Comparison of mechanical properties of natural silks and other synthetic fibers[a]. ([a] Data taken from refs. [3, 4]. [b] RH, relative humidity.)
\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\\n\\n\\n\\n\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n\n\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:"8244",leadTitle:null,fullTitle:"New Advances on Fermentation Processes",title:"New Advances on Fermentation Processes",subtitle:null,reviewType:"peer-reviewed",abstract:"In recent years, there has been an increase in the concern of society and industries about how food and beverages are produced, the production of natural compounds as well as the concern of industries on fermentation-based processes. Thus, there are several approaches worldwide that are looking for low time and low cost fermentation-based processes integrating not only molecular biology procedures but also engineering. This book contains eleven chapters written by international experts in the field of fermentation. It covers all recent aspects on fermentation-based processes with potential applications in many fields such as bio combustible production, food and beverage processing, and biomedicine.",isbn:"978-1-78985-314-8",printIsbn:"978-1-78985-313-1",pdfIsbn:"978-1-83968-554-5",doi:"10.5772/intechopen.78200",price:119,priceEur:129,priceUsd:155,slug:"new-advances-on-fermentation-processes",numberOfPages:240,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"d14302686630dee0aa70e9dda9540c27",bookSignature:"Rosa María Martínez-Espinosa",publishedDate:"February 5th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/8244.jpg",numberOfDownloads:12557,numberOfWosCitations:3,numberOfCrossrefCitations:14,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:38,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:55,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 21st 2019",dateEndSecondStepPublish:"March 13th 2019",dateEndThirdStepPublish:"May 12th 2019",dateEndFourthStepPublish:"July 31st 2019",dateEndFifthStepPublish:"September 29th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"914",title:"Biotechnology",slug:"materials-science-biochemistry-biotechnology"}],chapters:[{id:"69334",title:"Introductory Chapter: A Brief Overview on Fermentation and Challenges for the Next Future",doi:"10.5772/intechopen.89418",slug:"introductory-chapter-a-brief-overview-on-fermentation-and-challenges-for-the-next-future",totalDownloads:1038,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:null,signatures:"Rosa María Martínez-Espinosa",downloadPdfUrl:"/chapter/pdf-download/69334",previewPdfUrl:"/chapter/pdf-preview/69334",authors:[{id:"165627",title:"Dr.",name:"Rosa María",surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa"}],corrections:null},{id:"68145",title:"Current Status of Alkaline Fermented Foods and Seasoning Agents of Africa",doi:"10.5772/intechopen.87052",slug:"current-status-of-alkaline-fermented-foods-and-seasoning-agents-of-africa",totalDownloads:1833,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Fermented foods and seasoning agents play central roles in the food and nutrition security of nations across the world, but particularly so in Africa, Asia, South America and Oceania. As several people across the world gravitate back to “eating natural,” there is a new emphasis on these fermented foods and seasoning agents which are also critical cultural foods in countries and societies where they are important. The result is the growth in demand for these products beyond what the traditional kitchen technologies is able to cope with. In Africa, many of the seasoning agents are products of alkaline fermentation of legume seeds, pulses and in some cases animal proteins and sea foods. There is an upswing in the popularity of these seasoning agents and around them, new cottage industries are growing, as against the kitchen technology that sustained them through the ages. This chapter will explore the state of biotechnological developments around these foods and seasoning agents and point the way to good manufacturing practice and industrial development and the need to grow this value chain that has helped to sustain societies through ages.",signatures:"Jerry O. Ugwuanyi and Augustina N. Okpara",downloadPdfUrl:"/chapter/pdf-download/68145",previewPdfUrl:"/chapter/pdf-preview/68145",authors:[{id:"297797",title:"Prof.",name:"Jerry",surname:"Ugwuanyi",slug:"jerry-ugwuanyi",fullName:"Jerry Ugwuanyi"},{id:"297799",title:"Dr.",name:"Augustina",surname:"Okpara",slug:"augustina-okpara",fullName:"Augustina Okpara"}],corrections:null},{id:"67829",title:"Solid-State Fermentation of Cassava Products for Degradation of Anti-Nutritional Value and Enrichment of Nutritional Value",doi:"10.5772/intechopen.87160",slug:"solid-state-fermentation-of-cassava-products-for-degradation-of-anti-nutritional-value-and-enrichmen",totalDownloads:1154,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The cassava plant is grown in tropical and subtropical countries, which represents, alongside with its by-products, an important source of food and feed. Hence, this plant has the capacity to promote the economic development of those countries and provide food security. However, cassava has some disadvantages due to the antinutrient compounds produced in its tissues. In addition, the cassava roots have a low protein content. Due to the economic and practical advantages, the solid-state fermentation (SSF) has been used as a cost-effective and efficient processing method to detoxify the cassava products and enrich them in nutrients. This chapter reviews the solid-state fermentation technique of cassava products for the production of valuable components for food and feed applications, microorganisms involved in this process, and key factors used to optimize the SSF process.",signatures:"Mohamed Hawashi, Tri Widjaja and Setiyo Gunawan",downloadPdfUrl:"/chapter/pdf-download/67829",previewPdfUrl:"/chapter/pdf-preview/67829",authors:[{id:"297246",title:"Dr.",name:"Setiyo",surname:"Gunawan",slug:"setiyo-gunawan",fullName:"Setiyo Gunawan"},{id:"304847",title:"Prof.",name:"Tri",surname:"Widjaja",slug:"tri-widjaja",fullName:"Tri Widjaja"},{id:"304848",title:"Mr.",name:"Mohamed",surname:"Hawashi",slug:"mohamed-hawashi",fullName:"Mohamed Hawashi"}],corrections:null},{id:"67821",title:"Continuous Beer Production",doi:"10.5772/intechopen.86929",slug:"continuous-beer-production",totalDownloads:1271,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Although the barley and hop harvest is a batch process, the ingredients are storable to a certain extent, so malting and brewing can be performed continuously. The more expensive machinery and energy are becoming, the more continuous production is becoming efficient. The advantages are smaller capacities, less energy consumption and more recuperation. Most filling processes run semi continuously, and energy-consuming processes like malting can also run continuously around the clock. Disadvantages are necessary buffers, microbiological contamination and less flexibility in producing different types of beer or adjusting the production to seasonal fluctuations. Mistakes and errors increase, even if accuracy and in-line sensors help to keep quality stable for some time. This article discusses benefits and limits of continuous technology.",signatures:"Mark