IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
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Designed to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
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After a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
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Our innovative Book Series format brings you:
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Topic Focused Publications - Each topic showcases high impact subject areas
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Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
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Fast Publishing - quick turnaround which is unique for book publishing
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The benefit of ISSN and ISBN for increased citation and indexing possibilities
\n
\n\n\n\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
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Note: Edited in October 2021
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More focus is placed on relieving the symptoms instead of curing the disease. Mostly, patients are turned into lifetime medication-dependent individuals. New medicines are needed to overcome the side effects, complications, resistance, and intolerance caused by pharmacological and interventional therapies. In hopes of drug-free and painless alternative treatments with fewer complications, there has been a trend to revisit traditional methods that have been dismissed by modern medicine. Traditional medicine has to be reevaluated with modern scientific methods to complement and integrate with evidence-based modern medicine.",isbn:"978-1-78985-377-3",printIsbn:"978-1-78984-183-1",pdfIsbn:"978-1-78985-378-0",doi:"10.5772/intechopen.78452",price:119,priceEur:129,priceUsd:155,slug:"traditional-and-complementary-medicine",numberOfPages:110,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"60eadb1783d9bba245687adf284d4871",bookSignature:"Cengiz Mordeniz",publishedDate:"December 11th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8323.jpg",numberOfDownloads:8141,numberOfWosCitations:17,numberOfCrossrefCitations:29,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:42,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:88,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 5th 2018",dateEndSecondStepPublish:"October 8th 2018",dateEndThirdStepPublish:"December 7th 2018",dateEndFourthStepPublish:"February 25th 2019",dateEndFifthStepPublish:"April 26th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"214664",title:"Associate Prof.",name:"Cengiz",middleName:null,surname:"Mordeniz",slug:"cengiz-mordeniz",fullName:"Cengiz Mordeniz",profilePictureURL:"https://mts.intechopen.com/storage/users/214664/images/system/214664.jpeg",biography:"Cengiz Mordeniz is an associate professor at the Department of Anesthesiology and Intensive Care and Pain Medicine at Namık Kemal University, Turkey. He is the founder of the Traditional and Complementary Medical Center at The University Hospital where he also works. He obtained specialization in Anesthesiology and Intensive Care at Istanbul University and a master’s degree in Forensic Medicine and Clinical Deontology at Acibadem University, Turkey. He pursued research and clinical practice at Rigs Hospitalet, Denmark; Heidelberg and Giessen Universities, Germany; and Plovdiv University, Bulgaria. He was trained at Moscow Quantum Medicine Academy, Russia, and School of Advanced International Studies on Applied Theoretical and Non-Linear Methodologies of Physics, Italy. He completed the Clinical Research Program at Harvard University. He is a member of HeartMath Institute, USA.",institutionString:"Namık Kemal University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Namık Kemal University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"199",title:"TCM and Alternative Medicine",slug:"tcm-and-alternative-medicine"}],chapters:[{id:"67066",title:"Introductory Chapter: Traditional and Complementary Medicine",doi:"10.5772/intechopen.86373",slug:"introductory-chapter-traditional-and-complementary-medicine",totalDownloads:1230,totalCrossrefCites:8,totalDimensionsCites:11,hasAltmetrics:0,abstract:null,signatures:"Cengiz Mordeniz",downloadPdfUrl:"/chapter/pdf-download/67066",previewPdfUrl:"/chapter/pdf-preview/67066",authors:[{id:"214664",title:"Associate Prof.",name:"Cengiz",surname:"Mordeniz",slug:"cengiz-mordeniz",fullName:"Cengiz Mordeniz"}],corrections:null},{id:"67739",title:"Integration of Traditional and Complementary Medicine into Evidence-Based Clinical Practice",doi:"10.5772/intechopen.87061",slug:"integration-of-traditional-and-complementary-medicine-into-evidence-based-clinical-practice",totalDownloads:1186,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Traditional and complementary medicine regains popularity not only in developing countries but also in developed countries. Modern medicine often fails to cure and just tries to alleviate the symptoms. The patient feels better as long as the effect of the drug continues but his/her symptoms reappear after the elimination of the drug. In this way, instead of healing the patients, we turn them into life-time drug dependent. Traditional and complementary medicine, being turned scientifically into evidence-based medicine, will change the medical philosophy and treatment such as individualized and holistic approach. Complementary interventions are used together with conventional treatments, whereas alternative interventions are used instead of conventional medicine.",signatures:"Cengiz Mordeniz",downloadPdfUrl:"/chapter/pdf-download/67739",previewPdfUrl:"/chapter/pdf-preview/67739",authors:[{id:"214664",title:"Associate Prof.",name:"Cengiz",surname:"Mordeniz",slug:"cengiz-mordeniz",fullName:"Cengiz Mordeniz"}],corrections:null},{id:"65475",title:"African Traditional Medicine: South African Perspective",doi:"10.5772/intechopen.83790",slug:"african-traditional-medicine-south-african-perspective",totalDownloads:3772,totalCrossrefCites:19,totalDimensionsCites:23,hasAltmetrics:1,abstract:"African traditional medicine (ATM) has been used by African populations for the treatment of diseases long before the advent of orthodox medicine and continues to carry a part of the burden of health for the majority of the population. South Africa, as a member state of the World Health Organisation, has been set on the path of institutionalising African traditional medicine. This chapter outlines the processes and progress pertaining to the acceptance and acknowledgement of the role of ATM in health care. It sets out to describe the strides made with regard to the traditional health practitioners’ Act and other laws, research in ATM, education of both health care and traditional health practitioners, including the role of collaboration. An overview of the practice of African traditional medicine is provided.",signatures:"Mmamosheledi E. 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The development of the “Self-Organizing Factors of Biofield” (BioFAO) with complex of seven homeopathic medicines will be presented applied in life sciences. BioFAO corroborates Hering’s Healing Laws and obstacles to healing. Regardless of the point of view, innovations happen in Homeopathy, either in the stricto sensu or in the lato sensu of its classical known terminology. The La Gioconda effect mysteriously maintains Homeopathy for centuries, as well as Mona Lisa’s trajectory of magnetism over people, which made it become the most famous painting of mankind. Quantum theory brings elements that can fundamentally be connected with phenomena applied with living beings already observed.",signatures:"Silvio Leite Monteiro da Silva",downloadPdfUrl:"/chapter/pdf-download/65378",previewPdfUrl:"/chapter/pdf-preview/65378",authors:[{id:"219698",title:"Dr.",name:"Silvio",surname:"Leite Monteiro Da Silva",slug:"silvio-leite-monteiro-da-silva",fullName:"Silvio Leite Monteiro Da Silva"}],corrections:null},{id:"65194",title:"A Review on Natural Antioxidants",doi:"10.5772/intechopen.82636",slug:"a-review-on-natural-antioxidants",totalDownloads:1277,totalCrossrefCites:2,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Free radicals and related species have attracted a great deal of attention in recent years. Oxidative stress has been considered a major contributory factor to the diseases. They are mainly derived from oxygen (reactive oxygen species (ROS)) and nitrogen (reactive nitrogen species (RNS)) and are generated in our body by various endogenous systems and exposure to different physicochemical conditions or pathophysiological states. Free radical damage to protein can result in loss of enzyme activity. There are epidemiological evidences correlating higher intake of components/foods with antioxidant abilities to lower incidence of various human morbidities or mortalities. The sources and origin of antioxidants which include fruits and vegetables, meats, poultry, and fish were treated in this study. The classification and characteristics of antioxidant, its measurements and level in food and free radicals, were also documented. The chemistry of antioxidants which includes chain reactions, molecular structures, food antioxidants and reaction mechanisms, biochemical activity, therapeutic properties, and future choice of antioxidants was reported in this review.",signatures:"Arun Rasheed and Rinshana Fathima Abdul Azeez",downloadPdfUrl:"/chapter/pdf-download/65194",previewPdfUrl:"/chapter/pdf-preview/65194",authors:[{id:"277345",title:"Dr.",name:"Arun",surname:"Rasheed",slug:"arun-rasheed",fullName:"Arun Rasheed"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9050",title:"Hypnotherapy and Hypnosis",subtitle:null,isOpenForSubmission:!1,hash:"f5686a1d5917736fa774b2f46e7da8a5",slug:"hypnotherapy-and-hypnosis",bookSignature:"Cengiz Mordeniz",coverURL:"https://cdn.intechopen.com/books/images_new/9050.jpg",editedByType:"Edited by",editors:[{id:"214664",title:"Associate Prof.",name:"Cengiz",surname:"Mordeniz",slug:"cengiz-mordeniz",fullName:"Cengiz Mordeniz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8593",title:"Plant Extracts",subtitle:null,isOpenForSubmission:!1,hash:"93ae18175f7b16937a3dfddc10a51572",slug:"plant-extracts",bookSignature:"Aman Dekebo",coverURL:"https://cdn.intechopen.com/books/images_new/8593.jpg",editedByType:"Edited by",editors:[{id:"191684",title:"Dr.",name:"Aman",surname:"Dekebo",slug:"aman-dekebo",fullName:"Aman Dekebo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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In 1977, he served as a research assistant at the Institute of Structural Engineering, University of Tsukuba, Japan. He became a full professor at the same university in 1995. In 2012 he earned the title of Professor Emeritus and he is still active at the University of Tsukuba. Dr. Matsuuchi was a visiting professor at Khon Kaen University, Thailand, and a specially appointed professor at the Oguz Khan Engineering and Technology University of Turkmenistan.",institutionString:"University of Tsukuba",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Tsukuba",institutionURL:null,country:{name:"Japan"}}}],coeditorOne:{id:"321873",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Hasegawa",slug:"hiroaki-hasegawa",fullName:"Hiroaki Hasegawa",profilePictureURL:"https://mts.intechopen.com/storage/users/321873/images/system/321873.png",biography:"In 1989, Dr. Hiroaki Hasegawa started as a research engineer working on research and development of ramjet and jet engines at the Japan Defense Agency. In 1998, he earned the title of senior research engineer at the same agency. He obtained a Ph.D. in Engineering from the University of Tsukuba, Japan, in 1999. 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\n\t\t\t
1. Introduction
\n\t\t\t
Silicon carbide (SiC) became an important material whose popularity has been constantly increasing in the last period due to its excellent mechanical, electrical, optical and chemical properties, which recommend it in difficult and demanding applications.
\n\t\t\t
There are two main fields of applications of SiC. The first one is related to nano electronic [1] or even integrated circuits [2] which are using SiC (in monocrystalline or –sometimes- polycrystalline form) as basic structural material for high frequency [3], high power [4], high voltages [5], and/or high temperature devices [6] or combinations thereof [7]. In most of these applications, SiC act as are placement material for silicon which cannot be used under such extreme conditions.
\n\t\t\t
The second area of applications is related to sensors [8] and actuators, i.e. structures, devices, and/or Microsystems realized (or at least embedding some elements of) micro- and nano electro mechanical systems (MEMS & NEMS). In this area, the usage of SiC (but mainly in polycrystalline and amorphous form) is mainly due to its compatibility and easy integrability with Si and Si-based microfabrication technology. In this direction, a lot of miniaturized devices, such as chemical sensors [9], UV detectors [10], MEMS devices [11-13], and even NEMS [14], are using SiC thin films or substrates (6H-SiC or 4H-SiC).
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Polycrystalline-SiC (3C-SiC) thin films can be heteroepitaxially grown on Si substrates [14] due to the deposition temperature well below the Si melting point. [15] However, most of MEMS applications require thin films deposition methods at lower temperatures. This is necessary in order to ensure an overall low thermal budget for the entire fabrication of the SiC-based device(s), an essential prerequisite for postprocessing of MEMS structures on top of Si CMOS circuits, which ensures implementation of ‘smart sensors’. Plasma enhanced chemical vapor deposition (PECVD) of SiC in an amorphouos state (α-SiC) can be such a solution. Early studies have been done on the structural, optical and electronic properties of this material [16, 17]. More specifically, one of the key challenges for PECVD of SiC for MEMS and NEMS applications is achieving alow residual stress together, if possible, with a high deposition rate and good uniformity [16], [18-20].
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The main advantages of PECVD α-SiC deposition can be summarized as follows:
\n\t\t\t
Low temperature deposition, usually between 200-4000C (depending on the specific s of the machine and recipe employed for the deposition, as well as on the details of the device’s fabrication process).
As a direct consequence of the advantage mentioned previously, α-SiC is a highly suitable structural layer for surface micro machining applications using polyimide [21], amorphous silicon [22] or SiO2 [23] as sacrificial layer materials.
Stress control in a wide range (e.g. between −1200MPa and 400MPa [24] by tuning of deposition parameters [25], doping [26] or annealing [27].
The ability of the fabricated device to operate at relatively high temperatures.
Large mechanical strength of the deposited α-SiC layer.
Wide bandgap for the deposited α-SiC layer, making it an almost ideal optoelectronic material, transparent for all visible wave lengths above 0.5µm and thus highly suitable for guiding light in the visible and infrared optical spectrum [28].
A refractive index greater than 2.5 (significantly larger than that of SiO2 and even that that of Si3N4) also make α-SiC an excellent candidate for optical waveguides [29].
The deposited α-SiC has a coefficient of thermal expansion (CTE) relatively similar with that of Si. This means that the risks of both developing very high internal stress within the film and, therefore, of subsequent delamination, are minimized [31] when the devices are operated even at high temperatures.
The deposited α-SiC is highly suitable for applications requiring a high level of corrosion resistance and moderate operating temperatures (below 3000C) [32].
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This chapter will focus on the PECVD deposition of α-SiC layers for MEMS/NEMS applications. The chapter is organized in three major parts:
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A detailed description of the typical PECVD reactor and of the important aspects necessary for a competitive α-SiC deposition process.
The influence of main parameters on the deposition process and how one could achieve a low stress α-SiC film with anexcellent uniformity and a good deposition rate
Post-deposition processing of the PECVD α-SiC layerfor various devices and applications.
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2. PECVD reactors
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The deposition of α-SiC layers in a Plasma Enhanced Chemical Vapor Deposition (PECVD) reactor is facilitated by the plasma generated between two electrodes (radio frequency-RF- or DC discharge) in the presence of reacting gases, the substrate being connected at one of these electrodes. There is a very large diversity of types of PECVD reactors on the market, either for industrial applications or specially designed for dedicated R&D. Usually the R&D equipments are more complex but also may allow much more of flexibility and degrees of freedom in controlling the deposition, thus enabling to obtain different layers with distinct properties using the same reactor.
\n\t\t\t
The key elements in the selection of a PECVD reactor can be summarized as follows:
\n\t\t\t
\n\t\t\t\tDeposition chamber. The operating temperature for most of the PECVD reactors is between 200-400°C. In order to achieve a uniform deposition special attention has to be paid to the inlet of the reactive gases, which can be of three types: several inlets around the bottom chuck (electrode), or one inlet through the top electrode, or multiple inlets (shower) from the top electrode. The last solution seems to ensure a better distribution of reactive gases between the working electrodes with positive effect on the film‘s uniformity. Meanwhile, preheating the gases (using a heated gas distribution system) before their actual introduction into the deposition chamber may also improve the deposition uniformity. Heating the deposition chamber itself (usuallyat 50-100°C) generates gradients of temperature that avoid particle deposition on the substrate during processing. Of course, adding all these elements into a standard system would finally be reflected in a higher cost of the tool.
\n\t\t\t
\n\t\t\t\tLoadlock system. Two types of reactors can be distinguished, depending on whether a loading system is present or not: open systems (without lock load, i.e. relatively cheap reactors used only in research labs) and closed systems. The presence of a vacuumed loading system is also a critical element for good PECVD deposition, for a stable and repetitive process. There are two main aspects related to the presence of the load lock: one is related to safety while the other one is related tothe quality of the deposited layer. For the safety aspect, the presence of the loading system avoids the contact of the operator with the by-products resulted during processing, some of which are carcinogenic. As for the process quality, the fact that the chamber is kept permanently under vacuum results in excellent film quality with outstanding reproducibility.
\n\t\t\t
\n\t\t\t\tReconfiguration of the chamber. Cleaning of the chamber is also an important element in achieving good-quality layers. Most of the PECVD reactors also allow a „plasma cleaning“ process, which is applied once a certain thickness of the deposited layer is achieved (usually 5-10µm). This cleaning process is designed to remove the products deposited on the chamber’s walls or on electrodes, and it is performed mainly using CF4/O2 or C4F8/O2 as reactive gasses. The process is followed by a short pre-deposition of the material desired to be deposited in the reactor. Mechanical cleaning must be also performed periodically.
\n\t\t\t
\n\t\t\t\tGas precursors. The PECVD systems frequently used in R&D are equipped with a large number of inlets for the reactive gases. In most of the cases, the equipment is used for multiple depositions such as SiO2 (doped and undoped), Si3N4, α-Si or even TEOS (using a special Liquid Delivery System –LDS). In our case, for the deposition of α-SiC layers, silane (SiH4) and methane (CH4) are the most often used gas precursors, although other precursors, e.g. methyltrichlorosilane (MTCS) [33] or SiH4/acetylene (C2H2) [34], were also studied.
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3. Influence of the deposition parameters
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3.1. Materials and Methods
\n\t\t\t\t
This section describes the influence of the main deposition parameters on the film properties, being a practical guide of parameter selection for a desired characteristic of the deposited α-SiC thin film. The experiments were performed on 4 inch diameter, p type, 500μm-thick silicon wafers with a (100) crystallographic orientation. The wafers were initially cleaned in piranha (H2SO4:H2O2 in the ratio of 2:1) at 120°C for 20 minutes and rinsed in DI water. The native silicon oxide layer was then removed by immersing the wafers in a classical BOE solution for 30 seconds. Stress measurement was performed using a KLA Tencor FLX-2320 system while the thickness and thickness uniformity of the thin filmswere measured with a refractometer (Filmetrics F50, USA). The deposition of the tested α-SiC layers was performed using a STS Multiplex Pro-CVD PECVD system described in detail elsewhere [35, 36]. This system enables two RF deposition modes: a low frequency (LF) mode at 380 kHz with a tuning power between 0 to 1 kW, and/or a high frequency (HF) mode at 13.56 MHz with a selected power in the range between 0 to 600 W. The depositions of the α-SiC layers were performed using pure SiH4(pure) and CH4 as precursors, with Ar as an overall dilution gas.
