Isentropic molar compressibilities (104K2o(s), cm3 mol-1 bar-1) and hydration numbers of various monosaccharides and disaccharides. Errors of molar compressibility values and hydration numbers are shown in parentheses. [175,177]
\\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:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},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:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"6352",leadTitle:null,fullTitle:"Gastrointestinal Surgery - New Technical Proposals",title:"Gastrointestinal Surgery",subtitle:"New Technical Proposals",reviewType:"peer-reviewed",abstract:"In the recent years changes in gastrointestinal surgery have experienced great acceleration, based on a better understanding of the pathophysiology of the diseases, evolving technologies, and new therapies. In many areas of gastrointestinal surgery, new therapeutic and technical results have been accessible because of better connections with well-known pathological evolutions of diseases, more detailed diagnostic perspectives, and wide employment of mini-invasive and laparoscopic procedures.",isbn:"978-1-78923-605-7",printIsbn:"978-1-78923-604-0",pdfIsbn:"978-1-83881-424-3",doi:"10.5772/intechopen.69797",price:100,priceEur:109,priceUsd:129,slug:"gastrointestinal-surgery-new-technical-proposals",numberOfPages:100,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"f75fc66eb312d3a8a6be8256c5ffb279",bookSignature:"Vincenzo Neri",publishedDate:"September 5th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6352.jpg",numberOfDownloads:5228,numberOfWosCitations:3,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:5,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:9,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 12th 2017",dateEndSecondStepPublish:"July 3rd 2017",dateEndThirdStepPublish:"October 21st 2017",dateEndFourthStepPublish:"December 28th 2017",dateEndFifthStepPublish:"February 26th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"170938",title:"Prof.",name:"Vincenzo",middleName:null,surname:"Neri",slug:"vincenzo-neri",fullName:"Vincenzo Neri",profilePictureURL:"https://mts.intechopen.com/storage/users/170938/images/system/170938.jpeg",biography:"Vincenzo Neri is a former Professor of General Surgery (retired), Department of Medical and Surgical Sciences, University of Foggia, Italy. He also held positions such as Director of Division of General Surgery, Director of Residency School of General Surgery, Director of Department of Surgical Sciences, and President of Course of Degree of Medicine and Surgery at the same university. He also served as an assistant professor (1974–1982) and associate professor (1982–2001) at the School of Medicine and Surgery, University of Bari, Italy, where he obtained a degree in Medicine and Surgery and completed postgraduate training in General Surgery and Emergency Surgery. He obtained a diploma of 'Maitrise Universitaire en Pedagogie des Sciences de la Santè” from the University Paris-Nord Bobigny in 1995. Dr. Neri’s research interests include hepatobiliary pancreatic surgery, acute pancreatitis, and treatment of pancreatic and liver tumors. He has published research papers, reviews, congress proceedings, and book chapters. In the period 1991–2016, he attended the Hepatobiliarypancreatic Surgery Service of Beaujon Hospital, Universitè de Paris, Clichy. As part of the 2010–2011 ERASMUS Program, Dr. Neri developed a seminar on 'Cystic Tumours of the Pancreas” at Ghent University, Belgium. He is a member of several scientific associations including Società Italiana di Chirurgia (SIC), International Hepato-Pancreato Biliary Association (IHPBA), European Association for the Study of the Liver (EASL), New European Surgical Academy (NESA), and Society of Laparoscopic and Robotic Surgeons (SLS).",institutionString:"University of Foggia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"9",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"University of Foggia",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1138",title:"Abdominal Surgery",slug:"abdominal-surgery"}],chapters:[{id:"59313",title:"Metabolic and Bariatric Surgery: Evolution, Techniques, and Management",doi:"10.5772/intechopen.73676",slug:"metabolic-and-bariatric-surgery-evolution-techniques-and-management",totalDownloads:1084,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Metabolic and bariatric surgery involves more than altering the stomach and small bowel anatomy to provoke structural changes in the gastrointestinal tract from a mechanical point of view to treat morbid obesity. Its profound impact on the body’s metabolism goes beyond anatomy and enters the realm of physiology. This is one of the most challenging and influential surgical subspecialties today due to its proven beneficial impact on the worldwide obesity epidemic and its millions of patients. A brief but comprehensive overview of the history of this fascinating yet challenging discipline and its advancement into the minimally invasive arena will be presented. Moreover, the body of this chapter will provide evidence-based data dealing with its indications, approaches, minimally invasive techniques including robotic surgery, the most common operations and the most recently introduced procedures, and management of complications. The impact of the laparoscopic revolution at the end of the twentieth century and the relevance of the robotic revolution from this century will be emphasized. An important point that will be made is the very specialized discipline of revisional bariatric surgery and its crucial role on the treatment of complications and failures that require extensive training and experience.",signatures:"Rodolfo José Oviedo Barrera",downloadPdfUrl:"/chapter/pdf-download/59313",previewPdfUrl:"/chapter/pdf-preview/59313",authors:[{id:"204248",title:"Dr.",name:"Rodolfo J.",surname:"Oviedo",slug:"rodolfo-j.-oviedo",fullName:"Rodolfo J. Oviedo"}],corrections:null},{id:"59100",title:"Prosthetic Reconstruction of the Upper Digestive Tract",doi:"10.5772/intechopen.73101",slug:"prosthetic-reconstruction-of-the-upper-digestive-tract",totalDownloads:800,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In cases of locally advanced cancers involving the junction between the hypopharynx and cervical oesophagus, the curative surgical treatment is total circular laryngo-pharyngectomy with resection of the upper cervical oesophagus, coupled with modified radical neck dissection. Techniques used to re-establish the continuity of the digestive tract have been pectoral transposition flap, gastric pull-up, jejunum or colon transposition and free pedicled fascial-cutaneous flap reconstruction. Prosthetic reconstruction was thought of and used only as a temporary solution. In our clinic, we adapted the Montgomery oesophageal prosthesis as more than just a temporary solution and used it in 63 patients operated from 2004 to 2014 with advanced (stages III and IV) cancer involving most of the hypopharynx or extending towards the upper cervical oesophagus. Following total circular laryngo-pharyngectomy with bilateral modified radical neck dissection, prosthetic reconstruction was performed using the Montgomery oesophageal tube. Patients were followed up on, and their status was monitored. Favourable results encouraged the authors to further develop a new active prosthesis, with advanced design and materials that better mimic the anatomy and physiology of the replaced segment. Prosthetic reconstruction of the upper digestive tract following radical oncologic surgery is a viable option, with advantages compared to other laborious plastic techniques. The new active model is under development, hopefully offering soon a safe and more cost-effective alternative to the other techniques.",signatures:"Șerban V.G. Berteșteanu, Alexandru Nicolaescu, Bogdan Popescu\nand Raluca Grigore",downloadPdfUrl:"/chapter/pdf-download/59100",previewPdfUrl:"/chapter/pdf-preview/59100",authors:[{id:"216552",title:"Dr.",name:"Șerban V.G.",surname:"Berteșteanu",slug:"serban-v.g.-bertesteanu",fullName:"Șerban V.G. Berteșteanu"},{id:"216556",title:"Dr.",name:"Alexandru",surname:"Nicolaescu",slug:"alexandru-nicolaescu",fullName:"Alexandru Nicolaescu"},{id:"216562",title:"Dr.",name:"Raluca",surname:"Grigore",slug:"raluca-grigore",fullName:"Raluca Grigore"},{id:"222738",title:"Dr.",name:"Popescu",surname:"Bogdan",slug:"popescu-bogdan",fullName:"Popescu Bogdan"}],corrections:null},{id:"60419",title:"Choledochal Cyst (CDC)",doi:"10.5772/intechopen.72938",slug:"choledochal-cyst-cdc-",totalDownloads:1379,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Choledochal cysts are congenital bile duct anomalies. These cystic dilatations of the biliary tree can involve the extrahepatic biliary radicles, the intrahepatic biliary radicles, or both. The etiology remains unknown, but choledochal cysts are likely to be congenital in nature. Cyst excision is the definitive treatment of choice for choledochal cyst because of the high morbidity and high risk of carcinoma after internal drainage, a commonly used treatment in the past. CDC is a congenital anomaly involving cystic dilatation of various ducts of biliary tree. The precise etiology of extrahepatic cysts continues to remain unclear. The most commonly accepted theory is an anomalous pancreatobiliary duct junction (APBDJ) and abnormal function of the sphincter of Oddi. Proper imaging plays an essential role in preoperative planning. Proper diagnosis evaluation and management is essential for optimal management. Type I cysts are the most frequently encountered. Choledochal cysts can have variable presentations. Hepatobiliary ultrasound and MRCP are the present day standards for imaging; early diagnosis should be the norm to avoid possible late complications of cholangitis, cirrhosis, hepaticolithiasis and spontaneous perforation. Excision of the cyst with hepaticojejunostomy is the best approach.",signatures:"Raashid Hamid, Nisar A. Bhat, Mansoor Ahmad and Balvinder Singh",downloadPdfUrl:"/chapter/pdf-download/60419",previewPdfUrl:"/chapter/pdf-preview/60419",authors:[{id:"213319",title:"Dr.",name:"Raashid",surname:"Hamid",slug:"raashid-hamid",fullName:"Raashid Hamid"},{id:"233782",title:"Dr.",name:"Nisar",surname:"Bhat",slug:"nisar-bhat",fullName:"Nisar Bhat"},{id:"233784",title:"Dr.",name:"Mansoor",surname:"Ahmad",slug:"mansoor-ahmad",fullName:"Mansoor Ahmad"},{id:"251293",title:"Dr.",name:"Balvinder",surname:"Singh",slug:"balvinder-singh",fullName:"Balvinder Singh"}],corrections:null},{id:"62058",title:"Diverticular Disease",doi:"10.5772/intechopen.78763",slug:"diverticular-disease",totalDownloads:1010,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Diverticulosis