\r\n\tThis book will consist of chapters that are an elegant mix of reviews and current developments on the subject that will be useful both to an expert on the subject as well as a newcomer to this area of research.
",isbn:"978-1-83969-076-1",printIsbn:"978-1-83969-075-4",pdfIsbn:"978-1-83969-092-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"8a2fd9bbbbae283bf115881d9d5cc47a",bookSignature:"Dr. Ashim Kumar Dutta",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11857.jpg",keywords:"Frenkel Excitons, Wannier-Mott Excitons, Low Dimensional Solids, Molecular Crystals and Aggregates, Exciton Diffusion and Hopping, Exciton–Exciton Annihilation, Dynamics, Scaling Laws, Photoluminescence, Exciton Lifetime, Energy Harvesting, Semiconductors",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 19th 2022",dateEndSecondStepPublish:"June 23rd 2022",dateEndThirdStepPublish:"August 22nd 2022",dateEndFourthStepPublish:"November 10th 2022",dateEndFifthStepPublish:"January 9th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"5 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Ashim Kumar Dutta received his Ph.D. in physical chemistry from the Indian Association for the Cultivation of Science (IACS). He has worked on various international post-doctoral fellowships in Japan, Canada, and USA. Dr. Dutta has worked as head of research and product development in several companies, and presently works as vice-president for India Glycols Limited. He has authored/co-authored 36 articles in international journals and 21 patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"277477",title:"Dr.",name:"Ashim",middleName:"Kumar",surname:"Dutta",slug:"ashim-dutta",fullName:"Ashim Dutta",profilePictureURL:"https://mts.intechopen.com/storage/users/277477/images/system/277477.jpg",biography:"Dr. Ashim Kumar Dutta presently works as the vice president (R&D) with India Glycols Limited, one of the largest manufacturers of Green Surfactants in South East Asia. Earlier, he had worked with Unilever as a senior researcher and product development manager in their Home and Personal Care Category, with United Phosphorus Limited and Indofil as their global head for agrochemical formulations. He has authored/co-authored 36 articles in international journals and 19 patents. He received his Ph.D in physical chemistry from Indian Association for the Cultivation of Science (IACS) – a premiere research institute in India in 1993. Dr. Dutta has worked on various international post-doctoral fellowships in Japan, Canada and USA. His research interests include supramolecular assemblies, ultrathin nanostructured films, nanoparticles, novel surfactants, surfactant-polymer interactions, bio-membranes and spectroscopy of Langmuir-Blodgett films, tribology and rheology of complex systems.",institutionString:"India Glycols Limited",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440204",firstName:"Ana",lastName:"Cink",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440204/images/20006_n.jpg",email:"ana.c@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. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"8356",title:"Metastable, Spintronics Materials and Mechanics of Deformable Bodies",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"1550f1986ce9bcc0db87d407a8b47078",slug:"solid-state-physics-metastable-spintronics-materials-and-mechanics-of-deformable-bodies-recent-progress",bookSignature:"Subbarayan Sivasankaran, Pramoda Kumar Nayak and Ezgi Günay",coverURL:"https://cdn.intechopen.com/books/images_new/8356.jpg",editedByType:"Edited by",editors:[{id:"190989",title:"Dr.",name:"Subbarayan",surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"44072",title:"Innovative Models to Assess Multiple Myeloma Biology and the Impact of Drugs",doi:"10.5772/54312",slug:"innovative-models-to-assess-multiple-myeloma-biology-and-the-impact-of-drugs",body:'Tumor and its embedding microenvironment form a unique, dynamic system, largely orchestrated by cellular players, including fibroblasts and endothelial cells (EC), and surrounding extracellular matrix (ECM) with its distinctive physical, biochemical, and biomechanical properties. There is a general consensus that, beyond genetic mutations and epigenetic modifications, the dialogue that occurs between tumor and its microenvironment, through soluble factors and molecular interactions, may affect tumor cells survival, growth, proliferation, response to chemical/physical factors, and lies the basis for metastatization to distant, specific organs. This theory was proposed by Paget in the 1880s [1], who underlined the need, for investigating and targeting tumor, to focus not only on the cancer cell, “the seed”, but also on the “soil” where tumor homes and in which it derives its nutrients, oxygen and signals [2, 3]. Accordingly, tight links between tumor and surrounding microenvironment could determine the overall sensitivity to anti-cancer drugs and therefore represent an attractive therapeutic target [4].
Tumor microenvironment plays a critical role also in development and progression of haematological malignancies [5,6]. In this regard, Multiple Myeloma (MM) represents a paradigmatic condition [5,6]. Indeed, MM plasma cells almost exclusively home and thrive inside Bone Marrow (BM) microenvironment, which confers anti-apoptotic and pro-survival signals and resistance to drugs. In turn, tumor cell interactions with BM cells and matrix result in re-shaping of microenvironment, and architectural changes involve in particular the vascular compartment [7].
The establishment of tight links between MM plasma cells and their microenvironment underlines the need for appropriate models for studying MM biology and predicting the impact of drugs.
In the present paper, we briefly summarize the role of BM microenvironment and, particularly, of MM associated angiogenesis, in MM pathogenesis, progression and prognosis. We then provide an overview of the currently available MM models, including animal models and a new three-dimensional (3D), gel-based,
MM is a B-cell tumor, characterized by clonal proliferation of malignant plasma cells inside the BM, production of a monoclonal paraprotein, and associated clinical features, including lytic bone lesions, renal insufficiency, hypercalcemia and anemia. It accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. Albeit significant advances have been recently achieved in the treatment of MM, the disease still remains incurable, prompting the development of new therapeutic strategies [8].
MM is thought to evolve from a pre-malignant syndrome known as Monoclonal Gammopathy of Uncertain Significance (MGUS), that progresses to smoldering (asymptomatic) myeloma and, finally, to symptomatic myeloma. In addition to genetic abnormalities accumulating in MM cells, BM microenvironment actively participates to the pathogenesis and progression of the disease. Indeed, host stromal components profoundly influence many steps of tumor progression, such as tumor proliferation, invasion, angiogenesis, metastasis, and even malignant transformation [9]. The BM, where MM cells specifically home, provides a highly specialized microenvironment, which optimally “soils” neoplastic plasma cells, and, in turn, is shaped by the interactions with MM cells [5,6,10].
BM microenvironment consists of a series of cellular components, including hematopoietic cells, immune cells, BM stromal cells (BMSC), osteoclasts, osteoblasts and endothelial cells (EC), all embedded in an extracellular matrix (ECM) (Fig.1).
MM cells specifically localize inside the BM milieu through the CXCR4/CXCL12-SDF1-alpha axis [11] and then interact with ECM and BM cellular components by means of adhesion molecules, including integrins. The complex interplay between MM cells and BM milieu, together with the ensuing pathogenetic events, are depicted in Fig. 2 (upper panel).
