Endocytosis pathways involved in exosome internalization in various cell types.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"9483",leadTitle:null,fullTitle:"Pain Management - Practices, Novel Therapies and Bioactives",title:"Pain Management",subtitle:"Practices, Novel Therapies and Bioactives",reviewType:"peer-reviewed",abstract:"Pain is a health issue that warrants significant attention and has an immense impact on global healthcare systems. This book focuses on pain, particularly on its management, by providing fresh perspectives and novel insights, while at the same time examining related topics that have often been overlooked. Given that there is no permanent cure for pain, the book primarily serves as an update to the existing knowledge. Topics covered include the biochemical pathways of pain as well as pharmaceutical and clinical management of pain to ensure health and wellbeing.",isbn:"978-1-83880-897-6",printIsbn:"978-1-83880-026-0",pdfIsbn:"978-1-83880-898-3",doi:"10.5772/intechopen.87267",price:119,priceEur:129,priceUsd:155,slug:"pain-management-practices-novel-therapies-and-bioactives",numberOfPages:300,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"864679ec29988a68364151a4df2511a0",bookSignature:"Viduranga Yashasvi Waisundara, Ines Banjari and Jelena Balkić",publishedDate:"March 24th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9483.jpg",numberOfDownloads:8740,numberOfWosCitations:0,numberOfCrossrefCitations:2,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:6,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:8,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 14th 2020",dateEndSecondStepPublish:"June 4th 2020",dateEndThirdStepPublish:"August 3rd 2020",dateEndFourthStepPublish:"October 22nd 2020",dateEndFifthStepPublish:"December 21st 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"13",totalChapterViews:"0",totalEditedBooks:"11",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"193500",title:"Ph.D.",name:"Ines",middleName:null,surname:"Banjari",slug:"ines-banjari",fullName:"Ines Banjari",profilePictureURL:"https://mts.intechopen.com/storage/users/193500/images/system/193500.png",biography:"Ines Banjari, Ph.D., is an Associate Professor at the Faculty of Food Technology, University of Osijek, Croatia, where she lectures a number of Human Nutrition courses at undergraduate, graduate, and postgraduate levels (both doctoral and specialist). She received her Ph.D. in Nutrition (Clinical Nutrition specialist) in November 2012 from the Faculty of Food Biotechnology, University of Zagreb, Croatia, and finished her postdoctoral fellowship at the University of Toronto, Faculty of Medicine, Canada. Since October 2019, she has been a guest professor at the Faculty of Agriculture and Food Technology, University of Mostar, Bosnia and Herzegovina. She has also been a guest researcher at the Jagiellonian University Medical College, Krakow, Poland (2019); the University of Oslo, Faculty of Medicine, Norway (2017); the University of Split, School of Medicine, Croatia (2016); and the University of Belgrade, School of Medicine, Serbia (2016). She is currently an expert in Public Health Nutrition for the Association of Schools of Public Health in the European Region (ASPHER) and has been working closely with the European Commission\\'s Joint Research Centre. She is PI of a scientific project with Slovenia (2020–2021) and was PI of a scientific project with Montenegro (2015–2016) and one NATO-funded project (2016–2017). She is also a collaborator on several national and international scientific projects. In 2014, she received the Danubius Young Scientist Award from the Austrian Federal Ministry of Science and Research and the Institute for the Danube Region and Central Europe. In 2016, she received the Young Scientist Award “Vera Johanides” from the Croatian Academy of Engineering. In 2019, she was awarded the International Visitor Leadership Program (IVLP) fellowship from the US Department of State. Dr. Banjari actively volunteers in civic organizations gathering Parkinson\\'s disease patients (Awakening) and oncology patients (OncoPut).",institutionString:"Josip Juraj Strossmayer University of Osijek, Faculty of Food Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Osijek",institutionURL:null,country:{name:"Croatia"}}},coeditorTwo:{id:"320755",title:"Dr.",name:"Jelena",middleName:null,surname:"Balkić",slug:"jelena-balkic",fullName:"Jelena Balkić",profilePictureURL:"https://mts.intechopen.com/storage/users/320755/images/system/320755.jpg",biography:"Jelena Balkić, Ph.D., was born in 1982 in Osijek, Croatia. She graduated from the Faculty of Food Technology, University of Osijek, Croatia, in 2008. She received her Ph.D. in Nutrition in 2017 with her thesis on chronic pain management with nutrition intervention. Since 2011, she has been employed at the University Hospital Osijek, Department of Dietetics and Nutrition, where she organizes, coordinates, and supervises the work of the department. She is actively involved in improving dietetics at the hospital by close collaboration with the IT sector on developing nutritional software for the hospital. Patient nutritional counseling is another important aspect of her work. Dr. Balkić has participated in several international and national conferences and is co-author of several scientific publications. She won the best poster award at Štampar Days in December 2019. She is also a collaborator on a scientific project in Slovenia (led by Dr. Banjari).",institutionString:"University Hospital Osijek",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1116",title:"Algiatry",slug:"algiatry"}],chapters:[{id:"73346",title:"What Do We Need to Consider for Pain Management?",doi:"10.5772/intechopen.93640",slug:"what-do-we-need-to-consider-for-pain-management-",totalDownloads:468,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Chronic pain in palliative care is viewed as an illness but remains as a subjective symptom. Hence, we must consider genetics, pain experience, coping skills, epigenetic effects, mental health, social determinants of health, interventions, and molecular biology. Acute pain transitions to chronic pain in some individuals following an injury, and there is poor evidence to stop such change. Acute, Chronic, and mixed pain can occur in patients with trauma, cancer, organ failure due to primary illness and other co-morbidities. The response to interventions may include biopsychosocial, non-pharmacological, surgery, radiation, chemotherapy, interventional radiology, pharmacological and depending upon survivorship, consider what is appropriate with peer reviewed medical evidence. Neurobiology is important in relation to physical and psychological issues; it affects an expression of pain. Manageable pain and relief are considered as being Human Right. Lack of adequate knowledge and treatment resources are common for care providers and patients. Cancer and noncancer pain ought to consider collaborating with interdisciplinary palliative approach, palliative care, and end of life care along with acute, chronic, and mixed pain management. Cancer patients with survivorship is increasing and risk management with chemicals, noncancer individuals appear similar. Barriers include health professional education, lack of treatment resources, medical, economic, ethical, and legal reasons. Pain management as an illness, care providers considers patient and family centered approach, useful to the community.",signatures:"Srini Chary",downloadPdfUrl:"/chapter/pdf-download/73346",previewPdfUrl:"/chapter/pdf-preview/73346",authors:[{id:"321924",title:"Dr.",name:"Srini",surname:"Chary",slug:"srini-chary",fullName:"Srini Chary"}],corrections:null},{id:"73607",title:"Regenerative Medicine",doi:"10.5772/intechopen.93717",slug:"regenerative-medicine",totalDownloads:329,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Chronic pain is a debilitating condition that affects millions of people world-wide, leading to physical incapacitation and financial strain. Common methods for treatment include physical therapy, oral medications, injections, surgery, and neuromodulation. Injectates with steroids and local anesthetics can be a temporizing measure with intolerable side effects. The use of autologous biologic injectates (e.g., platelet rich plasma, bone marrow aspirate concentrate, tissue grafts, and stem cells) is growing in therapeutic potential and enthusiasm, giving hope to a subset of patients that have either failed conventional therapy or are not candidates for traditional steroid injections. In this chapter, we will describe different cases in which regenerative medicine can help in painful conditions as well as neuro-degenerative conditions. Regenerative medicine can be the new frontier in providing long lasting relief through changes in cell-signaling cascades, however further trials are needed to validate their use.",signatures:"Armen Haroutunian, Tennison Malcolm and Thomas Zouki",downloadPdfUrl:"/chapter/pdf-download/73607",previewPdfUrl:"/chapter/pdf-preview/73607",authors:[{id:"256983",title:"Dr.",name:"Armen",surname:"Haroutunian",slug:"armen-haroutunian",fullName:"Armen Haroutunian"},{id:"322602",title:"Dr.",name:"Tennison",surname:"Malcolm",slug:"tennison-malcolm",fullName:"Tennison Malcolm"},{id:"322603",title:"Dr.",name:"Thomas",surname:"Zouki",slug:"thomas-zouki",fullName:"Thomas Zouki"}],corrections:null},{id:"73273",title:"Amputation Pain Management",doi:"10.5772/intechopen.93846",slug:"amputation-pain-management",totalDownloads:817,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Considerable number of new amputations yearly in the United States and internationally represent considerable population experiencing pain that is not just acutely from surgical insult but chronically that is related to phantom limb pain and residual limb pain. This chronic pain can last from weeks to years in these patients and lead to other debilitation such as depression, anxiety and even opioid addiction. Early interventions help lessen long-term pain for these patients. These interventions include nerve blockade as well as multi-modal therapy. Understanding the pathophysiology of the pain experienced by these patients will better allow any provider to care for these patients effectively and help alleviate chronic pain in the long term.",signatures:"Melinda S. Seering and Sangini Punia",downloadPdfUrl:"/chapter/pdf-download/73273",previewPdfUrl:"/chapter/pdf-preview/73273",authors:[{id:"323090",title:"Dr.",name:"Melinda S.",surname:"Seering",slug:"melinda-s.-seering",fullName:"Melinda S. Seering"},{id:"329349",title:"Dr.",name:"Sangini",surname:"Punia",slug:"sangini-punia",fullName:"Sangini Punia"}],corrections:null},{id:"73164",title:"Why Effective Pain Management Remains a Challenge",doi:"10.5772/intechopen.93612",slug:"why-effective-pain-management-remains-a-challenge",totalDownloads:391,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Pain is a subjective expression of neural impulses induced by a stimulus with a capacity to potentially damage tissues of the body. Simply put, pain is the reaction of the body to a potentially noxious or noxious stimulus, which threatens the normal homeostasis if unrelieved. Pain can be managed via pharmacological and non-pharmacological means, and pharmacological agents are the most widely accepted means, which have been shown to have variable effectiveness against pain. The barriers to effective pharmacological pain management in clinical practice are discussed in this chapter.",signatures:"Nnenna Ugwu",downloadPdfUrl:"/chapter/pdf-download/73164",previewPdfUrl:"/chapter/pdf-preview/73164",authors:[{id:"323565",title:"Dr.",name:"Nnenna",surname:"Ugwu",slug:"nnenna-ugwu",fullName:"Nnenna Ugwu"}],corrections:null},{id:"74491",title:"Empathy for Pain",doi:"10.5772/intechopen.95276",slug:"empathy-for-pain",totalDownloads:457,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Empathy is essential for being human for understanding and sharing other people’s affective and mood, including pain. Pain empathy is a mental ability that allows one person to understand another person’s pain and how to respond to that person effectively. The same neural structures as pain and empathy have recently been found to be involved in functional magnetic resonance imaging (fMRI) studies. When someone witnesses other’s pain, besides the visual cortex, various parts of the nervous system activate, including the neural network of empathy. Empathy includes not only pain but also other emotions, such as anger, sadness, fear, distress. These findings raised beg the question of whether empathy for pain is unique in its neural correlates. It is essential to know for revealing empathy is a specific context or in a state of chronic pain, depression or anxiety disorders. Because of this, pain empathy has been the central focus of empathy research in social neuroscience and other related fields, highlighting the importance of empathy for pain in daily life. Considering how pain plays a crucial role in the quality of life, determining its network and neurocognitive correlations in the empathy processing may provide a novel therapeutic approach for pain management. This area, which is still under investigation, can provide new information about pain. Under the recent studies and hypothesis, we have aimed to clarify the term of pain empathy, its components, and its neural correlates.",signatures:"Ece Ozdemir Oktem and Seyda Cankaya",downloadPdfUrl:"/chapter/pdf-download/74491",previewPdfUrl:"/chapter/pdf-preview/74491",authors:[{id:"325492",title:"Dr.",name:"Ece",surname:"Ozdemir Oktem",slug:"ece-ozdemir-oktem",fullName:"Ece Ozdemir Oktem"},{id:"341997",title:"Dr.",name:"Seyda",surname:"Cankaya",slug:"seyda-cankaya",fullName:"Seyda Cankaya"}],corrections:null},{id:"73911",title:"Review of Psychological Interventions in the Management of Arthritic Pain: The Case of Africa",doi:"10.5772/intechopen.93633",slug:"review-of-psychological-interventions-in-the-management-of-arthritic-pain-the-case-of-africa",totalDownloads:296,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter reviewed the scientific reports of the prevalence of arthritis pain and the potential of applying various psychological techniques in arthritis pain management among Africans. It initially reviewed the publications on arthritic disease-types, causes and prevalence among Africans and the current status of arthritic treatment options in Africa, cognitive, emotional, and behavioral components of arthritic pain experience, and then later focused on potential application of psychotherapies as part of comprehensive pain management protocol in African clinics and hospitals. The chapter discussed psychological