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3.2. Pressure
\n\t\t\t\t
The α-SiC deposition‘s uniformity is strongly dependent on the pressure in the reactor chamber (Fig. 1a).
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Figure 1.
Variation of: (a)uniformity, and (b)deposition rate, with the pressure for α-SiC PECVD deposition in a STS Multiplex Pro-CVD PECVD system.
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Below 800mTorr, large non-uniformity values were observed, but the deposition uniformity linearly improved as the pressure was varied between 500 to 800mTorr, finally settling to a constant valueof the uniformities under 2% for all the pressures in the range 900 to 1400mTorr. The thickness uniformity‘s map presented a “donut“ shape, which means that the gas molecules present a high velocity, increasing the deposition rate at the edge of the wafer.
\n\t\t\t\t\n\t\t\t\t
Another important aspect of the pressure is its influence on the deposition rate (Fig. 1b): low pressures reduce the concentration of reactive species thus resulting in a low deposition rate, which increases quasi-linearly with pressure.
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3.3. RF Power
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Both the RF power and the power deposition mode are key parameters for tuning the optical and mechanical properties of the deposited PECVD α-SiC layer. A low value of the residual stress is required in MEMS applications where free standing structure is fabricated. Meanwhile, a high deposition rate is desired mainly in industrial applications. Fig. 2 illustrates the variation of the deposition rate and residual stress versus the RF power for the HF mode. The linear dependence of the deposition rate on the HF power noticed for power levels below 300W can be explained by the proportional increase in the dissociation of reactant gases with increasing the power. After a ‘threshold’ value (300W) the dissociation into reactive species is no longer a crucial factor as probably all reactive species are easily and fully dissociated, hence further increasing the power has little effect on the deposition rate.
\n\t\t\t\t
Figure 2.
Variation of the deposition rate and residual stress with the HF power in the STS Multiplex Pro-CVD PECVD reactor. The deposition temperature was 300°C, the pressure 1100mTorr, and the gas flow rates of SiH4, CH4 and Ar were 45, 300 and 700sccm, respectively.
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An interesting characteristic of PECVD α-SiC thin films deposited using the dual mode technique, particularly when compared to other PECVD deposition methods, is the very low value of the internal average stress, which can range between 50MPa and −70MPa. Fig. 2 shows the variation of this residual average with the RF power. Our results indicate that the average stress variation of a α-SiC film deposited in the HF deposition regime is not due to modifications of the film’s chemical composition, but rather due to internal structural re-arrangement because the increasingly higher values of HF power quickly provide enough energy for the adsorbed species to migrate and find the more energetically favorable sites for the film growth to take place.
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The refractive index was almost constant in the range between 2.5 and 2.6 while the uniformity of the deposition and uniformity of the refractive index was below 1.5%.
\n\t\t\t\t\n\t\t\t\t
Figure 3.
Variation of the deposition rate and residual stress with the LF power in the same PECVD reactor under the same conditions as in Fig. 2.
\n\t\t\t\t
The variation of the deposition rate and residual stress of PECVDα-SiC films deposited in LF mode are presented in Fig. 3. The differences between HF mode and LF mode are quite evident if one compares the results shown in Fig. 3 with those shown in Fig. 2. The deposition rate depends linearly with the LF power. However, for low values of LF power, the stress is highly compressive (even below −1200MPa) but quickly reduces to about −500MPa and remains almost constant at this value for any LF power above 300W. This variation can be explained by the densification of the layer determined by the increasingly more energetic ion bombardment with increasing the LF power, which characterizes the LF deposition mode. At high frequencies, only the electrons are able to follow the RF field while the ions cannot follow the instantaneous variations of the electric field due to their heavier mass. The cross over frequency at which the ions start following the electric field is between 1 and 5MHz depending upon the mass of the ions. Consequently, below 1MHz, the ion bombardment is significantly higher, which not only enhances chemical reactions but also densifies the film. However, the refractive index of α-SiC film decreases with the increasing the LF power (from 2.9 to 2.5). It can be concluded that, for a low value of the residual stress in the α-SiC layers, the HF deposition mode is more suitable. Meanwhile, the HF mode assures a better dissociation of the gasses that is reflected in a higher deposition rate.The deposition in LF mode is more suitable when PECVD α-SiC is used as masking layer or in applications for harsh environments (due to the densification of the layer).
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\n\t\t\t\t
3.4. Temperature
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A very interesting characteristic of the PECVD α-SiC deposition in the LF mode and which can be useful in many applications is that the deposition rate as well as the residual stress do not present relevant variations as a function of temperature [37]. In contrast, in the HF mode, temperature has an important effect on the stress value, although the deposition rate is not much affected by temperature in HF mode as well [37]. As is depicted in Figure 4, the internal average stress is compressive (around −110MPa) when the α-SiC layers are deposited at 200°C, but it becomes more and more tensile with increasing the deposition temperature,the stress (for temperature between 350 and 400°C). Most remarkable is the fact the stress is very low (around zero) when the deposition temperature is situated between 300 and 350°C.
\n\t\t\t\t
The refractive index value remained almost constant at 2.6 for all the films deposited in the HF mode which proves that the stress variation is resulted from the film’s structural re-arrangement, not from modifications of its chemical composition [37].
\n\t\t\t\t
Figure 4.
Variation of the average residual stress of PECVD α-SiC films with the deposition temperature. The films were deposited in the HF mode at a power of 150W, at a pressure of 1100mTorr, and with gas flow rates of SiH4, CH4 and Ar of 45, 300 and 700sccm, respectively.
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\n\t\t\t
\n\t\t\t\t
3.5. SiH4/CH4 ratio
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The influence of the SiH4/CH4 gas flow ratio, illustrated in Fig. 5, shows a linear dependence of the (compressive) residual stress on the SiH4/CH4 ratio for depositions in the HF mode. As expected, increasing the SiH4 content from 1:10 to 2:10 in the gas flow makes the deposited α-SiC film more „Si-rich“ and at the same time decreases the magnitude of the compressive stress from about −70MPa to −20MPa, while at the same time the refractive index increases from 2.6 to 2.8.
\n\t\t\t\t
Figure 5.
Variation of the average residual stress with the SiH4/CH4ratio for PECVD α-SiC films deposited at 300°C. The SiH4 flow rate was kept constant at 45sccm, while all the other deposition conditions were the same as those indicated in Fig. 4.
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To conclude, an optimized process recipe for the deposition of a low stress α-SiC film using a STSP PECVD reactor has the following parameters:
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\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tProcess parameters/ Characteristic of the deposition process\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tValue\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Pressure
\n\t\t\t\t\t\t\t
1400mTorr
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Power (HF mode)
\n\t\t\t\t\t\t\t
600W
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
SiH4, CH4 and Ar gas flows
\n\t\t\t\t\t\t\t
70, 500, and 700sccm
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Deposition temperature
\n\t\t\t\t\t\t\t
400OC
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Refractive index
\n\t\t\t\t\t\t\t
2.62
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Residual Stress
\n\t\t\t\t\t\t\t
± 5MPa
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Deposition rate
\n\t\t\t\t\t\t\t
180nm/min
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Uniformity (refractive index & thickness)
\n\t\t\t\t\t\t\t
<1%
\n\t\t\t\t\t\t
\n\t\t\t\t\t
Table 1.
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\n\t\t\t
4. MEMS application of PECVD α-SiC layers
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\n\t\t\t\t
4.1. Patterning of SiC layers
\n\t\t\t\t
Micro patterning of thin α-SiC film layer deposited in PECVD reactor is similar to the patterning of crystalline or polycrystalline SiC layers. The patterning can be done in Reactive Ion Etching (RIE) or Inductive Coupled Plasma (ICP) deep RIE (DRIE) equipments by fluorine chemistry, i.e. using a fluorine-containing gas (CF4,SF6 or even CHF3) and O2 and using photoresist as masking layer. It must be mentioned that the selectivity of the etching process to Si (used as substrate), SiO2, or even to photoresist is not outstanding (ranging from 1.2 up to 0.5) [16]. Metal masking layers have thus been initially been choosen [38, 39]. However, metal masks cause a major problem, namely the micromasking effect: as dry etching progresses, metallic particles are extracted from the mask and re-deposited onto the film/substrate where they can continue to have a protective role, resulting in a very uneven and rough final surface. For instance, aNF3/O2 chemistry was tested for etching a SiC layer [40] using to photoresist is mask, achieving etching rates of 0.135µm/min. Similarly, HBr/Cl2 etching chemistries using SiO2 etch masks have been developed [41]. This latter chemistry allowed a high selectivity (20:1) of etching SiC with respect to SiO2, but the price to pay was a very low etching rate (0.02µm/min). In a more recent work, Senesky and Pisano reported the usage of AlN as masking layer for SiC structures in an ICP DRIE reactor using SF6/O2 chemistry [42]. The etching process yielded a SiC etch rate of 0.4μm/min, having a high selectivity (SiC/AlN) of 16:1. Moreover, the anisotropy of the process was very good, as features with a sidewall angle of 10° were reported. In another work,Cl2 chemistry was used in an ICP DRIE reactor (by Pandraud et al.) for uniform patterning of a PECVD α-SiC layer for wave guide applications [43].
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
4.2. PECVD α-SiC as masking layer
\n\t\t\t\t
The intrinsic chemical inertness of SiC makes PECVD α-SiC an interesting candidate as masking layer for harsh wet and dry etching.
\n\t\t\t\t
\n\t\t\t\t\t
4.2.1. Masking layer for orientation dependent etching of Si in alkaline solutions
\n\t\t\t\t\t
A low etching rate of 78nm/h of low stress PECVDα-SiC in a 30%KOH solution was reported [19, 24, 37], while etching rates lower than 2nm/h in both 33%KOH at 85°C as well as in 25% TMAH are reported by Sarro in [16]. As expected, the etching rate depends on both the composition of the deposited α-SiC layer and its density. However, in general, the reported results are in the same range with the etch rate values of PECVD Si3N4 (13 nm/h) in KOH 20% at 85°C [36] but much better than the etch rate of thermal SiO2 (462 nm/h)in the same etchant [44]. As the reported etch rates of PECVD α-SiC have such relatively low values, we can conclude that PECVD α-SiC can be successfully used as a mask in silicon bulk micromachining processes. Furthermore, we have practically tested this hypothesis and demonstrated the feasibility of using PECVD α-SiC as masking layer, as is detailed in the next section.
\n\t\t\t\t
\n\t\t\t\t
\n\t\t\t\t\t
4.2.2. Masking layer for etching in HF based solutions
\n\t\t\t\t\t
Deep wet etching of glass is an important technology for microfluidic applications [45]. The main etchant for glass materials is highly concentrated HF [46] (sometimes with a small amount of HCl [47] or H3PO4 added [48]). PECVD α-SiC is almost an inert material in these solutions, exhibiting etching rates lower than 10Å/h [37]. Such an extremely low etching rate in highly concentrated HF solutions combined with the reduced value of the stress are the main request of a good masking layer for deep wet etching of glasses [46, 49-51]. In our tests, a compound masking multilayer ‘sandwich’ made to low stress α-Si/low stress α-SiC/photoresist seemed to be the best solution in terms of depth of the etch achieved without any damage of the mask (through- etching of 1 mm thick Pyrex glass wafers, equivalent of a 2.5 hour exposure to 49% HF). The experimental results of processing Pyrex glass wafers (Corning 7740) in such a manner are presented in Fig. 6. It can be noticed that the mask is fully intact after the etching process while the shape of the etched hole describes a perfect isotropic process. The α-Si was used in this case as an adhesion layer. If only PECVD α-SiC is used as masking layer, a hugely isotropical etching process can still be observed [50].
\n\t\t\t\t\t
Figure 6.
(a) Optical image of a glass wafer coated with PECVD α-Si/PECVD α-SiC/Photoresist after etching through in HF 49%, and (b) a SEM picture of one of the resulted etch-through holes in the glass wafer.
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\n\t\t\t\t
\n\t\t\t\t\t
4.2.3. Masking layer for dry release structure in XeF2\n\t\t\t\t\t
\n\t\t\t\t\t
Dry release in XeF2 is an emerging technology in surface and bulk micromachining of MEMS free-standing structures. The PECVD α-SiC films present a low etching rate in XeF2 gas (around 7 Å/min) which makes the α-SiC very suitable as a structural layer for any dry-release processes using α-Si or polysilicon as a sacrificial layer. Fig. 7 presents SEM images with PECVD α-SiC cantilevers fabricated using dry released in XeF2 [24].
\n\t\t\t\t\t
Figure 7.
PECVD α-SiC cantilevers fabricated using dry-released process in XeF2.\n\t\t\t\t\t\t\t
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\n\t\t\t\t
\n\t\t\t\t\t
4.2.4. Protective layer for harsh environment
\n\t\t\t\t\t
PECVD α-SiC films are also very suitable for structures intended to operate in harsh environments, due to α-SiC ‘s large hardness (2.48kg/m2) [52], high fracture strength, high modulus [53], excellent wear resistance [54] and chemical inertness in acid or based solutions, low oxidation rate and strong covalent Si-C bonds [52]. Early work proved the potential of PECVD α-SiC as a potential material for encapsulation of micromachined transducers due to its good resistance in a large range of media such as piranha solution, HF and KOH [55].
\n\t\t\t\t\t
The good mechanical strength and anti-stiction surface properties of PECVD α-SiC [56] as well as its inertness in corrosive environment recommends this material for diverse applications. An illustrating example is that of a 1µm-thick PECVD α-SiC combined together with Teflon like fluoro-polymer coatings to reduce the demolding energy by a factor of about 10, compared to a bare silicon mold [57]. In another similar application PECVD α-SiC was used for its hardness and for its good step-coverage (improving the wall roughness generated during the deep RIE process) while the Teflon layer acted as an anti-stiction layer [58]. Decreasing the demolding energy, in this application, is equivalent with the increasing of the life-time of the Si mold (used usually for rapid prototyping on hot embossing tools).
\n\t\t\t\t\t
In another application [30], a 1µm-thick PECVD α-SiC layer was used as an anti-erosion coating layer of a piezoresistive pressure sensor. In order to reduce the residual stress in the α-SiC protection layer (initially evaluated at −450MPa), annealing was performed at 450°C for 1h. The resulting stress value was of only +60MPa. The α-SiC protective layer also showed a good coverage of the Al metallization layer. The erosion testing was performed in 45%KOH solution at 80°C. The final PECVD α-SiC-coated pressure sensor showed a small decrease in sensitivity, but exhibited a high erosion resistance and less temperature dependence. A similar application was also reported [59], in which low stress PECVD α-SiC layer was used for a capacitive pressure sensor fabricated using surface micromachining. Aluminum was used as material for electrodes while polyimide was selected as a sacrificial layer.
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\n\t\t\t
\n\t\t\t
\n\t\t\t\t
4.3. Fabrication of free standing structuresof PECVD α-SiC using to surface micromachining
\n\t\t\t\t
The opportunity of using thick α-Si (amorphous silicon) layers [22] (up to 20µm thick, from our own experience) in surface micromachining gives rise to new processing opportunities, especially for microfluidic applications. The α-Si sacrificial layer can be easily removed by wet etching in an alkaline solution (TMAH or KOH) or by dry release in XeF2. The PECVD α-SiC presents a high chemical inertness to all the etchants of the above mentioned processes, and, therefore, is a very attractive candidate as a structural layer for surface micromachining processes in which amorphous silicon is used as a sacrificial layer. An example of such a process used a 3µm-thick free standing structure fabricated from PECVD α-SiC on a glass substrate using 9 µm-thick PECVD α-Si as sacrificial layer [22]. The structure was released using wet etching in 30% KOH at 80°C. The structure (presented in Fig. 8) shows also that the PECVD deposition process ensured a very good step coverage, the thickness of the vertical wall being identical with that of the layer on the horizontal surfaces [22]. In another example of using PECVD α-SiC as structural material for surface micromachining, 1µm-thick self-sustaining microbridges and microtunnels were fabricated from PECVD α-SiC films (deposited at 320°C using CH4 and SiH4 as reactive gases), using a SiOxNyfilm as a sacrificial layer [60]. In a similar manner, self-sustained grids have also been fabricated [61].
\n\t\t\t\t
Figure 8.
SEM image of asuspended structure fabricated by surface micromachining using thick low-stress α-Si as sacrificial layer and PECVD α-SiC as a structural layer [22].
\n\t\t\t\t
PECVD α-SiC was used in shunt capacitor RF MEMS microbridge-based switches [23]. In this application 300 nm and 500 nm thick PECVD α-SiC films were used as structural layers, while 2µm-thick PECVD SiO2 was used as a sacrificial layer. The structures were released in BOE, followed by CO2 supercritical drying in order to eliminate anystiction possibility. Polyimide was the choice for the sacrificial layer in an application which also used PECVD α-SiC as structural layer [21]. The main advantage of using polyimide is the opportunity of using a dry release process (in O2 plasma), thus more easily overcoming stiction problems often encountered in wet sacrificial etching technology than by using XeF2 or CO2 supercritical drying, solutions which require much more complex and expensive achiness.
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\n\t\t\t
\n\t\t\t\t
4.4. Biological applications of PECVD α-SiC
\n\t\t\t\t
MEMS materials are suitable for applications in cell culture and tissue engineering [62]. In this direction, a special attention is given to the layers achieved by PECVD deposition especially α-Si3N4 [63], [64-66] and α-SiC [37]. The main motivation in using these materials and PECVD as deposition method are related to:
\n\t\t\t\t
Both α-Si3N4 and α-SiC can be used for the fabrication of 2-3µm thick membranes using classical micromachining processes.
PECVD deposition allows a good control of the residual stress in the layer, a critical aspect in achieving free standing structures.
Both α-Si3N4 and α-SiC are optically transparent, so the classical inverted microscopes use in biology can be easily used to monitor bio-samples in structures realized with these materials, for example, in assays emplying red/green fluorescence.
Using microfabrication, these membranes are attached to a supporting Si ring which makes the structure easy to be handle (comparing with polymeric membranes where no such rim support is present) [66].
Porous PECVD α-SiC and α-Si3N4 membranes can be fabricated with a good control of the pore size and with a uniform distribution of the pores can be achieved.