Interactions between MM cells and ECM and cellular components (Fig. 2, lower panel) trigger the release of soluble factors, which, in turn, determine autocrine/paracrine loops of MM survival/proliferation and also promote osteoclastogenesis, defective immune functions and the “angiogenic switch”, overall leading to MM cells growth, survival, and resistance to chemotherapeutic agents [10]. In particular, adhesion of MM cells to BMSC and to ECM components triggers anti-apoptotic signals and also the release of the pro-survival factor Interleukin (IL)-6. Moreover, MM plasma cells and BM stroma release osteoclast-acivating factors, including IL-1, IL-6, tumor necrosis factor (TNF)-α, RANK-L(Ligand) and Macrophage Inflammatory Protein (MIP)-1α. MM cells have also a unique ability to evade immune surveillance through several mechanisms, including impairment of cytotoxic activity and induction of dendritic cells dysfunction (Fig. 2).
Angiogenesis, the sprouting of capillaries from existing blood-vessels, is a complex, dynamic and tightly regulated process, that occurs physiologically during normal growth, wound repair after injury and regeneration [12,13]. Angiogenesis is controlled by the balance between positive and negative regulators. In a tumor microenvironment, the exaggerate expression of pro-angiogenic cyto-chemokines starts the ‘‘angiogenic switch’’, leading to increased micro vessel density (MVD) [14]. The occurrence of an “angiogenic switch”, responsible for the transition from the avascular “dormant” phase to the vascular phase of exponential tumor growth [15,16], has also been proposed for MM. Pro- and anti-angiogenic soluble molecules are produced and released by myeloma cells and components of microenvironment, including MMEC, stromal cells and inflammatory cells [17-19] (Fig.2 A, upper panel). Major angiogenic cytokines are VEGF-A, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Both EC in general, and in particular MMEC, and MM cells secrete VEGF and express its receptors, thereby contributing to autocrine/paracrine pathways of tumor growth, survival and angiogenesis [19]. Finally, Angiopoietins (Angs, Ang-1 and-2) are important mediators in vasculature homeostasis and their circulating levels are considered of prognostic significance in MM [20].
Overall, BM angiogenesis in MM contributes to disease progression; accordingly, new anti-myeloma agents target not only MM cells, but also the microenvironment, and in particular vessels [21]. This notion is exemplified by the proteasome inhibitor Bortezomib (PS-341, Velcade), which has been approved for treatment of patients with relapsed and refractory MM and more recently used in front-line therapy for the disease.
Since BM microenvironment is of most importance in supporting myeloma cell growth and survival, experimental models of MM should provide insights into the mechanisms that, at molecular level, regulate the complex interplay between MM cells and biochemical and physical cues coming from BM ECM and cell components.
Traditional two-dimensional (2D)
Table 1 illustrates the principal characteristics of 3D
\n\t\t\t\t\t \n\t\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\t | \n\t\t\t
\n\t\t\t\t | \n\t\t|||
\n\t\t\t\t | \n\t\t\tMonolayer Lack of 3D physical cues | \n\t\t\tMultilayer Nano- and micro-topographies are recreated | \n\t\t\t34-37 | \n\t\t
\n\t\t\t\t | \n\t\t\tUnidirectional, passive fluid diffusion Lack of chemical gradients and reduced gas supply high ECM stiffness (more than 1 GPa) | \n\t\t\tPluri-directional active fluid diffusion Gradients of nutrient and gas can be generated Efficient waste removal in dynamic bioreactors ECM stiffness lower than in 2D (variable from 1 to 100 kPa) | \n\t\t\t26, 38-41 | \n\t\t
\n\t\t\t\t | \n\t\t\tReduced interactions between neighbouring cells | \n\t\t\tIncreased interactions between neighbouring cells | \n\t\t\t25 | \n\t\t
\n\t\t\t\t | \n\t\t\tFlat: geometrically-constrained baso-apical polarity Limited spatial distribution of adhesions to ECM Limited cell survival rate | \n\t\t\tSpheroid: free cell polarity guided by ECM Whole cell surface distribution of adhesions to ECM High cell survival rate | \n\t\t\t3142-44 | \n\t\t
\n\t\t\t\t | \n\t\t\tLack the major physiological cues (biochemical, chemical, physical, mechanical) of the original tissue Low cell differentiation state and function Absent or abnormal neo- synthesized ECM (qualitatively and quantitatively) | \n\t\t\t3D models are closer to the High differentiation state and functional competence ECM characteristics may vary, according to the culture model, from synthetic, natural and de-cellularized ECM, but 3D models are closer to the physiological context | \n\t\t\t41, 45,46, 47 | \n\t\t
\n\t\t\t\t | \n\t\t|||
\n\t\t\t\t | \n\t\t\t- | \n\t\t\t++ | \n\t\t\t48 49 | \n\t\t
\n\t\t\t\t | \n\t\t\tOrganized | \n\t\t\tDisruption of tissue organization, as in i | \n\t\t\t50 | \n\t\t
\n\t\t\t\t | \n\t\t\tHigher growth-/ metabolic- related gene expression Activation of mitochondrial and ribosomal gene clusters Gene expression is, generally, quite different from | \n\t\t\tGrowth-arrest related genes are activated Closer to tumour tissue | \n\t\t\t51-53 | \n\t\t
\n\t\t\t\t | \n\t\t\t+/- | \n\t\t\t++ | \n\t\t\t54,55 | \n\t\t
\n\t\t\t\t | \n\t\t\t+ | \n\t\t\t++ | \n\t\t\t55 | \n\t\t
\n\t\t\t\t | \n\t\t\tLow (high) | \n\t\t\tHigh (low) | \n\t\t\t56-58 | \n\t\t
\n\t\t\t\t | \n\t\t\t- | \n\t\t\t+/ +++ | \n\t\t\t56 59,60 | \n\t\t
In an effort to reproduce
Within this context, 3D
The simplest way to generate an animal model of cancer consists in the injection of tumor cells into an immune-deficient mouse. This approach, known as the xenograft model, has been extensively employed for solid tumors [64,65] and then extended to MM. The xenograft model of MM consists in the subcutaneous injection of 1-2 x 107 human myeloma cells (from RPMI-8226, U266, ARH-77 or OPM-2 cell lines) into the flanks of Severe Combined Immune-Deficient (SCID), nonobese diabetic (NOD), SCID/NOD and SCID/beige, mice [66,67] (Fig.3A). The resulting plasmacytoma is palpable, and tumor burden measurable with a pair of caliper or, when lines are transduced with the eGFP-luc fusion gene, by bioluminescence imaging [68]. After harvesting, tumor mass is suitable for histological examination, allowing identification of vasculature and determination of cell proliferation/apoptosis. The model is currently used to assess the activity of new drugs on MM tumor growth and to establish the effective, minimally toxic, dose. As an example, this model has been employed to investigate the
While the xenograft model is extremely practical, particularly for drug testing, it still suffers from several limitations. In fact, it does not accurately mimic human disease, since myeloma cell lines do not behave as primary myeloma cells, more closely resembling the aggressive stage of plasma cell leukemia. More importantly, it fails to recapitulate the reciprocal interactions between MM cells and their microenvironment, which follow MM cell localization and retention inside the BM. As a result, drug efficacy can be over-estimated, lacking implanted MM cells the specific, proper human context of ECM and non-malignant accessory cells.
Murine models of MM, including the 5TMM model, contribute to overcome this latter limitation.
