Substituents of the six types of anthocyanins.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{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"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"10942",leadTitle:null,fullTitle:"Fiber-Reinforced Plastics",title:"Fiber-Reinforced Plastics",subtitle:null,reviewType:"peer-reviewed",abstract:"This book deepens the study and knowledge on fiber-reinforced plastics (FRPs), which are composite materials made of a polymer matrix reinforced with fibers. The fibers are usually glass, carbon, or aramid, although other fibers such as paper, wood, or asbestos are sometimes used. The polymer is usually an epoxy, vinyl ester, or polyester thermosetting plastic, and phenol-formaldehyde resins are still in use. Among, the most prominent applications of FRPs are in the aerospace, automotive, marine, and construction industries. The development of FRPs has a very promising future with a marked annual increase and with a wide range of sources. This book presents comprehensive information on FRPs and their wide variety of applications in the industry worldwide.",isbn:"978-1-80355-076-3",printIsbn:"978-1-80355-075-6",pdfIsbn:"978-1-80355-077-0",doi:"10.5772/intechopen.95632",price:119,priceEur:129,priceUsd:155,slug:"fiber-reinforced-plastics",numberOfPages:192,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"50dc791b1036b236a6676986cb295c6f",bookSignature:"Martin Alberto Masuelli",publishedDate:"April 20th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/10942.jpg",numberOfDownloads:1090,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 24th 2021",dateEndSecondStepPublish:"September 15th 2021",dateEndThirdStepPublish:"November 14th 2021",dateEndFourthStepPublish:"February 2nd 2022",dateEndFifthStepPublish:"April 3rd 2022",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"99994",title:"Dr.",name:"Martin",middleName:"Alberto",surname:"Masuelli",slug:"martin-masuelli",fullName:"Martin Masuelli",profilePictureURL:"https://mts.intechopen.com/storage/users/99994/images/system/99994.png",biography:"Martin A. Masuelli is a Inv. Adj. professor at the Instituto de Física Aplicada, National Scientific and Technical Research Council (CONICET), and an associate professor at the National University of San Luis (UNSL), Argentina. He holds a master’s degree and a Ph.D. in Membrane Technology from UNSL. He has served as the director of the Physics Chemistry Service Laboratory, UNSL, since 2014. He is an expert in polysaccharides and the physical chemistry of macromolecules. Dr. Masuelli has authored or co-authored more than thirty-two peer-reviewed international publications, eight book chapters, and seventy communications in international congresses. He has also edited seven books. He is a member of the Sociedad Argentina de Ciencia y Tecnología Ambiental, Asociación Argentina de Fisicoquímica y Química Inorgánica, and Asociación Argentina de Tecnólogos de Alimentos. He is editor in chief and founder of the Journal of Polymer and Biopolymers Physics Chemistry and an editorial board member for various other journals. His research interests include hydropolymers, biopolymers (separative, purification processes, and characterization), physiochemistry of macromolecules, membrane technology and design (NF-UF-MF), and separative processes.",institutionString:"National University of San Luis",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"National University of San Luis",institutionURL:null,country:{name:"Argentina"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"156",title:"Composite Materials",slug:"materials-science-composite-materials"}],chapters:[{id:"79165",title:"Self-Healing Polymers and Composite Materials",doi:"10.5772/intechopen.100908",slug:"self-healing-polymers-and-composite-materials",totalDownloads:178,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In order to overcome the challenges and limitations related to conventional maintenance and repair methods in structural composites during service, the concept of self-healing for polymeric materials has been developed in the last decades. Inspired by biological systems, ideal self-healing materials must be able to repair damages continuously during the service life of the component, recovering its performance. Several techniques have been proposed in the last years to manufacture self-healing polymers and fiber-reinforced composites to provide healing of microcracks in the composite structure without or with less intervention, extending service life and safety of the components and reducing maintenance time and cost. This book chapter proposes an overview of the most promising self-healing approaches for thermoset and polymer matrix composites developed in recent year.",signatures:"Allana Azevedo do Nascimento",downloadPdfUrl:"/chapter/pdf-download/79165",previewPdfUrl:"/chapter/pdf-preview/79165",authors:[{id:"427098",title:"M.Sc.",name:"Allana",surname:"Azevedo do Nascimento",slug:"allana-azevedo-do-nascimento",fullName:"Allana Azevedo do Nascimento"}],corrections:null},{id:"80891",title:"Design, Simulation, and Analysis of the Extrusion Process of a PVC Thermoplastic Profile to Optimize the Design of the Die and the Machine Parameters",doi:"10.5772/intechopen.100909",slug:"design-simulation-and-analysis-of-the-extrusion-process-of-a-pvc-thermoplastic-profile-to-optimize-t",totalDownloads:45,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The objective of this work is to verify the design of an existing die for the manufacture of an extruded profile using the simulation of the flow in the head using a simulation software that uses computational fluid dynamics and also the experimental design and construction of a calibrator by means of the extrusion the geometry and desired dimensions of the profile. The rheological behavior of rigid PVC in the extruded molten state was investigated, which in itself is a difficult target due to the intrinsic weakness of this polymer that degrades when heated above 140°C. By means of a special capillary rheometer, rheological data, k and n of the power law, were obtained to introduce them, together with the process input parameters and the flow channel geometry in the simulation software. The flow channel was drawn with the head and calibrator using CAD-3D software. The different parts of the calibrator were manufactured and assembled into the equipment. The extrusion was performed with the process parameters: screw speed and material temperature used in the simulation software. The results obtained by the extrusion, geometry and final dimensions of the profile, mass flow, pressure, and temperature in the head were compared with those delivered by the software, being the same satisfactory.",signatures:"Carlos José Salvador Tomassini",downloadPdfUrl:"/chapter/pdf-download/80891",previewPdfUrl:"/chapter/pdf-preview/80891",authors:[{id:"427374",title:"Prof.",name:"Carlos",surname:"José Salvador Tomassini",slug:"carlos-jose-salvador-tomassini",fullName:"Carlos José Salvador Tomassini"}],corrections:null},{id:"79552",title:"Unidirectional Carbon Fiber Reinforced Thermoplastic Tape in Automated Tape Placement Process",doi:"10.5772/intechopen.101110",slug:"unidirectional-carbon-fiber-reinforced-thermoplastic-tape-in-automated-tape-placement-process",totalDownloads:141,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Thermoplastic matrix composites are finding new applications in the different industrial areas, thanks to their intrinsic advantages related to environmental compatibility and process-ability. The tape placement process is one of the few techniques that have the potential to continuously process thermoplastic composites in large industrial applications. Fiber-reinforced thermoplastic tapes are subjected to high heating and cooling rates during the tape placement process. The application of laser heating for the tape placement process requires a thorough understanding of the factors involved in the process. Qualitative experimental analysis is presented to identify the important phenomena during the tape placement of carbon (PEEK, PEKK, PAEK PPS) tapes. The present chapter focuses on the input parameters in the process of manufacturing composite parts. The mechanical performance of the final parts depend on a number of parameters. It should be void-free and well consolidated for reliable use in the structure. In the present work, it is becoming increasingly wiser to introduce the production of high-quality laminates, using laser AFP and ATL with quality consolidation during the laying process. The experimental results in this chapter help to better understand the consolidation process during LATP.",signatures:"Svetlana Risteska",downloadPdfUrl:"/chapter/pdf-download/79552",previewPdfUrl:"/chapter/pdf-preview/79552",authors:[{id:"425132",title:"Prof.",name:"Svetlana",surname:"Risteska",slug:"svetlana-risteska",fullName:"Svetlana Risteska"}],corrections:null},{id:"79224",title:"Mechanically Improved and Multifunctional CFRP Enabled by Resins with High Concentrations Epoxy-Functionalized Fluorographene Fillers",doi:"10.5772/intechopen.100141",slug:"mechanically-improved-and-multifunctional-cfrp-enabled-by-resins-with-high-concentrations-epoxy-func",totalDownloads:84,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"To meet the maximum potential of the mechanical properties of carbon fiber reinforced plastics (CFRP), stress transfer between the carbon fibers through the polymer matrix must be improved. A recent promising approach reportedly used reinforcing particles as fillers dispersed in the resin. Carbon based fillers are an excellent candidate for such reinforcing particles due to their intrinsically high mechanical properties, structure and chemical nature similar to carbon fiber and high aspect ratio. They have shown great potential in increasing the strength, elastic modulus and other mechanical properties of interest of CFRPs. However, a percolation threshold of ~1% of the carbon-based particle concentration in the base resin has generally been reported, beyond which the mechanical properties deteriorate due to particle agglomeration. As a result, the potential for further increase of the mechanical properties of CFRPs with carbon-based fillers is limited. We report a significant increase in the strength and elastic modulus of CFRPs, achieved with a novel reinforced thermoset resin that contains high loadings of epoxy-reacted fluorographene (ERFG) fillers. We found that the improvement in mechanical performance of CFRPs was correlated with increase in ERFG loading in the resin. Using a novel thermoset resin containing 10 wt% ERFG filler, CFRPs fabricated by wet layup technique with twill weaves showed a 19.6% and 17.7% increase in the elastic modulus and tensile strength respectively. In addition, because of graphene’s high thermal conductivity and high aspect ratio, the novel resin enhanced CFRPs possessed 59.3% higher through-plane thermal conductivity and an 81-fold reduction in the hydrogen permeability. The results of this study demonstrate that high loadings of functionalized particles dispersed in the resin is a viable path towards fabrication of improved, high-performance CFRP parts and systems.",signatures:"Junhua Wei",downloadPdfUrl:"/chapter/pdf-download/79224",previewPdfUrl:"/chapter/pdf-preview/79224",authors:[{id:"426142",title:"Dr.",name:"Junhua",surname:"Wei",slug:"junhua-wei",fullName:"Junhua Wei"}],corrections:null},{id:"79965",title:"Composite Materials with Natural Fibers",doi:"10.5772/intechopen.101818",slug:"composite-materials-with-natural-fibers",totalDownloads:95,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The materials involved in the fabrication of biocomposites have dissimilar physical and chemical properties. More important, the newly created materials exhibit anisotropy and their performance is strongly influenced by the hydrophobic nature of the natural fibers used as reinforcement materials. Beyond a compressive discussion regarding the potential of composite materials with natural fibers in engineering applications, the chapter focuses on simulation of their behavior under applied loads. Modern experimental approaches for defining and validating computer simulations are also introduced. Finally, health hazards and biodegradability issues are evaluated. The new trends in biocomposites materials for engineering applications are briefly discussed.",signatures:"Nicholas Lambrache, Ora Renagi, Lidia Olaru and Brian N’Drelan",downloadPdfUrl:"/chapter/pdf-download/79965",previewPdfUrl:"/chapter/pdf-preview/79965",authors:[{id:"438068",title:"Prof.",name:"Nicholas",surname:"Lambrache",slug:"nicholas-lambrache",fullName:"Nicholas Lambrache"},{id:"440101",title:"Dr.",name:"Ora",surname:"Renagi",slug:"ora-renagi",fullName:"Ora Renagi"},{id:"440102",title:"Mrs.",name:"Lidia",surname:"Olaru",slug:"lidia-olaru",fullName:"Lidia Olaru"},{id:"440103",title:"Mr.",name:"Brian",surname:"N'Drelan",slug:"brian-n'drelan",fullName:"Brian N'Drelan"}],corrections:null},{id:"79625",title:"Sisal Fibre Based Polymeric Composites",doi:"10.5772/intechopen.101107",slug:"sisal-fibre-based-polymeric-composites",totalDownloads:79,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Nature origin fibres have drawn in extraordinary consideration from commercial and specialists for the use of polymer composites as a result of their ‘greener’ nature and commitment to maintainable practice. Different enterprises have moved towards reasonable innovation to work on the harmony between the climate and social and financial concerns. Innovative work has demonstrated that normal fibres have been effectively applied as fortifications in the composites business, for example, for transportation, inside