The commercially available and presently used polymeric membranes are hydrophobic materials, and metabolites (albumin, urea) are absorbed in this membrane with effect on cell viability.
The thickness of polymeric porous membrane is usually ranging from tens to hundreds of microns. Consequently, the mass transfer of (bio) chemical substances across/through the membrane is strongly affected by the thickness of the membrane and its nature (hydrophilic/hydrophobic).
The presence of functional groups, such as amine (-NH2), and methyl (-CH3), on the surface of α-Si3N4 and α-SiC membranes can significantly enhance the cell adhesion on these materials.
The α-SiC and α-Si3N4 membranes can be easily cleaned: complete removal of all organic contaminants can be achieved in piranha solution, followed by subsequent rinsing, drying and if necessary even sterilization can also be performed, in order to ensure complete reusability.
\n\t\t\t\t
Figure 9.
Optical images with the adhesion of fibroblast NIH3T3 cells on PECVD α-SiC membrane treated in NH4F after 24h and 48h cell culture.
\n\t\t\t\t
As an illustrative example, chips with 2.5µm-thick PECVD α-SiC membranes were fabricated by bulk micromachining in order to test the biocompatibility of the α-SiC [37]. Fibroblast NIH3T3 cells were used in this study as the model cell line. It was observed that the presence of CH3 groups on the surface of the membranes improved the cell adhesion. Moreover, dipping for 1 minute in 40% NH4F, which was performed mainly to reduce the density of native silicon oxide groups on the α-SiC surface, also improved the adhesion of the cells on the membranes’ surfaces. Fig. 9 shows cell culture images taken 24 hours and 48 hours after starting the culturing.
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\n\t\t
\n\t\t
\n\t\t\t
5. Concluding remarks
\n\t\t\t
We can conclude that PECVD α-SiC is a very attractive and promising material. Its PECVD deposition enable low temperature processing and thus ensures compatibility with CMOS processing, which is essential when (bio) MEMS/NEMS structures need to be combined together with signal processing and data conditioning circuits, a sine qua non condition of realizing “smart sensors”. Additionally, PECVD deposition enables the user to modify various deposition parameters (temperature, pressure, precursors gas flow ratios) which can allow the user to optimize –at least in principle- the desired film properties: chemical composition internal average stress and refractive index. However, in practice such multi-dimensional optimization may prove difficult to achieve, and the presence of some extra degrees of freedom is welcome. An example to the point is -in our case- the presence of dual LF and HF modes for the STS Multiplex Pro-CVD PECVD reactor, which provided valuable flexibility in usage and in varying independently various characteristics of the film (e.g. minimizing the stress) without compromising the others (e.g. the refractive index). In some cases, when such a machine is not available, some more maneuvering room is given by adding an anneal process, which always reduces (sometimes significantly) the film’s stress.
\n\t\t\t
Application-wise, the long list of extremely desirable properties exhibited by α-SiC (large hardness, high fracture strength, high modulus, excellent wear resistance, superb chemical inertness and excellent stability even at high temperatures and/or under corrosive conditions) ensure it can be used in a very large area of applications, particularly in harsh environments, where Si devices cannot be used. Moreover, the same properties recommend PECVD α-SiC as the material of choice for a large range of MEMS postprocessing fabrication techniques. Thus, it can be used as mold material (or mold-coating protective layer), masking material or active structural material in surface micromachining.
\n\t\t\t
Finally, we should also highlight that α-SiC can has also been employed in bio-related applications. Our own tests have shown that PECVD α-SiC membranes fabricated by bulk micromachining can be used successfully in cell cultures. Here the intrinsic properties of α-SiC ensure very good chemical stability, possibility to easily functionalize the surface for, e.g., increased cell adhesion, and improved mechanical resistance and easy handling.
\n\t\t
\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/39120.pdf",chapterXML:"https://mts.intechopen.com/source/xml/39120.xml",downloadPdfUrl:"/chapter/pdf-download/39120",previewPdfUrl:"/chapter/pdf-preview/39120",totalDownloads:3954,totalViews:1037,totalCrossrefCites:2,totalDimensionsCites:10,totalAltmetricsMentions:3,introChapter:null,impactScore:3,impactScorePercentile:83,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"March 8th 2012",dateReviewed:"July 4th 2012",datePrePublished:null,datePublished:"October 16th 2012",dateFinished:"September 17th 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/39120",risUrl:"/chapter/ris/39120",book:{id:"3129",slug:"physics-and-technology-of-silicon-carbide-devices"},signatures:"Ciprian Iliescu and Daniel P. Poenar",authors:[{id:"152764",title:"Dr.",name:"Ciprian",middleName:null,surname:"Iliescu",fullName:"Ciprian Iliescu",slug:"ciprian-iliescu",email:"bigci@nus.edu.sg",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/152764/images/4002_n.jpg",institution:{name:"National University of Singapore",institutionURL:null,country:{name:"Singapore"}}},{id:"152820",title:"Prof.",name:"Daniel",middleName:null,surname:"Poenar",fullName:"Daniel Poenar",slug:"daniel-poenar",email:"epdpuiu@ntu.edu.sg",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Nanyang Technological University",institutionURL:null,country:{name:"Singapore"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. PECVD reactors",level:"1"},{id:"sec_3",title:"3. Influence of the deposition parameters",level:"1"},{id:"sec_3_2",title:"3.1. Materials and Methods",level:"2"},{id:"sec_4_2",title:"3.2. Pressure",level:"2"},{id:"sec_5_2",title:"3.3. RF Power",level:"2"},{id:"sec_6_2",title:"3.4. Temperature",level:"2"},{id:"sec_7_2",title:"3.5. SiH4/CH4 ratio",level:"2"},{id:"sec_9",title:"4. MEMS application of PECVD α-SiC layers",level:"1"},{id:"sec_9_2",title:"4.1. Patterning of SiC layers",level:"2"},{id:"sec_10_2",title:"4.2. PECVD α-SiC as masking layer",level:"2"},{id:"sec_10_3",title:"4.2.1. Masking layer for orientation dependent etching of Si in alkaline solutions",level:"3"},{id:"sec_11_3",title:"4.2.2. Masking layer for etching in HF based solutions",level:"3"},{id:"sec_12_3",title:"4.2.3. Masking layer for dry release structure in XeF2\n\t\t\t\t\t",level:"3"},{id:"sec_13_3",title:"4.2.4. Protective layer for harsh environment",level:"3"},{id:"sec_15_2",title:"4.3. Fabrication of free standing structuresof PECVD α-SiC using to surface micromachining",level:"2"},{id:"sec_16_2",title:"4.4. Biological applications of PECVD α-SiC",level:"2"},{id:"sec_18",title:"5. 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Lett.\n\t\t\t\t\t27\n\t\t\t\t\t6\n\t\t\t\t\t463\n\t\t\t\t\t465\n\t\t\t\t\n\t\t\t'},{id:"B2",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPatil\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiao-An\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAnupongongarch\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMehregany\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarverick\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tProc. IEEE Compound Semicond. Int. Circuit Symp.\n\t\t\t\t\t1\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B3",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarazin\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorvan\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tdi Forte Poisson\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOualli\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaquiere\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJardel\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDrisse\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTordjman\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMagis\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDelage\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tIEEE Electron Dev. Lett.\n\t\t\t\t\t31\n\t\t\t\t\t1\n\t\t\t\t\t11\n\t\t\t\t\t13\n\t\t\t\t\n\t\t\t'},{id:"B4",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeftitsis\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTolstoy\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAntonopoulos\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRabkowski\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJang-Kwon\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBakowski\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNee\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tIEEE Transactions on Power Electr.\n\t\t\t\t\t27\n\t\t\t\t\t1\n\t\t\t\t\t28\n\t\t\t\t\t36\n\t\t\t\t\n\t\t\t'},{id:"B5",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoongje\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVan Brunt\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaliga\n\t\t\t\t\t\t\tB. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tA. Q.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tIEEE Electron Dev.Lett.\n\t\t\t\t\t32\n\t\t\t\t\t7\n\t\t\t\t\t880\n\t\t\t\t\t882\n\t\t\t\t\n\t\t\t'},{id:"B6",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNikiforov\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomás García\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPetrushina\n\t\t\t\t\t\t\tI. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChristensen\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBjerrum\n\t\t\t\t\t\t\tN. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tInt. J. Hydrogen Energy\n\t\t\t\t\t36\n\t\t\t\t\t10\n\t\t\t\t\t5797\n\t\t\t\t\t5805\n\t\t\t\t\n\t\t\t'},{id:"B7",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSingh\n\t\t\t\t\t\t\tN. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWagner\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerghmans\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKnuteson\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Laughlin\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKahler\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThomson\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKing\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tCrystal Growth & Design\n\t\t\t\t\t10\n\t\t\t\t\t8\n\t\t\t\t\t3508\n\t\t\t\t\t3514\n\t\t\t\t\n\t\t\t'},{id:"B8",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMyers\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheng\n\t\t\t\t\t\t\tK. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJamshidi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAzevedo\n\t\t\t\t\t\t\tR. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSenesky\n\t\t\t\t\t\t\tD. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMehregany\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWijesundara\n\t\t\t\t\t\t\tM. B. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPisano\n\t\t\t\t\t\t\tA. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tJ. Micro-Nanolithogr. MEMS MOEMS\n\t\t\t\t\t8\n\t\t\t\t\t2\n\t\t\t\t\n\t\t\t'},{id:"B9",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoo\n\t\t\t\t\t\t\tM. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheong\n\t\t\t\t\t\t\tK. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoor\n\t\t\t\t\t\t\tA. F. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tSens. Actuator B-Chem.\n\t\t\t\t\t151\n\t\t\t\t\t1\n\t\t\t\t\t39\n\t\t\t\t\t55\n\t\t\t\t\n\t\t\t'},{id:"B10",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBorchi\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMacii\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBruzzi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScaringella\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tNuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment\n\t\t\t\t\t658\n\t\t\t\t\t1\n\t\t\t\t\t121\n\t\t\t\t\t124\n\t\t\t\t\n\t\t\t'},{id:"B11",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAzevedo\n\t\t\t\t\t\t\tG. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJones\n\t\t\t\t\t\t\tG. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJog\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJamshidi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMyers\n\t\t\t\t\t\t\tR. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tX.-a.\n\t\t\t\t\t\t\tFu\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMehregany\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWijesundara\n\t\t\t\t\t\t\tB. J. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPisano\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t145-146\n\t\t\t\t\t0\n\t\t\t\t\t2\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B12",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheung\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHedley\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHassan\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarris\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurdess\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMehregany\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZorman\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t1128\n\t\t\t\t\t2\n\t\t\t\t\t376\n\t\t\t\t\t386\n\t\t\t\t\n\t\t\t'},{id:"B13",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHyun\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPark\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoon\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChoi\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tN. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoo\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tProgress in Solid State Chemistry\n\t\t\t\t\t33\n\t\t\t\t\t2-4\n\t\t\t\t\t309\n\t\t\t\t\t315\n\t\t\t\t\n\t\t\t'},{id:"B14",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZorman\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMehregany\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tProc. of IEEE Sensors\n\t\t\t\t\t2\n\t\t\t\t\t1109\n\t\t\t\t\t1114\n\t\t\t\t\n\t\t\t'},{id:"B15",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarraro\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPisano\n\t\t\t\t\t\t\tA. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaboudian\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t20\n\t\t\t\t\t3\n\t\t\t\t\n\t\t\t'},{id:"B16",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeboer\n\t\t\t\t\t\t\tC. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorkmaz\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaros\n\t\t\t\t\t\t\tJ. M. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t67\n\t\t\t\t\t1-3\n\t\t\t\t\t175\n\t\t\t\t\t180\n\t\t\t\t\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEl Khakani\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChaker\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJean\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoily\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKieffer\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Hern\n\t\t\t\t\t\t\tM. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRavet\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRousseaux\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1994\n\t\t\t\t\tJ. Mat. Research\n\t\t\t\t\t9\n\t\t\t\t\t1\n\t\t\t\t\t96\n\t\t\t\t\t103\n\t\t\t\t\n\t\t\t'},{id:"B18",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoper\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHowe\n\t\t\t\t\t\t\tR. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaboudian\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t16\n\t\t\t\t\t12\n\t\t\t\t\t2736\n\t\t\t\t\t2739\n\t\t\t\t\n\t\t\t'},{id:"B19",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAvram\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPopescu\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDumitrescu\n\t\t\t\t\t\t\tD. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoenar\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSterian\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVrtacnik\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmon\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSterian\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tJ. Optoel. Adv. Mat.\n\t\t\t\t\t13\n\t\t\t\t\t4\n\t\t\t\t\t387\n\t\t\t\t\t394\n\t\t\t\t\n\t\t\t'},{id:"B20",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t82\n\t\t\t\t\t1-3\n\t\t\t\t\t210\n\t\t\t\t\t218\n\t\t\t\t\n\t\t\t'},{id:"B21",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBagolini\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPakula\n\t\t\t\t\t\t\tT. L. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScholtes\n\t\t\t\t\t\t\tH. T. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPham\n\t\t\t\t\t\t\tP. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrench\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t12\n\t\t\t\t\t4\n\t\t\t\t\t385\n\t\t\t\t\t389\n\t\t\t\t\n\t\t\t'},{id:"B22",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t18\n\t\t\t\t\t1\n\t\t\t\t\t15024\n\t\t\t\t\n\t\t\t'},{id:"B23",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParro\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScardelletti\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVaraljay\n\t\t\t\t\t\t\tN. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZimmerman\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZorman\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tSolid-State Electronics\n\t\t\t\t\t52\n\t\t\t\t\t10\n\t\t\t\t\t1647\n\t\t\t\t\t1651\n\t\t\t\t\n\t\t\t'},{id:"B24",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tB. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWei\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tThin Solid Films\n\t\t\t\t\t516\n\t\t\t\t\t16\n\t\t\t\t\t5189\n\t\t\t\t\t5193\n\t\t\t\t\n\t\t\t'},{id:"B25",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAvram\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAvram\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBragaru\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoenar\n\t\t\t\t\t\t\tD. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tProc. of the 33rdIEEE Int. Semicond. Conf.\n\t\t\t\t\t239\n\t\t\t\t\t242\n\t\t\t\t\n\t\t\t'},{id:"B26",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPham\n\t\t\t\t\t\t\tH. T. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Boer\n\t\t\t\t\t\t\tC. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKwakernaak\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSloof\n\t\t\t\t\t\t\tW. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tProc. of SPIE\n\t\t\t\t\t272\n\t\t\t\t\t279\n\t\t\t\t\n\t\t\t'},{id:"B27",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOliveira\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarreno\n\t\t\t\t\t\t\tM. N. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tJ. Non-Crystalline Solids\n\t\t\t\t\t352\n\t\t\t\t\t9-20\n\t\t\t\t\t1392\n\t\t\t\t\t1397\n\t\t\t\t\n\t\t\t'},{id:"B28",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPandraud\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrench\n\t\t\t\t\t\t\tP. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t142\n\t\t\t\t\t1\n\t\t\t\t\t61\n\t\t\t\t\t66\n\t\t\t\t\n\t\t\t'},{id:"B29",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPandraud\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrench\n\t\t\t\t\t\t\tP. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tMicrow. Opt. Technol. Lett.\n\t\t\t\t\t47\n\t\t\t\t\t3\n\t\t\t\t\t219\n\t\t\t\t\t220\n\t\t\t\t\n\t\t\t'},{id:"B30",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t17\n\t\t\t\t\t3\n\t\t\t\t\t426\n\t\t\t\t\t431\n\t\t\t\t\n\t\t\t'},{id:"B31",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSlack\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBartram\n\t\t\t\t\t\t\tS. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1975\n\t\t\t\t\tJ. Appl. Phys.\n\t\t\t\t\t46\n\t\t\t\t\t1\n\t\t\t\t\t89\n\t\t\t\t\t98\n\t\t\t\t\n\t\t\t'},{id:"B32",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAzevedo\n\t\t\t\t\t\t\tR. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJingchun\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJones\n\t\t\t\t\t\t\tD. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMyers\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJog\n\t\t\t\t\t\t\tA. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJamshidi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWijesundara\n\t\t\t\t\t\t\tM. B. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaboudian\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPisano\n\t\t\t\t\t\t\tA. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tProc. of IEEE 20th Int. Conf. on Micro Electro Mechanical Systems, MEMS.\n\t\t\t\t\t643\n\t\t\t\t\t646\n\t\t\t\t\n\t\t\t'},{id:"B33",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIvashchenko\n\t\t\t\t\t\t\tV. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDub\n\t\t\t\t\t\t\tS. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPorada\n\t\t\t\t\t\t\tO. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIvashchenko\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSkrynskyy\n\t\t\t\t\t\t\tP. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStegniy\n\t\t\t\t\t\t\tA. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tSurf. Coat. Technol.