Parameters of the magnetic fluid.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"3761",leadTitle:null,fullTitle:"Theory and Novel Applications of Machine Learning",title:"Theory and Novel Applications of Machine Learning",subtitle:null,reviewType:"peer-reviewed",abstract:"Even since computers were invented, many researchers have been trying to understand how human beings learn and many interesting paradigms and approaches towards emulating human learning abilities have been proposed. The ability of learning is one of the central features of human intelligence, which makes it an important ingredient in both traditional Artificial Intelligence (AI) and emerging Cognitive Science. Machine Learning (ML) draws upon ideas from a diverse set of disciplines, including AI, Probability and Statistics, Computational Complexity, Information Theory, Psychology and Neurobiology, Control Theory and Philosophy. ML involves broad topics including Fuzzy Logic, Neural Networks (NNs), Evolutionary Algorithms (EAs), Probability and Statistics, Decision Trees, etc. Real-world applications of ML are widespread such as Pattern Recognition, Data Mining, Gaming, Bio-science, Telecommunications, Control and Robotics applications. This books reports the latest developments and futuristic trends in ML.",isbn:null,printIsbn:"978-3-902613-55-4",pdfIsbn:"978-953-51-5842-4",doi:"10.5772/56681",price:139,priceEur:155,priceUsd:179,slug:"theory_and_novel_applications_of_machine_learning",numberOfPages:388,isOpenForSubmission:!1,isInWos:1,hash:"2703f4beb52021731818c16292070f66",bookSignature:"Meng Joo Er and Yi Zhou",publishedDate:"January 1st 2009",coverURL:"https://cdn.intechopen.com/books/images_new/3761.jpg",numberOfDownloads:45817,numberOfWosCitations:25,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,hasAltmetrics:0,numberOfTotalCitations:25,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 22nd 2013",dateEndSecondStepPublish:"June 12th 2013",dateEndThirdStepPublish:"September 16th 2013",dateEndFourthStepPublish:"December 15th 2013",dateEndFifthStepPublish:"January 14th 2014",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"121367",title:"Dr.",name:"Er",middleName:null,surname:"Meng Joo",slug:"er-meng-joo",fullName:"Er Meng Joo",profilePictureURL:"https://mts.intechopen.com/storage/users/121367/images/system/121367.jpg",biography:"Professor Er Meng Joo is currently a Full Professor in Electrical and Electronic Engineering, Nanyang Technological University, Singapore. He served as the Founding Director of Renaissance Engineering Programme and an elected member of the NTU Advisory Board and from 2009 to 2012. He served as a member of the NTU Senate Steering Committee from 2010 to 2012.\n\nHe has authored five books entitled “Dynamic Fuzzy Neural Networks: Architectures, Algorithms and Applications” and “Engineering Mathematics with Real-World Applications” published by McGraw Hill in 2003 and 2005 respectively, and “Theory and Novel Applications of Machine Learning” published by In-Tech in 2009, “New Trends in Technology: Control, Management, Computational Intelligence and Network Systems” and “New Trends in Technology: Devices, Computer, Communication and Industrial Systems”, both published by SCIYO, 18 book chapters and more than 500 refereed journal and conference papers in his research areas of interest.\n\nProfessor Er was bestowed the Web of Science Top 1 % Best Cited Paper and the Elsevier Top 20 Best Cited Paper Award in 2007 and 2008 respectively. In recognition of the significant and impactful contributions to Singapore’s development by his research projects, Professor Er won the Institution of Engineers, Singapore (IES) Prestigious Engineering Achievement Award twice (2011 and 2015). He is also the only dual winner in Singapore IES Prestigious Publication Award in Application (1996) and IES Prestigious Publication Award in Theory (2001). Under his leadership, the NTU Team emerged first runner-up in the Freescale Technology Forum Design Challenge 2008. He received the Teacher of the Year Award for the School of EEE in 1999, School of EEE Year 2 Teaching Excellence Award in 2008, the Most Zealous Professor of the Year Award in 2009 and the Outstanding Mentor Award in 2014. He also received the Best Session Presentation Award at the World Congress on Computational Intelligence in 2006, Best Paper Award (First Prize) at the International Automatic Control Conference 2016 and Best Presentation Award at the IEEE International Conference on Intelligent Control, Power and Instrumentation (ICICPI) 2016. On top of this, he has more than 60 awards received at international and local competitions.