Indication and properties of MSC products impact their manufacturing.
\\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:"11016",leadTitle:null,fullTitle:"Maize Genetic Resources - Breeding Strategies and Recent Advances",title:"Maize Genetic Resources",subtitle:"Breeding Strategies and Recent Advances",reviewType:"peer-reviewed",abstract:"Maize is one of the most economically important food crops worldwide. It is used for livestock feeds and human nutrition. Recent strategies have been adopted for improving maize crops. This book brings together recent advances, breeding strategies, and applications in the biological control, breeding, and genetic improvement of maize genetic resources. It also provides new insights and sheds light on new perspectives and future research work that have been carried out for further improvement of maize crops. This book is a useful resource for students, researchers, and scientists.",isbn:"978-1-80355-016-9",printIsbn:"978-1-80355-015-2",pdfIsbn:"978-1-80355-017-6",doi:"10.5772/intechopen.95713",price:119,priceEur:129,priceUsd:155,slug:"maize-genetic-resources-breeding-strategies-and-recent-advances",numberOfPages:180,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"5e0422e2f711a4b69c3cbc3ec31e9afb",bookSignature:"Mohamed Ahmed El-Esawi",publishedDate:"April 20th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11016.jpg",numberOfDownloads:780,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:3,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 15th 2021",dateEndSecondStepPublish:"September 16th 2021",dateEndThirdStepPublish:"November 15th 2021",dateEndFourthStepPublish:"February 3rd 2022",dateEndFifthStepPublish:"April 4th 2022",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"191770",title:"Dr.",name:"Mohamed A.",middleName:null,surname:"El-Esawi",slug:"mohamed-a.-el-esawi",fullName:"Mohamed A. El-Esawi",profilePictureURL:"https://mts.intechopen.com/storage/users/191770/images/system/191770.jpeg",biography:"Dr. Mohamed A. El-Esawi is a visiting research fellow at the University of Cambridge, United Kingdom, and Associate Professor of Molecular Genetics, Botany Department, Faculty of Science, Tanta University, Egypt. Dr. El-Esawi received his BSc and MSc from Tanta University, and his Ph.D. degree in Plant Genetics and Molecular Biology from Dublin Institute of Technology, Technological University Dublin, Ireland. After obtaining his Ph.D., Dr. El-Esawi joined the University of Warwick, United Kingdom; University of Sorbonne, France; and University of Leuven (KU Leuven), Belgium as a visiting research fellow. His research focuses on plant genetics, genomics, molecular biology, molecular physiology, developmental biology, plant-microbe interaction, and bioinformatics. He has authored several international peer-reviewed articles, book chapters, and books, and has participated in more than sixty conferences and workshops worldwide. Dr. El-Esawi is currently involved in several biological science research projects.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"9",institution:{name:"Tanta University",institutionURL:null,country:{name:"Egypt"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"305",title:"Plant Genetics",slug:"agricultural-science-plant-genetics"}],chapters:[{id:"79187",title:"Silicon, Potassium and Nitrogen Accumulation and Biomass in Corn under Hydroponic Conditions",doi:"10.5772/intechopen.100628",slug:"silicon-potassium-and-nitrogen-accumulation-and-biomass-in-corn-under-hydroponic-conditions",totalDownloads:78,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The aim of the research was to evaluate the effect of the interaction of silicon, potassium, and nitrogen on the foliar area, the accumulation of these elements in the aerial part and the dry biomass in corn plants. The research was developed under hydroponic conditions in Jaboticabal Sao Pablo, Brasil using the 30A77HX hybrid. Two silicon concentrations were evaluated (0 and 2 mmol L−1); two concentrations of potassium (1 and 12 mmol L−1) and four nitrogen concentrations: (1, 10, 15, and 20 mmol L−1). A completely randomized design was used, with factorial arrangement 2 × 2 × 4 and three replications. The foliar area, the dry biomass and, nitrogen, potassium, and silicon content were determined. The application of silicon at a high concentration of K causes an increase in the accumulation of K, which is reflected in an increment of the total dry biomass in the plants of corn, while excess and a deficit of N diminish the accumulation of Si in the aerial part of the plant, which is more evident at a low concentration of K in the nutritious solution, affecting the accumulation of the total dry biomass.",signatures:"Leónides Castellanos González, Renato de Mello Prado and Cid Naudi Silva Campos",downloadPdfUrl:"/chapter/pdf-download/79187",previewPdfUrl:"/chapter/pdf-preview/79187",authors:[{id:"438080",title:"Dr.",name:"Leonides",surname:"Castellanos González",slug:"leonides-castellanos-gonzalez",fullName:"Leonides Castellanos González"},{id:"438398",title:"Dr.",name:"Renato",surname:"de Mello Prado",slug:"renato-de-mello-prado",fullName:"Renato de Mello Prado"},{id:"438399",title:"Dr.",name:"Cid Naudi",surname:"Silva Campos",slug:"cid-naudi-silva-campos",fullName:"Cid Naudi Silva Campos"}],corrections:null},{id:"80131",title:"Improved Technological Processes on the Nutritional Quality of Maize",doi:"10.5772/intechopen.101646",slug:"improved-technological-processes-on-the-nutritional-quality-of-maize",totalDownloads:67,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"As global food security and staple food, maize has become one of the most widely used cereals for fundamental research. Several important discoveries are reported, some of which are technological processes being used to improve maize crops’ dietetic, phenotypic, genotypic, and organoleptic properties. This chapter provides insight into improved technological techniques such as crossbreeding, genetic cloning, and functional genomics and how they improve the nutritional quality of maize crops. The use of these technological processes could be one of the sustainable strategies in meeting the dietary needs and livelihood of Africa, Mexico, and Latin America’s growing populace.",signatures:"Cebisa Noxolo Nesamvuni, Khavhatondwi Rinah Netshiheni and Oluwaseun Funmi Akinmoladun",downloadPdfUrl:"/chapter/pdf-download/80131",previewPdfUrl:"/chapter/pdf-preview/80131",authors:[{id:"201856",title:"Dr.",name:"Khavhatondwi",surname:"Rinah Netshiheni",slug:"khavhatondwi-rinah-netshiheni",fullName:"Khavhatondwi Rinah Netshiheni"},{id:"305143",title:"Dr.",name:"Cebisa Noxolo",surname:"Nesamvuni",slug:"cebisa-noxolo-nesamvuni",fullName:"Cebisa Noxolo Nesamvuni"},{id:"427880",title:"Mrs.",name:"Oluwaseun",surname:"Funmi Akinmoladun",slug:"oluwaseun-funmi-akinmoladun",fullName:"Oluwaseun Funmi Akinmoladun"}],corrections:null},{id:"80762",title:"Maize (Zea mays) Response to Abiotic Stress",doi:"10.5772/intechopen.102892",slug:"maize-em-zea-mays-em-response-to-abiotic-stress",totalDownloads:48,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The most extensively produced crop globally is Maize (Zea mays). Its response to diverse environmental stressors is dynamics and complicated, and it can be plastic (irreversible) or elastic (reversible). There is a wide range of soil and climatic conditions in which Maize can be grown. Climate change, for example, has the potential to impair grain quality and productivity of Maize all over the world. For the best harvest yield, the maize crop requires the right temperature. As a result of climate change, environmental stress factors such as abiotic and biotic stress factors are projected to intensify and become more common. Abiotic stress such as drought, temperature, and salinity are the major constraints limiting Maize’s worldwide production (Z. mays L.). In places prone to various stresses, the development of stress-tolerant crop types will be useful. Drought, salinity, and temperature extremes are examples of abiotic factors that can significantly impact the development and growth of the plant. Furthermore, various management options available may aid in the development of strategies for better maize performance in abiotic stress conditions to understand the maize response to resistance mechanisms and abiotic stress. Therefore, this chapter will focus on the impact of abiotic stress regarding temperature on Maize.",signatures:"Yousaf Ali, Taufiq Nawaz, Nazeer Ahmed, Muhammad Junaid, Mehwish Kanwal, Fazli Hameed, Saeed Ahmed, Rafi Ullah, Muhammad Shahab and Fazli Subhan",downloadPdfUrl:"/chapter/pdf-download/80762",previewPdfUrl:"/chapter/pdf-preview/80762",authors:[{id:"420070",title:"Mr.",name:"Saeed",surname:"Ahmed",slug:"saeed-ahmed",fullName:"Saeed Ahmed"},{id:"420222",title:"Dr.",name:"Rafi",surname:"Ullah",slug:"rafi-ullah",fullName:"Rafi Ullah"},{id:"423681",title:"Dr.",name:"Yousaf",surname:"Ali",slug:"yousaf-ali",fullName:"Yousaf Ali"},{id:"445125",title:"Dr.",name:"Nazeer",surname:"Ahmed",slug:"nazeer-ahmed",fullName:"Nazeer Ahmed"},{id:"456159",title:"Dr.",name:"Taufiq",surname:"Nawaz",slug:"taufiq-nawaz",fullName:"Taufiq Nawaz"},{id:"456161",title:"Dr.",name:"Muhammad",surname:"Junaid",slug:"muhammad-junaid",fullName:"Muhammad Junaid"},{id:"456162",title:"Dr.",name:"Mehwish",surname:"Kanwal",slug:"mehwish-kanwal",fullName:"Mehwish Kanwal"},{id:"456163",title:"Dr.",name:"Fazli",surname:"Hameed",slug:"fazli-hameed",fullName:"Fazli Hameed"},{id:"456164",title:"Dr.",name:"Muhammad",surname:"Shahab",slug:"muhammad-shahab",fullName:"Muhammad Shahab"},{id:"456165",title:"Dr.",name:"Fazli",surname:"Subhan",slug:"fazli-subhan",fullName:"Fazli Subhan"}],corrections:null},{id:"79206",title:"Climate-Smart Maize Breeding: The Potential of Arbuscular Mycorrhizal Symbiosis in Improving Yield, Biotic and Abiotic Stress Resistance, and Carbon and Nitrogen Sink Efficiency",doi:"10.5772/intechopen.100626",slug:"climate-smart-maize-breeding-the-potential-of-arbuscular-mycorrhizal-symbiosis-in-improving-yield-bi",totalDownloads:36,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Maize is part of the essential food security crops for which yields need to