explanations of pain and theoretical bases for pain management. It provided information on chronic arthritic pain assessment from a psychological perspective, beneficial psychotherapies and techniques applicable to this health condition. In general, the chapter explained the importance of incorporating psychological interventions as part of a comprehensive treatment plan to help improve the health outcome of arthritic patients presenting at hospitals in Africa. Psychological interventions are recommended to achieve better treatment outcomes for arthritis patients in African nations.",signatures:"Ann Ukachi Madukwe",downloadPdfUrl:"/chapter/pdf-download/73911",previewPdfUrl:"/chapter/pdf-preview/73911",authors:[{id:"323097",title:"Dr.",name:"Ann",surname:"Ukachi Madukwe",slug:"ann-ukachi-madukwe",fullName:"Ann Ukachi Madukwe"}],corrections:null},{id:"73088",title:"Clinical Insights into the Importance of Scars and Scar Release in Paediatric Chronic Myofascial Pain",doi:"10.5772/intechopen.93525",slug:"clinical-insights-into-the-importance-of-scars-and-scar-release-in-paediatric-chronic-myofascial-pai",totalDownloads:774,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Humans exhibit biotensegrity, whereby the whole body is a three-dimensional visco-elastic vehicle whatever position it adopts: bones form non-contact compression struts embedded in a networked and tensioned myofascial matrix; each part of the organism combines with the mechanical system to create an integrated functional movement unit and contributes to the stability of the whole system. When tissue at/below the dermis is breached by surgery/injury, healing leads to scar tissue formation. Scars can cause local and distant effects that are not purely cutaneous. Restriction of normal movement of underlying tissues from defective fascial sliding generates anomalous tension that affects the fascial continuum leading to distorted biomechanics, altered biotensegrity and chronic pain. Scars are common in children and significant contributors to chronic pain presentations. Scars can be released (soft tissue mobilization and/or needling) to sustainably improve pain, flexibility and range of motion. This chapter outlines the importance of skin and fascia in the biotensegrity model. Emphasis is placed on the fundamental need to assess scar history and scar characteristics to determine if scars should be treated as a component of multidisciplinary chronic pain management. Case studies outline some key clinical observations. Appropriately controlled research studies are required to fully demonstrate the highlighted benefits.",signatures:"Gillian Lauder and Nicholas West",downloadPdfUrl:"/chapter/pdf-download/73088",previewPdfUrl:"/chapter/pdf-preview/73088",authors:[{id:"76532",title:"Dr.",name:"Gillian",surname:"Lauder",slug:"gillian-lauder",fullName:"Gillian Lauder"},{id:"106522",title:"Mr.",name:"Nicholas",surname:"West",slug:"nicholas-west",fullName:"Nicholas West"}],corrections:null},{id:"74213",title:"Suffering as a Diagnostic Indicator",doi:"10.5772/intechopen.94146",slug:"suffering-as-a-diagnostic-indicator",totalDownloads:371,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Pain is the subjective sensation closely related to disease and treatment. Very often its diagnosis is more an expression of the diagnostician’s experience than a description of the patient’s actual condition. In particular, orthopedic and neurological patients who develop Complex Regional Pain Syndrome are misdiagnosed because the intensity of their sensations is disbelieved. Based on case studies, it seems appropriate to introduce an additional category of patient experience that will enable prompt recognition and appropriate treatment. The misdiagnoses under evaluation also exhibit frequent improper practitioner responses to patients’ experience, ranging from open expressions of disbelief, through indifference, to helplessness and pessimism. This article presents case studies in which patients’ expressions of suffering were not used to modify the treatment. Rather, medical professionals accepted the pain as normal under the circumstances and resulting from tissue damage. However, in these cases, the pain was a symptom of a new disease entity, in development since the original diagnosis. With improved patient communication and treatment procedures, such oversights can be avoided and new disease entities will be more readily diagnosable.",signatures:"Marek Rózycki and Robert Tobias",downloadPdfUrl:"/chapter/pdf-download/74213",previewPdfUrl:"/chapter/pdf-preview/74213",authors:[{id:"254855",title:"Mr.",name:"Marek",surname:"Rózycki",slug:"marek-rozycki",fullName:"Marek Rózycki"},{id:"329403",title:"Mr.",name:"Robert",surname:"Tobias",slug:"robert-tobias",fullName:"Robert Tobias"}],corrections:null},{id:"73184",title:"Perceptions of Women toward Non-Pharmacological Methods for Pain Relief during Labor",doi:"10.5772/intechopen.93271",slug:"perceptions-of-women-toward-non-pharmacological-methods-for-pain-relief-during-labor",totalDownloads:474,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The experience of childbirth is subjective and has multidimensional components through which every woman passes in different ways. It is one of the most beautiful episodes in mother’s life, related to happiness and celebration. However, childbirth is also associated with negative emotions such as anxiety, low sense of safety, and expectation of pain. Strong and persistent pain that is associated with labor may negatively affect both mother and fetus. During labor, a woman is dealing not only with the contractions but also with the belief that the culture has made for her. Although childbirth is viewed as a normal physiological process, it can produce significant pain that requires effective pain management. The non-pharmacological approach includes a wide variety of methods to address labor pain, which prevent suffering by enhancing the psychological and spiritual components. The non-pharmacological methods of labor pain relief require patient’s preparation and antenatal education. The non-pharmacological methods that used to relief labor pain are massage, acupuncture, continuous support, positioning, breathing techniques, water immersion, music therapy, and biofeedback are some of the techniques used to achieve an effective coping level for women. The aim of this chapter is to explore women’s perception toward non-pharmacological methods during labor.",signatures:"Teketel Ermias Geltore and Abiy Tadesse Angelo",downloadPdfUrl:"/chapter/pdf-download/73184",previewPdfUrl:"/chapter/pdf-preview/73184",authors:[{id:"321781",title:"Mr.",name:"Teketel Ermias",surname:"Geltore",slug:"teketel-ermias-geltore",fullName:"Teketel Ermias Geltore"},{id:"321787",title:"Mr.",name:"Abiy",surname:"Tadesse Angelo",slug:"abiy-tadesse-angelo",fullName:"Abiy Tadesse Angelo"}],corrections:null},{id:"73147",title:"Supporting Communication Vulnerable Children to Communicate Their Pain",doi:"10.5772/intechopen.93588",slug:"supporting-communication-vulnerable-children-to-communicate-their-pain",totalDownloads:759,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Communication vulnerable children need an alternative way to express their pain to receive appropriate pain management. In this chapter, the concept of communication vulnerability will be explained by using the social-communication model of pain as a theoretical framework. The concept of pain is difficult to describe due to its subjective nature and individuals’ different experiences to pain. Clinicians and researchers find it challenging to understand the dynamic interplay between the biological, psychological and social determinants of pain. Understanding any episode of acute or chronic pain therefore necessitates considering the holistic pain picture to analyse the essentials at biological, psychological and social levels. The chapter concludes with suggestions to use augmentative and alternative strategies to support communication vulnerable children to communicate their pain.",signatures:"Ensa Johnson",downloadPdfUrl:"/chapter/pdf-download/73147",previewPdfUrl:"/chapter/pdf-preview/73147",authors:[{id:"297274",title:"Dr.",name:"Ensa",surname:"Johnson",slug:"ensa-johnson",fullName:"Ensa Johnson"}],corrections:null},{id:"75480",title:"Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis",doi:"10.5772/intechopen.95919",slug:"nutraceutical-alternatives-to-pharmaceutical-analgesics-in-osteoarthritis",totalDownloads:473,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Chronic pain is a considerable health concern worldwide, effecting almost 30% of all European adults. Osteoarthritis (OA), a progressive pro-inflammatory condition, is one of the leading causes of chronic pain (effecting 13% of all \ufeffthose over 50 years, globally) and is the most common cause of joint pain. The prevalence of non-steroidal anti-inflammatory drug (NSAIDs) and analgesic use has been well studied and is abundant throughout the western world, with women being the greatest users and ibuprofen generally being the most \ufeffreported NSAID. In the US, 65% of all OA patients are prescribed NSAIDs for pain management and form part of the current recommended strategy for OA clinical management. While some NSAIDs and analgesics are effective at improving pain and physical function, they come with significant and harmful side effects such as gastrointestinal complications, renal disturbances and severe cardiovascular events. Given these side-effects, any reduction in NSAID and analgesia use (and the resulting potentially harmful side effects) is of particular importance to OA public health. As such, a number of non-pharmaceutical alternatives (bioactive nutraceuticals) have been developed that may reduce NSAID and analgesia use while maintaining pain reduction and improvements in physical function. This chapter will discuss select nutraceuticals that are not currently in mainstream use but may have the potential to aid in the treatment of OA.",signatures:"Shane M. Heffernan and Gillian E. Conway",downloadPdfUrl:"/chapter/pdf-download/75480",previewPdfUrl:"/chapter/pdf-preview/75480",authors:[{id:"322446",title:"Dr.",name:"Shane M.",surname:"Heffernan",slug:"shane-m.-heffernan",fullName:"Shane M. Heffernan"},{id:"341083",title:"Dr.",name:"Gillian E.",surname:"Conway",slug:"gillian-e.-conway",fullName:"Gillian E. Conway"}],corrections:null},{id:"73126",title:"Multimodal Pharmacological Analgesia in Pain Management",doi:"10.5772/intechopen.93620",slug:"multimodal-pharmacological-analgesia-in-pain-management",totalDownloads:776,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The knowledge of the pathophysiology of pain has gradually evolved in recent years, allowing the development of new management strategies, more specifically addressing single pain types and patient profiles. Despite these advancements, pain management still remains an open issue, given the limitations of single agent therapies, the potential abuse/misuse of opioids and the risk of adverse events. The advent of multimodal analgesic strategies paves the way for major improvements in pain management, combining increased efficacy with better tolerability and an opioid-sparing effect. The association of analgesics with different mechanisms of action represents a successful strategy for a wide range of pain conditions, minimizing side effects and taking advantage of the additive or synergistic actions of individual agents. Last but not least, the increasing availability of oral fixed-dose combinations of analgesics will offer further advantages over extemporaneous combinations, by increasing ease of administration and patient adherence to treatment.",signatures:"Antonella Paladini and Giustino Varrassi",downloadPdfUrl:"/chapter/pdf-download/73126",previewPdfUrl:"/chapter/pdf-preview/73126",authors:[{id:"191581",title:"Prof.",name:"Giustino",surname:"Varrassi",slug:"giustino-varrassi",fullName:"Giustino Varrassi"},{id:"328764",title:"Prof.",name:"Antonella",surname:"Paladini",slug:"antonella-paladini",fullName:"Antonella Paladini"}],corrections:null},{id:"73348",title:"The Role of Cupping Therapy in Pain Management: A Literature Review",doi:"10.5772/intechopen.93851",slug:"the-role-of-cupping-therapy-in-pain-management-a-literature-review",totalDownloads:1076,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Cupping therapy is an ancient method which has been used for centuries for various painful conditions. It is performed by applying cups to selected skin points most commonly in the back aiming to create areas of sub-atmospheric pressure. It has been classified as either dry or wet type of therapy. Its mechanism of action is not well understood but several proposed mechanisms are described in the literature. It is relatively safe with a few reported side effects which include scar formation and skin infection. In this paper, a review of the literature will be presented to determine its potential benefits in pain management particularly in musculo-skeletal conditions such as low back and neck pain.",signatures:"Asma Al-Shidhani and Abdulaziz Al-Mahrezi",downloadPdfUrl:"/chapter/pdf-download/73348",previewPdfUrl:"/chapter/pdf-preview/73348",authors:[{id:"248467",title:"Dr.",name:"Abdulaziz",surname:"Al-Mahrezi",slug:"abdulaziz-al-mahrezi",fullName:"Abdulaziz Al-Mahrezi"},{id:"322652",title:"Dr.",name:"Asma",surname:"Al-Shidhani",slug:"asma-al-shidhani",fullName:"Asma Al-Shidhani"}],corrections:null},{id:"73965",title:"Analgesics",doi:"10.5772/intechopen.94319",slug:"analgesics",totalDownloads:370,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"It is the responsibility of the professional care team to develop an effective person-centred Pain Management strategy which appropriately assesses patients, analyses the results of the assessment and devises a person centred plan to manage pain while allowing the person to remain as independent and functional as possible. The medications useful in treating acute pain are similar to those used in treating other types of pain. The World Health Organization (WHO) analgesic ladder developed for treating patients with cancer pain also provides a useful approach to treat acute pain. At the lowest level (mild pain) are recommended nonopioid analgesics such as paracetamol or/plus nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. ibuprophen). Such drugs have an analgesic ceiling; above a certain dose, no further analgesia is expected. For moderate pain, are recommended combining paracetamol and/or a NSAID with an opioid (a weak opoid). The inclusion of paracetamol limits the amount of opoids that should be used within 24 hour period, with many benefits which will be discussed later in the chapter. For