Subgroups of clay minerals.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"7168",leadTitle:null,fullTitle:"Sarcoidosis and Granulomatosis - Diagnosis and Management",title:"Sarcoidosis and Granulomatosis",subtitle:"Diagnosis and Management",reviewType:"peer-reviewed",abstract:"Sarcoidosis is a multi-organ, granulomatous disease the etiology of which remains unknown. It is characterized by T-cell dysfunction and B-cell hyperactivity with increased local immune activity and inflammation that leads to the formation of noncaseating granulomas in the organs involved. The lung and lymphatic system are the most commonly affected organs, however virtually any organ may be affected. Other common sites of involvement include the skin, eye, central nervous system, and the heart. Patients may present different symptoms related to the disease stage and the specific organ involved. Sarcoidosis is a global disease, and its prevalence has increased twofold over the past years. Due to the clinical heterogeneity and variable diagnostic criteria in different countries, it is difficult to calculate the exact prevalence and incidence of sarcoidosis. Age, sex, race, and geographic origin significantly influence the incidence of sarcoidosis. The book at hand seeks to assess the current diagnostic techniques, imaging techniques, differential diagnosis of this disease, as well as other granulomatous diseases mimicking sarcoidosis.",isbn:"978-1-83962-833-7",printIsbn:"978-1-83881-035-1",pdfIsbn:"978-1-83962-834-4",doi:"10.5772/intechopen.73968",price:119,priceEur:129,priceUsd:155,slug:"sarcoidosis-and-granulomatosis-diagnosis-and-management",numberOfPages:178,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"af4ff1c85383b3aa8131e3475e235654",bookSignature:"Mohammad Hosein K. Motamedi",publishedDate:"July 29th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7168.jpg",numberOfDownloads:6656,numberOfWosCitations:0,numberOfCrossrefCitations:2,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 14th 2018",dateEndSecondStepPublish:"September 18th 2019",dateEndThirdStepPublish:"November 17th 2019",dateEndFourthStepPublish:"February 5th 2020",dateEndFifthStepPublish:"April 5th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"90148",title:"Dr.",name:"Mohammad Hosein",middleName:"Kalantar",surname:"Motamedi",slug:"mohammad-hosein-motamedi",fullName:"Mohammad Hosein Motamedi",profilePictureURL:"https://mts.intechopen.com/storage/users/90148/images/system/90148.jpg",biography:"Dr. Mohammad Hosein Kalantar Motamedi is a Professor of Oral and Maxillofacial Surgery at the Trauma Research Center, BMSU, and attending faculty of OMF Surgery at the Azad University of Medical Sciences, Tehran. He received his American Diploma from Pennington High School, in Pennington, VA, USA (honor student) and his Iranian Diploma from Hurr High School in Tehran (honor student). After graduation he was accepted at the University of Houston, Texas, USA where he studied predent. Two years later he transferred to the University of Tehran College of dentistry where he received his Doctorate of Dental Surgery Degree (DDS). He completed his Residency in Oral and Maxillofacial Surgery at SBUMS from 1987-1991, and was valedictorian of the National Board Exams in 1991. In 1995 he completed his fellowship at the University of Basel, Switzerland; he obtained full Professorship in 2007. He has published 25 books, 61 international conferences proceedings, supervised 63 doctorate dissertations, and published 185 papers indexed in PUBMED with an h-index of 21. He is Editor-in-Chief of TRAUMA MONTHLY journal and one of the founders of the BMSU Trauma Research Center and more recently the Craniomaxillofacial Research Center. He was granted 1st place prize at the Bagher Alum National Research Festival in 2010 and awarded 2nd Place Prize at the 16th International Razi Research Festival on Medical Sciences. The Iranian Society of OMF Surgeons awarded him “Most Published” in 2009 and 2010, and he was chosen for membership in the National Elite Foundation. In 2013 he was accepted in the Academy of Medical Sciences and he is listed in the Marquis Book \\'Who’s Who in the World” (1999-2020).",institutionString:"BMSU and AUMS",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"7",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"Baqiyatallah University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1035",title:"Clinical Immunology",slug:"immunology-allergology-and-rheumatology-clinical-immunology"}],chapters:[{id:"64993",title:"Introductory Chapter: Orofacial Sarcoidosis and Noncaseating Granulomatosis",doi:"10.5772/intechopen.83364",slug:"introductory-chapter-orofacial-sarcoidosis-and-noncaseating-granulomatosis",totalDownloads:779,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Sharareh Kamfar, Taghi Azizi and Mohammad Hosein Kalantar Motamedi",downloadPdfUrl:"/chapter/pdf-download/64993",previewPdfUrl:"/chapter/pdf-preview/64993",authors:[{id:"90148",title:"Dr.",name:"Mohammad Hosein",surname:"Motamedi",slug:"mohammad-hosein-motamedi",fullName:"Mohammad Hosein Motamedi"}],corrections:null},{id:"71951",title:"Current Diagnostic Techniques in Sarcoidosis",doi:"10.5772/intechopen.90692",slug:"current-diagnostic-techniques-in-sarcoidosis",totalDownloads:481,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Sarcoidosis is an enigmatic disorder with a propensity for lung involvement in the majority of cases (~90%) and is characterized by noncaseating granulomatous inflammation on histological analysis. The techniques to establish the diagnosis have evolved over time, and a clear diagnostic algorithm for the clinicians dealing with this disease is desirable. Thoracic computed tomography is the imaging modality of choice in pulmonary sarcoidosis and provides accurate assessment of staging, parenchymal involvement, and response to immunomodulatory therapies. The advent of EBUS-TBNA has been a step forward with an excellent diagnostic yield in the presence of mediastinal/hilar lymphadenopathy and has replaced the traditional approach of obtaining biopsy samples via transbronchial and endobronchial routes. The preferred initial investigation for the confirmation of diagnosis is dependent on the organ involvement and the expertise available. A core biopsy of cervical lymph nodes is a less invasive and economical alternative in selected cases of suspected pulmonary sarcoidosis and warrants further evaluation in prospective manner to establish if it can be considered as a first-line investigation in all new cases suspected to have pulmonary sarcoidosis. A multidisciplinary approach is crucial for the diagnosis and management, and a simplified algorithm is proposed to help guide clinicians dealing with this disease of myriad clinical and radiological manifestations.",signatures:"Rajarajan Anandavelu and Ahmed Fahim",downloadPdfUrl:"/chapter/pdf-download/71951",previewPdfUrl:"/chapter/pdf-preview/71951",authors:[{id:"311258",title:"Dr.",name:"Ahmed",surname:"Fahim",slug:"ahmed-fahim",fullName:"Ahmed Fahim"},{id:"315762",title:"Dr.",name:"Rajarajan",surname:"Anandavelu",slug:"rajarajan-anandavelu",fullName:"Rajarajan Anandavelu"}],corrections:null},{id:"71820",title:"Early Diagnosis of Sarcoidosis",doi:"10.5772/intechopen.90523",slug:"early-diagnosis-of-sarcoidosis",totalDownloads:488,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Sarcoidosis is a rare unknown etiology multisystem inflammatory disease in which noncaseating granulomas (a collection of inflammatory cells) forms and growth in various organs, involving predominantly lungs, intrathoracic lymph node, skin, and eyes. Most commonly, affecting patients between 20 and 40 years old of age, although could be observed at any age (female predominance; rare in Asians). The areas of the body usually affected by sarcoidosis are lungs, skin, or lymph nodes; pulmonary and mediastinal involvement is seen in over 90% of patients. Less commonly eyes, liver, heart, and brain are involved. Any organ, however, can be affected. Early diagnosis of sarcoidosis can be difficult due to few signs and symptoms in its early stages, and when disease does occur, it may mimic other pathologies, and it is achieved through chest X-ray, computed tomography (CT)-high resolution CT (HRCT), gallium scans. Fluoro-deoxy glucose-positron emission tomography (FDG-PET) is another useful tool to assess the extent of disease and has a potential to evaluate the clinical management of patients responding or not to the treatment. Imaging gives, moreover, an important contribution to the evaluation of prognosis and follow-up.",signatures:"Marica Tina Maccarone",downloadPdfUrl:"/chapter/pdf-download/71820",previewPdfUrl:"/chapter/pdf-preview/71820",authors:[{id:"311355",title:"Dr.",name:"Maccarone",surname:"Marica Tina",slug:"maccarone-marica-tina",fullName:"Maccarone Marica Tina"}],corrections:null},{id:"71952",title:"Pathology of Sarcoidosis and Differential Diagnostics of other Granulomatous Diseases",doi:"10.5772/intechopen.90693",slug:"pathology-of-sarcoidosis-and-differential-diagnostics-of-other-granulomatous-diseases",totalDownloads:896,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Granulomatous diseases are the heterogeneous group of the conditions of different etiologies with a variety of clinic syndromes and morphological features and nonuniform sensitivity to therapy, and the existence of granulomas as general dominate histological expression. Granuloma is indicative of chronic inflammation involving cells of the macrophage system and other inflammatory cells. After the antigen exposure, the activation of T-lymphocytes, macrophages, and epithelioid histiocytes leads to granuloma formation. Granuloma also contains the extracellular matrix produced by fibroblasts, which provide the boundary and isolation of antigen. Their etiology may classify granulomatous diseases as infectious and noninfectious. However, recent studies demonstrate that pathogenic microorganisms may cause the granuloma formation in diseases previously considered as noninfectious. In some cases, differentiation between infectious and noninfectious processes may be problematic. This chapter aims to highlight the multiformity of granulomatous diseases, characterize the pathologic features of different infectious and noninfectious granulomatosis, and delineate the diagnostic approach.",signatures:"Maria V. Samsonova and Andrey L. Chernyaev",downloadPdfUrl:"/chapter/pdf-download/71952",previewPdfUrl:"/chapter/pdf-preview/71952",authors:[{id:"311531",title:"Dr.",name:"Maria",surname:"Samsonova",slug:"maria-samsonova",fullName:"Maria Samsonova"}],corrections:null},{id:"72701",title:"Clinical Manifestations of Sarcoidosis and Granulomatous Disorders",doi:"10.5772/intechopen.92236",slug:"clinical-manifestations-of-sarcoidosis-and-granulomatous-disorders",totalDownloads:671,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Sarcoidosis is a multisystem granulomatous disease, mainly involving the lungs, mediastinal and peripheral lymph nodes, liver, eyes, and skin. Cutaneous manifestations of sarcoid are variable and behave as “great imitators” of other cutaneous disorders. Cutaneous lesions are classified as specific and nonspecific forms. A large number of systemic sarcoidosis patients have specific cutaneous lesions, and this may be the presenting feature; isolated skin lesions may also present in some patients. Specific lesions of sarcoid are red-brown or red-violaceous in color, asymptomatic, and usually multiple in number. Different types of lesions may present in the same patient. This clinical appearance is due to the presence of epithelioid cell granulomas in the dermis.",signatures:"Suchibrata Das",downloadPdfUrl:"/chapter/pdf-download/72701",previewPdfUrl:"/chapter/pdf-preview/72701",authors:[{id:"312307",title:"Associate Prof.",name:"Suchibrata",surname:"Das",slug:"suchibrata-das",fullName:"Suchibrata Das"}],corrections:null},{id:"66224",title:"Granulomatous Interstitial Nephritis in Children Resulting from Wegener’s Granulomatosis, Crohn’s Disease, or Sarcoidosis",doi:"10.5772/intechopen.84491",slug:"granulomatous-interstitial-nephritis-in-children-resulting-from-wegener-s-granulomatosis-crohn-s-dis",totalDownloads:616,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Granulomatous interstitial nephritis (GIN) is a rare type of kidney disease, the precise etiology of which is obscure, but is most commonly seen following drug therapy and infection. The main infections seen in the onset of this pathology, especially in immunocompromised patients, include mycobacteria and fungi. Granulomatous interstitial nephritis can be a manifestation of systemic diseases, such as Wegener’s granulomatosis, Crohn’s disease, or sarcoidosis. We present our experience with GIN diagnosis and management.",signatures:"Galina Makovetskaya, Lilia Mazur and Elena Balashova",downloadPdfUrl:"/chapter/pdf-download/66224",previewPdfUrl:"/chapter/pdf-preview/66224",authors:[{id:"259110",title:"Prof.",name:"Galina",surname:"Makovetskaya",slug:"galina-makovetskaya",fullName:"Galina