\n\t\t\t\t\t200\n\t\t\t\t\t22-23\n\t\t\t\t\t6533\n\t\t\t\t\t6537\n\t\t\t\t\n\t\t\t'},{id:"B34",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBehnel\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFuchs\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeidel\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tProc. of Int. Conf. on Solid-State Sens., Act. and Microsyst., TRANSDUCERS\n\t\t\t\t\t2009\n\t\t\t\t\t740\n\t\t\t\t\t742\n\t\t\t\t\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChung\n\t\t\t\t\t\t\tC. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsai\n\t\t\t\t\t\t\tM. Q.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsai\n\t\t\t\t\t\t\tP. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t15\n\t\t\t\t\t1\n\t\t\t\t\t136\n\t\t\t\t\t142\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTay\n\t\t\t\t\t\t\tF. E. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWei\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t16\n\t\t\t\t\t4\n\t\t\t\t\t869\n\t\t\t\t\t874\n\t\t\t\t\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoenar\n\t\t\t\t\t\t\tD. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tY. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tSens. Actuator B-Chem.\n\t\t\t\t\t129\n\t\t\t\t\t1\n\t\t\t\t\t404\n\t\t\t\t\t411\n\t\t\t\t\n\t\t\t'},{id:"B38",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanaka\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRajanna\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbe\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEsashi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tJ. Vac. Sci. Technol. B\n\t\t\t\t\t19\n\t\t\t\t\t6\n\t\t\t\t\t2173\n\t\t\t\t\t2176\n\t\t\t\t\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChabert\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tJ. Vac. Sci. Technol. B\n\t\t\t\t\t19\n\t\t\t\t\t4\n\t\t\t\t\t1339\n\t\t\t\t\t1345\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchmid\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEickhoff\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRichter\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrotz\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchmitt-Landsiedel\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t94\n\t\t\t\t\t1-2\n\t\t\t\t\t87\n\t\t\t\t\t94\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tM. B. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWijesundara\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarraro\n\t\t\t\t\t\t\tR. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHowe\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaboudian\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tIEEE Sens. J.\n\t\t\t\t\t4\n\t\t\t\t\t4\n\t\t\t\t\t441\n\t\t\t\t\t448\n\t\t\t\t\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSenesky\n\t\t\t\t\t\t\tD. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPisano\n\t\t\t\t\t\t\tA. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tProc. of 23rd IEEE Int. Conf. on Micro Electro Mechanical Systems (MEMS)\n\t\t\t\t\t352\n\t\t\t\t\t355\n\t\t\t\t\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPandraud\n\t\t\t\t\t\t\tH. T. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPham\n\t\t\t\t\t\t\tP. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrench\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tOptics & Laser Technology\n\t\t\t\t\t39\n\t\t\t\t\t3\n\t\t\t\t\t532\n\t\t\t\t\t536\n\t\t\t\t\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilliams\n\t\t\t\t\t\t\tK. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGupta\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWasilik\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tJ. Microelectromech. Syst.\n\t\t\t\t\t12\n\t\t\t\t\t6\n\t\t\t\t\t761\n\t\t\t\t\t778\n\t\t\t\t\n\t\t\t'},{id:"B45",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTaylor\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAvram\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiao\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranssila\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tBiomicrofluidics\n\t\t\t\t\t6\n\t\t\t\t\t1\n\t\t\t\t\t016505\n\t\t\t\t\t016516\n\t\t\t\t\n\t\t\t'},{id:"B46",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiao\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tSens. Actuator A- Phys.\n\t\t\t\t\t143\n\t\t\t\t\t1\n\t\t\t\t\t154\n\t\t\t\t\t161\n\t\t\t\t\n\t\t\t'},{id:"B47",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJing\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTay\n\t\t\t\t\t\t\tF. E. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiao\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tSurf. Coat. Tech.\n\t\t\t\t\t198\n\t\t\t\t\t1-3\n\t\t\t\t\t314\n\t\t\t\t\t318\n\t\t\t\t\n\t\t\t'},{id:"B48",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerthold\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaugere\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchellevis\n\t\t\t\t\t\t\tC. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Boer\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaros\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuijt\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tVellekoop Electrophoresis\n\t\t\t\t\t23\n\t\t\t\t\t20\n\t\t\t\t\t3511\n\t\t\t\t\t3519\n\t\t\t\t\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tF. E. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTay\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiao\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t133\n\t\t\t\t\t2\n\t\t\t\t\t395\n\t\t\t\t\t400\n\t\t\t\t\n\t\t\t'},{id:"B50",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tG. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tZ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t17\n\t\t\t\t\t4\n\t\t\t\t\t775\n\t\t\t\t\t780\n\t\t\t\t\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoenar\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarp\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeck\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t139\n\t\t\t\t\t1-2\n\t\t\t\t\t162\n\t\t\t\t\t171\n\t\t\t\t\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\n\t\t\t\t\t\n\t\t\t\t\t\tZorman\n\t\t\t\t\t\tA.\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\tBarnes\n\t\t\t\t\t\tA. C.\n\t\t\t\t\t\n\t\t\t\t\n\t\t\t\t2012\n\t\t\t\tin Silicon Carbide Biotechnology\n\t\t\t\tElsevier\n\t\t\t\tOxford\n\t\t\t\t351\n\t\t\t\t376\n\n\t\t\t'},{id:"B53",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharpe\n\t\t\t\t\t\t\tW. N.\n\t\t\t\t\t\t\tJr.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJadaan\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeheim\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQuinn\n\t\t\t\t\t\t\tG. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNemeth\n\t\t\t\t\t\t\tN. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tJ. Microelectromech. Syst.\n\t\t\t\t\t14\n\t\t\t\t\t5\n\t\t\t\t\t903\n\t\t\t\t\t913.\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAshurst\n\t\t\t\t\t\t\tW. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWijesundara\n\t\t\t\t\t\t\tM. B. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarraro\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaboudian\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tTribology Letters\n\t\t\t\t\t17\n\t\t\t\t\t2\n\t\t\t\t\t195\n\t\t\t\t\t198\n\t\t\t\t\n\t\t\t'},{id:"B55",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFlannery\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMourlas\n\t\t\t\t\t\t\tN. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStorment\n\t\t\t\t\t\t\tC. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsai\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTan\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeck\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMonk\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGogoi\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKovacs\n\t\t\t\t\t\t\tG. T. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tSens. Actuator A-Phys.\n\t\t\t\t\t70\n\t\t\t\t\t1-2\n\t\t\t\t\t48\n\t\t\t\t\t55\n\t\t\t\t\n\t\t\t'},{id:"B56",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSummers\n\t\t\t\t\t\t\tJ. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScardelletti\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParro\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZorman\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tin MEMS/MOEMS Components and Their Applications IV, edited by S. A. Tadigadapa, R. Ghodssi and A. K. Henning\n\t\t\t\t\tProc. Spie-Int Soc Optical Engineering\n\t\t\t\t\t6464\n\t\t\t\t\tH4640\n\t\t\t\t\tH4640\n\t\t\t\t\n\t\t\t'},{id:"B57",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTaylor\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoning\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIliescu\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t21\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B58",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYeo\n\t\t\t\t\t\t\tL. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChan-Park\n\t\t\t\t\t\t\tM. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiao\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYan\n\t\t\t\t\t\t\tY. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tJ. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLam\n\t\t\t\t\t\t\tY. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYue\n\t\t\t\t\t\t\tC. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tJ. Microelectromech. Syst.\n\t\t\t\t\t15\n\t\t\t\t\t1\n\t\t\t\t\t84\n\t\t\t\t\t93\n\t\t\t\t\n\t\t\t'},{id:"B59",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPakula\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPham\n\t\t\t\t\t\t\tH. T. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrench\n\t\t\t\t\t\t\tP. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarro\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tJ. Micromech. Microeng.\n\t\t\t\t\t14\n\t\t\t\t\t11\n\t\t\t\t\t1478\n\t\t\t\t\t1483\n\t\t\t\t\n\t\t\t'},{id:"B60",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarreño\n\t\t\t\t\t\t\tM. N. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLopes\n\t\t\t\t\t\t\tA. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tJ. 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Technol.\n\t\t\t\t\t11\n\t\t\t\t\t2\n\t\t\t\t\t167\n\t\t\t\t\t176\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ciprian Iliescu",address:"ciliescu@ibn.a-star.edu.sg",affiliation:'
Institute of Bioengineering and Nanotechnology, Singapore
'},{corresp:null,contributorFullName:"Daniel P. Poenar",address:null,affiliation:'
Microelectronics Centre, School of Electrical & Electronics Engineering, Nanyang Technological University, Singapore
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Beisenkhanov",reviewType:"peer-reviewed",authors:[{id:"56747",title:"Prof.",name:"Kair",middleName:null,surname:"Nussupov",fullName:"Kair Nussupov",slug:"kair-nussupov"}]},{id:"37749",type:"chapter",title:"Etching of Silicon Carbide Using Chlorine Trifluoride Gas",slug:"etching-of-silicon-carbide-using-chlorine-trifluoride-gas",totalDownloads:3198,totalCrossrefCites:0,signatures:"Hitoshi Habuka",reviewType:"peer-reviewed",authors:[{id:"17197",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Habuka",fullName:"Hitoshi Habuka",slug:"hitoshi-habuka"}]},{id:"39120",type:"chapter",title:"PECVD Amorphous Silicon Carbide (α-SiC) Layers for MEMS Applications",slug:"pecvd-amorphous-silicon-carbide-sic-layers-for-mems-applications",totalDownloads:3954,totalCrossrefCites:2,signatures:"Ciprian Iliescu and Daniel P. 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Yoshida",reviewType:"peer-reviewed",authors:[{id:"18137",title:"Dr.",name:"Yasuto",middleName:null,surname:"Hijikata",fullName:"Yasuto Hijikata",slug:"yasuto-hijikata"},{id:"18271",title:"Prof.",name:"Hiroyuki",middleName:null,surname:"Yaguchi",fullName:"Hiroyuki Yaguchi",slug:"hiroyuki-yaguchi"},{id:"18272",title:"Dr.",name:"Sadafumi",middleName:null,surname:"Yoshida",fullName:"Sadafumi Yoshida",slug:"sadafumi-yoshida"},{id:"152822",title:"Dr.",name:"Shuhei",middleName:null,surname:"Yagi",fullName:"Shuhei Yagi",slug:"shuhei-yagi"}]},{id:"39997",type:"chapter",title:"Materials and Processing for Gate Dielectrics on Silicon Carbide (SiC) Surface",slug:"materials-and-processing-for-gate-dielectrics-on-silicon-carbide-sic-surface",totalDownloads:5829,totalCrossrefCites:3,signatures:"Sanjeev Kumar Gupta, Jitendra Singh and Jamil Akhtar",reviewType:"peer-reviewed",authors:[{id:"39067",title:"Dr.",name:"Sanjeev Kumar",middleName:null,surname:"Gupta",fullName:"Sanjeev Kumar 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1. Introduction
Adenosine 5′-triphosphate (ATP) is abundantly generated in the cytosol through respiration and glycolysis. Primarily, these are the “energy currency” of the cell as ATP hydrolysis release energy and is essential to maintain the cellular homeostasis and activity [1]. Extracellular activity of ATP was first described by Drury and Szent-Györgyi in 1929 [2]. Later, in 1970s, ATP was shown to be involved in non-adrenergic, non-cholinergic nerve-mediated responses, and further its function as a neurotransmitter was established that led to introduction of the term “purinergic signaling” [3]. Burnstock has described about the purinergic signaling and purinergic systems in very detail, which consists of (a) purine or pyrimidine derivatives that serve as an “extracellular messenger,” (b) “membrane transporter” that are responsible for the extracellular release of these nucleotides or nucleosides, (c) “metabolizing enzymes” present on the cell surface that hydrolyze the ATP to adenosine diphosphate (ADP) then to adenosine monophosphate (AMP) and adenosine and, (d) “purinergic receptors” that sense the extracellular purine or pyrimidine derivatives [3, 4, 5, 6, 7].
In the beginning, purinergic signaling was determined to have a role in neuronal signaling but now, their role in immune responses, inflammation, pain, exocrine and endocrine secretion, platelet aggregation, and endothelial-mediated vasodilatation had been explored and established [3, 4, 6, 8]. Additionally, cross talk of purinergic signaling with other signaling network also associates with the impact on cell proliferation, differentiation, and death that occur during the development and regeneration processes. Under normal condition, purinergic signaling operate in a very well-regulated manner to maintain the physiological function of different organ systems. Dysregulation in any component of the purinergic signaling network depending on the expression or activation of purinergic receptors, ectonucleotidases or release of agonist from damaged cell resulting from stress, inflammation serves as a potent modulator of inflammation and key promoters of host defenses, immune cells activation, pathogen clearance, and tissue repair that contributes to the disease pathogenesis [9]. Thus, their knowledge is of great importance for a full understanding of the pathophysiology of acute and chronic inflammatory diseases and will give an insight on novel therapeutic approaches to overcome inflammation. This chapter describes the component of purinergic system, its cross talk with immune signaling. Major focus of this chapter is to present the dynamics of purinergic signaling under normal physiological condition and its role in modulating the immune and inflammatory response under various diseased conditions like autoimmunity, and microbial infection.
2. Purinergic system and its component on immune cells: an immunomodulator
2.1 Mechanism of release of nucleotides
Extracellular ATP (eATP) has been well established as a ligand for autocrine and paracrine signaling that has a pathophysiological role. In addition, to eATP other nucleotides and nucleosides such as the adenosine, adenosine monophosphate (AMP), adenosine diphosphate (ADP), uridine diphosphate (UDP), uridine triphosphate (UTP), and nicotinamide adenine dinucleotide (NAD+) also serve as a potent purinergic signaling modulator. The release of nucleotides into the extracellular space occurs via regulated and unregulated mechanisms. Regulated mode of release of nucleotide is mediated through classical exocytosis [10] or conductive ATP release through ATP-permeable channels [11]. Currently, five groups of ATP-release channels are known such as: connexin hemichannels, Pannexin (PANX), calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs), and maxi-anion channels (MACs) [12].
The ATP release by exocytosis is an active release mechanism that involves vesicular nucleotide transporter (VNUT). It is responsible for the accumulation and exocytosis of ATP from exocytotic vesicles that occurs in a proton-dependent electrochemical gradient manner generated by a vacuolar-ATPase (v-ATPase). Further, intracellular Ca+2 level and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) drives the fusion of the exocytotic vesicles with the plasma membrane ultimately resulting in the release of nucleotides into the extracellular space [13, 14]. Hemichannels are the ATP permeable channels that support the release of ATP under specific pathological condition. Primarily, these channels contribute to various cellular and physiological functions by forming gap junctions or hemichannels, to allow intercellular communication. They are categorized into two based on their functions, [1] connexins that has both gap junction and form hemichannel function whereas [2] PANX only form hemichannel [15]. These channels are in closed state under normal condition to avoid the loss of vital ionic, energetic, and metabolic gradients. However, chemical and biochemical stimuli resulting from pathological conditions trigger their opening and lead to release of ATP. Till date, 21 isoforms of connexins are reported in human of which connexin-43, -37, -26, and -36 have been shown to support ATP release [16]. Connexin-43 is widely expressed and very well studied. It is activated by increase in the intracellular Ca+2 concentration, plasma membrane depolarization, reactive oxygen species (ROS) or nitric oxide (NO) [17, 18]. The PANX (PANX) family is comprised of three members, PANX-1, -2, and -3 of which PANX-1 and -3 are widely expressed in different tissues, while PANX-2 is exclusively found in the brain [19]. In resting state, PANX channels are closed, mainly due to the blockage of the pore by C-terminal tail from the intracellular side [18]. However, in response to apoptosis or pyroptosis, C-terminal tail gets cleaved by caspase-3, -7, or -11 leading to opening of PANX-1 and allows nucleotides to cross the plasma membrane [20, 21]. Additionally, other stimuli such as intracellular calcium increase, redox potential changes, mechanical stress, and activation of the P2X7R can trigger PANX-1 channel opening [22].
Another mechanism involves the disruption of the cell membrane by apoptosis, necrosis, pyroptosis, or netosis, which leads to the unregulated leakage of ATP as well as other large cytosolic molecules including enzymes [11, 23, 24].
2.2 Metabolism of extracellular nucleotides and nucleosides
The life span of eATP is controlled by purinergic ectoenzymes that coordinate a sequential two-step process of hydrolyzing ATP into AMP and then into the potent anti-inflammatory adenosine. This make ectonucleotidases enzymes a crucial component of the purinergic system, which balance the level of eATP as well as other nucleotide derivatives UTP, NAD+, and their metabolites, thereby controlling the activation of purinergic receptors and biochemical composition of the inflammatory microenvironment. These enzymes are classified into four major families: (a) ectonucleoside triphosphate phosphohydrolases (NTPDases): This group of enzymes are further classified into 8 subfamilies—NTPDase 1 (CD39), 2, 3, and 8, which are expressed on the cell surface, whereas NTPDases 4–7 are present in the intracellular organelles. Of these 8 subfamilies, NTPDase1 (CD39) is the best characterized that hydrolyses ATP to ADP and further to AMP. CD39 is expressed on wide variety of immune cell, e.g., monocytes, dendritic cells (DCs), T regulatory (Treg) cells, and natural killer (NK) cells. (b) nicotinamide adenine dinucleotide glycohydrolase (NAD glycohydrolase/CD38): CD38 is a cell surface glycoprotein highly expressed in hematopoietic tissues such as the bone barrow and lymph nodes. Among immune cells, CD38 is highly expressed on monocytes, macrophages, DCs, neutrophils, innate lymphoid cells (ILC), NK cells, T and B cells. It hydrolyses NAD+ to cyclic-ADP ribose (cADPR) and then to AMP. (c) ecto-5′-nucleotidase (NT5E/CD73): CD73 degrades AMP generated by CD39 or CD38 to adenosine. It is expressed on stromal cells, follicular DCs, endothelial cells, neutrophils, macrophages, and subpopulations of T cells. and (d) ectonucleotide pyrophosphatase/phosphodiesterase (NPPs): NPPs include 7 members NPP 1–7. NPP1–3 degrade nucleoside triphosphates and diphosphates, NAD+, UDP-sugars, and di-nucleoside polyphosphates. NPP2 also known as autotaxin (ATX) has unique property of hydrolyzing nucleotide as well as phospholipids but acts more efficiently on later to generate the bioactive phospholipid mediator’s lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). NPP6 and 7 hydrolyzes phospholipids only, whereas catalytic properties of NPP4 and 5 are not known. Some NPPs are expressed on liver and intestinal epithelia, neuronal cells; NPP1 is also expressed on B and T cells [25, 26, 27, 28]. The ectonucleotidases are present on almost all types of immune cells, but their expression pattern changes in a function dependent manner and controls the pro-inflammatory and anti-inflammatory condition to avoid any pathological conditions like autoimmunity, cancer, and infectious disease.