severe level of pain, a strong opoid such as morphine is a better choice; such opoids have no analgesic ceiling. Most postoperative or trauma patients initially respond better to a morphine-equivalent opoid. At the moment when the patient is eating and drinking, a combination of oral analgesics including opoids and paracetamol plus/minus NSAID are most of the time an adequate choice.",signatures:"Mihai Botea",downloadPdfUrl:"/chapter/pdf-download/73965",previewPdfUrl:"/chapter/pdf-preview/73965",authors:[{id:"322907",title:"Dr.",name:"Mihai",surname:"Botea",slug:"mihai-botea",fullName:"Mihai Botea"}],corrections:null},{id:"73347",title:"NSAIDs, Opioids, and Beyond",doi:"10.5772/intechopen.93843",slug:"nsaids-opioids-and-beyond",totalDownloads:424,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Medications are prescribed throughout the world for a variety of reasons including pain. NSAIDs, opioids, and other non-opioid modalities have been used to treat both acute and chronic pain. In this chapter we will discuss the pharmacokinetics, indications, function and associated complications for commonly used pain medications to include NSAIDs, opioids, antidepressants, cannabinoids, and ketamine.",signatures:"Coti Phillips, Edwin Contreras and Jessica Oswald",downloadPdfUrl:"/chapter/pdf-download/73347",previewPdfUrl:"/chapter/pdf-preview/73347",authors:[{id:"322274",title:"Dr.",name:"Coti",surname:"Phillips",slug:"coti-phillips",fullName:"Coti Phillips"},{id:"329215",title:"Dr.",name:"Jessica",surname:"Oswald",slug:"jessica-oswald",fullName:"Jessica Oswald"},{id:"329467",title:"Dr.",name:"Edwin",surname:"Contreras",slug:"edwin-contreras",fullName:"Edwin Contreras"}],corrections:null},{id:"72869",title:"Analgesic Potential of Monoterpenes from Citrus Essential Oils",doi:"10.5772/intechopen.93265",slug:"analgesic-potential-of-monoterpenes-from-citrus-essential-oils",totalDownloads:490,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Chronic pain is a noteworthy health issue with immense impact on global healthcare systems. Although this issue has not come into the limelight as other noncommunicable diseases, it should be highlighted that modern medicine still has no efficient treatment to curb chronic pain. In this aspect, essential oils have been used for the prevention of several disease conditions including pain management. These odorous products, obtained from botanically defined raw material, have a variable and complex composition. Their composition largely depends on the extraction technique used, from simple hydro-distillation, to supercritical or microwave-assisted extraction. Monoterpenoids are some of the most biologically active and highly researched compounds when it comes to antinociceptive effects. They are volatile oils, primarily composed of two isoprene units with highly distinctive aromas and flavors. More than 90% of the essential oils of medicinal plants consist of monoterpenoids like limonene, myrcene, α-terpineol, linalool, pinene, p-cymene, and nerol. Besides strong anti-inflammatory effect, all essential oils with high D-limonene content pose a significant free radical scavenging effect, predominantly disabling the production of reactive oxygen species. Further studies in humans are encouraged to determine the real long-term potential in treating chronic pain.",signatures:"Ines Banjari, Jelena Balkić and Viduranga Yashasvi Waisundara",downloadPdfUrl:"/chapter/pdf-download/72869",previewPdfUrl:"/chapter/pdf-preview/72869",authors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara"},{id:"320755",title:"Dr.",name:"Jelena",surname:"Balkić",slug:"jelena-balkic",fullName:"Jelena Balkić"},{id:"203069",title:"Dr.",name:"Ines",surname:"Banjari",slug:"ines-banjari",fullName:"Ines Banjari"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5505",title:"Superfood and Functional Food",subtitle:"An Overview of Their Processing and Utilization",isOpenForSubmission:!1,hash:"1c054794ab111a6e0a6bfebeb77baa8e",slug:"superfood-and-functional-food-an-overview-of-their-processing-and-utilization",bookSignature:"Viduranga Waisundara and Naofumi Shiomi",coverURL:"https://cdn.intechopen.com/books/images_new/5505.jpg",editedByType:"Edited by",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. 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Toxicity, Human Health and Environment",slug:"nanomaterials-toxicity-human-health-and-environment",publishedDate:"February 19th 2020",bookSignature:"Simona Clichici, Adriana Filip and Gustavo M. do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/8137.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64160",title:"Prof.",name:"Simona",middleName:null,surname:"Clichici",slug:"simona-clichici",fullName:"Simona Clichici"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"251730",title:"Dr.",name:"Guilherme",middleName:"Fredeico Bernardo",surname:"Lenz E Silva",fullName:"Guilherme Lenz E Silva",slug:"guilherme-lenz-e-silva",email:"guilhermelenz@usp.br",position:null,institution:null},{id:"286148",title:"Dr.",name:"Camila",middleName:null,surname:"Viana",fullName:"Camila Viana",slug:"camila-viana",email:"camilaoviana@gmail.com",position:null,institution:{name:"Centro de Desenvolvimento da Tecnologia Nuclear",institutionURL:null,country:{name:"Brazil"}}},{id:"286149",title:"Dr.",name:"Fernanda",middleName:null,surname:"Vieira",fullName:"Fernanda Vieira",slug:"fernanda-vieira",email:"fevieira2001@gmail.com",position:null,institution:{name:"Centro de Desenvolvimento da Tecnologia Nuclear",institutionURL:null,country:{name:"Brazil"}}},{id:"286151",title:"M.Sc.",name:"Danieli",middleName:"Silva",surname:"Domingues",fullName:"Danieli Domingues",slug:"danieli-domingues",email:"danielisilva@ymail.com",position:null,institution:{name:"Centro de Desenvolvimento da Tecnologia Nuclear",institutionURL:null,country:{name:"Brazil"}}}]}},chapter:{id:"66689",slug:"risk-assessment-and-health-safety-and-environmental-management-of-carbon-nanomaterials",signatures:"Guilherme Lenz e Silva, Camila Viana, Danieli Domingues and Fernanda Vieira",dateSubmitted:null,dateReviewed:"February 26th 2019",datePrePublished:"April 11th 2019",datePublished:"February 19th 2020",book:{id:"8137",title:"Nanomaterials",subtitle:"Toxicity, Human Health and Environment",fullTitle:"Nanomaterials - 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Blood transfusion medicine has become a sophisticated and specialized field of medicine. Some aspects will be discussed in this book. The book has been divided into three sections. The first section includes chapters describing the immunological and coagulation-assisting functions of red blood cells and methods to measure their life span. The second section discusses the role of platelets in inflammatory processes. The third section reviews functional dose of RBC transfusions and transfusion practice in various clinical settings.",isbn:"978-953-51-3320-9",printIsbn:"978-953-51-3319-3",pdfIsbn:"978-953-51-4759-6",doi:"10.5772/66265",price:119,priceEur:129,priceUsd:155,slug:"transfusion-medicine-and-scientific-developments",numberOfPages:128,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"b5a95b51b34becb58f940bdc6cc2c26e",bookSignature:"A.W.M.M. 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Rada",authors:[{id:"114650",title:"Dr",name:"Eugen",middleName:null,surname:"Culea",fullName:"Eugen Culea",slug:"eugen-culea"},{id:"114653",title:"Dr.",name:"Simona",middleName:null,surname:"Rada",fullName:"Simona Rada",slug:"simona-rada"}]},{id:"36169",title:"Water in Rocks and Minerals - Species, Distributions, and Temperature Dependences",slug:"water-in-rocks-and-minerals-species-distributions-and-temperature-dependences",signatures:"Jun-ichi Fukuda",authors:[{id:"105384",title:"Dr.",name:"Jun-Ichi",middleName:null,surname:"Fukuda",fullName:"Jun-Ichi Fukuda",slug:"jun-ichi-fukuda"}]},{id:"36170",title:"Attenuated Total Reflection - Infrared Spectroscopy Applied to the Study of Mineral - Aqueous Electrolyte Solution Interfaces: A General Overview and a Case Study",slug:"attenuated-total-reflection-infrared-spectroscopy-applied-to-the-study-of-mineral-aqueous-el",signatures:"Grégory Lefèvre, Tajana Preočanin and Johannes Lützenkirchen",authors:[{id:"108416",title:"Dr.",name:"Johannes",middleName:null,surname:"Lützenkirchen",fullName:"Johannes Lützenkirchen",slug:"johannes-lutzenkirchen"},{id:"111675",title:"Dr.",name:"Gregory",middleName:null,surname:"Lefevre",fullName:"Gregory Lefevre",slug:"gregory-lefevre"},{id:"111676",title:"Prof.",name:"Tajana",middleName:null,surname:"Preocanin",fullName:"Tajana Preocanin",slug:"tajana-preocanin"}]},{id:"36171",title:"Research of Calcium Phosphates Using Fourier Transform Infrared Spectroscopy",slug:"research-of-calcium-phosphates-using-fourier-transformation-infrared-spectroscopy",signatures:"Liga Berzina-Cimdina and Natalija Borodajenko",authors:[{id:"110522",title:"Prof.",name:"Liga",middleName:null,surname:"Berzina-Cimdina",fullName:"Liga Berzina-Cimdina",slug:"liga-berzina-cimdina"},{id:"112181",title:"MSc.",name:"Natalija",middleName:null,surname:"Borodajenko",fullName:"Natalija Borodajenko",slug:"natalija-borodajenko"}]},{id:"36172",title:"FTIR Spectroscopy of Adsorbed Probe Molecules for Analyzing the Surface Properties of Supported Pt (Pd) Catalysts",slug:"ftir-spectroscopy-of-adsorbed-probe-molecules-for-analyzing-the-surface-properties-of-supported-pt-p",signatures:"Olga B. Belskaya, Irina G. Danilova, Maxim O. Kazakov, Roman M. Mironenko, Alexander V. Lavrenov and Vladimir A. Likholobov",authors:[{id:"107715",title:"Dr.",name:"Olga",middleName:null,surname:"Belskaya",fullName:"Olga Belskaya",slug:"olga-belskaya"},{id:"140198",title:"Dr.",name:"Irina",middleName:null,surname:"Danilova",fullName:"Irina Danilova",slug:"irina-danilova"},{id:"140200",title:"Dr.",name:"Maxim",middleName:null,surname:"Kazakov",fullName:"Maxim Kazakov",slug:"maxim-kazakov"},{id:"140202",title:"Mr.",name:"Roman",middleName:"Mikhailovich",surname:"Mironenko",fullName:"Roman Mironenko",slug:"roman-mironenko"},{id:"140203",title:"Dr.",name:"Alexander",middleName:null,surname:"Lavrenov",fullName:"Alexander Lavrenov",slug:"alexander-lavrenov"},{id:"140204",title:"Prof.",name:"Vladimir",middleName:null,surname:"Likholobov",fullName:"Vladimir Likholobov",slug:"vladimir-likholobov"}]},{id:"36173",title:"Hydrothermal Treatment of Hokkaido Peat - An Application of FTIR and 13C NMR Spectroscopy on Examining of Artificial Coalification Process and Development",slug:"hydrothermal-treatment-of-hokkaido-peat-an-application-of-ftir-and-13c-nmr-spectroscopy-on-examinin",signatures:"Anggoro Tri Mursito and Tsuyoshi Hirajima",authors:[{id:"104786",title:"Dr.",name:"Anggoro Tri",middleName:null,surname:"Mursito",fullName:"Anggoro Tri Mursito",slug:"anggoro-tri-mursito"},{id:"110978",title:"Prof.",name:"Tsuyoshi",middleName:null,surname:"Hirajima",fullName:"Tsuyoshi Hirajima",slug:"tsuyoshi-hirajima"}]},{id:"36174",title:"FTIR - An Essential Characterization Technique for Polymeric Materials",slug:"ftir-an-essential-characterization-technique-for-polymeric-materials",signatures:"Vladimir A. Escobar Barrios, José R. Rangel Méndez, Nancy V. Pérez Aguilar, Guillermo Andrade Espinosa and José L. Dávila Rodríguez",authors:[{id:"12709",title:"Dr.",name:"Jose Rene",middleName:null,surname:"Rangel-Mendez",fullName:"Jose Rene Rangel-Mendez",slug:"jose-rene-rangel-mendez"},{id:"12711",title:"Dr.",name:"Vladimir Alonso",middleName:null,surname:"Escobar Barrios",fullName:"Vladimir Alonso Escobar Barrios",slug:"vladimir-alonso-escobar-barrios"},{id:"112164",title:"Dr.",name:"Guillermo",middleName:null,surname:"Andrade-Espinosa",fullName:"Guillermo Andrade-Espinosa",slug:"guillermo-andrade-espinosa"},{id:"112165",title:"Dr.",name:"José Luis",middleName:null,surname:"Dávila-Rodríguez",fullName:"José Luis Dávila-Rodríguez",slug:"jose-luis-davila-rodriguez"},{id:"112167",title:"Dr.",name:"Nancy Verónica",middleName:null,surname:"Pérez-Aguilar",fullName:"Nancy Verónica Pérez-Aguilar",slug:"nancy-veronica-perez-aguilar"}]},{id:"36175",title:"Preparation and Characterization of PVDF/PMMA/Graphene Polymer Blend Nanocomposites by Using ATR-FTIR Technique",slug:"preparation-and-characterization-of-pvdf-pmma-graphene-polymer-blend-nanocomposites-by-using-ft-ir-t",signatures:"Somayeh Mohamadi",authors:[{id:"108556",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohamadi",fullName:"Somayeh Mohamadi",slug:"somayeh-mohamadi"}]},{id:"36176",title:"Reflectance IR Spectroscopy",slug:"fundamental-of-reflectance-ir-spectroscopy",signatures:"Zahra Monsef Khoshhesab",authors:[{id:"111629",title:"Dr.",name:"Zahra",middleName:null,surname:"Monsef Khoshhesab",fullName:"Zahra Monsef Khoshhesab",slug:"zahra-monsef-khoshhesab"}]},{id:"36177",title:"Evaluation of Graft Copolymerization of Acrylic Monomers Onto Natural Polymers by Means Infrared Spectroscopy",slug:"evaluation-of-graft-copolymerization-of-acrylic-monomers-onto-natural-polymers-by-means-infrared-spe",signatures:"José Luis Rivera-Armenta, Cynthia Graciela Flores-Hernández, Ruth Zurisadai Del Angel-Aldana, Ana María Mendoza-Martínez, Carlos Velasco-Santos and Ana Laura Martínez-Hernández",authors:[{id:"37761",title:"Prof.",name:"Ana Laura",middleName:null,surname:"Martinez-Hernandez",fullName:"Ana Laura Martinez-Hernandez",slug:"ana-laura-martinez-hernandez"},{id:"107855",title:"Dr.",name:"Jose Luis",middleName:null,surname:"Rivera Armenta",fullName:"Jose Luis Rivera Armenta",slug:"jose-luis-rivera-armenta"},{id:"108894",title:"MSc.",name:"Cynthia Graciela",middleName:null,surname:"Flores-Hernández",fullName:"Cynthia Graciela Flores-Hernández",slug:"cynthia-graciela-flores-hernandez"},{id:"108896",title:"MSc.",name:"Ruth Zurisadai",middleName:null,surname:"Del Angel Aldana",fullName:"Ruth Zurisadai Del Angel Aldana",slug:"ruth-zurisadai-del-angel-aldana"},{id:"108898",title:"Dr.",name:"Carlos",middleName:null,surname:"Velasco-Santos",fullName:"Carlos Velasco-Santos",slug:"carlos-velasco-santos"},{id:"108905",title:"Dr.",name:"Ana Maria",middleName:null,surname:"Mendoza-Martínez",fullName:"Ana Maria Mendoza-Martínez",slug:"ana-maria-mendoza-martinez"}]},{id:"36178",title:"Applications of FTIR on Epoxy Resins - Identification, Monitoring the Curing Process, Phase Separation and Water Uptake",slug:"applications-of-ftir-on-epoxy-resins-identification-monitoring-the-curing-process-phase-separatio",signatures:"María González González, Juan Carlos Cabanelas and Juan Baselga",authors:[{id:"107857",title:"Prof.",name:"Juan",middleName:null,surname:"Baselga",fullName:"Juan Baselga",slug:"juan-baselga"},{id:"138113",title:"Dr.",name:"María",middleName:null,surname:"González",fullName:"María González",slug:"maria-gonzalez"},{id:"138114",title:"Dr.",name:"Juan C.",middleName:null,surname:"Cabanelas",fullName:"Juan C. Cabanelas",slug:"juan-c.