tremendously increase to support future population growth expectations with their accompanying food and feed demand. However, current yield increases trends are sub-optimal due to an array of biotic and abiotic factors that will be compounded by future negative climate scenarios and continued land degradations. These negative projections for maize yield call for re-orienting maize breeding to leverage the beneficial soil microbiota, among which arbuscular mycorrhizal fungi (AMS) hold enormous promises. In this chapter, we first review the components relevant to maize-AMF interaction, then present the benefits of arbuscular mycorrhizal symbiosis (AMS) to maize growth and yield in terms of biotic and abiotic stress tolerance and improvement of yield and yield components, and finally summarize pre-breeding information related to maize-AMF interaction and trait improvement avenues based on up-to-date molecular breeding technologies.",signatures:"Arfang Badji, Issa Diedhiou and Abdoulaye Fofana Fall",downloadPdfUrl:"/chapter/pdf-download/79206",previewPdfUrl:"/chapter/pdf-preview/79206",authors:[{id:"424057",title:"Dr.",name:"Arfang",surname:"Badji",slug:"arfang-badji",fullName:"Arfang Badji"},{id:"439754",title:"Dr.",name:"Issa",surname:"Diedhiou",slug:"issa-diedhiou",fullName:"Issa Diedhiou"},{id:"439755",title:"Dr.",name:"Abdoulaye",surname:"Fofana Fall",slug:"abdoulaye-fofana-fall",fullName:"Abdoulaye Fofana Fall"}],corrections:null},{id:"80106",title:"Aflatoxins and Fumonisins Contamination of Maize in Bangladesh: An Emerging Threat for Safe Food and Food Security",doi:"10.5772/intechopen.101647",slug:"aflatoxins-and-fumonisins-contamination-of-maize-in-bangladesh-an-emerging-threat-for-safe-food-and-",totalDownloads:60,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Maize (Bhutta) is one of the important growing cereal crops in Bangladesh. Toxigenic fungi such as Aspergillus and Fusarium infect stored maize grains. Enzyme-linked immusorbent assay (ELISA) was used to determine total aflatoxins and fumonisins contamination in stored maize grains collected from 15 Bangladeshi maize-producing areas. The highest total concentration of aflatoxins (103.07 µg/kg) and fumonisin (9.18 mg/kg) was found in Chuadanga and Gaibandha, whereas the lowest was detected for aflatoxins (1.07 µg/kg) and (0.11 mg/kg) in Dinajpur and Cumilla, respectively. The findings clearly demonstrated that aflatoxin concentrations in samples from six regions and fumonisin concentrations in samples from 10 regions were beyond the regulatory limit of aflatoxin (10 ppb) and fumonisin (1 ppm), respectively, as set by European Union (EU). However, a positive correlation between aflatoxins with toxigenic A. flavus, and fumonisins with toxigenic Fusarium spp. was observed. The fungi associated with maize grains were identified by sequencing of ITS regions. Moreover, toxigenic A. flavus was confirmed using primers specific to nor, apa2, omtA and primer FUM1 for F. proliferatum and F. oxysporum. Since the Bangladesh Food Safety Authority has not authorized any precise regulation limits for maize mycotoxin contamination, these results will serve as a benchmark for monitoring mycotoxin contamination in maize and also to develop globally practiced biocontrol approach for producing safe food and feed.",signatures:"Muhtarima Jannat, Md. Mostafa Masud, Mushfika Nusrat, Samrin Bashar, Mamuna Mahjabin Mita, Muhammad Iqbal Hossain, Md. Zahangir Alam, Sabina Yeasmin and Md. Rashidul Islam",downloadPdfUrl:"/chapter/pdf-download/80106",previewPdfUrl:"/chapter/pdf-preview/80106",authors:[{id:"354303",title:"Prof.",name:"Md. Rashidul",surname:"Islam",slug:"md.-rashidul-islam",fullName:"Md. Rashidul Islam"},{id:"416140",title:"BSc.",name:"Md. Mostafa",surname:"Masud",slug:"md.-mostafa-masud",fullName:"Md. Mostafa Masud"},{id:"416143",title:"MSc.",name:"Md. Zahangir",surname:"Alam",slug:"md.-zahangir-alam",fullName:"Md. Zahangir Alam"},{id:"429301",title:"Mrs.",name:"Muhtarima",surname:"Jannat",slug:"muhtarima-jannat",fullName:"Muhtarima Jannat"},{id:"429302",title:"BSc.",name:"Samrin",surname:"Bashar",slug:"samrin-bashar",fullName:"Samrin Bashar"},{id:"429304",title:"BSc.",name:"Mamuna Mahjabin",surname:"Mita",slug:"mamuna-mahjabin-mita",fullName:"Mamuna Mahjabin Mita"},{id:"442413",title:"MSc.",name:"Muhammad Iqbal",surname:"Hossain",slug:"muhammad-iqbal-hossain",fullName:"Muhammad Iqbal Hossain"},{id:"465659",title:"Dr.",name:"Sabina",surname:"Yeasmin",slug:"sabina-yeasmin",fullName:"Sabina Yeasmin"},{id:"465660",title:"Dr.",name:"Mushfika",surname:"Nusrat",slug:"mushfika-nusrat",fullName:"Mushfika Nusrat"}],corrections:null},{id:"79472",title:"Critical Dry Spell Prediction in Rain-Fed Maize Crop Using Artificial Neural Network in Nigeria",doi:"10.5772/intechopen.100627",slug:"critical-dry-spell-prediction-in-rain-fed-maize-crop-using-artificial-neural-network-in-nigeria",totalDownloads:71,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Prediction of yearly mid-growing season first and second critical dry spells using artificial neural networks (ANN) for enhanced maize yield in nine stations in Nigeria is performed. The ANN model uses nine meteorological parameters to predict onset dates and lengths of the critical dry spells. The daily dataset is from 1971 to 2013 of which about 70% is used for training while 30% is for testing. Seven ANN models are developed for each station with a view to measuring their predictive ability by comparing predicted values with the observed ones. Prediction lead times for the two critical dry spell onset dates generally range from about 2 weeks to 2 months for the nine stations. Error range during testing for the onset dates and lengths of first and second critical dry spells is generally ±4 days. The root-mean-square error (RMSE), coefficient of determination, Nash-Sutcliffe coefficient of efficiency, Wilmott\\'s index of agreement, and RMSE observation standard deviation ratio range from 0.46 to 3.31, 0.58 to 0.93, 0.51 to 0.90, 0.82 to 0.95, and 0.30 to 0.69, respectively. These results show ANN capability of making the above reliable predictions for yearly supplementary irrigation planning, scheduling, and various other decision makings related to sustainable agricultural operations for improved rain-fed maize crop yield in Nigeria.",signatures:"Nnadozie Okonkwo Nnoli, Ahmed Balogun, Jerome Omotosho and Samuel Agele",downloadPdfUrl:"/chapter/pdf-download/79472",previewPdfUrl:"/chapter/pdf-preview/79472",authors:[{id:"270732",title:"Prof.",name:"Samuel",surname:"Agele",slug:"samuel-agele",fullName:"Samuel Agele"},{id:"429151",title:"Ph.D. Student",name:"Nnadozie",surname:"Okonkwo Nnoli",slug:"nnadozie-okonkwo-nnoli",fullName:"Nnadozie Okonkwo Nnoli"},{id:"429153",title:"Prof.",name:"Ahmed",surname:"Balogun",slug:"ahmed-balogun",fullName:"Ahmed Balogun"},{id:"429154",title:"Prof.",name:"Jerome",surname:"Omotosho",slug:"jerome-omotosho",fullName:"Jerome Omotosho"}],corrections:null},{id:"79507",title:"Improving Maize Shelling Operation Using Motorized Mobile Shellers: A Step towards Reducing Postharvest Losses in Low Developing Countries",doi:"10.5772/intechopen.101039",slug:"improving-maize-shelling-operation-using-motorized-mobile-shellers-em-a-step-towards-reducing-postha",totalDownloads:199,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Maize shelling is still a challenge in low developing countries with more efforts required to advance this operation. In Uganda, motorized immobile maize shellers have been fabricated locally to enhance the shelling operation. However, their performance has not elated the farmers. The unsatisfactory performance is a result of these shellers being fabricated by local artisan with finite understanding of the maize grain characteristics and operation factors to optimize maize shelling. In addition, farmers in these countries have a deficiency of power to operate the motorized maize shellers available. Transportation of these motorized maize shellers is also still a challenge and it imposes an extra cost to the farmers hence reducing their profits from maize growing. In this chapter, we reviewed maize shelling process in low developing countries particularly the categories of maize shelling, maize sheller design requirements, use of equations to design sheller parts, modification of the motorized maize shellers and case studies on the mobile maize shellers, comparing them with immobile maize shellers. The study concluded that on addition to other sheller performance attributes, motorized mobile maize shellers can solve transportation challenges associated with motorized immobile maize shellers.",signatures:"Denis Nsubuga, Isa Kabenge, Ahamada Zziwa, Nicholas Kiggundu, Joshua Wanyama and Noble Banadda",downloadPdfUrl:"/chapter/pdf-download/79507",previewPdfUrl:"/chapter/pdf-preview/79507",authors:[{id:"425479",title:"Ph.D. Student",name:"Denis",surname:"Nsubuga",slug:"denis-nsubuga",fullName:"Denis Nsubuga"},{id:"436644",title:"Dr.",name:"Isa",surname:"Kabenge",slug:"isa-kabenge",fullName:"Isa Kabenge"},{id:"436645",title:"Dr.",name:"Ahamada",surname:"Zziwa",slug:"ahamada-zziwa",fullName:"Ahamada Zziwa"},{id:"436646",title:"Dr.",name:"Nicholas",surname:"Kiggundu",slug:"nicholas-kiggundu",fullName:"Nicholas Kiggundu"},{id:"436647",title:"Dr.",name:"Joshua",surname:"Wanyama",slug:"joshua-wanyama",fullName:"Joshua Wanyama"},{id:"436648",title:"Dr.",name:"Noble",surname:"Banadda",slug:"noble-banadda",fullName:"Noble Banadda"}],corrections:null},{id:"79085",title:"Advances and Trends in the Physicochemical Properties of Corn Starch Blends",doi:"10.5772/intechopen.101041",slug:"advances-and-trends-in-the-physicochemical-properties-of-corn-starch-blends",totalDownloads:99,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Corn starch is one of the most widely used biopolymers in the world for various applications, due to its high production, renewable, low cost, non-toxic, biodegradable and provide great stereochemical diversity by presenting a complex structure with unique qualities that they depend on multiple factors to obtain special properties for a specific use and/or of interest. From the synthesis of the starch granule to its extraction for its subsequent