may provide an effective means to evaluate therapeutic approaches to ameliorate the damage to the thalassemic cell in β thalassemia intermedia in order to prolong RBC survival and reduce transfusions [23, 25, 26, 27, 40].
\nThis work was supported by grants from Canadian Blood Services and Health Canada. The views expressed herein do not necessarily represent the view of the federal government of Canada. We thank the Canada Foundation for Innovation and the Michael Smith Foundation for Health Research for infrastructure funding at the University of British Columbia Centre for Blood Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
\nThere are no conflicts of interest.
General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed.
',metaTitle:"Horizon 2020 Compliance",metaDescription:"General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed. ",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\\n\\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\\n\\nIn other words, publishing with IntechOpen guarantees compliance.
\\n\\nRead more about Open Access in Horizon 2020 here.
\\n\\nWhich scientific publication to choose?
\\n\\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\\n\\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\\n\\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\n\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\n\nIn other words, publishing with IntechOpen guarantees compliance.
\n\nRead more about Open Access in Horizon 2020 here.
\n\nWhich scientific publication to choose?
\n\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\n\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\n\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5766},{group:"region",caption:"Middle and South America",value:2,count:5228},{group:"region",caption:"Africa",value:3,count:1717},{group:"region",caption:"Asia",value:4,count:10370},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15791}],offset:12,limit:12,total:118192},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"ebgfFaeGuveeFgfcChcyvfu"},books:[],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:16},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:4},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:8},{group:"topic",caption:"Computer and Information Science",value:9,count:6},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:19},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:3},{group:"topic",caption:"Materials Science",value:14,count:5},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:24},{group:"topic",caption:"Neuroscience",value:18,count:2},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:3},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:0,limit:12,total:null},popularBooks:{featuredBooks:[{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9671",title:"Macrophages",subtitle:null,isOpenForSubmission:!1,hash:"03b00fdc5f24b71d1ecdfd75076bfde6",slug:"macrophages",bookSignature:"Hridayesh Prakash",coverURL:"https://cdn.intechopen.com/books/images_new/9671.jpg",editors:[{id:"287184",title:"Dr.",name:"Hridayesh",middleName:null,surname:"Prakash",slug:"hridayesh-prakash",fullName:"Hridayesh Prakash"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10432",title:"Casting Processes and Modelling of Metallic Materials",subtitle:null,isOpenForSubmission:!1,hash:"2c5c9df938666bf5d1797727db203a6d",slug:"casting-processes-and-modelling-of-metallic-materials",bookSignature:"Zakaria Abdallah and Nada Aldoumani",coverURL:"https://cdn.intechopen.com/books/images_new/10432.jpg",editors:[{id:"201670",title:"Dr.",name:"Zak",middleName:null,surname:"Abdallah",slug:"zak-abdallah",fullName:"Zak Abdallah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5240},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9671",title:"Macrophages",subtitle:null,isOpenForSubmission:!1,hash:"03b00fdc5f24b71d1ecdfd75076bfde6",slug:"macrophages",bookSignature:"Hridayesh Prakash",coverURL:"https://cdn.intechopen.com/books/images_new/9671.jpg",editors:[{id:"287184",title:"Dr.",name:"Hridayesh",middleName:null,surname:"Prakash",slug:"hridayesh-prakash",fullName:"Hridayesh