-cabanelas"}]},{id:"36179",title:"Use of FTIR Analysis to Control the Self-Healing Functionality of Epoxy Resins",slug:"use-of-ft-ir-analysis-to-control-the-self-healing-functionality-of-epoxy-resins",signatures:"Liberata Guadagno and Marialuigia Raimondo",authors:[{id:"106836",title:"Prof.",name:"Liberata",middleName:null,surname:"Guadagno",fullName:"Liberata Guadagno",slug:"liberata-guadagno"}]},{id:"36180",title:"Infrared Analysis of Electrostatic Layer-By-Layer Polymer Membranes Having Characteristics of Heavy Metal Ion Desalination",slug:"infrared-analysis-of-electrostatic-layer-by-layer-polymer-membranes-having-characteristics-of-heavy",signatures:"Weimin Zhou, Huitan Fu and Takaomi Kobayashi",authors:[{id:"110384",title:"Dr.",name:"Takaomi",middleName:null,surname:"Kobayashi",fullName:"Takaomi Kobayashi",slug:"takaomi-kobayashi"}]},{id:"36181",title:"Infrared Spectroscopy as a Tool to Monitor Radiation Curing",slug:"infrared-spectroscopy-as-a-tool-to-monitor-radiation-curing",signatures:"Marco Sangermano, Patrick Meier and Spiros Tzavalas",authors:[{id:"112286",title:"Dr.",name:"Spiros",middleName:null,surname:"Tzavalas",fullName:"Spiros Tzavalas",slug:"spiros-tzavalas"},{id:"114382",title:"Prof.",name:"Marco",middleName:null,surname:"Sangermano",fullName:"Marco Sangermano",slug:"marco-sangermano"},{id:"114384",title:"Dr",name:"Patrick",middleName:null,surname:"Meier",fullName:"Patrick Meier",slug:"patrick-meier"}]},{id:"36182",title:"Characterization of Compositional Gradient Structure of Polymeric Materials by FTIR Technology",slug:"characterization-of-compositional-gradient-structure-of-polymeric-materials-by-ft-ir-technology",signatures:"Alata Hexig and Bayar Hexig",authors:[{id:"20867",title:"Dr.",name:"Bayar",middleName:null,surname:"Hexig",fullName:"Bayar Hexig",slug:"bayar-hexig"},{id:"111986",title:"Dr.",name:"Alata",middleName:null,surname:"Hexig",fullName:"Alata Hexig",slug:"alata-hexig"}]},{id:"36183",title:"Fourier Transform Infrared Spectroscopy - Useful Analytical Tool for Non-Destructive Analysis",slug:"fourier-trasform-infrared-spectroscopy-useful-analytical-tool-for-non-destructive-analysis",signatures:"Simona-Carmen Litescu, Eugenia D. Teodor, Georgiana-Ileana Truica, Andreia Tache and Gabriel-Lucian Radu",authors:[{id:"24425",title:"Dr.",name:"Simona Carmen",middleName:null,surname:"Litescu",fullName:"Simona Carmen Litescu",slug:"simona-carmen-litescu"},{id:"24429",title:"Prof.",name:"Gabriel-Lucian",middleName:null,surname:"Radu",fullName:"Gabriel-Lucian Radu",slug:"gabriel-lucian-radu"},{id:"108318",title:"Dr.",name:"Eugenia D.",middleName:null,surname:"Teodor",fullName:"Eugenia D. Teodor",slug:"eugenia-d.-teodor"},{id:"108323",title:"Dr.",name:"Georgiana-Ileana",middleName:null,surname:"Badea",fullName:"Georgiana-Ileana Badea",slug:"georgiana-ileana-badea"},{id:"136337",title:"Ms.",name:"Andreia",middleName:null,surname:"Tache",fullName:"Andreia Tache",slug:"andreia-tache"}]},{id:"36184",title:"Infrared Spectroscopy in the Analysis of Building and Construction Materials",slug:"infrared-spectroscopy-of-cementitious-materials",signatures:"Lucia Fernández-Carrasco, D. Torrens-Martín, L.M. Morales and Sagrario Martínez-Ramírez",authors:[{id:"107401",title:"Dr.",name:"Lucia J",middleName:null,surname:"Fernández",fullName:"Lucia J Fernández",slug:"lucia-j-fernandez"}]},{id:"36185",title:"Infrared Spectroscopy Techniques in the Characterization of SOFC Functional Ceramics",slug:"infrared-spectroscopy-techniques-in-the-characterization-of-sofc-functional-ceramics",signatures:"Daniel A. Macedo, Moisés R. Cesário, Graziele L. Souza, Beatriz Cela, Carlos A. Paskocimas, Antonio E. Martinelli, Dulce M. A. Melo and Rubens M. Nascimento",authors:[{id:"102015",title:"MSc.",name:"Daniel",middleName:null,surname:"Macedo",fullName:"Daniel Macedo",slug:"daniel-macedo"},{id:"112309",title:"MSc",name:"Moisés",middleName:"Romolos",surname:"Cesário",fullName:"Moisés Cesário",slug:"moises-cesario"},{id:"112310",title:"Ms.",name:"Graziele",middleName:null,surname:"Souza",fullName:"Graziele Souza",slug:"graziele-souza"},{id:"112311",title:"MSc.",name:"Beatriz",middleName:null,surname:"Cela",fullName:"Beatriz Cela",slug:"beatriz-cela"},{id:"112312",title:"Prof.",name:"Carlos",middleName:null,surname:"Paskocimas",fullName:"Carlos Paskocimas",slug:"carlos-paskocimas"},{id:"112314",title:"Prof.",name:"Antonio",middleName:null,surname:"Martinelli",fullName:"Antonio Martinelli",slug:"antonio-martinelli"},{id:"112315",title:"Prof.",name:"Dulce",middleName:null,surname:"Melo",fullName:"Dulce Melo",slug:"dulce-melo"},{id:"112316",title:"Dr.",name:"Rubens",middleName:"Maribondo Do",surname:"Nascimento",fullName:"Rubens Nascimento",slug:"rubens-nascimento"}]},{id:"36186",title:"Infrared Spectroscopy of Functionalized Magnetic Nanoparticles",slug:"infrared-spectroscopy-of-functionalized-magnetic-nanoparticles",signatures:"Perla E. García Casillas, Claudia A. Rodriguez Gonzalez and Carlos A. Martínez Pérez",authors:[{id:"104636",title:"Dr.",name:"Perla E.",middleName:null,surname:"García Casillas",fullName:"Perla E. García Casillas",slug:"perla-e.-garcia-casillas"},{id:"112440",title:"Dr.",name:"Carlos A.",middleName:null,surname:"Martínez Pérez",fullName:"Carlos A. Martínez Pérez",slug:"carlos-a.-martinez-perez"},{id:"112441",title:"Dr.",name:"Claudia A.",middleName:null,surname:"Rodriguez Gonzalez",fullName:"Claudia A. Rodriguez Gonzalez",slug:"claudia-a.-rodriguez-gonzalez"}]},{id:"36187",title:"Determination of Adsorption Characteristics of Volatile Organic Compounds Using Gas Phase FTIR Spectroscopy Flow Analysis",slug:"determination-of-adsorption-characteristics-of-volatile-organic-compounds-using-gas-phase-ftir-spect",signatures:"Tarik Chafik",authors:[{id:"107310",title:"Prof.",name:"Tarik",middleName:null,surname:"Chafik",fullName:"Tarik Chafik",slug:"tarik-chafik"}]},{id:"36188",title:"Identification of Rocket Motor Characteristics from Infrared Emission Spectra",slug:"identification-of-rocket-motor-characteristics-from-infrared-emission-spectra",signatures:"N. Hamp, J.H. Knoetze, C. Aldrich and C. Marais",authors:[{id:"112229",title:"Prof.",name:"Chris",middleName:null,surname:"Aldrich",fullName:"Chris Aldrich",slug:"chris-aldrich"},{id:"112232",title:"Prof.",name:"Hansie",middleName:null,surname:"Knoetze",fullName:"Hansie Knoetze",slug:"hansie-knoetze"},{id:"135327",title:"Ms.",name:"Corne",middleName:null,surname:"Marais",fullName:"Corne Marais",slug:"corne-marais"}]},{id:"36189",title:"Optical Technologies for Determination of Pesticide Residue",slug:"optical-technology-for-determination-of-pesticide-residue",signatures:"Yankun Peng, Yongyu Li and Jingjing Chen",authors:[{id:"113343",title:"Prof.",name:"Yankun",middleName:null,surname:"Peng",fullName:"Yankun Peng",slug:"yankun-peng"},{id:"116636",title:"Dr.",name:"Yongyu",middleName:null,surname:"Li",fullName:"Yongyu Li",slug:"yongyu-li"},{id:"116637",title:"Dr.",name:"Jingjing",middleName:null,surname:"Chen",fullName:"Jingjing Chen",slug:"jingjing-chen"}]},{id:"36190",title:"High Resolution Far Infrared Spectra of the Semiconductor Alloys Obtained Using the Synchrotron Radiation as Source",slug:"high-resolution-spectra-of-semiconductor-s-alloys-obtained-using-the-far-infrared-synchrotron-radi",signatures:"E.M. Sheregii",authors:[{id:"102655",title:"Prof.",name:"Eugen",middleName:null,surname:"Sheregii",fullName:"Eugen Sheregii",slug:"eugen-sheregii"}]},{id:"36191",title:"Effective Reaction Monitoring of Intermediates by ATR-IR Spectroscopy Utilizing Fibre Optic Probes",slug:"effective-reaction-monitoring-of-intermediates-by-atr-ir-spectroscopy-utilizing-fibre-optic-probes",signatures:"Daniel Lumpi and Christian Braunshier",authors:[{id:"109019",title:"Dr.",name:"Christian",middleName:null,surname:"Braunshier",fullName:"Christian Braunshier",slug:"christian-braunshier"},{id:"111798",title:"MSc.",name:"Daniel",middleName:null,surname:"Lumpi",fullName:"Daniel Lumpi",slug:"daniel-lumpi"}]}]}],publishedBooks:[{type:"book",id:"10",title:"Coherence and Ultrashort Pulse Laser Emission",subtitle:null,isOpenForSubmission:!1,hash:"e1bd25a76712d1cb8792820acf2ff001",slug:"coherence-and-ultrashort-pulse-laser-emission",bookSignature:"F. J. Duarte",coverURL:"https://cdn.intechopen.com/books/images_new/10.jpg",editedByType:"Edited by",editors:[{id:"13752",title:"Dr.",name:"F. J.",surname:"Duarte",slug:"f.-j.-duarte",fullName:"F. J. Duarte"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11",title:"Multi-Robot Systems",subtitle:"Trends and Development",isOpenForSubmission:!1,hash:null,slug:"multi-robot-systems-trends-and-development",bookSignature:"Toshiyuki Yasuda",coverURL:"https://cdn.intechopen.com/books/images_new/11.jpg",editedByType:"Edited by",editors:[{id:"5669",title:"Dr.",name:"Toshiyuki",surname:"Yasuda",slug:"toshiyuki-yasuda",fullName:"Toshiyuki Yasuda"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12",title:"Numerical Simulations",subtitle:"Examples and Applications in Computational Fluid Dynamics",isOpenForSubmission:!1,hash:null,slug:"numerical-simulations-examples-and-applications-in-computational-fluid-dynamics",bookSignature:"Lutz Angermann",coverURL:"https://cdn.intechopen.com/books/images_new/12.jpg",editedByType:"Edited by",editors:[{id:"13342",title:"Prof.",name:"Lutz",surname:"Angermann",slug:"lutz-angermann",fullName:"Lutz Angermann"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"13",title:"Paths to Sustainable Energy",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"paths-to-sustainable-energy",bookSignature:"Jatin Nathwani and Artie Ng",coverURL:"https://cdn.intechopen.com/books/images_new/13.jpg",editedByType:"Edited by",editors:[{id:"13730",title:"Dr.",name:"Artie",surname:"Ng",slug:"artie-ng",fullName:"Artie Ng"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"14",title:"Traveling Salesman Problem",subtitle:"Theory and Applications",isOpenForSubmission:!1,hash:null,slug:"traveling-salesman-problem-theory-and-applications",bookSignature:"Donald Davendra",coverURL:"https://cdn.intechopen.com/books/images_new/14.jpg",editedByType:"Edited by",editors:[{id:"2961",title:"Prof.",name:"Donald",surname:"Davendra",slug:"donald-davendra",fullName:"Donald Davendra"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"66799",title:"Cellular-Defined Microenvironmental Internalization of Exosomes",doi:"10.5772/intechopen.86020",slug:"cellular-defined-microenvironmental-internalization-of-exosomes",body:'\nIntercellular communication is essential to homeostasis and is largely dependent on the cellular secretome [1]. An emerging awareness of the role that the extracellular environment plays is evident in the field of secreted vesicles. The vesicular contribution to the tumor microenvironment (TME) has furthered our understanding of the communication between cells and the surrounding stroma [2]. This relationship has also elucidated many potential therapeutic targets and possible transporters of chemotherapeutics [3, 4]. There are multiple extracellular vesicle types, characterized by biogenesis, size, and common protein markers [5, 6]. Of these, exosomes are the smallest, with sizes ranging from 30 to 150 nm [6]. These vesicles have the most complex synthesis, emerging from the endocytic pathway. They arise from intraluminal invaginations into a multivesicular body (MVB) and are released from the cell when the MVB fuses with the plasma membrane. Exosomes consist of intracellular material surrounded by a lipid membrane that reflects the cellular membrane of the host cell [7]. These specific vesicles have demonstrated promise in several fields of research, including rheumatoid arthritis [8, 9] and neurodegenerative disease [10], but primarily in cancer [11, 12]. Tumor-derived exosomes (TEX) contain oncoproteins and oncogenes from the cell of origin and thus are very influential in intercellular communication. Numerous studies have used these luminal proteins and genes to better understand tumor growth and metastasis, as well as for improving diagnostic, prognostic, and therapeutic methods [13, 14].
\nWhile there has been an exponential growth in research focused on exosome biology, clarification on the mechanisms of transport between the cell of origin and the recipient cell is essential to maximizing on exosome potential in treating and diagnosing disease. The methods by which exosomes influence the cells with which they interact are still under review. Some exosomes have been shown to fuse to the recipient cell [15, 16], while others are internalized by specific receptor-ligand interactions [17, 18] or by stimulating an indirect uptake by macropinocytosis [19]. Exosome binding to cells has been seen both as a mechanism of transferring luminal contents [15, 16] and as an initial step in the endocytosis process [17, 20]. The significance of the effects of cell-exosome binding in comparison to internalization is still unknown. Most types of endocytosis have been described in the process of exosome uptake [21], but which factors determine the specific mechanism used, are still unclear. Previous reviews have clearly identified a number of ligands and receptors involved in exosome trafficking [21, 22, 23], but little is known about the dependence of uptake mechanism on cell-type. This review presents the current understanding of the endocytosis process utilized by specific cells involved in exosomal internalization.
\nEndocytosis is a basic cellular function that is performed by all cell types in the process of maintaining homeostasis. Many of the molecules essential for cellular function are small enough to cross the cell membrane either passively or actively, however, other structures, such as exosomes, are too large and require a more complicated process. This general process of internalization is called endocytosis and is separated into various types based on the shape [24] and the size of particles internalized [25]. There are many well-written reviews covering the specifics of the endocytic pathways [25, 26], but here we will address them only superficially. Classification under the umbrella of endocytosis varies, but the major methods include phagocytosis, macropinocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, and clathrin/caveolin-independent or lipid raft-mediated endocytosis [25, 26]. Receptor-mediated endocytosis (RME) is an additional type that is often considered to be a subcategory under several of those previously mentioned (Figure 1).
\nEndocytosis pathways involved in exosome uptake: (A) Phagocytosis, (B) Macropinocytosis, (C) Clathrin-mediated endocytosis, (D) Caveolin-mediated endocytosis, (E) Lipid Raft-dependent or clathrin−/caveolin-independent endocytosis, (F) Receptor-mediated endocytosis.