segments, building, airplane.",signatures:"Archana Nigrawal, Arun Kumar Sharma and Fozia Zia Haque",downloadPdfUrl:"/chapter/pdf-download/79625",previewPdfUrl:"/chapter/pdf-preview/79625",authors:[{id:"257011",title:"Dr.",name:"Archana",surname:"Nigrawal",slug:"archana-nigrawal",fullName:"Archana Nigrawal"},{id:"437736",title:"Dr.",name:"Arun Kumar",surname:"Sharma",slug:"arun-kumar-sharma",fullName:"Arun Kumar Sharma"},{id:"437737",title:"Dr.",name:"Fozia",surname:"Zia Haque",slug:"fozia-zia-haque",fullName:"Fozia Zia Haque"}],corrections:null},{id:"79700",title:"Functional Application for the Corn Leaf Fibre to Make Reinforced Polymer Composites Sheet",doi:"10.5772/intechopen.101656",slug:"functional-application-for-the-corn-leaf-fibre-to-make-reinforced-polymer-composites-sheet",totalDownloads:141,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This research work has mainly utilized agricultural waste material to make a good-quality composite sheet product of the profitable, pollution free, economical better for farmer and industries. In this study, from corn leaf fibre to reinforced epoxy composite product has been utilized with minimum 35 to maximum range 55% but according to earlier studies, pulp composite material was used in minimum 10 to maximum 27%. Natural fibre-based composites are under intensive study due to their light weight, eco-friendly nature and unique properties. Due to the continuous supply, easy of handling, safety and biodegradability, natural fibre is considered as better alternative in replacing many structural and non-structural components. Corn leaf fibre pulp can be new source of raw material to the industries and can be potential replacement for the expensive and non-renewable synthetic fibre. Corn leaf fibre as the filler material and epoxy as the matrix material were used by changing reinforcement weight fraction. Composites were prepared using hand lay-up techniques by maintaining constant fibre and matrix volume fraction. The sample of the composites thus fabricated was subjected to tensile, impact test for finding the effect of corn husk in different concentrations.",signatures:"Ramratan Guru, Anupam Kumar and Rohit Kumar",downloadPdfUrl:"/chapter/pdf-download/79700",previewPdfUrl:"/chapter/pdf-preview/79700",authors:[{id:"336997",title:"Dr.",name:"Ramratan",surname:"Guru",slug:"ramratan-guru",fullName:"Ramratan Guru"},{id:"337607",title:"Prof.",name:"Anupam",surname:"Kumar",slug:"anupam-kumar",fullName:"Anupam Kumar"},{id:"337608",title:"Mr.",name:"Rohit",surname:"Kumar",slug:"rohit-kumar",fullName:"Rohit Kumar"}],corrections:null},{id:"79103",title:"Fabricating Natural Biocomposites for Food Packaging",doi:"10.5772/intechopen.100907",slug:"fabricating-natural-biocomposites-for-food-packaging",totalDownloads:147,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Nowadays, there are dominant scientific breakthroughs to advance the packaging industry to identify innovative and emerging fruitful results for making the food packaging systems, in particular, more efficient, resilient, and sustainable. Therefore, friendliness packaging research has been gaining momentum, thanks to global environmental awareness, and also consumer ecological consciousness, and leading companies are committing to a more holistic worldview of packaging in response to more sustainable processes to reduce pollution and any depletion of resources. High-yielding and cost-effective production and design of packaging, involving synthetic materials use reduction and development of new bio-based packaging materials, are very much part of this holistic approach. Thus, in comparison with petroleum-based materials, potential bio-based materials may have benefits for all agents comprised: the producers, customers as well as the whole environment. This chapter explores a review of relative topics across all disciplines that could accelerate understanding toward this goal. It walks through conventional materials, and then important natural and synthetic polymers from the context of food packaging. Moreover, it provides an overview of the performance of bioplastics and their limitations. State-of-the-art main trends on green biocomposites thereof, their potential to transform the food industry, are also herein considered.",signatures:"Liqaa Hamid and Irene Samy",downloadPdfUrl:"/chapter/pdf-download/79103",previewPdfUrl:"/chapter/pdf-preview/79103",authors:[{id:"427722",title:"Associate Prof.",name:"Irene",surname:"Samy",slug:"irene-samy",fullName:"Irene Samy"},{id:"437221",title:"Mrs.",name:"Liqaa",surname:"Hamid",slug:"liqaa-hamid",fullName:"Liqaa Hamid"}],corrections:null},{id:"79811",title:"FRP for Marine Application",doi:"10.5772/intechopen.101332",slug:"frp-for-marine-application",totalDownloads:144,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Fiber Reinforced Plastics (FRPs) are widely used in marine sector owing to their high specific strength and resistance to marine corrosion. For naval application, additional advantages are transparency to radar wave and better vibration damping than metals. The use of various FRPs in off-shore structures and marine vessels needs analysis of desired properties considering the types of matrices and fiber. The common consideration is effect of sea water on the properties of the FRP. This chapter gives a brief on use of different FRPs in various areas such as off-shore pillars, Reinforced Cement Concrete (RCC) enclosers, primary and secondary marine components. A brief discussion is included here on diffusion models and estimation of durability by a time-temperature superposition principle applied to water ingress and corresponding change in mechanical strength of FRPs with examples. The effect of microbial activity on the damage of FRP is not very much reported in literature. It is known that sulfate-reducing bacteria (SRB) are the most damaging microbes for FRP. In conclusion, it is highlighted that vinyl-ester-based FRPs using glass and carbon fibers are best for marine application. To determine the realistic service life in marine environment, Vinyl Ester- FRP (VE-FRP) are to be simultaneously studied for damage due to sea water and the microbes such SRB.",signatures:"Bikash Chandra Chakraborty",downloadPdfUrl:"/chapter/pdf-download/79811",previewPdfUrl:"/chapter/pdf-preview/79811",authors:[{id:"427043",title:"Dr.",name:"Bikash",surname:"Chandra Chakraborty",slug:"bikash-chandra-chakraborty",fullName:"Bikash Chandra Chakraborty"}],corrections:null},{id:"80884",title:"Mechanical Properties and Chemical Stability of Bathroom Wall Composites Manufactured from Recycle Polyethylene Terephthalate (PET) Mixed with Cocoa Hull Powder",doi:"10.5772/intechopen.102457",slug:"mechanical-properties-and-chemical-stability-of-bathroom-wall-composites-manufactured-from-recycle-p",totalDownloads:36,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The recovery of plastic waste and agricultural residues has led us to develop composites based on polyethylene terephthalate (PET) filled with cocoa shell powder. These shells have been previously treated with the organosolv process to improve the fiber-matrix interaction. The objective of this work is to develop wall covering materials to replace tiles which require a lot of energy and from PET. The composites were made by the method of melt mixing followed by compression molding. The mechanical, physico-chemical properties and stability to environmental conditions were evaluated. The results showed that the incorporation of 20–30% of powder in the matrix made of PET gave rise to a composite material with good properties for application in construction, as a wall covering replacing the tile. The study showed that the optimum powder weight ratio for optimum composite properties was achieved at a powder weight ratio of 30%. The maximum tensile strength of 60.3 MPa, bending strength of 19.5 MPa, impact strength of 10.3 MPa and water absorption of 1.34% were obtained. Compared with ceramic tile, this water absorption test value is within the range and shows that this composite tile is suitable for use as a bathroom tile.",signatures:"Paul Nestor Djomou Djonga, Ahmat Tom, Hambate Gomdje Valery and Georges Elambo Nkeng",downloadPdfUrl:"/chapter/pdf-download/80884",previewPdfUrl:"/chapter/pdf-preview/80884",authors:[{id:"353783",title:"Prof.",name:"Hambate",surname:"Gomdje Valery",slug:"hambate-gomdje-valery",fullName:"Hambate Gomdje Valery"},{id:"356476",title:"Dr.Ing.",name:"Paul Nestor",surname:"Djomou Djonga",slug:"paul-nestor-djomou-djonga",fullName:"Paul Nestor Djomou Djonga"},{id:"441072",title:"Dr.",name:"Ahmat",surname:"Tom",slug:"ahmat-tom",fullName:"Ahmat Tom"},{id:"466164",title:"Dr.",name:"Georges",surname:"Elambo Nkeng",slug:"georges-elambo-nkeng",fullName:"Georges Elambo Nkeng"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"2828",title:"Fiber Reinforced Polymers",subtitle:"The Technology Applied for Concrete Repair",isOpenForSubmission:!1,hash:"4922c593466cc822b281fe7cc7d7fef6",slug:"fiber-reinforced-polymers-the-technology-applied-for-concrete-repair",bookSignature:"Martin Alberto Masuelli",coverURL:"https://cdn.intechopen.com/books/images_new/2828.jpg",editedByType:"Edited by",editors:[{id:"99994",title:"Dr.",name:"Martin",surname:"Masuelli",slug:"martin-masuelli",fullName:"Martin Masuelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8504",title:"Pectins",subtitle:"Extraction, Purification, Characterization and Applications",isOpenForSubmission:!1,hash:"ff1acef627b277c575a10b3259dd331b",slug:"pectins-extraction-purification-characterization-and-applications",bookSignature:"Martin Masuelli",coverURL:"https://cdn.intechopen.com/books/images_new/8504.jpg",editedByType:"Edited by",editors:[{id:"99994",title:"Dr.",name:"Martin",surname:"Masuelli",slug:"martin-masuelli",fullName:"Martin Masuelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6320",title:"Advances in Glass Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6d0a32a0cf9806bccd04101a8b6e1b95",slug:"advances-in-glass-science-and-technology",bookSignature:"Vincenzo M. 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Renna, Rodrigo Garcia, Jesica Ramirez and Roberto M.\nMiatello",dateSubmitted:"May 26th 2016",dateReviewed:"January 16th 2017",datePrePublished:null,datePublished:"April 5th 2017",book:{id:"5682",title:"Physiologic and Pathologic Angiogenesis",subtitle:"Signaling Mechanisms and Targeted Therapy",fullTitle:"Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy",slug:"physiologic-and-pathologic-angiogenesis-signaling-mechanisms-and-targeted-therapy",publishedDate:"April 5th 2017",bookSignature:"Dan Simionescu and Agneta Simionescu",coverURL:"https://cdn.intechopen.com/books/images_new/5682.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"66196",title:"Dr.",name:"Dan",middleName:"T.",surname:"Simionescu",slug:"dan-simionescu",fullName:"Dan Simionescu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"192616",title:"Dr.",name:"Nicolás",middleName:null,surname:"Renna",fullName:"Nicolás Renna",slug:"nicolas-renna",email:"nicolasfede@gmail.com",position:null,institution:{name:"National University of Cuyo",institutionURL:null,country:{name:"Argentina"}}},{id:"202536",title:"Dr.",name:"Rodrigo",middleName:"Damián",surname:"García",fullName:"Rodrigo García",slug:"rodrigo-garcia",email:"rodridg@hotmail.com",position:null,institution:null},{id:"202537",title:"Dr.",name:"Jesica",middleName:null,surname:"Ramirez",fullName:"Jesica Ramirez",slug:"jesica-ramirez",email:"jesicamagali@hotmail.com",position:null,institution:null},{id:"202539",title:"Dr.",name:"Roberto M.",middleName:null,surname:"Miatello",fullName:"Roberto M. 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Renna, Rodrigo Garcia, Jesica Ramirez and Roberto M.\nMiatello",dateSubmitted:"May 26th 2016",dateReviewed:"January 16th 2017",datePrePublished:null,datePublished:"April 5th 2017",book:{id:"5682",title:"Physiologic and Pathologic Angiogenesis",subtitle:"Signaling Mechanisms and Targeted Therapy",fullTitle:"Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy",slug:"physiologic-and-pathologic-angiogenesis-signaling-mechanisms-and-targeted-therapy",publishedDate:"April 5th 2017",bookSignature:"Dan Simionescu and Agneta Simionescu",coverURL:"https://cdn.intechopen.com/books/images_new/5682.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"66196",title:"Dr.",name:"Dan",middleName:"T.",surname:"Simionescu",slug:"dan-simionescu",fullName:"Dan Simionescu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"192616",title:"Dr.",name:"Nicolás",middleName:null,surname:"Renna",fullName:"Nicolás Renna",slug:"nicolas-renna",email:"nicolasfede@gmail.com",position:null,institution:{name:"National University of Cuyo",institutionURL:null,country:{name:"Argentina"}}},{id:"202536",title:"Dr.",name:"Rodrigo",middleName:"Damián",surname:"García",fullName:"Rodrigo García",slug:"rodrigo-garcia",email:"rodridg@hotmail.com",position:null,institution:null},{id:"202537",title:"Dr.",name:"Jesica",middleName:null,surname:"Ramirez",fullName:"Jesica Ramirez",slug:"jesica-ramirez",email:"jesicamagali@hotmail.com",position:null,institution:null},{id:"202539",title:"Dr.",name:"Roberto M.",middleName:null,surname:"Miatello",fullName:"Roberto M. 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\r\n\tThis book will aim to be a self-contained collection of scholarly papers targeting an audience of practicing researchers, academics, psychologists, social workers, mentors, motivational speakers, life coaches, students, and other scientists. The contents of the book are intended to be written by multiple authors and experts from different related fields of psychology, philosophy, education, public health, human resource, and other human social sciences.