is a common problem, especially in industrialized countries. The main risk factors for the development of diverticular disease are physical inactivity and consumption of a low-fiber diet. Among the population with diverticulosis, only 10–25% of the patients develop diverticulitis. Computed tomography (CT) scans are very helpful for diagnosis and deciding the treatment strategy. Patients with acute diverticulitis usually have a good response to conservative therapy. However, some of the patients present with complications such as perforation, fistula, abscess, stricture, and obstruction. Depending on disease severity, they commonly require surgical or radiologic intervention. Despite lots of contradictory results on treatment approaches, recent guidelines tend to be less invasive than the ones in the past. As a result, less invasive treatment protocols, including nonsurgical follow-up, percutaneous drainage, minimally invasive surgery and resection with primary anastomosis, are more commonly used than the more invasive Hartmann procedure. In this chapter, we discuss the clinical characteristics, diagnostic workup and different treatment approaches in the management of diverticular diseases.",signatures:"Can Konca, Suleyman Utku Celik and Cihangir Akyol",downloadPdfUrl:"/chapter/pdf-download/62058",previewPdfUrl:"/chapter/pdf-preview/62058",authors:[{id:"202689",title:"Associate Prof.",name:"Cihangir",surname:"Akyol",slug:"cihangir-akyol",fullName:"Cihangir Akyol"},{id:"202709",title:"Dr.",name:"Suleyman",surname:"Celik",slug:"suleyman-celik",fullName:"Suleyman Celik"},{id:"207202",title:"Dr.",name:"Can",surname:"Konca",slug:"can-konca",fullName:"Can Konca"}],corrections:null},{id:"59338",title:"Gastrointestinal Stromal Tumors (GIST)",doi:"10.5772/intechopen.74290",slug:"gastrointestinal-stromal-tumors-gist-",totalDownloads:961,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, occurring predominantly in the stomach and small intestine. These tumors account for up to 3% of all gastrointestinal malignancies, with a reported annual incidence of 10–15 cases per million population. GISTs are thought to originate from interstitial cells of Cajal (ICC) or ICC precursor cells, and are characterized by activating mutations in the KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRα) proto-oncogenes in 85–95% of all cases. The clinical presentation and tumor biology of GISTs are widely variable, with several advances being made over the past two decades in the understanding of GIST tumor biology and pathophysiology. This has led to a paradigm shift in management from the purely surgical approach of the past, to a multi-modality treatment strategy with a greater role for targeted therapies in the form of tyrosine kinase inhibitors, resulting in significantly improved patient outcomes.",signatures:"Rahman G. Barry, Thao T. Wolbert and David A. 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He has been a practicing gastroenterologist for twenty-four years. He has a special interest in biliary diseases, gastrointestinal bleeding, colon cancer, inflammatory bowel disease, eosinophilic esophagitis, gastrointestinal motility disorders, and dysphagia. 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\r\n\tCurrently, numerous biomaterials-based studies are being conducted, including research into chitin and chitosan, the second most abundant polysaccharide after cellulose. Chitin is obtained at an industrial scale from a variety of natural sources including, crustacean and insect exoskeletons, fungi cell walls, squid pen, etc. Chitosan is biodegradable, biocompatible, non-toxic, water-soluble under acidic conditions, and linear cationic amino polysaccharide derived from the deacetylation of chitin. It contains free amino and hydroxyl groups that can be functionalized by binding with the cationic and anionic groups. It has numerous applications, especially in the environmental remediation, biomedical, pharmaceutical, agriculture, and food industries.
\r\n\r\n\tThis book will present an update of articles addressing isolation, properties, and certain applications of chitin and chitosan, including films, fibers, nanoparticles, composite materials, hydrogels, polymeric complexes, water purification, antimicrobials, textile, cosmetics, biosensors, nanoporous scaffolds, and membranes. We invite world-class researchers from around the world, industry, academia, government, and private research institutions are encouraged to publish research or review articles on chitin and chitosan.
",isbn:"978-1-80356-693-1",printIsbn:"978-1-80356-692-4",pdfIsbn:"978-1-80356-694-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"69f009be08998711eecfb200adc7deca",bookSignature:"Dr. Brajesh Kumar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11670.jpg",keywords:"Solvent, Acidic, Microwave, Binding, Biodegradable, Biocompatible, FTIR, NMR, XRD, Fibers, Nanoparticles, Composite Materials",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 23rd 2022",dateEndSecondStepPublish:"May 26th 2022",dateEndThirdStepPublish:"July 25th 2022",dateEndFourthStepPublish:"October 13th 2022",dateEndFifthStepPublish:"December 12th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Brajesh Kumar is a pioneering researcher in nanoscience and green chemistry. 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His research interest is in the development of sustainable and eco-friendly techniques for (a) nanoparticles synthesis and their applications for environmental remediation, (b) active films of organic solar cells, (c) nanomedicine, (d) sensors, (e) natural product extraction, purification, and analysis,(f) natural polymers, (g) peptide chemistry, (h) microwave and ultrasound-assisted organic synthesis and (i) organic synthesis. Dr. Brajesh Kumar has been credited for different national and international fellowships and he has also worked as a faculty member in various universities of India, Ecuador, and South Korea. He has also published numerous SCI/ SCIE/ Scopus research articles (h index = 29, Citations 2917) and is also an active reviewer of more than 50 Journals. 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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"}},{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:"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:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"42487",title:"Ice Recrystallization Inhibitors: From Biological Antifreezes to Small Molecules",doi:"10.5772/54992",slug:"ice-recrystallization-inhibitors-from-biological-antifreezes-to-small-molecules",body:'Recrystallization is a phenomenon that is well documented in the geological and metallurgical literature. In metallurgy, the phenomenon can be formally defined as the process by which deformed grains are replaced by a new set of non-deformed grains that nucleate and grow until the original grains have been entirely consumed. A more precise definition is difficult as this process is quite complex. The phenomenon of recrystallization also occurs in ice, where it is similarly defined as the growth of large ice crystals (or grains) at the expense of small ones. Regardless of the definition or context in which recrystallization is discussed, it is a thermodynamically driven process which results in an overall reduction in the free energy of the system in which it is occurring.
While the exact mechanism(s) by which the phenomenon of recrystallization occurs remains controversial, the industrial significance and the benefits of preventing this process have been realized for hundreds of years. Within the context of ice, recrystallization has a direct impact on many areas such as glaciology, food preservation and cryo-medicine. However, it has been considerably less studied than the process of recrystallization in areas like metallurgy, materials and geology. This may not be entirely surprising as ice itself has very unique physical and chemical properties. While ice exists in several forms, ice Ih (pronounced “ice one h”) is the most common form of ice found on Earth. The unique properties of ice and the complications these pose for the detailed study of ice will be described in this chapter with particular emphasis placed upon the efforts to identify and/or design inhibitors of the ice recrystallization process. While inhibitors of ice recrystallization have applications in preventing recrystallization processes in other substances, this review will focus on inhibiting ice recrystallization and its impact in cryopreservation.
As the phenomenon of recrystallization has origins in metallurgy, geology and materials a general discussion of this process with reference to these areas is necessary (Section 2.0), followed by a discussion on the structure and properties of ice and ice recrystallization (Section 3.0) and the importance of inhibiting ice recrystallization (Section 4.0). Finally, inhibitors of ice recrystallization and proposed mechanism(s) of action will be addressed, beginning with the first known inhibitors of ice recrystallization, biological antifreezes (Section 5.0), and concluding with novel synthetic peptides, glycopeptides, polymers and small molecules (Section 6.0). This chapter will conclude with a summary of the role of ice recrystallization in cryo-injury and a discussion on the cryoprotective ability of compounds that exhibit the ability to inhibit ice recrystallization, with the benefits and/or drawbacks of their use during cryopreservation (Section 7.0).
As stated in the introduction, the process of recrystallization has been extensively studied and reviewed throughout the metallurgic literature. [1,2] While the mechanism is quite complex, it is generally defined as the thermally induced change in grain structure facilitated by the formation and/or migration of high angle grain boundaries and is driven by the stored energy of deformation. [1] A grain is defined as the microstructure that constitutes metals and alloys. In a metal, each grain consists of an ordered arrangement of atoms (depicted in Figure 1). [3,4] A grain boundary is the interface where two or more grains of different orientations meet and is considered a defect within the crystal structure. A grain boundary contains atoms that are not well aligned with neighboring grains, leading to less efficient packing and a less ordered structure within the grain boundary. [5] Thus, grain boundaries have a higher internal energy than ordered grains. [5,6] At elevated temperatures, atoms within grains are able to transfer between grain boundaries and neighboring grains. [3,4]
An illustration of grains and grain boundaries in polycrystalline metals and/or alloys.