Makovetskaya"},{id:"270215",title:"Prof.",name:"Lilia",surname:"Mazur",slug:"lilia-mazur",fullName:"Lilia Mazur"},{id:"270216",title:"Dr.",name:"Elena",surname:"Balashova",slug:"elena-balashova",fullName:"Elena Balashova"}],corrections:null},{id:"68648",title:"Cardiac Sarcoidosis",doi:"10.5772/intechopen.85310",slug:"cardiac-sarcoidosis",totalDownloads:613,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Sarcoidosis is a systemic disease of unknown origin characterized by the infiltration of non-necrotizing granulomas that can affect any organ. The presentation of cardiac involvement can range from slight infiltration to complete atrioventricular block, ventricular arrhythmia, or cardiac failure. The diagnosis requires a high index of suspicion; approach to treatment depends upon the presence, or absence, of extracardiac sarcoidosis; sometimes a biopsy of the myocardial tissue is the only way to obtain an accurate diagnosis. Nuclear magnetic resonance imaging is the imaging technique which can provide information useful in diagnosis of this condition. If there is active inflammation, the fundamental form of treatment is immunosuppression therapy. Other concomitant treatments can be required such as the implantation of devices or modulation of arrhythmias. The prognosis is conditioned depending upon the extent of the disease and response to the therapy.",signatures:"Jhan Carlos Altamar Castillo and Miguel Jose Tejeda Camargo",downloadPdfUrl:"/chapter/pdf-download/68648",previewPdfUrl:"/chapter/pdf-preview/68648",authors:[{id:"260250",title:"Ph.D.",name:"Jhan Carlos",surname:"Altamar",slug:"jhan-carlos-altamar",fullName:"Jhan Carlos Altamar"},{id:"269921",title:"Dr.",name:"Miguel",surname:"Tejeda",slug:"miguel-tejeda",fullName:"Miguel Tejeda"}],corrections:null},{id:"71953",title:"Particularities of Hepatic Sarcoidosis",doi:"10.5772/intechopen.90694",slug:"particularities-of-hepatic-sarcoidosis",totalDownloads:664,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Liver sarcoidosis is usually an underdiagnosed disease, which can have severe implications in the evolution of a patient. Due to the fact that sarcoidosis is a disease based on immunological disorders, it is only natural that the liver should be one of the first organs to be affected. The imaging of liver sarcoidosis is of marked importance, especially in the differential diagnosis of the disease. While the histology aspect of sarcoidosis is relatively clear and should prompt a positive diagnosis, finding a liver granuloma in ultrasonography raises a multitude of questions and implies extensive testing for diagnosis. Furthermore, treatment of liver sarcoidosis is controversial, taking into account the possibility of developing end-stage liver disease in patients with a long history of sarcoidosis. This chapter aims to review diagnostic and treatment options for liver sarcoidosis and to determine the best management of these patients.",signatures:"Laura Iliescu and Letitia Toma",downloadPdfUrl:"/chapter/pdf-download/71953",previewPdfUrl:"/chapter/pdf-preview/71953",authors:[{id:"312218",title:"Dr.",name:"Laura",surname:"Iliescu",slug:"laura-iliescu",fullName:"Laura Iliescu"},{id:"312302",title:"Dr.",name:"Letitia",surname:"Toma",slug:"letitia-toma",fullName:"Letitia Toma"}],corrections:null},{id:"71970",title:"Sarcoid Granulomas in Malignancy",doi:"10.5772/intechopen.92182",slug:"sarcoid-granulomas-in-malignancy",totalDownloads:396,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Noncaseating epithelioid granulomas without accompanying systemic symptoms of sarcoidosis have been described in association with many primary tumors where they are designated as sarcoid-like (SL) reaction. Morphologically, this SL reaction is similar to granulomas found in systemic sarcoidosis comprising of focal accumulation of epithelioid cells and multinucleated giant cells. They can be seen either adjacent to the primary malignancy or in local draining lymph nodes. Additionally, sarcoid-like granulomas can affect other organs distant from the primary neoplasm, such as the spleen, bone marrow, and skin. This sarcoid-like reaction is thought to occur as an immunologic T-cell-mediated response to antigens expressed by the neoplastic cells or soluble tumor antigens. Whether the presence of this sarcoid-like reaction has any prognostic significance in the associated neoplasm is unclear.",signatures:"Komal Arora, Neeraj Kaur and Jae Y. Ro",downloadPdfUrl:"/chapter/pdf-download/71970",previewPdfUrl:"/chapter/pdf-preview/71970",authors:[{id:"213660",title:"Dr.",name:"Komal",surname:"Arora",slug:"komal-arora",fullName:"Komal Arora"},{id:"288705",title:"Prof.",name:"Jae Y.",surname:"Ro",slug:"jae-y.-ro",fullName:"Jae Y. Ro"},{id:"316464",title:"Dr.",name:"Neeraj",surname:"Kaur",slug:"neeraj-kaur",fullName:"Neeraj Kaur"}],corrections:null},{id:"71879",title:"Sarcoid Involvement of the Mammary Gland",doi:"10.5772/intechopen.92183",slug:"sarcoid-involvement-of-the-mammary-gland",totalDownloads:421,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Sarcoidosis is a systemic granulomatous disease of unknown cause. Mammary involvement is rare, less than 1% of all cases. In addition, it makes necessary an appropriate differential diagnosis in order to rule out malignant pathology as the main diagnosis. Therefore, it is necessary to carry out different tests as mammography, ultrasound, and histological confirmation if necessary. When the diagnosis of mammary sarcoidosis is suspected by fine needle aspiration cytology, exceptional procedures should be also considered to examine for the possibility of a coexisting carcinoma. In such cases, excisional biopsy or resection is strongly recommended. There are some cases of mammary sarcoidosis associated with breast cancer. Breast cancer may develop in patients with sarcoidosis, sarcoidosis may develop in patients with breast cancer, the two diseases may develop in tandem, or breast cancer may induce a sarcoidosis-like granulomatous response. Sarcoidosis is possibly linked to silicone gel breast implants. The silicone might cause a sarcoidlike reaction as the result of an acceleration of an already existing hypersensitivity response, resulting in mammary sarcoidosis. The management of sarcoidosis in the breast usually is an excisional biopsy. At the same time, we confirm diagnosis and the treatment is done. The prognosis of mammary sarcoidosis remains unknown.",signatures:"Patricia López Arribas, Elena Martínez Gómez and Álvaro Zapico Goñi",downloadPdfUrl:"/chapter/pdf-download/71879",previewPdfUrl:"/chapter/pdf-preview/71879",authors:[{id:"311527",title:"Dr.",name:"Patricia",surname:"Lopez Arribas",slug:"patricia-lopez-arribas",fullName:"Patricia Lopez Arribas"},{id:"311529",title:"Dr.",name:"Elena",surname:"Martinez Gomez",slug:"elena-martinez-gomez",fullName:"Elena Martinez Gomez"},{id:"315890",title:"Dr.",name:"Álvaro",surname:"Zapico Goñi",slug:"alvaro-zapico-goni",fullName:"Álvaro Zapico Goñi"}],corrections:null},{id:"72193",title:"Granulomatous Diseases Mimicking Sarcoidosis",doi:"10.5772/intechopen.92233",slug:"granulomatous-diseases-mimicking-sarcoidosis",totalDownloads:632,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Granulomatous diseases are not infrequent in daily clinical practice. Granulomas are the expression of a sufficiently (partial) functioning immune system. Many diseases, with different etiologies (infection, autoimmunity, inflammatory, foreign bodies, malignancy, metabolites, chemicals, etc.) can cause granulomatous manifestations. The differential diagnostic process of a granulomatous disease should always be made in an interdisciplinary cooperation. Diagnostic procedures should be oriented to the clinical symptoms suggestive microbiological studies, and radiography but the diagnosis of a granulomatous disease should always be confirmed by histopathology when possible, sampling for histology or cytology. From a pathogenic point of view, they are divided into noninfectious and infectious granulomas. In the case of proven granulomatous inflammation, an infectious etiology should first be excluded (including mycobacteria, parasites, and fungi). From a clinical point of view, it is useful to separate granulomatosis into localized and disseminated forms, although this distinction can be sometimes artificial. Three types of localized granulomatous lesions can be distinguished: infectious granulomas, palisaded granulomas (granuloma annulare, necrobiosis lipoidica, and rheumatoid nodules), and foreign body granulomas. Disseminated granulomas can be divided into infectious, in particular tuberculosis, and noninfectious forms (autoimmune, neoplasia, etc.).",signatures:"Angel Robles-Marhuenda",downloadPdfUrl:"/chapter/pdf-download/72193",previewPdfUrl:"/chapter/pdf-preview/72193",authors:[{id:"259580",title:"Dr.",name:"Angel",surname:"Robles-Marhuenda",slug:"angel-robles-marhuenda",fullName:"Angel Robles-Marhuenda"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"2988",title:"A Textbook of Advanced Oral and Maxillofacial Surgery",subtitle:null,isOpenForSubmission:!1,hash:"b5d9f2be309d43646fca5ce2cd1e3d19",slug:"a-textbook-of-advanced-oral-and-maxillofacial-surgery",bookSignature:"Mohammad Hosein Kalantar Motamedi",coverURL:"https://cdn.intechopen.com/books/images_new/2988.jpg",editedByType:"Edited by",editors:[{id:"90148",title:"Dr.",name:"Mohammad 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An Overview of PET Radiopharmaceuticals in Clinical Use: Regulatory, Quality and Pharmacopeia Monographs of the United States and Europe",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/66068.pdf",downloadPdfUrl:"/chapter/pdf-download/66068",previewPdfUrl:"/chapter/pdf-preview/66068",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/66068",risUrl:"/chapter/ris/66068",chapter:{id:"62269",slug:"an-overview-of-pet-radiopharmaceuticals-in-clinical-use-regulatory-quality-and-pharmacopeia-monograp",signatures:"Ya-Yao Huang",dateSubmitted:"February 25th 2018",dateReviewed:"May 31st 2018",datePrePublished:"November 5th 2018",datePublished:"July 24th 2019",book:{id:"7373",title:"Nuclear Medicine Physics",subtitle:null,fullTitle:"Nuclear Medicine Physics",slug:"nuclear-medicine-physics",publishedDate:"July 24th 2019",bookSignature:"Aamir Shahzad and Sajid Bashir",coverURL:"https://cdn.intechopen.com/books/images_new/7373.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"288354",title:"Dr.",name:"Aamir",middleName:null,surname:"Shahzad",slug:"aamir-shahzad",fullName:"Aamir Shahzad"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"247754",title:"Prof.",name:"Ya-Yao",middleName:null,surname:"Huang",fullName:"Ya-Yao Huang",slug:"ya-yao-huang",email:"careyyh@ntuh.gov.tw",position:null,institution:{name:"National Taiwan University Hospital",institutionURL:null,country:{name:"Taiwan"}}}]}},chapter:{id:"62269",slug:"an-overview-of-pet-radiopharmaceuticals-in-clinical-use-regulatory-quality-and-pharmacopeia-monograp",signatures:"Ya-Yao Huang",dateSubmitted:"February 25th 2018",dateReviewed:"May 31st 2018",datePrePublished:"November 5th 2018",datePublished:"July 24th 2019",book:{id:"7373",title:"Nuclear Medicine Physics",subtitle:null,fullTitle:"Nuclear Medicine Physics",slug:"nuclear-medicine-physics",publishedDate:"July 24th 2019",bookSignature:"Aamir Shahzad and Sajid Bashir",coverURL:"https://cdn.intechopen.com/books/images_new/7373.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"288354",title:"Dr.",name:"Aamir",middleName:null,surname:"Shahzad",slug:"aamir-shahzad",fullName:"Aamir Shahzad"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"247754",title:"Prof.",name:"Ya-Yao",middleName:null,surname:"Huang",fullName:"Ya-Yao Huang",slug:"ya-yao-huang",email:"careyyh@ntuh.gov.tw",position:null,institution:{name:"National Taiwan University Hospital",institutionURL:null,country:{name:"Taiwan"}}}]},book:{id:"7373",title:"Nuclear Medicine Physics",subtitle:null,fullTitle:"Nuclear Medicine Physics",slug:"nuclear-medicine-physics",publishedDate:"July 24th 2019",bookSignature:"Aamir Shahzad and Sajid Bashir",coverURL:"https://cdn.intechopen.com/books/images_new/7373.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"288354",title:"Dr.",name:"Aamir",middleName:null,surname:"Shahzad",slug:"aamir-shahzad",fullName:"Aamir Shahzad"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"9476",leadTitle:null,title:"Craniosynostosis - New Perspectives of Prevention and Treatment",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tCraniosynostosis (CS) is defined as the premature fusion of cranial sutures, resulting in an abnormal skull shape. CS can be isolated (non-syndromic) or it can be part of multiple congenital abnormalities syndromes (syndromic craniosynostosis - SCS). Different etiologies have been reported for CS but a genetic cause is found overall in 20% of cases, especially mutations in the FGF/TWIST pathways cause the majority of these conditions of syndromic CS.