Strobl",downloadPdfUrl:"/chapter/pdf-download/67821",previewPdfUrl:"/chapter/pdf-preview/67821",authors:[{id:"298220",title:"Dr.",name:"Mark",surname:"Strobl",slug:"mark-strobl",fullName:"Mark Strobl"}],corrections:null},{id:"70255",title:"Craft Beers: Current Situation and Future Trends",doi:"10.5772/intechopen.90006",slug:"craft-beers-current-situation-and-future-trends",totalDownloads:1344,totalCrossrefCites:3,totalDimensionsCites:9,hasAltmetrics:1,abstract:"During the twentieth century, the consolidation of large multi-national beer companies and the homogenization of the specified beer types have led to a considerable growth in the beer industry. However, the growing demand by consumers of a single and distinctive product, with a higher quality and better sensory complexity, is allowing for a new resurgence of craft beer segment in recent years. This chapter reviews some different alternatives of innovation in the craft brewing process: from the bottle fermented beers with non-Saccharomyces yeast species, to the use of special malts or specific adjuncts, hop varieties, water quality, etc. All of them open a lot of new possibilities to modulate flavor and other sensory properties of beer, reaching also new consumers looking for a specific story in one of the oldest fermented beverages.",signatures:"María Jesús Callejo, Wendu Tesfaye, María Carmen González and Antonio Morata",downloadPdfUrl:"/chapter/pdf-download/70255",previewPdfUrl:"/chapter/pdf-preview/70255",authors:[{id:"180952",title:"Prof.",name:"Antonio",surname:"Morata",slug:"antonio-morata",fullName:"Antonio Morata"},{id:"201383",title:"Prof.",name:"María Jesús",surname:"Callejo",slug:"maria-jesus-callejo",fullName:"María Jesús Callejo"},{id:"201384",title:"Prof.",name:"Carmen",surname:"González",slug:"carmen-gonzalez",fullName:"Carmen González"},{id:"287144",title:"Dr.",name:"Wendu",surname:"Tesfaye",slug:"wendu-tesfaye",fullName:"Wendu Tesfaye"}],corrections:null},{id:"68154",title:"A Comprehensive Overview of the Potential of Tequila Industry By-Products for Biohydrogen and Biomethane Production: Current Status and Future Perspectives",doi:"10.5772/intechopen.88104",slug:"a-comprehensive-overview-of-the-potential-of-tequila-industry-by-products-for-biohydrogen-and-biomet",totalDownloads:820,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Nowadays, the use of agro-industrial by-products as alternative sustainable resources to generate bioenergy and high-value bioproducts is one of the most important research topics to tackle environmental concerns related to the excessive consumption of fossil-based fuels and rapid urbanization and industrialization. This chapter provides a broad overview of the potential of the main tequila industry by-products, agave bagasse and tequila vinasse, for biohydrogen (bioH2) and biomethane (bioCH4) production via dark fermentation and anaerobic digestion, respectively. First, pretreatment or conditioning steps commonly applied to tequila by-product streams before downstream biological processes are highlighted. The operational performance of bioH2- and bioCH4-producing reactors is subsequently reviewed, with a focus on reactor configuration and performance, microbial metabolic pathways, and the characterization of microbial communities. Additionally, the development of multi-stage anaerobic digestion processes is comprehensively discussed from a practical point of view. Finally, limitations and potential improvements in the field of bioH2 and bioCH4 production are presented.",signatures:"Octavio García-Depraect, Daryl Rafael Osuna-Laveaga and Elizabeth León-Becerril",downloadPdfUrl:"/chapter/pdf-download/68154",previewPdfUrl:"/chapter/pdf-preview/68154",authors:[{id:"273360",title:"Dr.",name:"Elizabeth",surname:"León-Becerril",slug:"elizabeth-leon-becerril",fullName:"Elizabeth León-Becerril"},{id:"299053",title:"MSc.",name:"Octavio",surname:"García-Depraect",slug:"octavio-garcia-depraect",fullName:"Octavio García-Depraect"},{id:"306990",title:"MSc.",name:"Daryl Rafael",surname:"Osuna-Laveaga",slug:"daryl-rafael-osuna-laveaga",fullName:"Daryl Rafael Osuna-Laveaga"}],corrections:null},{id:"68047",title:"Biodegradability during Anaerobic Fermentation Process Impacted by Heavy Metals",doi:"10.5772/intechopen.87161",slug:"biodegradability-during-anaerobic-fermentation-process-impacted-by-heavy-metals",totalDownloads:744,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In the past decades, biotechnologies for reutilizing the biomass harvested from the metal-contaminated land draw attention to many scientists. Among those technologies, anaerobic fermentation is proven as an efficient conversion process for biowaste reduction with simultaneous recovery of biogas as an energy source. During the process of anaerobic fermentation, the release of metals from the biomass will impact the growth and performance of microorganisms in reactors, which then results the variation of substrate degradation. In this chapter, the impact of metals on the degradation of substrate at different stages of fermentation process, as indicated by variations of lignocelluloses, chemical oxygen demands (COD), volatile fatty acids (VFAs), etc., will be summarized. The objective is to rationalize the relationship between metal presence and substrate degradability and give suggestions for future research on metal-contaminated biomass reutilization.",signatures:"Yonglan Tian, Huayong Zhang and Edmond Sanganyado",downloadPdfUrl:"/chapter/pdf-download/68047",previewPdfUrl:"/chapter/pdf-preview/68047",authors:[{id:"286598",title:"Dr.",name:"Yonglan",surname:"Tian",slug:"yonglan-tian",fullName:"Yonglan Tian"},{id:"304954",title:"Prof.",name:"Huayong",surname:"Zhang",slug:"huayong-zhang",fullName:"Huayong Zhang"},{id:"304955",title:"Dr.",name:"Edmond",surname:"Sanganyado",slug:"edmond-sanganyado",fullName:"Edmond Sanganyado"}],corrections:null},{id:"69244",title:"Lactic Acid Bacteria as Microbial Silage Additives: Current Status and Future Outlook",doi:"10.5772/intechopen.89326",slug:"lactic-acid-bacteria-as-microbial-silage-additives-current-status-and-future-outlook",totalDownloads:1155,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Silage making is not a novel technique. However, the agricultural industry has made great strides in improving our understanding of—and efficiency in—producing high-quality silage for livestock. Silage microbiology research has been using the newest molecular techniques to study microbial diversity and metabolic changes. This chapter reviews important research that has laid the foundation for field-based utilization of silage inoculants. We also outline areas of current, and future, research that will improve global livestock production through the use of silage.",signatures:"Pascal Drouin, Lucas J. Mari and Renato J. Schmidt",downloadPdfUrl:"/chapter/pdf-download/69244",previewPdfUrl:"/chapter/pdf-preview/69244",authors:[{id:"85142",title:"Dr.",name:"Pascal",surname:"Drouin",slug:"pascal-drouin",fullName:"Pascal Drouin"},{id:"185246",title:"Dr.",name:"Lucas",surname:"Mari",slug:"lucas-mari",fullName:"Lucas Mari"},{id:"308858",title:"Dr.",name:"Renato J.",surname:"Schmidt",slug:"renato-j.