use, it promotes innovative characteristics, presenting infinite functionalities applicable and/or as a substitute for synthetic polymers. However, some limitations of hydrophilicity, thermal and mechanical properties, rapid degradability and strong intra and intermolecular bonds of the polymer chains make their use difficult in the medium and long term. Enzymatic, chemical and physical methods continue to be used today, creating by-products such as polluting waste and which can be costly. Therefore, the polymeric modification of the starch granule is necessary to mitigate limitations and by-products, currently the use of starch blends is a promising trend to produce new and innovative desirable properties. This chapter describes the advances and trends in the physicochemical properties of corn starch blends Zea mays L. as a potential material, leader for its attractive properties and benefits that it has to offer, demonstrating that when combined with other starches from different botanical sources and/or molecular structure present unique and unequaled synergisms.",signatures:"Ulin Antobelli Basilio-Cortes, Daniel González-Mendoza, Carlos Enrique Ail-Catzim, Carlos Ceceña-Durán, Onésimo Grimaldo-Juárez, Dagoberto Durán-Hernández, Olivia Tzintzun-Camacho, Luis Antonio González-Anguiano, Ángel Manuel Suárez-Hernández, Aurelia Mendoza-Gómez, Juan Carlos Vásquez-Angulo, Adabella Suárez-Vargas, David Cervantes-García and Gabriel Luna-Sandoval",downloadPdfUrl:"/chapter/pdf-download/79085",previewPdfUrl:"/chapter/pdf-preview/79085",authors:[{id:"435349",title:"Ph.D.",name:"Ulin",surname:"Basilio-Cortes",slug:"ulin-basilio-cortes",fullName:"Ulin Basilio-Cortes"},{id:"440007",title:"Dr.",name:"Daniel",surname:"González-Mendoza",slug:"daniel-gonzalez-mendoza",fullName:"Daniel González-Mendoza"},{id:"440009",title:"Dr.",name:"Carlos Enrique",surname:"Ail-Catzim",slug:"carlos-enrique-ail-catzim",fullName:"Carlos Enrique Ail-Catzim"},{id:"440010",title:"M.Sc.",name:"Carlos",surname:"Ceceña-Durán",slug:"carlos-cecena-duran",fullName:"Carlos Ceceña-Durán"},{id:"440011",title:"Dr.",name:"Adabella",surname:"Suarez-Vargas",slug:"adabella-suarez-vargas",fullName:"Adabella Suarez-Vargas"},{id:"440012",title:"Dr.",name:"Onésimo",surname:"Grimaldo-Juárez",slug:"onesimo-grimaldo-juarez",fullName:"Onésimo Grimaldo-Juárez"},{id:"440013",title:"Dr.",name:"Dagoberto",surname:"Durán-Hernández",slug:"dagoberto-duran-hernandez",fullName:"Dagoberto Durán-Hernández"},{id:"440014",title:"Dr.",name:"Olivia",surname:"Tzintzun-Camacho",slug:"olivia-tzintzun-camacho",fullName:"Olivia Tzintzun-Camacho"},{id:"440015",title:"Dr.",name:"Ángel Manuel",surname:"Suárez-Hernández",slug:"angel-manuel-suarez-hernandez",fullName:"Ángel Manuel Suárez-Hernández"},{id:"440016",title:"Dr.",name:"Aurelia",surname:"Mendoza-Gómez",slug:"aurelia-mendoza-gomez",fullName:"Aurelia Mendoza-Gómez"},{id:"440017",title:"Dr.",name:"Juan Carlos",surname:"Vásquez-Angulo",slug:"juan-carlos-vasquez-angulo",fullName:"Juan Carlos Vásquez-Angulo"},{id:"440018",title:"M.Sc.",name:"Luis Antonio",surname:"González-Anguiano",slug:"luis-antonio-gonzalez-anguiano",fullName:"Luis Antonio González-Anguiano"},{id:"440019",title:"Dr.",name:"David",surname:"Cervantes-García",slug:"david-cervantes-garcia",fullName:"David Cervantes-García"},{id:"441974",title:"Dr.",name:"Gabriel",surname:"Luna-Sandoval",slug:"gabriel-luna-sandoval",fullName:"Gabriel Luna-Sandoval"}],corrections:null},{id:"79453",title:"The Impact of Climate Change on Changing Pattern of Maize Diseases in Indian Subcontinent: A Review",doi:"10.5772/intechopen.101053",slug:"the-impact-of-climate-change-on-changing-pattern-of-maize-diseases-in-indian-subcontinent-a-review",totalDownloads:122,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Climate change influences the occurrence, prevalence, and severity of plant pathogens. Global temperatures are predicted to rise by 2–4°C due to human activities and increased market globalization, coupled with rising temperatures, leads to a situation favorable to pest movement and establishment. Maize is an important crop after wheat and rice. Changes in rainfall distribution and temperature may result in temporary excessive soil moisture or water logging or drought in some maize producing areas leading to alterations in biotic stress factors. In Indian subcontinent warming trend in climate along the west coast, central, interior peninsula and northeast regions creates favorable conditions for diseases in maize like sorghum downy mildew (SDM) and Turcicum leaf blight (TLB). The decreasing trend of monsoon, seasonal rainfall in North India, Central India, parts of Gujarat and Kerala is suitable for post flowering stalk-rot (PFSR) which is gaining importance in maize. The outcome for any host-pathogen interaction under changing climate is not readily predictable. This review assesses the potential effects of climate change on maize pathogens and consequently on plant health. The evidence assessed indicates that climate change has already expanded pathogen’s host range and geographical distribution increasing the risk of introduction of pathogens into new areas.",signatures:"Meena Shekhar and Nirupma Singh",downloadPdfUrl:"/chapter/pdf-download/79453",previewPdfUrl:"/chapter/pdf-preview/79453",authors:[{id:"228027",title:"Dr.",name:"Meena",surname:"Shekhar",slug:"meena-shekhar",fullName:"Meena Shekhar"},{id:"426641",title:"Dr.",name:"Nirupma",surname:"Singh",slug:"nirupma-singh",fullName:"Nirupma Singh"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5781",title:"Phytohormones",subtitle:"Signaling Mechanisms and Crosstalk in Plant Development and Stress Responses",isOpenForSubmission:!1,hash:"054eaa85c13ebe3d04fb8852005d2bad",slug:"phytohormones-signaling-mechanisms-and-crosstalk-in-plant-development-and-stress-responses",bookSignature:"Mohamed El-Esawi",coverURL:"https://cdn.intechopen.com/books/images_new/5781.jpg",editedByType:"Edited by",editors:[{id:"191770",title:"Dr.",name:"Mohamed A.",surname:"El-Esawi",slug:"mohamed-a.-el-esawi",fullName:"Mohamed A. 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\r\n\tNanocatalysis, a subdiscipline of nanoscience, that bridges the core advantages of homogenous and heterogeneous catalysis for achieving high efficiency and selectivity of chemical reactions and simple recovery, high stability, and reusability of the catalytic materials. Nanocatalysis is considered to be one of the most fast-growing fields in chemistry. Several existing research articles and reviews illustrate the scientific developments in the field of nanocatalysis. The preparation technique, structure, nature of active sites and the high surface‐to‐volume ratio of nano-sized catalytic materials are the key factors in nanocatalysis. In fact, specific reactivity can be anticipated owing to the nano-sized materials that can afford specific properties that cannot be achieved with regular, non-nano-sized materials. Indeed, nanocatalysis has very recently been playing a tremendous role in various industrially important organic reactions, new energy conversion, and environmental remediation. This book offers detailed information on the concept and potential applications of this field, nanocatalysis. This book also accommodates new studies that update the novel preparation methods and applications of nano-sized materials.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"f9749a2b9019823b07535f10cb8c724e",bookSignature:"Prof. Gopiraman Mayakrishnan and Dr. Prabhakarn Arunachalam",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10070.jpg",keywords:"Nanocatalysis, Nanomedicine, Nanofullerenes, Organic reactions, Nanoenergy, Nano-effect, Nanoparticles, Carbon nanostructures, Multi-component reactions, Molecular interaction, Supercapacitors, Dry synthesis",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 23rd 2019",dateEndSecondStepPublish:"November 13th 2019",dateEndThirdStepPublish:"January 12th 2020",dateEndFourthStepPublish:"April 1st 2020",dateEndFifthStepPublish:"May 31st 2020",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"247516",title:"Prof.",name:"Gopiraman",middleName:null,surname:"Mayakrishnan",slug:"gopiraman-mayakrishnan",fullName:"Gopiraman Mayakrishnan",profilePictureURL:"https://mts.intechopen.com/storage/users/247516/images/system/247516.jpg",biography:"Dr. M GOPIRAMAN\r\nAssociate Professor\r\nDepartment of Applied Bioscience\r\nCollege of Life and Environmental Science\r\nKonkuk University\r\n120 Neungdong-ro\r\nGwangjin-gu, Seoul\r\nSouth Korea (05029)\r\n+82 10 5909 4987; gopiramannitt@gmail.com, gopiraman@konkuk.ac.kr\r\n\r\nDr. Mayakrishnan Gopiraman is an associate professor in the Department of Applied Bioscience, College of Life and Environmental Science at Konkuk University, Seoul, South Korea. He obtained his Ph.D. in Nanocatalysis from Shinshu University, Japan. After his Ph.D., he worked as a postdoctoral fellow (2014-2015), and as an assistant professor (2015-2016) in the division of the interdisciplinary graduate school of science and technology at Shinshu University, Japan. He has more than 65 publications in reputed journals, 5 international patents and contributed 4 book chapters as well. His work is mainly focused on the development of transition metals-based heterogeneous nanocatalysts for highly efficient organic transformations. At present, he is actively working on the development of 2D and 3D-activated carbons from biomass for energy storage systems. 