\r\n\r\n\tUnfortunately, even though in this age of molecular therapy the identification of potential targets for molecular or pharmacological therapy that could assist the delineation of a non-surgical treatment of CS, is currently still not available. Therefore, surgery is still considered the only treatment for CS. Gold standard for complex syndromic CS and for the presurgical planning is the 3D-CT scan, but nowadays it is valuable and less invasive the ultrasound examination of cranial sutures, as first-line imaging when a clinical diagnosis of craniosynostosis is suspected. Surgery should be carried out during the first year of life to achieve the best results, clinical and cosmetic, and to reduce the development of learning disabilities and symptoms of intracranial hypertension. Furthermore, even if the standard of surgical treatment for the craniosynostoses is the cranial vault remodeling, this implies for the infant a prolonged anesthesia, a risk of brisk bleeding related to the wide cranial exposure not only during surgery but also in the immediate postoperative period in case of a poor haemostasis, and a medium-long hospitalization. For these reasons, many centers are using the minimally invasive endoscopic suturectomy with postoperative helmet therapy for both single-suture and complex CS.
\r\n\r\n\tIndeed, each patient should be discussed in a multidisciplinary team, including clinical and molecular geneticist, neurosurgeon, maxillary surgeon, ophthalmologist, ENT, radiologist, pediatrician, in order to evaluate every aspect of the complexity of CS. One of the main concerns of this book is to present the state-of-the-art and to deal with the debated aspects of the craniosynostoses, especially regarding the chance to prevent the CS by identifying specific biomarkers, or the chance to treat the CS with effective target therapies, thanks to recent advances in the understanding of the molecular pathophysiology of CS.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"f41fe5819d0828befc916bd0f3f46628",bookSignature:"Dr. Raffaella Messina and Dr. Valeria Blè",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9476.jpg",keywords:"Craniosynostosis, Syndromic, Non-syndromic, Clinical Features, Isolated CS, Complex CS, Minimally Invasive Surgery, Targeted Therapies, Biomarkers, Prenatal Diagnosis, Early Diagnosis, Risk Factors",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 23rd 2020",dateEndSecondStepPublish:"July 14th 2020",dateEndThirdStepPublish:"September 12th 2020",dateEndFourthStepPublish:"December 1st 2020",dateEndFifthStepPublish:"January 30th 2021",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Italian board-certified neurosurgeon currently working as a Consultant Neurosurgeon at the University Hospital in Bari, Italy as well as the Doctoral Fellow in Neuroscience and Assistant Professor in the Department of Basic Medical Science, Neurosciences and Sense Organs at the University of Bari Aldo Moro.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"291148",title:"Dr.",name:"Raffaella",middleName:null,surname:"Messina",slug:"raffaella-messina",fullName:"Raffaella Messina",profilePictureURL:"https://mts.intechopen.com/storage/users/291148/images/system/291148.jpg",biography:"Dr. Raffaella Messina is an Italian board-certified neurosurgeon. She was trained in neurosurgery at the University Hospital of Bari, Italy. She has held a fellowship in pediatric neurosurgery at the IRCCS Institute for Treatment and Research - Bambino Gesù Children\\'s Hospital, Rome. She is currently pursuing a Ph.D. in Neurosciences and has been an assistant professor at the\nUniversity of Bari “Aldo Moro,” Italy, since 2010. Her major field of interest is pediatric neurosurgery, in which she has focused her main scientific activity. She had the opportunity to improve her surgical skills and to achieve board certification for the European Society for Pediatric Neurosurgery (ESPN), attending the three-year cycle of ESPN.",institutionString:'University of Bari Medical School "Aldo Moro"',position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Bari Aldo Moro",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:{id:"327232",title:"Dr.",name:"Valeria",middleName:null,surname:"Blè",slug:"valeria-ble",fullName:"Valeria Blè",profilePictureURL:"https://mts.intechopen.com/storage/users/327232/images/system/327232.jpeg",biography:"Dr. Valeria Blé is an Italian board-certified neurosurgeon. She was trained in neurosurgery at the University Hospital of Bari, Italy, and was an observer in pediatric neurosurgery at Hôpital Femme Mère Enfant, Lyon, France, and fellow at the IRCCS Institute for Treatment and Research - Bambino Gesu Children\\'s Hospital, Rome. \n\nShe is a consultant neurosurgeon in the University Hospital in Bari, Italy. Her major field of interest is pediatric neurosurgery, and she is currently taking a post-graduate course in Pediatric Neurosurgery.",institutionString:'University of Bari Medical School "Aldo Moro"',position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Bari Aldo Moro",institutionURL:null,country:{name:"Italy"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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For sedimentologists, a clay is a raw material whose grain size is less than 2 μm. Like clays, in turn, there are rocks made up of clay minerals and may contain other minerals such as quartz, feldspar, mica, calcite, hematite, and organic matter as accessories [2]. A clay, once ground and mixed with water, in addition to presenting excellent workability in the fresh state, after drying, becomes extremely rigid. After burning normally above 800°C, it acquires great resistance [3]. Clays are used worldwide in the ceramic industry, especially in bricks, coatings, and others. However, clays are formed from the weathering of explosion and can be contaminated with several minerals among them or carbonate, which can alter the shape that causes the following burns. Limestone may be present in colloidal form, or coarse particles. However, in all cases it is impossible to separate or calculate this. Some researchers have tried to reduce the size of the variations to improve the chemical changes. According to Barba et al. [4], calcium carbonate and magnesium carbonate are the main constituents of carbonate sedimentary rocks. Anionic carbonate groups are strongly activated units and share oxygen with each other. They are responsible for the properties of these minerals. The most important anhydrous carbonates belong to three isostructural groups: the calcite group, the aragonite group, and the dolomite group. Among these, the minerals most used in the ceramic industry are calcite and dolomite, as they are low-cost raw materials, in addition to having favorable physical and chemical properties and available deposits. Second, Padoa [5] adds that when CaCO3 is small, a decomposition can be complete and the calcium oxide reaches later with other mass components forming calcium silicates and silicon aluminates (wollastonite, anortite, gehlenite etc.) during sintering. Barba et al. [4] mentioned that the raw materials of clay when burned at high temperatures produce crystal phases that influence the properties of ceramic products. Calcite exerts a bleaching action on burnt products when added to a formulated mass of clays (in proportions above 5% and less than 30%) and at the same time decreases its expansion by legislation, as it forms crystalline and liquid phases, including cycles temperature and firing adopted. Calcite and dolomite are the most important representatives of carbonates in the ceramic industry. They are used as main components in the manufacture of ceramic tiles with high water absorption. These coatings include “porous coatings” or “tiles.” These products are designed or used on walls and are not suitable for application on floors, as they have undesirable technical characteristics, such as mechanical resistance, incompatibility with use. According to Amorós [6], properties of parts of a ceramic product are registered by crystalline phases formed based on calcium and magnesium as ghelenite (SiO2⋅Al2O3⋅2CaO) and anortite (2SiO2⋅Al2O3⋅CaO). To achieve these phases, use the dolomite calcium oxide and/or magnesium reaction with a remaining clay structure proven by its thermal decomposition.
The calculation in general can affect the ceramic product in two ways: low percentages (up to 3%) and high temperature (above 1180°C) result in flow agents, that is, materials that contribute to reduce water absorption and increase the resistance of ceramic products. Above 3%, they can act as a foundation at temperatures above 1170°C [7].
In this chapter, we will highlight properties of limestone clays and their application in the ceramic industry.
Clays are hydrated aluminum silicates with crystalline structure arranged in layers, consisting of continuous sheets of SiO4 tetrahedrons, ordered in a hexagonal shape, condensed with octahedral sheets of di and trivalent metal hydroxides, usually below 2 μm. They are materials that in contact with water become plastic, a fundamental characteristic for conformation of ceramic products because it provides mechanical resistance in the pressing, extrusion, or gluing process. Clays are mixtures of various clay minerals such as kaolinite, illite, and montmorillonite, which may or may not contain impurities [3, 8].
The kaolinite with structural formula Al2O3⋅2SiO2⋅2H2O has a dioctahedral structure, which consists of a tetrahedral layer linked by an octahedral layer. Pure kaolinites usually have low plasticity, see Figure 1.
Kaolinite structure. (a) Si▬O tetrahedra on the bottom half of the layer and Al▬O,OH octahedra on the top half. (b) Dioctahedral structure.
Montmorillonites are a set of family of clay minerals, composed of dioctahedral and trioctahedral silicate sheets, see Figure 2(a) and (b). The most outstanding feature of these minerals is their ability to absorb water molecules [8, 9]. It has 80% of exchangeable cations in the galleries and 20% on the lateral surfaces. The modification of montmorillonite clays has aroused scientific and technological interest for providing significant improvements when incorporated into pure polymeric materials and conventional composites. The clay modification process occurs preferably through the ionic exchange of the exchangeable cations of its crystalline structure.
Crystalline structure of a montmorillonite. (a) Montmorillonite structure, composed of Si, Al, and O. (b) Sheets of dioctahedral and trioctahedral silicates.
The basic structural unit of the illites is the same as that of the montmorillonites except that in illites, the silicon atoms in the silica layers are partially replaced by aluminum. Therefore, there are free valences in the boundary layers of the structural units, which are neutralized by K cations, arranged between the overlapping units. The structural scheme of the illites is shown in Figure 3. The K cation is the one that best adapts to the hexagonal meshes of the oxygen planes of the layers of silica tetrahedron and is not displaced by other cations. The water adsorption and cation exchange capacity is due only to the broken connections at the ends of the layers. The average diameter of the illites varies between 0.1 and 0.3 μm. When the replacement of silicon in the tetrahedron layers by aluminum in the illites is small, the connections between the structural units provided by the K cations may be deficient and will allow water to enter. When this occurs, the properties of the illites are close to the properties of montmorillonites [3].