Prakash"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10432",title:"Casting Processes and Modelling of Metallic Materials",subtitle:null,isOpenForSubmission:!1,hash:"2c5c9df938666bf5d1797727db203a6d",slug:"casting-processes-and-modelling-of-metallic-materials",bookSignature:"Zakaria Abdallah and Nada Aldoumani",coverURL:"https://cdn.intechopen.com/books/images_new/10432.jpg",editors:[{id:"201670",title:"Dr.",name:"Zak",middleName:null,surname:"Abdallah",slug:"zak-abdallah",fullName:"Zak Abdallah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editedByType:"Edited by",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editedByType:"Edited by",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editedByType:"Edited by",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9669",title:"Recent Advances in Rice Research",subtitle:null,isOpenForSubmission:!1,hash:"12b06cc73e89af1e104399321cc16a75",slug:"recent-advances-in-rice-research",bookSignature:"Mahmood-ur- Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9669.jpg",editedByType:"Edited by",editors:[{id:"185476",title:"Dr.",name:"Mahmood-Ur-",middleName:null,surname:"Rahman Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-Ur- Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"90",title:"Computer Science and Engineering",slug:"computer-science-and-engineering",parent:{title:"Computer and Information Science",slug:"computer-and-information-science"},numberOfBooks:33,numberOfAuthorsAndEditors:771,numberOfWosCitations:907,numberOfCrossrefCitations:646,numberOfDimensionsCitations:1200,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"computer-science-and-engineering",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"8423",title:"Security and Privacy From a Legal, Ethical, and Technical Perspective",subtitle:null,isOpenForSubmission:!1,hash:"dc4f0b68a2f903e7bf1ec7fbe042dbf2",slug:"security-and-privacy-from-a-legal-ethical-and-technical-perspective",bookSignature:"Christos Kalloniatis and Carlos Travieso-Gonzalez",coverURL:"https://cdn.intechopen.com/books/images_new/8423.jpg",editedByType:"Edited by",editors:[{id:"219671",title:"Associate Prof.",name:"Christos",middleName:null,surname:"Kalloniatis",slug:"christos-kalloniatis",fullName:"Christos Kalloniatis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8511",title:"Cyberspace",subtitle:null,isOpenForSubmission:!1,hash:"8c1cdeb133dbe6cc1151367061c1bba6",slug:"cyberspace",bookSignature:"Evon Abu-Taieh, Abdelkrim El Mouatasim and Issam H. Al Hadid",coverURL:"https://cdn.intechopen.com/books/images_new/8511.jpg",editedByType:"Edited by",editors:[{id:"223522",title:"Dr.",name:"Evon",middleName:"M.O.",surname:"Abu-Taieh",slug:"evon-abu-taieh",fullName:"Evon Abu-Taieh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6958",title:"High Performance Parallel Computing",subtitle:null,isOpenForSubmission:!1,hash:"dd811128360e48c520a91871f0279659",slug:"high-performance-parallel-computing",bookSignature:"Satyadhyan Chickerur",coverURL:"https://cdn.intechopen.com/books/images_new/6958.jpg",editedByType:"Edited by",editors:[{id:"239076",title:"Dr.",name:"Satyadhyan",middleName:null,surname:"Chickerur",slug:"satyadhyan-chickerur",fullName:"Satyadhyan Chickerur"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6715",title:"Petri Nets in Science and Engineering",subtitle:null,isOpenForSubmission:!1,hash:"b0b98cd043ed2dc582d8365630929d33",slug:"petri-nets-in-science-and-engineering",bookSignature:"Raul Campos-Rodriguez and Mildreth Alcaraz-Mejia",coverURL:"https://cdn.intechopen.com/books/images_new/6715.jpg",editedByType:"Edited by",editors:[{id:"178524",title:"Dr.",name:"Raul",middleName:null,surname:"Campos-Rodriguez",slug:"raul-campos-rodriguez",fullName:"Raul Campos-Rodriguez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5368",title:"Radio Frequency Identification",subtitle:null,isOpenForSubmission:!1,hash:"c86dd0c6a48afce125a9f8f2363fd4b8",slug:"radio-frequency-identification",bookSignature:"Paulo Cesar Crepaldi and Tales Cleber Pimenta",coverURL:"https://cdn.intechopen.com/books/images_new/5368.jpg",editedByType:"Edited