The 5T model has been developed in the late seventies upon injection of mice with syngeneic murine MM cells, spontaneously arising in elderly C57BL/KaLwRij mice [73,74]. The group of MM murine models collectively indicated as 5TMM mice comprises different types of mice, each bearing different tumor cells and having distinct characteristics (Figure 3B). The most commonly used, the 5T2MM and the 5T33MM models, display selective localization of cells in the BM, the presence of a serum M component and increased BM angiogenesis. The first one is characterized by moderate growth and development of osteolytic lesions more closely reproducing the human disease, while the second one displays a more aggressive behaviour with rapid growth [75].
Studies based on these models, substantially contributed by Karin Vanderkerken’s group, have provided valuable insights into MM biology, and in particular on the mechanisms responsible for bone disease, MM-associated neoangiogenesis, and MM cell homing to the BM [75]. Indeed, taking advantage from these models, it has been possible to dissect the single steps which participate to the homing process, including chemo-attraction, adhesion, trans-endothelial migration and invasion, and also to identify the molecular pairs involved [75]. Moreover, these models allow the assessment of the impact of drugs on MM cells inside their proper microenvironment. In particular, the 5T2MM model allowed to unravel the anti-tumor activity, in addition to prevention of bone resorption, of the amino-biphosphonate zolendronic acid [76]. More recently, the novel ‘second-generation’ pyrimidyl-hydroxamic acid-based histone deacetylase inhibitor JNJ-26481585 was found to reduce tumor burden and also to affect angiogenesis and osteolysis [77].
A major limitation of the model is represented by the limited availability of different 5T cell lines, which fails to recapitulate the high variability both in terms of genetics and of tumor behaviour which characterize MM developing in humans. Moreover, the results obtained with 5T models should be interpreted with caution, given the potential differences in the biology of human vs murine myeloma.
In an attempt to “humanize” murine models, in 1997 Urashima established an
More recently, Pierfrancesco Tassone and Filippo Causa developed the so-called “SCID-synth-hu” model (Figure 3D), based on the implantation of artificial bone scaffolds repopulated with human BMSC into SCID mice, followed by injection of purified MM cells from patients [82] (Fig. 3D). This model represents a further advancement over the previously described SCID-hu mouse (Fig. 3C). In fact, the use of 3D poly-β-caprolactone polymeric scaffolds, closely reproducing the micro-architecture of a human bone, overcomes the restricted availability of human fetal bones for implant, and also allows to perform studies in the context of an autologous setting [82].
As for SCID-hu models, in SCID-synth-hu mice injected human MM cells were found to optimally engraft the implanted “niche” and to interact with the human bone milieu, as demonstrated not only by histological and immunohistochemical analyses of the retrieved implants, but also by demonstration of immungloglobulin production
Both systems thereby offer the possibility to investigate human MM cells-BM microenvironment interactions and to perform pre-clinical testing of anti-MM drugs in a clinically relevant context.
MM cells accumulate a series of somatic mutations in the initiating and progressing phases of the disease [10], thus justifying development of genetically modified MM murine models, which recapitulate and explore the genetics of MM [83]. Recently, a model has been developed based on the enforced B cell lineage-directed transgene expression of XBP-1s [84]. XBP-1 is a major regulator of the Unfolded Protein Response (UPR) and plasma cell differentiation. Moreover, XBP-1 over-expression has been implicated in human carcinogenesis and tumor growth in solid tumors and also in MM [84]. XBP-1 transgenic mice spontaneously develop MGUS which progresses to MM, exhibiting remarkable clinical features common to human MM. In particular, BM involvement with clonal MM cells, serum M spike, bone lytic lesions and renal Ig deposition could be demonstrated [84].
Another model exploited the deregulated expression of Myc. Myc activation occurs in post-germinal center malignancies, including Burkitt’s lymphoma, and is a common feature in MM; in particular its over-expression is generally considered of prognostic significance [85]. Mice engineered to express c-Myc under the control of mouse immunoglobulin kappa (IgK) light-chain gene–regulatory elements (Vk-Myc mice) were developed [86]. Myc is a strong oncogene, and its constitutive expression in early B cells of Vk-Myc mice led to a very aggressive lymphoma, with extra-medullary localization [86].
To create a transgenic mouse model more closely resembling human MM, in their elegant work Chesi and co-workers selected the C57Bl6 strain, genetically predisposed to develop MGUS, and generated a vector (Vk*Myc) containing a stop codon insertion in the human c-myc oncogene, which prevented its expression [87] (Fig. 3E). Myc could be then sporadically activated in post-germinal B cells as a result of somatic hypermutation, leading to the transition from the spontaneous monoclonal gammopathy to a disease that fully recapitulate the biological and clinical features of human MM. In fact, Vk*Myc mice are characterized by the accumulation of slowly proliferating plasma cells exclusively inside the BM. Moreover, high levels of monoclonal antibody are detectable and end-organ damage develops, including anemia, kidney failure and lytic bone disease [87]. The model was found to be highly predictive of the activity of anti-myeloma drugs [88], including those that target microenvironment, and may potentially help to select new agents for evaluation in clinical trials.
Due to inter-species differences, animal models have incomplete predictive value for human MM disease and drug response. New models are, therefore, needed that more closely resemble the
Kirshner and her group have reconstructed,
It is well known that the metabolic requirements of complex 3D cell constructs are substantially higher than those needed for the maintenance of traditional cell monolayers (2D culture) kept in liquid media under static conditions. Dynamic bioreactors were primarily developed to modulate mass transfer, a crucial element for guaranteeing gas/nutrient supply and waste elimination, essential factors for maintaining cell viability within large 3D cell/tissue masses. Despite a wide array of fluid-dynamic bioreactors has been devised [47,90], the low-shear environment and optimal mass transfer, needed for the long-term culture of functional 3D tissue constructs and explants, were attained only with the introduction of the microgravity-based
On this basis, we successfully employed the microgravity-based RCCSTM technology for the generation (and long-term maintenance) of viable human-derived MM tissue explants and 3D cell constructs. Fig. 4 shows the culture chamber of the RCCS™ microgravity-based bioreactor, and histo-morphological images of the
The suitability of our method for the culture of human tissue samples was, firstly, proved by using skin biopsies, which retained intact epidermal and dermal architecture, including keratin stratum and skin annexes. Moreover, both blood and lymphatic vasculature was identifiable and exhibited normal morphology, in particular patent lumen and complete endothelial lining (Fig.4C). The 3D culture of thick sections of human MM tissue explants fully preserved tissue architecture and microenvironment integrity (Fig.4D) for extended periods of time. Moreover, the system was suitable for the assessment of drug sensitivity, not only of tumor compartment, but also of angiogenic vessels (Fig.4D). Indeed, quantification of MVD in treated specimens could represent a unique method to assess the anti-angiogenic effect of a drug in human samples
A major challenge in cancer biology and cancer therapy relies in the availability of suitable models that recapitulate the complex tumor-host interplay and responsiveness to drugs. This is especially true for MM, where the existence of tight links between MM cells and BM microenvironment has hampered for long the development of adequate animals and
The availability of more and more sophisticated systems is expected to pave the way to a deeper understanding of pathogenetic events and also to development of novel patients-tailored therapeutic strategies.