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Mantia-Smaldone and Nathalie Scholler",authors:[{id:"68654",title:"Dr.",name:"Nathalie",middleName:null,surname:"Scholler",fullName:"Nathalie Scholler",slug:"nathalie-scholler"},{id:"79179",title:"Dr.",name:"Gina",middleName:null,surname:"Mantia-Smaldone",fullName:"Gina Mantia-Smaldone",slug:"gina-mantia-smaldone"}]},{id:"28504",title:"Screening for Ovarian Cancer in Women",slug:"screening-of-ovarian-cancer-in-women",signatures:"Duangmani Thanapprapasr and Sarikapan Wilailak",authors:[{id:"68992",title:"Dr.",name:"Duangmani",middleName:null,surname:"Thanapprapasr",fullName:"Duangmani Thanapprapasr",slug:"duangmani-thanapprapasr"},{id:"70896",title:"Prof.",name:"Sarikapan",middleName:null,surname:"Wilailak",fullName:"Sarikapan Wilailak",slug:"sarikapan-wilailak"}]},{id:"28505",title:"Borderline and Malignant Surface Epithelial – Stromal Tumors of the Ovary",slug:"malignant-and-borderline-surface-epithelial-stromal-tumors-of-the-ovary",signatures:"Susanna Syriac, Faith Ough and Paulette Mhawech-Fauceglia",authors:[{id:"71765",title:"Prof.",name:"Paulette",middleName:null,surname:"Mhawech-Fauceglia",fullName:"Paulette Mhawech-Fauceglia",slug:"paulette-mhawech-fauceglia"},{id:"71790",title:"Dr.",name:"Susanna",middleName:null,surname:"Syriac",fullName:"Susanna Syriac",slug:"susanna-syriac"},{id:"118737",title:"Dr.",name:"Faith",middleName:null,surname:"Ough",fullName:"Faith Ough",slug:"faith-ough"}]},{id:"28506",title:"Central Nervous System Involvement from Epithelial Ovarian Cancer",slug:"central-nervous-system-involvement-from-epithelial-ovarian-cancer",signatures:"Gennaro Cormio, Maddalena Falagario and Luigi E. Selvaggi",authors:[{id:"67540",title:"Prof.",name:"Gennaro",middleName:null,surname:"Cormio",fullName:"Gennaro Cormio",slug:"gennaro-cormio"},{id:"76880",title:"Dr.",name:"Maddalena",middleName:null,surname:"Falagario",fullName:"Maddalena Falagario",slug:"maddalena-falagario"},{id:"76881",title:"Prof.",name:"Luigi E.",middleName:null,surname:"Selvaggi",fullName:"Luigi E. Selvaggi",slug:"luigi-e.-selvaggi"}]},{id:"28507",title:"Peripheral Neuropathy in Ovarian Cancer",slug:"peripheral-neuropathy-in-ovarian-cancer",signatures:"Yi Pan",authors:[{id:"67906",title:"Dr.",name:"Yi",middleName:null,surname:"Pan",fullName:"Yi Pan",slug:"yi-pan"}]},{id:"28508",title:"Therapeutic Strategies in Ovarian Cancer",slug:"therapeutic-strategies-in-ovarian-cancer",signatures:"Dan Ancuşa, Octavian Neagoe, Răzvan Ilina, Adrian Carabineanu, Corina Şerban and Marius Craina",authors:[{id:"71624",title:"Dr.",name:"Marius",middleName:null,surname:"Craina",fullName:"Marius Craina",slug:"marius-craina"}]},{id:"28509",title:"Combined Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for the Treatment of Advanced Ovarian Cancer",slug:"cytoreductive-surgery-and-perioperative-intraperitoneal-chemotherapy-for-the-treatment-of-locally-ad",signatures:"Antonios-Apostolos K. Tentes, Nicolaos Courcoutsakis and Panos Prasopoulos",authors:[{id:"67930",title:"Dr.",name:"Antonios-Apostolos",middleName:null,surname:"Tentes",fullName:"Antonios-Apostolos Tentes",slug:"antonios-apostolos-tentes"},{id:"79059",title:"Prof.",name:"Nicos",middleName:null,surname:"Kourcoutsakis",fullName:"Nicos Kourcoutsakis",slug:"nicos-kourcoutsakis"},{id:"79060",title:"Prof.",name:"Panos",middleName:null,surname:"Prasopoulos",fullName:"Panos Prasopoulos",slug:"panos-prasopoulos"}]},{id:"28510",title:"Minimally Invasive Surgical Procedures for Patients with Advanced and Recurrent Ovarian Cancer",slug:"minimally-invasive-surgical-techniques-for-advanced-and-recurrent-ovarian-cancer",signatures:"Samir A. Farghaly",authors:[{id:"69680",title:"Dr.",name:"Samir",middleName:"A",surname:"Farghaly",fullName:"Samir Farghaly",slug:"samir-farghaly"}]},{id:"28511",title:"Management of Recurrent or Persistent Ovarian Cancer",slug:"ovarian-cnacer-the-management-of-recurrent-or-persistent-disease",signatures:"Constantine Gennatas",authors:[{id:"79990",title:"Prof.",name:"Constantine",middleName:null,surname:"Gennatas",fullName:"Constantine Gennatas",slug:"constantine-gennatas"}]},{id:"28512",title:"Antiprogestins in Ovarian Cancer",slug:"antiprogestins-in-ovarian-cancer",signatures:"Carlos M. Telleria and Alicia A. Goyeneche",authors:[{id:"67512",title:"Dr.",name:"Carlos",middleName:null,surname:"Telleria",fullName:"Carlos Telleria",slug:"carlos-telleria"},{id:"77375",title:"Dr.",name:"Alicia",middleName:null,surname:"Goyeneche",fullName:"Alicia Goyeneche",slug:"alicia-goyeneche"}]},{id:"28513",title:"Intraperitoneal Radionuclide Therapy – Clinical and Pre-Clinical Considerations",slug:"intraperitoneal-radionuclide-therapy-clinical-and-pre-clinical-considerations",signatures:"J. Elgqvist, S. Lindegren and P. Albertsson",authors:[{id:"67453",title:"Dr.",name:"Jörgen",middleName:null,surname:"Elgqvist",fullName:"Jörgen Elgqvist",slug:"jorgen-elgqvist"},{id:"120211",title:"Dr.",name:"Sture",middleName:null,surname:"Lindegren",fullName:"Sture Lindegren",slug:"sture-lindegren"},{id:"120212",title:"Dr.",name:"Per",middleName:null,surname:"Albertsson",fullName:"Per Albertsson",slug:"per-albertsson"}]},{id:"28514",title:"Vitamin K2 as a Chemotherapeutic Agent for Treating Ovarian Cancer",slug:"vitamin-k2-as-a-chemotherapeutic-agent-for-treating-ovarian-cancer",signatures:"K. Nakaya, Y. Masuda, T. Aiuchi and H. Itabe",authors:[{id:"71420",title:"Prof.",name:"Hiroyuki",middleName:null,surname:"Itabe",fullName:"Hiroyuki Itabe",slug:"hiroyuki-itabe"},{id:"71426",title:"Prof.",name:"Kazuyasu",middleName:null,surname:"Nakaya",fullName:"Kazuyasu Nakaya",slug:"kazuyasu-nakaya"},{id:"71429",title:"Dr.",name:"Toshihiro",middleName:null,surname:"Aiuchi",fullName:"Toshihiro Aiuchi",slug:"toshihiro-aiuchi"},{id:"71431",title:"Dr.",name:"Yutaka",middleName:null,surname:"Masuda",fullName:"Yutaka Masuda",slug:"yutaka-masuda"}]},{id:"28515",title:"Second-Line Chemotherapy for Platinum- and Taxane-Resistant Epithelial Ovarian Cancer: Pegylated Liposomal Doxorubicin (PLD), Irinotecan, and Combination Therapies at Lower Doses",slug:"second-line-combination-therapy-for-platinum-and-taxane-resistant-epithelial-ovarian-cancer",signatures:"Toru Sugiyama",authors:[{id:"57785",title:"Prof.",name:"Toru",middleName:null,surname:"Sugiyama",fullName:"Toru Sugiyama",slug:"toru-sugiyama"}]},{id:"28516",title:"HER2 as a Therapeutic Target in Ovarian Cancer",slug:"her2-as-a-therapeutic-target-for-ovarian-cancer",signatures:"Lukas C. Amler, Yulei Wang and Garret Hampton",authors:[{id:"76392",title:"Dr",name:"Lukas",middleName:"C.",surname:"Amler",fullName:"Lukas Amler",slug:"lukas-amler"},{id:"81090",title:"Dr.",name:"Garret",middleName:null,surname:"Hampton",fullName:"Garret Hampton",slug:"garret-hampton"}]},{id:"28517",title:"Sexuality After Ovarian Cancer Therapy",slug:"sexuality-after-ovarian-cancer-therapy",signatures:"Juliane Farthmann and Annette Hasenburg",authors:[{id:"68704",title:"Prof.",name:"Annette",middleName:null,surname:"Hasenburg",fullName:"Annette Hasenburg",slug:"annette-hasenburg"},{id:"77244",title:"Dr",name:"Juliane",middleName:null,surname:"Farthmann",fullName:"Juliane Farthmann",slug:"juliane-farthmann"}]},{id:"28518",title:"Quality of Life of Patients with Ovarian Cancer",slug:"quality-of-life-of-patients-with-ovarian-cancer",signatures:"Wei-Chu Chie and Elfriede Greimel",authors:[{id:"69634",title:"Prof.",name:"Wei-Chu",middleName:null,surname:"Chie",fullName:"Wei-Chu Chie",slug:"wei-chu-chie"},{id:"69788",title:"Dr.",name:"Elfriede",middleName:null,surname:"Greimel",fullName:"Elfriede Greimel",slug:"elfriede-greimel"}]}]}],publishedBooks:[{type:"book",id:"951",title:"Topics on Cervical Cancer With an Advocacy for Prevention",subtitle:null,isOpenForSubmission:!1,hash:"fedfb0b32d856abf87bdb68b8ce9791c",slug:"topics-on-cervical-cancer-with-an-advocacy-for-prevention",bookSignature:"Rajamanickam Rajkumar",coverURL:"https://cdn.intechopen.com/books/images_new/951.jpg",editedByType:"Edited by",editors:[{id:"120109",title:"Dr.",name:"Rajamanickam",surname:"Rajkumar",slug:"rajamanickam-rajkumar",fullName:"Rajamanickam Rajkumar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3449",title:"Ovarian Cancer",subtitle:"A Clinical and Translational Update",isOpenForSubmission:!1,hash:"d86076194a3c65286c370cafd587fe7d",slug:"ovarian-cancer-a-clinical-and-translational-update",bookSignature:"Iván Díaz-Padilla",coverURL:"https://cdn.intechopen.com/books/images_new/3449.jpg",editedByType:"Edited by",editors:[{id:"157073",title:"Dr.",name:"Ivan",surname:"Diaz-Padilla",slug:"ivan-diaz-padilla",fullName:"Ivan Diaz-Padilla"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10342",title:"Ovarian Cancer",subtitle:"Updates in Tumour Biology and Therapeutics",isOpenForSubmission:!1,hash:"25a0adac7f6afa7bcd0b6daa3ef6b538",slug:"ovarian-cancer-updates-in-tumour-biology-and-therapeutics",bookSignature:"Gwo-Yaw Ho and Kate Webber",coverURL:"https://cdn.intechopen.com/books/images_new/10342.jpg",editedByType:"Edited by",editors:[{id:"297757",title:null,name:"Gwo-Yaw",surname:"Ho",slug:"gwo-yaw-ho",fullName:"Gwo-Yaw Ho"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10789",title:"Cervical Cancer",subtitle:"A Global Public Health Treatise",isOpenForSubmission:!1,hash:"3f7a79875d0d0ae71479de8c60276913",slug:"cervical-cancer-a-global-public-health-treatise",bookSignature:"Rajamanickam Rajkumar",coverURL:"https://cdn.intechopen.com/books/images_new/10789.jpg",editedByType:"Edited by",editors:[{id:"120109",title:"Dr.",name:"Rajamanickam",surname:"Rajkumar",slug:"rajamanickam-rajkumar",fullName:"Rajamanickam Rajkumar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"69881",title:"Bioprocess Development for Human Mesenchymal Stem Cell Therapy Products",doi:"10.5772/intechopen.90029",slug:"bioprocess-development-for-human-mesenchymal-stem-cell-therapy-products",body:'\nCell therapy is a growing clinical research and healthcare sector in which living cells are introduced into a patient in an attempt to ameliorate or cure a disease. Stem cell therapy is one of the most promising fields within this sector because the introduced cells have the capacity to differentiate, allowing the repopulation of diseased organs with healthy cells, or to allow even complete organ regeneration. This chapter will focus on one specific type of stem cell (MSCs), which are variously defined as mesenchymal stem cells, mesenchymal stromal cells, or (most recently) medicinal signaling cells [1]. These various definitions reflect the controversial origin and functionality of MSCs and uncertainty about their clinical potential [2, 3]. Following encouraging initial results, the unclear or disappointing outcomes of some MSC clinical trials have clouded the picture [4], but the pioneers of this approach still regard MSCs as a promising therapeutic option [5]. One of the key issues in the deployment of MSCs is ensuring they are safe and effective, which requires a well-characterized manufacturing process.