\n\nCurrently, Professor Er serves as the Editor-in-Chief of 3 international journals, namely International Journal of Intelligent Autonomous Systems, Transactions on Machine Learning and Artificial Intelligence and the International Journal of Electrical and Electronic Engineering and Telecommunications. He also serves an Area Editor of International Journal of Intelligent Systems Science and an Associate Editor of 14 refereed international journals, namely IEEE Transaction on Cybernetics, Information Sciences, Neurocomputing, Asian Journal of Control, International Journal of Fuzzy Systems, ETRI Journal, International Journal of Humanoid Robots, International Journal of Modelling, Simulation and Scientific Computing, International Journal of Applied Computational Intelligence and Soft Computing, International Journal of Business Intelligence and Data Mining, International Journal of Fuzzy and Uncertain Systems, International Journal of Automation and Smart Technology, International Journal of Intelligent Information Processing and an editorial board member of the Open Automation and Control Systems Journal and the EE Times. \n\nProfessor Er has been invited to deliver more than 60 keynote speeches and invited talks overseas. He has also been active in professional bodies. Under his leadership, the IEEE CIS Singapore Chapter won the CIS Outstanding Chapter Award in 2012 (The Singapore Chapter is the first chapter in Asia to win the award). He was bestowed the IEEE Outstanding Volunteer Award (Singapore Section) and the IES Silver Medal in 2011. He is listed in Who’s Who in Engineering, Singapore, Edition 2013.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"252216",title:"Dr.",name:"Yi",middleName:null,surname:"Zhou",slug:"yi-zhou",fullName:"Yi Zhou",profilePictureURL:"https://mts.intechopen.com/storage/users/252216/images/system/252216.jpg",biography:"Research Areas:\nHuman-Machine Interfaces, Robotics, Automation & Control\nEducation\nPhD, Electrical & Electronics Engineering, Nanyang Technological University (NTU), Singapore, 2008\nB. Eng (First Class Hons.), Electrical and Electronic Engineering, Nanyang Technological University (NTU), Singapore, 2004\nAwards\nExcellent Teaching Journal Award, Singapore Polytechnic, 2011\n3rd Place of RoboCup World Champion Competition: Festo Logistics Competition, 2010.\nR&D Publication Award, School of Electrical and Electronic Engineering, Singapore Polytechnic, 2008.\nGold prize for the most popular research award in College of Engineering Exhibition (COE), NTU, 2006.\nBronze EEE Color Award, for excellent achievements in academe and activities NTU, 2004.\nCertificate of merit for publication award (student category, Institution of Engineers), Singapore, 2004.\n1st Class Freshman Award, Zhejiang University, China, 1999.\nResearch\nResearch Interests\n\nMachine learning\nFuzzy neural networks\nOptimization\nAutonomous and unmanned system\nRobotics\nMulti-agent system\nResearch Projects\n\nCollaborator/Co-PI for the RFID-based Autonomous Navigation of AGVs for Port Automation, MOE-TIF 2011-2013;\nPI for Tele-robotics system for education and assistive applications, Toteboard R&D model project, 2009-2011;\nCo-PI for Development of emotional expression system for social robots, Toteboard R&D model project, 2009-2011;\nCo-PI for Underwater robot swarm, Toteboard R&D model project, 2007-2010;\nPublications\nMeng Joo Er and Yi Zhou, Theory and novel applications of machine learning, book editors, published by Intechweb publisher, 2009.