\r\n\r\n\tCombining Motivation and Success as a book title demonstrates that these are complementary goods. When two goods are complements, they experience join demand. Meaning that the demand for one good is linked to the demand for another good. Indeed, our esteemed authors will aim to put together their scholarly work to showcase the importance of motivation leading to success and vice versa. Defined as a drive or a need, motivation is a driving force inside an individual to pursue a designated goal. While success is a state of meeting a targeted goal. This simply implies that motivated individuals are most successful and this is the core theme of the book.
",isbn:"978-1-83768-021-4",printIsbn:"978-1-83768-020-7",pdfIsbn:"978-1-83768-022-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"f660b7cd35b9af94bdfc3564df138161",bookSignature:"Dr. Simon George Taukeni",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11783.jpg",keywords:"Inner Motivation, Self-Regulation, Self-Control, Exercise, Sport, External Motivation, Secrets Behind Success, Being Physically Active, Feeling Successful, Theories Behind Success, Adversity, Motivational Speech",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 10th 2022",dateEndSecondStepPublish:"July 15th 2022",dateEndThirdStepPublish:"September 13th 2022",dateEndFourthStepPublish:"December 2nd 2022",dateEndFifthStepPublish:"January 31st 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"15 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher within the biopsychosocial model and health psychology. He also works as an editor, internal and external examiner, and principal project investigator.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"202046",title:"Dr.",name:"Simon George",middleName:null,surname:"Taukeni",slug:"simon-george-taukeni",fullName:"Simon George Taukeni",profilePictureURL:"https://mts.intechopen.com/storage/users/202046/images/system/202046.jpg",biography:"Simon George Taukeni is an author, editor, and academic. He has been working at the University of Namibia since 2011. He is also a part-time tutor at Namibia University of Science and Technology (NUST). He is a former post-doctoral research fellow at the University of Fort Hare, South Africa.\n\nDr. Taukeni has a Ph.D., MPH, MEd, and BEd, as well as a specialized postgraduate diploma in Behavioral and Emotional Disorders. \n\nHe has collaborated with many local and international researchers and scholars in his capacity as an editor, internal and external examiner, and principal project investigator.",institutionString:"University of Namibia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of Namibia",institutionURL:null,country:{name:"Namibia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466998",firstName:"Dragan",lastName:"Miljak",middleName:"Anton",title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/466998/images/21564_n.jpg",email:"dragan@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. A unique name with a unique work ethic right at your service."}},relatedBooks:[{type:"book",id:"6494",title:"Behavior Analysis",subtitle:null,isOpenForSubmission:!1,hash:"72a81a7163705b2765f9eb0b21dec70e",slug:"behavior-analysis",bookSignature:"Huei-Tse Hou and Carolyn S. 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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:"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"}}]},chapter:{item:{type:"chapter",id:"67871",title:"Natural vs Synthetic Colors",doi:"10.5772/intechopen.86887",slug:"natural-vs-synthetic-colors",body:'Anthocyanins are the most important group of water-soluble compounds responsible for the colors red, purple, and blue that appear in flowers, fruits, and other plant tissues. For centuries, these compounds have been ingested by humans due to their bright colors, anti-inflammatory, and antioxidant properties, without any evident harmful effects. Anthocyanins are a good potential replacement for synthetic food colorings, particularly for those that have been banned because of their association with disease.
Anthocyanins are extracted from vegetable tissues, and the most common method is liquid-liquid extraction. However, other methods are also available, such as an alternative methodology developed by Japanese scientists who extracted these compounds by fermenting vegetable matrices.
The stability of anthocyanins in processed products has also been a topic of research, and it has been shown that certain acid anthocyanins are highly stable after the extraction. Since these compounds are antioxidants, they play an important role in reducing the risk of several human degenerative diseases.
Anthocyanins belong to a class of substances known as flavonoids, one of the largest categories of phenolic compounds. The basic structure of anthocyanins is made up of a flavylium cation (C6-C3-C6), which may be attached to different sugars, as well as to hydroxyl and methoxy groups, resulting in over 635 different anthocyanins identified to date. The most common sugar associated to anthocyanins is glucose, although rhamnose, xylose, galactose, arabinose, and rutinose have also been found as part of these molecules [1]. Anthocyanins may be mono-, di-, or tri-glycosides, depending on the number of sugar molecules they contain. Durst and Wrolstad [2] reported that anthocyanins are glycoside groups that belong to the family of flavonoids; their structure contains two aromatic rings A and B, joined by a three-carbon link (Figure 1). The structural variations that occur in ring B result in six different anthocyanins as shown in Table 1.
Structure of anthocyanins [
Aglycone | Substitution R1 | Substitution R2 | Absorbance (nm) visible spectrum |
---|---|---|---|
Pelargonidin | H | H | 494 (orange) |
Cyanidin | OH | H | 506 (orange-red) |
Delphinidin | OH | OH | 508 (blue-red) |
Peonidin | OCH3 | H | 506 (orange-red) |
Petunidin | OCH3 | OH | 508 (blue-red) |
Malvidin | OCH3 | OCH3 | 510 (blue-red) |
Substituents of the six types of anthocyanins.
Anthocyanins are the most important natural pigments, soluble in water, that give colors red, purple, and blue to flowers, fruits, and other parts of the plant. Besides coloring, these pigments play other roles in plants, such as attracting pollinizers in order to disperse pollen and seeds, as well as protecting the tissue against UV radiation and harmful virus and bacteria. Given the above, the scientific interest on anthocyanin pigments has increased in the past few years, particularly on their role in the reduction of heart disease, cancer, diabetes, anti-inflammatory effects, and improvement of visual acuity [3]. For centuries, these compounds have been a part of the human diet due to their attractive bright colors, anti-inflammatory, and antioxidant properties, without any evident harmful side effects. Anthocyanins are regarded as a potential alternative in the replacement of artificial food colorings, some of which have been associated to certain diseases. Several sources of anthocyanins have been studied in order to find acidified anthocyanins with greater stability at different pH conditions, at an affordable cost. Stability is a relevant factor since the color of these compounds is easily affected by several conditions, mainly pH [4]. Predominant structures of anthocyanins at different pH values are shown in Figure 2.
Anthocyanins biosynthesis pathway [
The color of anthocyanins depends on the number and orientation of hydroxyl and methoxy groups. Increases in hydroxylation produce color changes toward the blue side of the color spectrum, while increases in methoxylation produce red colorations [3].
The color changes in anthocyanins given by variations of pH are due to the glycoside substitutions (mono-, di-, or tri-saccharides) in positions 3 and/or 5 of the B ring (Figure 1), and this also helps to increase solubility. Some examples of glycosylated saccharides are glucose, galactose, xylose, arabinose, rutinose, sambubiose, and gentiobiose. Another cause of the color displacement toward purple in the molecule is the aromatic acylations in the position 5 of carbon B in the structure [6].
Figure 2 shows the biosynthesis of anthocyanins as established experimentally, where ring A is synthesized via the malonic acid pathway, by condensing three molecules of the malonyl-CoA. On the other hand, ring B is synthesized via the shikimic acid pathway. The enzyme phenylalanine ammonia lyase (PAL) reacts with phenylalanine, which converts into
The use of natural anthocyanin pigments as food colorings in processed products is getting increasing attention, since they are very attractive to consumers, while having beneficial health effects. Anthocyanin pigments are permitted as natural food colors in the United States under the fruit (21 CFR 73.250) and vegetable categories (21 CFR 73.260) [8].
Different varieties of
Nowadays, the food and cosmetic industries demand an ample variety of additives and colorings, in order to improve the appearance of a product and make it attractive to consumers. Industrial food colorings are found in many products that we use or buy on a daily basis, such as juice, jellies, pastries, soft drinks, paints, cosmetics, and more. Most of these additives are synthetically produced and may cause adverse health consequences: allergic reactions, digestive problems, cancer, and asthma, among others [11].
Natural food colors are found in fruits such as acai, cherries, cranberries, elderberries, raspberries, blueberries, black and blue grapes, plums, strawberries, figs, pomegranate, and red apple [12]. Other important sources are found in vegetables: beets, purple lettuce, green onion, radish, purple cabbage, red bell peppers, eggplant, as well as cereals such as blue corn (
The growing concern about the use of synthetic colorings in processed foods, cosmetics, and pharmaceuticals is caused by their potential harmful effects. Countries like Australia, Japan, Norway, and Switzerland have banned the use of some synthetic colorings, such as Red No. 20 and 40, since they have been related to hyperactivity in children of school age. This effect may be considered as an acute neuronal illness; however, these food additives are still being used in the United States [24].
Regulatory policies dealing with the use of colorings derived from anthocyanins vary from country to country. The United States is the most restrictive country on the use of anthocyanins as natural colorings, where four out of the 26 colorings that are approved for their use in foods are derived from grape peel, vegetable, and fruit juice [25]. In Mexico, there is no regulator policy for natural colorings at this point.