The popularization of general anesthesia by William Morton in the 1840’s and the concept of antisepsis introduced by Joseph Lister would lead to a paradigm shift and the emergence of modern surgery [1, 2]. The mastery of surgery was no longer associated with speed or flamboyance, but instead focused on meticulous dissection, careful handling of tissues, hemostasis, and correct approximation of tissue planes to promote adequate healing. Among operative specialties, this transition from “art” to “science” of surgery was most profound in the neurosurgical field, enabling rapid advances to occur.
\nEarly in the evolution of modern surgery, the issue of hemostatic control became prominent, as the heavily vascularized central nervous system and its propensity to bleed resulted in limitations of procedures and posed significant challenges [3, 4, 5]. Surgical ligation was utilized sparingly for fear of vessel rupture or vascular occlusion that may compromise entire vascular distributions. The instruments and techniques in neurosurgical armamentarium therefore relied predominately on application of pressure with gauze to combat bleeding [3, 6]. As a result, a search and incorporation of novel alternatives in hemostatic techniques would effectively lead to the development of modern neurosurgery as represented by Horsley’s use of bone wax and other pioneering hemostatic maneuvers [7, 8] and the introduction of electrosurgery by Cushing and Bovie in the 1920’s [9, 10]. Later in the revolutionary era of neurosurgery, biosurgical materials were introduced [6, 11].
\nIn its broadest sense, the term biosurgery relates to the utilization of biomaterials that are defined as systemically and pharmacologically inert substances designed for implementation within or incorporation with living systems [12, 13, 14]. In the context of the current chapter, biosurgical materials (BSMs) are defined as biomaterials that are intended as adjuncts in attaining surgical hemostasis [15, 16]. The gradual development of hemostatic techniques has greatly impacted not only the field of neurosurgery, but all of surgery. The application of biosurgical agents first developed in the neurosurgical theater proved immensely valuable across virtually all surgical applications.
\nOne of the earliest neurosurgical applications of biosurgical hemostats involved the control of bleeding in inaccessible areas with difficult tissue topography and in situations where use of electrocautery, sutures, or clips may simply not be feasible [4, 13, 17]. This chapter will review the categories, mechanism of action, efficacy, advantages, disadvantages, and complications of the various biological materials currently available for hemostasis in neurosurgery.
\nThe abundance of biosurgical materials available for use requires a system of categorization. These agents can be divided into specific categories based on their mechanism of action, including passive or active hemostatics, flowable agents, and sealants [18, 19, 20]. Passive or mechanical agents act through contact with the site of bleeding to promote platelet aggregation [21, 22]. They form a matrix type network at the site of bleeding, thereby activating the coagulation pathway to provide a platform for platelet aggregation and clot formation. At the same time, these agents will be ineffective if used on patients with known coagulopathies due to factor deficiencies or platelet dysfunction. These products include gelatins, collagens, cellulose, and polysaccharide spheres. They require no special storage, minimal or no preparation, and are relatively inexpensive [23, 24].
\nActive hemostatic agents act biologically and directly participate in the coagulation cascade to stimulate fibrinogen at the site of bleeding to produce a fibrin clot [21, 25]. These agents primarily include the different forms of thrombin, and are useful in patients with coagulopathies or platelet dysfunction [18, 26]. However, they rely on the presence of fibrinogen in the patient’s blood to be effective. In general, they control bleeding more effectively than passive agents, are more costly, and are prepared/available in various forms and formulations.
\nFlowable hemostatic agents consist of various combinations of active and passive components within a single application [20, 27]. This category includes products that work by providing a physical barrier to blood flow while actively converting fibrinogen in blood into fibrin at the bleeding site [26, 28]. Finally, sealants work by the formation of a barrier impervious to flow [24, 29]. There are several types of sealants currently available for use. Our subsequent discussion will focus on each of the various types of biosurgicals utilized, with emphasis on neurosurgical applications.
\nThis material contains 1-μm microcrystals of purified bovine dermal collagen available as flour-like or sheet-like format [30, 31]. The microcrystalline collagenous network provides surface for platelets to aggregate while coagulation factors are released [30, 31]. The effectiveness of microfibrillar materials may be decreased in cases of severe thrombocytopenia (<10,000 mL) [32]. The material should be kept dry prior to use because moisture may decrease its activity and the hydrophilic nature of product results in adherence to surgical gloves and possible mis-application. Consequently, the material is best handled with sterile forceps. As with other biologic hemostats, optimally the smallest amount required to arrest bleeding should be utilized, although this may not be precisely known in every situation.
\nOf importance, microfibrillar collagen is considered a foreign substance and can therefore serve as a nidus for infection and/or foreign body reaction [33]. The small particles of the flour-like material are useful for arresting bleeding from cancellous bone. In this setting, it has demonstrated superior efficacy when compared with other agents, such as thrombin alone or thrombin combined with gelfoam [7]. It also does not seem to interfere with bone healing in contrast to oxidized cellulose or bone wax [34]. It is recommended to firmly pack product into bone surface followed by direct pressure for 5–10 minutes. In terms of clinical application considerations, it should not be used in areas where it may exert pressure on adjacent structures because of fluid absorption and expansion. Also, excessive expansion along a dural sinus may lead to occlusion after bone flap replacement. Although collagen is relatively less antigenic and only results in minor inflammation there remains the very small risk of allergic reactions [35, 36]. Finally, it can also lead to infection, abscess, pseudo-abscess or granuloma formation [37, 38, 39].
\nThis type of biomaterial was developed in the 1940’s to help facilitate hemostasis [40, 41]. It is available as pads, strips or powder [40, 42, 43]. It can absorb seven to ten times its own weight [44]. This ubiquitous hemostatic agent is one of the most frequently used. Upon contact with blood, the material reacts to form a reddish black gelatinous mass containing hematin (accounts for the color change) [45]. The oxidation of cellulose results in a product of low pH with resultant bacteriostatic properties [46, 47]. Despite the antimicrobial properties the rates of infection do appear to correlate with the amount of retained product [48]. Consequently, though often left in place in surgical beds, excess amounts should be removed prior to wound closure. Of note, the addition of saline or thrombin to oxidized regenerated cellulose may decrease its effectiveness in addition to inactivating thrombin as a result of the acidic environment [49]. It may also interfere with bone healing and may cause blood vessel compression [49]. Finally, there are reports of excessive postoperative swelling of this type of biomaterial [50].
\nAlso introduced in the 1940’s this type of hemostatic material consists of water-insoluble sponges prepared from purified porcine skin gelatin [11]. It provides hemostasis by absorbing up to 45x its weight in fluid, thus restricting blood flow and providing stable matrix for clot formation [51]. Gelfoam with gentle pressure can tamponade and treat most dural sinus bleeding without occlusion of the sinus. Although hemostatically beneficial, this capacity to expand physically can lead to compression of neural (and vascular) structures [52]. Absorbable gelatin material is considered relatively nonreactive, however there have been case reports of giant-cell granuloma formation at the implantation site [53, 54]. Although generally non-antigenic, this type of biosurgical material is considered a foreign body and can serve as a nidus for infection [55].
\nThis is a relatively new category of biosurgicals, derived from vegetable starch containing no animal or human components [56, 57, 58]. It is available in powder form with a bellows-type applicator [56, 59]. The material requires no mixing and is available for immediate use. It produces a hydrophilic effect to dehydrate blood and concentrate solid components to increase barrier formation [59, 60]. It poses little risk to patients since it lacks any human or animal components and should not be used in closed spaces because of physical expansion / swelling.