Phagocytosis is the mechanism by which specialized cells (such as macrophages and monocytes) engulf large particles (>0.5 μm) by way of receptor/ligand interactions [25, 27] (Figure 1A). Promiscuous receptors allow for a broad range of ligand recognition and binding, facilitating a key role phagocytes play in clearing apoptotic cells [27]. Exosomes, derived from a diverse population of cells, present a vast array of available ligands that make phagocytes ideal recipient cells. This process of phagocytosis is designed to not only internalize extracellular material by enveloping it, but also to regulate the immune response by presenting degraded proteins as antigens on the phagocyte surface [25]. Tumor-derived exosomes influence immune involvement in the tumor [28, 29] which may be facilitated by this mechanism of endocytosis. Other non-phagocytic cells, such as epithelial cells, Sertoli, liver endothelial, astrocytes, and cancer cells have also been shown to perform phagocytosis [27], potentially expanding the impact of exosomal communication. It is therefore important to define how the process of phagocytosis influences exosome function and if that influence is cell type dependent.
\nWhile phagocytosis or “cell eating” involves ingestion of large molecules, macropinocytosis (“cell drinking”) internalizes slightly smaller particles (>1 μm) [25] (Figure 1B). This method is a way for cells to sample the external environment without specific receptors or ligands. It is a constitutive process in specialized antigen presenting cells, but is stimulated by growth factors in most others [30]. Macropinocytosis has a unique membrane ruffling process caused by projections from the cell surface encircling extracellular fluid and fusing to the membrane [25], resulting in an increased membrane surface area and volume of engulfed material. Nakase et al., showed that stimulation of the epidermal growth factor (EGF) receptor, either by soluble EGF or exosome-bound, increased exosome internalization 27-fold through the activation of macropinocytosis [19].
\nThe next three mechanisms, clathrin-dependent, caveolae-dependent, and clathrin/caveolae-independent, are facilitated by specific membrane proteins/structures: clathrin, caveolae, and lipid rafts. Clathrin is an intracellular protein that forms a coat around an invaginating vesicle facilitating formation and internalization [31] (Figure 1C). These vesicles internalize material around 120 nm [25], which is within the exosome size range. Stimulation can occur through receptor/ligand mediation or can be constitutive, depending on cell-type and receptor presence, but clathrin-mediated endocytosis (CME) occurs in all cell types [31]. Data continues to show that the extracellular cargo of these clathrin-coated vesicles can drive the specific mechanisms and protein interactions of internalization [32], giving way for exosome surface proteins to influence uptake. Two proteins used extensively to describe the details of CME are transferrin (Tf) and low density lipoprotein (LDL) and their respective receptors [25], which are all (except LDL) found on the surface of exosomes [33, 34]. Overexpression of transferrin receptors on cancer cells [35] may also contribute to increased exosomal uptake and clathrin-mediated endocytosis in tumors, as there have been shown to be 50–80 percent more receptors on the cancer cell compared to the non-cancer cell [36].
\nCaveolin is similar to clathrin, as it forms a coat around membrane invaginations called caveolae and facilitates the entry of extracellular material (Figure 1D). These are particularly prevalent on endothelial cells but have been found on a wide distribution of cell types [25]. Caveolae are about half the size of clathrin-coated vesicles, limiting their cargo to smaller structures [25] but still covering some of the exosome size range. This type of endocytosis as well as lipid raft-dependent uptake, plays a key role in lipid transport and homeostasis [25]. One of the defining factors of the exosome membrane is its slightly altered lipid profile, which has been shown to influence internalization [37]. Two proteins commonly active in caveolae-dependent endocytosis, which have also been identified on the surface of exosomes, are the insulin receptor and albumin [34, 38, 39]. The cellular insulin receptor itself has also recently been found to influence exosome uptake [18].
\nLipid dependence is not only characteristic of caveolae-dependent endocytosis, but also clathrin/caveolae-independent processes. Lipid raft-dependent (or clathrin/caveolae-independent) endocytosis is similar to caveolae-dependent, except for the absence of the protein cav-1. Lipid rafts are 40-50 nm sections of the membrane with a high percentage of glycosphingolipids and cholesterol, and are anchoring points for many membrane proteins [40]. Lipid rafts are involved in exosome biogenesis and trafficking [41, 42, 43] and exosome uptake has been reduced by blocking lipid raft endocytosis [44] (Figure 1E).
\nAs mentioned previously, RME is an endocytosis pathway that can fit under several of the other categories (Figure 1F). The term and pathway were originally considered to be interchangeable with CME, but it is now understood that not all RME is dependent on clathrin [25]. Receptor-ligand interactions play a role in phagocytosis [25, 27], macropinocytosis [19], and lipid raft-dependent endocytosis [40]. Exosome internalization has been linked to multiple receptor-ligand interactions in each of these pathways [19, 20]. Each subtype of endocytosis has been identified in the exosome internalization process (Table 1) but additional research is needed to determine the driving factors behind the specific mechanisms. One hypothesized factor is that the recipient cell type may determine the specific type of internalization.
\nEndocytosis pathway | \nRecipient cell type | \nRecipient cell line | \nExosome cell of origin | \nReferences | \n
---|---|---|---|---|
Phagocytosis | \nMacrophage | \nRAW264.7 | \nLeukemia cell (K562 or MT4) | \n[20] | \n
\n | Macrophage | \nJ774 | \nRat reticulocyte | \n[52] | \n
\n | Macrophage | \nPrimary | \nTrophoblast (Sw71) | \n[58] | \n
\n | Monocytes | \nPrimary | \nActivated T cell | \n[50] | \n
\n | Macrophage | \nPeritoneal | \nMouse melanoma cell (B16BL6) | \n[51] | \n
\n | Macrophage | \nMouse bone marrow-derived | \nMouse CRC (CT-26) | \n[54] | \n
\n | Microglia | \nMG6 | \nPheochromocytoma (PC12) | \n[117] | \n
\n | Microglia | \nBV-2 | \nNeuron (N2a) | \n[49] | \n
\n | Dendritic cell | \nMouse primary | \nMouse dendritic cell | \n[15] | \n
\n | Epithelial | \nOvarian cancer (SKOV3) | \nOvarian cancer cell (SKOV3) | \n[97] | \n
\n | Epithelial | \nAlveolar cells (A549) | \nDendritic cell | \n[66] | \n
Macropinocytosis | \nEpithelial | \nCervical cancer (HeLa) | \nEpidermoid carcinoma (A431) | \n[90] | \n
\n | Epithelial | \nEpidermoid carcinoma (A431), Pancreatic carcinoma (MIA PaCa-2) | \nCervical cancer cell (HeLa) | \n[19] | \n
\n | Epithelial | \nOvarian cancer (SKOV3) | \nOvarian cancer cell (SKOV3) | \n[97] | \n
\n | Epithelial | \nBreast cancer (MCF7) | \nNormal breast epithelial cell (MCF-10A)—exosome mimetics | \n[96] | \n
\n | Endothelial | \nCerebral vascular (hCMEC D3) | \nMacrophage (RAW264.7) | \n[89] | \n
\n | Microglia | \nPrimary mouse | \nMouse oligodendrocyte (Oli-neu) | \n[56] | \n
\n | Neuron precursor cell | \nPheochromocytoma (PC12) | \nPheochromocytoma (PC12) | \n[114] | \n
Clathrin-mediated endocytosis | \nEpithelial | \nOvarian cancer (SKOV3) | \nOvarian cancer cell (SKOV3) | \n[97] | \n
\n | Epithelial | \nAlveolar cells (A549) | \nDendritic cell | \n[66] | \n
\n | Epithelial | \nGastric cancer (AGS, MKN1) | \nGastric cancer cell (AGS, MKN1) | \n[94] | \n
\n | Epithelial | \nBreast cancer (MCF7) | \nNormal breast epithelial cell (MCF-10A)—exosome mimetics | \n[96] | \n
\n | Endothelial | \nCerebral vascular endothelial (hCMEC D3) | \nMacrophage (RAW264.7) | \n[89] | \n
\n | Endothelial | \nBrain microvascular endothelial | \nEmbryonic kidney cell (Hek293T) | \n[87] | \n
\n | Neuron | \nCortical mouse neuron | \nOligodendrocyte (Oli-neu) | \n[115] | \n
\n | Neuron precursor cell | \nPheochromocytoma (PC12) | \nPheochromocytoma (PC12) | \n[114] | \n
Caveolin-dependent endocytosis | \nEpithelial | \nCervical cancer (HeLa) | \nEpidermoid carcinoma (A431) | \n[90] | \n
\n | Epithelial | \n(CNE1, HONE1, NU-GC-3, A549) | \nEBV-infected B cells | \n[95] | \n
\n | Epithelial | \nBreast cancer (MCF7) | \nNormal breast epithelial cell (MCF-10A)—exosome mimetics | \n[96] | \n
\n | Endothelial | \nCerebral vascular endothelial (hCMEC D3) | \nMacrophage (RAW264.7) | \n[89] | \n
\n | Endothelial | \nBrain microvascular endothelial | \nEmbryonic kidney cell (Hek293T) | \n[87] | \n
Lipid raft-dependent endocytosis | \nDendritic cell | \nMouse primary | \nMouse dendritic cell | \n[15] | \n
\n | Dendritic cell (DC), T cell | \nMonocyte derived primary DC, T cell (Jurkat) | \nT cell (Jurkat) | \n[75] | \n
\n | Epithelial, endothelial | \nGlioblastoma (U87), umbilical vein endothelial (HUVEC) | \nGlioblastoma (U87) | \n[43] | \n
\n | Epithelial | \nOvarian cancer (SKOV3) | \nOvarian cancer cell (SKOV3) | \n[97] | \n
\n | Epithelial | \nBreast carcinoma (BT549) | \nBreast carcinoma (BT549) | \n[44] | \n
\n | Epithelial, macrophage, endothelial | \nMelanoma (A375), (RAW264.7), dermal microvascular endothelial (HMVEC) | \nMelanoma (A375) | \n[46] | \n
\n | Endothelial | \nBrain microvascular endothelial | \nEmbryonic kidney cell (Hek293T) | \n[87] | \n
\n | B cell | \nMantle cell lymphoma (Jeko1) | \nMantle cell lymphoma (Jeko1) | \n[61] | \n
Endocytosis pathways involved in exosome internalization in various cell types.
As introduced previously, some cells are uniquely designed to internalize extracellular material through phagocytosis. Those cells generally considered “professional” phagocytes are monocytes, macrophages, and neutrophils [25] with dendritic cells, osteoclasts, and eosinophils occasionally included [27]. Phagocytosis is dependent on receptor/ligand interactions, relying on a vast array of different receptors and ligands. Some of the established receptors include Fc receptors, integrins, pattern-recognition receptors, phosphatidylserine (PS) receptors, and scavenger receptors [45]. Macrophage uptake of exosomes has been shown to involve many of these receptors including scavenger receptors [46, 47, 48], PS/PS receptors [20, 48, 49, 50, 51], lectins [17, 52, 53] and Fc receptors [54].
\nHowever, internalization of extracellular material by phagocytes does not always fit perfectly with the hallmarks of phagocytosis. Some phagocytic receptors, such as integrins (αvβ3), scavenger receptors (CD68 and CD36), and CD14, facilitate the tethering of apoptotic cells to the phagocyte surface, but then are unable to initiate internalization without other means, such as PS and PS receptor binding [55]. The PS/PS receptor interaction also stimulates membrane ruffling and vacuole appearance—classic hallmarks of macropinocytosis [55]. Phagocytes are primarily involved in phagocytosis, but this evidence supports the idea that multiple modes of endocytosis are operational in the same cell. This is not unique to apoptotic cell uptake, but has been seen with exosome internalization by microglia (phagocytic cells in the brain) exhibiting a dependence on PS in a macropinocytic manner [49, 56]. Cooperation between multiple receptors appears to be an important characteristic of endocytosis in phagocytic cells. Plebenak et al., showed that the scavenger receptor SR-B1 on macrophages, when blocked, reduces exosome uptake, but with further testing on melanoma cells this blocking was dependent both on the receptor as well as on cholesterol flux in the lipid rafts [46], broadening the endocytosis landscape of phagocytes to include lipid raft-dependent endocytosis.
\nThe dependence of phagocytosis on extracellular- facing PS, which on healthy cells is expressed only on the cytosolic side of the membrane, is evidence that the material to be ingested influences the endocytic pathway of phagocytes. Further support of this interaction is found in the hypothesis that exosomes “target” specific recipient cells [48, 57]. Macrophage uptake (Figure 2A) of TEX is dependent on the presence of cellular scavenger receptors or exosomal PS [20, 46, 48, 51, 56], while non-tumor cell-derived exosomes require the presence of a heterogeneity of receptors. When internalized by macrophages and monocytes, hepatic stellate cell-derived exosomes require Fc receptors [54]; B cell, dendritic cell and reticulocyte-derived exosomes use lectins [52, 53]; trophoblast-derived exosomes bind to integrins [58]; and T cell-derived exosomes need scavenger receptors [50] (Table 2). Costa-Silva et al., showed that when comparing TEX to normal cell-derived exosomes, Kupffer cells, liver-specific macrophages, preferentially internalized TEX [57]. The significance of the exosome surface topography is therefore influential in directing a specific endocytosis pathway. Phagocytes are responsible for internalization of extracellular material and are so named based on the primary use of phagocytosis, but as seen above, other endocytic pathways are utilized, especially in the context of exosomal internalization.
\nCell-specific internalization of exosomes by antigen presenting cells: (A) macrophage, (B) B cell and (C) Dendritic cells each employ multiple endocytic pathways in the uptake of exosomes. Macrophages utilize multiple endocytic pathways in the uptake of exosomes. B Cells and dendritic cells (DC) both employ multiple endocytic pathways in the uptake of exsomes. Lipid rafts, integrins and adhesion molecules are used by B cells while tetraspanins and adhesion molecules are the more common receptors found in DC-exosome interactions. Intercellular adhesion molecule 1 (ICAM-1), Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN).