The process of “plastic deformation” causes a permanent change in the shape of the metal or alloy. During this process, energy is stored mainly in the form of dislocations, ultimately changing the grain shape. [1,2,7] Dislocations are areas where atoms are out of position in the crystalline structure and are linear defects within the grain due to the misalignment of atoms. The amount of dislocations present after deformation is significantly greater than the amount of dislocations prior to deformation. [7] Consequently, the amount of stored energy and the amount of grain strain after deformation is also increased. Heating and annealing of the metal or alloy at or above the recrystallization temperature allows strain-free grains to nucleate and/or migrate within the polycrystalline lattice to minimize the amount of dislocations present within this new set of grains. Thus, the driving force of recrystallization in metals is to eliminate dislocations present in the material to reduce this amount of stored energy in the system. [2]
Recrystallization is an important step in the processing of metals and alloys and can be a desirable or undesirable effect. This is attributed to the fact that recrystallization in metals and alloys ultimately results in a decrease in the strength of the metal. Polycrystalline metals containing smaller grains and more dislocations are significantly stronger than those with larger grains according to the Hall-Petch relationship. [7-9] However, during recrystallization strain-free grains grow to reduce the amount of stored energy from dislocations. As such, the metal is softened and its ductility is increased due to the formation of larger strain-free grains. This process can be a significant problem in metals and/or alloys when these materials are used for structural support where a decrease in metal strength is often detrimental. In contrast, recrystallization can also be beneficial and purposely induced to soften and restore the ductility of metals and alloys that have been hardened by low temperature deformation or cold work, or to control the grain structure of the final metal or alloy product. [1,2,10] For example, metals and alloys that have been deformed by “cold working” (deformation below the recrystallization temperature of the metal or alloy) become stronger and more brittle. [7] Inducing recrystallization will anneal the material to allow it to be deformed further without the risk of cracking or breaking.
Ice has many different polymorphic forms. Individual water molecules in ice can possess different arrangements within three-dimensional space and this is dependent upon temperature and pressure. The most common form of ice below 0 °C and atmospheric pressure is the hexagonal ice Ih lattice unit. [11,12] It possesses a regular crystalline structure in which a single oxygen atom is hydrogen-bonded to two hydrogen atoms. The hexagonal ice Ih lattice unit is characterized by four axes,
Schematic representation of the hexagonal ice Ih lattice unit illustrating the
When ice is in an aqueous solution, the interface between the ice lattice and bulk water is not an abrupt transition. Studies have indicated that a semi-ordered layer exists in between the highly ordered ice lattice and the less ordered bulk water surrounding ice crystals [14,16-22]. This layer has been named the quasi-liquid layer (QLL). While more than 150 years ago Michael Faraday proposed that the surface of ice when near the melting temperature is covered by a thin liquid layer, Fletcher was the first to propose a model for the existence of the QLL in 1962, which was subsequently revised in 1968. [16,17] Important insights on the properties of the QLL was described by Haymet where using molecular dynamic simulations and the TIP4P model of water, the structure and dynamics of the ice/water interface was studied. [18,19] Data from these simulations made it possible to calculate the density profile, molecular orientation and diffusion constants of water molecules in the QLL. The thickness of interface region between ice lattice and bulk water is approximately 10-15 Å thick, but this has been shown to be temperature dependent. [18,19,23] The average density profile, translational and orientational order and diffusion constants of water within the QLL interface also vary depending on the face of ice from which they are calculated. Studies have suggested that the QLL is thicker on the basal and prism faces than on the pyramidal and secondary prism planes. [14]
The exact molecular nature and thickness of the QLL interface has been debated throughout the literature and a wide variety of techniques have been used to study it including atomic force microscopy, [24] X-ray diffraction, [25] infrared spectroscopy, [26] proton-backscattering, [27] Raman spectroscopy, [28] quartz-crystal microbalance measurements, [29] light scattering techniques, [30-32] photoelectron spectroscopy, [33] optical ellipsometry, [22,34,35] optical reflection [36] and mechanical measurements. [37] Ellipsometric studies measuring the refractive index on the basal and prism faces of ice have suggested that the interface is more water-like in nature, rather than ice-like. [20-22,24,33,34] In contrast, other studies have suggested that the orientation and motion of water molecules in the QLL closely resembles that of ice. [25,27,36] The thickness of the QLL has been shown to be temperature dependent, [29,33] such that at temperatures approaching the melting point of ice (at -0.03 °C) the thickness was 15 nm, corresponding to approximately 40 monolayers water. [26] However, below -10 °C the thickness was less than 0.3 nm, approximately one monolayer of water. The effect of temperature and thickness also varies depending on the face of ice (prism or basal) from which it is calculated, [20,22] and studies have also reported that there is twice as much anisotropy of the water molecules in the QLL for the prism face than the basal face. [34] Light scattering techniques have shown that ice crystals grow into the QLL and not into the bulk water layer. [38,39]
The recrystallization of ice in polycrystalline aqueous solutions is believed to occur through either grain boundary migration or Ostwald ripening. Grain boundary migration in ice is similar to grain boundary migration in metals and alloys where large ice grains grow larger at the expense of small ice grains. In metallurgy a grain consists of an ordered arrangement of atoms and a grain boundary is the interface where two (or more) grains meet. However, in ice a grain consists of the crystallographic orientation of the water molecules commonly observed in ice Ih (Figure 2). Grain boundaries are therefore the interfaces between different oriented ice grains. [40,41] Grain boundary migration occurs as individual molecules transfer from unfavorably oriented ice grains to favorably oriented ice grains. The boundaries of individual ice grains tend to be curved and the degree of curvature is proportional to the size of the grain. Boundaries of small ice crystals have a higher degree of curvature making them more convex (bulge outwards) and thus have a higher amount of surface energy. Large ice crystals have more concave grain boundaries and have a lower amount of surface energy. Grain boundaries migrate towards their center of curvature to reduce the overall degree of curvature, resulting in ice grains with concave boundaries (larger crystals) growing larger while those with convex boundaries (smaller crystals) decrease in size (depicted in Figure 3). [42,43] Thus, the driving force of grain boundary migration in ice arises from a reduction in grain boundary curvature, which results in an overall reduction in the energy of the system.
Representation of a liquid-layer (shaded) in a curved boundary between two ice grains. Large ice grains with concave boundaries (grain 2) grow larger while small grains with convex boundaries (grain 1) decrease in size to reduce the overall degree of grain boundary curvature. Arrows indicate the direction of boundary migration.
Grain boundary migration of polycrystalline ice assumes that water molecules are transferred directly from the shrinking ice grain to the growing grain. This assumption often neglects the presence of bulk-water or the QLL in between individual ice grains as the system is treated below -10 °C. [42] However, Ostwald ripening of polycrystalline ice in an aqueous solution considers the whole ice crystal/liquid water system and thus accounts for the presence of bulk-water and the QLL. In ice, Ostwald ripening is the thermodynamically driven process whereby large ice crystals grow larger at the expense of small crystals, resulting in an overall reduction in energy of the ice crystal/bulk-water interface. [44-46] Throughout the Ostwald ripening process a constant ice volume is maintained. Smaller ice crystals have a higher surface area to volume ratio, giving them higher surface free energy since water molecules on the surface are less stable than the water molecules within the ice crystal. [44,45] However, larger ice crystals have a greater volume to surface area ratio and thus are thermodynamically more stable than small ice crystals. As the total overall volume of ice remains constant during the Ostwald ripening process, water molecules transfer from the surface of smaller ice crystals to bulk-water and then are transferred onto the surface of larger ice crystals. The net result is an increase in the average ice crystal size and a decrease in the total number of ice crystals at a constant total ice volume, resulting in an overall reduction in the free energy of the system. [46]
Ice recrystallization is particularly problematic in the areas of frozen foods and cryopreservation of biological samples (cells, tissues etc.). Freezing of foods is a well-established process as it helps decrease the rates of deterioration. In the last 30 years, the frozen food industry has taken significant steps to improve the freezing and storage process of various food products, recognizing that all frozen food products have a finite shelf. [47] Changes in texture, taste and overall quality of a frozen food product are a direct result of the ice recrystallization process. It is well established that ice morphology is an important factor in determining food texture and quality. For example, ice cream containing small ice crystals has better texture and taste. [48]
In medicine, cryostorage is an important process to preserve biological materials or precious cell types such as stem cells (or other progenitors) as well as red blood cells. However, as with any cold storage practice, ice recrystallization remains a major problem and is a significant cause of cellular damage and cell death. [49,50] Section 7.1 of this chapter provides a detailed discussion on the role of ice recrystallization in cryo-injury however, to address these problems effective inhibitors of ice recrystallization are urgently required. Naturally occurring biological antifreezes are very effective inhibitors of ice recrystallization. Biological antifreezes (BAs) are peptides or glycopeptides typically found in organisms inhabiting sub-zero environments. The biological purpose of these compounds is to prevent the seeding of ice crystals
The first biological antifreezes were reported in the late 1950s. [51,52] Given their ability to prevent cryoinjury upon exposure to cold temperatures, [53-55] they have attracted a great deal of interest in the scientific and industrial communities. [56] Biological antifreezes are a complex class of compounds with dramatically different structures, making it difficult to understand how they inhibit ice recrystallization. Nevertheless, this important class of compounds is the foundation upon which all “rationally designed” novel ice recrystallization inhibitors are based, including the more recently reported small molecule inhibitors of ice recrystallization. [57-62]
In the late 1950s and early 1960s it was observed by Scholander and colleagues that marine teleost fish did not freeze during the winter despite the water temperature being -1.9 °C, over a degree below the freezing point of their blood serum. [51,52] DeVries and Wohlschlag later attributed their survival to the presence of circulating proteins and glycoproteins. [53-55] These proteins later became known as biological antifreezes, specifically antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs). A variety of AFPs and AFGPs have since been identified in a number of different fish, insects, plants and bacteria.