\nYi Zhou and Meng Joo Er: An evolutionary approach toward dynamic self-generated fuzzy inference systems, IEEE Transactions on Systems, Man, and Cybernetics, Part B, Vol. 38, No. 4, pp. 963-969, August, 2008.\nMeng Joo Er and Yi Zhou: Automatic generation of fuzzy inference systems via unsupervised learning, Neural Networks, Vol. 21, No. 10, pp. 1556-1566, December 2008.\nMeng Joo Er and Yi Zhou: A novel framework for automatic generation of fuzzy neural networks, Neurocomputing, Vol. 71, pp. 584-591, 2008.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"520",title:"Machine Learning",slug:"computer-and-information-science-artificial-intelligence-machine-learning"}],chapters:[{id:"6180",title:"A Drawing-Aid System using Supervised Learning",doi:"10.5772/6670",slug:"a_drawing-aid_system_using_supervised_learning",totalDownloads:1352,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Kei Eguchi",downloadPdfUrl:"/chapter/pdf-download/6180",previewPdfUrl:"/chapter/pdf-preview/6180",authors:[null],corrections:null},{id:"6181",title:"Supervised Learning with Hybrid Global Optimisation Methods. 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China",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/73132.pdf",downloadPdfUrl:"/chapter/pdf-download/73132",previewPdfUrl:"/chapter/pdf-preview/73132",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/73132",risUrl:"/chapter/ris/73132",chapter:{id:"72647",slug:"soil-erosion-influencing-factors-in-the-semiarid-area-of-northern-shaanxi-province-china",signatures:"Ning Ai, Qingke Zhu, Guangquan Liu and Tianxing Wei",dateSubmitted:"February 25th 2020",dateReviewed:"May 22nd 2020",datePrePublished:"June 29th 2020",datePublished:"March 24th 2021",book:{id:"8937",title:"Soil Moisture Importance",subtitle:null,fullTitle:"Soil Moisture Importance",slug:"soil-moisture-importance",publishedDate:"March 24th 2021",bookSignature:"Ram Swaroop Meena and Rahul Datta",coverURL:"https://cdn.intechopen.com/books/images_new/8937.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"313528",title:"Associate Prof.",name:"Ram 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in Healthcare",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe issues in healthcare today are exploding. Every week we hear about both advances and setbacks in various technologies--CRISPR-Cas- 9, genetic testing, drug-resistant diseases, organ transplantation, brain death, etc. Bioethicists need to work collaboratively with one another globally not only to address these critical issues but also to offer some guidance on how to move forward in the best interests of humanity. Scientists, politicians, public policy advocates, pharmaceutical representatives, business executives are all searching for answers that will address the medical, ethical, and legal issues facing humanity. The role of the Bioethicist is to identify challenges, analyze issues, collaborate with colleagues to coordinate possible positions, and then help to implement changes.
\r\n\r\n\tThis book will challenge those in the medical, legal, and ethical fields to perform these tasks for the common good of humanity. This is an ambitious agenda but one that must be undertaken so that the public is made aware of these issues and what can be done to reach viable conclusions.
\r\n\t
Magnetohydrodynamic (MDH) effect is a physical phenomenon that describes the motion of charge conducting fluid flowing which his influenced by an external magnetic field. Its applications have been studied extensively across multiple disciplines ranging from the study of solar winds [1, 2] to MHD-driven biomedical sensors [3] and actuators [4, 5, 6, 7]. This chapter narrows the focus of MHD applications to biomedical sciences. The chapter introduces four primary MHD biomedical applications: (1) magnetohydrodynamic-based laser beam scanning, (2) nanoparticle manipulations for biomedical applications, (3) biomedical imaging contrast enhancement, and (4) targeted drug delivery.
\nThis chapter aims to present the current state of the art in the field with regards to biomedical and clinical applications of the MHD effect.