In the European Union, Chile, Colombia, Iran, Israel, South Korea, Malta, Peru, Saudi Arabia, and the Emirates, all colorings derived from anthocyanins are regarded as natural [26].
The stability of anthocyanins in processed products has been studied, demonstrating that some acid anthocyanins are stable after extraction. These compounds have antioxidant properties and play an important role in reducing the risk of developing several human degenerative diseases [27].
The interest in anthocyanin pigments is not only due to a potential replacement of artificial food colorings, but is also due to their pharmacological and therapeutic properties. Table 2 shows different investigations on the biological properties of anthocyanins from several substrates.
Biological property | Studies | Authors |
---|---|---|
Therapeutic | Reduction of coronary heart disease, anticarcinogenic effects, antitumor, anti-inflammatory, and antidiabetic | Miyazawa et al. [28] |
Antioxidant activity | Stabilization of oxygen reactive species, inhibition of lipoprotein oxidation, and platelet aggregation (wine anthocyanins) | Ghiselli et al. [29] |
Antioxidant activity | Anthocyanin-rich foods show a high antioxidant activity against hydrogen peroxide (H2O2), peroxide radicals (ROO), superoxide (O2), hydroxyl (OH), and singlet oxygen (O2) | Wang and Jiao [30] |
Antitumor and anticarcinogenic activities | Sweet purple potatoes and blue cabbage were fed to lab rats causing tumor suppression | Hagiwara et al. [31] |
Antitumor effects | Soy red bean extract, containing cyanidin conjugated with glucose and rhamnose, was fed to rats | Koide et al. [32] |
Anticarcinogenic activity | Fractions of red wine anthocyanins suppressed cancer HCT-15 cells from human colon and carcinogenic gastric AGS cells. | Kamei et al. [33] |
Anticarcinogenic activity | Essays demonstrate that cranberries inhibit the initiation, promotion, and progression stages of carcinogenesis | Chang et al. [34] |
Anti-inflammatory activity | Concentrated anthocyanin extracts showed inhibitory effect in the production of nitrous oxide in activated macrophages | Wang and Mazza [35] |
Anti-inflammatory activity | Anthocyanin extracts from raspberry inhibited EG2 prostaglandin, a synonym of anti-inflammatory activity | Vuorela et al. [36] |
Functional properties attributed to anthocyanins.
Anthocyanins may be extracted from different vegetable tissues, the most common method being the solid-liquid extraction. However, novel methods have been developed, such as the methodology developed by Japanese researchers where anthocyanins are extracted after fermenting the vegetable matrices that contain them [37].
Nowadays, anthocyanin extracts are usually applied without separating the individual components, since all the compounds have shown antioxidant activity, not only those with color [38].
On the other hand, the polar nature of the anthocyanin molecule permits solubility in a variety of solvents, such as alcohols, acetone, and water. However, their stability is easily affected by structural modifications by hydroxyl and methoxy groups, glycosides, and particularly acyl groups, as well as by environmental factors such as temperature and light [25].
Amongst those technologies, those currently available for anthocyanin extraction are the use of polar organic solvents, such as ethanol and methanol, and sometimes acidified media. In many cases, the solvents or chemical synthesis involved in the extraction are derived from petroleum, which leaves a strong carbon print on the environment [39].
Extraction of natural colorings by organic solvents has been the method of choice for decades. The toxicity of these solvents complicates the marketing of the final product due to their toxicity and environmental concerns. Many technologies for exploitation of agro-industrial residues have been developed out of the need of solving the problem of accumulation of solid organic residues. Green and clean technologies focus on lessening the environmental impact, while helping the processing and marketing of the final products [40].
Novel methods for the extraction of anthocyanins are ultrasound-assisted extraction [41] and extraction using supercritical fluid CO2 [42].
A viable method for anthocyanin extraction is the use of hydrolytic enzymes, which accelerate the reaction at which a substance is broken down into simpler components when reacting with water. This is the case of cellulase and pectinase that hydrolyze cellulose and pectin, respectively; both are found in the cell wall of fruits and vegetables [43].
A response surface methodology based on the Box-Behnken design may also be used to optimize an extraction method [44]. Identification and quantification of anthocyanins are based on the use of chromatographic methods, mainly the HPLC and UHPLC liquid analyses; mass spectrophotometry is also very helpful for the identification of individual compounds [44].
Antioxidants are molecules that inhibit or delay the oxidation in two ways: by trapping free radicals, in which case they are known as primary antioxidants (phenolic compounds) and are destroyed in the induction process, or by mechanisms such as chelation with heavy metals, capture of oxygen, conversion of hyperoxides into nonradical species, absorption of UV radiation, or inactivation of singlet oxygen; substances exhibiting these properties are known as secondary antioxidants [45].
Antioxidant activity is defined as the capacity of one or several compounds within a substance to inhibit oxidative degradation of another compound, acting mainly on free radicals [46].
Most of the chemical compounds of biological relevance are made by atoms joined together by covalent bonds, where two different atoms share a pair of electrons in the same orbital, and each electron rotates in the opposite direction to its pair. In the cells, chemical reactions that break these bonds heterolytically take place continuously, making one of the parts take two electros and generating unstable nucleophilic or electrophilic compounds, known as anions and cations. However, some chemical reactions, electromagnetic radiation, and other factors may break bonds homolytically, resulting in two parts that have one electron each; these are known as free radicals [47].
Generally speaking, a free radical is an atom or molecule that has one or more unpaired electrons in the external orbitals and is capable of existing independently. It is very reactive and tends to reduce in order to stabilize, which means that subtracts an electron from stable atoms or molecules that are in turn oxidized. Once the free radical has obtained its missing electron, the stable molecule is oxidized and is left with an unpaired electron, which makes it a new free radical that initiates a chain reaction [6].
Figure 3 is a summary of the oxidation mechanisms of a cell, as well as the action that the antioxidant exerts to prevent oxidation. Cell respiration is shown, where molecular oxygen is converted into a superoxide anion, followed by hydrogen peroxide, then a hydroxyl radical and finally water, while the central illustration explains how cell metabolism may form free radicals (superoxide anion and hydroxyl) [48].
Pathways of free radical production and action of antioxidants [
According to Londoño [46], when the superoxide anion suffers a mutation catalyzed by the superoxide dismutase enzyme, it becomes less reactive but is still toxic for tissues; therefore, it is converted into water by the action of the catalase enzymes, which reduce hydrogen peroxide by oxidizing glutathione; this in turn is generated by the action of glutathione reductase, which uses NADPH as a cofactor. Hydrogen peroxide may also be converted into a hydroxyl radical via a Fenton-type reaction, which is catalyzed by iron. Once produced, the hydroxyl radical attacks proteins, nucleic acids, and mainly polyunsaturated fatty acids, thus generating lipid radicals that quickly react with oxygen to produce peroxyl radicals.
Stabilization of free radicals derived from lipids may be accomplished by phenolic antioxidants such as flavonoids and tocopherols, which stabilize the free radicals (phenoxyl and tocopheryl, respectively). Stabilization may happen inside the molecule by displacement or by reaction with ascorbic acid to generate a reduced compound [49].
Consumption of anthocyanins is generally recognized as safe for humans, since they have been a part of our diets for generations, and so far, no harmful effects have been reported. This may be associated with their low absorption and bioavailability. Nevertheless, the use of nutritional supplements based on anthocyanins is a growing trend among consumers, and this has raised some concern because the doses recommended by manufacturers are generally much higher than that given by natural foods. Furthermore, no regulation is available for such dietetic supplements in the United States, among other countries, which may result in fraudulent/adulterated products. It is also likely that people looking to benefit from anthocyanins are also using other supplements or pharmaceuticals. Anthocyanins are treated as xenobiotics [50] and, therefore, are able to modulate biochemical activities or compete for several enzymes that metabolize or transport medications [51]. This increases the risk for potential adverse effects and toxicity due to interactions with pharmaceuticals. However, so far, no reports have demonstrated adverse effects on anthocyanins in levels associated to a healthy diet.
Several studies show the possibility of replacing artificial food colorings for anthocyanins, such as those derived from flowers. When mixed into dairy matrices such as yogurt, there are some improvements in the production and final product [17]. Furthermore, the addition of anthocyanins is not only recommended for their color and bioactivity, since recent studies propose their use during processing and/or storage of the final product by their inclusion into intelligent films based on biodegradable polymers, which work as biosensors due to their high sensitivity to pH changes. In this manner, freshness of meat and fish may be monitored [52, 53]. Both studies used
The authors thank the support of the PROFAPI-ITSON as funded with the PFCE 2019 resource for the realization of the present.
For more than a century, it is a known fact that cancer is an inflammatory disease and that immunotherapy (IT) can be used as a strategy for fighting it. Coley’s toxin, utilized as early as 1893, can be considered the first IT approach in cancer [1].
At the beginning, the research was focused on the activation of the immune response using antitumor vaccines or direct stimulation with recombinant cytokines, e.g., interferons and interleukin-2 [2, 3].
Interferon alpha-2 (IFN-ᾳ2) was the first immunotherapeutic agent approved by the US Food and Drug Administration (FDA) in 1995, for adjuvant treatment of stages IIB-III melanoma patients, based on the results of the ECOG EST 1684 trial [4]. Previous outcomes of phase I/II studies demonstrated a tumor response rate of ~16%, but with a modest median duration of response (of ~4 months) for the treatment of disseminated melanoma [5, 6]. A meta-analysis of 13 trials published in 2018 showed a median relapse-free survival of 2.2 years (1.2–3.3 years) for the patients who received different IFN-ᾳ2b regimens, compared with 1.9 months for the patients that did not receive any adjuvant treatment for stages II and III [7].
The second cytokine approved by FDA in 1998 for the treatment of metastatic melanoma was Interleukin 2 (IL-2), due to its proven potential for durable disease control [8]. The administration of two cycles of high-dose IL-2 (HD-IL-2), each of them receiving 600,000 to 720,000 IU/Kg/per dose intravenously, every 8 hours, for up to a maximum of 14 doses per cycle, leads to clinical responses in ~16% of patients, including ~6% who had complete responses [9].
Unfortunately, the responses were infrequent and associated with severe side effects, especially for HD-IL-2, such as capillary leak syndrome (with hypotension, pulmonary edema, and renal failure), hepatic, gastrointestinal, endocrine, and cutaneous toxicities, arrhythmias, and psychiatric disturbances [10]. These toxicities generally resolve in a few days after stopping HD-IL-2 therapy, but the mortality rate related to this treatment is 1–2% [11].
The combination of cytokines, IFN-ᾳ and/or IL-2, with chemotherapeutic agents (e.g., cisplatin, vinblastine, and dacarbazine), also named bio-chemotherapy, can enhance the response rates, but at the cost of significantly increased toxicity. Multiple prospective randomized clinical trials failed to demonstrate significant improvement in survival compared to chemotherapy alone [12].
The understanding of the mechanisms through which the immune system fights against cancer represents one of the greatest breakthroughs in medicine over the last 15 years [13].
The interaction between Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4) and Programmed cell death 1 (PD-1) receptors and their ligands, discovered by the teams that won the 2018 Nobel Prize for Medicine, led by James Allison [14, 15] and Tasuku Honjo [16, 17], became the foundation of the development of immune checkpoint inhibitors (ICI).