There are four classes of structurally diverse fish AFPs that have been identified. These are type I, [13,63-72] type II, [73-81] type III, [73-77,82-87] and type IV AFPs. [88-90] The four types of fish AFPs have a wide variation in their size, which can range from 3-12 kDa, and in their secondary structures, which can be α-helices, β-rolls, random coils and globular structures. AFGPs are also present in fish, and are comprised of a tripeptide repeat of (Thr-Ala-Ala)
Classification and structural differences between fish antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs).
A number of other AFPs have been identified in other organisms. Various insect AFPs have been identified such as those from the spruce budworm moth (
Biological antifreezes exhibit two types of antifreeze activities. The first and the most studied is thermal hysteresis (TH). This is defined as a selective depression of the freezing point of a solution relative to the melting point. [133-135] TH activity is the direct result of the binding of a BA to the surface of a seeded ice crystal. [136,137] The binding of the BA to the surface of ice facilitates a localized freezing point depression and induces a change in the ice crystal habit. This change in ice crystal habit is referred to as dynamic ice shaping (DIS) and is illustrated in Figure 5A. A more detailed description of this process is described in Section 5.3. The standard assay used to measure TH activity is nanolitre osmometry. [138] In this assay, a single ice crystal in an aqueous solution of the biological antifreeze is obtained, and the growth and behavior of the crystal upon increasing/decreasing the temperature can be observed. TH activity is reported as the difference between the observed freezing and melting points in Kelvin or degrees Celsius.
Photographs illustrating dynamic ice shaping (DIS) and ice recrystallization inhibition (IRI) activity.
The second type of antifreeze activity exhibited by biological antifreezes is their ability to inhibit ice recrystallization (referred to as ice recrystallization inhibition (IRI) activity). [41,139] An illustration of this process is shown in Figure 5B. Inhibiting ice recrystallization results in very small ice crystals within a frozen sample. The ability to maintain small ice crystal size within a frozen solution is a highly desirable property and compounds exhibiting this property have tremendous medical, commercial and industrial applications.
While there are various methods for assessing IRI activity such as the capillary method assay [140,141] or the use of wide-angle X-ray scattering (WAXS) and differential scanning calorimetry (DSC), [142-144] the most commonly used is the splat-cooling assay. [139] In the splat-cooling assay recrystallization can be observed by the change in size of individual ice grains. Briefly, the sample solution is frozen as a thin circular wafer by either dropping a small aliquot onto a precooled (-80 °C) polished aluminum block from a height of approximately 2 meters, [139] or by pressing the solution between two coverslips and freezing. [117] The samples are then annealed at a temperature below 0 °C and the ice crystal size distribution of the sample after a given time is observed. Ice crystal size can be quantified by measuring the mean largest ice grain dimension along any axis [59,145] or by measuring the mean ice grain area. [46,146] Thus, smaller ice crystal sizes represent greater IRI activity. Commonly, analytes are assayed in a salt solution (NaCl, CaCl2 or phosphate buffered saline (PBS)) or a 30-45% sucrose solution, and the solutions without analyte are used as positive controls for ice recrystallization for comparison. The presence of salt or other small solutes is very important as it ensures that liquid is present between ice crystal boundaries and the presence of these solutes negates non-specific IRI effects that can be observed in pure water. [41] While the original version of this assay was subjective in nature, it has recently been improved using Domain Recognition Software (DRS). [146] IRI can now be reliably quantified, providing accurate comparisons between samples and information on small and subtle changes in IRI activity within a series of analogues.
The most widely accepted mechanism for thermal hysteresis (TH) involves an irreversible adsorption-inhibition process. [133-137] In this mechanism, BAs irreversibly bind to specific planes of a growing ice crystal. Preferential binding occurs on the prism faces of ice, thus inhibiting ice growth along the
Formation of hexagonal bipyramidal ice crystals by inhibition of growth on the prism faces due to adsorption of BAs.
The irreversible binding of a BA to the surface of ice crystals results in a localized freezing point depression. This occurs
Illustrations of thermal hysteresis (TH) activity and the two models of ice growth inhibition.
There are two models that described how BAs inhibit ice growth within the thermal hysteretic gap. The first (illustrated in Figure 7B) was proposed by Raymond and DeVries and is known as the step pinning model. In this model, the growth of a step is inhibited by the BA which has pinned ice growth across the ice surface. [133] However, this model assumes that ice crystal growth occurs in steps advancing across the plane that the BA is adsorbed. The second model (illustrated in Figure 7C) is a three-dimensional model known as the mattress model and was proposed by Knight and DeVries. In this model, the adsorbed BA molecules exhibit inhibition by pinning ice growth normal (perpendicular) to the ice surface. [136]
Both of these models assume an irreversible adsorption of the BA onto the surface of ice. However, there have been reports suggesting that the adsorption is reversible. The main argument in favour of this is that if adsorption were truly irreversible then significant levels of adsorption would be observed in the presence of very low concentrations of BAs, [67] however this has not been definitively observed. Furthermore, a large free energy of adsorption of BAs would be expected, but it has been observed that the free energy of adsorption is close to zero. [153] Consequently, alternative mechanisms have been proposed describing ice growth inhibition of BAs. [153-156] Regardless of these alternate mechanisms, sufficient data exists to suggest an irreversible adsorption-inhibition mechanism, and consequently this model is the generally accepted mechanism by which BAs exhibit TH activity.
It should be emphasized that the ability to bind to ice is believed to be a property unique to BAs. However, it has been reported that polyvinyl alcohol (PVA) can bind to ice and exhibit a small degree of thermal hysteresis. [157] It was originally proposed that adsorption of BAs to the surface of ice occurred through the hydrogen bonding of hydrophilic groups to the oxygen atoms in the ice lattice. [12,158] However, this is contradictory to the current mechanism of action for AFPs where the importance of hydrogen bonding between polar residues and ice has been questioned. Alternatively, it has been demonstrated that entropic and enthalpic contributions from hydrophobic residues are crucial for ice binding. [159-161] The importance of hydrophobic residues has been validated with a number of different AFPs through site-specific mutagenesis studies, [82,159,162,163] and in general it is believed that the ice-binding site of these AFPs is hydrophobic and has a discrete complementarity with the planes of ice to which it binds. [82,162-165]
In contrast to AFPs, the current hypothesis of how AFGPs bind to ice involves hydrogen bonding between the hydroxyl groups of the sugars and the ice lattice. [137] A landmark study conducted by Nishimura and co-workers investigated the key structural features of AFGPs that were crucial for ice binding and TH activity. [166] In this study it was reported that three key motifs were required for TH activity (shown in Figure 8): 1) the
Important structural motifs on AFGPs for TH activity as determined by Nishimura and co-workers. [
Despite the tremendous number of structure-function studies conducted on AFPs and AFGPs over the last three decades, in all cases only TH activity has been assessed and correlated to structural modifications. The ability of these analogues to inhibit ice recrystallization has not been assessed, and consequently the structural features necessary for potent ice recrystallization inhibition (IRI) activity are not known. This is unfortunate as IRI activity is a highly desirable property for a compound to exhibit due to the many potential medical and industrial applications. Furthermore, while BAs do possess potent IRI activity, they cannot be used effectively as cryoprotectants. The ice binding ability associated with the TH activity of BAs alters the habit of ice crystals, and since the temperatures employed during cryopreservation are outside of the TH gap, this exacerbates cellular damage. [168-170] However, during the last several years considerable amount of progress has been made in discovering novel ice recrystallization inhibitors, some of which are synthetic analogues of AFGPs, and the work that has been conducted in this area will be the focus of the next section.
Biological antifreezes are excellent inhibitors of ice recrystallization. However, as stated in the previous section, the dynamic ice shaping (DIS) capabilities prohibits their use in applications where ice recrystallization inhibition (IRI) activity is highly desirable. Thus, the purpose of the following section will be to summarize the progress towards designing molecules that exhibit the ability to inhibit ice recrystallization without the ability to bind to ice, and on understanding the key structural features that are important for the IRI activity exhibited by these molecules.