-schmidt",fullName:"Renato J. Schmidt"}],corrections:null},{id:"68641",title:"Development of an Anaerobic Digestion Screening System Using 3D-Printed Mini-Bioreactors",doi:"10.5772/intechopen.88623",slug:"development-of-an-anaerobic-digestion-screening-system-using-3d-printed-mini-bioreactors",totalDownloads:924,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"This study incorporated the concept of mini-bioreactors by employing additive manufacturing procedures. Limitations in experimental studies with large-scale equipment favor the use of mini-reactor systems and help to understand the phenomena of its large-scale counterpart better. 3D printing enables to reproduce the reaction engineering principles in a low-cost and ease of manufacture way and expedites the development of novel prototypes. Small anaerobic digesters of 40 mL were designed and fabricated to investigate the effect of downscaling on the stability and performance of the anaerobic digestion process. Baseline tests were conducted using a commercial 400-mL stirred bioreactor as reference for further comparison and validation. Miniature bioreactors showed similar stability and conversion efficiency. However, the biogas production rate and methane content of the 3D-printed bioreactors were lower than those in the baseline study bioreactors. Finally, 3D-printed systems were linked with efficient performances and are considered as an excellent opportunity for analyzing microbe-mediated bioenergy systems. This study demonstrated the high potential of miniaturized bioreactors as a process screening tool.",signatures:"Spyridon Achinas and Gerrit Jan Willem Euverink",downloadPdfUrl:"/chapter/pdf-download/68641",previewPdfUrl:"/chapter/pdf-preview/68641",authors:[{id:"241501",title:"Mr.",name:"Spyridon",surname:"Achinas",slug:"spyridon-achinas",fullName:"Spyridon Achinas"},{id:"299534",title:"Prof.",name:"Gert-Jan",surname:"Euverink",slug:"gert-jan-euverink",fullName:"Gert-Jan Euverink"}],corrections:null},{id:"67920",title:"Streamlining the Fermentation Process Using Mixed Cultures",doi:"10.5772/intechopen.87205",slug:"streamlining-the-fermentation-process-using-mixed-cultures",totalDownloads:805,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Fermentation technology is still being developed in all aspects, with the aim of improving the yields and qualities of products and reducing the costs of production. Increasing the yields of fermentation products can be accomplished by optimizing the factors that influence the process, including both the microbe itself and the environment. For example, the acetic acid production process from raw materials can be performed simultaneously with submerged batch fermentation using mixed cultures of anaerobic and facultative anaerobic S. cerevisiae and obligate aerobic A. aceti. This system is very simple because it only has one stage. In this system, efforts can be made to enhance the yields of acetic acid production, including evaluating the availability of nutrients in the medium and determining the optimum proportion of microbial abundance and agitation speed. Under optimal conditions, the resulting increases in acetic acid yields occur with high conversion efficiency. These results can then be applied on an industrial scale by integrating these findings with advanced technologies in the operating system.",signatures:"Keukeu Kaniawati Rosada",downloadPdfUrl:"/chapter/pdf-download/67920",previewPdfUrl:"/chapter/pdf-preview/67920",authors:[{id:"298463",title:"Dr.",name:"Keukeu Kaniawati",surname:"Rosada",slug:"keukeu-kaniawati-rosada",fullName:"Keukeu Kaniawati Rosada"}],corrections:null},{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",totalDownloads:1474,totalCrossrefCites:3,totalDimensionsCites:9,hasAltmetrics:1,abstract:"Mesenchymal stem cells (MSCs) are advanced therapy medicinal products used in cell therapy applications. Several MSC products have already advanced to phase III clinical testing and market approval. The manufacturing of MSCs must comply with good manufacturing practice (GMP) from phase I in Europe and phase II in the US, but there are several unique challenges when cells are the therapeutic product. Any GMP-compliant process for the production of MSCs must include the expansion of cells in vitro to achieve a sufficient therapeutic quantity while maintaining high cell quality and potency. The process must also allow the efficient harvest of anchorage-dependent cells and account for the influence of shear stress and other factors, especially during scale-up. Bioreactors are necessary to produce clinical batches of MSCs, and bioprocess development must therefore consider this specialized environment. For the last 10 years, we have investigated bioprocess development as a means to produce high-quality MSCs. More recently, we have also used bioreactors for the cocultivation of stem cells with other adult cells and for the production of MSC-derived extracellular vesicles. This review discusses the state of the art in bioprocess development for the GMP-compliant manufacture of human MSCs as products for stem cell therapy.",signatures:"Jan Barekzai, Florian Petry, Jan Zitzmann, Peter Czermak and Denise Salzig",downloadPdfUrl:"/chapter/pdf-download/69881",previewPdfUrl:"/chapter/pdf-preview/69881",authors:[{id:"297959",title:"Dr.",name:"Denise",surname:"Salzig",slug:"denise-salzig",fullName:"Denise Salzig"},{id:"312719",title:"MSc.",name:"Jan",surname:"Barekzai",slug:"jan-barekzai",fullName:"Jan Barekzai"},{id:"312720",title:"MSc.",name:"Florian",surname:"Petry",slug:"florian-petry",fullName:"Florian Petry"},{id:"312721",title:"Dr.",name:"Jan",surname:"Zitzmann",slug:"jan-zitzmann",fullName:"Jan Zitzmann"},{id:"312723",title:"Prof.",name:"Peter",surname:"Czermak",slug:"peter-czermak",fullName:"Peter Czermak"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7012",title:"Biochemical Testing",subtitle:"Clinical Correlation and Diagnosis",isOpenForSubmission:!1,hash:"1aa28a784b136633d827933ad91fe621",slug:"biochemical-testing-clinical-correlation-and-diagnosis",bookSignature:"Varaprasad Bobbarala, Gaffar Sarwar Zaman, Mohd Nasir Mohd Desa and Abdah Md Akim",coverURL:"https://cdn.intechopen.com/books/images_new/7012.jpg",editedByType:"Edited by",editors:[{id:"207119",title:"Dr.",name:"Varaprasad",surname:"Bobbarala PhD",slug:"varaprasad-bobbarala-phd",fullName:"Varaprasad Bobbarala PhD"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editedByType:"Edited by",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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\r\n\tAt first sight, a subject of this book may appear as a rather specialized topic; however, wetting and wettability are fundamental to many important phenomena, including adhesion, penetration of liquids into capillary structures, granulation and agglomeration of fines and powders, interfacial chemical reactions, spreading and retention of liquid sprays on the surface, particle floatation, cleaning, printing and so on. Wetting is also an indispensable part of fluid rheology and fluid dynamics. Therefore, it is an influential theme with countless practical applications including biology, pharmacy, healthcare, agrochemistry, petrochemistry, minerals and metals, ceramics, polymers, coatings, fibers, adhesives, etc. Even though wetting and wettability have been studied since long ago, this remains a very booming research area that reveals new opportunities for discoveries and innovations related to the nanoscale, advanced materials, novel measurement, characterization techniques, and data processing.