Immune checkpoints (IC) are negative regulators of T-cell activation. Along with co-stimulatory molecules, they have an important role in maintaining self-tolerance.
The anti-CTLA-4 monoclonal antibodies (mAbs) ipilimumab, a fully human IgG1, and tremelimumab, a fully human IgG2, were the first IC blocking drugs to enter clinical trials in oncology; however, the only one approved by FDA for metastatic melanoma was ipilimumab, in March 2011, initially as a single-therapy.
The approval of ipilimumab as monotherapy for unresectable stage III or stage IV melanoma was based on the results of two clinical trials, CA 184–002 [18] and CA 184–024 [19]. The first trial compared ipilimumab 3 mg/Kg, 4 cycles at 3-weeks interval, single-agent therapy or in combination with glycoprotein (gp-100) peptide vaccine, with gp-100 vaccine monotherapy [18]. The second trial compared ipilimumab 10 mg/Kg, 4 cycles at 3-weeks interval, in combination with dacarbazine, with dacarbazine alone until week 22; the responders (patients with stable disease or patients with an objective response, and no unresolved adverse events) received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy [19]. The results of both trials showed, for the patients who received ipilimumab, an improved response rate and an increase in the duration of the response, in addition to better results for PFS (progression-free survival) and OS (overall survival) for both previously treated [18] or untreated advanced melanoma patients [19]. The CA 184–169 clinical trial compared the standard and high doses of ipilimumab; the survival results were not significantly different [20].
Pooled data from several phases II and phase III trials demonstrate a median survival time of 11.4 months for ipilimumab monotherapy [21]. The survival curves reached a plateau after 3 years and appeared stable even after 10 years [21]. In CA 184–024 trial, approximately 20% of the patients treated with ipilimumab showed longer overall survival compared with chemotherapy (18.2% 5-year OS for ipilimumab in combination with dacarbazine versus 8.8% for dacarbazine alone) [22].
The real-world data from the Expanded Access Program for Ipilimumab confirmed the efficacity of this therapy for previously treated metastatic melanoma patients [23, 24, 25, 26, 27, 28, 29, 30]. More than 1600 patients were treated with single-agent ipilimumab 3 mg/Kg, 4 cycles at 3-weeks interval (induction phase). The median PFS and median OS were similar between 6 European countries and South Africa (Table 1).
Country | Patients number | median PFS (months) | median OS (months) | 1-year OS (%) | 2-year OS (%) |
---|---|---|---|---|---|
Czech Republic (23) | 196 | — | 7.5 | — | — |
Italy (24) | 855 | 3.7 | 7.2 | — | — |
Netherlands (25) | 31 | — | 7 | 45.2 | 28.8 |
Poland (26) | 50 | 3 | 8 | — | — |
Romania (27) | 89 | 4.13 | 6.3 | — | — |
Spain (28) | 144 | — | 6.5 | 32.9 | — |
South Africa (29) | 108 | 3.44 | — | 36 | 20 |
UK (30) | 193 | 2.8 | 6.1 | 31 | 14.8 |
The efficacity of ipilimumab monotherapy; results from expanded access program in 6 European countries and South-Africa (23–30).
Safety results showed a high risk, 10–15%, of severe (grade 3 and 4) immune-mediated adverse events (irAEs) for standard dose ipilimumab monotherapy [18], 30% for high-dose ipilimumab monotherapy [20], and 38% risk of severe irAEs for ipilimumab combined with dacarbazine [19]. The study CA 184–002 reported seven deaths caused by immune-mediated AEs [18].
As a result, clinical guidelines do not recommend the association of ipilimumab with dacarbazine due to high risk for severe adverse events, and the FDA-recommended dose of ipilimumab is now 3 mg/Kg instead of 10 mg/Kg, 4 cycles at 3-weeks interval (induction therapy) [31].
The second anti-CTLA-4 antibody, tremelimumab, also generated promising anticancer responses in early clinical trials [32]. Unfortunately, a phase III clinical trial of tremelimumab versus standard-of-care chemotherapy in advanced melanoma was stopped early due to a lack of survival benefits [33].
The anti-PD-1 monoclonal antibodies, pembrolizumab, and nivolumab, humanized immunoglobulins (IgG4), were both approved as single-agent therapies by FDA in 2014 for unresectable advanced or metastatic melanoma.
Pembrolizumab is administered intravenously at 2 mg/Kg body weight, or 200 mg fixed dose every 3 weeks until progression of the disease or until a severe toxicity develops. The treatment can be administered continuously, over a period of 1–2 years, depending on the response of the disease and the tolerance of the treatment. However, the optimal treatment duration has not been established until now [34].
The initial results from the phase I KEYNOTE-001 clinical trial showed a response rate of 34% and a median OS of 25.9 months for ipilimumab refractory metastatic melanoma [35]. The KEYNOTE-002 clinical trial compared two pembrolizumab doses (2 mg/Kg and 10 mg/Kg every 3 weeks) with chemotherapy for the same population as the previous study [36]. Long-term follow-up showed that both doses of pembrolizumab provide higher response rates (22–28%) and longer duration of response along with improvements in progression-free survival (16–22% PFS 2-year rate), compared with chemotherapy (4% response rate and < 1% PFS 2-year rate) [37]. Furthermore, pembrolizumab therapy was better tolerated than chemotherapy [38].
In the end, the results of phase III KEYNOTE-006 clinical trial support the recommendation of American (NCCN) and European (ESMO) guidelines that pembrolizumab should be considered as first-line therapy in patients with unresectable or metastatic melanoma [39, 40]. The clinical trial compared two pembrolizumab regimens (10 mg/Kg every 2 or every 3 weeks) with ipilimumab for the patients with metastatic melanoma previously untreated with ICI [41, 42]. All the study endpoints aligned: 36–37% response rate for pembrolizumab compared with 13% for ipilimumab (statistically significant), 28–31% PFS 2-year rate versus 14% for ipilimumab (statistically significant), and a trend to improve the OS 2-year rate for pembrolizumab [42].
The kinetics of the response to pembrolizumab reflects the response to immunotherapy. Long-term follow-up during clinical trials showed a late response to pembrolizumab therapy, more than a year after the start of the treatment; in addition, some partial responders may become complete responders over time [37, 41, 43].
Nivolumab is administered intravenously at 3 mg/Kg body weight or 240 mg fixed dose every 2 weeks, or 480 mg fixed dose every 4 weeks until progression of the disease or until a severe toxicity develops.
The phase III study CheckMate 037 compared nivolumab with chemotherapy for the patients with ipilimumab-refractory metastatic melanoma (BRAF wild-type) and for the patients with ipilimumab and BRAF inhibitors refractory metastatic melanoma (BRAF mutated) [44]. Immunotherapy improved the response rate (27% versus 10%) and the duration of the response compared with chemotherapy, but after 2 years, it did not improve neither median PFS (3.1 versus 3.7 months) nor median OS (15.7 versus 14.7 months) [44, 45].
The subsequent phase III CheckMate 066 and 067 clinical trials demonstrated nivolumab efficacy in unresectable stage III and metastatic stage IV melanoma. In CheckMate 066, nivolumab monotherapy was compared with chemotherapy [46, 47]. The response rate (40% versus 13.9%), median PFS (5.1 versus 2.2 months), and median OS (37.5 versus 11.2 months) were statistically significant in favor of immunotherapy [46, 47]. Nivolumab therapy led to long-term survival in up to 40% of patients, as the survival curves suggest [47].
In the CheckMate 067 clinical trial, the dual immune combination of CTLA-4 and PD-1 inhibitors was compared with nivolumab (monotherapy) and with ipilimumab (monotherapy) as first-line treatments for metastatic melanoma; the results demonstrated the superiority of dual immune combination and also of single-agent PD-1 inhibitor over ipilimumab monotherapy [48, 49, 50]. In monotherapy, nivolumab was superior to ipilimumab in terms of response rate (45% versus 19%), median PFS (6.9 versus 2.9 months), and median OS (36.9 versus 19.9 months) [48, 49, 50].
The kinetics of the response to nivolumab, ipilimumab, and pembrolizumab was almost identical, with late complete response seen more than a year after the start of the treatment [45, 48, 50]. Across clinical trials, response to nivolumab tends to persist after the discontinuation of the drug [48, 50].
Preclinical studies demonstrated that dual immune blockade with anti-CTLA-4 combined with anti-PD-1 was more effective than with either alone [51]. A phase I study of immune combination therapies found that the maximum tolerated dose of concurrent administration is 3 mg/Kg q3w for ipilimumab and 1 mg/Kg for nivolumab q3w; in this study, the overall response rate was 40% and the grade 3–4 AEs rate was 53% [52].
The nivolumab and ipilimumab combination arms from CheckMate 067 and CheckMate 069 clinical trials showed higher response rates (58% vs. 19%, p < 0.001 for CheckMate 067 and 59% vs. 11% for CheckMate 069), prolonged response durations, longer time to subsequent therapies, prolonged median PFS (11.5 vs. 2.9 months, p < 0.001 for CheckMate 067 and not reached vs. 3.0 months in CheckMate 069), and larger median OS compared with single-agent ipilimumab [50, 53]. These effects persisted during long-term follow-up, with 4-year survival rates of 53% for the combination arm compared with 46% for single-agent nivolumab and with 30% for single-agent ipilimumab in the CheckMate 067 study [48]. For a subgroup of patients with high levels of PD-L1 expression, the median OS and median PFS were similar for single-agent nivolumab compared with the ipilimumab and nivolumab combination, but the number of toxicities was smaller for monotherapy [48].
Long-term follow-up (6.5 years) in the CheckMate 067 study showed a longer median OS of 72.1, 36.9, and 19.9 months in the combination arm compared with nivolumab and ipilimumab monotherapy [54].
CheckMate 067 and 069 showed significantly increased toxicity of dual immune blockade versus monotherapy [50, 53]. The rate of grade 3–4 related adverse events (AEs) in CheckMate 067 was 59% for the ipilimumab and nivolumab arm compared with 21% for nivolumab alone and with 28% for ipilimumab monotherapy [50]. In CheckMate 069 the rate of AEs for the combination was 54%, compared with 20% for ipilimumab monotherapy [53].
A pooled analysis of the immune combination trials found that response rates, PFS, and OS of the patients who discontinued the treatment in the induction phase due to the AE, were similar to those of the patients who completed the treatment [55].
The kinetics of the response to combination therapy includes a late complete response (CR) that was seen more than a year after the start of treatment, with a double rate of CR, and increased response duration [48, 49].
Subgroup analysis, in both CheckMate clinical studies, demonstrated improved efficacy with nivolumab and ipilimumab combination therapy, regardless of BRAF mutation status [48, 49, 50, 53].
In order to identify a possible biomarker that could predict the response to immunotherapy, the researchers assessed PD-L1 expression in tumor samples from the patients included in CheckMate and KEYNOTE trials [45, 47, 48, 49, 50, 56]. In these randomized clinical studies, the improved response rate, PFS, and OS for anti-PD-1 therapy had a statistically significant correlation with increased PD-L1 expression, [45, 46, 48, 49, 50, 56].
However, it was not possible to identify an expression level cutoff for PD-L1 with a cert prognostic value. Furthermore, in these clinical trials, there were patients who experienced durable responses to anti-PD-1 inhibitors, regardless of the PD-L1 expression in biopsy specimens [56].