One of the first studies that examined ice recrystallization inhibition (IRI) activity of peptides and conventional polymers was conducted by Knight
This study ultimately suggested there was a correlation between TH and IRI activity in the type I AFP. [41,171] While it is well known that biological antifreezes exhibit both types of antifreeze activity, the relationship between TH and IRI has been debated throughout the literature. It was previously suggested that these two properties were directly correlated and derived from the ability of BAs to bind to ice. [139,153] In contrast, it has been suggested there is little or no correlation between TH and IRI as some plant AFPs typically exhibit a low degree of TH activity but a high degree of IRI activity. [119,120] Furthermore, the elevated TH activity exhibited by hyperactive insect AFPs is often not accompanied by highly potent IRI activity. [141] To date, few studies have emerged examining the relationship between TH and IRI activity in native BAs, and those that have, report IRI activity using methods other than the traditional splat-cooling assay, [141] making it difficult to ascertain definitive conclusions about the correlation between TH and IRI.
Payne and co-workers recently published a study in 2012 examining the correlation of glycopeptide/glycoprotein mass on both TH and IRI activity for a range of homogeneous synthetic AFGPs (synAFGPs). [167] A native chemical ligation-desulfurization approach was used for the first convergent synthesis of homogenous synAFGPs that ranged in molecular mass from 1.2 – 19.5 kDa (compounds
Structures of homogeneous synthetic AFGPs (synAFGPs) reported by Payne and co-workers. [
Most of the peptide and glycopeptides that have been assessed for IRI activity have been synthetic structural analogues of AFGPs. The Ben laboratory published the first series of analogues with dramatic structural modifications relative to the AFGP structure, and these analogues maintained the potent IRI activity exhibited by AFGP-8 at equimolar concentrations but did not exhibit TH activity. These analogues were carbon-linked or
Structure of first-generation lysine-based
The Ben laboratory has published two other
Structures of potently IRI active
Following the discovery of the two novel synthetic ice recrystallization inhibitors
Structures of
The second structure-function study examined how the distance between the galactosyl moiety and the polypeptide backbone influenced IRI activity. In this study, the distance between the carbohydrate and peptide backbone of derivative
Structures of
In addition to
Structures of AFGP analogues reported by Sewald and co-workers. [
Three studies have been reported where AFGP analogues containing triazole rings have been synthesized and assessed for their ability to inhibit ice recrystallization. The triazole ring was incorporated to provide a convergent synthetic approach to these analogues and to overcome the low yields often associated with glycosylation. The key step in the synthesis of these analogues was the Cu(I)-catalyzed Huisgen azide-alkyne cycloaddition (or “click” chemistry). [180-182] In 2009, the Brimble group described the synthesis of two AFGP derivatives in which a furanose carbohydrate moiety was conjugated to a polypeptide backbone with a triazole-linker (Figure 15, compounds
Structures of triazole-containing AFGP analogues reported by the Brimble (
All of the compounds discussed thus far that have exhibited the ability to inhibit ice recrystallization have been peptide or glycopeptide-based molecules. While some of these derivatives show great promise for the many applications of ice recrystallization inhibitors, the main limitation is that large-scale preparation of these compounds for
In 2003 Inada
In addition to PVA, a number of other water-soluble polymers have also been investigated for their ability to inhibit ice recrystallization. [95] In 2009, Gibson
Structures of synthetic polymers assessed for IRI activity. [
The Ben laboratory was the first group to report that small molecules, which were not peptide or polymer-based, could inhibit ice recrystallization. In 2008, Tam
\n\t\t\t\t | \n\t\t
The hydration layer or hydration shell of a carbohydrate can be defined as the number of tightly bound water molecules that surround the carbohydrate in aqueous solution. The hydration of carbohydrates has been the focus of many studies, and hypotheses for rationalizing observed hydration characteristics include hydration numbers, [185-188] anomeric effect, [189] hydrophilic volume, [190] hydrophobic index, [191] the ratio of axial versus equatorial hydroxyl groups [192,193] and the compatibility with bulk-water based upon the position of the next-nearest-neighbor hydroxyl group. [194,195] In the early 1990s, Galema
In the study conducted by Tam
The disaccharides assessed in this study also showed a strong linear correlation of their IRI activity to their hydration numbers (values give in table 1). [177] However, the increase in hydration numbers for disaccharides relative to monosaccharides was not reflected with an increase in IRI activity. For instance, melibiose has a hydration number of 15.5, yet it exhibited similar IRI activity to D-galactose, which has a hydration number of 8.7. Furthermore, D-galactose was significantly more IRI active than maltose, despite maltose having a much larger hydration number (8.7 for D-galactose and 14.5 for maltose). This was attributed to a difference in total steric volume between the monosaccharides (containing one carbohydrate unit) and disaccharides (containing two carbohydrate units). By dividing the carbohydrate hydration number by their partial molar volumes an indication of the degree of hydration per molar volume of carbohydrate was obtained. This value was referred to as the hydration index (HI) and it provided the degree of hydration of the substrate as a function of its size or volume. This metric was useful in justifying why highly hydrated monosaccharides exhibited similar IRI activity as highly hydrated disaccharides at 22 mM, despite hydration numbers for monosaccharides being almost half the value of disaccharides. [177] However, at higher carbohydrate concentrations, such as 220 mM, the disaccharides were twice as IRI active as the monosaccharides. [196] Thus, hydration numbers, not hydration indices, were better predictors of IRI activity at this concentration, but ultimately IRI activity still correlated with carbohydrate hydration.
Following the report that simple commercially available carbohydrates exhibit moderate IRI activity, the Ben laboratory has reported the ability of various other carbohydrate derivatives to inhibit ice recrystallization. Most of these compounds have been derivatives of D-galactose. [177]
Structures of D-galactose-based analogues assessed for IRI activity by the Ben laboratory. [
In addition to monosaccharide derivatives, structural analogues of the disaccharide β-D-galactosyl-(1-3)-α-
Structural disaccharide analogues of the native β-D-galactosyl-(1-3)-
While the small molecules described above had the ability to inhibit ice recrystallization, all exhibited only weak to moderate activity at much higher concentrations than those of the potently IRI active glycoconjugates. However, in 2012 the Ben laboratory reported the first examples of small carbohydrate-based molecules that were extremely potent inhibitors ice recrystallization, some that were highly IRI active at concentrations much lower than 22 mM. To date, these are the most potent IRI active small molecules. The molecules investigated were carbohydrate-based surfactants and hydrogelators (structures shown in Figures 19), two of which were found to exhibit potent IRI activity. [62] The carbohydrate-based non-ionic surfactant β-octyl-D-galactopyranoside (
Structures of carbohydrate-based non-ionic surfactants and hydrogelators assessed for IRI activity by the Ben laboratory. [
The second class of compounds investigated were carbohydrate-based hydrogelators, as in aqueous solution they were known to aggregate and sequester bulk-water forming fibres and hydrogels. D-glucose hydrogelator derivative
Cryopreservation is a very attractive process for the preservation of biological materials. While vitrification and hypothermic storage each offer their own unique advantages and their own limitations, cryopreservation has a major advantage. At the temperatures associated with cryopreservation (typically -190 oC) all biochemical processes are effectively stopped. However, cryopreservation is a complex process during which careful attention to sample volume, cooling rates and cryoprotectants (dimethyl sulfoxide and glycerol) are extremely important to ensure cells survive the process. Unfortunately, all cryoprotectants exhibit cytoxicity and this complicates the cryopreservation process as the cryoprotectant must often be removed during the thawing cycle. Indeed there is a common myth that cooling rates of 1 oC/min with 10% dimethyl sulfoxide (DMSO) is sufficient for all cryopreservation applications. Unfortunately, this is incorrect and there is an urgent need for novel cryoprotectants, especially in light of the recent developments in the field of regenerative medicine where the supply of various progenitor cells is problematic for the many clinical applications. To highlight the complexity of this process and the need for new and improved cryoprotectants a brief description of cellular injury during cryopreservation will be presented in the following section.
Traditionally, there exist three characterized mechanisms of cell death that occur during cryopreservation. These are cell rupture due to damage to the external cell membrane, necrosis and cold induced apoptosis. Cell rupture is usually the result of osmotic imbalance causing a loss in membrane integrity. [50] Cell necrosis is characterized by cellular swelling (due to an increase in immune response), compromised cell membrane integrity, random DNA fragmentation by cellular endonucleases, cell lysis and the release of cytokines. Apoptosis (programmed cell death) is a highly complex and closely regulated biochemical pathway (the details of which will not be covered in this chapter). It may appear at first that cell death due to apoptosis is not related to cryopreservation however, it has been demonstrated that cold-induced apoptosis is common in cryopreserved cells. [50,199]
The formation of ice under typical cryopreservation conditions is inevitable, but cooling rates become extremely important in mitigating the damage associated with ice formation. For every cell type there is an optimal cooling and warming rate that is determined by the permeability of the cell membrane to water and the cryoprotectant. Hence, cryopreservation is performed with either slow or fast cooling rates depending on cell type. In most instances, ice will prefer to form outside of the cell. [200] Formation of extracellular ice creates an increased osmotic pressure across the cell membrane. This “osmotic flux” intensifies as ice growth continues after the nucleation event. As the ice crystal grows all solutes are excluded from the ice lattice [201] and are concentrated in the extracellular medium. Cells with less permeable membranes will rupture with increasing osmotic pressure if they cannot dehydrate fast enough.