Crystalline structure of an illite. (a) Silicon atoms in the silica layers partially replaced by aluminum in the illites. (b) Structural scheme of illites.
Chlorites are minerals made up of four hydrated aluminum and magnesium silicate layers, containing Fe (II) and Fe (III) as shown in Figure 4.
Crystalline structure of chlorite [
The most common clay minerals are interstratified, characteristic of mixtures of clay minerals, classified by subgroup and mineralogical species, see most common classification in Table 1. Clay minerals are divided into several classes. A large majority of clays do not have in just one crystalline phase. Two or more chemical species may be present.
Subgroup | Chemical species | Minerals |
---|---|---|
Kaolin Xn(Y2O5)(OH)4 | Kaolinites | Nacrite (Al2(Si2O5)(OH)4) Dikite (Al2(Si2O5)(OH)4) Livesite (Al2(Si2O5)(OH)4) Halloysite (Al2(Si2O5)(OH)4) |
Talc XB(Y2O5)(OH)2ZmH2O | Montmorillonites | Montmorillonites (Al1,51Fe0,07Mg0,60)(Al0,28Si3,72)O10(OH)2Na0,33 |
Beidellite (Al1,46Fe0,50Mg0,08)(Al0,36Si3,64)O10(OH)2Na0,4 | ||
Nontronite (Fe1,67Mg0,33)(Si4O10)(OH)2Na0,33 and Fe2,22(AlSi3O10)(OH)2Na0,33 | ||
Hectorite (Mg2,67Li0,33)(Si4O10)(F,OH)2Na0,33 | ||
Saponite Mg3(Al0,33Si3,67)O10(OH)2Na0,33 | ||
Illites | Wide variety of minerals | |
Chlorite | Chlorites | Chlorite |
X2n(Y2O5)2(OH)2 | [Mg2(Al,Fe(III))(OH)6][Mg3(AlSi3O10)(OH)2] |
The clays used in the ceramic manufacturing process can be classified into:
Carbonitic clays: they are formed by associations of illitic-chloritic and eventually illitic-kaolinite clay minerals. The amount of calcium carbonate present can be variable. These clays give the dough plasticity. Generally, after burning they have colors ranging from beige to orange [4].
Non-carbonitic clays: they are characterized by the almost total absence of carbonates. The clay minerals present are of the illitic-chloritic type. It has the function of giving plasticity to the dough, and generally after firing they give rise to well-sintered materials.
White plastic clays: the clay matrix is kaolinitic, with little illite. They give plasticity to the dough, and after burning they have a white color.
Kaolinitic clays: clays of low plasticity and normally free of fluxing oxides such as K2O and Na2O, therefore, with refractory characteristics.
According to Mackenzie [10], when a ceramic raw material is subjected to the action of heat, it experiences volumetric variations, usually permanent and irreversible, which can be classified as:
Oxidation of organic matter
Decomposition of compounds containing oxygen, such as sulfates, carbonates, etc.
Dehydroxylation of the clayey mineral
Crystallization by increasing the temperature
Vitreous phase formation
Solid solutions: adjacent crystals of two different materials but of similar structure can react with each other, forming a solid solution.
Kaolinitic clay: the scheme according to Figure 5 shows an endothermic peak between 560 and 590°C referring to the elimination of hydroxyls from the constitution water present in the clays, and an exothermic peak between 980 and 1000°C, due to the formation of mullite, which can be represented by the reactions 1 and 2 [8].
Differential thermal analysis of a kaolinitic clay [
Montmorillonite: montmorillonites have water that lodges in the mineral structure, that is, hydration water of adsorbed ions. The elimination of hydroxyl groups occurs at 700°C. At 850°C, a small endothermic peak may occur due to the loss of montmorillonite crystallinity. Illites can present loss of adsorbed water between 100 and 200°C and water loss in the constitution between 550 and 600°C, see Figure 6.
Differential thermal analysis of a montmorillonite clay [
Quartz: it appears in clays in colored or colorless round grains, whose percentage ranges from 0 to 60%. For high levels of quartz, the clay is called sandy and has low plasticity [11].
Hematite: iron can be present in the forms of hematite (α-Fe2O3), goethite (α-FeO⋅OH), and lemonade (a mixture of iron oxides and hydroxides of a weakly crystalline nature), or simply as Fe3+ ions in the clay structure. In the illite group, Fe3+ ions can replace Al3+ ions in the octahedral structure [11]. Fe2O3 is formed during sintering under oxidation conditions and from minerals in the clays, giving a reddish color to ceramic materials.
Feldspar: feldspars refer to a group of aluminum silicate minerals. The feldspar contained in the clays is a source of sodium and potassium oxides and plays an important role in ceramic materials with quality of flow agents, temperatures such as sintering temperatures, porosity after firing and facilitating phase formation [6]. The most representative are the orthoclase (KAlSi3O8) and albite (NaAlSi3O8).
Carbonates: calcium or magnesium carbonates can appear as coarse or small grains. If they are presented as large grains (>125 μm), they may not react completely and the resulting oxides may rehydrate causing expansion according to reactions [12, 13].
Ceramic enamels and frits: can be used in matte enamels as a source of CaO to form crystals such as wollastonite, anorthite, gehlenite or in transparent enamels giving shine.
Masses for ceramic coating: as a source of CaO up to the limit of 3%, CaCO3 assists in the formation of the vitreous phase. CaO levels that vary from 8 to 14% favor the formation of crystalline phases such as gehlenite, wollastonite, pseudo wollastonite, and anortite.
Putties for limestone porcelain: calcium carbonates provide the CaO that are used as a flux in limestone porcelain masses.
Ceramic pigments: the calcium carbonate provides calcium oxide, which together with SnO2 produces pink pigments.
Glasses: glasses based on NaOH and CaO use CaCO3 in their composition.
Obtaining settlement mortars: as a plasticizing agent for water retention and aggregate incorporation.
Steel: CaCO3 acts as a flux and pH regulator in water treatment and as lubricant for drawing steel rebars.
Sánchez et al. [14] defined some specification parameters for choosing raw materials for formulations of coating masses, as shown in Table 2 below.
Product | (%) of carbonates | Max. particle size of CaCO3 (μm) | Organic matter (%) | Sulfate content max. (%) | IP (%) |
---|---|---|---|---|---|
Stoned | ≤3 | ≤125 | ≤0.3 | 0.2 | 20–40 |
Porous | ≤40 | ≤125 | ≤0.3 | 0.2 | 20–40 |
Specifications for choosing raw materials.
IP: index of plasticity.
Calcium or magnesium carbonates can appear as coarse or small grains. If they are presented as large grains (>125 μm), they may not react completely, and the resulting oxides may rehydrate causing expansion.
In compositions of ceramic floor covering with low water absorption, CaCO3 acts as a flux until the limit of 3%; above this value, CaCO3 increases porosity and can be accepted up to 40% in porous coatings.
Enrique [15] recommends that the CaCO3 particle size should be less than 125 μm, because particles of larger sizes, the CaO resulting from the dissociation of carbonates when calcined at 900°C, do not react with the SiO2 present in the clays and feldspars that should form the pseudo-wollastonite and wollastonite phases, which can give rise to Ca(OH)2 formed by the hydration of CaO, when the part comes into contact with the humidity of the air, generating problems of expansion by humidity, with consequent cracking.
The ceramic tile and brick industry have grown enormously in recent years in Brazil. The clays must have sufficient plasticity to provide mechanical resistance when forming by pressing, in order to guarantee the integrity of the piece in the path between the press and the oven. The feldspar contained in the clays are sources of sodium and potassium oxides, acting as fluxes at temperatures above 800°C for bricks and above 1100°C for ceramic tiles, which facilitates the formation of a vitreous phase and reduces porosity [16, 17].
Quartz is mixed with clay during geological formation. If it is present in a smaller proportion, it helps in the formation of the vitreous phase, in the degassing of organic matter and water. However, large proportions of quartz lead to a drastic reduction in mechanical strength after firing [18]. Iron oxide is present in ceramic raw materials in the form of hematite or goethite, giving the finished product a red color.
Calcite, which appears in most clays used in the production process of ceramic tiles of type BIIb, is a mineral that needs special care in its use due to its high loss to fire. When present in a proportion equal to or less than 3%, this mineral acts as a flux. However, in higher proportions, calcite can cause an increase in the final porosity of the product. In addition, the size of the calcite particle for processing ceramics must be less than 125 μm. For larger sizes, it is observed that the CaO resulting from the dissociation of carbonates can hydrate after burning, promoting variations in the dimension of the piece. Therefore, the use of limestone clays is a challenge, requiring care in processing and control in the formulation and burning of coatings. To ensure the correct sintering of the product, proper grinding and pressing of the raw material are necessary, in addition to efficient, fast burning with the lowest possible energy consumption.
Table 3 shows the chemical compositions of a typical Brazilian limestone clay used in ceramics [19]. The chemical compositions of the raw materials were determined by X-ray fluorescence spectroscopy by wavelength dispersion (WDFRX), in a Bruker S8 Tiger equipment, in which the percentages of constituent oxides were estimated by the method semi-quantitatively. For these measurements, samples with a mass of 10.0 g were pressed as discs with 40.0 mm diameter and 4.0 mm thickness. During measurements, the samples were kept in a vacuum of 10−6 bar. A mixture of P-10 (90% argon and 10% methane) was used in the proportional counter.
Oxide (%) | C1 | C2 | C3 | C4 |
---|---|---|---|---|
SiO2 | 63.0 | 52.1 | 50.2 | 45.3 |
Al2O3 | 16.7 | 18.6 | 15.5 | 14.1 |
Fe2O3 | 4.7 | 6.8 | 6.2 | 7.1 |
CaO | 0.9 | 2.1 | 7.2 | 12.7 |
K2O | 3.8 | 4.7 | 3.2 | 3.2 |
Na2O | 0.6 | 0.4 | 0.5 | 0.7 |
MgO | 1.5 | 2.3 | 2.2 | 2.3 |
TiO2 | 0.6 | 0.8 | 0.7 | 0.8 |
L.O.I | 8.2 | 12.1 | 14.3 | 13.8 |
The results show that all clays are composed mainly of SiO2 and Al2O3. These elements are associated with clay minerals, quartz, and feldspar structures [17]. The highest amount of SiO2 was determined for sample C1. This component is important for the manufacture of ceramic tiles, as it improves workability and favors compaction. However, SiO2 can also cause low mechanical strength of sintered ceramic bodies, in addition to reducing shrinkage during firing.
The amount of Fe2O3 detected in the samples was between 4.7 and 7.1%. These values are acceptable for use in ceramic tiles, such as bricks and tiles, this element being responsible for the reddish color of the sintered pieces as well as being a powerful flux [20]. The high content of calcium oxide in C4 (12%) and C3 (7%) stands out, characterizing these clays as limestone [21]. C4 clay was previously studied in Alcântara [16], which reports the formation of stains on the ceramic bodies produced with this material, after sintering at 1120°C. This behavior was associated with a high content of CaO, estimated at 10%, which during the burning phase, the dissociation of CaCO3, promotes a high mass loss. C4 (13%) generates many pores, reducing water absorption and resistance of the final product. Thus, the higher the CaO content, the higher the CaCO3 content and in addition, the higher the mass loss.
Analyzing the levels of alkaline oxides, it is observed that the sample C2 has the highest concentration of K2O, while the concentration of Na2O is approximately the same in the four samples studied. Alkaline and alkaline earth compounds have a melting effect, which facilitates the formation of liquid phase and linear shrinkage during burning [13].