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In 1985, he received a Ph.D. degree from the Dnipropetrovsk Metallurgical Institute (known since 1999 as the National Metallurgical Academy of Ukraine and since 2021 as the Ukrainian State University of Science and Technology). In 1998, he received the title of professor with the Ironmaking Chair. During 1999–2002, he was the dean of the Metallurgical Faculty. During 2002-2021, he was the vice-rector for Research and Education. Since 2022 he is a professor of the Ironmaking & Steelmaking Department. His research deals mainly with the properties of iron ore materials, physicochemical processes of ironmaking, recycling methods, sustainability analysis, etc. He is the author of over 180 research papers, 7 books, and 7 patents. He is the honorary professor at the Inner Mongolia University of Science and Technology, China, and a visiting professor at the University of Tokyo (2013). 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The ecological functions of the silk fibers are closely related to their properties. For example, orb-weaving spiders produce a variety of different silks with diverse properties, each tailored to achieve a certain task (Figure 1) [1]. Most arthropod species produce silks used for building structures to capture prey and protect their offspring against environmental hazards [2]. The most investigated categories that have piqued the greatest amount of interest are spider silk and dragline silk in particular, produced by major ampullate glands and the cocoon silk of
In contrast petrochemical-based synthetic polymers commonly used today, such as polyethylene, which is formed by polymerization of ethylene at high temperature and pressure, or under the presence of some metal-based catalysis,
Schematic overview of different silk types produced by female orb-weaving spiders (
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t | \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t7 | \n\t\t\t0.6 | \n\t\t\t18 | \n\t\t\t70 | \n\t\t
\n\t\t\t\t | \n\t\t\t15 | \n\t\t\t0.7 | \n\t\t\t28 | \n\t\t\t150 | \n\t\t
\n\t\t\t\t | \n\t\t\t10 | \n\t\t\t1.1 | \n\t\t\t27 | \n\t\t\t180 | \n\t\t
\n\t\t\t\t | \n\t\t\t0.003 | \n\t\t\t0.5 | \n\t\t\t270 | \n\t\t\t150 | \n\t\t
Wool (at 100% RH[b]) | \n\t\t\t0.5 | \n\t\t\t0.2 | \n\t\t\t5 | \n\t\t\t60 | \n\t\t
Elastin | \n\t\t\t0.001 | \n\t\t\t0.002 | \n\t\t\t15 | \n\t\t\t2 | \n\t\t
Nylon fiber | \n\t\t\t5 | \n\t\t\t0.95 | \n\t\t\t18 | \n\t\t\t80 | \n\t\t
Kevlar 49 fiber | \n\t\t\t130 | \n\t\t\t306 | \n\t\t\t2.7 | \n\t\t\t50 | \n\t\t
Carbon fiber | \n\t\t\t300 | \n\t\t\t4 | \n\t\t\t1.3 | \n\t\t\t25 | \n\t\t
High-tensile steel | \n\t\t\t200 | \n\t\t\t1.5 | \n\t\t\t0.8 | \n\t\t\t6 | \n\t\t
Artificial spinning is the most promising method of promoting the application of silk fibers, as it can output sufficient man-made fibers cost-effectively and with specific tailored properties. Remarkable efforts for silk fiber reproduction via reconstituted/recombinant silk fibroin are currently underway [9, 10]. Reconstituted silk protein is derived from
Thanks to recent developments in modern analytical techniques, significant progress has been made with respect to the structural characterization of silk. These techniques can provide molecular information about silk, including microscopic methods (atomic force microscopy (AFM), scanning and transmission electron microscopy (SEM and TEM), and scanning transmission x-ray microscopy (STXM)) and synchrotron x-ray diffraction (wide-angle x-ray diffraction (WAXD) and small-angle x-ray scattering (SAXS) combined with synchrotron radiation). Solid-state nuclear magnetic resonance (SS-NMR) is a powerful technique because it allows for the study of molecular structure and dynamics of semi-crystalline and amorphous materials. Raman and FTIR spectroscopy can provide the dominant conformational contents of a fiber. Raman microspectroscopy can be used to determine quantitative parameters characterizing the molecular structure (orientation and conformation, amino acid composition) of micrometer-sized biological samples. In this chapter, we will provide an overview of the current understanding of the silk fibers’ structure taken advantage of these analytic methods, then describe in detail the structure-property relationships and the formation processes of silk fiber. Additionally, we will explore material morphologies and applications of these silk fibers.
The structure-property relationship is one of the most intriguing ‘mysteries’ of silk fibers. Various studies have suggested that there is a strong connection between the structures of silk fibers and their physical (e. g., mechanical) properties. An understanding of the structure-property relationship requires background knowledge of local structure, including the component and composition of silk fiber, the conformation and orientation of constitutive units with respect to the fiber, and so on.
In principle, the full range of properties of silk fibers can be calculated from their structural morphology and chemical composition. On the macroscopic level, the morphological structure of
Examples of silk fibers produced by silkworms and spiders and a schematic illustration. (Reprinted from Ref. [
Silk fibers are normally polyamino acid-based fibrous proteins. In contrast, the synthetic polymers, which are usually homopolymers or copolymers consisting of one or several simpler monomer, the biopolymers − silk fibers, the primary sequence and linkage between the monomers are arranged in a strictly controlled manner and are responsible for the formation of well-defined structure [13]. A range of microscopy methods, including SEM, TEM, and AFM, have been used to investigate the microstructure of silk fiber [14-19]. The results confirmed that silk fibers are composed of well-oriented bundles of nanofibrils. Generally, the coatings of silk fibers function as glue. The sericin coating, which occupies 25-30% of the weight of
As two major families of silk proteins, fibroin is the chief component of silkworm silk fiber, while spidroin (also named spider fibroin) is the analogue in spider silk fiber. The
(a) Silkworm fibroin consisting of a covalently linked highly repetitive heavy and non-repetitive light chain. (b) Spider silk spidroins consist of a large repetitive core domain flanked by non-repetitive amino-(NRN) and carboxy-terminal (NRC) domains. (Figure slightly modified with permission from Ref. [
The primary sequence plays an important role in defining basic materials. Despite being quite different in their primary structure,
Typical amino acid sequences of repetitive core of
The primary structural motifs have a preferred secondary structure and give rise to structures higher up the hierarchy. NMR, circular dichroism (CD), IR and Raman spectroscopy were usually used to examine the chemical, conformational, and orientational information of secondary structures for silk proteins [41-51]. There are three major conformations of silk proteins: the random coil, the
The solid threads are characteristic of well-oriented
It is quite firmly believed that the (Ala)n domains in spider dragline silk fibers adopt a
It is expected that the mechanical properties of silk fibers will critically depend on the characters of
The non-crystalline regions are often described as amorphous, poorly orientated, or randomly coiled sections of the peptide. The structural organization in the amorphous phase is not well understood yet. The existence of
Recent computational approaches have been useful in modeling nanostructure of silk. Molecular modeling integrated the information known about the structures, and has been used to characterize the nanostructure of the silk. Based on a bottom-up molecular computational approach using replica exchange molecular dynamic, Keten
(a) The hierarchical structure of spider dragline and silkworm silk fiber. Both spider dragline and fibroin are composed of numerous minute fibrils, which are separated into crystalline and amorphous segments. (b) The minute fibrils in silkworm
According to the prevalent characterizations mentioned above, silk fiber is considered a semicrystalline polymer with a hierarchical structure in which highly oriented
Spider silk and
The mechanical properties of silk fibers can be described by stress-strain curve profiles, which are generated by stretching the fibers at a specific strain rate. The stress is expressed as force per cross-sectional area and the strain is defined as a normalized extensibility. Typical stress-strain curves for
Evidently, the attractive macroscopic mechanical properties of silk fiber can be ascribed to the structural effects. Most of the attention has focused on the nanometer scale: predominantly, primary and secondary structure, as well as organization and arrangement of protein molecules. In terms of primary structure of silk proteins, amino acid composition, sequential order and the number of the motifs in each module are important for the mechanical properties of the final fibers. For example, the primary structure of
The mechanical properties of silk fibers, also depend crucially on spinning conductions, such as humidity, temperature, and reeling speed, and so on [19, 104]. Variations in crystallinity and alignment can be found within the silk fiber due to variations in reeling speed of the collected sample. These variations have been mapped to mechanical properties by affecting the formation of the
Modern analytical technologies and tools have steadily contributed to the progress in experimental studies of the structure of silk fibers, as described above. However, it is still no consensus on the hierarchical structure of silk at the nanometer scale. Some models have been proposed to interpret the structure-property relationship of silk fibers. The first such model was Termonia’s early model [64]. The model hypothesized that silk is a hydrogen-bonded amorphous phase with embedded stiff crystal domains acting as multifunctional cross-links and creating a thin layer of high modulus in the amorphous regions. The stiff hydrogen bonds are first broken to give the fiber its high initial modulus. Meanwhile, it allows the dynamic rubber phase to redistribute the deformation field for prediction of the nonlinear large strain deformation. The simulated properties based on the theoretical model properly reproduce the combination of high initial modulus, strength and toughness of dragline silk fiber. However, in this model, a theoretical modulus of 160 GPa for rigid
Multi-scale experimental and simulation analyses are the key to improve our systematic understanding of how structure and properties are linked. The mechanical mechanism at the macroscopic scale, namely, the fibril, including morphology and its consequence for mechanical behavior and the mechanistic interplay with nanostructure of silk, has also been elucidated [115-117]. At the same time, many experiments have been employed to assess the effect of structural changes on the mechanical deformation of silk [118-121]. When mechanical load are applied to the fibers, conformation, reorientation, crystallite size, and some other structural characters are monitored to explain the structure-property relationships.