\nIn order to provide enough MSCs for cell therapy, donor cells must be isolated from tissue and then expanded
MSCs are classified as advanced therapeutic medicinal products (ATMPs) under regulations in Europe and the US. Many countries follow the regulations laid down by the US Food and Drug Administration (FDA), which defines MSCs as cell therapy products, whereas the European Medicines Agency (EMA) defines MSCs as cell-based medicinal products and distinguishes between somatic cell therapy medicinal products (SCTMPs) and tissue engineered products (TEPs) [7]. This means that clinical studies and drug approval are covered by a specific regulatory framework applied at the national or regional level. Manufacturing must therefore be compliant with good manufacturing practice (GMP) regulations that have been tailored for ATMPs, following strict criteria for product specification and release for clinical use. However, the regulatory framework for MSC manufacturing is confounded by ambiguous product definitions reflecting regional differences in the way the regulations are implemented. For example, the EMA requires GMP compliance and manufacturing authorization for phase I material, whereas the FDA does not apply this requirement until phases II and III, and in Canada, GMP compliance is not strictly required at any phase [8]. Even so, various MSC products have been manufactured under these different regulatory jurisdictions and have proceeded through clinical development, in some cases gaining market authorization from the local regulatory agency [9]. Most of these products are allogenic, which means that MSCs from one or more healthy donors are expanded, processed, and stored and then applied to patients as an off-the-shelf product (Table 1). In 2016, the allogenic MSC product TEMCELL (developed by Mesoblast) was licensed to JCR Pharmaceuticals, which received market authorization in Japan under a fast-track protocol for patients with steroid-refractory acute GvHD. Mesoblast also conducted a phase III trial with this product in the US, involving 60 patients of the same indication, achieving the primary endpoints (NCT02336230). In 2018, ALOFISEL (Takeda Pharma), an expanded allogenic adipose-derived MSC product, was approved by the EMA to treat complex perianal fistula in patients with Crohn’s disease. This was supported by a placebo-controlled trial involving 212 patients [10]. Stempeucel (Stempeutics), an expanded allogenic MSC product, received market authorization from the Drug Controller General of India to treat limb ischemia in patients with Buerger’s disease. However, it is limited to 200 patients on a cost-recovery basis, and a postmarket surveillance study is required. Ninety patients have already received an injection of this MSC product in a phase II trial, achieving a significantly better outcome than standard care [11]. CARTISTEM (Medipost) is an allogenic culture-expanded umbilical cord blood MSC product to treat knee articular cartilage defects in patients with osteoarthritis, grade IV, and following approval for the South Korean market in 2012, its clinical outcomes have remained stable over 7 years of follow-up studies [12]. Several autologous MSC products have also been approved in South Korea, meaning that the MSCs are isolated from the patient’s own tissue and then manipulated/expanded in a patented process and re-injected into the patient 4–6 weeks later. NEURONATA-R (Corestem) and Cellgram-AMI (Pharmicell) are autologous bone marrow-derived MSCs indicated for amyotrophic lateral sclerosis and acute myocardial infarction, respectively. Two other MSC products derived from adipose-tissue have been approved (Anterogen): a mixture of autologous adipose-derived MSCs with other cells for subcutaneous tissue defects (Queencell) and a pure adipose-derived MSC product for Crohn’s fistula treatment (Cupistem) [9]. NEURONATA-R has been designated as an orphan drug by the EMA and FDA.
\n\n | Product 1 | \nProduct 2 | \n
---|---|---|
Exemplary products | \nALOFISEL | \nQueencell | \n
Indication | \nCrohn’s disease, perianal fistula | \nRegeneration of subcutaneous tissue | \n
Patients per year | \n23,000 (in EU)* | \nn.d. | \n
Cell type | \nAllogenic MSCs | \nAutologous, patient-specific MSCs | \n
Cell source | \nAdipose tissue | \nAdipose tissue | \n
Cells per dose | \n1.2 × 108 MSCs | \n7 × 107** | \n
Therapeutic relevant cell properties*** | \nAnti-inflammation, immune modulation | \nRegeneration, anti-apoptosis | \n
Manufacturing type | \nBulk manufacturing | \nPatient-specific batch | \n
Batch size | \nLarge (min. 100–1000 doses per batch) | \nSmall (1 dose per batch) | \n
Scalability of production | \nScale up | \nScale out, several batches in parallel | \n
Product storage | \nFrozen, off-the-shelf | \nNo storage | \n
Stability under storage | \nStable >6 month, frozen | \nFresh, stable max. 24 hours | \n
Indication and properties of MSC products impact their manufacturing.
0.003% of all citizens (741 million) in Europe are putative patients.
Stromal vascular fraction contains MSCs and other cell types such as preadipocytes, endothelial progenitor cells, pericytes, mast cells, and fibroblast.
Following both products have different critical quality attributes (CQAs) and the manufacturing processes have different critical process parameters (CPPs).
n.d. not determined.
This brief survey of the market shows that the promise of MSC therapy is materializing, with positive efficacy data in controlled clinical trials followed by regulatory approval for a small number of products.
\nAlthough MSCs have been used in cell therapy applications for many years, the fundamental biology of these cells and their precise therapeutic properties are not fully understood. MSCs were initially isolated from bone marrow (bm-MSCs) based on their plastic adherence, but today they are usually isolated from adipose tissue (ad-MSCs) or umbilical cord blood (uc-MSCs), which are more accessible [13]. MSCs are also found in various other adult, fetal, and perinatal tissues [14]. Regardless of their origin, MSCs are heterogeneous and polyclonal cells, with at least three subpopulations defined based on morphology. Type I MSCs are spindle-shaped proliferating cells resembling fibroblasts. Type II MSCs are large, flat, epithelial-like cells, which are more senescent than type I cells and feature visible cytoskeletal structures and granules. Finally, type III MSCs are small round cells with a high capacity for self-renewal [15]. The heterogeneity of MSCs can be considered beneficial in that it ensures that some therapeutically active cells are present, but it reduces the maximum potential efficacy because some of the cells are inactive. However, even monoclonal MSCs become heterogeneous during expansion [16].
\nDespite the heterogeneity described above, the International Society of Cell Therapy has published a set of minimal criteria that must be met before cells can be defined as MSCs. Such cells must (i) show plastic adherence; (ii) be able to differentiate into cartilage, bone, and fat tissue
It is important to note that MSCs cannot be defined merely as a collection of surface markers because this says nothing about their therapeutic effect (Figure 1). Initially, the therapeutic potential of MSCs was believed to reflect their ability to migrate into damaged tissues, differentiate
Properties of MSCs and their mode of action. MSCs modulate the host immune systems, e.g., by secreting various trophic factors. Thereby, they reduce inflammation, promote neoangiogenesis, and prevent apoptosis and fibrosis. Further, they stimulate local stem cells to develop new tissue. TSG-6, tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein; STC1, stanniocalcin 1; IL-4/6/10, interleukins 4, 6 and 10; CCL20, macrophage inflammatory protein-3; IDO, indoleamine 2,3-dioxygenase; PGE2, prostaglandin E2; VEGF, vascular endothelial growth factor; FGF-2, basic fibroblast growth factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor 1; CXCL12, stromal cell-derived factor 1; MMP1/2/9, matrix metalloproteinase-1/2/9.
The immunomodulatory properties of MSCs and their secretion of anti-inflammatory molecules and extracellular vesicles are an important therapeutic functionality [14]. MSCs are therefore logical candidates for the treatment of immune disorders, including GvHD, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and diabetes [21]. MSCs also secrete peptides and factors that promote the regeneration of damaged tissue by stimulating cell proliferation and migration, promoting angiogenesis, and suppressing apoptosis and fibrosis [14]. The regenerative capacity of MSCs has been used to treat Alzheimer’s disease, bone and cartilage diseases, diabetes, myocardial infarction, and osteoarthritis [22]. Another advantage of MSCs is that they do not form teratomas
The biological complexity and heterogeneity of MSCs hamper the translation of laboratory-scale experiments into industrial processes for cost-effective and reliable manufacturing. This can be addressed by developing MSC manufacturing processes that adhere to quality-by-design (QbD) principles [24]. QbD provides a rational framework and integrates scientific knowledge and risk analysis into process development. It is guided by a thorough understanding of the fundamental biology and engineering principles underlying an MSC product and its production process. QbD begins with a description of the desired product quality characteristics, known as the quality target product profile (QTPP). This is used to identify critical quality attributes (CQAs), which are physical, chemical, and biological attributes that define the quality of the product. The QTPP for MSCs describes properties such as identity, purity, and potency, which will be unique for each MSC product and dependent on the therapeutic indication.