At the present time, we know the following [39]:
Anti-PD-1 therapy (nivolumab) and dual immune therapy (ipilimumab in combination with nivolumab) efficacies appear to improve with increasing PD-L1 expression; however, this biomarker is not the only one that predicts the response to ICI [48].
For high PD-L1 tumor expression, improvements in outcome with dual immune therapy or with nivolumab monotherapy were similar; instead, for low PD-L1 tumor expression, the outcome was better with dual immune therapy [48].
Unlike CTLA-4 inhibitor monotherapy, the dual immune therapy led to good responses even in patients with very low PD-L1 tumor expression [48].
PD-L1 tumor expression cannot be used in order to exclude patients from anti-PD-1 monotherapy [39]; however, the use of combination therapy for patients with low PD-L1 tumor expression, in order to increase efficacy, and the use of PD-L1 monotherapy for patients with a high level of PD-L1 tumor expression, in order to decrease the toxicity, prove effective and are consequently preferred [39].
Talimogen laherparepvec (T-VEC), an agent that uses a modified herpes simplex virus to induce tumor cell lysis and deliver a localized expression of GM-CSF is the main intralesional agent approved for this indication, according to the results of a phase 3 clinical study [57]. T-VEC produced local durable response rates (16.3% versus 2.1% for injection of GM-CSF) and remission of oligometastatic disease (bystander effect). The overall response rate was superior for intralesional T-VEC compared with intralesional GM-CSF (26.4% vs. 5.7%, p < 0.001) with higher rates of complete response (11% vs. 1%) [57].
The AEs rate produced by T-VEC injection was 20%, with 11% serious-AEs (grade 3–4). The most frequent AEs were local, e.g., injection-site reactions (cellulitis, pain, and peripheral edema), but also systemic toxicities appeared (fatigue, chills, pyrexia, and other flu-like symptoms) [57].
Treatment of melanoma BM is a real challenge for oncologists and radiotherapists. Clinical studies confirmed that immune therapy can be used safely and efficiently, especially in asymptomatic patients with BM. The CA 184–042 study demonstrates the superiority of HD-ipilimumab in asymptomatic patients (compared with symptomatic patients) in terms of response rate (16% vs. 5%), median PFS (2.6 vs. 1.3 months), and median OS (7.0 months vs. 3.7 months). Interestingly, good response rates were obtained for both intracranial and extracranial disease [60]. The patients with asymptomatic BM from the CA 184–169 trial had the same median OS for HD-ipilimumab and for standard ipilimumab doses [20].
For PD-1 inhibitors, used in the asymptomatic BM population, clinical studies showed good response rates, 30% for pembrolizumab [61] and 29% for nivolumab [62], and also high median OS (17 months for pembrolizumab and 18.5 months for nivolumab) [61, 62]. In the subset of patients with symptomatic BM and leptomeningeal disease, usually with bad prognostic, the CA 209–170 study finds a comparable response rate (25%), to the response rate (29%) for asymptomatic BM, but with much lower median OS (5.1 vs. 18. months) [62].
The real impact on asymptomatic BM patients was seen in the CA 209–170 clinical trial arm treated with a dual combination of ipilimumab and nivolumab, with 57% response rate for extracranial disease and 46% for intracranial disease; the median OS was not reached for immune combination, compared with 18.5 months for nivolumab monotherapy [62]. The good results for dual combination were confirmed by the CheckMate 204 clinical trial, with a more than 50% response rate for both extra and intracranial disease and with median OS not reached [63].
NCCN and ESMO guidelines concluded that ipilimumab and nivolumab combination is superior to anti-PD-1 monotherapy and that anti-PD-1 therapy provides higher response rates and better median OS compared with ipilimumab monotherapy, especially for asymptomatic BM melanoma patients [39, 40].
Accordingly, whole-brain radiotherapy (WBRT) is now reserved, only with palliative intent, for symptomatic BM patients [40]. Stereotactic radiosurgery (SRS) has replaced WBRT for non-bulky (< 3 cm), <5–10 asymptomatic BM, as upfront therapy. For more advanced disease, guidelines recommend first-line systemic therapy, mainly combination immune therapy; in this case, SRS will be used as salvage therapy for disease progression [40]. SRS and immune therapy can be administered simultaneously, but with close MRI evaluation, as a result of the increased risk for asymptomatic radio-necrosis (15% of patients) [64].
The current first-line standard therapies for inoperable stage III and IV BRAF wt melanoma are the PD-1 blockade (nivolumab or pembrolizumab) and the dual blockade CTLA-4 and PD-1 (ipilimumab and nivolumab) (Table 2) [39, 40]. Different regimens and doses from clinical guidelines are underlined in Table 3.
Inoperable stage III/IV melanoma | ||
---|---|---|
Therapy | Melanoma subtype | |
First-line | Immune therapy
| BRAF wt BRAF mutated |
Targeted therapy BRAFi + MEKi | BRAF mutated | |
Second-line | Clinical Trial (after IT) | BRAF wt |
IT rechallenge:
| BRAF wt | |
Switched therapy (TT after IT or IT after TT) | BRAF mutated | |
Subsequent lines | BRAF wt | |
| BRAF mutated |
Treatment | Dosing | Treatment duration |
---|---|---|
Nivolumab | 240 mg q2w or 480 mg q4w |
|
3 mg/Kg q2w |
| |
Pembrolizumab | 200 mg q3w |
|
2 mg/Kg q3w 10 mg/Kg q2w or q3w |
| |
Ipilimumab / Nivolumab combination | 1 mg/Kg nivo + 3 mg/kgc ipi q3w for 4 doses, followed by nivo 240 mg q2w or 480 mg q4w |
|
1 mg/kg nivo + 3 mg/kgc ipi q3w for 4 doses, followed by 3 mg/kg nivo monotherapy q2w |
|
T-VEC is also an option for in-transit unresectable melanoma.
For second-line treatment and beyond, ESMO guidelines [40] recommend clinical trials if available, or ICI rechallenge.
Immune therapy rechallenge includes at least 3 options [40]:
Ipilimumab after PD-1 monotherapy (nivolumab or pembrolizumab) [65]
Nivolumab or pembrolizumab if another line of treatment was given after ICI failure (e.g., chemotherapy)
Ipilimumab and nivolumab combination if not given previously [66]
Two clinical trials demonstrated that immune therapy with ipilimumab or with the dual combination ipilimumab and anti-PD-1 should be considered a viable treatment option after failure of anterior PD-1 therapy [65, 66]. The combination appeared to be highly effective in terms of response rate, duration of the response, and median OS compared with ipilimumab monotherapy (20.4 vs. 8.8 months for median OS) [66]. The grade 3–5 toxicities for both groups were the same [66].
The NCCN guidelines have additional recommendations [39]:
Pembrolizumab + low-dose ipilimumab combination for tumors that progressed after prior anti-PD-1 therapy [66]
HD-IL-2
Ipilimumab + intralesional T-VEC combination
Pembrolizumab + lenvatinib combination
The combination of anti-PD-1 (pembrolizumab) with VEGF inhibitor (lenvatinib) produces a higher overall response rate of 48% compared with pembrolizumab alone, in a small phase I/II trial [67].
In particular cases, other options can be considered, such as imatinib for tumors with activating mutations of Kit, larotrectinib, and entrectinib for NTRK gene fusion-positive tumors [68] and cytotoxic agents.
The current first-line treatment for inoperable stage III and IV BRAF-mutated melanoma is also immune therapy (IT), or the dual combination of BRAF inhibitors with MEK inhibitors (TT, Targeted Therapy) (Table 2). The best sequence of IT and TT is currently unknown [69]. No direct randomized comparison exists between IT and TT, but one meta-analysis suggests a better outcome after 1 year in favor of IT [70, 71], despite a very good response rate to TT in the first 12 months [72]. The main advantage of immune therapy as a first option is long-term/durable disease control even after treatment is ended [73].
There are several ongoing trials that study the optimal sequence for the first-line treatment, TT-IT or IT-TT (SECOMBIT, DREAMseq). Randomized three-arm phase 2 study (SECOMBIT / NCT02631447) revealed a better trend for OS and total PFS at 2 and 3 years for the arm with upfront ipilimumab and nivolumab combination and for the arm with short targeted therapy followed by immune combination therapy, compared with upfront targeted therapy with BRAFi + MEKi [74]. A randomized DREAMseq trial was designed to compare the efficacy and toxicity of the sequence IT-TT (Ipilimumab + nivolumab – dabrafenib + trametinib) with the sequence TT-IT. OS and duration of overall response (DOR) were better for upfront immune combination therapy (2-year OS of 72% vs. 52% p = 0.0095 and median DOR not reached for upfront immune therapy, and 12.7 months for targeted therapy) [75].
ESMO recommendation [76]:
Elevated LDH level: ipilimumab and nivolumab combination preferred.
LDH >1x and ≤ 2x ULN – anti-PD-1 monotherapy preferred.
The tumor burden is not clearly defined yet.
Switching TT to IT after short therapy should not be considered outside clinical trials.
First-line therapy selection for BRAF-mutated melanoma should be based on treatment goals (short-term benefit or long-term benefit), on the clinical characteristics of the disease (LDH level, organs involved, number of metastases or tumor burden, disease progression kinetics), on co-morbidities and performance status of the patient, and on the patient’s preference and compliance for oral or iv agents [76]. However, it seems prudent to start with immune therapy for the cases with tumors that do not progress very quickly and do not immediately threaten an important organ or function [40].
ESMO recommendation [76]:
Patients treated by TT-IT sequence can be rechallenged with targeted therapy.
Patients treated by IT-TT sequence can be rechallenged with anti-PD-1 therapy (no data exist for ipilimumab and nivolumab combination).
Patients treated with first-line anti-PD1 monotherapy and second-line TT might benefit from ipilimumab-based treatment.
Finally, after using all options, rechallenge with the drugs that showed the best response should be considered.
As a second-line treatment, NCCN and ESMO guidelines recommend the switch from one treatment to another, depending on the previously used first-line therapy (Table 2) [39, 40].
Subsequent lines are not well established; as an option, clinical trials or rechallenge with both TT and IT can be considered. Another option can be chemotherapy with single-agent DTIC or Temozolomide, and Paclitaxel + Carboplatin combination, with palliative intent or as “bridging therapy” (Table 2).
ESMO recommendation [76]:
Stopping anti-PD-1 therapy for patients with CR that persist on radiological evaluation and who received treatment for at least 6 months should be considered.
Stopping anti-PD-1 therapy for patients with PR and SD after 2 years of treatment should be considered.
Stopping targeted therapy outside clinical trials is not recommended.
Sixty-seven patients from KEYNOTE-001 trial stopped the pembrolizumab therapy after complete response (CR) was confirmed by radiological evaluation and after completing minimum 6 months of treatment [43]. The 2-years DFS from the time of CR was ~90% [77]. In KEYNOTE-006 the patients stopped the treatment after 2 years and 85.4% did not suffer a relapse after 5 years of follow-up [77].
Both CheckMate 067 and KEYNOTE-006 trials revealed a good Hazard Ratio (HR) for progressive disease (PD) after 2 years with anti-PD-1 monotherapy (nivolumab, respectively pembrolizumab) for responders (partial response – PR and stable disease – SD) [43, 48].
ESMO recommendation [76]:
The patients with primary resistance should be treated with another option.
The patients with acquired resistance can be treated with the same treatment option or with another agent.