A schematic model demonstrating how the silkworm and spider dragline fibers respond when they are subjected to stretching. There are two components in the alanine-rich regions of spider dragline silk:
The experimental and computational investigations shown above have explored mechanical properties of
Furthermore, unlike
The remarkable mechanical properties of silk fibers have spawned great interests in determination of their origin. Systematic studies of the natural spinning process of silk fibers have shown a highly sophisticated hierarchical process, allowing for the transformation of soluble silk protein into solid fibers with specific mechanical and functional properties. Although much is already known about the characteristics of the silk proteins and silk fibers themselves, the process for silk assembly and spinning into fibers is yet to be resolved. A detailed knowledge of silk fiber formation is critical for the biomimetic production of tough silk-like fibers.
In nature, silk proteins are secreted and stored in the glands until they are processed into fibers. Morphological and histological studies demonstrate that the silk glands of
The major gland responsible for the dragline silk of
The formation of a solid fiber from soluble silk proteins is a remarkable process owing to complex biochemical and physical changes. For silk spinning, several assembly models, such as liquid spinning theory [136] and micelle theory [144] have been proposed for the fiber formation, whereas the details remain to be elucidated. In order to understand the mechanisms of silk proteins assembly and fiber formation, the structure of proteins stored in
It has reported that
Schematic formation mechanism of the hierarchical assembly from molecular silk fibroin to microfibers.(Reprinted from Ref. [
Experiments made
Actually, the chemical and mechanical stimuli together are likely to influence the fold of nonrepetitive amino-terminal and carboxy-terminal and the hydrophilic spacers within the hydrophobic core domain [37, 135, 158, 164-166]. Due to the larger hydrophilic blocks at the chain ends of the protein molecules having charged groups, it is possible that they might play an important role in the molecular assembly and conformational transition at a specific pH through decreased electrostatic repulsion. A significant step towards understanding the effect of the terminal domains in assembly was the determination of atomistic structures of the nonrepetitive terminal regions of MaSp proteins. Kessler and Scheibel’s group reported the structure of carboxy-terminal domain of
Traditionally, silk has been utilized in the construction of textiles. Current research in silk fibers involves their innovative trends and advanced applications. Basically, the rich proportion of essential amino acids in silk fibers indicates high nutritive value, meaning that silk fibroin can be used as a dietary additive [167-169]. Furthermore, the amino acids, glycine, alanine, serine and tyrosine are of vital for nourishing the skin. The crystalline structure of silk protein reflects UV radiation, acting as protective buffer between the skin and environment. The extracts of silk protein are used in soap making, personal care and cosmetic products. The silk protein is also applied to enhance glossy, brightness, and softness of products. In addition, the production of advanced man made super-fibers such as Kevlar involves petrochemical processing, which contributes to pollution. Interest in silk fibers is mainly due to the combination of the mechanical properties and eco friendly way in which they are made. Spider silk fibers have been envisioned to be applied in a variety of technical textiles, including parachute cords, protective clothing and composite materials in aircrafts, which demand high toughness in combination with sleaziness.
Possible structure and technical applications of the silk fibers. The dotted line shows an example of the versatility of silk and the multiple possible applications. (Figure slightly modified with permission from Ref. [
Silks are biocompatible, biodegradable and have implant ability, as well as morphologic flexibility. Silk fiber has been used as extremely thin suture for eye or nerve surgery for long history [170]. Nowadays, one attractive application of silk fibers is act as a source of novel biomaterials. Recent progress with processing of silk fibers into various material forms, usually via the formation of the fibroin/spidroin solution, including thread, hydrogels, tubes, sponges, microspheres, particles and films [9, 171], promotes the field of applications for silk fibers in general (Figure 8) [172]. Silk protein can be modified by chemical treatment or used in combination with other materials and the silk-based biomaterials have been transformed for high-technology uses, with promising futures in the fields of biomedicine and material engineering. Numerous studies have demonstrated that fibroin supports cell attachment and proliferation for a variety of cell types [173-178]. Studies have established a potential for silk-based biomaterials use as tissue engineering scaffolds, such as skeletal tissue like bone [179], ligaments [180], and cartilage [181, 182], as well as skin [183], blood vessels [184] and nerve [185]. Silks can be designed and offer another biomedical applications, such as delivery of small molecule drugs, proteins and genes [186]. Silk fibroin possesses remarkable optical properties, such as near-perfect transparency in a visible range. It has been identified as a suitable material for the development of biophotonic components [187-189] in biomedical device performing electronics or sensors [190-198]. Surely, these impressive biopolymers are extremely promising for their potential applications in material science and engineering.
Our review in current chapter concentrated on
The authors thank the financial support from the National Science Foundation of China (NSFC) under Grant 51073113, 91027039 and the Natural Science Foundation of the Jiangsu Higher Education Institutions of China under Grant 10KJA540046. This work was also supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). We also acknowledge support from the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Qing Lan Project for Excellent Scientific and Technological Innovation Team of Jiangsu Province (2012) and Project for Jiangsu Scientific and Technological Innovation Team (2013). The author, Xinfang Liu, especially thank the support of the Postdoctoral Science Foundation of Jiangsu province (No. 1201030B).
Macrophages represent up to 50% of the cells infiltrating into the tumor microenvironment (TME) and modulation of macrophage polarization is an interesting and novel therapeutic approach in preclinical or clinical cancer research.
An increasing number of studies have also shown that tumor-associated macrophages (TAMs) can antagonize, augment or mediate the antitumor effects of cytotoxic agents, tumor irradiation, anti-angiogenic/vascular damaging agents and checkpoint inhibitors [1].
In the tumor microenvironment, TAMs are one of the major contributors in
TAMs often exhibit an array of activation states. In general, they are skewed away from the “classically” activated, tumoricidal phenotype (sometimes referred to as M1) toward an “alternatively” activated tumor-promoting one (M2) [1]. The classically activated M1 macrophages are stimulated by microbial substrates such as lipopolysaccharide, Toll-like receptor ligands and cytokines such as IFN-γ. They are characterized by secretion of pro-inflammatory cytokines such as interleukins IL-6, IL-12, IL-23 and TNF-α and express high levels of major histocompatibility complex class II (MHC-II), CD68, and CD80 and CD86 costimulatory molecules. The alternatively activated M2 macrophages are stimulated by IL-4 and IL-13, secrete IL-10 and TGF-β and express low levels of MHC-II and feature expression of CD163 and CD206 [3].