\nFor MSCs, identity often means the cell phenotype, but as discussed above, there is no agreement on a single definition. Identity is often demonstrated by confirming a typical morphology and/or karyotype [25] and by detecting the presence or absence of surface markers. The minimal criteria for MSCs (see above) have led to a misconception that cells meeting these criteria are equivalent in identity and therapeutic functionality. In polyclonal MSC populations, the presence of multiple cell types can be a clinical benefit as stated above [26], and this should be reflected in the identity attributes.
\nThe functionality and potency of MSCs are closely linked to their therapeutic efficacy and thus the clinical outcome, but potency is used to demonstrate manufacturing consistency for batch release so a measurable property is required. Viability can fulfill the role of a potency indicator because only living cells can act as a therapeutic entity. Potency can also be measured using
If the therapeutic effect of MSCs is conferred by the secretome, then the differentiation potential may not be the primary determinant of potency. The profile of secreted factors would be a more appropriate measure, and this could be determined by multiplex enzyme-linked immunosorbent assays (ELISAs) or mass spectroscopy [31]. However, a clear link between the secretome profile and
Impurities are unwanted components from within the process, whereas contaminants come from outside the process. Impurities during MSC manufacturing include unwanted cell types, particles (e.g., residual microcarriers, or plastics and fibers from manufacturing equipment and materials), or components of culture medium. Contaminants include bacteria, fungi, viruses, endotoxins, and mycoplasma. The heterogeneity of MSCs makes it difficult to detect unwanted cell types. MSC preparations should ideally be pure, but fibroblasts are often present as impurities. Cell-specific sorting based on the marker CD166 (which is expressed at higher levels on MSCs) and CD9 (which is expressed at higher levels on fibroblasts) may help to achieve sufficient purity [33]. In other cases, it may be sufficient if most of the cells in the final product (>98%) fulfill the ISCT minimal criteria based on MSC surface markers. All other impurities and contaminants must be measured and the maximum residual levels must be defined to ensure safety and efficacy. A final sterilization step is not possible when the product is living cells, so the entire MSC production process must be carried out under aseptic conditions.
\nFrom the QTPP list, CQAs must be identified, which directly influence the safety and efficacy of the MSC product. This means that a risk assessment is carried out to reduce the QTPP list to the most influential attributes based on impact and certainty. According to ICHQ8, a CQA is “
Therapeutic applications of MSCs require at least 1 × 108 cells per dose, which is many more than can be isolated by tissue aspiration. All MSC production processes must therefore include an
The properties of MSCs are strongly influenced by the environment because MSCs in nature interact with surrounding cells and tissues, with the extracellular matrix and with various bioactive molecules. Even in an artificial environment like a bioreactor or T-flask, MSCs are very sensitive to their environment, and the most influential factors give rise to CPPs. By identifying CPPs that affect MSC quality, the process can be designed to favor the recovery of MSCs with specific phenotypes of interest, in this case those with the greatest therapeutic efficacy [34, 35]. The CPPs affecting MSC quality are discussed in more detail below.
\nDuring MSC isolation, the seeding density is important because all sources contain different quantities of MSCs. For example, only 1 in 100,000 bone marrow cells is an MSC, whereas in adipose tissue, the ratio is nearer to 1 in 100 [36]. If plastic adherence is selected as a strategy for MSC isolation, the number of adherent cells therefore differs according to the source if a similar number of tissue cells are seeded. Standardization during this step can be achieved by isolating MSCs using a strategy of surface marker sorting, allowing a defined number of cells to be seeded into the culture vessel. The seeding density selected for the
Several basal media have been shown to influence MSC expansion and potency, including Dulbecco’s modified Eagle’s medium (DMEM), Iscove’s modified Dulbecco’s medium (IMDM), and MEM alpha (αMEM) [37]. One of the key components of these media is glucose, which is the main carbon source for MSCs. Glucose may be provided at physiological concentrations (1 g/L) or higher (up to 4.5 g/L), the latter variously described as having a negative effect on MSC proliferation and growth factor secretion [38] or no effect at all [39]. Glutamine as a second carbon source is present at concentrations of 2–4 mM and appears essential for MSC growth [40], but its impact on MSC properties is complex, with contradictory results [41, 42, 43]. Glutamine is unstable at 37°C and spontaneously degrades to form ammonia. GlutaMAX (dipeptide Ala-Gln) is recommended instead of glutamine to promote MSC expansion [44]. Lactate and ammonia are the most abundant waste products formed by MSCs, and both therefore have the potential to inhibit growth. It therefore follows that glucose, glutamine, lactate, and ammonia levels should be considered as CPPs for the production of MSCs. Several other amino acids may also be relevant, given that the amino acid metabolism of MSCs differs from that of commercial cell lines such as Chinese hamster ovary (CHO) cells [42].
\nBasal media formulations must be supplemented to achieve MSC expansion. The most important supplement is fetal calf serum (FCS), which is added to a final concentration of 5–20%. FCS strongly influences MSC growth and phenotype, but the specific effectors are unknown because the composition of FCS is variable and lot-dependent [45]. The use of FCS for the manufacture of clinical MSC products is discouraged nowadays, in line with the drive to eliminate all raw materials of animal origin. The complex, uncertain, and variable composition of FCS also makes it difficult to validate for GMP-compliant processes. Finally, the manufacturing process must accommodate steps to eliminate FCS from the final product to avoid potential immunogenicity and allergenicity [46]. FCS can be replaced with human serum and its derivatives, such as human platelet lysate, which promotes MSC growth [47]. However, the same lot-dependent quality issues described above for FCS also apply to human serum [48]. The most acceptable alternative is serum-free or preferably chemically-defined medium, the latter not only serum-free but also lacking any hydrolysates or supplements of unknown composition. MSCs grow well in several commercial serum-free media, including BD Mosaic MSC Serum-free (BD Biosciences), RoosterNourish (Rooster Bio), Mesencult-XF (Stemcell Technologies), StemPro MSC SFM Xeno-Free (Invitrogen), TheraPEAK MSCGM-CD (Lonza), and PPRF-msc6, STK1 and STK2 (Abion) [49]. Growth in chemically-defined medium has also been demonstrated [50]. However, although MSCs showed excellent growth in these serum-free media, they reached senescence earlier, and there were changes in morphology, surface marker profiles, and potency [51]. This does not mean that serum-free and chemically-defined media should be avoided‑it is still better to use these media for MSC expansion in order to meet GMP requirements‑but further investigations are required to optimize the media composition. The development of serum-free media is mainly driven by companies, which tend not to disclose the precise composition, making it difficult for other researchers to build on the results. In serum-free and defined media, supplemental growth factors such as FGF2 and PDGF are needed to stimulate MSC proliferation, but they also influence MSC potency [18]. Accordingly, chemically-defined media would be preferable for the
MSCs are aerobic cells and any culture vessel must therefore ensure an adequate supply of oxygen. However, the oxygen saturation in standard T-flasks (21% O2) is far removed from nature (5–7% O2) [34]. MSCs therefore tend to be oversaturated with oxygen, which can increase the concentration of damaging reactive oxygen species (ROS). Several studies have confirmed that hypoxia enhances MSC proliferation, stabilizes their cell fate, and prevents apoptosis by reducing the levels of caspase-3 [52]. However, rather than imposing hypoxia by preconditioning the cells, it may be better to impose hypoxia during the entire expansion phase, because this mimics their natural niche [53].
\nIn addition to oxygen saturation, temperature and pH are CPPs in every process and can be monitored and controlled very easily. Typically,
Other CPPs include the parameters grouped under the term hydrodynamics, referring to the potential impact of aeration and agitation. Aeration is required to supply oxygen to the MSCs, but as well as affecting the oxygen saturation, it also generates forces that cause physical stress. In T-flasks, aeration is achieved by the diffusion of oxygen through the surface of the medium, whereas bioreactors must be actively aerated by, e.g., bubbling gas into the liquid. The bursting gas bubbles (cavitation) generate strong forces that can damage cells, although the stress can be reduced by controlling the bubble size [55]. Agitation in bioreactors is generally achieved with impellers, which help to disperse gas (and therefore contribute to aeration) but also maintain a homogenous suspension of cells and nutrients. The creation of a homogenous environment is advantageous because it avoids gradients of pH, nutrients, or waste products, whose effect on MSCs is unpredictable. Homogenization can also be achieved using pumps or is facilitated by air bubbles. Agitation always generates shear forces, so it is necessary to balance the homogeneity of the cultivation system and the impact of the hydrodynamic forces on the MSCs. Although excessive shear stress is detrimental, hydrodynamic forces can also stimulate MSC growth and increase potency [43]. For these reasons, the mode and rate of aeration and the method and intensity of agitation are CPPs that must be carefully optimized for each process.
\nMSCs are anchorage-dependent cells, so the properties of the growth surface also have a significant impact on the process and must be investigated and selected carefully. However, unlike the parameters discussed above, the growth surface does not have to be monitored or controlled during MSC production, so it falls outside the technical definition of a CPP. The expression of certain surface markers by MSCs reflects the stiffness of the growth surface, so it is clear that the surface affects the phenotype [56]. As stated above, the ability to adhere to plastic surfaces is one of the minimal criteria that define MSCs, and tissue-culture plastic is therefore the most commonly-used growth surface. Although all commercial tissue-culture plasticware has a polypropylene base, the surface is often treated differently, and this changes the behavior and properties of the adherent MSCs [37]. MSCs further grow on other surface materials, e.g., glass [57] or dextran [58]. When MSCs are cultivated in serum-free medium, cell growth often requires that the surface is coated with further adhesion-promoting factors, such as fibronectin, vitronectin, or the peptide RGD.
\nGiven that MSCs are anchorage-dependent cells, the harvesting of cells at the end of the
All the approved allogenic MSC products described earlier are cryopreserved, allowing them to be offered as off-the-shelf products that can be stored until quality control and batch release are completed. The use of cryopreserved allogeneic MSCs is the only feasible therapeutic strategy for acute tissue injury syndromes such as stroke, sepsis, or myocardial infarction, because the patient is likely to die before sufficient quantities of autologous MSCs could be prepared. However, cryopreservation and thawing have a massive impact on the potency of MSCs [66]. Indeed, even without optimization, fresh MSCs are much more potent than frozen ones [35]. A rule of thumb is to freeze the cells slowly (e.g., 1°C/min) but to thaw them quickly (e.g., direct transfer from storage to a 37°C water bath). The impact of multiple freeze-thaw cycles must be evaluated carefully [67]. The composition of the freezing medium is also important because it often contains dimethyl sulfoxide (DMSO) and FCS as cryoprotectants, the first being cytotoxic and the second undesirable for the reasons already discussed above. Nontoxic alternatives lacking DMSO and FCS have been tested and may be more compatible with MSCs intended for clinical applications [68, 69, 70].