Protein | \nCell type | \nExosome origin | \nReferences | \n
---|---|---|---|
Scavenger receptor | \nMacrophage | \nHek293 (embryonic kidney cells) | \n[47] | \n
Phosphatidylserine (PS) | \nMacrophage, microglia | \nNeuron, melanoma, oligodendrocytes | \n[49, 50, 51, 56] | \n
PS receptor | \nMacrophage | \nActivated T cells | \n[50] | \n
TIM4 | \nMacrophage | \nK562, MT4 (leukemia cell lines) | \n[20] | \n
Lectins | \nLymph node cells, splenic cells, pancreatic adenocarcinoma, lung fibroblast, macrophage, dendritic cell, hCMEC/D3(brain endothelial cells), platelet, HeLa | \nPancreatic adenocarcinoma, reticulocyte, B cell, macrophage, mesenchymal stem cell | \n[17, 48, 52, 53, 65, 89, 72, 103] | \n
Fc receptors | \nMacrophage | \nCT26 (colon carcinoma cells) | \n[54] | \n
Integrins | \nMacrophage, B cell | \nTrophoblast, pancreatic adenocarcinoma cells | \n[17, 58] | \n
Tetraspanins | \nB cell, pancreatic adenocarcinoma, endothelial cell | \nPancreatic adenocarcinoma cells | \n[17, 48, 106] | \n
EGFR | \nA431 (epidermoid carcinoma cells) | \nHeLa cells | \n[19] | \n
CD11c | \nLymph node cells/splenic cells | \nPancreatic adenocarcinoma cells | \n[17] | \n
CD11b | \nLymph node cells/splenic cells | \nPancreatic adenocarcinoma cells | \n[17] | \n
CD44 | \nLymph node cells/splenic cells | \nPancreatic adenocarcinoma cells | \n[17] | \n
CD49d/CD106 | \nLymph node cells/splenic cells | \nPancreatic adenocarcinoma cells | \n[17] | \n
Tspan8 | \nEndothelial cell | \nPancreatic adenocarcinoma cells | \n[48, 106] | \n
ICAM-1/LFA-1 | \nDendritic cell, hCMEC/D3 (brain endothelial cells), aortic endothelium, HUVEC | \nDendritic cells, pancreatic adenocarcinoma cells, T cells, macrophage | \n[16, 17, 37, 65, 69, 89] | \n
DC-SIGN | \nDendritic cell | \nBreast milk | \n[70] | \n
HSPG | \nU87 (glioblastoma cells), CAG (myeloma), HUVEC, SW780 (bladder cancer cells) | \nU-87 cells, myeloma cells, SW780 cells | \n[63, 99, 100, 101] | \n
Cad-11 | \nPC3-mm2 (prostate cancer cells) | \nOsteoblasts | \n[104] | \n
Syncytin | \nChoriocarcinoma cells | \nTrophoblasts | \n[105] | \n
SNAP 25 | \nNeuron | \nMesenchymal stromal cells | \n[116] | \n
CD62L | \nLymph node cells, splenic cells, pancreatic adenocarcinoma, lung fibroblasts | \nPancreatic adenocarcinoma | \n[17, 48] | \n
Galectin 5 | \nMacrophage | \nReticulocyte | \n[52] | \n
CD169/ α2,3-linked sialic acid | \nLymph node cells, splenic cells | \nB cell | \n[53] | \n
C-type lectin/C-type lectin receptor | \nDendritic cell, brain endothelial cell (hCMEC/D3) | \nMacrophage | \n[65, 89] | \n
P-selectin/PSGL-1 | \nPlatelet | \nMacrophage | \n[72] | \n
Proteins involved in exosomal uptake.
The antigen presenting cells (APCs) include primary phagocytes such as macrophages, but also B cells and dendritic cells [59]. The immune response is heavily dependent on the recognition of foreign structures, such as peptides, for activation. These APCs sample the extracellular environment, digest and display peptides on their surface, and then present these peptides to immune cells that can execute the response. The intercellular trafficking of immune regulating proteins, such as the major histocompatibility complexes (MHC) [28], by exosomes has the potential to either stimulate or block the immune response, dependent on the exosomal contents [17]. Uptake of exosomes plays an important role in B cell and DC cell proliferation, protein presentation, and interactions with other immune cells [17].
\nB cells perform multiple functions as an immune cell, including presenting antigens to T cells in order to stimulate additional immune responses. B cells traditionally operate though clathrin-mediated endocytosis, relying heavily on the B-cell receptor [60]. However, when it comes to exosome internalization, B cells have shown a greater dependence on lipid rafts and various receptors, such as adhesion molecules and tetraspanins [17] than on clathrin, indicating a preference for clathrin-independent and receptor-mediated endocytosis (Figure 2B). In analyzing B cell uptake of exosomes, using the mantle cell lymphoma (mutated immature B cell) cell line, Jeko-1, Hazan-Halevy et al., found dynamin, epidermal growth factor receptor (EGFR), and cholesterol to be involved in exosome internalization instead of clathrin [61]. EGFR is a well-established target in cancer therapy, particularly with lung cancer [62] and its role in exosome internalization may lend clarity and power to multiple existing and future chemotherapeutics. Additional exosomal surface proteins, with receptor functions, have been identified as participants in B cell internalization of TEX, including integrins (CD49) and cell adhesion molecules (intercellular adhesion molecule 1—ICAM-1/CD54 and CD62L) [17].
\nThese protein interactions between the cell and the exosomal membranes are essential steps in the influence the exosome has on the recipient cell. Exosomes derived from myeloma cells, cancerous plasma (mature B) cells, are dependent on the interaction between exosomal fibronectin and cellular heparan sulfate in order to form a bond between cell and exosome, resulting in modification of intracellular signaling [63]. As seen with these cells, the effects caused by the exosomes are not entirely dependent on uptake, even though the standard operation of APCs requires internalization. Some exosome-cell binding (as opposed to internalization) may be sufficient, or specifically designed, to alter intracellular processes, including signaling, as is also seen with dendritic cell-derived exosomes and T cell function [16]. While the influence of heparan sulfate on internalization in B cells is still unclear, there is evidence linking heparan sulfate proteoglycans to exosomal internalization which indicates that while it wasn’t assessed in these cells, the uptake may still be present [21, 22, 23]. Whether these differing mechanisms and protein participants of uptake in the B cell population are dependent on normal versus oncologic physiology of recipient cells, or on the origin of the exosome population (tumor-derived versus non-tumor derived) is yet to be determined.
\nThese heterogeneous protein profiles are specific to each cell type and contribute to the comparative ability of each cell to internalize exosomes. In line with the role of B cells, it was found that they readily take in exosomes, in contrast to other immune cells such as T cells and natural killer cells [61, 64]. This suggests that certain immune cells are more effective at endocytosing exosomes than others, consistent with the primary functions of these specific cell types. Additional groups have shown that while B cells internalize exosomes, the uptake is significantly less than that of macrophages and dendritic cells, but similar to T cells [17]. This was shown in non-mutated mouse cells and may also illustrate important differences between cancer cell and normal cell internalization mechanisms.
\nDendritic cells (DC) can be classified as both APCs and as phagocytes since internalization of extracellular material is a crucial part of their role in the immune system. Endocytosis pathways involved in exosome uptake in these cells have been tested with various endocytic blockers, including cytochalasin D (inhibits actin polymerization), EDTA (chelates calcium), and decreased temperature (reducing active cellular processes) [15, 37, 65, 66]. As dendritic cells mature, their mode of endocytosis changes; starting first with macropinocytosis, and then in the mature cell, receptor-mediated endocytosis and phagocytosis prevails [67] (Figure 2C). Despite the evidence of phagocytosis in mature DCs, it was demonstrated that immature DCs are more adept at exosomal uptake [37, 68]. Developmental preference for exosome uptake may shed light on why cancer cells, which often have similar profiles to developing cells and are subject to continuous proliferation, are so responsive to modification by exosomes. Also, immature DCs play a role in immunologic tolerance and so are less likely to activate T cells, while mature DCs activate T cell immunity [15]. This down-regulation of the adaptive immune response by immature DCs would be advantageous for tumors and so TEX may specifically target immature DCs, explaining the increase in uptake. While the mechanism is still unknown, dendritic cells are also more likely to take up TEX or DC-derived exosomes than B and T cells, as seen with fluorescent staining
Many of the studies of exosome internalization by DCs have revealed dependence on various adhesion molecules. The ubiquity of these proteins on exosomes, leukocytes, and endothelial cells promotes the non-specific internalization characteristic of DCs. The involvement of ICAM-1 and/or its ligand, lymphocyte function-associated antigen (LFA-1), in DC-exosome interaction has been shown both
In addition to binding to membrane receptors, dendritic cell endocytosis is dependent on lipid rafts and the lipid components of the cell membrane, particularly with viral or bacterial uptake [73, 74]. As viruses and exosomes are similar in size, endocytosis mechanisms are often common between these two structures [22]. Lipid-dependent endocytosis is evident in exosome uptake by DCs as illustrated with DC- and T-cell derived exosomes [15, 75]. While proteins have been the most common structure analyzed in connection with exosomal uptake, the membrane cholesterol concentration of recipient cells [15] as well as the lipid profile of the exosomal membrane [75] both play a role in uptake of exosomes by dendritic cells and need further clarification.
\nIn addition to the previously mentioned cells, two other circulating cells/structures have also been found to endocytose exosomes, platelets and T cells. Platelets are cell fragments involved in blood coagulation that are unique in their formation as they are devoid of a nucleus and some organelles. Despite a reduced intracellular load, they are involved in binding extracellular vesicles. They do so through the interaction of cellular P-selectin and vesicular P-selectin glycoprotein ligand-1 (PSGL-1) as well as PS [72]. Data suggests that binding facilitates fusion of the exosomes to the platelets, transferring of material and enhancing platelet coagulation activity [72]. This speaks to the impact of these exosomes on intracellular communication, both in the variability and specificity of recipient cells, since binding and fusion occurred preferentially in the activated platelets [72] (Figure 3A). The exosomes in this study came from monocytes, suggesting this interaction could be a key player in coagulation at a site of injury.
\nCell-specific internalization of exosomes: (A) Platelet-exosome interactions have been linked to fusion as well as the binding to PSGL-1 and phosphatidylserine, (B) T cell are influenced through their surface interactions with exosomes.
T cells are the effector cells of the immune system and intercellular communication is essential for activation. Endocytosis, while not a primary function of T cells, is important to T cell receptor signaling [76] as well as other functions. Dynamin-dependent endocytosis [76], phagocytosis [77], and RME [78] are some of the mechanisms involved in T cell interaction with its surrounding environment. In relation to exosomes, T cells operate through RME [17, 79, 80] and lipid raft-dependent endocytosis [75]. However, T cells do not always readily uptake exosomes as was found in a comparison with other blood cell types. In a peripheral blood mononuclear cell culture, when uptake by monocytes was blocked, internalization by T-cells increased [47], suggesting that T cell uptake may be an adaptive response to increased exosome concentration. When exosome uptake was compared to multiple splenic leukocytes [15] or peripheral blood leukocytes [64], T cells showed minimal internalization. T cell activity is often regulated by surface interactions with other cells, such as with the T cell receptor and the MHC II/antigen interaction with APCs. Exosomal influence on T cells may therefore operate similarly with surface interaction instead of exosome internalization (Figure 3B). When cultured with DC or DC-derived exosomes, T cells acquired functional surface molecules including MHC II from exosomes through direct exosome interaction with the T cell membrane, while still showing little evidence of internalization [81]. Mouse T cells do not express MHC II and after incubation with these exosomes, this protein was identified on the surface of the T cell, suggesting the binding of exosomes to cellular membranes is sufficient to transfer material, without internalization [81]. Further research into the transfer of material between exosomes and immune cells may elucidate the role exosomes play in immune regulation in the tumor microenvironment. Depending on the cell type involved, exosome-mediated communication and manipulation may not be entirely dependent on endocytosis.
\nEpithelial and endothelial cells are responsible for lining most of the organs, spaces, and blood vessels in the body. They are in a prime position to be exposed to and actively endocytose a wide variety of extracellular material. Due to this broad selection, the specific mechanisms utilized are dependent on the cell subtype as well as the character of the endocytosed material [82, 83, 84]. With such variability, it is no surprise that exosome uptake by epithelial and endothelial cells is just as diverse (Figure 4). Cellular location of these cells is crucial in cancer biology as most of the TEX will be in close proximity to epithelial and endothelial cells either in the circulatory system or during paracrine spread in solid tumors. While there have been many studies on cell-exosome interaction in these cells, there is still much work needed to clearly understand all of the factors that dictate the endocytic mechanism of epithelial and endothelial cells from different tissues.
\nCell-specific internalization of exosomes: (A) epithelial and (B) endothelial cells. Epithelial cells and endothelial cells show the most diversity in exosome uptake of all the cell types. Multiple receptor involved in the internalization process are expressed on both cell types, including tetraspanins, adhesion molecules, and heparan sulfate peptidoglycans (HSPG). Intercellular adhesion molecule 1 (ICAM-1).
A unique finding in exosome studies with epithelial and endothelial cells is the dependence of uptake on intracellular signaling. Svensson et al., discovered that exosome internalization is dependent on the proper functioning of the signaling pathway, ERK1/2-HSP27 [43]. The promotion of endocytosis through intracellular signaling has been shown previously with EGFR-cSrc-ERK1/2 pathways in epithelial cells [85] and the Ras-PI3K pathway with virus uptake by fibroblasts [86]. However, little is known about how these pathways facilitate exosome internalization. The ability of exosomes to cross the blood–brain barrier and be endocytosed by the microvascular endothelial cells in the brain is also dependent on signaling. Tumor necrosis factor (TNFα) signaling, as is seen in stroke models, enhances exosome uptake [87]. Intracellular signaling may provide a regulatory mechanism to control exosome internalization. Some studies described previously have shown that fusion of exosomes to the cell membrane, without endocytosis, can influence intracellular signaling [63], but these are the first to show how intracellular signaling specifically impacts the endocytosis mechanism of exosomes. These results illustrate the complexity of exosome-cell interactions and where additional research is needed. The interdependence of exosome-cell interactions and intracellular signaling are unexplored areas with vast therapeutic potential and are necessary to better understand how extracellular vesicles influence their environment.
\nOther characteristics are influential in directing endocytosis in epithelial cells including vesicle size, lipid profile, and protein profile (Figure 4A). In epithelial cells, particle size dictates entry mechanism with macropinocytosis as one of the pathways operative at a size range that corresponds with exosomes [88]. This pattern is supported by multiple studies where exosome internalization was decreased when key aspects of macropinocytosis were targeted. Macropinocytosis was blocked with an inhibitor of Na+/H+ exchange (which affects Rac1 activation and actin reorganization) in human cerebral microvascular endothelial cells (hCMEC/D3) [89] and HeLa cells, as well as with an inhibitor of phosphoinositide 3-kinase (PI3K) (influences membrane ruffling and macropinosome formation) [19, 90] with concomitant decreases in exosome internalization. Assessing the same pathway but from an activating instead of inhibiting direction, exosome internalization was stimulated by activation of epidermal growth factor receptor (which activates Rac family members) in HeLa cells [19]. Membrane extensions, or filopodia, that facilitate the formation of the macropinosome and are regulated by Rac1 activation have also been shown to influence exosome internalization in hepatocyte (Huh7) and kidney (Hek293) cells [91], furthering the support that exosomes utilize macropinocytosis in multiple epithelial cell lines.