The process of dehydration during freezing is somewhat of a “double-edged sword”. In one instance, the amount of intracellular water decreases, reducing the chance for intracellular ice formation – a lethal process. However, it has been shown that dehydration and exposure to excessively high concentrations of electrolytes is also lethal to the cell. [202] This is referred to as solute damage or the “solute effect” and it facilitates damage to the cell membrane that is irreparable. [202] Conversely, when cells are frozen very slowly, dehydration and excessive cell shrinkage facilitates cell death. Excessive dehydration can be prevented using cryoprotectants. Two classes of cryoprotectant are commonly employed. Non-penetrating cryoprotectants do not cross the cell membrane and hence remain outside the cell, thereby increasing the osmolality of the extracellular solution, facilitating dehydration of the cell prior to freezing and preventing formation of intracellular ice. Penetrating cryoprotectants, such as DMSO and glycerol, readily cross the cell membrane and decrease the concentration of intracellular electrolytes while maintaining greater cell volumes. The major problem with penetrating cryoprotectants is cytotoxicity due to the disruption of intracellular signaling. [203] In summary, cryopreservation of cells using slow-freezing results in dehydration of the cell in response to increasing osmotic pressures as electrolytes are concentrated outside the cell during extracellular ice growth. While dehydration of the cells helps to prevent intracellular ice growth, it is also detrimental to cell survival.
Cryopreservation using high cooling rates traps water inside the cell promoting the formation intracellular ice. [204] The exact mechanism by which this occurs is not clear [205] however, most cryobiologists believe that intracellular ice formation results in cell death. Hence, practical fast-freezing protocols must dehydrate cells prior to freezing in order to mitigate intracellular ice formation. [206] Of course cryoprotectants are necessary to accomplish this, but the role of the cryoprotectant during fast cooling is different than during slow cooling. Non-penetrating cryoprotectants are employed in an effort to dehydrate the cell and minimize the chance of intracellular ice formation. Interestingly, while the correlation between intracellular ice formation and cell death has been recognized, there is evidence to suggest that formation of intracellular ice does not directly kill cells. [200] Studies have shown that survival of cells post-cryopreservation is dependent upon the rate at which the cells are warmed during thawing and that cell death associated with intracellular ice formation is not caused by the initial nucleation of ice but by an alternate process during warming. [207,208] Possible mechanisms by which intracellular ice damages cells have been reviewed extensively in the literature and it has been concluded that cell death is occurring as a result of ice recrystallization. [202,209] This hypothesis is supported by the fact that may freeze-tolerant organisms inhabiting sub-zero environments produce large quantities of recrystallization-inhibitors
Cellular damage due to ice recrystallization occurs during the storage and thawing cycles of cryopreservation and, given the cryoprotective nature of BAs, it is not surprising that they have been investigated as cryoprotectants to increase cell viability post-thaw. In principle, BAs have the advantage of being relatively non-toxic compared to common cryoprotectants such as DMSO and glycerol. While BAs seem like ideal cryoprotectants, they have not been very effective and often fail to protect mammalian cells from cryoinjury at temperatures outside of the TH gap. This section will discuss specific examples where BAs were used to cryopreserve biological materials, including the benefits and problems associated with their use.
BAs have been examined as protective agents for the hypothermic storage and cryopreservation of various biological materials. AFPs have been reported to protect cell membranes during hypothermic storage. For instance, Rubinsky and co-workers demonstrated that AFPs [211] and AFGPs [212] of various molecular weights and in concentrations ranging from 1-40 mg/mL can successfully preserve the structural integrity of pig oolemma and bovine immature oocytes. Furthermore, these oolemma and oocytes underwent successful
In addition to hypotherminc storage, BAs have also been utilized for cryostorage of biological materials. Several studies have reported benefits of using AFPs and AFGPs as cryoprotectants. Rubinsky and co-workers observed dramatically improved morphological integrity of immature oocytes and two-cell-stage embroys of mice and pigs that were subjected to vitrification in the presence of 40 mg/mL AFGPs. [219,220] Similar results were observed with mature mouse oocytes [221], bovine and ovine embryos at the morula/blastocyst stage, [222] ram spermatozoa, [217] chimpanzee spermatozoa [218] and porcine oocytes. [223] While post-thaw viabilities were increased in the presence of BAs with ram and chimpanzee spermatozoa and porcine oocytes, cytotoxic effects during cooling were also observed. [217,218,223]
In contrast, other investigations have reported that BAs fail to protect cells during cryopreservation and actually facilitate cellular damage during cryopreservation. For instance, no specific benefits were observed in survival rates of vitrified bovine blastocysts, [224] two-step-cryopreserved oyster oocytes [225] and equine embroys using various AFPs. [226] Freezing of red blood cells in the presence of glycerol with AFPs (at concentrations between 25 and 1000
In contrast to native biological antifreezes, the benefit of analogues possessing “custom-tailored” antifreeze activity for cryopreservation has been demonstrated. In 2011, the Ben laboratory demonstrated that
While Nature has provided various organisms with peptides and glycopeptides to mitigate cellular damage during exposure to cold temperatures, these compounds have failed to be effective cryoprotectants in various medical and commercial applications. This is somewhat ironic as these compounds are potent inhibitors of ice recrystallization, a process that contributes significantly to cellular injury. The recent discovery that IRI activity can be selectively enhanced while suppressing TH activity in various analogues of biological antifreezes is a significant advancement towards the rational design of novel cryoprotectants. Some of these molecules have even demonstrated the ability to enhance cell viabilities post-thaw. While these compounds do not yet exhibit viabilities comparable to 10 % DMSO solutions, it is feasible that with a better understanding of the structural features necessary for potent IRI activity future analogues will be efficient cryoprotectants replacing conventional ones such as DMSO and glycerol. The recent discovery that small molecules are extremely potent inhibitors of ice recrystallization represents a “quantum leap” forward in this area. Further studies with these compounds
A dosimetric procedure aims to estimate a quantity to guarantee the delivery of the correct prescribed dose to a patient or the dose resulting from a diagnostic procedure.
To achieve this purpose, one must ensure that:
the measurement results represent the best possible value reported with its typical uncertainties, using the appropriate calibration coefficients and the correction factors necessary to adjust the measured value to the true value;
the measurement results made by different institutions must be comparable when performed under similar reference conditions such as those established by international protocols, i.e., TRS#398-IAEA [1] TRS # 469 [2];
the clinical results of different institutions can be comparable if the air Kerma or absorbed dose, in addition to the biological clinical parameters, is well known and fully described.
To fulfill those premises, the radiation detectors must be calibrated following a universal protocol agreed among the professional societies, and the quantities referenced to the standards at the BIPM as it was decided by the Metro Convention. The dissemination of these quantities until the final user is done through the calibration laboratory in each country either national or secondary following a logical chain of events as described in Figure 1.
The main steps involved in the implementation of the quantities: (a) air kerma and (b) absorbed dose to water.
At this point, one must highlight the importance of a network called: International Metrological Network, which fundamentally seeks to standardize the processes and the methodologies among the various laboratories in the world. As a result, the measurement of the main quantities of interest in radiotherapy, radiology, and radioprotection such as air Kerma and absorbed dose to water allows the clinical results and the biological effects to be compared scientifically among different users, with an acceptable level of uncertainties for each area.
The two steps shown above in Figure 1 constitute a simplification of the various levels of complexity that represent the metrological chain, and the algorithms used now are best illustrated now in Figure 2.
The international network of ionizing radiation metrology showing the traceability process between the primary standards coordinated by the BIPM followed by the network of the secondary laboratories traceable to the IAEA Laboratories, the BIPM or any other primary laboratory and the final user [
The concept and structure of the various levels of laboratories can be defined as:
Location where instruments with the highest metrological quality are used, the quantities are measured according to their definition, that is, in an absolute way. To reach this level, very sophisticated equipment, computer control systems, experimental arrangement, and very skilled staff are required, resulting in very small uncertainties, results impossible to be reproduced at the end user’s environment.
Those laboratories use free air chambers for air kerma standards in the low and medium energy X-ray beams; water or graphite calorimeters for absorbed dose standard to water or graphite; Fricke dosimeter is a standard for absorbed dose to water and ionization chambers with a well-known volume as standard for either air Kerma for gamma ray beams emitted by a collimated 60Co or absorbed dose to graphite using a large variety of photons and electron beams.
To carry out periodical comparisons involving all National laboratories to ensure the appropriate metrological consistency within the metrological network in a decision agreed by tall country’s signatories of the Metro Convention, the BIPM was designated to carry out this task, as shown in Figure 3.
Typical example of the result of one of the comparisons conducted by BIPM with several national laboratories for the quantity of absorbed dose to water using three different methods: Water calorimeter, graphite calorimeter, and the Fricke system [
Location where high-quality metrological instruments are used, though its calibration by one of the PSDL is required to assure that the users’ instruments are traceable to the national and international metrological network. In some situations, the IAEA- SSDL Laboratory provides periodical calibration to the members of the IAEA-SSDL network, and QA auditing is also conducted.
The SSDL are recognized and accredited by the country’s metrological authority such as the National Laboratory, as it is responsible for disseminating the quantities to the final user in their country ensuring the proper metrological coherence among users with reference to their standards [1, 2]. Since it is possible to find more than one SSDL in one country, an internal network must be established, and periodic comparison must be carried out by the National Laboratory.