by",editors:[{id:"38288",title:"Prof.",name:"Paulo",middleName:"Cesar",surname:"Crepaldi",slug:"paulo-crepaldi",fullName:"Paulo Crepaldi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6038",title:"Wireless Sensor Networks",subtitle:"Insights and Innovations",isOpenForSubmission:!1,hash:"e63cb7f71bc1fed54902b371cbe21a2a",slug:"wireless-sensor-networks-insights-and-innovations",bookSignature:"Philip Sallis",coverURL:"https://cdn.intechopen.com/books/images_new/6038.jpg",editedByType:"Edited by",editors:[{id:"10893",title:"Prof.",name:"Philip John",middleName:null,surname:"Sallis",slug:"philip-john-sallis",fullName:"Philip John Sallis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5966",title:"Heuristics and Hyper-Heuristics",subtitle:"Principles and Applications",isOpenForSubmission:!1,hash:"da699185a8b84a430d96d54bc35acdb2",slug:"heuristics-and-hyper-heuristics-principles-and-applications",bookSignature:"Javier Del Ser Lorente",coverURL:"https://cdn.intechopen.com/books/images_new/5966.jpg",editedByType:"Edited by",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5745",title:"Recent Progress in Parallel and Distributed Computing",subtitle:null,isOpenForSubmission:!1,hash:"dba64b23d703d16339860ebf4a13f022",slug:"recent-progress-in-parallel-and-distributed-computing",bookSignature:"Wen-Jyi Hwang",coverURL:"https://cdn.intechopen.com/books/images_new/5745.jpg",editedByType:"Edited by",editors:[{id:"108614",title:"Prof.",name:"Wen-Jyi",middleName:null,surname:"Hwang",slug:"wen-jyi-hwang",fullName:"Wen-Jyi Hwang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5707",title:"Computer Simulation",subtitle:null,isOpenForSubmission:!1,hash:"9eec1723d4d4775dc9755db55aa387a6",slug:"computer-simulation",bookSignature:"Dragan Cvetkovic",coverURL:"https://cdn.intechopen.com/books/images_new/5707.jpg",editedByType:"Edited by",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5183",title:"Face Recognition",subtitle:"Semisupervised Classification, Subspace Projection and Evaluation Methods",isOpenForSubmission:!1,hash:"d693acce19fca9cbf40d8f3f759e491d",slug:"face-recognition-semisupervised-classification-subspace-projection-and-evaluation-methods",bookSignature:"S. Ramakrishnan",coverURL:"https://cdn.intechopen.com/books/images_new/5183.jpg",editedByType:"Edited by",editors:[{id:"116136",title:"Dr.",name:"Srinivasan",middleName:null,surname:"Ramakrishnan",slug:"srinivasan-ramakrishnan",fullName:"Srinivasan Ramakrishnan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5150",title:"Electronics Cooling",subtitle:null,isOpenForSubmission:!1,hash:"b95856cfcc87ef3cb7d7c7c7bac4010d",slug:"electronics-cooling",bookSignature:"S M Sohel Murshed",coverURL:"https://cdn.intechopen.com/books/images_new/5150.jpg",editedByType:"Edited by",editors:[{id:"24904",title:"Prof.",name:"S. M. Sohel",middleName:null,surname:"Murshed",slug:"s.-m.-sohel-murshed",fullName:"S. M. Sohel Murshed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4655",title:"Applications of Digital Signal Processing through Practical Approach",subtitle:null,isOpenForSubmission:!1,hash:"b20308efd28e8a487949997c8d673fb8",slug:"applications-of-digital-signal-processing-through-practical-approach",bookSignature:"Sudhakar Radhakrishnan",coverURL:"https://cdn.intechopen.com/books/images_new/4655.jpg",editedByType:"Edited by",editors:[{id:"26327",title:"Dr.",name:"Sudhakar",middleName:null,surname:"Radhakrishnan",slug:"sudhakar-radhakrishnan",fullName:"Sudhakar Radhakrishnan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:33,mostCitedChapters:[{id:"50801",doi:"10.5772/62898",title:"Performance Evaluation of Nanofluids in an Inclined Ribbed Microchannel for Electronic Cooling Applications",slug:"performance-evaluation-of-nanofluids-in-an-inclined-ribbed-microchannel-for-electronic-cooling-appli",totalDownloads:2017,totalCrossrefCites:45,totalDimensionsCites:79,book:{slug:"electronics-cooling",title:"Electronics Cooling",fullTitle:"Electronics Cooling"},signatures:"Mohammad Reza Safaei, Marjan Gooarzi, Omid Ali Akbari, Mostafa\nSafdari