\nThe lipid profile of the exosomes and membrane integrity of the cell are also important contributors to vesicle uptake in several different types of epithelial and endothelial cells. While macrophages readily recognize external-facing PS, these cells can also utilize exosomal PS in the process of internalization, as was shown when pre-incubating exosomes with Annexin V inhibited uptake by HeLa cells (cervical cancer epithelial cells), A375 and A431 cells (squamous skin cancer cells) [92] and in human umbilical vein endothelial cells (HUVEC) [93]. Disruption of cellular lipid raft integrity through cholesterol depletion or sequestration reduced exosome uptake in U87 human glioblastoma epithelial cells [43], hCME/D3 human cerebral microvascular cells [89], HeLa cells [43, 90], HUVECs [43, 46], and A375 cells [46]. Lipid rafts play a key role in many of the functions of epithelial cells, including the protein binding interactions between cell and extracellular environment. Also, some of the most central components to epithelial cell function are proteins that interact closely with the environment such as integrins and adhesion molecules, and are anchored into lipid rafts.
\nProtein interactions are essential to epithelial and endothelial function and are closely tied to several of the most common endocytosis pathways used by these cells. Clathrin-dependent endocytosis has been shown in gastric [94], nasopharyngeal [95], breast [96], ovarian cancer epithelial cells [97] and HUVECs [98]. Caveolin-dependence was seen in breast [96] and nasopharyngeal cancer [95], however, caveolin-1 showed negative regulation in glioblastoma cell lines [43] (Figure 4B). General receptor-mediated uptake has been shown with several proteins including heparan sulfate peptidoglycan (HSPG) in glioblastoma cells and HUVECs [99, 100] and in the transitional epithelial cells of the bladder [101]; intercellular adhesion molecule (ICAM1) in hCMEC/D3 cells [89], rat aortic endothelial cells [48], and HUVECs [102]; lectins in cervical cancer [103], HUVECs [102], rat aortic endothelial cells [48] and hCMEC/D3 cells [89]; cad-11 in prostate cancer [104]; syncytin proteins in choriocarcinoma [105] and tetraspanins in an
The extracellular matrix (ECM) and stroma are important contributors to cellular homeostasis and function. This is particularly evident in tumors when evaluating the role of the tumor microenvironment (TME) on the survival and progression of the tumor cells. Fibroblasts are the major component of this extracellular environment. In normal physiology, they promote stromal stability, while in cancer, they contribute to altered ECM, increased angiogenesis, and metastasis [108]. These cells are in a pivotal position to interact with circulating exosomes and their internalization can have a compounding effect on the surrounding environment. Fibroblasts have been shown to participate primarily in clathrin-mediated endocytosis [109, 110] and occasionally receptor-mediated endocytosis [111]. Interestingly, RME [48, 106] and macropinocytosis [91] are the mechanisms by which fibroblasts have been shown to internalize exosomes (Figure 5). Tetraspanins are important proteins in fibroblast function and migration [112]. This protein family is well represented on the exosomal surface and is key to the uptake in many different cell types [48]. Additionally, evidence shows that the smaller the size of the vesicle, the more likely the fibroblast is to use receptors to internalize particles [111]. These three qualities lend support to the evidence of RME as a key pathway for fibroblasts to endocytose exosomes.
\nCell-specific internalization of exosomes: fibroblasts. Fibroblasts take up exosomes with tetraspanins and utilize multiple endocytic pathways.
The nervous system is a uniquely isolated environment with limited connection to the systemic circulation. This characteristic has long impeded therapeutic delivery for brain pathologies. The potential of exosome transport, however, is particularly poignant, as exosomes have been observed selectively targeting neurons and glial cells, successfully crossing the blood brain barrier [113]. Improving our understanding of endocytosis mechanisms involved in these particular cells is essential to therapeutic progression. Clathrin-mediated endocytosis is the most commonly observed pathway with exosomal trafficking between neurons and glial cells [114, 115]. However, some neurons also utilize macropinocytosis [114] and specific receptors, such as SNAP25 (a SNARE family protein) [116], to take up exosomes (Figure 6). Microglia performs phagocytosis similar to their counterparts in the extra-neuronal environment [117]. Using exosomes from two different sources, Chivet et al., illustrated the specificity of exosome targeting seen elsewhere in the body, is also evident in the nervous system. Exosomes from a neuroblastoma cell line (N2a) were preferentially internalized by astrocytes and oligodendrocytes, whereas exosomes from cortical neurons were primarily taken up by hippocampal neurons [118]. It was also shown that pre-synaptic regions were the primary site of internalization of these exosomes [118]. Endocytosis is an important process in the pre-synaptic membrane to recycle released synaptic vesicles [119], indicating that the exosomes may capitalize on this constitutive process for entrance to the neuron. Whether exosomes primarily utilize the specific clathrin-mediated endocytosis in this region [119] or are simply taken by chance with the constant bulk endocytosis [120] still remains unclear. Exosome uptake is a developing area of neuro-research, but with significant potential for therapeutics, it is growing rapidly.
\nCell-specific internalization of exosomes: neurons. Neurons use similar pathways but receptor/ligand binding has less variability. Synaptosomal associated protein 25 (SNAP25).
Exosomes are internalized by a multitude of cell types and play an important role in cellular physiology. Our grasp of the mechanisms of this internalization is growing as we are better able to identify characteristics of the cell and the vesicles that facilitate uptake. Pathologic states, such as cancer, have played an integral role in our understanding of how the cellular-exosomal interaction proceeds. Clarity is still needed to better understand the mechanisms by which exosome internalization is so varied from cell to cell and within the same cell. As we have seen with fibroblasts, the vesicle size can dictate mechanism of uptake [111]. The presence or abundance of specific proteins such as scavenger receptors on macrophages [46, 47, 48] and lipid profiles in several types of cells, such as external-facing phosphatidylserine [20, 48, 49, 56] all contribute to the specificity of uptake. As has been discussed, cell type can dictate uptake mechanism, particularly with phagocytic cells and professional antigen presenting cells, but even within these specialized cells, differing mechanisms occur regularly and further evaluation is needed to parse the primary determinants.
\nVarious types of endocytosis have been identified as possible mechanisms of intercellular transport of exosomal contents to include macropinocytosis [19, 56, 114], phagocytosis [20], clathrin-mediated [52, 114], caveolin-dependent [95], lipid raft-dependent [43, 46], and clathrin- /caveolin-independent [61] endocytosis. Though much about these processes is unique, there are some aspects where functional overlap exists between them. Macropinocytosis is a form of endocytosis that consists of membrane ruffles forming intracellular vesicles to internalize large amounts of extracellular fluid [30]. This varies from other forms of endocytosis in its formation of separate and distinct intracellular vesicles (macropinosomes) and the internalization of material that is considered non-specific exosomal has been recorded in microglia [56], human epidermoid carcinoma-derived A431 cells stimulated by endothelial growth factor receptor (EGFR) and by the pancreatic cancer MiaPaCa-2 cell line [19]. Macropinocytosis is not selective in which molecules are internalized from the extracellular environment, and so uptake may be dictated simply by proximity to the cells and not targeted by the exosome specifically [121]. However, it has been shown that some exosomes naturally induce macropinocytosis internalization [90] and others, through manipulation of exosomal content, can selectively activate this mechanism in order to increase uptake [122]. Phagocytosis is a much more common method of taking up exosomes, especially with phagocytic cells of the immune system. Feng et al., showed that two leukemia cell lines, K562 and MT4, solely utilized phagocytosis for exosome internalization [20, 121].
\nFour other general categories of endocytosis focus on specific cellular proteins that facilitate the uptake of particles. Clathrin and caveolin are both cytosolic proteins that form specific pits with which to internalize various substances [25]. The exact reasons why and when a cell uses clathrin, caveolin, or neither, is still incompletely understood but particle size and cell type seem to play a role [43, 115, 121]. Caveolin-dependent endocytosis is important in albumin uptake, cholesterol transport, and intracellular signaling. Due to the small size of the caveolae, its endocytosed material tends to be smaller than 60 nm [25]. Clathrin-dependent mechanisms however can internalize particles up to 120 nm. The size restrictions may indicate, with further investigation into which uptake mechanism is utilized by which cells, a possible functional difference between vesicle sizes within the current exosome size range [121]. The clathrin-dependent process is involved in many different cell types and functions ranging from vesicle recycling in the neuronal synapse to organ development and ion homeostasis [25]. Many of the common, well-known endocytosis receptors utilize clathrin coated pits, such as low-density lipoprotein receptor (LDLR) and transferrin receptor (TfR). One of the most commonly used ways to determine which of these mechanisms is in operation is through inhibitory drugs or knocking down certain key players [121]. Dynamin, a GTPase, facilitates the fission of the intracellular clathrin coated vesicle [25, 123]. Dynasore, an inhibitor of dynamin, has been utilized to effectively block endocytosis of extracellular vesicles and establish clathrin-mediated endocytosis as a mechanism of uptake for these vesicles [21, 52, 56]. Following siRNA downregulation of caveolin-1 (the primary protein involved in caveolae-dependent endocytosis), exosome internalization was significantly reduced in B cells [95, 121]. Inhibitory drugs have also been useful in the determination of a third mechanism, lipid-raft mediated endocytosis. The lipid raft is a small portion of the plasma membrane, rich in sphingolipids and sterols, that facilitates various cellular processes [124]. Use of methyl-β-cyclodextrin (MβCD), which alters the cholesterol content of the membrane and disrupts lipid rafts, has been seen by several groups to impair exosomal internalization [43, 44, 97]. While lipid raft-dependent endocytosis is the primary clathrin- and caveolae-independent mechanism, other pathways and independent interactions have been described in the internalization of exosomes [61, 124]. Endocytosis is the primary method of exosomal delivery of its contents but research is still needed to understand what determines the specific mechanism whether it is cell type, exosome type, or condition specific [121].
\nExosome stability, ubiquitous presence, and influential contents make them ideal candidates for therapeutic modalities in a wide variety of pathologies. The significance of exosomal contribution to the cellular network throughout the body still carries untapped potential for conquering some of the most pressing current health challenges including cancer and neurodegeneration. Understanding how these exosomes interact with and enter the myriad of cells in the body will empower our ability to capitalize on this natural social network.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
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\n\nWork - a Chapter, including Conference Papers, a Scientific Article and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
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\n\nScientific Journal – Periodical publication intended to further the progress of science.