Briefly, CD39 has an anti-inflammatory property that controls the extracellular level of ATP by converting it into adenosine in conjunction with CD73. CD39 and CD73 exhibit an immunosuppressive activity as shown by its expression on Tregs cells [29, 30, 31]; CD8 T cells [32] and B cells [33] and inhibits the pathogenic T cells. Breakdown of eATP by CD39 prevents the activation of P2X7R and attenuates the secretion of IL-1β and IL-18 [34]. The expression pattern of CD38 varies during the differentiation and maturation of B and T cells [35, 36]. The enzymatic activity of CD38 generates cADPR/ADPR and triggers Ca+2 release from intracellular stores and Ca+2 influx from the extracellular space that have role in transmigration and chemotaxis of neutrophils, monocytes and DCs, and cytokine release [37]. Elevated level of cADPR/ADPR and intracellular Ca+2 regulates cellular chemotaxis [38], phagocytosis [39], and antigen presentation [40] in a CD38 dependent manner. Thus, dysregulation of CD38 has been implicated in several inflammatory pathologies such as autoimmunity and cancer [37, 41]. It is important to note that cADPR is generated by hydrolysis of NAD+, disruption in the metabolism of NAD+ has been associated with multiple pathological conditions [42]. Different types of NPPs have been implicated in a various of pathologic conditions such as tumor invasion and metastasis, inflammation, and angiogenesis (NPP2), tissue calcification and bone development (NPP1), and hemostasis and platelet aggregation (NPP4) [43]. However, NPP2 (ATX) is widely studied, ATX-LPA signaling axis induces inflammatory mediators such as IL-8, IL-6, TNF-α, and growth factors such as the vascular endothelial growth factor (VEGF) and the granulocyte colony-stimulating factor (G-CSF) thereby augmenting the cytokine production and lymphocyte infiltration that ultimately aggravates the inflammation in conditions such as asthma, pulmonary fibrosis, and rheumatoid arthritis [44, 45].
2.3 Purinergic receptors
Purinergic receptors are divided into two subtypes based on their binding tendency to different purine derivatives—P1 receptor (P1R) has affinity to bind adenosine only, whereas P2 can bind ATP, ADP, UDP-glucose, UDP and UTP [46]. Adenosine receptors (AR) belong to rhodopsin-like family of G protein receptors and consist of four subtypes such as A1, A2A, A2B, and A3. Adenosine generated by the hydrolysis of extracellular ATP, ADP, or AMP are either metabolized by adenosine deaminase (ADA) or shuttled back to the cells via two types of transporters, the equilibrate nucleoside transporters (ENTs) and the concentrative nucleoside transporters (CNTs) to stimulate various intracellular pathways like AMP-activated protein kinase, adenosine kinase and S-adenosyl homocysteine hydrolase [47]. Although it may depend on the concentration of adenosine and the given P1 receptor subtype engaged, but adenosine primarily, have anti-inflammatory and immune suppressive functions. The immunosuppressant activity of adenosine relies on the inhibition of virtually all immune cell populations such as T and B lymphocytes, NK cells, DCs, granulocytes, monocytes, and macrophages.
P2 receptors further categorized into two families based on molecular structure and second messenger systems, namely P2X ionotropic ligand-gated ion channel receptors that only binds to ATP and P2Y metabotropic G protein-coupled receptors (GPCR) can bind to ADP, UDP- glucose, UDP, and UTP [46]. The family of P2X receptors comprises seven members (P2X1–7), which perform tissue-specific functions by forming homo- or hetero-trimeric complexes. At least three P2X subunits assemble to form hetero- (e.g., P2X2/3 and P2X1/5) or homo-trimeric (P2X7) channels. This kind of assembly confers to P2X receptors a large repertoire of physiological functions in different tissues. Among P2XRs, the P2X7R has a special place in inflammation since its stimulation promotes NLRP3 inflammasome assembly and the associated IL-1β secretion. There are eight subtypes of P2Y receptors, which is further characterized into two subfamilies P2Y1 and P2Y12 based on their coupling to Gq and Gi, respectively. P2Y1 subfamily includes P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors. The second subfamily is P2Y12, which contains P2Y12, P2Y13, and P2Y14 receptors. Each P2Y receptors has different affinity towards different nucleotides and has a tissue-specific function. For instance, P2YR11 has affinity for ATP; P2YR1, P2YR12, and P2YR13 for ADP; P2YR2 and P2YR4 for UTP; P2YR6 for UDP; and P2YR14 for UDP-glucose and UDP-galactose [5].
The purinoceptors are expressed on almost all kinds of peripheral tissues and are involved in short-term as well as long-term regulation of variety of functions, ranging from neuromuscular and synaptic transmission to secretion in gut, kidney, liver, and reproductive systems. Their contribution in immune signaling is enormous, as these receptors are expressed on almost all types of immune cells. The purine nucleotides orchestrate the onset, magnitude duration, and resolution of the inflammatory response through the activation of purinergic receptors, which is also governed by the activity of ectonucleotidases (Figures 1 and 2). Any alterations in the purinergic machinery could contribute to the pathophysiological processes underlying the onset and development of immunological diseases, neurodegeneration, cancer, diabetes, and hypertension [7, 46, 48].
Figure 1.
Cartoon depicting the components of purinergic system and their functions. Mechanism of nucleotide release from the intact cells via exocytosis or transport channels as well as leakage of ATP from apoptotic and netosis (bottom of the image). The nucleotide triggers the activation of immune cells via specific purinergic receptor (top of the image). Activation of purinergic receptors ATP or their hydrolyzed metabolites ADP/AMP and adenosine by ectonucleotidases (middle of the image).
Figure 2.
Pictorial representation of cross talk of purinergic and immune signaling during normal physiological condition and inflammatory condition.
3. Interplay of purinergic signaling and immune signaling on inflammatory response
Beyond the physical and chemical barrier of skin and mucous lining, our body is guarded from the pathogens as well as self-attacking/cancerous cells by two different kinds of immune responses that acts in a coordinated manner. This includes (a) innate immune response comprising myeloid lineage derived cells (monocytes, macrophages, neutrophils, and DCs) and NK cells derived from lymphoid progenitors, and (b) adaptive immune response consists of B and T cells. Innate immune response provides the first line of defense against pathogens. It is an antigen-independent defense mechanism that is elicited when immune cells encounter pathogens. This response has no memory and remains similar during the lifetime. On the other hand, adaptive immune response is an antigen dependent, antigen specific, and has the tendency to form memory cells to elicit rapid response based on the previous encounter with the similar kind of antigen or pathogenic exposure. Innate and adaptive immune responses are not mutually exclusive defense mechanisms. They work in a very organized fashion and complement the functions, as activation of T cells requires antigen presentation by professional antigen presenting cells (dendritic cells, B-cells, or macrophages), together with the major histocompatibility complex (MHC) type I or II [49]. Defects in any of the component increases the vulnerability towards infection and disease.
ATP and adenosine are the key modulators of the immune response, ATP being an immunostimulant, whereas adenosine has an immunosuppressive effect thus balance between the two is crucial for the proper functioning of immune system. Extracellular signals by ATP and adenosine are detected and transduced by P2 and P1 receptors (Figure 2), respectively which is present on all kinds of immune cells, thus purinergic signaling affects all aspects of immunity and inflammation [50], which is described in detail in further section.
3.1 Effect on innate immune signaling
3.1.1 Monocytes/macrophages
Macrophages are the subset of myeloid cells that have immune surveillance function and sense even a minute changes in the tissue microenvironment. They express a variety of pattern recognition receptors (PRRs) that are present either on the surface, cytosol or in the endosome such as toll like receptors (TLRs), NOD like receptor (NLRs), retinoic acid inducible gene I like receptors (RLR), transmembrane C-type lectin receptors, and absent in melanoma (AIM)2-like receptors (ALRs) that recognize either pathogen associated or damage associated molecular patterns (PAMP and DAMP, respectively). These cells are highly plastic that could undergo profound metabolic modifications after sensing the pathogens or damage signal via PRRs to elicit the immune response. In addition, macrophages are endowed with purinergic P1, P2X, and P2Y receptors that also respond to damage associated molecules, extracellular nucleotides, and their derivatives, and undergo reprogramming from pro-inflammatory profile M1-like phenotype to an anti-inflammatory M2-like phenotype. As indicated by Elliott et al., that monocytes or macrophages sense extracellular nucleotide as a danger signal for “find me” or “eat me” to engulf and phagocytose the dying cells [24]. These cells not only sense the distant signal but also amplify the signaling for chemotaxis by releasing ATP by “autocrine purinergic loop” via P2Y2 and A3 receptors [51, 52]. Macrophages control their activation state in an autoregulatory mechanism by inducing the production of ATP and extracellular degradation to adenosine. Deficiency of CD39 promotes a sustained inflammatory activation state and inhibits the switch to an immunosuppressive phenotype [53]. Presence of extracellular adenosine stimuli in macrophages drives the polarization towards M2 phenotype with diminished expression of inflammatory genes TNF-α and IL-6 and increased expression of anti-inflammatory cytokines such as IL-10 and VEGF via A2A and A2B receptors [54]. Furthermore, macrophages exhibit a unique repertoire of P2X receptors such as expression of P2X1, P2X4, as well as P2X7 [55]. Among P2Y receptors, P2Y1 and P2Y4 receptors play minor roles, whereas the functions of P2Y2, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14 are more established in the macrophage biology as described elsewhere [56]. A recent study demonstrated that bone marrow derived macrophages display unique expression pattern of purinergic receptors that correlates with a M1or M2 inflammatory phenotype. M1 phenotype exhibit a unique and more pronounced P2X7 negative macrophage population, which associates with decreased inflammasome formation. P1 receptors A2A and A2B are upregulated in M1 and M2. P2Y1 and P2Y6 exclusively upregulated in M2, whereas P2Y13 and P2Y14 are overexpressed in M1 [57]. This unique feature demonstrates capability of purinergic receptors on macrophages to adapt to pro- and anti-inflammatory macrophage differentiation with functional consequences to nucleotide stimulation.
3.1.2 Dendritic cells
DCs are professional antigen-presenting cells (APCs), which has a crucial role in initiating and regulating the adaptive immune response by directing the activation and differentiation of naive T cells. Immature DCs (iDCs) sense the danger signals in the similar fashion as monocytes and macrophages do, however upon exposure, DCs lose their phagocytotic capacity, migrate to secondary lymphoid organs and transition to a mature DC (mDC) by acquiring MHC and costimulatory molecules, such as CD54, CD80, CD83, and CD86. Migration of DCs to the inflamed tissue is mediated by A1 and A3 ARs [58]. Adenosine upregulates the expression of co-stimulatory molecules on mDCs [59]. Both, A2A and A2B ARs suppress maturation of DCs as well as their capacity to initiate Th1 response, however, it increases pro-angiogenic VEGF, IL-10 and cytokines that contribute to Th17 cell polarization [59, 60]. Adenosine also mediates the attraction of DC and Treg cells, which is crucial for the immunosuppressive activity of Treg cells [61]. Similarly, ATP also acts as a chemoattractant for iDCs, and enhance the migration by autocrine signaling loop mechanism via P2X7. This signaling is further amplified by the release of ATP by PANX-1 channels [62]. Furthermore, eATP had been shown to activate P2X7R to promote the maturation of dendritic cells via NF-κB (p65) pathway [63]. On the other hand, P2Y6 has inhibitory role in the maturation and activation of DCs via NF-κB by inhibiting the production of IL-12 and IL-23 and the polarization of Th1 and Th17. Loss of P2Y6 enhances the DC mediates differentiation of Th1 and Th17 subsets [64]. The ATP-P2X7 signaling axis of DCs also promotes interleukin (IL)-1β and IL-18 secretion by activating NLRP3 inflammasome and induces Th2/Th17 differentiation [65]. P2X4 acts in conjunction with P2X7 to regulate IL-1β production by DCs [66]. As described previously, the balance of proinflammatory-ATP and anti-inflammatory adenosine is regulated by CD39 and CD73 present on the immune cells. In context of DCs, their expression fine tunes the DCs function either as tolerance (higher expression) or as immunity (lower expression) ensues [67, 68].
3.1.3 Neutrophils
Neutrophils belongs to the granulocyte family, which has a major role during the early stages of the inflammatory response. They are the first cell to arrive at the inflammation site, which employ an extracellular ATP-dependent mechanism to generate a chemotactic gradient and orientate its migration. Remarkably, the purinergic system regulates many effector functions of neutrophils such as phagocytosis, oxidative burst, degranulation, and neutrophil extracellular traps (NETs) formation via Netosis [69, 70]. Apoptotic neutrophils release ATP to stimulate mononuclear phagocytic cell influx and promote engulfment and clearance functions. Nucleotides released as a result of the apoptosis and netosis serve as danger or find me signal to initiate immune cell chemotaxis via P2Y2 receptor towards inflamed tissue and fine-tuned control local inflammation and promote phagocytosis and clearance [24, 71]. Similar to other phagocytic cells such as monocytic and dendritic cells, neutrophils in the immune microenvironment also release ATP via PANX-1 to induce chemotaxis by autocrine stimulation of P2Y2 [51, 52, 62, 72]. On the other hand, P1 receptor, A2A (activated by adenosine) blocks the chemoattractant signaling, whereas alternative binding of adenosine to A3 receptors, stimulate immune migration. Thus, P2Y2 and A3 receptors are responsible for the amplification of the chemotaxis signal via feedback loop mechanism [52]. P2Y2 receptors play crucial role in neutrophil activation by regulating the release of IL-8, a major chemokine for neutrophils chemotaxis [73]. IL-8 secretion is in turn controlled by CD39 [74]. Thus, the local microenvironment composed by ATP and the consequent degradation to adenosine by CD39 and CD73 ectoenzymes influence reprogramming of the innate immune cells and their response towards pathogens and other diseased condition.
3.1.4 Natural killer cells
NK cells are considered as a component of innate immune system due to the lack antigen-specific cell surface receptors but morphologically they resemble lymphocytes as they originate from the common lymphoid progenitor cell in the bone marrow. NK cells exert sophisticated biological functions that attribute to both innate and adaptive immunity, thus the functional boundary between these two arms of the immune response is obscure [75]. These cells express a repertoire of activating (NKG2 C-H) and inhibitory receptors (NKG2 A and B) through which it interacts with pathogens by recognizing MHC-I molecule [76]. Activation of the NK cell leads to cytolytic killing of infected cells. Adenosine receptors A1, A3 and A2A, A2B have an antagonistic effect in controlling the intracellular cAMP levels. A1, A3 inhibits the adenylyl cyclase and decreases the intracellular cAMP level, which has a stimulatory effect on NK cell and promote the cytotoxic activity whereas, A2A and A2B has the immunosuppressive effects on NK cells [76, 77]. NAD+ and ADP-ribose inhibited human NK proliferation [78]. Nucleotide triphosphates (ATP, GTP) have high potency in inhibiting NK cell-mediated cytotoxicity, this tendency however decreases with reduced negative charge due to less phosphate group [(ADP, GDP) > (AMP, GMP)]. Ectonucleotidases do not have any significant role in modulating the cytolytic effect of NK cells by extracellular ATP/ADP/AMP [79]. NK cells express lower level of CD73 even with IL-15 and IL-12 priming [74]. Decreased expression of P2Y6 promotes the development of the NK precursor cells into immature NK and mature NK cells suggesting P2Y6 as a negative regulator of NK cell maturation and function [80]. Among other extracellular purine derivatives, NKT cells display higher sensitivity to NAD+ and induce cell death via P2X7 pathway [81, 82]. Furthermore, another phenotypically heterogeneous NKT cells subset includes invariant natural killer T (iNKT), which are CD4 and CD8 negative but express NK cell marker and produce IL-4 and IFNγ. iNKT recognizes lipid antigens combined with CD1d on the surface [83]. Activation of iNKTs in vitro induces the expression of purinergic signaling genes A2A, P2X7R, CD38, CD39, NPP1, CD73, PANX-1, and ENT1, which has an anti-inflammatory role [84]. iNKT cells interact with DCs and monocytes via P2X7 dependent and an independent manner, respectively [85, 86]. Overall, NK cells alter their functional responses to adenosine signaling via mechanisms that are sensitive to specific cytokine activation programs.
3.2 Effect on adaptive immune signaling
3.2.1 T cells
Activation of T cell immune response is the key in adaptive immune system functions, which elicits both cellular and humoral immunity. Naïve T cells are activated by APCs, but they require two subsequent signals, first one is the binding of TCR to peptide–MHC complex and the second one is the co-stimulatory interaction at the interface between APCs and T cells via B7/CD28, LFA-1/ICAM-1 and ICAM2, and CD2/LFA-3 ligand and receptor complex [87]. Di Virgilio et al. was the first to show T cell responsiveness to extracellular ATP (eATP), back to 1989 [88]. Once T cells are activated, they release ATP via PANX-1 channels, resulting in the activation of P2X1, P2X4, and P2X7 receptors that promotes downstream signal transduction pathways leading to IL-2 expression and T cell proliferation via Ca+2 influx [89]. P2X7 receptor stands out among P2X family members as the most important regulator of T cell function [90]. The released ATP stimulates purinergic receptors that also contributes to the amplification of co-stimulatory TCR/CD28 signal at the immune synapse by autocrine stimulation of P2X7 [91] and P2Y1 receptors [92]. In addition, the T cell activation via P2X7R inhibits the immunosuppressive Tregs cells [93]. P2X7R is also crucial for the activation of CD8 T cells, and its expression increases as they differentiate to TCM (central memory) and TRM (tissue-resident memory) suggesting its key role in generating long-lived memory CD8 T cells [94]. However, another study demonstrated that eATP treatment can trigger cell death in the naive CD8 (CD44loCD45RBhi) subset, but it is unable to induce these cellular activities in the effector/memory CD8 (CD44hiCD45RBhi) subset. Even though both subsets express similarly low levels of P2X7R, but they demonstrate different sensitivity to ATP depending on the stage of differentiation instead of P2X7R expression levels [95]. Importantly, expression of CD39 and CD73, the ecto-5′-nucleotidase that degrades extracellular AMP into adenosine, by other immune and tissue-resident cells can dramatically condition the outcome of T cell responses [96]. On the other hand, A2A receptor signal inhibits Th1 cell generation and IFN-γ production, triggering the induction of FoxP3 + Treg cell subset and the production of TGF-β. ATP catabolism and generation of retaliatory metabolite adenosine is a typical suppression mechanism of regulatory cells involving Treg, type-1 regulatory (Tr1) T cells, and myeloid-derived suppressor cells (MDSCs) [97]. These regulatory cells express CD39 and CD73 to abrogate ATP-related effects and enable the inhibitory properties. P2X7R can imprint distinct outcomes to the T cell depending on the metabolic fitness and/or developmental stage via autocrine signaling or microenvironment’s clues. The peculiarity of P2X7R function as cationic channel and cytolytic pore could be responsible for some apparently contradictory findings on P2X7R dependent responses in particular T cell subsets in different experimental settings [94, 95, 96].