\nThere are three forms of thrombin products differentiated based on type of plasma used to provide concentrated thrombin to rapidly convert fibrinogen to fibrin clot [61, 62, 63]. This class of biosurgicals should be used in cases of mild to moderate bleeding, mainly because such products tend to be easily washed off in the setting of brisk arterial bleeding or surgical irrigation [64]. In addition, thrombin-based hemostatic agents may be less effective in situations of severe fibrinogen deficiency [15]. Finally, thrombin products should not be allowed to enter the vascular system as intravascular thrombosis can occur [65].
\nAntibody formation represents a risk with the use of bovine thrombin, leading to coagulopathy and even death in rare cases [66, 67]. In fact, there is a “Black Box” warning associated with this complication. The use of bovine thrombin is contraindicated if the patient is allergic or has known sensitives to materials of bovine origin [23, 68]. On the other hand, pooled human plasma carries a potential risk of viral or prion disease transmission since multiple units of blood are required to manufacture each lot of product [69, 70].
\nThese products represent a combination of absorbable passive and active hemostatic components [71, 72]. One of the flowables currently available is a combination of bovine gelatin particles and pooled human thrombin [73, 74], while the other consist of absorbable porcine gelatin particles combined with stand-alone thrombin [27, 75]. In order to become effective, the flowables require direct contact with blood as fibrinogen source [76]. Reconstitution is required, with these products having a paste-like consistency and the ability to “remain in place” compared to liquid thrombin [43]. Flowables are applied with a syringe-like applicator and require 2–3 minutes of preparation time [28, 77]. Direct injection into emissary veins or venous sinuses should be avoided to decrease the risk of dural venous sinus thrombosis and post-operative venous stroke.
\nThis group of agents consists of concentrated fibrinogen and thrombin. They increase the rate of blood clot formation by providing higher concentrations of both fibrinogen and thrombin [78]. There are three available types: (a) Pooled human plasma [79, 80]; (b) Individual human plasma, bovine collagen, and bovine thrombin [81]; and (c) Pooled human plasma and equine collagen [82].
\nSealants may be used in coagulopathic patients with insufficient fibrinogen [64, 78, 83]. These agents can also be used in heparinized patients since they do not rely on host factors for hemostasis [84, 85, 86]. Typical indications are hemostasis during cardiopulmonary bypass, splenic injuries, and a number of less commonly utilized general surgical applications [23]. However, they are widely used as hemostatic adjuncts and sealants during neurosurgical procedures, including the prevention of cerebrospinal fluid (CSF) leaks [87, 88].
\nThere are three different product types in this class of biosurgicals [89, 90]. They tend to be most efficacious when used on a relatively dry field to allow sufficient time for polymerization [91]. One type of polyethylene glycol polymers (PGPs) consists of a combination of 2 polyethylene glycol (PEG) polymers that cross-link to each other and contact tissue following application [92]. In effect, the PGP-based network acts as a sealant to tissue fluids as well as barrier to cell ingrowth and adhesion formation [92, 93].
\nAnother type of PGP material consists of a combination of PEG polymer, trilysine amine, and blue dye [94, 95]. This particular component mix produces a hydrogel able to help with dural closure because of its ability to form a watertight seal [96]. A modified derivative using a reduced molecular weight PEG component can be used in sutured dural repair during spinal surgery [96, 97]. The built-in blue dye is used to provide accurate placement of sealant [98, 99]. Some concerns about this particular material being associated with cases of postoperative spinal cord compression have been voiced [94, 100, 101, 102]. As such, specific non-expanding formulations exist for usage in the spinal canal [103].
\nThe third class of PEG polymer compound consists of a combination with human serum albumin. This substance is biodegradable and fairly well studied in terms of safety and effectiveness [104]. It provides a strong barrier, as evidenced by the FDA approval for use on visceral pleura to close air leaks of >2 mm during pulmonary surgeries [105]. There may also be associated economic benefits of using this type of biologic sealant [106].
\nIt is important to realize that biosurgical agents are adjuncts to hemostasis when standard methods like direct pressure, suturing, or cautery are impractical or ineffective [107, 108]. Good knowledge of the mechanism of action of different available biosurgical hemostats is critical, with multiple considerations including the patient’s anticoagulation status, the rate of bleeding, the presence of thrombocytopenia, fibrinogen level assessment, and many other factors. The choice of a specific biosurgical product should be dependent on the type of surgery, site of bleeding, other anatomic considerations, cost, and preference of the operating neurosurgeon [3, 16, 32, 109, 110].
\nThe continuous oozing encountered from dilated varicose intraspinal veins and bone during spinal surgery can be effectively managed with topical hemostats [111, 112]. With that said, such materials should not be left in contact with intra or extradural nerve roots due to possibility of granuloma formation [39, 53, 54, 113]. There have been reports of paraplegia from use of oxidized cellulose during thoracotomy from passage of material through the intervertebral foramen resulting in spinal cord compression [114, 115]. Therefore, it is recommended to use only the minimum required amount and any excess material should be removed once adequate hemostasis is attained.
\nBiosurgical materials are increasingly applied during spinal cord surgery to help with hemostasis since opportunities for electrocautery use are limited in this setting. Bipolar cautery, although more focused than monopolar cautery, can also allow dissipation of heat from the tips inducing thermal injury to vascular and neural structures. Fibrin glues are commonly used as hemostatic agents in neurosurgical procedures, including the management of epidural, cortical, and dural sinus bleeding [116].
\nDuring surgical resection of brain tumors, from craniotomy to extradural hemostasis following dural closure, one will find that these agents are generally used throughout the procedure. For example, oxidized regenerated cellulose is widely used during ablation of lesion(s) and at the end to prevent and abate any bleeding in the remaining cavity. However, excess agent should not be left along the surgical cavity. A single layer of oxidized regenerated cellulose should be sufficient for hemostasis without significant risk. Evaluations of the efficacy and safety of polysaccharide hemospheres reported no adverse events after use in brain surgery. There have been several reports of signal anomalies on post-operative imaging mimicking residual tumor or early recurrence, or even abscess when oxidized regenerated cellulose or gelatin sponges are left in the operative field. A pediatric case series of 3 patients who underwent intracerebral surgery with use of microfibrillar collagen reported that all required second surgery for new or recurrent seizures [38]. An MRI of preoperatively suspected tumor recurrence or abscess subsequently confirmed to be microfibrillar collagen-centric necrotizing granuloma surrounded with macrophages and eosinophils. One must remain aware of the above considerations and remove any local hemostatic agent prior to dural closure.
\nBleeding during surgery on the pituitary via a transsphenoidal approach may significantly impede visualization while not being conducive of the use of electrocautery [117]. The use of oxidized cellulose and Floseal (Baxter, Deerfield, IL) can be useful in this situation. Mild persistent oozing from brain tissue following excision can be controlled with application of oxidized regenerated cellulose followed by its removal from the remaining cavity prior to closure. Defects of the skull base in some cases require filling of the defect with bone graft, followed by suture and/or grafting of the dura reinforced with fibrin sealant. A minimally invasive treatment of spontaneous supratentorial intracerebral hemorrhage was also described using Floseal. Floseal was placed in 31 patients without evidence of vascular anomalies or coagulopathy following evacuation of hematoma from a 3 cm craniotomy. Hemostasis was achieved in all but 1 patient who required re-exploration [118].