Table 4 was arranged according to the increasing amount of CaO present in the clays. Note that C1 and C2 have CaO content below 3%. According to Enrique [15], CaO acts as a flux until the limit of 3% in masses of ceramic coating. The percentage of alkali oxides (Na2O and K2O), also presented in Table 3, is another major factor for the densification process, due to the great tendency of liquid phase formation during burning. Considering the sum of the percentages of CaO and alkali oxides in samples C3 and C2, it can be concluded that C2 has a higher proportion of fluxing oxides, suggesting that this sample is the most promising. On the other hand, clays with a high limestone content, such as C3 and C4, tend to have greater porosity and less mechanical resistance after firing. Additionally, these two raw materials have lower alkaline oxide ratios than those observed for C3 and C2.
Clay | CaO (%) | Na2O + K2O (%) |
---|---|---|
C1 | 0.9 | 4.4 |
C2 | 2.1 | 5.1 |
C3 | 7.2 | 3.7 |
C4 | 12.7 | 3.9 |
The X-ray diffraction patterns of the clays are shown in Figure 7 and correlate positively with the results observed by X-ray fluorescence. The X-ray diffractometry (XRD) technique was used to determine the crystalline phases. The samples were dried in an oven at 110 °C for 24 h, ground, and passed through a 150-μm mesh sieve. The diffraction patterns were obtained in a Rigaku D-MAX 100 equipment, using Cu Kα1 radiation (λ = 1.5418 Å). All measurements were carried out in the continuous scanning mode with speed of 1°/min, in the range of 5 to 65° and in the range of 2 to 15° in samples saturated with ethylene glycol for 1 h to identify montmorillonite by displacing the diffraction peaks at smaller angles compared to dry sample testing. The crystalline phases were identified through Match! (Phase Identification by Powder Diffraction) in the demo version, according to the ICSD (Inorganic Crystal Structure Database).
X-ray diffraction patterns of the clays [
The main phases identified were quartz, kaolinite, muscovite, montmorillonite, calcite, feldspar, and hematite. Minerals from kaolinite and montmorillonite clay were identified in all analyzed clays. According to Celik [20], these clay minerals provide the necessary plasticity to guarantee conformation through the pressing process. The percentage of each crystalline phase present in the samples was estimated from the relative intensity of the main peaks in each phase. The values are shown in Table 5. The percentage of carbonates increases from 0.9% in C1 to 12.4% in C4.
Minerals (%) | C1 | C2 | C3 | C4 |
---|---|---|---|---|
Quartz | 55.7 | 51.8 | 65.1 | 57.1 |
Kaolinite | 6.3 | 10.7 | 7.4 | 5.5 |
Muscovite | 11.8 | 14.0 | 11.2 | 12.1 |
Montmorillonite | 5.6 | 4.9 | 4.6 | 6.7 |
Calcite | 8.6 | 2.8 | 1.1 | 13.7 |
Feldspar | 6.3 | 9.9 | 6.2 | 3.2 |
Hematite | 5.7 | 5.9 | 4.4 | 1.7 |
Mineralogical compositions of clays determined by XRD.
To verify the dimensional changes of expansion and thermal retraction of the samples, dilatometry tests were performed on a Netzsch dilatometer, model DIL 402PC, under synthetic air flow at 130 ml/min. For these analyses, the samples were compacted in a cylindrical shape, 12.0 mm in length and 6.0 mm in diameter. Under a constant heating rate of 10°C/min, the length of the compacted body is measured as a function of time and temperature, which varied from room temperature to 1150°C.
In Figure 8 we can observe a slight expansion in all curves up to approximately 850°C, and at 573°C, the expansion was more pronounced due to the transformation of α quartz to β [22, 23], except for C2, which presents a lower percentage of free quartz. From 573°C, there was a gradual reduction in the expansion rate, occurring or starting with sintering, followed by an exponential retraction [22].
Dilatometric curves of clays at a heating rate of 10°C/min [
The results shown in Table 5 with the percentages of CaO, Na2O, and K2O recommended by XRF measurements point out that sample C2 has a greater amount of funds (calcium carbonate up to a limit of 3% and alkaline oxides), or what is known as a greater linear shrinkage. Despite its advantages over the other samples, the C2 clay underwent deformation during firing up to 1150°C. This effect, known as pyroplastic deformation, may be due to the large proportion of funds in the sample, a high content of Fe2O3, and, even, the amount of organic matter [24]. One of the ways to control deformation during firing is to adjust the thermal cycle through the dilatometric curves, so that the plate remains within the required standards [25].
Clays containing limestone when subjected to burning, CaCO3 after heating, in the temperature range between 850 and 920°C, form CaO and release CO2. An intense endothermic peak of approximately 35–44% of the mass loss can be observed in differential thermal analysis. In ternary diagrams, it is observed that there is a eutectic point (above 1170°C), which reduces the dimensional stability in ceramic products, which can melt quickly (Figure 9).
Ternary diagram of CaO, SiO2, and Al2O3.
Clays when mixed with limestone can behave differently, as shown by Sánchez [25]. Figure 10 shows a standard clay with 5 and 10% of incorporated limestone. It was observed that as the limestone and temperature increase, respectively, the dimensional instability increases. In other words, the retraction increases constantly, when it undergoes an exponential increase, reaching the melting point.
Ceramic coating mass with incorporated calcite waste.
This phenomenon can be explained as follows: when exhibiting CaO up to the limit of 3%, this, associated with SiO2 and Al2O3 present in clays and feldspars, helps in the formation of eutectic systems at 1170°C, with consequent formation of liquid phase and contributing to obtain the desired mechanical strength and porosity. When introduced in percentages above 4%, CaCO3 levels are increased, and the composition moves from the eutectic line, forming crystalline phases such as CaSiO3 (pseudo-wollastonite) and 2CaO⋅Al2O3⋅SiO2 (gehlenite). So, a larger number of pores is left by the eliminated CO2. In this way, the porosity of the final product is increased, as shown in Figure 11. In Figure 12 is shown a photo of a clay mass with 10% calibration in which the porosity exerted can be observed.
Firing curve of a calcite clay.
Scanning electron microscopy of a ceramic with 10% of CaO.
Limestone is a contaminant for clay that above 125 μm can cause expansion and consequently cracks.
Rapid tests that mix clay with HCl can promote effervescence due to the release of CO2 and contribute to decrease the amount of limestone.
In the ceramic industry, wet grinding of components is carried out in ball mills and grinding will be more efficient if the sieves are 150 to 325 μm. In ceramic mass formulations, the amount of CaO up to 3% contributes to the formation of the vitreous phase, however, between 8 and 14%, it favors the formation of crystalline phases, reducing the absorption of water and increasing the mechanical resistance.
Globally, eye diseases and consequential visual impairment are considered as the nation’s absolute threat, compromising physical and mental health. As reported by the World Health Organization, worldwide, the number of people suffering from visual impairment is more than 2.2 billion [1]. Additionally, an analysis by Lancet Glob Health stated that, as population gets older, the number of moderate to severe vision impairment and blindness cases would increase to 600 million and 115 million by 2050, respectively [1].
Anatomically speaking, the human eye consists of two regions: the anterior segment including aqueous humor, cornea, conjunctiva, iris, ciliary body, and lens. Whereas the posterior segment includes vitreous humor, retina, choroid, and optic nerve. In other words, the eye consists of several attached tissue layers. In the anterior segment, the collagenous layer providing the mechanical strength is the cornea that is responsible for focusing the light on the retina. In the posterior segment, the opaque collagenous layer is the fibrous sclera. The middle layer in the anterior segment is called Uvea, which involves the iris and ciliary body. The ciliary body contains smooth muscles that produce the aqueous humor. The latter has many functions such as suppling nutrients to the avascular tissues in the anterior segment, maintaining the intraocular pressure, and drainage of waste from lens and cornea. In the posterior segment, the middle layer comprises enormous network of capillaries called vascular choroid that provides the retina with all the essential nutrients. The innermost layer is the retina, which transports the light signal to the brain [2].
Based on the aforementioned background, the eye comprises unique anatomical and physiological barriers hindering effective intraocular drug delivery that would be discussed in the following section.
The eye consists of numerous barriers and defense mechanisms to protect it from the environment. Barriers to intraocular drug delivery are categorized as physiological and anatomical. Physiological barriers involve blinking, tear turn over and naso-lachrymal drainage. Whereas anatomical barriers include various static and dynamic barriers that impede drug entry into the eye segment [3].
In the anterior chamber, the static barriers are corneal epithelium, stroma, and blood aqueous barrier (BAB). Whereas dynamic barriers are the conjunctival blood and lymph flow along with tear drainage. BAB consists of tight junctions between the non-pigmented epithelial cells in the ciliary body, junctions of the iridial tissues as well as the blood vessels of the iris. BAB restricts the movement of molecules from blood to aqueous humor through iris ciliary capillaries [3].
In the posterior chamber, static barriers are sclera, bruch’s membrane in choroid, and blood retinal barrier (BRB), which involves tight junctions in retinal capillary endothelial cells and retinal pigmented epithelium. While dynamic barriers comprise the drainage of administered drugs by blood and lymphatic vessels [3].
It is worth mentioning that the blood ocular barrier consists of both BAB and BRB. Its function is to maintain optimum intraocular pressure via preserving the fluid composition of the eye [3].
Mucin, covering the corneal and conjunctival surfaces for protection, constitutes an additional ocular barrier for diffusion of large drugs molecules. Moreover, the expression of many efflux pumps (P-glycoprotein, multidrug-resistant protein, and breast cancer resistant protein) on the capillary endothelium represents another barrier limiting drug ocular bioavailability [3].
Absorption of drug into the inner eye occurs through two major pathways, either corneal or non-corneal. The corneal route is considered as the major pathway for ocular drug absorption after topical administration. This route involves the penetration of the administered drug through the corneal epithelium. Afterward, the drug gets to the corneal stroma, endothelium, and aqueous humor. Subsequently, the drug may either be eliminated by the drainage of the aqueous humor through trabecular meshwork into Schlemm’s canal, or it may reach the iris-ciliary body blood vessels and then enter the systemic circulation. Additionally, drugs also may distribute to a lesser extent to the lens and vitreous humor from the aqueous humor [4].
On the other hand, the non-corneal route for ocular drug absorption encompasses the passage of drugs across the conjunctiva and sclera. After that, they reach the ciliary body followed by the iris without access to the aqueous humor. Concerning the non-corneal route, it is important to highlight that the conjunctiva contains numerous blood vessels. Accordingly, a large portion of the drug dose is suspected to enter the blood circulation rather than diffusing into the sclera [4].
The next section designates the different factors affecting intraocular drug bioavailability, which makes ocular delivery challenging.
Poor ocular bioavailability of the topically administered drugs represents a main concern associated with ophthalmic dosage forms. The presence of numerous physiological and anatomical constraints resulted in absorption of a very small portion of the topically instilled dose. The several factors affecting drug ocular bioavailability will be discussed in detail in the following subsections.
It constitutes one of the major reasons for poor ocular drug absorption. A large portion of the topically instilled volume (~80–90%) is drained into the nasolacrimal duct. The nasolacrimal drainage aids in preserving a fixed volume of the precorneal fluid (~7–10 μl). Consequently, it represents a natural protective physiological mechanism that is responsible for loss of any excess fluid.