3.2.2 B cells
Another important arm of adaptive immune response is the humoral immunity, which is mediated by B cells. These cells are also necessary for the development of T-cell immunity because they serve as an APC, providing costimulatory signals and producing cytokines necessary for effector functions of T cells. B cells exhibit expression of the membrane B cell receptor (BCR), which can recognize antigens in their native forms, thus B cells do not need antigen presentation for activation. Antigen recognition, together with signals from activated Th2 cells, induces B cells to proliferate and generate effector plasma cells and memory B cells. B cells expresses ectonucleotidases—CD39 and CD73, P1 receptors—A1, A2A, and A3, and P2 receptors—P2X1, P2X2, P2X4, and P2X7 [33, 98, 99]. The function and activity of B cells are largely governed by the concentration of adenosine and ATP in the microenvironment. Adenosine imposes suppressive effect on B cells, whereas increased ATP release and production are associated with activated B cells thereby exerting pro-inflammatory effect on the target tissue and IgM release [100]. In vitro activated B cells exhibit downregulation of CD73, which mainly produces AMP, and inhibits T-cell proliferation and cytokine production, whereas overexpress A3 receptor in activated state [98]. Accumulation of pericellular ATP occurring in B cells activates the P2X7 receptor, which results in shedding of CD21, CD23, and CD62L from the cell surface [101, 102]. This process is involved in transendothelial migration of B cells. There is also evidence showing that P2X7 is directly involved in the release of IgM from B cells after T cell independent activation [103]. Moreover, CD73 is progressively upregulated on germinal center (GC) B cells following immunization, and is expressed at even higher levels among T follicular helper cells but is absent among plasma cells and plasmablasts. CD73-dependent adenosine signaling is prominent in the mature GC, maintenance of plasma cell compartment and necessary for immunoglobulin class switching [100, 104]. Thus, any disruption in the balance of ATP signaling that is dominant in activated B cells and adenosine signaling, which seems crucial in achieving immunocompetence by activated cells [100] could lead to severe immunological disorder.
4. Implication of purinergic signaling in various pathological conditions
A healthy individual has a practically insignificant amount ATP in the extracellular microenvironment (at the nanomolar range), whereas, they have significantly higher concentration of ATP in the intracellular environment (reaching several millimolar), as ATPs are the powerhouse of the cell. Inflammatory stress due to the increased production of proinflammatory mediators associates with release of ATP and other nucleotides into the extracellular space (Figure 1). These extracellular nucleotides trigger a stimulation of purinergic receptors, which is a normal physiological phenomenon and beneficial for preventing tissue damage ensuring host survival, it may also be detrimental for clearance of pathogens or dying cells. However, failure in the fine tuning of the immune response alters inflammatory and regulatory microenvironments, leading to unbalanced stimulation and culminates a hyperinflammatory condition generating numerous pathologies such as autoimmunity, chronic infectious diseases, and cancer (Figure 2).
4.1 Purinergic signaling in autoimmune disease
Autoimmune diseases are characterized by diverse clinical manifestations including dysregulated innate and adaptive immune signaling, chronic inflammation, autoreactive immune cells, generation of autoantibodies to self-nuclear and cytoplasmic component. Based on the target organ and tissues, they are represented as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjogren’s syndrome (SS), systemic sclerosis (SSc), etc. As described previously that some of the purinergic receptors are coupled with inflammasome assembly, pro-inflammatory cascades, secretion of IL-1β, IL-18, and T and B cell activation, and maturation, all these events play a pivotal role in autoimmunity [105].
4.1.1 Systemic lupus erythematosus
SLE is an inflammatory autoimmune disease that affects many organs, including the skin, joints, the central nervous system, and the kidneys. A frequent and serious manifestation of SLE includes glomerulonephritis (GN), a condition that can cause proteinuria and progresses to kidney failure. These diverse clinical features include hematological and serological abnormalities, such as decreased levels of complement and increased levels of autoantibodies [106, 107]. SLE has multiple etiology like genetic, environmental, and hormonal factor but involvement of dysfunctional innate and the adaptive system is prominent [108]. Purinergic signaling is another key pathway that connects with the inflammatory signaling cascade and contributes to the immunopathogenesis of SLE.
Till date, more than 180 autoantibodies have been documented in SLE patients [107]. Source of the diverse pool of autoantigens are apoptosis [109], netosis [110], and pyroptosis [111]. Simultaneously, SLE patient also exhibit impairment of phagocytotic clearance and NET degradation [112, 113], which together represent a mechanism that trigger to breakdown of the self-tolerance against autoantigens and leading to initiation of SLE. Defects in the purinergic signaling and its role in SLE pathogenesis and disease severity had been described at several instances. Therefore, P2X7R activation by ATP or by extracellular complexes, such as NETs, might have a dual pathogenetic role in promoting inflammation in lupus: on one hand, it directly triggers inflammation by stimulating the NLRP3 inflammasome, and on the other it has an indirect pro-inflammatory effect by inducing pyroptotic cell death [114]. Presence of the NETs in the microenvironment induce NLRP3 inflammasome, in macrophages and results in the amplification of inflammation by releasing of IL-1β and IL-18, which is mediated via P2X7R [115]. Induction of inflammasome and IL-1β and IL-18 release have been shown to contribute to the cardiovascular, skin, and nephritis manifestations [116, 117, 118]. Evidence suggests the higher P2X7R in renal tissue of lupus nephritis patients [119]. In that context, a study demonstrated substantial up-regulation of P2X7R, NLRP3, and ASC, in the kidneys of MLR/lpr mice compared to control mice and inhibition of P2X7R ameliorates the disease phenotype mainly diminished both the severity of nephritis and levels of circulating anti-dsDNA antibodies [120, 121]. The presence of single nuclear polymorphism (SNP) 489C>T in P2X7 receptor had been associated with increased inflammasome activation in SLE patients and shows involvement in pericarditis [122, 123]. Th1, Th17, and Regulatory T (Treg) cells in SLE patients display higher expression of P2X7 receptor, which correlates with active SLE disease and increased levels of IFN-γ, IL-1β, IL-6, IL-17A, and IL-23 cytokines [124]. Monocytes and lymphocytes from SLE patients and RA patients show reduced expression of P2X7R gene. They show reduced tendency to induce apoptosis and cytokine release in vitro compared to cells from healthy individual [125].
Furthermore, P2X7R has an important function of restricting the expansion of T follicular helper (Tfh) cells by pyroptosis and controls the development of pathogenic ICOS+ IFN-γ–secreting cells and in turn prevents the overproduction of autoantibodies and activation of T cells that ultimately controls the production of autoantibodies conditions [126]. SLE patients exhibit deletion of P2X7R genes that have deleterious effect of autoantibody generation [126]. Another study had reported that deletion of P2X7R could amplify the defect in peripheral T cell homeostasis due to the FAS mutation and thus contribute to the autoimmune pathology [127]. In similar way, another purinergic receptor P2Y8R restricts the proliferation of self-tolerant B cells. Distinct variant of P2Y8R had been shown to be downregulated in SLE patients and these are associated with the loss of function, which leads to increased expansion of self-reactive B cells, resulting in the increased autoantibody production. P2Y8R correlated with lupus nephritis and increased age-associated B cells and plasma cells indicating a role of P2Y8R in immunological tolerance and lupus pathogenesis [128].
The role of CD39 in the maintenance of immune tolerance is associated with its capacity of degrading ATP and consequently inhibiting the production of IL-17, which stimulates B cells to produce autoantibodies. Ectonucleotide provides protection in by converting eATP to adenosine. Deletion of ectonucleotides mainly, CD39 and CD73 lead to higher levels of anti-RNP antibodies in response to pristane, with CD73 deletion in particular promoting expansion of splenic B cell and T cell populations that likely contribute to autoantibody production [129]. B cells show the highest CD73 surface expression among human circulating immune cells. In SLE patients, the activity of CD73 and CD38 was found to be selectively silenced in B cells. Since CD73 is the bottleneck of extracellular nucleotide degradation to anti-inflammatory adenosine, this pathway is likely to be a crucial step in the pathophysiology of SLE involving B cell immune cell interactions [130].
4.1.2 Rheumatoid arthritis
RA is a chronic inflammatory disease of joints characterized by damage of bone and cartilage, which leads to joint destruction and disability. Primarily, it is driven by proliferation of synovial fibroblasts, inflammatory response of innate and adaptive immune response, differentiation of macrophage into osteoclasts, and impaired differentiation of mesenchymal stem cells into osteoblasts. The incidence is about 5 per 1000 people and can lead to severe joint damage and disability [131]. Studies have shown a critical role for P2 receptors in osteoblastogenesis and mineralization, synoviocytes proliferation, inflammation of immune cells, and differentiation of macrophages into osteoclasts [132]. Specifically, P2X7, P2Y14, P2Y12, P2Y6, P2Y1, P2Y2, and P2X4 receptors are involved in modulating bone and joint biology [133]. Pain is the major symptom of RA, which associates with the involvement of P2X4R had been reported in chronic arthritis [134]. Knockout of this gene in mice model alleviates the pain [135]. P2X4R control the production of Th17 cells, as shown by the inhibition of P2X4 receptor which reduced the production of IL-17 but not of IFN-γ by effector/memory CD4+ T cells isolated from patients with rheumatoid arthritis [136]. Inhibition of P2X4R associated with the attenuation of synovial inflammation and joint destruction as well as decreased the levels of serum IL-1β, TNF-α, IL-6, and IL-17 via NLRP1 [137]. Similar to SLE, SNP in P2X7 is associated with increased inflammatory response and susceptibility to RA [123, 125]. P2X7 receptor-mediates the release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases and is important for osteoclastogenesis [138]. It also regulates the differentiation of Th17 cells and type II collagen-induced arthritis in mice [139]. P2Y receptor also contribute to the development of RA such as P2Y11 receptor induce inflammation in primary fibroblast-like synoviocytes [140], P2Y12 and P2Y14 receptors induce bone lysis by activating osteoclasts [141, 142, 143]. RA patients demonstrate differential expression of adenosine receptors on synovium with preferential expression of A3 and its variant. However, in a separate RA cohort treated with methotrexate shows overexpression A2A and A2B indicating the anti-inflammatory property via these adenosine receptors [144]. Under hypoxia condition, bone resorption is increased in RA patients via A2B receptors. Inhibition of A2B receptors potentially prevent the hypoxia-mediated pathological osteolysis in RA [145].
The expression of CD39 in Tregs is limited by single nucleotide polymorphisms (SNP). It has been shown that AA genotype of the rs10748643 SNP, a low-expressing CD39 variant, is involved in the regulation of the immune system in autoimmunity [146]. A reduced response to methotrexate (MTX) in patients with rheumatoid arthritis was also shown to be related to an SNP that decreases the frequencies of CD39-expressing Tregs, the rs7071836 SNP [147]. Lower expression of CD73 in lymphocytes at the sites of inflammation has been associated with disease severity in juvenile idiopathic arthritis [148].
4.1.3 Multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, characterized by the presence of focal lesions in white and gray matter, which is associated with pathological and progression neurological dysfunction. Presence of peripheral immune cells infiltration is a main diagnostic hallmark of the disease. Purinergic receptors control immune cell function as well as neuronal and oligodendroglia survival, and the activation of astrocytes and microglia, the endogenous brain immune cells. Genetic variation in P2X4 and P2X7 receptors show susceptibility to MS. Functionally, the variants impair the expression of P2X7 on the surface resulting in the inhibition of ATP-induced pore function and phagocytic activity [149]. Cortical microglia from MS patient exhibit loss of P2Y12 receptor, which associates with the pro-inflammatory and neuronal damaging profile in MS [150]. On the other hand, P2Y12 is the markers of platelet and megakaryocyte activation. Its increased expression in MS patients associates with cardiovascular disease [151]. A study in mice model show that the loss of P2Y6 develop more severe experimental autoimmune encephalomyelitis compared with wild-type mice as it has pivotal role in DCs regulation [64]. Lymphocytes from MS patients also exhibit upregulation of A2A receptor, which modulates the release of proinflammatory cytokine TNF-α, IFN-γ, IL-6, IL-1β, IL-17 via NF-κB. A2A receptor upregulation was observed in lymphocytes from MS patients in comparison with healthy subjects. The stimulation of these receptors mediated a significant inhibition of TNF-α, IFN-γ, IL-6, IL-1β, IL-17, and cell proliferation as well as very late antigen (VLA)-4 expression and NF-κB activation [152].
CD39 expressing Treg cells controls the neuroinflammation in MS by suppressing the pathogenic Th17 cells and IL-17 production [31]. Its activity and the frequency were elevated in relapsing MS patients [153]. Furthermore, a study on animal model demonstrated that overexpression of CD39 on reactive microglia/macrophages that associates with either pro-inflammatory (M1-subtype) or neuroprotective (M2-subtype) at different stages of the disease. At the peak of EAE, CD39 immunoreactivity showed much higher co-occurrence with Arg1 immunoreactivity in microglia and macrophages, compared to iNOS, implying its stronger association with M2-like reactive phenotype [154]. Thus, modulation of purinergic signaling using an agonist or antagonist provides a new avenue for treatment of disease [155, 156].
4.2 Purinergic signaling during bacterial and viral infection
Infectious diseases are caused by the invasion of pathogenic microorganisms. After infection, host immune system elicits the anti-microbial immune response and at the same time microorganisms develop strategies to evade host defense mechanism. This involves generation of a variety of inflammatory and suppressive responses along with regulatory feedback systems to eliminate the pathogens but also to restore the homeostatic condition following infection or injury [157]. The purinergic system has the dual function of regulating the immune response and triggering effector antimicrobial response against bacterial and viral infections. During the infections, the ATP release initiates a cascade that activates purinergic receptors. This receptor activation enhances the secretion of pro-inflammatory cytokines and performs the chemotaxis of macrophages and neutrophils, generating an association between the immune and the purinergic systems. Immunomodulation by purinergic signaling has been widely discussed elsewhere [26, 158]. Some instances of involvement of purinergic signaling in bacterial infection include, reduced CD73 expression was associated with macrophage phagocytosis and an efficient clearance of Salmonella infection [159]. Likewise, depletion of CD39 on CD4, CD8, and Treg cells augments the T cells response to Listeria and Mycobacterium infections [160, 161]. On the other hand, transgenic mice with overexpression of CD39 in lung epithelia shows increased recruitment of neutrophils and macrophages in lungs upon Pseudomonas aeruginosa infection. The CD39 activity associates with efficient clearance of infection [162]. CD39, due to ATP-scavenging property it limits P2X7 receptor mediated pro-inflammatory responses. Thus, deletion of CD39 exacerbates sepsis-induced liver injury [163]. P2X7R signaling has a detrimental role in severe tuberculosis infection. ATP release and activation of P2X7R cause macrophage necrosis resulting in the spread of bacterial particles, leukocyte infiltration, and tissue damage [164]. Deletion of P2X7 receptor or blockage of P2X7R, or scavenging of eATP may attenuated inflammation, largely preventing increased cytokine secretion and tissue damage [163, 165].
Immunomodulation of purinergic signaling had been implicated in wide variety of viral infections such as human immunodeficiency virus (HIV)-1, hepatitis virus, dengue virus, and SARS-CoV2 [166, 167, 168, 169]. HIV-1 primarily infects CD4 T cells, but also affects myeloid dendritic cells and monocyte, macrophages populations that express CD4 receptor. Infected patients exhibit decreased CD4 T cell counts and a reversed CD4/CD8 T cells ratio. Adenosine has an immunosuppressive effect, patients with HIV infection show upregulated CD39 on Treg cells which is inversely related with the CD4 T cell count [167, 170]. In contrast to CD39, CD73 expression was diminished on CD4 T cells, which represent a phenotypically and functionally different subpopulation of CD73+ CD4 T cells. This T cell subsets are preferentially reduced in HIV patients, which suggests the effect of an adenosine diminished microenvironment that cannot prevent persistent immune activation. CD73+ CD4+ T cell counts were inversely associated with T cell activation, as well as plasma C reactive protein levels [171]. Besides, CD73 is involved in the expansion of HIV-specific CD8 T cells, whereas CD73 expression is higher in memory CD8+ T cell subset. The frequency of CD73+ CD8+ T cells is inversely associated with cell activation and plasma viral load [172]. PANX-1 hemichannel opening, activation of P2Y2R, P2X1R are involved in the mediating the effective viral entry and replication in CD4 or target cells [173, 174, 175]. Blocking the P2X1 and P2X7 receptors inhibits the viral entry and fusion [176]. Similarly, the P2X1R, P2X4R and P2X7R expression increased in during hepatitis C virus infection and Dengue virus infection [168, 177]. Blocking P2X receptor with antagonist improves the anti-viral response and T cell function [168, 178].
Given the pathophysiological role of purinergic signaling in highly prevalent viral infections has developed a potential interest in investigating the effects of purinergic system in severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2). SARS-CoV-2 infection had impacted more than millions of people worldwide since its emergence in December 2019, in Wuhan, China. The clinical manifestations of SARS-CoV-2 include pneumonia, acute respiratory distress syndrome (ARDS), and hyperinflammation. SARS-CoV-2 primarily invade the alveolar epithelia of respiratory tract and lungs where they replicate, triggers the activation of the immune system resulting in the release of cytokines as a defense mechanism, but the response become exaggerated and prompt the so-called “cytokine storm.” This is a state of hyperinflammatory response, which develops acute respiratory syndrome (SARS). This is characterized by fever, cough, and difficulty breathing, which can progress to pneumonia, failure of different organs, and death. Patients with SARS-CoV-2 infection exhibit increased purinergic signaling, which has been suggested to have a role in hyperinflammatory state [179]. The mechanisms have been described in very detail in review articles [169, 180]. The increased inflammations resulting from activated purinergic signaling in SARS-Cov-2 infections are also associated with different pathological conditions such as neuropathy [181], thrombopathy [182, 183]. As observed in other viral infections patients with SARS-CoV-2 shows reduced expression of CD73 on circulating CD8, NK, and NKT cells. However, cells lacking CD73 exhibit increased cytotoxic effector capacity compared to their counterpart CD73+ [184]. P2X7R-NLRP3 signaling axis are the key driver of inflammation in SARS-CoV-2 [185]. Therefore, P2X7R could serve as a potential therapeutic target to control the inflammation [186]. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function [169]. Understanding this biology is very crucial as anti-inflammatory drugs are not effective and sometimes accompanied by serious adverse effects.