\nA multicenter, prospective randomized study with 237 patients undergoing elective cranial surgery demonstrated PEG hydrogel (DuraSeal, Integra LifeSciences, Princeton, NJ) similarly safe when used with common dural sealing techniques (eg, sutures, autologous grafts, gelatin or collagen sponges, fibrin glues) or when used as dural closure augmentation in cranial surgery [99]. The incidences of neurosurgical complications, surgical site infections and CSF leaks were similar between treatment groups using PEG hydrogel and the control group using standard dural sealing techniques. DuralSeal was also found to be statistically significantly superior to fibrin sealant at preventing CSF leaks following posterior fossa craniotomy or craniectomy [119]. However, the special formulation of DuraSeal Exact should be used in areas where expansion can lead to neurologic compromise – such as the spinal canal [120]. This is because neurologic compromise after expansion has been described in the literature [101, 121]. This again emphasizes mindfulness to use to least amount of material to achieve closure and/or hemostasis while precluding migration or expansion of any excess materials.
\nHemostasis in neurosurgery – more so that many other surgical disciplines – is challenged by the closed space environment of the brain, spinal cord, and other critical structures [3, 122, 123]. Unlike other areas in which the “bulk” or space-occupying characteristics of biosurgicals may represent a potential benefit as they expand, this is less desirable in neurosurgical applications. In the closed environment of the skull, brain, or the spinal cord – even if bone is removed to help minimize the effect of swelling from edema – a relatively small amount of compression, especially in critical areas, like the brain stem, can have devastating consequences. As discussed in previous sections of this chapter, such compressive complications, if left untreated can result in irreversible neurologic damage [94, 100, 101, 102], with resultant “Black Box” warnings clearly outlining biomaterial-specific restrictions.
\nOf growing concern in all aspects of surgery is the increasing utilization of anticoagulants and anti-platelet therapies – and often various combinations of both [124, 125]. While the indications for such therapies are outside of the scope of this review, it is clear that more and more patients are being prescribed agents belonging to these broad medication classes. This is of special significance in the elderly population, where anticoagulants and antiplatelet drugs are used for stroke reduction (e.g., in non-valvular atrial fibrillation); various prophylaxis indications (e.g., orthopedic surgery); and of most concern, being used without any clear indications [126]. However, many clinical factors that prompt physicians to initiate antiplatelet or anticoagulant use also increase the neurosurgical risk associated with even minor traumatic events (e.g., falls and minor head injuries). Under such circumstances, even minor neurological injuries can quickly evolve into bleeding-related catastrophes when patients are anticoagulated [127, 128, 129].
\nNeurosurgical interventions in the setting of traumatic (or even spontaneous) subdural, epidural, and intraventricular hemorrhage, when confounded by drugs that inherently interfere with hemostasis can compound the difficulties and risks of an already complex clinical scenario [130, 131]. The overall challenge can be magnified even further as acute reversal agents tend to be expensive, may not always be available, reliable/effective, and could result in thrombotic complications in high-risk scenarios such as multi-trauma or massive transfusion [131, 132, 133, 134]. Furthermore, reversal algorithms and guidelines, while helpful do not always definitively address the acute problem once significant bleeding starts, and regardless of the mechanism and defect in the clotting cascade, a consumptive process may be triggered that might require a multi-faceted approach to effectively and timely manage the associated coagulopathy [134, 135, 136, 137]. Similar to other surgical scenarios, such as major trauma and cardiothoracic surgery, at times the best way of managing bleeding is via a timely and aggressive operative intervention. The above concepts are critical in the setting of neurosurgical applications of biosurgical hemostats in that it must be recognized that “bleeding” is a complex problem and often requires a combination of tools to control. Such basic tools require an understanding of the primary question – why is this patient bleeding?
Other patient factors and comorbidities can have unpredictable effects on hemostasis, but must be considered in the bleeding neurosurgical patients. Elderly, debilitated, and frail patients might be malnourished and hence have impaired protein stores which contribute to diminished clotting factor reserves – even in the setting of normal clotting tests. Patients might be taking herbal supplements (which might not even be reported in a medical record or medication lists) that have been correlated with bleeding risks [140, 141, 142].
Each of the above considerations requires a focused approach and highly specific management strategy. It is important to recognize that good surgical technique must be augmented with a broader understanding of the biologic mechanisms that contribute to the overall disease process and that there is no single tool that is ideal for all circumstances [108, 138]. Conversely, it must be recognized that there is a growing concern that using the wrong or inappropriate therapy for a given clinical scenario can be just as problematic, if not intrinsically ineffective or potentially dangerous. More so than ever in the past, optimal management of the neurosurgical patient (especially one who is bleeding) requires an in-depth and comprehensive understanding of the complex mechanisms of hemostasis pathways and the clotting cascade while also recognizing those variables, such as pharmaceutical therapies, that might adversely impact the normal balance between clotting and bleeding.
\nIn summary, in the setting of neurosurgical bleeding management, several key concepts must be recognized:
Use the right tool for the right job
Sometimes more than one approach is necessary to control bleeding
Different types of bleeding might require different management strategies
Difficult to access areas
Risk for post-operative re-bleeding
Compressive or expanding agents can cause devastating complications
Recognizing the differences between arterial and venous bleeding and how management of each might be different
Understanding the specific reasons why bleeding is occurring and what interventions – such as biosurgical agents – should be central to the overall hemostatic management.
Sometimes the best approach to managing bleeding is preventing it in the first place with strict attention to surgical technique and anatomy. It might sound inherently obvious, but the best way to avoid a dural sinus bleeding is to avoid injury in the first place.
Uncontrolled or difficult to control bleeding in neurosurgery is a challenging clinical problem and one that is becoming more common with wider use of anti-coagulant and anti-platelet agents in a population that is aging, becoming more frail, has more co-morbidities, and is at increasingly greater risk for neurotrauma. In addition, as more patients are undergoing major surgical interventions and re-interventions for complex neuro-axial pathologies the risks for bleeding complications also increase. Effective management of bleeding and bleeding related morbidity requires a thorough understanding of the mechanisms of bleeding and potential biologic defects in the normal hemostatic process. With such an understanding, management can be more focused and targeted towards the specific problem. Hence, an understanding of the adjuvant therapies, such as the full-spectrum of biosurgical agents that can be used to manage bleeding is imperative in achieving optimal patient outcomes.
\nThe authors would like to acknowledge Dr. Roy S. Hwang, for his support and expertise during the preparation of this manuscript.