The factors affecting the drainage rate include the Instilled volume, viscosity, pH, tonicity, and drug type. Concerning the instilled volume, the larger the volume, the more the drainage. For viscosity, increasing viscosity of an instilled dose results in prolongation of its ocular residence time. Regarding the pH effect, instillation of alkaline or acidic solutions gives rise to excessive lacrimation and hence loss of the administered medication. Therefore, the pH of the ophthalmic formulations must be adjusted to 7–7.7 to mimic the physiological pH of tear fluid (7.4). Regarding tonicity, preparations intended for ocular use should be isotonic with tear fluid. Severe irritation with excessive tear secretion occurs upon instillation of hypertonic solutions. As for drug type, it was reported that certain drugs can affect tear secretion. For instance, epinephrine can induce lacrimation, while tetracaine can suppress it [3].
The protein content of the tear fluid is ~0.7% of total body protein. Binding of drugs to tear proteins may bring about a significant decrease in drug concentration reaching the target site [3].
Concerning melanin binding, certain drugs such as ephedrine and timolol were reported to possess a high binding affinity to melanin pigment present in the iris and ciliary body, thereby lowering their ocular bioavailability [3].
It may occur either directly from the conjunctival blood capillaries or after drainage of the instilled solution to the nasal cavity. Accordingly, this can result in remarkable drug loss into the systemic circulation, hence lowering its ocular bioavailability [3].
Cornea is a complex tissue that is made of six different layers. It plays an essential role in decreasing drug ocular bioavailability acting as a physical constraint impeding drug permeability [3].
Several metabolizing enzymes (cytochrome P450, cyclooxygenases, aldehyde oxidases, and monoamine oxidases) are expressed in various ocular tissues as cornea, lens, iris, ciliary body, and retina. These enzymes have the ability to metabolize the instilled drugs, decreasing their ocular bioavailability [3].
As illustrated previously, drug delivery to the eye is challenging for formulators owing to its barrier nature. Additionally, the chronic nature of various ocular diseases necessitates frequent administration of drugs. In this context, nanocarriers are elaborated to overcome the limitations of conventional ocular formulations as well as guarantee controlled and targeted drug delivery [5].
Nano delivery systems are colloidal systems with a particle size in the nanometer range (10–1000 nm) and a certain surface charge. They have various biomedical applications depending on their size. Additionally, their surface charge contributes to their retention at the specific site. For example, the negative charge on the surface of both the corneal and conjunctival tissues paves the way for cationic nanoparticles to be interacted to these tissues via electrostatic attraction. Consequently, increasing their residence in the anterior segment of the eye [5].
Based on the aforementioned background, nanocarriers are predicted to overcome the numerous ocular barriers thanks to their unique nano-size and surface characteristics. The different nanocarriers and their targeting ability for ocular drug delivery will be presented in detail in the following subsections.
Nanomicelles are nanostructures (10–100 nm) formed spontaneously in the aqueous environment by the self-assembly of certain block copolymers having amphoteric properties. They have many advantages for ocular drug delivery such as enhancing the aqueous solubility and stability for the hydrophobic drugs, prolongation of drugs’ ocular retention, improving drug corneal permeability, and modification of drug release [1]. The amphoteric nature of the nanomicelles facilitates their penetration through both lipophilic (corneal epithelial and endothelial cells) and hydrophilic matrices. As well, their small size permits their uptake by the corneal cells. Moreover, they were reported to improve drug bioavailability by inhibiting the efflux transporter proteins by the use of the proper surfactants in their backbone structure [1, 6].
Accordingly, nanomicelles have attracted increasing attention as noninvasive ocular drug delivery systems owing to their unique properties.
Concerning the targeting potential of the nanomicelles to the anterior segment of the eye, several studies have reported that the administration of the drug in a nanomicellar formulation rather than ointment, suspension, or emulsion formulations resulted in improved corneal, trans-corneal, and conjunctival uptake [7]. The clear Cyclosporine-A nanomicellar formulation prepared by Cholkar et al. [8] for treatment of dry eye disease in rabbits was approved by the United States Food and Drug Administration (FDA) in 2018. Cequa® (cyclosporine-A 0.09%) is a unique nanomicellar formulation, that is a clear solution approved for clinical use. In another study, Safwat et al. [9] prepared poly ethylene glycol-block-poly lactic acid nanomicelles containing triamcinolone acetonide. The selected formulations were dispersed into chitosan hydrogel to evaluate their anti-inflammatory potential in a carrageenan-induced ocular inflammatory rabbit model. The prepared micelles had good in-vitro characteristics (size: 176.80 ± 2.25 nm, drug loading: 15–25%, sustained drug release over a period of 1 week and 10-fold increase in drug aqueous solubility). Furthermore, the elaborated micellar hydrogel formulation resulted in complete disappearance of the corneal inflammatory signs in tested rabbits based on histopathological examination [9].
For targeting posterior segment of the eye, Xu et al. [10] prepared chitosan oligosaccharide-valylvaline-stearic acid nanomicelles to actively target peptide transporter-1 for topical ocular dexamethasone delivery to treat macular edema. Fluorescence microscopical images of frozen sections for various ocular tissues from tested animals indicated that the coumarin-6 labeled nanomicelles reached the posterior segment mainly through conjunctival route. Following topical administration, dexamethasone concentration in the posterior segment reached the therapeutic levels at 0.5 h and 1 h and can still be detected at 1.5 h post administration [10].
Polymeric nanoparticles made of biodegradable polymers and having sizes from 10 to 100 nm are widely used in ocular therapy. These nanocarriers consist of various polymers, in which the drug may be just adsorbed on the surface or incorporated into the polymer matrix. Polymeric nanoparticles offer numerous advantages for ocular delivery, which mainly related to their unique properties, as biodegradability, biocompatibility, and muco-adhesiveness. Therefore, pericorneal retention time is prolonged, and hence drug bioavailability is improved. For that purpose, many researchers prepared ocular drug delivery systems coated with mucoadhesive polymers (poloxamers, hyaluronic acid, chitosan, sodium alginate, among others) to increase drug ocular bioavailability [11].
For instance, Radwan et al. [12] prepared bovine serum albumin nanoparticles coated with chitosan by the desolvation method for the topical delivery of tetrandrine for management of glaucoma. The optimized formulation had a size of 237.9 nm and zeta potential of 24 mV and high % EE > 95% with a sustained-release drug profile. Moreover, the prepared nanosystem exhibited a significantly enhanced ex -vivo transcorneal permeation with improved in-vitro antioxidant and antiproliferative action on corneal stromal fibroblasts. In addition, the elaborated formulation succeeded to increase the drug bioavailability in the aqueous humor of treated rabbits by twofold compared with the free drug together with a remarkable reduction in intraocular pressure in a rabbit model for glaucoma.
In order to achieve active targeting to the posterior eye chamber for treatment of diabetic retinopathy, apatinib -loaded bovine serum albumin nanoparticles coated with hyaluronic acid were developed [13]. Hyaluronic acid was exploited to achieve a dual role as a mucoadhesive polymer with capability to target the CD44 receptors expressed on retinal cells. The elaborated nanoplatform had good colloidal and mucoadhesive properties with no in-vitro cytotoxicity on rabbit corneal epithelial cells. The in-vivo evaluation revealed the ability of the topically instilled nano formulation to alleviate the corneal histopathological manifestations in diabetic retinopathy rat model with improved retinal accumulation as evidenced by confocal microscopy [13].
Solid lipid nanoparticles (SLNs) are nanocarrier systems (10–500 nm) consist of lipids dispersed in an aqueous surfactant system. They are reserved for the delivery of hydrophobic drugs. The main method of their preparation depends on solidification of the produced nanoemulsion. SLNs were reported to have enhanced retinal permeation in addition to prolongation of drug ocular retention [5].
Nanostructured lipid carriers (NLCs) were introduced as next-generation lipid nanocarriers to overcome the limitations of SLNs, such as low drug loading capacity due to its expulsion by crystallization of lipids. NLCs are composed of both solid and liquid lipids and thereby have asymmetric structure, which prevents drug expulsion and brings about comparatively slower drug release [5].
The aqueous dispersion of lipid nanoparticles is mainly applied topically for delivery of the entrapped medication to the anterior segment of the eye. The aim of the use of this nanocarrier is to prolong retention time at surface of the cornea by muco-adhesion as well as enhance corneal permeation.
For this purpose, cationic lipid nanoparticles were prepared by using cationic lipids [14, 15] that can interact with the negatively charged mucus. Additionally, coating lipid nanoparticles with bio-adhesive polymers such as hydroxypropyl methyl cellulose [16], hyaluronic acid [17], and chitosan [18, 19, 20] was also employed.
For example, Wang et al. [18] prepared chitosan-coated solid lipid nanoparticles loaded with methazolamide for glaucoma treatment. Their findings proved the enhanced lowering in intraocular pressure effect of the coated formulation compared with either the uncoated one or a commercial methazolamide eye drop.
Furthermore, the lipid nanocarrier could be incorporated in a thermo-sensitive gel aiming to increase corneal contact time [20].
Nanostructured lipid carriers as well have gained popularity in ocular drug delivery [21, 22, 23, 24, 25]. They were reported as an efficient drug delivery system for the posterior segment of the eye due to their lipid nature, high drug-loading capacity, and enhanced trans-corneal penetration [5]. For instance, palmitoylethanolamide-loaded nanostructured lipid carrier was prepared for treatment of diabetic retinopathy in rat model [25]. In-vivo evaluation of the developed system confirmed its ability to reach the retina upon topical administration as evidenced by the significant inhibition in the levels of retinal tumor necrosis factor-α compared with the free drug in diabetic rats [25].
Nanosuspensions are a nanometric colloidal dispersions of hydrophobic drugs stabilized by polymers or surfactants. The ocular bioavailability of many hydrophobic drugs could be improved using nanosuspension technology via increasing their retention time [26]. Numerous corticosteroids such as prednisolone, dexamethasone [27], and hydrocortisone [27, 28] were formulated as nanosuspensions for their anti-inflammatory effect in the anterior eye segment. This resulted in elimination of the expected adverse effects associated with administration of large doses of theses corticosteroids such as production of glaucoma, cataract, and the most serious optic nerve degeneration [27]. Moreover, other drugs such as the cyclosporine [29] and antibacterial sparfloxacin [30] demonstrated a sustained drug release profile with better therapeutic efficacy when prepared as in nanosuspension form.
They are spherical lipid vesicles composed mainly of phospholipids and cholesterol. A good biocompatibility, sustained release properties together with their ability to encapsulate both hydrophobic and hydrophilic drugs make liposomes ideal candidates for ocular drug delivery to both anterior and posterior segments of the eye [26]. Liposomes as an ocular delivery system were first introduced in 1981 for the delivery of the antiviral idoxuridine for treatment of keratitis [31]. Afterward, they were widely used to deliver various drugs to the eye.
For anterior eye disorders, Cyclosporine A-liposomes showed a significantly higher AUC 0–24 h in rabbits tears film compared with Restasis® (commercial cyclosporin A emulsion) with lower irritation potential [32]. Additionally, ciprofloxacin loaded liposomes exhibited a three-fold increase in ocular bioavailability in rabbits when compared with Ciprocin® eye drops [33]. Similarly, in-vivo evaluation of cationic liposomes containing ibuprofen versus ibuprofen eye drops revealed improved precorneal retention time and ocular bioavailability [34].
For posterior eye disorders, liposomes were extensively studied for effective drug delivery to the back of the eye. For instance, a novel liposomal formulation succeeded to enhance the bioavailability of flurbiprofen by 11.3 times compared with the free drug in the vitreous humor after intravitreal injection in rabbits [35]. In addition, the use of multivesicular liposomes to deliver the antibody Bevacizumab to the posterior eye chamber after intravitreal injection in rabbits was reported in treatment of choroidal neovascularization [36]. The elaborated system demonstrated an increase in intravitreal retention time as confirmed by in-vivo imaging of rat vitreous cavity, and hence the number of injection times was reduced [36]. Interestingly, the topical application of triamcinolone acetonide loaded chitosan-coated liposomes achieved better therapeutic outcomes in management of retinal edema instead of intravitreal injection of the drug [37, 38].