Unfortunately, M2 cells are the most representative cells of the TAM population within the tumor promoting genetic instability, local immunosuppression and stem cell nurturing [4] and providing essential support for a malignant phenotype [5].
In the early stages of cancers of the lung, colon and stomach, the macrophages in the normoxic milieu display an M1 phenotype and are associated with good prognosis, but within avascular areas of the tumor, TAMs alter the gene expression profile, favoring a protumor M2 phenotype, correlated with a bad prognosis [6]. In Table 1 are showed recent conclusions concerning the correlation between TAMs and clinical prognostics in several tumor types. In human breast carcinomas, high TAM density is also associated with poor prognosis [7]. TAMs in renal cell carcinoma show a mixed M1/M2 phenotype. CD68 alone has a poor predictive value, while low CD11+ and high CD206+ as single variables correlated with reduced survival [8]. There is strong evidence for an inverse relationship between TAM density and clinical prognosis in solid tumors of the breast, prostate, ovary and cervix. Type I and II endometrial carcinomas had significantly higher macrophage density in both epithelial and stromal compartments than benign endometrium [9]. Type II cancers have nearly twice the TAM density of type 1 cancers and this difference may be due to M1 macrophage predominance in the stroma of type II cancers [10].
Cancer type | TAMs as prognostic factors | Reference |
---|---|---|
Breast | CD68 as a biomarker for TAMs to evaluate the risk is better than CD163 or CD206 alone; high infiltration of TAMs was significantly associated with negative hormone receptor status and malignant phenotype | [18] |
Gastric | The amount of TAMs in tumor stroma predicts the size, stage and metastasis of the gastric tumor Invasive front-/stroma-dominant pattern having worse outcomes Although CD68+ TAMs infiltration has the neutral prognostic effects on OS, the M1/M2 polarization of TAMs are predicative factors of prognosis in gastric cancer patients | [11, 12, 19] |
Lung | The prognostic value of tumor-infiltrating TAMs in lung cancer is still controversial. M2 subset and TAMs in tumor stroma were associated with worse survival, while M1 subset and TAMs in tumor islet were associated with favorable survival of lung cancer. CD204-positive TAMs are the preferable marker for prognostic prediction in NSCLC Although the density of total CD68+ TAMs is not associated with overall survival, the localization and M1/M2 polarization of TAMs are potential prognostic predictors of NSCLC | [13, 20, 21] |
Cervix | Tumor-infiltrating CD204+ M2 macrophages may predict poor prognosis in patients with cervical adenocarcinoma | [22] |
Ovarian | CD163+ TAM infiltration was associated with poor prognosis of ovarian cancer and high M1/M2 macrophage ratio in tumor tissues predicted better prognosis | [23] |
Pancreatic | Although TAM populations in tumor stroma are high, marking them as a probable prognostic factor, the multiple roles that TAMs play in pancreatic cancer progression have not yet been delineated. Additional mechanistic insight into the pathways that regulate the differentiation of TAMs from monocytes is required The density of TAMs has an impact on the overall survival of pancreatic cancer patients. M2-TAMs can be recognized as a prognostic indicator in pancreatic cancer | [24, 25] |
Renal | CD68 alone has a poor predictive value, while low CD11+ and high CD206+ as single variables correlated with reduced survival | [8] |
Glioblastoma | TAM, accounting for approximately 30% of the GBM bulk cell population, may explain, at least in part, the immunosuppressive features of GBMs | [26] |
Hepatocellular carcinoma | The prognostic value of TAMs in patients with hepatocellular carcinoma (HCC) is still controversial. TAMs could serve as independent predictive indicators and therapeutic targets for HCC. Further trials are needed to elucidate the exact relationship and the underlying mechanism | [27] |
Melanoma | Independent of their intratumoral distribution, the prevalent accumulation of M2 TAMs in MM is statistically confirmed to be a poor indicator of patients’ outcome | [28] |
Non-Hodgkin’s lymphoma | High-density CD68+ and CD163+ TAMs, and also high CD163+/CD68+ TAMs ratio is significantly correlated with poor overall survival | [29] |
Hodgkin’s lymphoma | High density of either CD68+ or CD163+ TAMs is a robust predictor of adverse outcomes in adult cHL | [30] |
Colorectal (CRC) | The role of tumor-associated macrophages (TAMs) in predicting the prognosis of CRC remains controversial. Still, high-density CD68+ macrophage infiltration can be a good prognostic marker | [31] |
Squamous cell carcinoma of the head and neck (SCCHN) | CD68+ marker has no prognostic utility in patients with SCCHN; the M2-like marker CD163+ predicts poor prognosis | [32] |
TAMs as potential predictive indicators in several tumor types.
TAMs’ distribution pattern could be an independent prognostic factor for the overall survival of gastric cancer patients, invasive front-/stroma-dominant pattern having worse outcomes [11]. Studies have shown that the amount of TAMs in tumor stroma predicts the size, stage and metastasis of the gastric tumor [12]. In lung cancer, M2 subset and TAMs in tumor stroma were associated with worse survival, while M1 subset and TAMs in tumor islet were associated with favorable survival of lung cancer [13].
While most cancer research has focused upon these changes and most therapeutics are directed against these tumor cells, it is now apparent that the non-malignant cells in the microenvironment evolve along with the tumor and provide essential support for their malignant phenotype [5]. The knowledge of TAM activation status may allow the therapeutic targeting of TAMs, once TAMs’ targeting/modulating agents pass clinical trials and become widely available [6, 14]. The role of macrophages in tumor progression remains to be fully elucidated, in part due to the contrasting roles they play depending on their polarization [15]. Both the systemic and local environments play a tumor-initiating role through the generation of persistent inflammatory responses to a variety of stimuli [16]. To support this correlative data between macrophage-mediated inflammation and cancer induction, genetic ablation of the anti-inflammatory transcription factor STAT3 in macrophages results in a chronic inflammatory response in the colon that is sufficient to induce invasive adenocarcinoma. However, it is unclear whether macrophages in some inflammatory situations can kill aberrant cells before they become tumorigenic and thus be antitumoral [17].
Targeting a single signaling axis that promotes the immunosuppressive and protumoral functions of macrophages is inadequate as there are multiple signals involved in the communication between tumor cells and TAMs. Identifying and inhibiting key driver pathways, which are critical for both cancer cell survival and TAM activation, may offer therapeutic advantages as they disrupt the vicious positive feedback loop between tumor and TAMs [33]. Prevention of TAM accumulation and reduction of TAM presence by depleting existing TAMs represent novel strategies for an indirect cancer therapy specifically aimed at tumor-promoting cells within the microenvironment, but the challenge with this approach is to find ways for local administration of such drugs to the tumor [15]. Targeting TAM polarity toward an M1 phenotype also became a real immunotherapeutical approach in cancer, recalling responses from both innate and adaptive immune systems, leading to tumor regression [4].
Triple combination of anti-CTLA-4, anti-PD-1 and G47Δ-mIL12 was associated with macrophage influx and M1-like polarization in two glioma models [34]. A combination of a bivalent ganglioside and β-glucan, a yeast-derived polysaccharide, able to differentiate TAMs into an M1 phenotype is currently under investigation in a phase I clinical trial of patients with neuroblastoma [35]. Vadimezan, a fused tricyclic analog of flavone acetic acid, was found to repolarize macrophages in M1 phenotype, and it has been the subject of numerous preclinical studies and clinical trials [36]. Zoledronic acid, a clinical drug for cancer therapy, has been found to inhibit spontaneous mammary carcinogenesis by reverting macrophages from the M2 phenotype to the M1 phenotype [37].