Shadloo and Mahidzal Dahari",authors:[{id:"178854",title:"Dr.",name:"Mohammad Reza",middleName:null,surname:"Safaei",slug:"mohammad-reza-safaei",fullName:"Mohammad Reza Safaei"},{id:"179807",title:"Dr.",name:"Mostafa",middleName:null,surname:"Safdari Shadloo",slug:"mostafa-safdari-shadloo",fullName:"Mostafa Safdari Shadloo"},{id:"179809",title:"Dr.",name:"Mahidzal",middleName:null,surname:"Dahari",slug:"mahidzal-dahari",fullName:"Mahidzal Dahari"},{id:"179813",title:"MSc.",name:"Marjan",middleName:null,surname:"Goodarzi",slug:"marjan-goodarzi",fullName:"Marjan Goodarzi"},{id:"185093",title:"MSc.",name:"Omid",middleName:null,surname:"Ali Akbari",slug:"omid-ali-akbari",fullName:"Omid Ali Akbari"}]},{id:"5184",doi:"10.5772/6180",title:"From the Lab to the Real World: Affect Recognition Using Multiple Cues and Modalities",slug:"from_the_lab_to_the_real_world__affect_recognition_using_multiple_cues_and_modalities",totalDownloads:3183,totalCrossrefCites:34,totalDimensionsCites:51,book:{slug:"affective_computing",title:"Affective Computing",fullTitle:"Affective Computing"},signatures:"Hatice Gunes, Massimo Piccardi and Maja Pantic",authors:null},{id:"5197",doi:"10.5772/6167",title:"Generating Facial Expressions with Deep Belief Nets",slug:"generating_facial_expressions_with_deep_belief_nets",totalDownloads:3194,totalCrossrefCites:1,totalDimensionsCites:46,book:{slug:"affective_computing",title:"Affective Computing",fullTitle:"Affective Computing"},signatures:"Joshua M. Susskind, Geoffrey E. Hinton, Javier R. Movellan and Adam K. Anderson",authors:null}],mostDownloadedChaptersLast30Days:[{id:"68505",title:"Research Design and Methodology",slug:"research-design-and-methodology",totalDownloads:17520,totalCrossrefCites:1,totalDimensionsCites:3,book:{slug:"cyberspace",title:"Cyberspace",fullTitle:"Cyberspace"},signatures:"Kassu Jilcha Sileyew",authors:null},{id:"51031",title:"Face Recognition: Issues, Methods and Alternative Applications",slug:"face-recognition-issues-methods-and-alternative-applications",totalDownloads:10496,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"face-recognition-semisupervised-classification-subspace-projection-and-evaluation-methods",title:"Face Recognition",fullTitle:"Face Recognition - Semisupervised Classification, Subspace Projection and Evaluation Methods"},signatures:"Waldemar Wójcik, Konrad Gromaszek and Muhtar Junisbekov",authors:[{id:"24059",title:"Dr.Ing.",name:"Konrad",middleName:null,surname:"Gromaszek",slug:"konrad-gromaszek",fullName:"Konrad Gromaszek"}]},{id:"56541",title:"Routing Protocols for Wireless Sensor Networks (WSNs)",slug:"routing-protocols-for-wireless-sensor-networks-wsns-",totalDownloads:4459,totalCrossrefCites:9,totalDimensionsCites:13,book:{slug:"wireless-sensor-networks-insights-and-innovations",title:"Wireless Sensor Networks",fullTitle:"Wireless Sensor Networks - Insights and Innovations"},signatures:"Noman Shabbir and Syed Rizwan Hassan",authors:[{id:"206600",title:"Mr.",name:"Noman",middleName:null,surname:"Shabbir",slug:"noman-shabbir",fullName:"Noman Shabbir"},{id:"206601",title:"Mr.",name:"Syed Rizwan",middleName:null,surname:"Hassan",slug:"syed-rizwan-hassan",fullName:"Syed Rizwan Hassan"}]},{id:"50065",title:"Heat Pipes for Computer Cooling Applications",slug:"heat-pipes-for-computer-cooling-applications",totalDownloads:4135,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"electronics-cooling",title:"Electronics Cooling",fullTitle:"Electronics Cooling"},signatures:"Mohamed H.A. Elnaggar and Ezzaldeen Edwan",authors:[{id:"178453",title:"Dr.",name:"Mohamed",middleName:null,surname:"Elnaggar",slug:"mohamed-elnaggar",fullName:"Mohamed Elnaggar"},{id:"184278",title:"Dr.",name:"Ezzaldeen",middleName:null,surname:"Edwan",slug:"ezzaldeen-edwan",fullName:"Ezzaldeen Edwan"}]},{id:"5175",title:"Facial Expression Recognition Using 3D Facial Feature Distances",slug:"facial_expression_recognition_using_3d_facial_feature_distances",totalDownloads:3914,totalCrossrefCites:5,totalDimensionsCites:10,book:{slug:"affective_computing",title:"Affective Computing",fullTitle:"Affective