The decision should be taken in accordance with BRAF status
A multicenter randomized clinical study with 300 metastatic melanoma patients (56% BRAF wt and 44% BRAF mutated) evaluated the treatment for the patients who stopped responding after the initial response (acquired resistance) [78]. The most commonly used agent after the first progression was anti-PD-1 (51% of patients from the cohort study), followed by targeted therapy (19%), dual immune combination CTLA-4 and PD-1 (12%), investigational drugs (11%), and ipilimumab monotherapy (6%). The ORR was 46% for anti-PD-1 monotherapy, 67% for TT, 56% for immune combination therapy, 20% for the investigational agent, and 0% for CTLA-4 monotherapy, but no difference in OS after about 2 years of follow up was observed [78]. Another clinical trial demonstrated a higher response rate for the patients treated with the immune dual combination, compared with ipilimumab monotherapy for patients with progressive metastatic melanoma after first-line anti-PD-1 therapy (31% vs. 13%) [66].
A multicenter randomized clinical trial, that focused on the treatment of recurrence after adjuvant therapy, demonstrated a very good response to immune checkpoint inhibitors, similar to the response rate for the patients treated by first-line immune therapy; the three-year OS was 79% for anti-PD-1 based therapy (monotherapy or dual immune combination), 55% for targeted therapy rechallenge, and 25% for ipilimumab monotherapy [80].
The current treatments for melanoma produce high-grade toxicity rates, with 55–59% for ipilimumab and nivolumab combination, 20% for nivolumab alone, and 27% for ipilimumab alone [78]. The most common AEs associated with immune checkpoint inhibitors are autoimmune (iAEs). The most frequent immune toxicities to ICI, across all options (anti-PD-1 monotherapy, anti-CTLA-4 monotherapy, or dual immune combination), were cutaneous (pruritus, maculopapular rash, and vitiligo), gastrointestinal (diarrhea/colitis) and fatigue [39]. The most common high-grade, potentially life-threatening iAEs were endocrinopathies (hypophysitis, adrenal insufficiency, and hypo- or hyperthyroidism), pancreatitis, and hepatic AEs (elevated ALT, AST, hepatitis) [39]. Other potentially lethal iAEs were nephritis, pneumonitis, and myocarditis.
A retrospective study from the WHO pharmacovigilance database identified 613 fatal ICI toxic events, reported from 2009 to 2018. The most death-related AEs were pneumonitis, hepatitis, and neurotoxic effects, for the dual immune combination and colitis for anti-CTLA-4 treatment [81]. A meta-analysis of 112 trials showed higher toxicity-related fatality rates for CTLA-4 and PD-1 combination (1.23%) and for anti-CTLA-4 monotherapy (1.08%), compared with single-agent anti-PD-1 (0.36%) [81].
The treatment with ICI requires a routine monitoring for immune toxicities, with physical examination, anamnesis for autoimmune or infectious diseases (screening for HIV, hepatitis A, B, and C), complete blood count, comprehensive metabolic panel, cardiac evaluation with ECG and measurements of oxygen saturation, and endocrine evaluation (TSH, FT4 and serum cortisone), at baseline and periodically, for the entire treatment duration [82]. The NCCN elaborated a comprehensive guideline for the management of immunotherapy-related toxicities [82].
The kinetics of iAEs is different for different types of immune-related toxicities. The first toxicities that become evident are skin-related AEs (median time to onset 3 weeks), but the risk persists throughout treatment. Later, gastrointestinal (median time to onset 7 weeks) and hepatic toxicities appear, and finally pulmonary, endocrine, and renal AEs may develop [83, 84]. The patients who experienced AEs of any grade had a significantly higher objective response rate [83]. Most treatment-related AEs resolve completely after specific treatment, with the exception of endocrinopathies, which require long-term hormone replacement therapy [84]. Median time to resolution for grade 3–4 iAEs was under 5 weeks, apart from endocrinopathies excepted [84].
ESMO recommendation [76]:
Restrictive use of empirical antibiotics in melanoma patients treated by immune checkpoint inhibitors
Specific species of gut microbiome or microbiota can influence antitumoral responses, either through innate or adaptive immune pathways. In severely immunocompromised patients, the modification of intestinal flora through diet or fecal microbiota transplants could improve the response to ICI [85].
On the other hand, the excessive use of antibiotics decreases the diversity of gut microbiome and eliminates the most immunogenic bacteria, having thus a negative impact on patients treated with ICI [86].
Lymphocyte-activation gene 3 (LAG-3) is a cell-surface receptor on activated CD4+ T cells and represents an alternate immune checkpoint [87]. The anti-LAG-3 agent relatlimab and anti-PD-1 agent nivolumab were combined in phase II/III RELATIVITY-047 clinical study [88]. The study compared the dual immune combination relatlimab and nivolumab with nivolumab monotherapy, favoring the immune combination in terms of median PFS (10.1 months for combination vs. 4.6 months for monotherapy, with HR for progression or death of 0.75). The obtained results were better for a subgroup of patients with positive LAG-3 expression (≥ 1%). The rate of AEs was 18.9% for the combination and 9.7% for the monotherapy group [88].
In the CheckMate 067 clinical trial, PFS for the nivolumab and ipilimumab combination, the current first-line indication for stage III and IV inoperable melanoma, was 11.5 months, with a 59% rate of AEs [48]. If the first results of the RELATIVITY-047 clinical study will be supported also by better overall survival rates, it would give good grounds for the expectation that the relatlimab and nivolumab combination will replace the ipilimumab and nivolumab combination in the first-line treatment of metastatic melanoma [89].
Anti-VISTA small molecule ICI (CA 170) combined with nivolumab and anti-Tim-3 antibody combined with spartalizumab (anti-PD-1) are among the most promising immune combinations for the treatment of advanced melanoma [90, 91]. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative regulator of T-cell function; anti-VISTA agents show synergistic effects with anti-PD-1 agents [90]. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a cell surface molecule expressed on lymphocytes, dendritic cells, and tumor cells (including melanoma cells) that breaks off T-cell activation and diminishes antitumor immunity [91]. Anti-Tim-3 monoclonal antibody stops T-cell inhibition and amplifies tumor cell disintegration.
Other potential new immune combinations are the associations between anti-PD-1 inhibitors with agonists of IL-2 described in the PIVOT-02 phase II clinical trial [92], or between anti-PD-1 agents and different oncolytic viruses (e.g., polio, coxsackie, herpes simplex or poxvirus) [93].
ACT with the use of tumor-infiltrating lymphocytes (TILs) can be a future option for solid tumors, including metastatic melanoma [69, 94]. The clinical development of TILs started more than 40 years ago, but it was not approved by FDA for melanoma treatment, despite the good response rates [93]. The combination of TILs with chemotherapy and IL-2 was associated with a 24% CR and with 55% ORR among patients with disease recurrence after previous systemic treatment [94]. Because of high rates of potentially lethal AEs, this therapy can be safely administered only in a high-facility oncological center, trained for IL-2 administration.
One of the pivotal multicenter clinical trials was designed to evaluate TILs administration (lifileucel, an autologous, centrally manufactured TILs) in conjunction with IL-2, followed by sequential ICI, in patients with solid tumors, including melanoma (NCT 02360579) [95]. The ORR was 36%, with 2 from 66 patients with CR and 22 from 66 patients with PR. Median duration of response was not reached after 18.7 months of median follow-up. This treatment could be used as salvage therapy for metastatic melanoma patients, refractory to anti-PD-1 and targeted therapy [95].
Systemic treatment for metastatic melanoma improved dramatically in the last 10 years with enhanced long-term survival of these patients. Immune therapy is part of the change of the treatment paradigm in melanoma; shifting from direct cytotoxic tumor destruction to increasing the immune system activity in order to destroy the cancer cells. Undoubtedly, the near future will be the time of different dual immune combinations, with or without new targeted therapy approaches.
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Abdul Khalil"},{id:"140857",title:"Dr.",name:"Mohammad",middleName:null,surname:"Jawaid",slug:"mohammad-jawaid",fullName:"Mohammad Jawaid"},{id:"155097",title:"Prof.",name:"Azman",middleName:null,surname:"Hassan",slug:"azman-hassan",fullName:"Azman Hassan"},{id:"158082",title:"Prof.",name:"Paridah Md",middleName:null,surname:"Tahir",slug:"paridah-md-tahir",fullName:"Paridah Md Tahir"},{id:"158083",title:"Dr.",name:"Zaidon",middleName:null,surname:"Ashaari",slug:"zaidon-ashaari",fullName:"Zaidon Ashaari"}]},{id:"16971",doi:"10.5772/18127",title:"Fracture Toughness Determinations by Means of Indentation Fracture",slug:"fracture-toughness-determinations-by-means-of-indentation-fracture",totalDownloads:13697,totalCrossrefCites:11,totalDimensionsCites:54,abstract:null,book:{id:"1046",slug:"nanocomposites-with-unique-properties-and-applications-in-medicine-and-industry",title:"Nanocomposites with Unique Properties and Applications in Medicine and Industry",fullTitle:"Nanocomposites with Unique Properties and Applications in Medicine and Industry"},signatures:"Enrique Rocha-Rangel",authors:[{id:"30489",title:"Dr.",name:"Enrique",middleName:null,surname:"Rocha",slug:"enrique-rocha",fullName:"Enrique Rocha"}]},{id:"18845",doi:"10.5772/18264",title:"Composite Materials from Natural Resources: Recent Trends and Future Potentials",slug:"composite-materials-from-natural-resources-recent-trends-and-future-potentials",totalDownloads:18088,totalCrossrefCites:22,totalDimensionsCites:53,abstract:null,book:{id:"202",slug:"advances-in-composite-materials-analysis-of-natural-and-man-made-materials",title:"Advances in Composite Materials",fullTitle:"Advances in Composite Materials - Analysis of Natural and Man-Made Materials"},signatures:"Mohini Saxena, Asokan Pappu, Anusha Sharma, Ruhi Haque and Sonal Wankhede",authors:[{id:"27516",title:"Dr.",name:"Asokan",middleName:null,surname:"Pappu",slug:"asokan-pappu",fullName:"Asokan Pappu"},{id:"30902",title:"Dr.",name:"Mohini",middleName:"-",surname:"Saxena",slug:"mohini-saxena",fullName:"Mohini Saxena"},{id:"47206",title:"Prof.",name:"Anusha",middleName:null,surname:"Sharma",slug:"anusha-sharma",fullName:"Anusha Sharma"},{id:"47207",title:"MSc",name:"Ruhi",middleName:null,surname:"Haque",slug:"ruhi-haque",fullName:"Ruhi Haque"},{id:"47208",title:"Prof.",name:"Sonal",middleName:null,surname:"Wankhede",slug:"sonal-wankhede",fullName:"Sonal Wankhede"}]},{id:"67052",doi:"10.5772/intechopen.86225",title:"Novel Applications of Aluminium Metal Matrix Composites",slug:"novel-applications-of-aluminium-metal-matrix-composites",totalDownloads:2794,totalCrossrefCites:25,totalDimensionsCites:49,abstract:"Advanced materials have offered the materials designer a wide range of options in the specification and selection of materials for various applications. Material properties are continually being improved to meet safety and operational standards in line with prevailing technological developments. Modern technological requirements, together with the consumers’ demands for systems and machines that are more energy efficient, stronger, light-weight, cost-effective, etc., dictate that the search for new and advanced materials will remain a subject of interest all the time. The difficulty in designing materials for such stringent specifications cannot be overstated, owing to the conflicting nature of these specifications. Aluminium metal matrix composites (AlMMCs) are a class of materials that have proven successful in meeting most of the rigorous specifications in applications where light-weight, high stiffness