\nIn summary, the expansion of MSCs in bioreactors involves multiple CPPs including (i) the source of the initial MSCs before expansion, (ii) the impact of cell density and age, (iii) the effects of the culture medium, (iv) the properties of the bioreactor and aeration/agitation systems, and (iv) the method used for cell harvest and storage. The impact of these CPPs on the quality of MSCs can only be determined by designing robust assays for (i)
For the 989 interventional clinical trials involving MSCs reported thus far (www.clinicaltrials.gov, search term: mesenchymal stem cell OR mesenchymal stromal cell, 2019/09/27), the MSCs were expanded
The manufacture of protein therapeutics is almost always carried out in bioreactors because they are scalable, controllable via integrated process analytical technology, and most process steps can be automated. This is not the case for MSC products, and a survey of GMP manufacturing at US academic centers has revealed major differences in the various process steps (cell isolation, expansion, and characterization). In the context of cell expansion, 80% of the centers surveyed above used T-flasks or cell factories, whereas only 20% mainly used bioreactors. A broad range of seeding densities was used for cultivation (50–2500 cells/cm2) and the cultivation time ranged from 1 to 28+ days. The cultivation medium was supplemented with FCS (lot-selected or not) or donor-pooled human platelet lysate (in-house product or commercial product) [71]. All of the centers expanded MSCs under GMP conditions, but with huge variations in the protocol. The production of MSCs in T-flasks is adequate for a small number of patients (30 T-flasks each with a growth surface of 175 cm2 would be required per patient, assuming each patient is dosed with 416 million cells and the harvesting efficiency is 8 × 104 cells/cm2 [72]). But for larger clinical trials with >100 patients, the resources required for cell culture would become unsupportable (assuming the conditions stated above, a trial with 140 patients would require 4200 T-flasks filling 32 standard 160-L incubators and 9 full-time personnel to handle the cells). Expansion in T-flasks might also be sufficient for autologous cell therapy, given that only a single patient is involved and it would not be necessary to produce more than 10 doses. However, even for small-scale manufacturing, an automated bioreactor system would offer several advantages over manual cultivation. Given that the entire manufacturing process must be aseptic, closed bioreactors provide much better insurance against contamination than an open culture system based on T-flaks. For allogenic MSC products, where up to 1 million doses are produced per batch, bioreactors are the only feasible manufacturing option (Figure 2).
\nManufacturing of autologous and allogenic MSC products. Autologous MSC products are isolated from the patient’s own tissue, whereas for allogenic MSC products a healthy donor from the same specie donates cells. In the isolation and expansion, there are few differences between the two types of MSC products. Most common sources are bone marrow, adipose tissue, and umbilical cord (blood), all three giving different amount of MSCs. The expansion for both MSC product types differs in scale. Storage is only needed for allogenic MSC products. If we expect that 0.4 × 106 MSC are isolated per donation and one dose to treat a single patient is about 120 × 106 MSCs, an expansion factor of at least 300-fold is needed. If more doses should be produced from one isolate, e.g., because the patient needs several treatments or in case of allogenic MSC products, the expansion factor dramatically increases.
When an MSC product advances from research to commercial manufacturing, the
Stirred tank reactors are the most widely-used devices for large-scale MSC expansion. They are often used with microcarriers, which are small beads that increase the surface area available for cell attachment, although MSCs can also be grown in bioreactors as aggregates or spheroids. The expansion of MSCs growing on microcarriers is typically a batch-mode manufacturing process because the cells are harvested at a predetermined density. However, fed-batch processes involve a smaller inoculum (100 cells/cm2, equivalent to five cells per microcarrier) and can thus achieve better economy and a higher expansion factor [77, 78]. There should be minimal (if any) agitation at the beginning of the expansion phase to allow for cell attachment to the microcarriers (if used) or otherwise for the formation of aggregates. However, agitation is required following attachment in order to homogenize the suspension and avoid the formation of large clumps. As discussed above, agitation is an important CPP and the parameters must be optimized based on the unique combination of system properties (e.g., impeller type/speed and microcarrier size/amount) to keep microcarriers or aggregates in suspension without causing shear damage, and these parameters must be optimized at different manufacturing scales [79].
\nFixed bed reactors are also widely used for MSC expansion, and in this case, the cells are grown either on macrocarriers or as capsules (500 μm diameter), both of which form a stable bed at the reactor base. The production of homogeneous conditions in the bed can be frustrated by the development of channels and gradients in the bed, particularly in large-scale systems [80]. The shear forces in fixed bed reactors are low (~0.5 × 10−5 N/cm2) and consistent throughout the reactor with no peaks near the impeller; the shear forces also remain constant at all scales [81]. The
The earlier sections highlighted several challenges that must be overcome to develop robust processes for the expansion of MSCs in bioreactors, which are summarized briefly below. Furthermore, our current understanding of the CPPs affecting MSC production is rudimentary at best, and more work is required to determine the impact of hydrodynamic factors on the CQAs. Precise online monitoring tools are needed to control CPPs effectively and to measure their influence on cell viability, potency, and secretory profiles. An increase in process understanding will facilitate process modeling, to fulfill the requirements of process analytic technology as a prerequisite for GMP manufacturing.
\nThe major challenge for MSC therapy is the development of an
Polyclonal MSCs often show the most potent therapeutic effects, but clonal impoverishment occurs during lengthy expansion phases and this must be avoided if potency is compromised. However, even monoclonal MSCs become heterogeneous over time, generating subpopulations with different morphologies and surface marker profiles. The therapeutic outcome can only be predicted if the MSC pool does not change during expansion, and the well-controlled conditions in bioreactors can therefore help to ensure that the cell products remain homogeneous.
\nUltimately, even bioreactor-based processes for MSC expansion are constrained by the inbuilt replication limit of MSCs, which leads to senescence after a certain number of generations. Stem cells by definition have an unlimited capacity for self-renewal, but this property is lost
The production of MSCs with standardized properties would be facilitated by the development of standardized validated potency assays so that results obtained in different laboratories are truly comparable. The ISCT has taken steps in this direction by publishing standards for the harmonization of potency assays. In a matrix assay approach, they propose to use quantitative RNA analysis for selected gene products, flow cytometry to detect functionally-relevant surface markers, and protein-based assays to map the secretome and determine the immunomodulatory potency of MSCs [88].
\nMSCs are typically the sole product of any MSC cultivation process, but in some applications, the MSCs are used as helper cells to deliver a different product or they are used as a vehicle to produce a specific cellular component. In each case, the CQAs differ significantly from the standard MSC manufacturing process and other CPPs must therefore be considered. We discuss two examples below.
\nMSCs are potent therapeutics, but researchers are seeking new ways to achieve the same therapeutic effect without the drawbacks associated with MSC manufacturing, such as the limited availability of potent cells, the complex transfusion process, and the entrapment of MSCs in nontarget organs [89]. As discussed earlier, the therapeutic effect of MSCs reflects the secretion of cytokines, growth factors, and other paracrine signaling molecules, particularly via the release of extracellular vesicles that interact directly with target cells and deliver their contents into the cytosol. The advantage of these vesicles over whole MSCs is their much greater stability, which means they can be manufactured, stored, and shipped without losing therapeutic efficacy [90, 91].
\nThe large-scale manufacturing of extracellular vesicles requires the cultivation of MSCs, which secrete these vesicles directly in the culture medium. Scalable production methods are not yet available, and vesicles are currently produced in T-flasks or cell factories without process monitoring. Bioreactors could be used to scale up production, and given there is no need to harvest the MSCs, it would be possible to consider a wider range of bioreactor systems than the relatively narrow selection favored for MSC manufacturing. A fixed bed bioreactor has been used for the continuous production and harvesting of extracellular vesicles, which increased the yield 10-fold compared to T-flasks [92]. Stirred tank reactors with microcarriers might also be suitable, but they have not yet been used for vesicle production [57]. The cells would be exposed to shear forces caused by the impellers and air bubble cavitation, and this may influence vesicle production and potency [93].
\nThe effect of different process parameters on the production of MSC-derived extracellular vesicles has been investigated at the laboratory scale. For example, hMSCs and their vesicles are primed by hypoxic conditions or changes in medium composition, such as the removal of FCS or the addition of priming factors like IFNγ and TNFα [34, 35]. The yield of extracellular vesicles can also be increased by preparing spheroids that mimic
There is currently no standardized large-scale production platform for primed hMSC-derived vesicles, but even if such a platform existed, a corresponding purification process would be required. The laboratory-scale purification of vesicles captured from the culture medium is currently based on a combination of ultracentrifugation, dead-end filtration, precipitation, and size exclusion chromatography, which are difficult to scale up [94, 95]. However, tangential-flow filtration can also be used for large-scale purification, washing, and buffer exchange, and this method should be investigated in more detail for vesicle purification [94, 96]. Extracellular vesicles are even more sensitive to process changes than MSCs, so the influence of multiple cell-dependent, culture, and process parameters on the potency of these vesicles must be determined.
\nThe ability of MSCs to restore the activity of dysfunctional cells
The major challenge of cocultivation is to balance the demands of two completely different cell types. In large scales, the distribution of cells becomes heterogeneous, which can lead to instability within the bioreactor and lower cell viability. A well-balanced and tightly controlled culture environment is needed to stabilize large-scale cocultures. Because secreted factors are important for the cocultivation of MSCs and beta cells, the hydrodynamic forces in bioreactors, which influence the distribution of secreted molecules, must be considered at an early stage [100]. Furthermore, the optimal cocultivation ratio of the cells must be determined. Established processes can be modified to achieve a new process setup for cocultivation, but it is often beneficial to separate cell expansion from cocultivation (i.e., first expand the pure cultures to generate the cells needed for the coculture and then combine them to improve the function of beta cells in a second process step). For the expansion step, it can be sufficient to improve the growth of beta cells using conditioned medium from the cultivation of MSCs. Alternatively, the expansion and functionalization of beta cells can be combined in one process step [101]. The CPPs for such a complex process can be difficult to identify, but the CQAs of the beta cells are most relevant if the aim of the process is to produce functionalized beta cells for drug screening or cell therapy. Even so, the potency of the MSCs must not be neglected because they are required to stimulate the beta cells. Accordingly, the MSCs must be expanded under controlled and standardized conditions that maximize their beneficial impact on beta cells. In the future, cocultivation bioreactor concepts for MSCs and beta cells must be tested to allow the completely aseptic expansion and cocultivation of both cell types.