\nAdaptive optics (AO) enables correcting of complex aberrations for a broad range of applications [1, 2]. Conventional AO systems use spatial light modulators [3, 4] or solid deformable mirrors (DM) [5, 6] to compensate the phase changes resulting from non-uniformity in the properties of the medium through which light travels or from faults in the geometry of the component. There is two types of spatial light modulators operating in reflective and transmission modes. Due to using small liquid crystals, this type of wavefront shaping able to provide very high spatial resolution. However, there is a limitation in the correction magnitude which is usually in the range of a few micrometers. To resolve this issue, solid deformable mirrors have been developed and adopted widely to correct wavefront in optical systems. It consists of a solid reflecting surface connected to an actuator structure. By controlling the actuators, the shape of the reflective surface can be changed to compensate the wavefront distortions. The high cost of the actuators and intricate fabrication process are the main problems of the solid deformable mirrors. The current solid deformable mirrors can only provide small inter-actuator strokes, with the maximum deflection in the range of tens of micrometers.
\nAO systems have been used in laser beam shaping [7, 8, 9] and eye imaging systems [10, 11, 12] to effectively address both the low-intensity high-order aberrations and the high-intensity low-order aberrations. For example, high-resolution retinal imaging using AO plays a vital role in vision science and will help the early clinical diagnosis of eye diseases. For dealing with the ocular aberrations for a large population, e.g., myopic eyes, adaptive optics using two deformable mirrors have been designed [10, 11, 12]. The large-stroke DM with a limited number of actuators is used to correct large-intensity low-order aberrations. The second DM with a low stroke and a high spatial correction resolution is used to address the small-intensity high-order aberrations. However, its application in ophthalmology is limited by the complexity and the high cost. A new type of liquid deformable mirror [13, 14, 15] has been designed based on the actuation of the magnetic fluid. Although the liquid mirrors are constrained to the horizontal setup, the magnetic fluid deformable mirrors (MFDM) offer large strokes, low cost, and easy fabrication. Using the single inter-actuator, the strokes more than 100 μm can obtain with less power consumption. However, to produce a large mirror surface deformation, the size of the electromagnetic coils needs to be large. This makes the density of actuators low, and it is not suitable for high-order aberrations. A full-order correction with the high spatial resolution is achieved using a two-layer design layout with small electromagnetic coils has been designed. New wavefront corrector, MFDM, has major advantages such as large stroke, low cost, easy fabrication process, which can be easily customized for different applications. In the following sections, we will explain the technology and possible applications in
The main elements of the MFDM are a layer of magnetic fluid, a thin film of a reflective material coated on the free surface of the fluid, a two-layer layout of the miniature electromagnetic coils placed beneath the fluid layer, and a Maxwell coil(s) (see Figure 1). The properties of the magnetic fluid used in the study are given in Table 1. Based on the definition, the magnetic fluid is a stable colloidal suspension of nano-sized, single-domain ferri/ferromagnetic particles. The fluid can be coated with a silver liquid-like thin film to improve the reflectance.
\nSchematic design of the magnetic fluid deformable mirror (MFDM) (adapted from [
Magnetic fluid | \nParameters | \n
---|---|
Saturation magnetization | \n22 mT | \n
Relative permeability | \n2.89 | \n
Density | \n1190 kg/m3\n | \n
Viscosity | \n3 cp | \n
Thickness | \n1 mm | \n
Parameters of the magnetic fluid.
To achieve the correction of full-order aberrations with a high spatial resolution, the new design of MFDM is presented (see Figure 1 for the details). The upper layer actuators of small size and high density are used to compensate for small-amplitude high-order aberrations, and the lower layer actuators with big size and low density are used to correct for large amplitude low order aberrations. The electromagnetic coils are circular coils wound on a cylindrical core. Table 2 shows the physical parameters are of the coil. Each layer of the coil is arranged in a hexagonal array. The upper layer coils are radially spaced at 2.1 mm from the center to center, and the lower layer coils are radially spaced at 4.2 mm, respectively.
\nMagnetic fluid | \nParameters | \n|
---|---|---|
Position | \nUpper | \nLower | \n
Core-type | \nAir-cored | \nAir-cored | \n
Material | \nCopper | \nCopper | \n
Wire gauge | \nAWG37 | \nAWG36 | \n
Internal diameter | \n1 mm | \n2 mm | \n
External diameter | \n2 mm | \n4 mm | \n
Length | \n1 mm | \n8 mm | \n
Parameters of the miniature electromagnetic coil.