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S. Lisar, Rouhollah Motafakkerazad, Mosharraf M. Hossain and Ismail M. M. Rahman",authors:[{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman"}]},{id:"62247",doi:"10.5772/intechopen.77315",title:"Application of Biosorption for Removal of Heavy Metals from Wastewater",slug:"application-of-biosorption-for-removal-of-heavy-metals-from-wastewater",totalDownloads:7633,totalCrossrefCites:75,totalDimensionsCites:149,abstract:"Fresh water accounts for 3% of water resources on the Earth. Human and industrial activities produce and discharge wastes containing heavy metals into the water resources making them unavailable and threatening human health and the ecosystem. Conventional methods for the removal of metal ions such as chemical precipitation and membrane filtration are extremely expensive when treating large amounts of water, inefficient at low concentrations of metal (incomplete metal removal) and generate large quantities of sludge and other toxic products that require careful disposal. Biosorption and bioaccumulation are ecofriendly alternatives. These alternative methods have advantages over conventional methods. Abundant natural materials like microbial biomass, agro-wastes, and industrial byproducts have been suggested as potential biosorbents for heavy metal removal due to the presence of metal-binding functional groups. Biosorption is influenced by various process parameters such as pH, temperature, initial concentration of the metal ions, biosorbent dose, and speed of agitation. Also, the biomass can be modified by physical and chemical treatment before use. The process can be made economical by regenerating and reusing the biosorbent after removing the heavy metals. Various bioreactors can be used in biosorption for the removal of metal ions from large volumes of water or effluents. The recent developments and the future scope for biosorption as a wastewater treatment option are discussed.",book:{id:"6137",slug:"biosorption",title:"Biosorption",fullTitle:"Biosorption"},signatures:"Sri Lakshmi Ramya Krishna Kanamarlapudi, Vinay Kumar\nChintalpudi and Sudhamani Muddada",authors:[{id:"238433",title:"Associate Prof.",name:"Sudhamani",middleName:null,surname:"Muddada",slug:"sudhamani-muddada",fullName:"Sudhamani Muddada"},{id:"244937",title:"Mrs.",name:"S L Ramyakrishna",middleName:null,surname:"Kanamarlapudi",slug:"s-l-ramyakrishna-kanamarlapudi",fullName:"S L Ramyakrishna Kanamarlapudi"},{id:"244938",title:"Mr.",name:"Vinay Kumar",middleName:null,surname:"Chintalpudi",slug:"vinay-kumar-chintalpudi",fullName:"Vinay Kumar Chintalpudi"}]},{id:"53211",doi:"10.5772/66416",title:"Biofloc Technology (BFT): A Tool for Water Quality Management in Aquaculture",slug:"biofloc-technology-bft-a-tool-for-water-quality-management-in-aquaculture",totalDownloads:16954,totalCrossrefCites:64,totalDimensionsCites:147,abstract:"Biofloc technology (BFT) is considered the new “blue revolution” in aquaculture. Such technique is based on in situ microorganism production which plays three major roles: (i) maintenance of water quality, by the uptake of nitrogen compounds generating in situ microbial protein; (ii) nutrition, increasing culture feasibility by reducing feed conversion ratio (FCR) and a decrease of feed costs; and (iii) competition with pathogens. The aggregates (bioflocs) are a rich protein-lipid natural source of food available in situ 24 hours per day due to a complex interaction between organic matter, physical substrate, and large range of microorganisms. This natural productivity plays an important role recycling nutrients and maintaining the water quality. The present chapter will discuss some insights of the role of microorganisms in BFT, main water quality parameters, the importance of the correct carbon-to-nitrogen ratio in the culture media, its calculations, and different types, as well as metagenomics of microorganisms and future perspectives.",book:{id:"5355",slug:"water-quality",title:"Water Quality",fullTitle:"Water Quality"},signatures:"Maurício Gustavo Coelho Emerenciano, Luis Rafael Martínez-\nCórdova, Marcel Martínez-Porchas and Anselmo Miranda-Baeza",authors:[{id:"146126",title:"Dr.",name:"Maurício Gustavo Coelho",middleName:null,surname:"Emerenciano",slug:"mauricio-gustavo-coelho-emerenciano",fullName:"Maurício Gustavo Coelho Emerenciano"},{id:"186970",title:"Prof.",name:"Marcel",middleName:null,surname:"Martínez-Porchas",slug:"marcel-martinez-porchas",fullName:"Marcel Martínez-Porchas"},{id:"186971",title:"Prof.",name:"Anselmo",middleName:null,surname:"Miranda-Baeza",slug:"anselmo-miranda-baeza",fullName:"Anselmo Miranda-Baeza"},{id:"195101",title:"Dr.",name:"Luis Rafael",middleName:null,surname:"Martínez-Córdoba",slug:"luis-rafael-martinez-cordoba",fullName:"Luis Rafael Martínez-Córdoba"}]}],mostDownloadedChaptersLast30Days:[{id:"69568",title:"Water Quality Parameters",slug:"water-quality-parameters",totalDownloads:10140,totalCrossrefCites:14,totalDimensionsCites:36,abstract:"Since the industrial revolution in the late eighteenth century, the world has discovered new sources of pollution nearly every day. So, air and water can potentially become polluted everywhere. Little is known about changes in pollution rates. The increase in water-related diseases provides a real assessment of the degree of pollution in the environment. This chapter summarizes water quality parameters from an ecological perspective not only for humans but also for other living things. According to its quality, water can be classified into four types. Those four water quality types are discussed through an extensive review of their important common attributes including physical, chemical, and biological parameters. These water quality parameters are reviewed in terms of definition, sources, impacts, effects, and measuring methods.",book:{id:"7718",slug:"water-quality-science-assessments-and-policy",title:"Water Quality",fullTitle:"Water Quality - Science, Assessments and Policy"},signatures:"Nayla Hassan Omer",authors:null},{id:"58138",title:"Water Pollution: Effects, Prevention, and Climatic Impact",slug:"water-pollution-effects-prevention-and-climatic-impact",totalDownloads:21541,totalCrossrefCites:18,totalDimensionsCites:38,abstract:"The stress on our water environment as a result of increased industrialization, which aids urbanization, is becoming very high thus reducing the availability of clean water. Polluted water is of great concern to the aquatic organism, plants, humans, and climate and indeed alters the ecosystem. The preservation of our water environment, which is embedded in sustainable development, must be well driven by all sectors. While effective wastewater treatment has the tendency of salvaging the water environment, integration of environmental policies into the actor firms core objectives coupled with continuous periodical enlightenment on the present and future consequences of environmental/water pollution will greatly assist in conserving the water environment.",book:{id:"6157",slug:"water-challenges-of-an-urbanizing-world",title:"Water Challenges of an Urbanizing World",fullTitle:"Water Challenges of an Urbanizing World"},signatures:"Inyinbor Adejumoke A., Adebesin Babatunde O., Oluyori Abimbola\nP., Adelani-Akande Tabitha A., Dada Adewumi O. and Oreofe Toyin\nA.",authors:[{id:"101570",title:"MSc.",name:"Babatunde Olufemi",middleName:null,surname:"Adebesin",slug:"babatunde-olufemi-adebesin",fullName:"Babatunde Olufemi Adebesin"},{id:"187738",title:"Dr.",name:"Adejumoke",middleName:"Abosede",surname:"Inyinbor",slug:"adejumoke-inyinbor",fullName:"Adejumoke Inyinbor"},{id:"188818",title:"Dr.",name:"Abimbola",middleName:null,surname:"Oluyori",slug:"abimbola-oluyori",fullName:"Abimbola Oluyori"},{id:"188819",title:"Mrs.",name:"Tabitha",middleName:null,surname:"Adelani-Akande",slug:"tabitha-adelani-akande",fullName:"Tabitha Adelani-Akande"},{id:"208501",title:"Dr.",name:"Adewumi",middleName:null,surname:"Dada",slug:"adewumi-dada",fullName:"Adewumi Dada"},{id:"208502",title:"Ms.",name:"Toyin",middleName:null,surname:"Oreofe",slug:"toyin-oreofe",fullName:"Toyin Oreofe"}]},{id:"45422",title:"Urban Waterfront Regenerations",slug:"urban-waterfront-regenerations",totalDownloads:14168,totalCrossrefCites:4,totalDimensionsCites:12,abstract:null,book:{id:"3560",slug:"advances-in-landscape-architecture",title:"Advances in Landscape Architecture",fullTitle:"Advances in Landscape Architecture"},signatures:"Umut Pekin Timur",authors:[{id:"165480",title:"Dr.",name:"Umut",middleName:null,surname:"Pekin Timur",slug:"umut-pekin-timur",fullName:"Umut Pekin Timur"}]},{id:"24941",title:"Tsunami in Makran Region and Its Effect on the Persian Gulf",slug:"tsunami-in-makran-region-and-its-effect-on-the-persian-gulf",totalDownloads:7552,totalCrossrefCites:4,totalDimensionsCites:7,abstract:null,book:{id:"406",slug:"tsunami-a-growing-disaster",title:"Tsunami",fullTitle:"Tsunami - A Growing Disaster"},signatures:"Mohammad Mokhtari",authors:[{id:"52451",title:"Dr.",name:"Mohammad",middleName:null,surname:"Mokhtari",slug:"mohammad-mokhtari",fullName:"Mohammad Mokhtari"}]},{id:"66307",title:"Bio-hydrogen and Methane Production from Lignocellulosic Materials",slug:"bio-hydrogen-and-methane-production-from-lignocellulosic-materials",totalDownloads:2947,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"This chapter covers the information on bio-hydrogen and methane production from lignocellulosic materials. Pretreatment methods of lignocellulosic materials and the factors affecting bio-hydrogen production, both dark- and photo-fermentation, and methane production are addressed. Last but not least, the processes for bio-hydrogen and methane production from lignocellulosic materials are discussed.",book:{id:"7608",slug:"biomass-for-bioenergy-recent-trends-and-future-challenges",title:"Biomass for Bioenergy",fullTitle:"Biomass for Bioenergy - Recent Trends and Future Challenges"},signatures:"Apilak Salakkam, Pensri Plangklang, Sureewan Sittijunda, Mallika Boonmee Kongkeitkajorn, Siriporn Lunprom and Alissara Reungsang",authors:null}],onlineFirstChaptersFilter:{topicId:"12",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82754",title:"Impact of Revegetation on Ecological Restoration of a Constructed Soil in a Coal Mining in Southern Brazil",slug:"impact-of-revegetation-on-ecological-restoration-of-a-constructed-soil-in-a-coal-mining-in-southern-",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.105895",abstract:"The main problems in the constructed soils are the generation of acid mine drainage promoted by the presence of coal debris in the overburden layer and the compaction of the topsoil promoted by the machine traffic when the material used in the overburden cover is more clayey. This book chapter aimed to show an overview of the impact of more than a decade of revegetation with different perennial grasses on the chemical, physical, and biological quality of constructed soil after coal mining. The study was carried out in a coal mining area, located in southern Brazil. The soil was constructed in early 2003 and the perennial grasses, Hemarthria altissima; Paspalum notatum cv. Pensacola; Cynodon dactylon cv Tifton; and Urochloa brizantha; were implanted in November/December 2003. In 11.5, 17.6 and 18 years of revegetation soil samples were collected and the chemical, physical, and biological attributes were determined. Our results show that liming is an important practice in the restoration of these strongly anthropized soils because this positively impacts the plants’ development, facilitating the roots system expansion. Biological attributes such as soil fauna and the microorganism’s population are the attributes that possibly takes longer to establish itself in these areas.",book:{id:"11663",title:"Vegetation Dynamics, Changing Ecosystems and Human Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11663.jpg"},signatures:"Lizete Stumpf, Maria Bertaso De Garcia Fernandez, Pablo Miguel, Luiz Fernando Spinelli Pinto, Ryan Noremberg Schubert, Luís Carlos Iuñes de Oliveira Filho, Tania Hipolito Montiel, Lucas Da Silva Barbosa, Jeferson Diego Leidemer and Thábata Barbosa Duarte"},{id:"82936",title:"Soil Degradation Processes Linked to Long-Term Forest-Type Damage",slug:"soil-degradation-processes-linked-to-long-term-forest-type-damage",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.106390",abstract:"Forest degradation impairs ability of the whole landscape adaptation to environmental change. The impacts of forest degradation on landscape are caused by a self-organization decline. At the present time, the self-organization decline was largely due to nitrogen deposition and deforestation which exacerbated impacts of climate change. Nevertheless, forest degradation processes are either reversible or irreversible. Irreversible forest degradation begins with soil damage. In this paper, we present processes of forest soil degradation in relation to vulnerability of regulation adaptability on global environmental change. The regulatory forest capabilities were indicated through soil organic matter sequestration dynamics. We devided the degradation processes into quantitative and qualitative damages of physical or chemical soil properties. Quantitative soil degradation includes irreversible loss of an earth’s body after claim, erosion or desertification, while qualitative degradation consists of predominantly reversible consequences after soil disintegration, leaching, acidification, salinization and intoxication. As a result of deforestation, the forest soil vulnerability is spreading through quantitative degradation replacing hitherto predominantly qualitative changes under continuous vegetation cover. Increasing needs to natural resources using and accompanying waste pollution destroy soil self-organization through biodiversity loss, simplification in functional links among living forms and substance losses from ecosystem. We concluded that subsequent irreversible changes in ecosystem self-organization cause a change of biome potential natural vegetation and the land usability decrease.",book:{id:"11457",title:"Forest Degradation Under Global Change",coverURL:"https://cdn.intechopen.com/books/images_new/11457.jpg"},signatures:"Pavel Samec, Aleš Kučera and Gabriela Tomášová"},{id:"82828",title:"Vegetation and Avifauna Distribution in the Serengeti National Park",slug:"vegetation-and-avifauna-distribution-in-the-serengeti-national-park",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.106165",abstract:"In order to examine the bird species changes within different vegetation structures, the variations were compared between Commiphora-dominated vegetations with those of Vachellia tortilis and Vachellia robusta-dominated vegetations, and also compared the birds of grassland with those of Vachellia drepanolobium and Vachellia seyal-dominated vegetations. This study was conducted between February 2010 and April 2012. A total of 40 plots of 100 m × 100 m were established. Nonparametric Mann-Whitney U-test was used to examine differences in bird species between vegetations. Species richness estimates were obtained using the Species Diversity and Richness. A total of 171 bird species representing 103 genera, 12 orders, and 54 families were recorded. We found differences in bird species distribution whereby V. tortilis has higher bird species richness (102 species), abundance, and diversity when compared with Commiphora with 66 species and V. robusta with 59 species. These results suggest that variations in bird species abundance, diversity, and distribution could be attributed to differences in the structural diversity of vegetation. Therefore it is important to maintain different types of vegetation by keeping the frequency of fire to a minimum and prescribed fire should be employed and encouraged to control wildfire and so maintain a diversity of vegetation and birds community.",book:{id:"11663",title:"Vegetation Dynamics, Changing Ecosystems and Human Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11663.jpg"},signatures:"Ally K. Nkwabi and Pius Y. Kavana"},{id:"82808",title:"Climate Change and Anthropogenic Impacts on the Ecosystem of the Transgressive Mud Coastal Region of Bight of Benin, Nigeria",slug:"climate-change-and-anthropogenic-impacts-on-the-ecosystem-of-the-transgressive-mud-coastal-region-of",totalDownloads:8,totalDimensionsCites:0,doi:"10.5772/intechopen.105760",abstract:"The transgressive mud coastal area of Bight of Benin is a muddy coastal complex that lies east of the Barrier/lagoon coast and stretches to the Benin River in the northwestern flank of the Niger Delta Nigeria. It constitutes a fragile buffer zone between the tranquil waters of the swamps and the menacing waves of the Atlantic Ocean. Extensive breaching of this narrow coastal plain results in massive incursion of the sea into the inland swamps with serious implications for national security and the economy. Climate change impacts from the results of meteorological information of the regions shows a gradual degradation in the past 30 years. Temperature, rainfall and humidity increase annually depict climate change, resulting from uncontrolled exploitation of natural resources is rapidly pushing the region towards ecological disasters. The ecosystem is very unique being the only transgressive mud coastal area of the Gulf of Guinea. The chapter describes the geomorphology, tidal hydrology, relief/drainage, topography, climate/meteorology, vegetation, economic characteristics, anthropogenic activities and their impacts on the ecosystem.",book:{id:"11663",title:"Vegetation Dynamics, Changing Ecosystems and Human Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11663.jpg"},signatures:"Patrick O. Ayeku"},{id:"82697",title:"Analyzing the Evolution of Land-Use Changes Related to Vegetation, in the Galicia Region, Spain: From 1990 to 2018",slug:"analyzing-the-evolution-of-land-use-changes-related-to-vegetation-in-the-galicia-region-spain-from-1",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106015",abstract:"Considering the complex dynamics, patterns, and particularities that the Galicia region present—e.g., the fragility, shown to achieve sustainable development and growth—a study that analyzes the Land-Use related to the vegetation of this region is seen as pivotal to identifying barriers and opportunities for long-term sustainable development. Using GIS (Geographic Information Systems), the present chapter enables us to identify the dynamics and patterns of the evolution of the Land-Use Changes related to vegetation in the Galicia Region from 1990 to 2018 (years 1990, 2000, 2012, and 2018 using CORINE (Coordination of Information on the Environment) data). This study permits us to reinforce that the Land-Use Changes related to vegetation in the Galicia Region have undergone multiple changes—marked by increasing and decreasing periods. Also, can be considered a surveying baseline for the comparative analysis of similar works for different Land-Use Changes related to vegetation trends in Europe or worldwide. Land-Use Changes related to vegetation studies are reliable tools to evaluate the human activities and footprint of proposed strategies and policies in a territory. This chapter also enables us to understand that the main actors should design development policies to protect, preserve and conserve these incomparable landscapes, environments, ecosystems, and the region as a whole.",book:{id:"11663",title:"Vegetation Dynamics, Changing Ecosystems and Human Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11663.jpg"},signatures:"Sérgio Lousada and José Manuel Naranjo Gómez"},{id:"80404",title:"Biotisation of Vegetables",slug:"biotisation-of-vegetables",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.102551",abstract:"The research proposes a biofertiliser from mycorrhiza and rhizobium evaluating its antagonistic capacity and biotisation in the cultivation of vegetables with a DCA, the sample considers the potato, pea, and barley in the Huasahuasi Peruvian District, with nine treatments in three formulas, considering a control group without inoculation and two repetitions. 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He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}}]}},subseries:{item:{id:"9",type:"subseries",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11405,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. His research interests include biomaterials, nanomaterials, bioengineering, biosensors, drug delivery systems, and tissue engineering.",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343"},editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",slug:"cecilia-cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",slug:"gil-goncalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",slug:"johann-f.-osma",fullName:"Johann F. 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