\n"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
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However, the current system evaluation toolkit does not recommend specific areas required for further improvement. The objective of this chapter was to identify those constructs and their attributes that were the most suitable candidates for managerial intervention by applying partial least squares structural equation modeling. In doing so, the quantitative survey was adopted from the past studies together with new items creation representing system quality, records quality, service quality, and knowledge quality as the predictors while effective use and user performance as the outcomes. When extending the findings in importance‐performance map analysis, two‐system quality attributes (workflows fit and work styles fit) and all‐knowledge quality attributes exhibited higher importance rank for managerial actions. 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It is defined as premature deaths from selected disease groups that are considered either treatable through the timely and effective health care (amenable mortality), or preventable by public health interventions (preventable mortality). The purpose of study is to analyse the impact of four lists of causes of death created by researchers on amenable mortality by country, sex and cause of death. Data on deaths were obtained from the WHO database for 20 European Union countries in 2014. We applied the method of direct standardisation using the European Standard Population, Spearman rank‐order correlation with statistical significance tests and confidence intervals. We found that the selection of diseases considered as amenable has not significantly impact on the cross‐country comparison, but the weight of selected list of causes of death is significant at the national level. The concept has several limitations relating to selection of diseases and setting age threshold over time, availability of health care resources, prevalence of diseases or variation of causes of death coding among countries. 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The former communist countries of the Central and Eastern Europe and Central Asia needed to reform the financing of their health‐care systems and make efforts to strengthen the role of primary care while limiting the role of hospital care. The growing health needs and, consequently, costs resulted in the increased attention paid to the performance of health systems. The aim of this chapter is to determine the efficiency of health systems in post‐communist countries. The data envelopment analysis method was used. The effective health systems were identified and recommendations for the inefficient countries were formulated.",book:{id:"5808",slug:"advances-in-health-management",title:"Advances in Health Management",fullTitle:"Advances in Health Management"},signatures:"Justyna Kujawska",authors:[{id:"198853",title:"Dr.",name:"Justyna",middleName:null,surname:"Kujawska",slug:"justyna-kujawska",fullName:"Justyna Kujawska"}]},{id:"56415",doi:"10.5772/intechopen.69954",title:"Low-Cost Health/Medical Tourism of Italians",slug:"low-cost-health-medical-tourism-of-italians",totalDownloads:1176,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"In recent years, becoming a form of spatial mobility of people is mainly called “medical tourism or health tourism”. In Italy the adoption of the expression “turismo sanitario” is often used as an international expression synonymous with “medical tourism or health tourism”: this situation raises a number of conceptual problems. In fact, the Italian public health service is one of the most developed in the world and is distinguished by many nations to the fact to offer its citizens free of charge and many health care services. In this situation, the Italian citizen in need of medical care is not convenient to travel to other places and is not obliged to do so. In fact, the Italian citizen tends to move for medical and health care that the Italian public health service does not deliver at no charge: such as dental care, we will deal with this case illustrating some examples of dental tourism low cost of the Italians. However, from our point of view, tourism period may be coupled to the trips to the health or well-being only in cases where the journey is “voluntary.” All this will be discussed in this paper.",book:{id:"5808",slug:"advances-in-health-management",title:"Advances in Health Management",fullTitle:"Advances in Health Management"},signatures:"Tullio Romita and Antonella Perri",authors:[{id:"204991",title:"Dr.",name:"Tullio",middleName:null,surname:"Romita",slug:"tullio-romita",fullName:"Tullio Romita"},{id:"213614",title:"Dr.",name:"Antonella",middleName:null,surname:"Perri",slug:"antonella-perri",fullName:"Antonella Perri"}]},{id:"73241",doi:"10.5772/intechopen.93604",title:"Epidemiology of Obesity in Children and Adolescents",slug:"epidemiology-of-obesity-in-children-and-adolescents",totalDownloads:708,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The childhood overweight and obesity epidemic has become a global emergency in public health and a crucial challenge of the twenty-first century. Nowadays, childhood and adolescent obesity represent a significant public health problem both in developing and developed countries. Globally, above 340 million children and adolescents aged 5–19 years were overweight or obese in 2016. Childhood obesity is a critical burden because it can be associated with a higher possibility of obesity, premature death, and disability in adults, as well as early markers of cardiovascular disease. In Europe, childhood obesity remains a significant health challenge and is distributed disparately across and between countries and population groups. In 2019, over 398,000 children aged 6–9 years were severely obese in Europe. Particularly, Southern European countries such as Greece, Italy, Malta, San Marino, and Spain had one in five children obese in 2018. In Europe, different initiatives and actions have been launched in recent years to fight childhood obesity. However, the progress on combating obesity in children has been slow and inconsistent across the region. In this chapter, we have discussed the prevalence of obesity in children and existing policies to combat childhood obesity in the World Health Organization (WHO) European Region.",book:{id:"9559",slug:"teamwork-in-healthcare",title:"Teamwork in Healthcare",fullTitle:"Teamwork in Healthcare"},signatures:"Giulio Nittari, Stefania Scuri, Getu Gamo Sagaro, Fabio Petrelli and Iolanda Grappasonni",authors:[{id:"322429",title:"Dr.",name:"Giulio",middleName:null,surname:"Nittari",slug:"giulio-nittari",fullName:"Giulio Nittari"},{id:"322447",title:"Prof.",name:"Iolanda",middleName:null,surname:"Grappasonni",slug:"iolanda-grappasonni",fullName:"Iolanda Grappasonni"},{id:"322448",title:"Dr.",name:"Stefania",middleName:null,surname:"Scuri",slug:"stefania-scuri",fullName:"Stefania Scuri"},{id:"323556",title:"Prof.",name:"Fabio",middleName:null,surname:"Petrelli",slug:"fabio-petrelli",fullName:"Fabio Petrelli"},{id:"323558",title:"Dr.",name:"Getu Gamo",middleName:null,surname:"Sagaro",slug:"getu-gamo-sagaro",fullName:"Getu Gamo Sagaro"}]}],mostDownloadedChaptersLast30Days:[{id:"73280",title:"Teamwork in a Surgical Department",slug:"teamwork-in-a-surgical-department",totalDownloads:1166,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Teamwork is essential in surgery. A surgeon alone cannot fulfill his daily tasks. Surgical departments are divided into surgical teams: the surgical team in the operating theater, the surgical ward team, and the surgical emergency team. The common task of those teams is adequate patient care. The characteristics of team members describe necessary abilities such as: open communication, effective coordination skills, collaboration willingness, interdependency, mutual performance monitoring, backup behavior, adaptability, team orientation, and personality type. Team processes are recurring and ongoing short-term courses that occur in the team. The team developmental model separates the development of a team in four stages over a longer period of time. In the last stage, the team reaches the highest level of teamwork performance. Each team must be assessed for their nontechnical skills with team measurement tools. Surgical teams are insufficiently measured. There are possible disadvantages in teamwork, which must be considered and discussed versus the obvious benefits. Leadership is a process where the leading team member sets the direction for the others. There are different styles of leadership, whereby the dominant role of the leader is more or less pronounced. Leadership and teamwork are not contradicting characteristics of teams in the surgical department.",book:{id:"9559",slug:"teamwork-in-healthcare",title:"Teamwork in Healthcare",fullTitle:"Teamwork in Healthcare"},signatures:"Nikolai