Computing"},signatures:"Hamit Soyel and Hasan Demirel",authors:null},{id:"56900",title:"Mobile Wireless Sensor Networks: An Overview",slug:"mobile-wireless-sensor-networks-an-overview",totalDownloads:1933,totalCrossrefCites:10,totalDimensionsCites:15,book:{slug:"wireless-sensor-networks-insights-and-innovations",title:"Wireless Sensor Networks",fullTitle:"Wireless Sensor Networks - Insights and Innovations"},signatures:"Velmani Ramasamy",authors:[{id:"206195",title:"Dr.",name:"Velmani",middleName:null,surname:"Ramasamy",slug:"velmani-ramasamy",fullName:"Velmani Ramasamy"}]},{id:"49264",title:"Application of DSP Concept for Ultrasound Doppler Image Processing System",slug:"application-of-dsp-concept-for-ultrasound-doppler-image-processing-system",totalDownloads:1504,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"applications-of-digital-signal-processing-through-practical-approach",title:"Applications of Digital Signal Processing through Practical Approach",fullTitle:"Applications of Digital Signal Processing through Practical Approach"},signatures:"Baba Tatsuro",authors:[{id:"65121",title:"Dr.",name:"Baba",middleName:null,surname:"Tatsuro",slug:"baba-tatsuro",fullName:"Baba Tatsuro"}]},{id:"52156",title:"Case Study: Installing RFID Systems in Supermarkets",slug:"case-study-installing-rfid-systems-in-supermarkets",totalDownloads:1639,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"radio-frequency-identification",title:"Radio Frequency Identification",fullTitle:"Radio Frequency Identification"},signatures:"María-Victoria Bueno‐Delgado, Francesc Burrull and Pablo Pavón‐\nMariño",authors:[{id:"186584",title:"Dr.",name:"M.V.",middleName:null,surname:"Bueno-Delgado",slug:"m.v.-bueno-delgado",fullName:"M.V. Bueno-Delgado"},{id:"194375",title:"Dr.",name:"Francesc",middleName:null,surname:"Burrull",slug:"francesc-burrull",fullName:"Francesc Burrull"},{id:"194376",title:"Prof.",name:"Pablo",middleName:null,surname:"Pavón-Mariño",slug:"pablo-pavon-marino",fullName:"Pablo Pavón-Mariño"}]},{id:"24300",title:"Complex Digital Signal Processing in Telecommunications",slug:"complex-digital-signal-processing-in-telecommunications",totalDownloads:11126,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"applications-of-digital-signal-processing",title:"Applications of Digital Signal Processing",fullTitle:"Applications of Digital Signal Processing"},signatures:"Zlatka Nikolova, Georgi Iliev, Miglen Ovtcharov and Vladimir Poulkov",authors:[{id:"18206",title:"Dr.",name:"Vladimir",middleName:null,surname:"Poulkov",slug:"vladimir-poulkov",fullName:"Vladimir Poulkov"},{id:"21534",title:"Dr.",name:"Georgi",middleName:null,surname:"Iliev",slug:"georgi-iliev",fullName:"Georgi Iliev"},{id:"21536",title:"Associate Prof.",name:"Zlatka",middleName:null,surname:"Valkova-Jarvis",slug:"zlatka-valkova-jarvis",fullName:"Zlatka Valkova-Jarvis"},{id:"71205",title:"MSc.",name:"Miglen",middleName:null,surname:"Ovtcharov",slug:"miglen-ovtcharov",fullName:"Miglen Ovtcharov"}]},{id:"70973",title:"Social Media, Ethics and the Privacy Paradox",slug:"social-media-ethics-and-the-privacy-paradox",totalDownloads:939,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"security-and-privacy-from-a-legal-ethical-and-technical-perspective",title:"Security and Privacy From a Legal, Ethical, and Technical Perspective",fullTitle:"Security and Privacy From a Legal, Ethical, and Technical Perspective"},signatures:"Nadine Barrett-Maitland and Jenice Lynch",authors:[{id:"311821",title:"Ph.D. Student",name:"Nadine",middleName:null,surname:"Barrett-Maitland",slug:"nadine-barrett-maitland",fullName:"Nadine Barrett-Maitland"},{id:"311822",title:"Ms.",name:"Jenice",middleName:null,surname:"Lynch",slug:"jenice-lynch",fullName:"Jenice Lynch"}]}],onlineFirstChaptersFilter:{topicSlug:"computer-science-and-engineering",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/151489/davide-turco",hash:"",query:{},params:{id:"151489",slug:"davide-turco"},fullPath:"/profiles/151489/davide-turco",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var t;(t=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(t)}()