5. Conclusion
This chapter has highlighted the importance of purinergic signaling in modulating the immune system in various therapeutic areas. Purinergic system is capable of fine tuning the levels of nucleotides and their derivative in the extracellular space thereby controlling the chemotaxis, proliferation, differentiation of various immune cell presents locally or far from the infectious site. Dysregulation of purinergic signaling because of genetic factor or escape mechanism employed by the microbes or regulatory cell leads to overt inflammation that contributes to the disease. Special attention has been paid to the mechanisms through which alterations in the various compartments of the purinergic system could contribute to the patho-pathophysiology of autoimmune disease and microbial infection. This chapter could help in gaining insight on the possibility of counteracting such dysfunctions by means of pharmacological interventions on purinergic molecular targets.
\n',keywords:"ATP, adenosine, ectonucleotidases, CD39, CD73, purinergic signaling, systemic lupus erythematosus, rheumatoid arthritis, infectious disease, SARS-CoV2",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81799.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81799.xml",downloadPdfUrl:"/chapter/pdf-download/81799",previewPdfUrl:"/chapter/pdf-preview/81799",totalDownloads:49,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 28th 2022",dateReviewed:"April 19th 2022",datePrePublished:"May 15th 2022",datePublished:null,dateFinished:"May 15th 2022",readingETA:"0",abstract:"Purine derivatives like adenosine 5′-triphosphate (ATP) is the powerhouse of the cell and is essential to maintain the cellular homeostasis and activity. Besides this they also act as a chemical messenger when released into the extracellular milieu because of stress and cellular insult. The extracellular ATP (eATP) as well as its metabolite adenosine triggers purinergic signaling affecting various cellular processes such as cytokine and chemokine production, immune cell function, differentiation, and maturation, and mediates inflammatory activity. Aberrant purinergic signaling had been implicated in several diseased conditions. This chapter will focus on the dynamics of purinergic signaling and immune signaling in driving under various diseased conditions like autoimmunity and infectious disease.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81799",risUrl:"/chapter/ris/81799",signatures:"Richa Rai",book:{id:"10801",type:"book",title:"Purinergic System",subtitle:null,fullTitle:"Purinergic System",slug:null,publishedDate:null,bookSignature:"Dr. Margarete Dulce Bagatini",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-784-7",printIsbn:"978-1-80355-783-0",pdfIsbn:"978-1-80355-785-4",isAvailableForWebshopOrdering:!0,editors:[{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Purinergic system and its component on immune cells: an immunomodulator",level:"1"},{id:"sec_2_2",title:"2.1 Mechanism of release of nucleotides",level:"2"},{id:"sec_3_2",title:"2.2 Metabolism of extracellular nucleotides and nucleosides",level:"2"},{id:"sec_4_2",title:"2.3 Purinergic receptors",level:"2"},{id:"sec_6",title:"3. Interplay of purinergic signaling and immune signaling on inflammatory response",level:"1"},{id:"sec_6_2",title:"3.1 Effect on innate immune signaling",level:"2"},{id:"sec_6_3",title:"3.1.1 Monocytes/macrophages",level:"3"},{id:"sec_7_3",title:"3.1.2 Dendritic cells",level:"3"},{id:"sec_8_3",title:"3.1.3 Neutrophils",level:"3"},{id:"sec_9_3",title:"3.1.4 Natural killer cells",level:"3"},{id:"sec_11_2",title:"3.2 Effect on adaptive immune signaling",level:"2"},{id:"sec_11_3",title:"3.2.1 T cells",level:"3"},{id:"sec_12_3",title:"3.2.2 B cells",level:"3"},{id:"sec_15",title:"4. Implication of purinergic signaling in various pathological conditions",level:"1"},{id:"sec_15_2",title:"4.1 Purinergic signaling in autoimmune disease",level:"2"},{id:"sec_15_3",title:"4.1.1 Systemic lupus erythematosus",level:"3"},{id:"sec_16_3",title:"4.1.2 Rheumatoid arthritis",level:"3"},{id:"sec_17_3",title:"4.1.3 Multiple sclerosis",level:"3"},{id:"sec_19_2",title:"4.2 Purinergic signaling during bacterial and viral infection",level:"2"},{id:"sec_21",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Dunn J, Grider MH. Physiology, adenosine triphosphate. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021'},{id:"B2",body:'Drury AN, Szent-Györgyi A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. The Journal of Physiology. 1929;68(3):213-237'},{id:"B3",body:'Burnstock G. Purinergic nerves. Pharmacological Reviews. 1972;24(3):509-581'},{id:"B4",body:'Burnstock G. 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Autoimmune susceptibility gene critically influences CD39 T cell expression and function in modulating human inflammation (P3313). The Journal of Immunology. 2013;190(1 Supplement):175.174'},{id:"B147",body:'da Silva JLG, Passos DF, Bernardes VM, Leal DBR. ATP and adenosine: Role in the immunopathogenesis of rheumatoid arthritis. Immunology Letters. 2019;214:55-64'},{id:"B148",body:'Botta Gordon-Smith S, Ursu S, Eaton S, Moncrieffe H, Wedderburn LR. Correlation of low CD73 expression on synovial lymphocytes with reduced adenosine generation and higher disease severity in juvenile idiopathic arthritis. Arthritis & Rhematology. 2015;67(2):545-554'},{id:"B149",body:'Sadovnick AD, Gu BJ, Traboulsee AL, Bernales CQ , Encarnacion M, Yee IM, et al. Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis. Human Mutation. 2017;38(6):736-744'},{id:"B150",body:'van Olst L, Rodriguez-Mogeda C, Picon C, Kiljan S, James RE, Kamermans A, et al. Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration. Acta Neuropathologica. 2021;141(6):881-899'},{id:"B151",body:'Dziedzic A, Miller E, Saluk-Bijak J, Niwald M, Bijak M. The molecular aspects of disturbed platelet activation through ADP/P2Y(12) pathway in multiple sclerosis. International Journal of Molecular Sciences. 2021;22(12):657'},{id:"B152",body:'Vincenzi F, Corciulo C, Targa M, Merighi S, Gessi S, Casetta I, et al. Multiple sclerosis lymphocytes upregulate A2A adenosine receptors that are antiinflammatory when stimulated. European Journal of Immunology. 2013;43(8):2206-2216'},{id:"B153",body:'Álvarez-Sánchez N, Cruz-Chamorro I, Díaz-Sánchez M, Lardone PJ, Guerrero JM, Carrillo-Vico A. Peripheral CD39-expressing T regulatory cells are increased and associated with relapsing-remitting multiple sclerosis in relapsing patients. 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Overexpression of CD39 in mouse airways promotes bacteria-induced inflammation. Journal of Immunology. 2012;189(4):1966-1974'},{id:"B163",body:'Savio LEB, de Andrade MP, Figliuolo VR, de Avelar Almeida TF, Santana PT, Oliveira SDS, et al. CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. Journal of Hepatology. 2017;67(4):716-726'},{id:"B164",body:'Amaral EP, Ribeiro SC, Lanes VR, Almeida FM, de Andrade MR, Bomfim CC, et al. Pulmonary infection with hypervirulent mycobacteria reveals a crucial role for the P2X7 receptor in aggressive forms of tuberculosis. PLoS Pathogens. 2014;10(7):e1004188'},{id:"B165",body:'Li X, Kondo Y, Bao Y, Staudenmaier L, Lee A, Zhang J, et al. Systemic adenosine triphosphate impairs neutrophil chemotaxis and host defense in sepsis. Critical Care Medicine. 2017;45(1):e97-e104'},{id:"B166",body:'Taylor JM, Han Z. Purinergic receptor functionality is necessary for infection of human hepatocytes by hepatitis delta virus and hepatitis B virus. PLoS One. 2010;5(12):e15784'},{id:"B167",body:'Pacheco PA, Faria RX, Ferreira LG, Paixão IC. Putative roles of purinergic signaling in human immunodeficiency virus-1 infection. Biology Direct. 2014;9:21'},{id:"B168",body:'Corrêa G, de ALC, Fernandes-Santos C, Gandini M, Petitinga Paiva F, Coutinho-Silva R, et al. The purinergic receptor P2X7 role in control of dengue virus-2 infection and cytokine/chemokine production in infected human monocytes. Immunobiology. 2016;221(7):794-802'},{id:"B169",body:'Hasan D, Shono A, van Kalken CK, van der Spek PJ, Krenning EP, Kotani T. A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling. Purinergic Signal. 2022;18(1):13-59'},{id:"B170",body:'Nikolova M, Carriere M, Jenabian MA, Limou S, Younas M, Kök A, et al. CD39/adenosine pathway is involved in AIDS progression. PLoS Pathogens. 2011;7(7):e1002110'},{id:"B171",body:'Schuler PJ, Macatangay BJ, Saze Z, Jackson EK, Riddler SA, Buchanan WG, et al. CD4+CD73+ T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression. AIDS. 2013;27(10):1545-1555'},{id:"B172",body:'Tóth I, Le AQ , Hartjen P, Thomssen A, Matzat V, Lehmann C, et al. Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion. Journal of Leukocyte Biology. 2013;94(4):551-561'},{id:"B173",body:'Séror C, Melki MT, Subra F, Raza SQ , Bras M, Saïdi H, et al. Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. The Journal of Experimental Medicine. 2011;208(9):1823-1834'},{id:"B174",body:'Orellana JA, Velasquez S, Williams DW, Sáez JC, Berman JW, Eugenin EA. Pannexin1 hemichannels are critical for HIV infection of human primary CD4+ T lymphocytes. Journal of Leukocyte Biology. 2013;94(3):399-407'},{id:"B175",body:'Freeman TL, Swartz TH. Purinergic receptors: Elucidating the role of these immune mediators in HIV-1 fusion. Viruses. 2020;12(3):290'},{id:"B176",body:'Giroud C, Marin M, Hammonds J, Spearman P, Melikyan GB. P2X1 receptor antagonists inhibit HIV-1 fusion by blocking virus-coreceptor interactions. Journal of Virology. 2015;89(18):9368-9382'},{id:"B177",body:'Manzoor S, Akhtar U, Naseem S, Khalid M, Mazhar M, Parvaiz F, et al. Ionotropic purinergic receptors P2X4 and P2X7: Proviral or antiviral? An insight into P2X receptor signaling and hepatitis C virus infection. Viral Immunology. 2016;29(7):401-408'},{id:"B178",body:'Tsai CY, Liong KH, Gunalan MG, Li N, Lim DS, Fisher DA, et al. Type I IFNs and IL-18 regulate the antiviral response of primary human γδ T cells against dendritic cells infected with dengue virus. Journal of Immunology. 2015;194(8):3890-3900'},{id:"B179",body:'Zarei M, Sahebi Vaighan N, Ziai SA. Purinergic receptor ligands: The cytokine storm attenuators, potential therapeutic agents for the treatment of COVID-19. Immunopharmacology and Immunotoxicology. 2021;43(6):633-643'},{id:"B180",body:'Leão Batista Simões J, Fornari Basso H, Cristine Kosvoski G, Gavioli J, Marafon F, Elias Assmann C, et al. Targeting purinergic receptors to suppress the cytokine storm induced by SARS-CoV-2 infection in pulmonary tissue. International Immunopharmacology. 2021;100:108150'},{id:"B181",body:'Simões JLB, Bagatini MD. Purinergic signaling of ATP in COVID-19 associated Guillain-Barré syndrome. Journal of Neuroimmune Pharmacology. 2021;16(1):48-58'},{id:"B182",body:'Caillon A, Trimaille A, Favre J, Jesel L, Morel O, Kauffenstein G. Role of neutrophils, platelets, and extracellular vesicles and their interactions in COVID-19-associated thrombopathy. Journal of Thrombosis and Haemostasis. 2022;20(1):17-31'},{id:"B183",body:'Schultz IC, Bertoni APS, Wink MR. Purinergic signaling elements are correlated with coagulation players in peripheral blood and leukocyte samples from COVID-19 patients. Journal of Molecular Medicine (Berlin, Germany). 2022:100(4):569-584'},{id:"B184",body:'Ahmadi P, Hartjen P, Kohsar M, Kummer S, Schmiedel S, Bockmann JH, et al. Defining the CD39/CD73 axis in SARS-CoV-2 infection: The CD73(−) phenotype identifies polyfunctional cytotoxic lymphocytes. Cell. 2020;9(8):1750'},{id:"B185",body:'Ribeiro DE, Oliveira-Giacomelli Á, Glaser T, Arnaud-Sampaio VF, Andrejew R, Dieckmann L, et al. Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology. Molecular Psychiatry. 2021;26(4):1044-1059'},{id:"B186",body:'Di Virgilio F, Tang Y, Sarti AC, Rossato M. A rationale for targeting the P2X7 receptor in coronavirus disease 19. British Journal of Pharmacology. 2020;177(21):4990-4994'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Richa Rai",address:"richa.23m@gmail.com",affiliation:'
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From 1970 until 1974 Dr. Al-Haj Ibrahim was a Research Fellow at British Coke Research Association (Leeds University, England) after which he worked at Homs Oil Refinery, Syria (1974-1975). In 1975 Dr. Al-Haj Ibrahim became a Professor at Al Baath University (Syria) where he still works. He was also a Senior Researcher at Syrian Atomic Energy Commission (2000-2003) and Director of Quality Assurance, Al-Baath University, Syria (2003-2008, 2015-2017). Furthermore, Dr. Al-Haj Ibrahim was a visiting professor at a number of universities: Technical University of Aachen, Germany; University of Pittsburgh, U.S.A. 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He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',institutionURL:null,country:{name:"Romania"}}},{id:"169816",title:"Dr.",name:"Jit",surname:"Mandeep",slug:"jit-mandeep",fullName:"Jit Mandeep",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"169817",title:"Dr.",name:"Alyani",surname:"Ismail",slug:"alyani-ismail",fullName:"Alyani Ismail",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"169818",title:"Dr.",name:"Abdulmajeed",surname:"Aljumaily",slug:"abdulmajeed-aljumaily",fullName:"Abdulmajeed Aljumaily",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"169819",title:"Dr.",name:"Chandima",surname:"Gomes",slug:"chandima-gomes",fullName:"Chandima Gomes",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"170695",title:"Dr.",name:"Ali",surname:"Al-Saegh",slug:"ali-al-saegh",fullName:"Ali Al-Saegh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"team",title:"Team",intro:"
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Our Values
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Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
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Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
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Openness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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Disruptiveness - We are eager for discovery, for new ideas and for progression. We approach our work with creativity and determination, with a clear vision that drives us forward. We look beyond today and strive for a better tomorrow.
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Our Team
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Co-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
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But, one thing we have in common is -- we are all scientists at heart!
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Sara Uhac, COO
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Sara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
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Adrian Assad De Marco
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Adrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
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IntechOpen Board Members
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Dr Alex Lazinica
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Alex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
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Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
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Openness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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Disruptiveness - We are eager for discovery, for new ideas and for progression. We approach our work with creativity and determination, with a clear vision that drives us forward. We look beyond today and strive for a better tomorrow.
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Our Team
\n\n
Co-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
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But, one thing we have in common is -- we are all scientists at heart!