In this way, users of ionizing radiation sources will be tracked to the National and International Network with their intercomparable results.
Tips:
It is not forbidden that the user calibrates their instruments in a PSDL outside the country instead of their SSDL. The drawback is the calibration cost in addition to transportation, insurance, customs clearance expenses, which makes this option too onerous and objectively unnecessary;
Carrying out calibrations in the country’s laboratories reinforces the metrological consistency between users and the national laboratory.
Location where the calibration procedures of diagnostic and treatment machines are carried out under conditions such as those in which the instruments were calibrated. When using the formalism, for example, from the TRS#398 [1] or similar, it is essential that the measurement systems were calibrated in a laboratory traced to the metrological network.
In this situation, the instruments used can be classified as:
reference instrument (the one with the highest level of metrological quality in the institution);
field instrument (instrument used in daily routine that can be equal to the first one). This is recommended since some legislations require two sets, one of which could be the reference.
If the institution has only one treatment machine, it is recommended to leave a fixed dosimetry set on the control room bench with the cables passed through the wall of the treatment room, avoiding passing the cable under the door risking damaging it, and the other set as the institutional reference. If you have two treatment machines, leave each system fixed on each machine and as part of the periodic QA program, perform cross-calibration changing the electrometers and performing the measurements. If the values differ consistently by more than 1% between them, use another calibrated chamber on both machines.
The stability test of the dosimetry system shall be performed every three months with a source of 90Sr or 137Cs, as required by the regulatory authority. This test is accepted as a good indicator of the performance of the measurement set, which must include the leakage, repeatability, and linearity tests.
If the QA documentation demonstrates the stability of your system in other ways, it may also be accepted.
Since the numerical values of the uncertainties increase as we go down in the metrological chain, there is a demand for a high-quality measuring system, careful instrument handling procedures especially for the cables and connectors, instrument warm-up, proper documentation, and finally a consistency in positioning the experimental setup.
Measurement systems (ion chamber, electrometer, and cable) must be calibrated when purchased, unless they are calibrated by the manufacturer if it has an accredited laboratory, when they undergo any repairs, and every 2 years regardless of any problem. The calibration coefficient is given for the quantity of absorbed dose to water at the reference conditions. This coefficient is directly traceable to the national and international metrology network. It may be possible to calibrate the ion chamber separately from the electrometer and then use the chambers with different electrometers or vice versa.
In general, there is a certain conceptual confusion not only by the users but also by the manufactures when using the concepts of absolute dosimetry, reference dosimetry, and relative dosimetry. Andreo et al. [3] very clearly discuss the differences between the three concepts so that they can be used properly.
It refers to the measurement of a quantity with an instrument of the highest metrological quality, which allows its determination in accordance with its definition. In general, it is carried out in Primary Laboratories.
For example, the quantity Exposure, X, as defined by ICRU 33 [4], is the result of the quotient of
Measures of the quantity Exposure, because of the air Kerma, are of great importance as they constitute the stakes of the metrological chain. They are directly related to the absorbed dose calibrations of the high energy photon and electron beams used in radiotherapy, radiobiology studies, and radioprotection measurements; the latter for the moment entirely dependent on the quantity air Kerma.
The determination of the exposure can be obtained through two methods, both with an ionization chamber:
Method 1. Free air chamber.
Unlike wall chambers, free air chambers do not have walls, so the interaction process occurs within the air volume defined by the electric field defined between the guard ring and the collector plate inside the chamber, to obtain the electronic equilibrium. The thickness of the air layer varies depending on the energy fluence of the beam, and for this reason, two chambers with different volumes are used for energies up to 150 kVp and 300 kVp, respectively. A typical diagram of a free air chamber is illustrated in Figure 4.
Typical diagram of a free air chamber where several important components can be identified, such as the diaphragm or frontal collimator with an area a, the collector electrode, and the guard plates when subjected to the same collector potential define the sensitive volume of the chamber.
This process is more largely described by [5], where the formalism for estimating the quantity air Kerma, including typical correction factors, is described in the Eq. (1):
Where:
V = sensitive volume of the chamber in which charges are produced and collected;
Method 2. Cavity chamber.
This method uses a cavity chamber, with a known volume, with the formalism proposed by [6] and extended by [7]. One must consider the cavity dimensions, the presence of the wall and a central electrode, in addition to the various correction factors empirically derived such as environmental quantities and measurement statistics. The characteristics of a chamber of this type used in several primary laboratories are described in Figure 5.
Image represents the physical diagram, with the internal and external dimensions of the cylindrical chamber.
The final volume measured in the chamber described in Figure 5 is 1.076 ± 0.003 cm3, and the graphite caps are used to determine the wall attenuation using the extrapolation method. The graphite complements are added to the base of the chamber after the insertion of each cap to preserve the spatial conditions of scattering. Recently, the wall attenuation value was recalculated by [8] using the Monte Carlo technique, whose result, though slightly different than the experimental one, is more accurate and with less uncertainty.
The primary Standard shown in Figure 5 is a cylindrical graphite chamber built by the Austrian National Laboratory, with its volume defined by the same laboratory, constructed of ultra-pure graphite (99.99%) with an excellent insulating system to minimize the “leakage” and the polarization effects, guaranteeing an excellent long-term stability and a metrological quality compatible with similar standards, as reported by [9, 10, 11].
Its sensitive volume was estimated by the Ostereich Forschung Centrum and reported by [12] from the internal physical dimensions of the chamber, defined with an uncertainty of 0.1% after subtracting the electrode volume according to Figure 5, and including the additional sensitive volume in the electrode base.
Thus, according to the Bragg-Gray principle, the measure of ionization in the center of the chamber in its absence is defined by Eq. (2):
Where:
The determination of the air kerma (
Where:
The determination of the absorbed dose to air (Dair), measured by a standard instrument, is defined as the energy delivered to a mass of air of the well-known sensitive volume of the ionization chamber, defined by the relation:
Where.
This measurement may require the use of a set of factors necessary to correlate the reading of the measurement system with the final value of the quantity, such as absorbed dose. The measurements must be carried out under the well-standardized reference conditions, that is: radiation field of 10 x 10 cm2 on the surface of the phantom, SSD (source surface distance) equal to 100 cm, with the center of the chamber positioned at 5 cm depth, reference temperature of 22°C (reference in Brazil), atmospheric pressure of 101.3 kPa, and relative humidity between 30 and 70% (Table 1).
Method 1. Measurement performed using a graphite or water calorimeter.
A Calorimeter measures the quantity absorbed dose to water or to graphite according to its definition, that is, from the increase in temperature in the medium due to a process of radiation induction. This evaluation is done by thermistors installed in the calorimeter body filled with high-purity water, as reported by Malcolm [16]. The calorimeter, in this case, your heart (nucleus), is placed at the reference depth in a 30 cm x 30 cm x 30 cm phantom. The measured signal is generally very low, on the order of 1 mK for an absorbed dose of 2 Gy, and its reproducibility is an important factor. Due to its complexity, it is suitable for use not in clinical settings, but in National Metrology Laboratories or research (Figure 6).
Shows a schematic diagram of the Domen-type water calorimeter, built jointly with the Canadian McGill University and reported by Rosado and de Almeida [
An important parameter is the magnitude of the heat defect, that is, the fraction of energy that is not released in the form of heat, being material dependent, this effect being more significant in graphite.
The typical temperature fluctuation obtained when using a radiation source consists of three basic regions:
the pre-trend that is prior to the irradiation, where fluctuation is stable,
a constant and almost linear region, when the temperature rises; corresponds to the moment that the source enters the calorimeter being kept in a fixed position, this being the measurement point of the thermistors while the irradiation lasts;
the post-trend, which is the region that exhibits the behavior of water temperature at time intervals after removal of the source from the calorimeter. The post-trend has a characteristic thermal profile and includes a relative region of low temperature rise that is governed by the increase in temperature gradient created in the water due to direct dose deposition in the water. This can be followed by a sudden increase in temperature due to the decay process of the effect source reaching the measurement point.
Using a model of heat conduction in water, the onset time of this sudden temperature rise can be accurately predicted as a function of the distance between the measurement point and the source.
Specifically, for a standard of absorbed dose to water such as the calorimeter, the dose
where:
One of the advantages of the water calorimeter is that the quantity of absorbed dose to water is being measured directly in water, while in the case of using graphite, a graphite to water conversion factor is necessary.
Method 2. Measurement performed on the graphite phantom using a known volume ionization chamber.
In general, the measurement of the absorbed dose to water
Parallel plates graphite ionization chamber (1.8 gm/cm3) with 2.8 mm wall thickness, inner diameter of 45 mm, outer diameter of 50.5 mm, used by the BIPM and reported by Boutillon and Niatel [
The reference conditions include radiation field of 10 x 10 cm2 in the plane of the phantom surface, SSD = 100 cm, with the center of the chamber positioned at 5 g/cm2 depth in graphite, reference air temperature of 22°C, atmospheric pressure of 101.3 kPa, and humidity between 30 and 70%, according to the formalism:
where:
(
Fricke dosimetry consists of measuring the conversion, due to the ionizing radiation, of the ferrous ions present in the solution, into ferric ions through spectrophotometry. The Fricke dosimeter consists of a 96% water solution, therefore its attenuation to radiation is very similar to that of water and can be used in the dose range of 5 Gy–400 Gy with dose rates of up to 106 Gy/s.