Despite the huge research conducted in the field of liposomal ocular drug delivery, their industrial production is limited owing to poor long-term stability, limited drug loading capacity, and difficulty during sterilization [6].
Niosomes were developed to overcome the limitations encountered by liposomes. Similar to liposomes, they are nontoxic vesicles and can encapsulate both hydrophilic and hydrophobic drugs, but they are chemically stable and do not require special techniques for handling. Niosomes are submicron-sized non-ionic surfactant vesicles that have potential applications in ocular drug delivery [39].
There are tremendous research articles reporting the use of niosomes in ocular therapy. Niosomes have been investigated for the ocular delivery of wide range of drugs such as anticholinergic drugs, anti-inflammatory drugs, anti-glaucoma drugs, and antibiotics [40].
To name a few, the antibacterial vancomycin was incorporated in niosomes integrated in pH-sensitive in-situ gel aiming to minimize drug-induced ocular irritation and prolong its effect [41]. The prepared formulation succeeded to eradicate infection with methicillin-resistant
For glaucoma management, latanoprost-loaded niosomes in thermo-sensitive Pluronic® F127 gel were developed [42]. The in-vivo evaluation of the prepared gel in rabbits confirmed its biocompatibility besides its longer duration of action (3 days) as compared with the commercial eye drops [42].
Discosomes are considered as modified niosomal formulations. They differ from niosomes by the addition of solulan C24 (non-ionic surfactant derived from lanolin). Interestingly, their large size (12–16 μm) prevents their drainage into the systemic circulation. Furthermore, their disc shape guarantees better fitting into the conjunctival sac [2]. Discosomes were reported to entrap larger quantity of timolol maleate compared with niosomes, thus increasing ocular bioavailability [43].
They are elastic span containing vesicles that are composed of non-ionic surfactants (Span 40/60/80) and edge activators (sodium taurocholate, sodium deoxycholate, and Tween 80). The edge activators are responsible for providing flexibility to these vesicles. In addition, they were reported to be non-irritant and safe for ocular use. Furthermore, they are superior to niosomes in being highly deformable and thus can effectively deliver the entrapped drugs to the posterior eye segment. Therefore, the topical instillation of spanlastics can replace the intravitreal injections and hence increase patient compliance [44].
For instance, ketoconazole-loaded spanlastics demonstrated two times better corneal permeation compared with the niosomal formulation [45]. Fluorescently labeled spanlastics were detected in the virtuous humor of the rabbit’s eye after 2 hours from topical instillation confirming their entry to the back of the eye. Similar observations were reported for the use spanlastics to deliver fluconazole, which showed enhanced permeability coefficient compared with either niosomes or Zocon ® eye drops [46].
They are thin curved plastic lenses of disc shape that are placed on the cornea. Drug-releasing contact lenses are considered as drug reservoirs that permit continuous drug release near the tear fluid [47]. The first and most frequently used polymer for the manufacture of these lenses was poly hydroxy ethyl methacrylate cross-linked with ethylene glycol dimethyl acrylate. Recently, the use of silicone lenses was employed. Substantial research was conducted on the use of lenses as a drug carrier for ocular delivery. For example, they were investigated for many drugs such as ciprofloxacin [48], cyclosporine [49], dexamethasone [50], timolol [51], antifungal drugs [52], among others. Drug-eluting lenses were reported to increase drugs ocular bioavailability via prolongation of their duration of action and increase their corneal penetration [47].
Various methods of loading drugs on the contact lenses were reported. The simplest method is soaking the lenses with the drug solution. However, this method suffers from many limitations such as low drug loading capacity and rapid drug release within few hours failing to provide extended drug release [51]. In this context, Wei et al. [51] studied the effect of encapsulation of the antiglaucoma drug, timolol, into microemulsion before loading on contact lenses by soaking on the drug loading efficiency versus soaking the lenses with free drug solution. The use of microemulsion technology achieved a two-fold improvement in loading efficiency with sustained drug release pattern up to 48–96 h. In addition, it provided prolonged reduction in the intraocular pressure for 96 h in rabbit model for glaucoma. Additionally, they reported that the entrapment of timolol in microemulsion before loading on contact lenses did not alter either the swelling or the transmittance of the developed lenses [51]. Similar findings were reported for the ability of liposomes [53] or polymeric nanoparticles [54] to extend and control the release rate of the entrapped drugs from the contact lenses.
It is also worth mentioning that Johnson & Johnson company lunched Acuvue® Theravision™ (etafilcon A drug-eluting contact lens with ketotifen). This product is the world’s first and only drug-eluting contact lenses indicated for prevention of ocular itching due to allergic conjunctivitis upon daily application. Additionally, this product is used for vision correction in patients having no red eyes [55].
Implants are a solid form of a drug that is intended to achieve controlled drug release over an extended period of time. The implants can be surgically inserted in the subconjunctival, epidural, or vitreous areas. They provide sustained and localized drug delivery with higher patient compliance compared with the topical drops [47].
Surodex ® (Oculex Pharmaceuticals, Inc., Sunnyvale, CA, USA) is a dexamethasone containing a biodegradable implant (1×5 mm) made of poly (lactic-co-glycolic acid). It is inserted in the anterior segment of the eye for the relief of inflammation after cataract surgeries. The drug is released at a constant rate for 7–10 days [47].
Lux Biosciences produced a silicone-based episcleral implant (LX201) for delivery of cyclosporine-A to the anterior chamber of the eye for 1 year. LX 201 is also being assessed in phase III clinical trials for prevention of corneal graft rejection [47].
Vitrasert® (Bausch & Laumb, Inc.) is the first intravitreal delivery system loaded with ganciclovir for treatment of cytomegalovirus retinitis. It is designed to release the drug over a period of 6–8 month [47].
Retisert® is another intravitreal implant (Bausch & Laumb, Inc.) that can release fluocinolone acetonide up to 3 years into the vitreous humor. It is approved for treatment of posterior uveitis [47].
Fluocinolone acetonide is also included in the Iluvien® intravitreal implant (Alimera Sciences, Inc.). It is indicated for treatment of diabetic macular edema. Iluvien is being assessed in phase II clinical trials for its efficacy in dry and wet age-related macular degeneration as well as macular edema secondary to retinal vein occlusion compared with Lucentis® injection containing ranibizumab [47].
The Ozurdex® intravitreal dexamethasone implant is designed to release the drug for 3–6 months. It is approved for use in diabetic macular edema, posterior uveitis, and retinal vein occlusion [47].
Recently, a lot of sustained-release intraocular implants have been developed for glaucoma treatment. For example, Durysta™ (Allergan plc, Dublin, Ireland) is bimatoprost implant, which was approved by FDA in March 2020 for treatment of open-angle glaucoma and ocular hypertension. It can provide a sustained drug release up to 3–4 months [56]. Another example is the iDose® implant (Glaukos, California, USA) containing travoprost. It is a titanium implant of dimensions 1.8 mm x 0.5 m that is anchored within the trabecular meshwork. It achieves a zero-order drug release over a period of 6 months or longer. It showed promising results in phase II clinical trials versus topical solution of 0.5% timolol. Currently, the recruitment of patients for phase III clinical studies has started [56].
Microneedles (MNs) are a revolutionary delivery method that facilitates drug delivery to a variety of eye ailments with potential healthcare applications. MNs now allow localized, effective, less invasive, and targeted drug delivery in the eye. MNs were originally created as a painless, minimally invasive, and effective transdermal medication conveyance technique [57].
Microneedle applications on various ocular targets of the suprachoroid space of the rabbit eye [58, 59], the cornea of the mouse eye [60], and the sclera of a human cadaver eye [61] have been reported.
The use of MN in the eye may also have numerous advantages over invasive intraocular injections using long, typical hypodermic needles. MNs possess long enough dimensions to pass through the ocular obstacles of both the anterior and posterior sectors of the eye, allowing for targeted administration to the sclera, stroma, and suprachoroidal area [62].
MNs, as opposed to hypodermic needles, lower the risk of pain, tissue injury, and infection. Because little research has been done in this field, using MNs in ocular drug delivery is a relatively novel approach.
Applying MNs to biological membranes can establish microdimensional transport channels and improve drug penetration across biological membrane boundaries. They’re produced from a variety of materials, such as silicon, stainless steel, glass, and polymers, and available in a variety of shapes, including solid and hollow design [63]. Many techniques such as micro molding, laser drilling, and lithography can be used to fabricate microneedles [63].
Using MNs, it’s possible to deposit medicines or drug delivery systems into the sclera or the suprachoroidal region, which is the space between the sclera and the choroid (SCS). Micropuncturing the sclera layer may allow for more drugs or drug carriers to be deposited in the sclera, resulting in enhanced drug permeation into the deeper ocular tissues [64].
To inject particles of sizes 20–100 nm, a minimum pressure of 250 kPa and a minimum microneedle length of 800 μm should be maintained; on the other hand, a minimum pressure of 300 kPa and a needle length of 1000 μm are required for particles sizes between 500 and 1000 nm to penetrate the sclera [65].
Numerous research studies, according to Gupta and Yadava, have lately shown the use of MNs in ocular diseases such as glaucoma, age-related macular degeneration, uveitis, retinal vascular occlusion, retinitis pigmentosa, and others [66].
Patel et al. invented the hollow MN, which was injected into the SCS using a hollow glass microneedle [67]. SCS targeting allows for precise dosing and reduces medication exposure to non-targeted tissues. Patel et al. showed that clearance of molecules and particles injected into the SCS occurred at varying speeds depending on their size in a rabbit cadaver model [58].
Thakur et al. in 2014 utilized hollow MN devices of heights of 400, 500, and 600 μm made from hypodermic needles. These hollow MNs were used to inject a thermo-responsive poloxamer-based hydrogel containing sodium fluorescein as a model drug into the scleral tissue of a rabbit to form an in-situ implant within the micro-channels, resulting in a sustained release of fluorescein sodium over 24 hours in an in-vitro experiment. This type of implant production, which does not require surgery, would improve patient acceptability and could also deliver sustained medication levels, decreasing the need for frequent application of eye drops [68].
For targeted drug delivery, intrascleral hollow microneedles are being created. These microneedles can transport medications into the posterior portion of the eye via suprachoroidal, subconjunctival, and transcleral pathways. This delivery method can transfer nanoparticles, microparticles, and drugs solutions in a less intrusive way. However, to distribute microparticles, administration must be accompanied with spreading enzymes such as hyaluronidase and collagenase, which aid in the quick hydrolysis of the sclera’s collagenous and extracellular matrix structure [69].
Datta et al. developed a fast-dissolving polyvinyl pyrrolidone MN ocular patch to deliver cyclosporin-A (CsA) to the cornea. CsA diffuses slowly into deeper ocular tissues and promote drug retention in the excised porcine cornea and resulted in effective ocular administration [70].
Dissolvable polyvinyl alcohol and polyvinyl pyrrolidone matrix were used to produce a dissolving microneedle ocular patch in the shape of a contact lens. These MNs, which include either amphotericin B loaded liposome or free amphotericin B, were found to be efficient in treating
In 2022, Shi et al. created a dissolving microneedle array patch based on poly(D,L-lactide) (PLA) and hyaluronic acid (HA) and containing fluconazole to develop a minimally invasive delivery system for treating fungal keratitis (FK). Interestingly, the rabbit model of FK reveals that the medicated topical MN patch has superior effect compared with the traditional eye drop formulation and is also equivalent to the clinical intrastromal injection technique [72].