\nMSCs are potent therapeutic agents, but their complexity and environmental sensitivity make the GMP-compliant manufacturing of MSC products extremely challenging. Given the range of tissue sources, isolation procedures, and expansion protocols, it is unclear whether MSC products are similar enough across manufacturing sites and whether results can be considered comparable even within the same study. Moreover, the incomplete definition of MSCs makes it difficult to develop objective release criteria. These issues strongly argue for the harmonization and standardization of MSC manufacturing processes, release criteria, and potency assays. The regulatory standards for MSCs are still evolving, and different standards apply in different jurisdictions. MSCs are living cells and cannot be held to the same standards as chemical entities or biopharmaceuticals, both of which can be tested against rigorous and objective quality criteria. The regulations for MSCs should be more flexible, acknowledging that each MSC product is developed for a specific indication, and unique platform technologies, CQAs, and CPPs may therefore be necessary for each manufacturing process. One of the most important platform technologies is the use of bioreactors for cell expansion, because this is the only current strategy that can bring MSC therapy into routine practice. MSCs can also be used as production aids for other products, including beta cells for drug screening or diabetes therapy, and novel biological agents such as extracellular vesicles. In the future, they could even be used for commodity products such as artificial meat. But in all these applications, a robust and scalable manufacturing process will be necessary.
\nWe would like to thank the Hessen State Ministry of Higher Education, Research and the Arts for the financial support within the Hessen initiative for scientific and economic excellence (LOEWE-Program, LOEWE Center DRUID (Novel Drug Targets against Poverty-Related and Neglected Tropical Infectious Diseases)). We also received financial support from the Strategic Research Fund of the THM (University of Applied Sciences Mittelhessen). The authors acknowledge Dr. Richard M Twyman for revising the paper.
\nThe authors declare no conflict of interest.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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This will pose serious problems with food, water and energy supply, particularly in less-developed countries. Considering that the human pressure over natural resources has already reached critical levels, international agencies such as the World Bank and UN Food and Agriculture Organization (FAO) are soliciting scientific research in order to identify innovative solutions to support the primary sector. Nanotechnology is a rapidly evolving field with the potential to take forward the agriculture and food industry with new tools which promise to increase food production in a sustainable manner and to protect crops from pests. Such expectations are coupled with some uncertainties about the fate of nanomaterials in the agro-environment. However, the field application of engineered nanomaterials (ENMs) has not been properly investigated yet, and many aspects have only been considered theoretically or with models, which make it difficult to properly assess the usefulness of ENMs for plant fertilization and protection.",book:{id:"6763",slug:"new-visions-in-plant-science",title:"New Visions in Plant Science",fullTitle:"New Visions in Plant Science"},signatures:"Luca Marchiol",authors:[{id:"163884",title:"Prof.",name:"Luca",middleName:null,surname:"Marchiol",slug:"luca-marchiol",fullName:"Luca Marchiol"}]},{id:"67311",doi:"10.5772/intechopen.86341",title:"Wheat Production in India: Trends and Prospects",slug:"wheat-production-in-india-trends-and-prospects",totalDownloads:2364,totalCrossrefCites:27,totalDimensionsCites:39,abstract:"Trends in Indian wheat production before and after the inception of the All India Coordinated Research Project (AICRP) on wheat have been analyzed to show its significant progress over the years. A brief intercountry comparison of productivity, production and area coupled with regional comparison within India has been attempted to give an idea about the contribution of country and regions, respectively, for global and national food security. The milestones in Indian wheat programme and research outcomes were highlighted post-AICRP along with the vision and strategies set for 2050 against diverse production challenges. Regional disparities, zone-wise production constraints and research programmes for achieving the set production target were briefed. The chapter concludes with possible interventions in strengthening the complete wheat value chain for ensuring food security for the future generation.",book:{id:"8168",slug:"recent-advances-in-grain-crops-research",title:"Recent Advances in Grain Crops Research",fullTitle:"Recent Advances in Grain Crops Research"},signatures:"Sendhil Ramadas, T.M. 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Mostafa",authors:[{id:"68104",title:"Prof.",name:"Soha",middleName:"Sayed Mohammad",surname:"Mostafa",slug:"soha-mostafa",fullName:"Soha Mostafa"}]},{id:"68218",doi:"10.5772/intechopen.87069",title:"Neglected and Underutilized Legume Crops: Improvement and Future Prospects",slug:"neglected-and-underutilized-legume-crops-improvement-and-future-prospects",totalDownloads:1828,totalCrossrefCites:10,totalDimensionsCites:22,abstract:"Sustainable agricultural productivity is hampered by over-dependency on major staple crops, neglect and underutilization of others, climate change, as well as land deterioration. Challenges posed by these limiting factors are undoubtedly contributing to global food insecurity, increased rural poverty, and malnutrition in the less developed countries. Miscellaneous neglected and underutilized grain legumes (MNUGLs) are crops primarily characterized by inherent features and capabilities to withstand the effects of abiotic stress and climate change, significantly replenish the soil, as well as boost food and protein security. This chapter provides insight into the benefits of MNUGLs as food and nutritional security climate smart crops, capable of growing on marginal lands. Exploring and improving MNUGLs depend on a number of factors among which are concerted research efforts, cultivation and production, as well as utilization awareness across global populace geared toward reawakening the interest on the abandoned legumes. The emergence of the clustered regularly interspaced short palindromic repeat (CRISPR/cas9) technology combined with marker-assisted selection (MAS) offers great opportunities to improve MNUGLs for sustainable utilization. Advances in improvement of MNUGLs using omic technologies and the prospects for their genetic modification were highlighted and discussed.",book:{id:"8168",slug:"recent-advances-in-grain-crops-research",title:"Recent Advances in Grain Crops Research",fullTitle:"Recent Advances in Grain Crops Research"},signatures:"Jacob Popoola, Omena Ojuederie, Conrad Omonhinmin and Adegoke Adegbite",authors:[{id:"246358",title:"Prof.",name:"Conrad",middleName:null,surname:"Omonhinmin",slug:"conrad-omonhinmin",fullName:"Conrad Omonhinmin"},{id:"294662",title:"Dr.",name:"Omena",middleName:null,surname:"Ojuederie",slug:"omena-ojuederie",fullName:"Omena Ojuederie"},{id:"294740",title:"Dr.",name:"Jacob",middleName:null,surname:"Popoola",slug:"jacob-popoola",fullName:"Jacob Popoola"},{id:"294766",title:"Prof.",name:"Adegoke",middleName:null,surname:"Adegbite",slug:"adegoke-adegbite",fullName:"Adegoke Adegbite"}]}],mostDownloadedChaptersLast30Days:[{id:"63134",title:"Transgenic Plants: Gene Constructs, Vector and Transformation Method",slug:"transgenic-plants-gene-constructs-vector-and-transformation-method",totalDownloads:5560,totalCrossrefCites:9,totalDimensionsCites:21,abstract:"The human population has reached 7 billion by 2015 and is estimated to exceed 10 billion by the end of 2050. As such, crops which are the main food source must be produced at a higher pace in order to cater in tandem with the food demand. In the past, traditional plant breeders practice classical breeding techniques to propagate plants with desirable traits. However, traditional breeding technique lies in that only individuals of the same or closely related species can be crossbred. Moreover, traditional breeders will not be able to obtain traits which are not inherent within the gene pool of their target plants through classical breeding. With recent advancements in the field of genetic engineering, it is now possible to insert beneficial genes from a completely different species or even kingdom into a target plant, yielding transgenic plants with multiple ideal traits. To develop a transgenic plant, parameters such as vector constructions, transformation methods, transgene integration, and inheritance of transgene need to be carefully considered to ensure the success of the transformation event. Hence, this chapter aimed to provide an overview of transgenic plants’ development, its advantages and disadvantages, as well as its application for the betterment of mankind.",book:{id:"6763",slug:"new-visions-in-plant-science",title:"New Visions in Plant Science",fullTitle:"New Visions in Plant Science"},signatures:"Lee-Yoon Low, Shun-Kai Yang, De-Xian Andrew Kok, Janna Ong-\nAbdullah, Ngai-Paing Tan and Kok-Song Lai",authors:[{id:"195386",title:"BSc.",name:"Shun Kai",middleName:null,surname:"Yang",slug:"shun-kai-yang",fullName:"Shun Kai Yang"},{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai"},{id:"240035",title:"Ms.",name:"Lee Yoon",middleName:null,surname:"Low",slug:"lee-yoon-low",fullName:"Lee Yoon Low"},{id:"240036",title:"Mr.",name:"Kok",middleName:null,surname:"Andrew-De-Xian",slug:"kok-andrew-de-xian",fullName:"Kok Andrew-De-Xian"},{id:"257891",title:"Dr.",name:"Janna Ong",middleName:null,surname:"Abdullah",slug:"janna-ong-abdullah",fullName:"Janna Ong Abdullah"},{id:"257892",title:"Dr.",name:"Ngai Paing",middleName:null,surname:"Tan",slug:"ngai-paing-tan",fullName:"Ngai Paing Tan"}]},{id:"67311",title:"Wheat Production in India: Trends and Prospects",slug:"wheat-production-in-india-trends-and-prospects",totalDownloads:2364,totalCrossrefCites:27,totalDimensionsCites:39,abstract:"Trends in Indian wheat production before and after the inception of the All India Coordinated Research Project (AICRP) on wheat have been analyzed to show its significant progress over the years. A brief intercountry comparison of productivity, production and area coupled with regional comparison within India has been attempted to give an idea about the contribution of country and regions, respectively, for global and national food security. The milestones in Indian wheat programme and research outcomes were highlighted post-AICRP along with the vision and strategies set for 2050 against diverse production challenges. Regional disparities, zone-wise production constraints and research programmes for achieving the set production target were briefed. The chapter concludes with possible interventions in strengthening the complete wheat value chain for ensuring food security for the future generation.",book:{id:"8168",slug:"recent-advances-in-grain-crops-research",title:"Recent Advances in Grain Crops Research",fullTitle:"Recent Advances in Grain Crops Research"},signatures:"Sendhil Ramadas, T.M. 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Therefore, a full understanding of plant-NP interaction and phytotoxicological mechanism is required for accurate risk assessment to ensure the safe use of nanoparticle. A range of analytical techniques have been developed to detect and characterize the uptake, translocation, cellular internalization and intracellular biotransformation of nanoparticles in plants. Imaging methodologies, including various electron microscopy, spectrometry-based techniques, together with ICP-based techniques such as ICP-OES, ICP-MS and SP-ICP-MS, have been widely used to obtain information about NPs size, morphology, size distribution, cellular localization, elemental speciation, mass concentration and so on. Due to the complexity of biological samples to be analyzed, these techniques are often combined accordingly to provide complementary information regarding plant-NP interaction. 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