Ramadanov",authors:[{id:"322676",title:"Dr.",name:"Nikolai",middleName:null,surname:"Ramadanov",slug:"nikolai-ramadanov",fullName:"Nikolai Ramadanov"}]},{id:"54844",title:"Extending Health Information System Evaluation with an Importance‐Performance Map Analysis",slug:"extending-health-information-system-evaluation-with-an-importance-performance-map-analysis",totalDownloads:1465,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Evaluation of a health information system is necessary for determining effective use and for enhancing the productivity of medical practitioners. However, the current system evaluation toolkit does not recommend specific areas required for further improvement. The objective of this chapter was to identify those constructs and their attributes that were the most suitable candidates for managerial intervention by applying partial least squares structural equation modeling. In doing so, the quantitative survey was adopted from the past studies together with new items creation representing system quality, records quality, service quality, and knowledge quality as the predictors while effective use and user performance as the outcomes. When extending the findings in importance‐performance map analysis, two‐system quality attributes (workflows fit and work styles fit) and all‐knowledge quality attributes exhibited higher importance rank for managerial actions. 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Nowadays, childhood and adolescent obesity represent a significant public health problem both in developing and developed countries. Globally, above 340 million children and adolescents aged 5–19 years were overweight or obese in 2016. Childhood obesity is a critical burden because it can be associated with a higher possibility of obesity, premature death, and disability in adults, as well as early markers of cardiovascular disease. In Europe, childhood obesity remains a significant health challenge and is distributed disparately across and between countries and population groups. In 2019, over 398,000 children aged 6–9 years were severely obese in Europe. Particularly, Southern European countries such as Greece, Italy, Malta, San Marino, and Spain had one in five children obese in 2018. In Europe, different initiatives and actions have been launched in recent years to fight childhood obesity. However, the progress on combating obesity in children has been slow and inconsistent across the region. In this chapter, we have discussed the prevalence of obesity in children and existing policies to combat childhood obesity in the World Health Organization (WHO) European Region.",book:{id:"9559",slug:"teamwork-in-healthcare",title:"Teamwork in Healthcare",fullTitle:"Teamwork in Healthcare"},signatures:"Giulio Nittari, Stefania Scuri, Getu Gamo Sagaro, Fabio Petrelli and Iolanda Grappasonni",authors:[{id:"322429",title:"Dr.",name:"Giulio",middleName:null,surname:"Nittari",slug:"giulio-nittari",fullName:"Giulio Nittari"},{id:"322447",title:"Prof.",name:"Iolanda",middleName:null,surname:"Grappasonni",slug:"iolanda-grappasonni",fullName:"Iolanda Grappasonni"},{id:"322448",title:"Dr.",name:"Stefania",middleName:null,surname:"Scuri",slug:"stefania-scuri",fullName:"Stefania Scuri"},{id:"323556",title:"Prof.",name:"Fabio",middleName:null,surname:"Petrelli",slug:"fabio-petrelli",fullName:"Fabio Petrelli"},{id:"323558",title:"Dr.",name:"Getu Gamo",middleName:null,surname:"Sagaro",slug:"getu-gamo-sagaro",fullName:"Getu Gamo Sagaro"}]},{id:"73609",title:"Spiritual Environment Management Tool",slug:"spiritual-environment-management-tool",totalDownloads:545,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This chapter is about the spiritual environment management tool, which includes spirituality at work and spiritual practices. This management tool is divided into two steps: diagnostic of the worker’s perceptions about spirituality at work (first step) and spiritual practices design (second step). By meaning, spirituality at work can help healthcare managers to build effective teamwork in medicine. Spirituality at work has a multidimensional and measurable nature and is aligned with the three principles of the World Health Organization, based on two arguments: the new approach should be preventive and should promote partnership. This fact allows the managers as well the human resource department to classify the organizational environment on the next spiritual issues in the first step: meaningful work; opportunities for inner life; the sense of community; alignment with the organization’s value; emotional balance and inner peace. The reduction of medical errors to improve patient safety require the performance of multistep tasks of the great complexity of healthcare professionals, and this chapter pretends to show how the spiritual environment management tool can contribute with the “all working together” goal through a multi-disciplinary care team.",book:{id:"9559",slug:"teamwork-in-healthcare",title:"Teamwork in Healthcare",fullTitle:"Teamwork in Healthcare"},signatures:"Maria Joelle",authors:[{id:"230270",title:"Dr.",name:"Maria",middleName:null,surname:"Joelle",slug:"maria-joelle",fullName:"Maria Joelle"}]},{id:"54168",title:"European Health System Typologies: Last 30 Years Under Review",slug:"european-health-system-typologies-last-30-years-under-review",totalDownloads:1667,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The quest of the researcher to classify national health systems into homogeneous groups has a long history. In this paper, the last 30 years are divided in two periods (1985–2000 and 2000–2015) in order to present and briefly describe the most influential national health system typologies.",book:{id:"5808",slug:"advances-in-health-management",title:"Advances in Health Management",fullTitle:"Advances in Health Management"},signatures:"Aida Isabel Pereira Tavares",authors:[{id:"196819",title:"Prof.",name:"Aida Isabel",middleName:null,surname:"Tavares",slug:"aida-isabel-tavares",fullName:"Aida Isabel Tavares"}]}],onlineFirstChaptersFilter:{topicId:"461",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. 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Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"13633",title:"Prof.",name:"Abdelhamid",middleName:null,surname:"Mellouk",slug:"abdelhamid-mellouk",fullName:"Abdelhamid Mellouk",profilePictureURL:"https://mts.intechopen.com/storage/users/13633/images/1567_n.jpg",institutionString:null,institution:{name:"Paris 12 Val de Marne 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learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö 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Isler",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",institutionURL:null,country:{name:"Turkey"}}}]},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"1177",title:"Prof.",name:"Antonio",middleName:"J. 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Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. 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After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. 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Her fields of interest are entomology, toxicology, forensic entomology.",institutionString:"Classes et Events in Sciences (C.E.S.)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"7",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"12223",title:"Sustainable Management of Natural Resources",subtitle:null,isOpenForSubmission:!0,hash:"1881a08bbd8f5dc1102c5cb7c635bc35",slug:null,bookSignature:"Dr. Mohd Nazip Suratman and Dr. Engku Azlin Rahayu Engku Ariff",coverURL:"https://cdn.intechopen.com/books/images_new/12223.jpg",editedByType:null,submissionDeadline:"July 19th 2022",editors:[{id:"144417",title:"Dr.",name:"Mohd Nazip",middleName:null,surname:"Suratman",slug:"mohd-nazip-suratman",fullName:"Mohd Nazip Suratman",profilePictureURL:"https://mts.intechopen.com/storage/users/144417/images/system/144417.jpg",biography:"Mohd Nazip Suratman is a Professor of Forestry at the Faculty of Applied Sciences, and a Principal Fellow at the Institute for Biodiversity and Sustainable Development, Universiti Teknologi MARA (UiTM), Malaysia, He earned a B. Sc in Forestry from Universiti Putra Malaysia (UPM) and an M. S from the University of Nebraska-Lincoln (UNL), USA. He was then honored with a prestigious fellowship from the Canadian Commonwealth to pursue a Ph.D. degree at the University of British Columbia (UBC), Canada, where he worked on the application of remote sensing for forest resources management. He has been involved in numerous collaborative international research projects that led to publications in reputable journals. Altogether, he has published a total of 14 books and more than 200 research publications. His research interests cover several aspects of forestry, mainly forest modeling, forest ecology, and biodiversity. He received the UiTM’s Best Researcher and Top Talent Awards in 2015 and 2021, respectively. 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