AWG, American wire gauge.
To make the response of the actuators linear, the Maxwell coil was used to apply an external uniform magnetic field. The Maxwell coil consists of three individual coils, where both lateral/outer coils should have a radius of \n
Magnetic fluid | \nParameters | \n
---|---|
Nominal diameter of the middle coil | \n200 mm | \n
No. of turns in the middle coil | \n1152 | \n
No. of turn in the top and bottom coil | \n883 | \n
Average resistance of the middle coil | \n71.2 Ω | \n
Average resistance of the coils | \n42.3 Ω | \n
Wire gauge | \nAWG 25 | \n
Wire material | \nCopper | \n
Bobbin material | \nAluminum | \n
Parameters of the Maxwell coil(s).
\nFigure 2 shows the fabricated mirror in which two-layer layout of the coils are installed within the Maxwell coil. Ferrofluid with layer thickness of about 1 mm is placed on top of the miniature coils, which is coated with the thin silver liquid-like film.
\nAssembly of the prototype MFDM (adapted from [
The MFDM is demonstrated by a cylindrical layer of a magnetic fluid as shown in Figure 3. The top free surface of the fluid layer is coated with a reflective film to be the deformable surface of the mirror. The surface deflection at the point (rk, θk) is indicated by ζ(rk, θk, t), where k = 1, 2, 3, …, k is a discrete number of surface points. The magnetic field produced by any specific coil, centered at the horizontal location (rij, θij), is idealized as that of a point source of magnetic potential ψij(t), where i = 1, 2 is the
Geometric representation of a circular MFDM (adapted from [
Maxwell’s equations govern the magnetic field. Since the magnetic field of the miniature coils is taken as point sources of magnetic potential located at the fluid boundary, electromagnetic field can be considered as a current-free one. Using this assumption, the displacement currents in the fluid are negligible, Maxwell’s equations can be written as:
\nwhere
\n
where
Using Eqs. (2)–(4), the magnetic flux density \n
The magnetic flux intensity (B) meets the principle of superposition. Assume the fluid is irrotational, then based on the principles of conservation of mass and momentum and the theories on magnetic fields, the perturbation part of the surface dynamic governing equations can be written as [19].
\nwhere
The solutions concerning the input ψij(t) thus are obtained as follows:
\nwhere Jm(·) is the Bessel function of the first kind,
Considering that the miniature coils are located far from the walls of the fluid container, so at
For any coil
where
\n\n
The main idea of the derivation of Eq. (18) is similar to the result of MFDM with a single-layer layout of actuators and more details can be found in [19]. A similar set of equations can be obtained concerning the mode shape
where m and
The generalized displacements \n
\nEqs. (18)–(19) show that the surface response
This section introduced the current method to improve the correction performance of the MFDM for full-order aberrations, a new MFDM with a two-layer of actuators.
\nThe application of magnetic nanoparticles (NPs) has been extensively studied in biomedicine such as in imaging contrast enhancement [21] (see more detail in Section 4), magnetic separation [22], hyperthermia treatment [23], and targeted drug delivery [24] (see more detail in Section 5).
\nDue to their size, NPs can interact with biological systems at the molecular level and pass through biological barriers [24]. Using an external magnetic field to manipulate and to guide magnetic NPs to the wanted location has obtained special attention.
\nSeveral studies describe different magnetic nanoparticles as well as different delivery techniques [25]. Magnetite NPs (e.g., Fe3O4) are the most widely used due to several appealing properties [26]. This type of NPs exhibit superparamagnetism which means that they do not have magnetic moment when there is no external field but become magnetized when an external magnetic field is applied. This property is of great value for a variety of biomedical applications as magnetite NPs do not form into a mass together and can move easily through blood vessels [26]. The typical shape of these NPs is a sphere with the size of around 5–100 nm. Most importantly, Fe3O4 NPs are biocompatible which makes it suitable for many biomedical applications [27].