For treatment of corneal neovascularization, a flexible double-layer microreservoir polymeric eye patch with a row of biodegradable detachable microneedles demonstrated to be more effective than topical eye drops. These biodegradable microneedles can penetrate through ocular barriers and self-implanted as a drug reservoir matrix for controlled drug release. Furthermore, rapid diclofenac release followed by extended monoclonal antibody release produces a synergistic effect in the treatment of corneal neovascularization [60].
In conclusion, MNs are thought to have the capacity to deliver other substances such as protein pharmaceuticals and DNA across the corneal epithelium with excellent effectiveness, which needs further exploration. MNs may serve as micro-drug reservoirs for targeted, regulated, and efficient ocular medication administration. MNs are acceptable, harmless, and painless approach, resulting in a cost-effective treatment for a variety of ocular disorders.
Cell therapy is used to treat retinal degenerative illnesses by injecting cells into the subretina, usually with a microcatheter. Generally, in this method stem cells were injected into the retinal layers to stimulate cell regeneration. While animal studies imply that this approach is safe and nontoxic, the significant risk of consequences is an important concern [73]. Recently, Gandhi et al. have showed the safety and efficacy of degradable fibrin hydrogels for subretinal implantation to aid in the accurate implantation of retinal pigment epithelium monolayer. These promising hydrogels completely disintegrated after 8 weeks, making them the first fully biodegradable scaffold designed to treat macular degeneration disease [74].
The practice of transferring genetic material to remove, replace, repair, or introduce a gene to treat disorders is known as gene therapy [75]. Viral vectors, naked DNA, and nonviral vectors such as nanoparticles, microinjection, electroporation, sonoporation, and iontophoresis might all be used to deliver genes. Furthermore, cutting-edge approaches such as Genome Editing System, CRISPR-Cas Delivery, and siRNA treatment have been examined [76].
Retrovirus, adenovirus, and lentivirus are viral vectors that have shown excellent potential for transgene delivery to target cells in the eye because of the high transduction efficacy [75]. Kopone et al. reported that intraocular gene therapy for neovascularization has been found to be safe in clinical trials, with no serious side effects. Clinical trials, however, have not progressed beyond Phase II trials [75].
Although there are benefits to employing viral vectors, there are also numerous constraints. Preexisting immunity to viral vehicles (e.g., adenovirus) is a major concern, since it may result in low transduction rates and reduced expression of the therapeutic gene within cells. Furthermore, the residual viral proteins have the potential to trigger inflammation in their intended target [77].
Naked DNA can be used for gene therapy without a vector; however, its structural instability may limit adequate cell uptake [76]. Stechschulte et al. reported that naked DNA delivery to the cornea was safe, effective, titratable, and has the potential to alter the treatment of a wide variety of corneal and anterior segment diseases [78].
Nonviral vectors including metal [79], polymeric [80], lipid nanoparticle [81], and dendrimers [82] are also employed to deliver therapeutic genes to cells in the anterior and posterior portions of the eye. Nonviral vectors, in contrast to viral vectors, have been demonstrated to be more biologically safe, with reduced immunogenicity and pathogenicity. Nonviral vectors also have the advantage of being inexpensive and easy to produce. However, nonviral vehicles may have a lower transfection yield [83].
Physical methods are also applied to force DNA cellular entry, such as microinjection, electroporation, sonophoresis, and iontophoresis.
To facilitate plasmid gene transfer, electroporation uses high-intensity electric impulses to create pores within the cell membrane. To avoid corneal injury, edema, or inflammation, the ideal electrical field strength for this type of gene transfer is 200 V/cm. When compared with DNA injection alone, gene transfer in the cornea is 1000-fold higher [84].
On the other hand, sonoporation uses ultrasound waves to physically create transitory and limited pores inside cell membranes, allowing DNA to be transferred to the nucleus. Sonoporation can improve the amount of therapeutic gene expression by up to 15-fold when compared with naked DNA [85].
Concerning iontophoresis, it is a technique that uses low currents to create transitory and localized pores in the cell membrane, allowing ionized molecules to pass through. Iontophoresis has been shown to boost gene or drug transport across the cell membrane by 2.3 and 2.5 times in the cornea and 4.0 and 3.4 times in the conjunctiva, respectively; however, after the current was removed, the transfer recovered to baseline levels in rabbit cornea and conjunctiva [86].
Small interfering RNAs (siRNAs) are a type of non-coding, double-stranded RNA molecules with about 20–25 base pairs in length that influence mRNA gene expression. Several eye diseases have been treated with siRNAs, including retinal abnormalities, glaucoma, wound healing, and neovascularization [87]. The majority of these research used animal models, while some were evaluated in human disorders and other siRNAs still under clinical trials [88].
CRISPR-Cas9 genome editing is becoming a hot topic in gene therapy [76]. The effectiveness demonstrated in delivering this gene-editing system to the posterior eye [89] via viral and nonviral approaches provides a starting guide for additional research concerning anterior segment diseases.
In conclusion, the future development of efficient gene treatments will rely on a better knowledge of the mutations and mechanisms that cause visual abnormalities, as well as the development of more efficient clinical vectors.
Several drug devices and combinations have been designed to improve drug delivery to the eye, but only a few have reached the market. They boost medication retention and penetration while allowing for long-term drug release. They also have a lower level of toxicity and better patient compliance. Genes, drugs, and cell-based pharmaceuticals, as well as their combinations with medical devices, all fall within the category of advanced therapeutics medicinal products (ATMPs).
In 2017, Rupenthal reported that devices, namely collagen shield and contact lenses that gradually dissolve into a gel are effective for dry eye management and enhance wound healing after corneal surgery. They’re also employed as antibiotic and anti-inflammatory medicine reservoirs before and after surgery [90].
Yellepeddi et al. described a device known as punctal plugs (PPs) that prevents tears from draining via the canaliculi, which connects the eye to the nose. PPs are recommended in some cases of laser in situ keratomileusis and contact lens intolerance due to their capacity to preserve tears. The insertion of PPs has also been shown to increase tear film stability, tear osmolarity, and functional visual sharpness in dry eye patients. Silicone has been used to create PP designs. Another example produced by (Medenium, CA, USA) and commercialized as SmartPLUG™ was designed to improve PP retention in the puncta. SmartPLUG™ comprises a biocompatible hydrophobic thermosensitive copolymer [91].
In another study, PPs loaded with the antibiotic moxifloxacin (Ocular Therapeutix, MA, USA) were produced for prolonged drug administration in the treatment of bacterial conjunctivitis [92].
Eibl-Lindner and coworkers created erufosine-loaded intraocular lenses (IOLs) for prophylaxis against posterior capsule opacification. They stated that the designed IOP could have a therapeutic potential. They also reported that heparin-coated IOLs could be useful for reducing intraocular inflammation after cataract surgery [93].
Some of the devices mentioned in the literature are studied in clinical trials. For example, a live-cell delivery system that allows ciliary neurotrophic factor to be released from genetically engineered retinal pigment epithelium (RPE) cells. Implants utilizing this technique, designated as “Encapsulated Cell TechnologyR” (ECT) by the production company, have been shown to deliver protein drugs efficiently. ECT is made up of live cells loaded in an implanted matrix that acts as a medical device, allowing proteins generated by the cells to enter the body’s fluids.
Finally, we can assert that manufacturing these devices under a pharmaceutical quality assurance system is a crucial step toward a faster production and efficient clinical application. This necessitates the formation of diverse research teams as well as the creation of infrastructure that adheres to GMP standards and meets the regulatory requirements of pharmaceutical quality systems.
The development of innovative, noninvasive, safe, and patient-compliant drug delivery techniques is the focus of intense ocular research.
Numerous drug delivery carrier systems utilizing nanotechnology, cell-based systems, microneedles, contact lenses, implants, and different devices are being developed. Ocular gene therapy has recently emerged as a promising method for treating, curing, or preventing diseases by altering the gene expression in the eyes. However, the creation of future effective treatments using gene delivery will depend on a deeper comprehension of the mutations that lead to visual impairments.
Assessment of in-vivo effect utilizing ocular models of cell lines may help to further generate accurate data at the preclinical and clinical phases since many ocular drug delivery studies are only confined to in-vitro performances.
In spite of numerous research articles published in this field, there is still a large gap in the study on ocular therapeutic systems. The absence of valid and reliable ex-vivo models that can accurately simulate the physiology of the ocular tissues is the main essential obstacle to establishing highly optimized ocular drug delivery systems.
Finally, we might anticipate that within the next 10 years, the market would have a significant increase in the development of novel drug delivery technologies due to the pace at which ocular research and efforts are being done.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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\n\nPlease complete the publishing proposal form. The completed form should serve as an overview of your future Compacts, Monograph or Edited Book. Once submitted, your publishing proposal will be sent for evaluation, and a notice of acceptance or rejection will be sent within 10 to 30 working days from the date of submission.
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\n\nAt this step you will also be asked to accept the Copyright Agreement.
\n\n5. LANGUAGE COPYEDITING, TECHNICAL EDITING AND TYPESET PROOF
\n\nYour manuscript will be sent to Straive, a leader in content solution services, for language copyediting. You will then receive a typeset proof formatted in XML and available online in HTML and PDF to proofread and check for completeness. The first typeset proof of your manuscript is usually available 10 days after its original submission.
\n\nAfter we receive your proof corrections and a final typeset of the manuscript is approved, your manuscript is sent to our in house DTP department for technical formatting and online publication preparation.
\n\nAdditionally, you will be asked to provide a profile picture (face or chest-up portrait photograph) and a short summary of the book which is required for the book cover design.
\n\n6. INVOICE PAYMENT
\n\nThe invoice is generally paid by the author, the author’s institution or funder. The payment can be made by credit card from your Author Panel (one will be assigned to you at the beginning of the project), or via bank transfer as indicated on the invoice. We currently accept the following payment options:
\n\nIntechOpen will help you complete your payment safely and securely, keeping your personal, professional and financial information safe.
\n\n7. ONLINE PUBLICATION, PRINT AND DELIVERY OF THE BOOK
\n\nIntechOpen authors can choose whether to publish their book online only or opt for online and print editions. IntechOpen Compacts, Monographs and Edited Books will be published on www.intechopen.com. If ordered, print copies are delivered by DHL within 12 to 15 working days.
\n\nIf you feel that IntechOpen Compacts, Monographs or Edited Books are the right publishing format for your work, please fill out the publishing proposal form. For any specific queries related to the publishing process, or IntechOpen Compacts, Monographs & Edited Books in general, please contact us at book.department@intechopen.com
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',book:{id:"11082",title:"Operations Management",coverURL:"https://cdn.intechopen.com/books/images_new/11082.jpg"},signatures:"Yu Zhao"},{id:"1085559",title:"Assessment of Medical Equipment Maintenance Management",slug:null,totalDownloads:21,totalDimensionsCites:0,doi:"10.5992/intechopen.1000210",abstract:'Today's modern hospital is highly dependent on different types of medical equipment to help diagnose, monitor, and treat patients. Medical equipment maintenance is important to reduce costs, reduce patient dissatisfaction, treat the patient in a timely manner, and reduce mortality and risks during patient care. Good maintenance management is important to have well-planned and implemented programs through which hospitals can minimize medical device failures or other problems with the operation of medical equipment. Medical equipment plays an important role in the hospital system; therefore, the acquisition, maintenance, and replacement of medical equipment are key factors in hospitals for the implementation of the health service. Thus, in order to ensure the quality of medical devices for the provision of medical care, it is imperative to evaluate the safety of using hospital maintenance management. In order to achieve these goals, hospitals must develop checklists that identify the state of performance of medical equipment maintenance. It is essential for clinical managers and engineers not only to increase the capacity of the hospital but also to predict the risks of sudden failure. Given the lack of unique and comprehensive maintenance management checklists, the current goal is to design and develop medical equipment maintenance management checklists.
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