Research to date suggests that, despite the potency of cytotoxic anticancer agents and the high specificity that can be achieved by immunotherapy, neither of these two types of treatment is sufficient to eradicate the disease. Moreover, even in standard chemotherapy, there has been efficiency through the introduction into current practice of treatments with combinations of drugs [38]. In general, literature data show that the combination of conventional treatment with natural compounds exerts an additive effect caused by the alternative activation of signaling pathways that induce cell death or increase the activity of the chemotherapeutic agent. The involvement of these natural compounds (alone or in combination therapy) in the immunobiology of cancer is a branch that has not yet been studied but offers major therapeutic opportunities. Herbal compounds have many regulatory effects on macrophage polarization, but the specific mechanisms, signaling pathways and target genes involved remain incompletely understood [39]. Their effects, according to recent research studies, are summarized in Figure 1.
Herbal compounds and their main actions on TAMs in cancer progression.
Although natural products have historically been a critical source for therapeutic drugs, sometimes natural molecules may suffer from insufficient efficacy, unacceptable pharmacokinetic properties, undesirable toxicity or reduced availability, which impedes their direct therapeutic application. Poor availability of some natural compounds, despite their pharmacological effects, limits their clinical application. In recent years, there has been an increased interest in developing nanoformulations with increased bioavailability and fewer side effects. For instance, TAM-rich tumors, due to their enhanced permeability, demonstrated an elevated retention (>700%) of the nanotherapeutic (poly(d,l-lactic-
Triterpenic compounds, including corosolic acid, tigogenin, timosaponin AIII, neoaspidistrin and oleanolic acid, suppress the CD163 expression. Corosolic and oleanolic acids change M2 polarization to M1 polarization in human monocyte-derived macrophages (HMDMs) by suppressing STAT3 and NF-kB activation. The effects of these two compounds were exerted not only on macrophages but also on glioblastoma cells, suppressing tumor cell proliferation and sensitizing tumor cells to anticancer drugs [40, 41].
M2 polarization was switched also by astragaloside IV (AS-IV, 3-O-β-d-xylopyranosyl-6-O-β-d-glucopyranosyl cycloastragenol), a natural saponin extracted from
A potential role of celastrol, a pentacyclic triterpenoid in antimetastasis treatment, was suggested by Yang et al. [45], which found that this compound suppresses M2-like polarization by interfering with STAT6 signaling pathway after stimulation with IL-13. An active role in decreasing macrophage recruitment and tumor angiogenesis was showed for lupeol and stigmasterol in an
Treatment with 9-hydroxycanthin-6-one, a β-carboline alkaloid isolated from the
A regulatory effect on macrophage differentiation during tumor development exerts phlenumdines E, A, hupermine A and 12-epi-lycopodine-N-oxide isolated from the club moss
Sophoridine, a bioactive alkaloid extracted from the seeds of
In a model of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis, it was showed that isoliquiritigenin (6′-deoxychalcone) inhibits M2 macrophage polarization depending on the downregulation of the IL-6/STAT3 pathway [50]. The same mechanism was proposed by Sumiyoshi et al. [51], for xanthoangelol and 4-hydroxyderricin, chalcones isolated from
Macrophage infiltration and differentiation of macrophages into tumor-promoting M2 macrophage were decreased by epigallocatechin gallate (EGCG) treatment in murine tumor models and the molecular mechanism proposed was the downregulation of NF-κB pathway [53, 54]. EGCG can be rapidly degraded
Luteolin, 3 0,4 0,5,7-tetrahydroxyflavone, is a common flavonoid derived from various plants and inhibits IL-4–induced phosphorylation of STAT6 and the TAM phenotype, ameliorating the recruitment of monocytes and the migration of lung cancer cells by the reduction of chemokine CCL2 secretion from macrophages [56]. The antitumor mechanism of luteolin in non-small cell lung carcinoma (NSCLC) was mediated by downregulation of TAM receptor tyrosine kinases (RTKs), and it was found to decrease the protein levels of all three TAM RTKs in the A549 and A549/CisR cells in a dose-dependent manner [57]. In an
The regulation of M2 macrophage repolarization through inhibiting PI3K/Akt signal pathway is the mechanism proposed for baicalein (5,6,7-trihydroxyflavone), a widely used Chinese herbal medicine derived from the root of
It has been reported that a novel chrysin (5,7-dihydroxyflavone) analog 8-bromo-7-methoxychrysin has anticancer activities with more potent bioactivity than the lead compound [60]. It also has the capacity to regulate the tumor microenvironment by inhibition of NF-κB activation, suppressing significantly the expression of the M2 macrophage marker CD163 and modulating the secretion profile of TAM cytokines [61].
According to traditional Chinese medicine (TCM) theory, herbs with Qi-tonifying character are involved in improving the defense capacity of immune system. Total flavonoids from
Naringin (4′,5,7 trihydroxyflavanone-7-rhamnoglucoside) exert a potential inhibitory effect on tumor progression by inducing CD169-positive and M1-like macrophages, potentially correlating with cytotoxic T-cell activation [63].
Puerarin [4H-1-benzopyran-4-one, 8-β-d-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)] is the major bioactive ingredient isolated from the root of traditional Chinese medicine Ge-gen (
Another isoflavone, genistein, can inhibit the increased M2 polarization of macrophages and stemness of ovarian cancer cells by co-culture of macrophages with ovarian cancer stem-like cells through disrupting IL-8/STAT3 signaling axis [65].
Chlorogenic acid (5-caffeoylquinic acid, CA), the ester of caffeic acid, is a phenolic compound widely found in plants. It was showed that this compound inhibits growth of G422 glioma
Deoxyschizandrin, a major dibenzocyclooctadiene lignan present in
Several studies focused on a stilbene derivative, resveratrol (3,4′,5-trihydroxystilbene), a widely studied compound that exhibits potent preventive effects on lifestyle-related disorders such as hyperlipidemia, obesity, coronary heart disease and cancer, as well as on aging. In lung cancer tumors, resveratrol induced their sluggish growth by decreasing F4/80 positive expressing cells and M2 polarization (lower expression of M2 markers‑IL-10, Arg-1 and CD206), probably by STAT3 suppression [69]. Antitumor and antimetastatic effects of resveratrol (25 and 50 μM) based on the regulation of M2 macrophage activation and differentiation were confirmed by Kimura and Sumiyoshi [70], which also conducted a study for correlation of stilbene structure with biological activity. Among the nine stilbenes examined, 2,3-,3,4-, and 4,4′-dihydroxystilbene inhibited the production of MCP-1 in M2-polarized THP-1 macrophages at a concentration of 50 μM, demonstrating that the inhibitory effects of stilbenes with dihydroxy groups on the production of MCP-1 were greater than those with mono-hydroxyl groups. Dihydroxystilbene at 25 and 50 μM, 3,4-dihydroxystilbene at 50 μM, and 4,4′-dihydroxystilbene at 10, 25 and 50 μM significantly inhibited the production of IL-10 by M2 THP-1 macrophages. The three dihydroxystilbenes, 2,3-, 3,4-, and 4,4′-dihydroxystilbenes, at concentrations of 10–50 μM inhibited p-STAT3 increase during M2 THP-1 macrophage differentiation induced by IL-4 plus IL-13 [71].