and moderate strength are the requisite properties. With a variety of reinforcement materials and flexibility in their primary processing, AlMMCs offer great potential for the development of composites with the desired properties for certain applications. In this review, the development, utilisation and future potential of AlMMCs in various industrial and commercial applications is discussed, together with the existing challenges hindering their full market penetration.",book:{id:"8862",slug:"aluminium-alloys-and-composites",title:"Aluminium Alloys and Composites",fullTitle:"Aluminium Alloys and Composites"},signatures:"Francis Nturanabo, Leonard Masu and John Baptist Kirabira",authors:[{id:"286492",title:"Mr.",name:"Francis",middleName:null,surname:"Nturanabo",slug:"francis-nturanabo",fullName:"Francis Nturanabo"},{id:"299246",title:"Prof.",name:"Leonard",middleName:null,surname:"Masu",slug:"leonard-masu",fullName:"Leonard Masu"},{id:"299247",title:"Prof.",name:"John Baptist",middleName:null,surname:"Kirabira",slug:"john-baptist-kirabira",fullName:"John Baptist Kirabira"}]}],mostDownloadedChaptersLast30Days:[{id:"48473",title:"Transmission Electron Microscopy of Biological Samples",slug:"transmission-electron-microscopy-of-biological-samples",totalDownloads:4956,totalCrossrefCites:10,totalDimensionsCites:23,abstract:"During the last 70 years, transmission electron microscopy (TEM) has developed our knowledge about ultrastructure of the cells and tissues. Another aim is the determination of molecular structure, interactions and processes including structure-function relationships at cellular level using a variety of TEM techniques with resolution in atomic to nanometre range. Even with the best transmission electron microscope, it is impossible to obtain real results without optimal sample preparation, respecting both the structure and the antigenicity preservation. Preparation techniques for high-resolution study of both macromolecular complex and organelles within cellular complex are based on fast cryoimmobilisation process, where the sample is in the most native, hydrated state. Next, thin samples are directly visualised under cryo-transmission electron microscopy (cryo-TEM), while thicker samples require a thinning step via cryo-electron microscopy of vitreous sections (CEMOVIS) or cryo-focused ion beam (cryo-FIB) before visualisation. Alternatively, vitrified samples are freeze substituted and embedded in chosen resin for room temperature ultramicrotomy. This preparation technique is suitable for morphological study, 3D analysis of cellular interior and immunoelectron microscopy. A different route for immunolocalisation study is cryosectioning according to the Tokuyasu technique that is a choice for rare or methacrylate-sensitive antigens. Most recently, new hybrid techniques have been developed for difficult-to-fix organisms and antigens or labile and anoxia-sensitive tissues. Another preparation technique is, the oldest but still important, conventional chemical fixation dedicated in a wide range of research interest, involving morphological and immunolocalisation study. In this chapter, we present different sample preparation approaches for transmission electron microscopy of biological samples, including its methodological basis and applications.",book:{id:"4644",slug:"the-transmission-electron-microscope-theory-and-applications",title:"The Transmission Electron Microscope",fullTitle:"The Transmission Electron Microscope - Theory and Applications"},signatures:"Łukasz Mielańczyk, Natalia Matysiak, Olesya Klymenko and\nRomuald Wojnicz",authors:[{id:"174365",title:"M.Sc.",name:"Łukasz",middleName:null,surname:"Mielańczyk",slug:"lukasz-mielanczyk",fullName:"Łukasz Mielańczyk"},{id:"175977",title:"Dr.",name:"Natalia",middleName:null,surname:"Matysiak",slug:"natalia-matysiak",fullName:"Natalia Matysiak"},{id:"175978",title:"Dr.",name:"Olesya",middleName:null,surname:"Klymenko",slug:"olesya-klymenko",fullName:"Olesya Klymenko"},{id:"175979",title:"Prof.",name:"Romuald",middleName:null,surname:"Wojnicz",slug:"romuald-wojnicz",fullName:"Romuald Wojnicz"}]},{id:"61328",title:"Introductory Chapter: Adsorption and Ion Exchange Properties of Zeolites for Treatment of Polluted Water",slug:"introductory-chapter-adsorption-and-ion-exchange-properties-of-zeolites-for-treatment-of-polluted-wa",totalDownloads:2142,totalCrossrefCites:4,totalDimensionsCites:6,abstract:null,book:{id:"6499",slug:"zeolites-and-their-applications",title:"Zeolites and Their Applications",fullTitle:"Zeolites and Their Applications"},signatures:"Mohamed Nageeb Rashed and Pachagoundanpalayam\nNachimuthugounder Palanisamy",authors:[{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed"}]},{id:"63993",title:"Metamaterials in Application to Improve Antenna Parameters",slug:"metamaterials-in-application-to-improve-antenna-parameters",totalDownloads:4897,totalCrossrefCites:18,totalDimensionsCites:28,abstract:"In recent years, the demand for miniaturization and integration of many functions of telecommunication equipment is of great interest, especially devices that are widely used in life such as mobile communication systems, smart phones, handheld tablets, GPS receivers, wireless Internet devices, etc. To satisfy this requirement, the mobile device components must be compact and capable of multifunction, multifrequency band operation. An antenna is one of them; it means that it must be conformal to the body of device, reduced in size, and capable to operating at multiple frequencies of mobile communication systems that have been operating on one, so-called smart device. Nowadays, there are many technical solutions applied in the antenna construction to satisfy of those requirements. There are microstrip antenna technology miniaturized by means of high-permittivity dielectric substrate, using shorting wall, shorting pins, some deformation, as the fractal geometry is, and others. However, these methods have disadvantage such as narrow bandwidth and low gain. A new solution that is of great interest to designers is the use of electromagnetic metamaterials for antenna design. The use of metamaterials in antenna design not only dramatically reduces the size of the antenna but can also improve other antenna parameters such as enhancing bandwidth, increasing gain, or generating multiband frequencies of antennas operation.",book:{id:"6849",slug:"metamaterials-and-metasurfaces",title:"Metamaterials and Metasurfaces",fullTitle:"Metamaterials and Metasurfaces"},signatures:"Wojciech Jan Krzysztofik and Thanh Nghia Cao",authors:null},{id:"16729",title:"The Glass Transition Temperature in Dental Composites",slug:"the-glass-transition-temperature-in-dental-composites",totalDownloads:4469,totalCrossrefCites:1,totalDimensionsCites:8,abstract:null,book:{id:"1044",slug:"metal-ceramic-and-polymeric-composites-for-various-uses",title:"Metal, Ceramic and Polymeric Composites for Various Uses",fullTitle:"Metal, Ceramic and Polymeric Composites for Various Uses"},signatures:"J.C.S. Moraes, M.M.D.S. Sostena and Carlos Roberto Grandini",authors:[{id:"42590",title:"Dr.",name:"J.C.S.",middleName:null,surname:"Moraes",slug:"j.c.s.-moraes",fullName:"J.C.S. Moraes"},{id:"42878",title:"Dr.",name:"M.M.D.S.",middleName:null,surname:"Sostena",slug:"m.m.d.s.-sostena",fullName:"M.M.D.S. Sostena"},{id:"42880",title:"Prof.",name:"Carlos Roberto",middleName:null,surname:"Grandini",slug:"carlos-roberto-grandini",fullName:"Carlos Roberto Grandini"}]},{id:"71222",title:"Introduction to Composite Materials",slug:"introduction-to-composite-materials",totalDownloads:2463,totalCrossrefCites:15,totalDimensionsCites:23,abstract:"Composite materials have played an important role throughout human history, from housing early civilizations to enabling future innovations. Composites offer many benefits; the key among them are corrosion resistance, design flexibility, durability, light weight, and strength. Composites have permeated our everyday lives such as products that are used in constructions, medical applications, oil and gas, transportation, sports, aerospace, and many more. Some applications, such as rocket ships, probably would not get off the ground without composite materials. This chapter addresses the advantages of fibre composite materials as well as fundamental effects, product development, and applications of fibre composites, including material chemistry, designing, manufacturing, properties, and utilisation of the materials in various applications.",book:{id:"8768",slug:"composite-and-nanocomposite-materials-from-knowledge-to-industrial-applications",title:"Composite and Nanocomposite Materials",fullTitle:"Composite and Nanocomposite Materials - From Knowledge to Industrial Applications"},signatures:"Tri-Dung Ngo",authors:[{id:"208798",title:"Ph.D.",name:"Tri-Dung",middleName:null,surname:"Ngo",slug:"tri-dung-ngo",fullName:"Tri-Dung Ngo"}]}],onlineFirstChaptersFilter:{topicId:"156",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},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:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,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:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. 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After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"19",title:"Animal Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/19.jpg",editor:{id:"259298",title:"Dr.",name:"Edward",middleName:null,surname:"Narayan",slug:"edward-narayan",fullName:"Edward Narayan",profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",biography:"Dr. Edward Narayan graduated with Ph.D. degree in Biology from the University of the South Pacific and pioneered non-invasive reproductive and stress endocrinology tools for amphibians - the novel development and validation of non-invasive enzyme immunoassays for the evaluation of reproductive hormonal cycle and stress hormone responses to environmental stressors. \nDr. Narayan leads the Stress Lab (Comparative Physiology and Endocrinology) at the University of Queensland. A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",institutionString:null,institution:{name:"Universidade Paulista",institutionURL:null,country:{name:"Brazil"}}},{id:"191123",title:"Dr.",name:"Juan José",middleName:null,surname:"Valdez-Alarcón",slug:"juan-jose-valdez-alarcon",fullName:"Juan José Valdez-Alarcón",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBfcQAG/Profile_Picture_1631354558068",institutionString:"Universidad Michoacana de San Nicolás de Hidalgo",institution:{name:"Universidad Michoacana de San Nicolás de Hidalgo",institutionURL:null,country:{name:"Mexico"}}},{id:"161556",title:"Dr.",name:"Maria Dos Anjos",middleName:null,surname:"Pires",slug:"maria-dos-anjos-pires",fullName:"Maria Dos Anjos Pires",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS8q2QAC/Profile_Picture_1633432838418",institutionString:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}},{id:"209839",title:"Dr.",name:"Marina",middleName:null,surname:"Spinu",slug:"marina-spinu",fullName:"Marina Spinu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLXpQAO/Profile_Picture_1630044895475",institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",institutionURL:null,country:{name:"Romania"}}},{id:"92185",title:"Dr.",name:"Sara",middleName:null,surname:"Savic",slug:"sara-savic",fullName:"Sara Savic",profilePictureURL:"https://mts.intechopen.com/storage/users/92185/images/system/92185.jfif",institutionString:'Scientific Veterinary Institute "Novi Sad"',institution:{name:'Scientific Veterinary Institute "Novi Sad"',institutionURL:null,country:{name:"Serbia"}}}]},{id:"20",title:"Animal Nutrition",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. 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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:229,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"22",type:"subseries",title:"Applied Intelligence",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence",scope:"This field is the key in the current industrial revolution (Industry 4.0), where the new models and developments are based on the knowledge generation on applied intelligence. 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