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Sara Uhac, COO
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Sara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\n
Adrian Assad De Marco
\n\n
Adrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\n
IntechOpen Board Members
\n\n
Dr Alex Lazinica
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Alex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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Only bioactive glass possesses osteogenic property that stimulates proliferation and differentiation of osteoprogenitor cells and in some cases influencing the fibroblastic properties. But, this material has also some disadvantages such as short-term and low mechanical strength along with decreased fracture resistance; but, this was further minimised by ion doping that positively enhanced new bone formation. There are many metal ions such as magnesium (Mg), strontium (Sr), manganese (Mn), iron (Fe), zinc (Zn), silver (Ag) and some rare earths that have been doped successfully into bioactive glass to enhance their mechanical and biological properties. In some of the cases, mesoporous bioactive glass materials with or without such doping have also been employed (with homogeneous distribution of pores in the size ranging between 2 and 50 nm). These biomaterials can be served as scaffold for bone regeneration with adequate mechanical properties to restore bone defects and facilitate healing process by regeneration of soft tissues as well. This chapter encompasses the use of bioactive glass in bulk and mesoporous form with doped therapeutic ions, their role in bone tissue regeneration, use as delivery of growth factors as well as coating material for orthopaedic implants.",book:{id:"5164",slug:"advanced-techniques-in-bone-regeneration",title:"Advanced Techniques in Bone Regeneration",fullTitle:"Advanced Techniques in Bone Regeneration"},signatures:"Samit Kumar Nandi, Arnab Mahato, Biswanath Kundu and Prasenjit\nMukherjee",authors:[{id:"60514",title:"Dr.",name:"Samit",middleName:null,surname:"Nandi",slug:"samit-nandi",fullName:"Samit Nandi"}]},{id:"37120",doi:"10.5772/29607",title:"Trigeminocardiac Reflex in Neurosurgery - Current Knowledge and Prospects",slug:"the-trigeminocardiac-reflex-in-neurosurgery-current-knowledge-and-prospects",totalDownloads:3434,totalCrossrefCites:10,totalDimensionsCites:27,abstract:null,book:{id:"749",slug:"explicative-cases-of-controversial-issues-in-neurosurgery",title:"Explicative Cases of Controversial Issues in Neurosurgery",fullTitle:"Explicative Cases of Controversial Issues in Neurosurgery"},signatures:"Amr Abdulazim, Martin N. Stienen, Pooyan Sadr-Eshkevari, Nora Prochnow, Nora Sandu, Benham Bohluli and Bernhard Schaller",authors:[{id:"78171",title:"Prof.",name:"Bernhard",middleName:null,surname:"Schaller",slug:"bernhard-schaller",fullName:"Bernhard Schaller"},{id:"78525",title:"Mr.",name:"Amr",middleName:null,surname:"Abdulazim",slug:"amr-abdulazim",fullName:"Amr Abdulazim"},{id:"78530",title:"Dr",name:"Pooyan",middleName:null,surname:"Sadr-Eshkevari",slug:"pooyan-sadr-eshkevari",fullName:"Pooyan Sadr-Eshkevari"},{id:"126039",title:"Dr.",name:"Martin",middleName:"Nikolaus",surname:"Stienen",slug:"martin-stienen",fullName:"Martin Stienen"},{id:"126040",title:"Dr.",name:"Nora",middleName:null,surname:"Prochnow",slug:"nora-prochnow",fullName:"Nora Prochnow"},{id:"126041",title:"Dr.",name:"Benham",middleName:null,surname:"Bohluli",slug:"benham-bohluli",fullName:"Benham Bohluli"}]},{id:"26863",doi:"10.5772/26362",title:"The Bearing Surfaces in Total Hip Arthroplasty – Options, Material Characteristics and Selection",slug:"the-bearing-surfaces-in-total-hip-arthroplasty-options-material-characteristics-and-selection",totalDownloads:9526,totalCrossrefCites:10,totalDimensionsCites:21,abstract:null,book:{id:"938",slug:"recent-advances-in-arthroplasty",title:"Recent Advances in Arthroplasty",fullTitle:"Recent Advances in Arthroplasty"},signatures:"Hamid Reza Seyyed Hosseinzadeh, Alireza Eajazi and Ali Sina Shahi",authors:[{id:"66361",title:"Dr.",name:"Alireza",middleName:null,surname:"Eajazi",slug:"alireza-eajazi",fullName:"Alireza Eajazi"},{id:"74857",title:"Dr.",name:"Hamid Reza",middleName:null,surname:"Seyyed Hosseinzadeh",slug:"hamid-reza-seyyed-hosseinzadeh",fullName:"Hamid Reza Seyyed Hosseinzadeh"},{id:"173207",title:"Dr.",name:"Alisina",middleName:null,surname:"Shahi",slug:"alisina-shahi",fullName:"Alisina Shahi"}]}],mostDownloadedChaptersLast30Days:[{id:"65467",title:"Anesthesia Management for Large-Volume Liposuction",slug:"anesthesia-management-for-large-volume-liposuction",totalDownloads:6203,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The apparent easiness with which liposuction is performed favors that patients, young surgeons, and anesthesiologists without experience in this field ignore the many events that occur during this procedure. Liposuction is a procedure to improve the body contour and not a surgery to reduce weight, although recently people who have failed in their plans to lose weight look at liposuction as a means to contour their body figure. Tumescent liposuction of large volumes requires a meticulous selection of each patient; their preoperative evaluation and perioperative management are essential to obtain the expected results. The various techniques of general anesthesia are the most recommended and should be monitored in the usual way, as well as monitoring the total doses of infiltrated local anesthetics to avoid systemic toxicity. The management of intravenous fluids is controversial, but the current trend is the restricted use of hydrosaline solutions. The most feared complications are deep vein thrombosis, pulmonary thromboembolism, fat embolism, lung edema, hypothermia, infections and even death. The adherence to the management guidelines and prophylaxis of venous thrombosis/thromboembolism is mandatory.",book:{id:"6221",slug:"anesthesia-topics-for-plastic-and-reconstructive-surgery",title:"Anesthesia Topics for Plastic and Reconstructive Surgery",fullTitle:"Anesthesia Topics for Plastic and Reconstructive Surgery"},signatures:"Sergio Granados-Tinajero, Carlos Buenrostro-Vásquez, Cecilia\nCárdenas-Maytorena and Marcela Contreras-López",authors:[{id:"273532",title:"Dr.",name:"Sergio Octavio",middleName:null,surname:"Granados Tinajero",slug:"sergio-octavio-granados-tinajero",fullName:"Sergio Octavio Granados Tinajero"}]},{id:"42855",title:"Critical Care Issues After Major Hepatic Surgery",slug:"critical-care-issues-after-major-hepatic-surgery",totalDownloads:8935,totalCrossrefCites:2,totalDimensionsCites:2,abstract:null,book:{id:"3164",slug:"hepatic-surgery",title:"Hepatic Surgery",fullTitle:"Hepatic Surgery"},signatures:"Ashok Thorat and Wei-Chen Lee",authors:[{id:"52360",title:"Prof.",name:"Wei-Chen",middleName:null,surname:"Lee",slug:"wei-chen-lee",fullName:"Wei-Chen Lee"},{id:"157213",title:"Dr.",name:"Ashok",middleName:null,surname:"Thorat",slug:"ashok-thorat",fullName:"Ashok Thorat"}]},{id:"72175",title:"Fontan Operation: A Comprehensive Review",slug:"fontan-operation-a-comprehensive-review",totalDownloads:1299,totalCrossrefCites:3,totalDimensionsCites:2,abstract:"Since the first description of the Fontan operation in the early 1970s, a number of modifications have been introduced and currently staged, total cavopulmonary connection with fenestration has become the most commonly used multistage surgery in diverting the vena caval blood flow into the lungs. The existing ventricle, whether it is left or right, is utilized to supply systemic circuit. During Stage I, palliative surgery is performed, usually at presentation in the neonatal period/early infancy, on the basis of pathophysiology of the cardiac defect. During Stage II, a bidirectional Glenn procedure is undertaken in which the superior vena caval flow is diverted into the lungs at an approximate age of 6 months. During Stage IIIA, the blood flow from the inferior vena cava (IVC) is rerouted into the pulmonary arteries, typically by an extra-cardiac conduit along with a fenestration, generally around 2 years of age. During Stage IIIB, the fenestration is closed by transcatheter methodology 6–12 months after Stage IIIA. The evolution of Fontan concepts, the indications for Fontan surgery, and the results of old and current types of Fontan operation form the focus of this review.",book:{id:"9585",slug:"advances-in-complex-valvular-disease",title:"Advances in Complex Valvular Disease",fullTitle:"Advances in Complex Valvular Disease"},signatures:"P. Syamasundar Rao",authors:[{id:"68531",title:"Dr.",name:"P. Syamasundar",middleName:null,surname:"Rao",slug:"p.-syamasundar-rao",fullName:"P. Syamasundar Rao"}]},{id:"45712",title:"Serdev Sutures® in Middle Face",slug:"serdev-sutures-in-middle-face",totalDownloads:4952,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"2989",slug:"miniinvasive-face-and-body-lifts-closed-suture-lifts-or-barbed-thread-lifts",title:"Miniinvasive Face and Body Lifts",fullTitle:"Miniinvasive Face and Body Lifts - Closed Suture Lifts or Barbed Thread Lifts"},signatures:"Nikolay Serdev",authors:[{id:"32585",title:"Dr.",name:"Nikolay",middleName:null,surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}]},{id:"55812",title:"Postural Restoration: A Tri-Planar Asymmetrical Framework for Understanding, Assessing, and Treating Scoliosis and Other Spinal Dysfunctions",slug:"postural-restoration-a-tri-planar-asymmetrical-framework-for-understanding-assessing-and-treating-sc",totalDownloads:7701,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Current medical practice does not recognize the influence of innate, physiological, human asymmetry on scoliosis and other postural disorders. Interventions meant to correct these conditions are commonly based on symmetrical models of appearance and do not take into account asymmetric organ weight distribution, asymmetries of respiratory mechanics, and dominant movement patterns that are reinforced in daily functional activities. A model of innate, human asymmetry derived from the theoretical framework of the Postural Restoration Institute® (PRI) explicitly describes the physiological, biomechanical, and respiratory components of human asymmetry. This model is important because it gives an accurate baseline for understanding predisposing factors for the development of postural disorders, which, without intervention, will likely progress to structural dysfunction. Clinical tests to evaluate tri-planar musculoskeletal relationships and function, developed by PRI, are based on this asymmetric model. These tests are valuable for assessing patient’s status in the context of human asymmetry and in guiding appropriate exercise prescription and progression. Balancing musculoskeletal asymmetry is the aim of PRI treatment. Restoration of relative balance decreases pain, restores improved alignment, and strengthens appropriate muscle function. It can also halt the progression of dysfunction and improve respiration, quality of life, and appearance. PRI’s extensive body of targeted exercise progressions are highly effective due to their basis in the tri-planar asymmetric human model.",book:{id:"5816",slug:"innovations-in-spinal-deformities-and-postural-disorders",title:"Innovations in Spinal Deformities and Postural Disorders",fullTitle:"Innovations in Spinal Deformities and Postural Disorders"},signatures:"Susan Henning, Lisa C. Mangino and Jean Massé",authors:[{id:"204825",title:"Dr.",name:"Susan",middleName:null,surname:"Henning",slug:"susan-henning",fullName:"Susan Henning"},{id:"206242",title:"Dr.",name:"Lisa C",middleName:null,surname:"Mangino",slug:"lisa-c-mangino",fullName:"Lisa C Mangino"},{id:"206245",title:"Dr.",name:"Jean",middleName:null,surname:"Massé",slug:"jean-masse",fullName:"Jean Massé"}]}],onlineFirstChaptersFilter:{topicId:"202",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82020",title:"Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Novel Technique and Technology with Case Series",slug:"minimally-invasive-transforaminal-lumbar-interbody-fusion-a-novel-technique-and-technology-with-case",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.105187",abstract:"Minimally invasive spine surgery (MIS) transforaminal lumbar interbody fusion (MI-TLIF) has been utilized to treat a variety of spinal disorders. Like other minimally invasive spine surgery techniques and technology, the MI-TLIF approach has the potential to limit the morbidity associated with larger exposures required for open surgery. The MI-TLIF approach has a number of advantages over many other minimally invasive spine surgery approaches including direct decompression of neural elements, collection of morselized autograph from the surgical site to achieve high fusion rates, restoration of spinal canal diameter, foraminal diameter, disk height, and reduction of spondylolisthesis. In this chapter, we discuss a novel technique for performing MI-TLIF developed by the senior author who is a leading minimally invasive spine surgeon. The technique and technology illustrated in this chapter were developed out of a recognition of a need to reduce the learning curve for performing MI-TLIF, as well as need for a cost-effective method that provides a high fusion rate, excellent clinical outcomes, and low complication rate. The indications, surgical planning, postoperative care, complications, and patient outcomes in a large series will be reviewed using this novel MI-TLIF technique.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Mick Perez-Cruet, Ramiro Pérez de la Torre and Siddharth Ramanathan"},{id:"78335",title:"Safety and Efficiency of Cervical Disc Arthroplasty in Ambulatory Surgery Centers",slug:"safety-and-efficiency-of-cervical-disc-arthroplasty-in-ambulatory-surgery-centers",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.99589",abstract:"Introduction Anterior cervical surgeries have been safely performed in ambulatory surgery centers since 1995 with the first cases being one level anterior cervical discectomies without fusion, then in 1996, one level anterior cervical discectomies with fusion (ACDF). When it is was certain that outpatient fusion was safe, the number of ACDF levels slowly and methodically were increased to the now standard outpatient maximum of four level ACDF. During this evolution, with the introduction of arthroplasty surgery, one level arthroplasties were considered appropriate for outpatient surgery and now two-level outpatient cervical arthroplasties are routine and some three level arthroplasties have been performed with no additional morbidity compared to one level procedures. The author first reported a series of 27 patients in 2010 who underwent cervical disc replacement at an ASC. (Wohns, R. Safety and cost-effectiveness of outpatient cervical disc arthroplasty. Surg. Neurol. Int. 1, 77, 2010). The average operative time was 40 minutes and the patients were observed over a period of three hours prior to discharge. None of the patients had major complications and there were no reports of worsening or persistent pain. The results of a Delphi study in 2018 compared the safety and efficiency of one-level and two-level arthroplasty procedures performed in an ASC and in a hospital setting. (Gornet et al. Safety and Efficiency of Cervical Disc Arthroplasty in Ambulatory Surgery Centers vs Hospital Settings. Int’l J of Spine Surgery. Vol. 12, No.5, 2018, pp. 557-564). The study analyzed outcomes of 145 ASC patients, 348 hospital outpatients and 65 hospital inpatients and the conclusion was that both one and two-level arthroplasties may be performed safely in an ASC. Surgeries in ASCs are of shorter duration and performed with less blood loss without increased AEs. At the present time, there does not appear to be any contra-indication to performing the vast majority of cervical arthroplasties in an ambulatory surgery center (ASC). Furthermore, the cost of an outpatient arthroplasty is commonly 30% to 50% of the cost of hospital-based procedures.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Richard N.W. Wohns"},{id:"82255",title:"Minimally Invasive Laminectomy for Lumbar Stenosis with Case Series of Patients with Multi-level (3 or More Levels) Stenosis",slug:"minimally-invasive-laminectomy-for-lumbar-stenosis-with-case-series-of-patients-with-multi-level-3-o",totalDownloads:28,totalDimensionsCites:0,doi:"10.5772/intechopen.105186",abstract:"Lumbar stenosis is the most common pathology seen and treated by spine surgeons. It is often seen in the elderly population who frequently have multiple medical co-morbidities. Traditional approaches remove the spinous process and detach paraspinous muscles to achieve adequate canal decompression. This approach can damage the posterior tension band leading to permanent muscle damage, scar tissue formation, iatrogenic flatback syndrome, and increase risk of adjacent segment disease requiring reoperation. Performing lumbar laminectomy in a cost-effective manner is critical in effectively treating patients with lumbar stenosis. This chapter reviews a minimally invasive muscle-sparing approach to treating lumbar stenosis. The technique is performed through a tubular retractor. Direct decompression of the spinal stenosis is achieved while preserving the paraspinous muscle attachments and spinous process. This technique has multiple advantages and can potentially reduce load stress on adjacent levels and subsequent adjacent level pathology leading to further surgical intervention. In addition, the procedure shows how facet fusion is performed using the patient’s own locally harvested drilled morselized autograph to achieve bilateral facet fusion. By fusing the facets, we have shown that restenosis at the operative level is less likely to occur. This chapter will review a case series of multilevel lumbar stenosis including clinical outcomes.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Mick Perez-Cruet, Ramiro Pérez de la Torre and Siddharth Ramanathan"},{id:"80705",title:"Cervical Arthroplasty",slug:"cervical-arthroplasty",totalDownloads:37,totalDimensionsCites:0,doi:"10.5772/intechopen.102964",abstract:"Technological advances have allowed spine surgery to follow the trend toward minimally invasive surgery in general. Specifically, we have seen a corresponding rise in the popularity of cervical arthroplasty. For the treatment of cervical disc disease, arthroplasty is a less invasive option than the gold standard of cervical discectomy and arthrodesis, which by nature is more disruptive to surrounding tissues. Arthroplasty preserves the facets, maintains motion, and reduces the rate of adjacent segment breakdown. These factors counteract the negative impacts of fusion while maintaining the benefits. Arthroplasty implants themselves have become more streamlined to implant as well with less native bone destruction, and biomechanics more compatible with the native disc. While initial implants were ball and socket devices with complex fixation and plane-specific movements, later devices incorporated such motions as translation and compression. Viscoelastic components and materials more closely resembling native tissues afford a more biocompatible implant profile. Until cell-based therapies can successfully reproduce native tissue, we will rely on artificial components that closely resemble and assimilate them.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Jason M. Highsmith"},{id:"80605",title:"Minimally Invasive Treatment of Spinal Metastasis",slug:"minimally-invasive-treatment-of-spinal-metastasis",totalDownloads:42,totalDimensionsCites:0,doi:"10.5772/intechopen.102485",abstract:"Advancements in the treatment of systemic cancer have improved life expectancy in cancer patients and consequently the incidence of spinal metastasis. Traditionally, open spinal approaches combined with cEBRT (conventional external beam radiation therapy) allowed for local tumor control as well as stabilization and decompression of the spine and neural elements, but these larger operations can be fraught with one complications and delayed healing as well as additional morbidity. Recently, minimally invasive spine techniques are becoming increasingly popular in the treatment of spinal metastasis for many reasons, including smaller incisions with less perioperative complications and potential for expedited time to radiation therapy. These techniques include kyphoplasty with radiofrequency ablation, percutaneous stabilization, laminectomy, and epidural tumor resection through tubular retractors, as well as minimally invasive corpectomy. These techniques combined with highly conformal stereotactic radiosurgery have led to the advent of separation surgery, which allows for decompression of neural elements while creating space between neural elements and the tumor so adequate radiation may be delivered, improving local tumor control. The versatility of these minimally invasive techniques has significantly improved the modern management of metastatic disease of the spine by protecting and restoring the patient’s quality of life while allowing them to quickly resume radiation and systemic treatment.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Eric R. Mong and Daniel K. Fahim"},{id:"76620",title:"Minimally Invasive Lateral Approach for Anterior Spinal Cord Decompression in Thoracic Myelopathy",slug:"minimally-invasive-lateral-approach-for-anterior-spinal-cord-decompression-in-thoracic-myelopathy",totalDownloads:146,totalDimensionsCites:0,doi:"10.5772/intechopen.97669",abstract:"Myelopathy can result from a thoracic disc herniation (TDH) compressing the anterior spinal cord. Disc calcification and difficulty in accessing the anterior spinal cord pose an operative challenge. A mini-open lateral approach to directly decompress the anterior spinal cord can be performed with or without concomitant interbody fusion depending on pre-existing or iatrogenic spinal instability. Experience using stand-alone expandable spacers to achieve interbody fusion in this setting is limited. Technical advantages, risks and limitations of this technique are discussed. We conducted a retrospective chart review of all patients with thoracic and upper lumbar myelopathy treated with a lateral mini-open lateral approach. Review of the literature identified 6 other case series using similar lateral minimally invasive approaches to treat thoracic or upper lumbar disc herniation showing efficient and safe thoracic disc decompression procedure for myelopathy. This technique can be combined with interbody arthrodesis when instability is suspected.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Edna E. Gouveia, Mansour Mathkour, Erin McCormack, Jonathan Riffle, Olawale A. Sulaiman and Daniel J. Denis"}],onlineFirstChaptersTotal:12},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",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:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:"2753-6580",scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. 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from Tehran University of Medical Sciences, Iran. He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. 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