The resveratrol analogue, HS-1793 (4-(6-hydroxy-2-naphthyl)-1,3-benzenediol), was also shown to elevate the level of IFN-γ production conducting reprograming of TAMs M2 phenotype [72].
Curcumin ((1
It was showed that TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate (molar ratio C:E:R: 4:1:12.5) can shift TAM polarity in HPV-positive HNSCC by silencing the M2 TAM and activating/recruiting a discrete population of M1 TAM while maintaining a constant number of overall intra-tumor Iba1+ TAM, along with expression of activated STAT3 and induction of activated STAT1 and NF-kB (p65) [77]. Moreover, a liposomal formulation of TriCurin with increased bioavailability (TrLp) was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells [78].
In a urethane-induced lung carcinogenic model, lung carcinogenesis was ameliorated with increased M1 macrophages and decreased M2 macrophages in the lung interstitial by administration of 6-gingerol ((
Also, it was showed that paeoniflorin, one of the major active constituents of
It was suggested that modulation of TAM polarization was implicated in the antitumor immunostimulatory activity of polysaccharides from
In a murine model of sarcoma, immunotherapy with IAPS-2 (acidic polysaccharide, namely IAPS-2, from the root of
Esculetin (6,7-dihydroxycoumarin) and fraxetin (6-methoxy-7,8-dihydroxycoumarin) (50, 75 and 100 μM) inhibited the production of IL-10, MCP-1 and TGF-β-1 in macrophages and the phosphorylation of STAT 3 without affecting its expression during the differentiation of M2 macrophages. Esculetin also suppressed the increased production of these cytokines during M2 macrophage differentiation at 10–100 μM. On the other hand, daphentin (7,8-dihydroxycoumarin) had no such effects, revealing that coumarins with two hydroxyl groups at the 6 and 7 positions (esculetin) or coumarins with a methoxy group at the 6 and two hydroxyl groups at the 7 and 8 positions (fraxetin) are more active, exhibiting antitumor and antimetastatic actions in osteosarcoma LM8 cells [85]. The antitumor and antimetastatic actions of esculetin may be due to the dual actions at tumor and TAM sites: inhibition of the expression of cyclin D 1 and CDK4 in osteosarcoma LM8 cells, and also decreasing the STAT 3 phosphorylation in macrophages. In the case of fraxetin, the effects are partly attributed to the inhibition of M2 macrophage differentiation [85].
A classical formula of traditional Chinese medicine (TCM) to alleviate lung cancer–related symptoms is Bu-Fei decoction (BFD), consisting of six herbal Chinese medicines‑
It has been shown that emodin (6-methyl-1,3,8-trihydroxyanthraquinone), the active ingredient of several Chinese herbs including Rhubarb (
In oral squamous cell carcinoma (OSCC) animal models, highly pure super critical CO2 leaf extract of
Onionin A (ONA), a natural low molecular weight compound containing sulfur isolated from onions, inhibited the EOC cell-induced M2 polarization of HMDMs, and STAT3 activation was significantly inhibited by ONA treatment in all cell lines [92].
Adjunctive treatment with Withaferin A, the most abundant constituent of
Traditional Chinese medicine provides pharmacologically efficient preparates such as KSG-002, a hydroalcoholic extract of radices
Traditional Chinese medicine Jianpi Yangzheng Decoction (JPYZ) used for improving the quality of life and prolonging the survival of gastric cancer patients was more effective compared with Jianpi Yangzheng Xiaozheng Decoction (JPYZXZ) for inducing the phenotypic change in macrophages from M2 to M1. JPYZXZ inhibits the gastric cancer EMT more effectively than JPYZ, but JPYZ primarily works to regulate the phenotypic change in macrophages from M2 to M1 [96].
CXCL-1 was also found to be a cytokine secreted by tumor-associated macrophage, which recruits myeloid-derived suppressor cells to form pre-metastatic niche and led to liver metastasis from colorectal cancer. The current study demonstrated that after administration of XIAOPI formula (consisting of 10 herbs including
Macrophages, as key players in the tumor microenvironment, play essential roles in maintenance and progression of malignant state. Due to their plasticity, these cells balance between pro- and antitumoral effects in close correlation to specific factors. Recent immunotherapeutic strategies focus on tumor-associated macrophages in two main directions: to inhibit protumor macrophages and their suppressive effects (CCL2 inhibitors, trabectedin, zoledronic acid, JAK/STAT inhibitors, etc.) and to activate TAMs to an antitumor phenotype (TLR and CD40 agonists, PI3kδ inhibitor, VEGF and Ang2 inhibitors, etc.).
Several natural compounds/herbal extracts were studied as therapeutic/supportive agents for macrophage modulation in different types of cancers, most of them being able to change M2 polarization (protumoral) to M1 polarization (antitumoral). They belong to various classes of herbal compounds: saponins (corosolic and oleanolic acids, astragaloside, ginsenosides, celastrol, etc.), alkaloids (9-hydroxycanthin-6-one, phlenumdines E, A, hupermine A and 12-epi-lycopodine-N-oxide, sophoridine, etc.), flavonoids and polyphenolcarboxylic acids (isoliquiritigenin, xanthoangelol and 4-hydroxyderricin, baicalein, naringin, genistein, deoxyschizandrin, chlorogenic acid, curcumin, 6-gingerol and paeoniflorin), polysaccharides (isolated from various vegetal sources), coumarins (esculetin, fraxetin, etc.), and anthraquinones (emodin). This action is most probably achieved by downregulation of the STAT3, STAT 6 and NF-kB pathways with consecutive modulation of the secretory profile of TAM cytokines.
TCM supports the dual approach of cancer therapy, to destroy cancer cells on one hand and to improve patients’ immunological status on the other hand. For several preparations such as Jianpi Yangzheng Decoction, Bu-Fei decoction and XIAOPI formula, research studies proved the correlation between cancer cells and tumor microenvironment and the effective intervention of these herbal products in delaying/breaking the tumorigenic process.
Low solubility of some herbal compounds limits their clinical application and it conducted to designing of new analogs with improved bioavailability‑ginseng-derived nanoparticles, peracetate-protected EGCG, chrysin and resveratrol analogs.
By now, many herbal compounds have been shown to exhibit antitumor effects in various cancer types. Further, more researches need to be focused on the influence of these valuable compounds/preparations on modulation of the tumor microenvironment, as key element in the relation of tumor-host.
This research was financially supported by the Ministry of Research and Innovation in the frame of the project PN.16.41.01.01/2018, CORE Program.
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While manufacturing nonwovens, some conventional textile operations, such as carding, drawing, roving, spinning, weaving or knitting, are partially or completely eliminated. For this reason the choice of fiber is very important for nonwoven manufacturers. The commonly used fibers include natural fibers (cotton, jute, flax, wool), synthetic fibers (polyester (PES), polypropylene (PP), polyamide, rayon), special fibers (glass, carbon, nanofiber, bi-component, superabsorbent fibers). 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Various textile production methods used for the formation of textile preforms are explained. Composite fabrication methods are introduced. Engineering properties of textile composites are reviewed with regard to specific application areas. 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