The quantity determined by the Fricke chemical dosimetry system is the absorbed dose to the Fricke solution (
Where:
ε = molar absorptivity coefficient or molar extinction coefficient;
To determine the quantity of interest,
Where:
This method requires laboratories with several parameters under control such as temperature, dust, cleaning, laminar flow hoods, Milli Q water production, glassware, quartz cuvettes, high-resolution double-beam spectrophotometer with filters for your QA, and high-purity chemicals. For this reason, its use is restricted to laboratories and not to be used at clinical environments.
It refers to the measurement of the absorbed dose in water with an ionization chamber in the beam of the user’s Institution. The reference conditions used in the calibration laboratory must reproduced, and the influence quantities (T, P, U) are measured at the time of data acquisition and correction accordingly.
Step 1: Calibration of a user’s chamber at the level of the National Laboratory or of an SSDL according to interface [3].
where:
Step 2. With the calibration coefficient
These measurements are performed at the user’s institution with its reference chamber to obtain the absorbed dose to water with a beam of the same quality as the SSDL under the reference conditions: SSD =100 cm, radiation field 10 x 10 cm2 and depth of 5 cm in water according to the Eq. (10):
where:
As the calibration coefficient is normally defined for a 60Co gamma ray beam, if the user has a different beam (e.g., photons with 6, 10, 15 MV) a
where:
where:
Geometry that should be used for measurement of the quality of the Q beam, to obtain the
The numerical value of this factor varies with the type of materials used in the chambers, whose beam quality is expressed by the TPR20,10 ratio, which empirically represents the variation in the interaction and absorption behavior of each of the materials due to the different cross sections. Typical behavior of
Typical behavior of
The graph clearly shows a dependence of the
The measurement system that best suits this application at the user level is the ionization chamber, in which case there is no need to know its volume as the calibration coefficient considers the chamber’s response and not its real volume.
The TPR20,10 can also be estimated from the Percentage Depth Dose measurements using the empirical relationship, according to Eq. (12):
where,
In the clinical environment various measurements are performed under non-reference conditions where the calibration coefficient does not need to be used. These measurements are called relative, such as: dosimetry of other radiation fields (values compared with the reference field, output factors), wedge filter factor (ratio between readings performed with and without filter on the same geometry), measurements of depth dose (normalized to the values obtained at the maximum dose point for that specific radiation field and type of beam).
In these cases, there is a variety of detectors that can be used without compromising on having their values related to the true value of the quantity.
For example: diodes, TLDs, micro-cameras, detector array, alanine, film, MOSFET among others, all of them with their well-defined and different characteristics, such as (sensitivity, short term repeatability, long-term stability, angular, dose rate and energy dependence, detector size, leakage, signal fading) among others must be considered.
Check and consider, if applicable, the following:
energy dependence with depth of water.
Dose rate dependence, especially on FFF (flattening filter-free) beams.
Directional dependence due to the detector geometry and volume.
Signal-to-noise ratio as a function of field size, detector shape and size, and signal sensitivity.
Permanent defects caused by dose storage
volume that results in loss of spatial resolution.
Special cases where the reference conditions are not able to follow TRS#398 [1] recommendations are called non-reference conditions. Small fields used in radiosurgery show a more complex spectrum and require ionization chambers with other dimensions, additional geometric conditions, and specific formalism.
In this case, the TRS# 483 [20] should be used as a reference, the most suitable one at this time, where a relatively small variety of detectors are used, generally limited by the field size and the loss of lateral electronic balance.
Replace the entirety of this text with the main body of your chapter. The body is where the author explains experiments, presents, and interprets data of one’s research. Authors are free to decide how the main body will be structured. However, you are required to have at least one heading. Please ensure that either British or American English is used consistently in your chapter.
This entire chain of measurements and formalism must take into account the specific physical conditions of the interaction processes between the radiation beam with the detector in the measurement processes, aiming to ensure the least possible uncertainty in the dose delivered to the patient.
The different levels of complexity and duties of the metrological stakeholders are a result of the complexity of the experimental arrangements, the quality of the measurement systems, the degree of control over the environmental conditions and the high cost, which makes it not compatible with the clinical environment.
However, the metrological consistency between the different levels guarantees a level of final uncertainty of the dose delivered to the patient compatible with the recommendations of international organizations.
Therefore, if we keep the instruments (electrometer + cable + camera) accompanied by a quality assurance program, with its periodic calibrations and care to maintain its functional integrity, the final quality of the measurements will always be in accordance with the concept of the best practice.
The authors declare no conflict of interest.
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However, before attributing health benefits to these compounds, absorption, distribution, and metabolism of each phenolic compound in the body are important points that should be considered.",book:{id:"5609",slug:"phenolic-compounds-biological-activity",title:"Phenolic Compounds",fullTitle:"Phenolic Compounds - Biological Activity"},signatures:"Igor Otavio Minatel, Cristine Vanz Borges, Maria Izabela Ferreira,\nHector Alonzo Gomez Gomez, Chung-Yen Oliver Chen and\nGiuseppina Pace Pereira Lima",authors:[{id:"146379",title:"Dr.",name:"Giuseppina",middleName:null,surname:"Lima",slug:"giuseppina-lima",fullName:"Giuseppina Lima"},{id:"194002",title:"MSc.",name:"Cristine",middleName:null,surname:"Vanz Borges",slug:"cristine-vanz-borges",fullName:"Cristine Vanz Borges"},{id:"194003",title:"Prof.",name:"Igor Otavio",middleName:null,surname:"Minatel",slug:"igor-otavio-minatel",fullName:"Igor Otavio Minatel"},{id:"194004",title:"Dr.",name:"Maria Izabela",middleName:null,surname:"Ferreira",slug:"maria-izabela-ferreira",fullName:"Maria Izabela Ferreira"},{id:"194005",title:"Prof.",name:"Hector",middleName:null,surname:"Gomez-Gomez",slug:"hector-gomez-gomez",fullName:"Hector Gomez-Gomez"},{id:"194006",title:"Prof.",name:"Chung-Yen Oliver",middleName:null,surname:"Chen",slug:"chung-yen-oliver-chen",fullName:"Chung-Yen Oliver Chen"}]},{id:"45635",title:"Application of Cellulose and Cellulose Derivatives in Pharmaceutical Industries",slug:"application-of-cellulose-and-cellulose-derivatives-in-pharmaceutical-industries",totalDownloads:10343,totalCrossrefCites:58,totalDimensionsCites:135,abstract:null,book:{id:"3173",slug:"cellulose-medical-pharmaceutical-and-electronic-applications",title:"Cellulose",fullTitle:"Cellulose - Medical, Pharmaceutical and Electronic Applications"},signatures:"Javad Shokri and Khosro Adibkia",authors:[{id:"140056",title:"Prof.",name:"Javad",middleName:null,surname:"Shokri",slug:"javad-shokri",fullName:"Javad Shokri"}]},{id:"57200",title:"Introductory Chapter: Principles of Green Chemistry",slug:"introductory-chapter-principles-of-green-chemistry",totalDownloads:2811,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"6067",slug:"green-chemistry",title:"Green Chemistry",fullTitle:"Green Chemistry"},signatures:"Hosam El-Din Mostafa Saleh and M. 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Microorganisms produce these enzymes in a diverse nature which determines their efficiency in cellulose hydrolysis. During the cellulose degradation reaction, the enzyme targets the β-1,4-linkages in its polymeric structure. This is an essential ecological process as it recycles cellulose in the biosphere. The application of this same scenario for industrial purposes is identified as an emerging area of research. Biofuel production, textile polishing and finishing, paper and pulp industry, and lifestyle agriculture are among the key areas where cellulase enzyme shows a broader potential. The objective of this chapter is to discuss the structure, function, possible applications, as well as novel biotechnological trends of cellulase enzymes. Furthermore, possible low-cost, enzymatic pretreatment methods of lignocellulosic material in order to use it as an efficient raw material for biofuel production will be discussed.",book:{id:"7363",slug:"cellulose",title:"Cellulose",fullTitle:"Cellulose"},signatures:"Sandhya Jayasekara and Renuka Ratnayake",authors:null}],onlineFirstChaptersFilter:{topicId:"85",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"65119",title:"Introductory Chapter: Polyaniline - From Synthesis to Practical Applications",slug:"introductory-chapter-polyaniline-from-synthesis-to-practical-applications",totalDownloads:974,totalDimensionsCites:2,doi:"10.5772/intechopen.83397",abstract:null,book:{id:"7503",title:"Polyaniline - From Synthesis to Practical Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7503.jpg"},signatures:"Florin Nastase"}],onlineFirstChaptersTotal:1},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. 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His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}]},{type:"book",id:"6843",title:"Biomechanics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6843.jpg",slug:"biomechanics",publishedDate:"January 30th 2019",editedByType:"Edited by",bookSignature:"Hadi Mohammadi",hash:"85132976010be1d7f3dbd88662b785e5",volumeInSeries:4,fullTitle:"Biomechanics",editors:[{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. 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He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}}]}},subseries:{item:{id:"18",type:"subseries",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11414,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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