\nCurrently, one of the leading research interests is associated with the delivery of magnetic NPs to a target location. Several approaches have been proposed to address the issue. For example, the surface of magnetic NPs has been modified with biomolecules to identify and attach to target cells. Also, injection of magnetic NPs to some localized regions has been suggested [28]. Furthermore, using an external force to control the NPs in the desired direction remotely has been proposed [29]. When an electric current passes through the micro-coils, it generates a non-uniform magnetic field which attracts the NPs at its minimal. The magnitude of the magnetic field
As an example, this method [32] is used for focusing and selective destruction of red blood cells (RBCs) via magnetic NPs. The experiment was accomplished above the micro-electromagnet serving concurrently as a source of the magnetic field and as a local heater. The motion and focusing of the blood cells near wires which carry the electric current were observed in the previous study. It was also found that the increase of the electric current through the micro-electromagnet leads to the local cell hemolysis. All the previous results have been obtained for the case when the guiding magnetic field was produced by just one conducting contour. In this work, experimental data was obtained for the modified micro-electromagnet with two contours, where the current in each path can be individually controlled. This modification gives an extra degree of freedom to tune the magnetic field profile and to manipulate magnetic nanoparticles.
\nThe schematics of the micro-magnetic prototype with biological substance and the external electric circuit are shown in Figure 4(A). The device is fabricated on the top of a fused silica substrate. It consists of two Cu wires fabricated by standard optical lithography techniques. The width of the wires is 10 μm, and the height of the wires is 2 μm. The minimum spacing between the wires is 20 μm. Each of the two wires has individual contacts (1 mm × 1 mm) on the sides of the structure for connection with the outer electric circuit. The circuit includes a power source and two electrical relay switches allowing for the individual control of electric current in each wire. The wires are covered by a 300 nm thick layer of silicon dioxide deposited via PECVD which allows for both electrical insulations as well as corrosion protection for the Cu wires. The top part of the structure is the working area where the manipulation of biological cells takes place. As a test biological substance, human red blood cells (RBC) are obtained from fresh blood samples. RBC was selected both due to their availability as well as their robustness [33]. Samples were prepared by triple washing using centrifugation at 2000 rpm on an Eppendorf 5424 centrifuge in phosphate buffered saline solution (PBS) at room temperature. PBS was prepared from 10× PBS (Fisher Scientific, USA) concentrate solution with a final concentration of 2000–4000 cells/μl. From this RBC solution, 30 μl of the solution are then mixed with 1 μl of commercially available ferrofluid from Ferrotec containing 1.1% magnetite (Fe3O4) particles in aqueous solution.
\n(A) Schematics of the micro-electromagnet and the external electric circuit. The device is fabricated on the top of a fused silica substrate. It consists of two Cu wires fabricated by optical lithography. The width of the wires is 10 μm, and the height of the wires is 2 μm. The wires are covered by the 300 nm of silicon dioxide. The top part of the structure is the working area where solution with biological cells and magnetic nanoparticles is placed. (B) Results of numerical modeling showing the surface profile of the scaled magnetic energy B2 produced by the current-carrying wires. The red and the black curves show the scaled magnetic energy when 100 mA electric current is flowing through one of the contours. The blue curve shows the scaled magnetic energy when an electric current is flowing through both contours (adapted from [
The electric current passing through the wire generates a non-uniform magnetic field around it. The gradient of this non-uniform magnetic field causes the magnetic NPs to be attracted towards the wires. Therefore, the movement of magnetic NPs pulls biological cells in the same direction [32]. Figure 4(B) shows the numerical results of the magnetic energy above the two straight wires. The red and black curves show the magnetic energy when the current is 100 mA in one of the wires. The blue curve shows the magnetic energy when the current passes through both wires. There is an overlap between the magnetic fields in the region and the wires (as depicted by the red dashed line in Figure 4(B)). This overlap is important for sequential trapping of magnetic NPs by applying a current through one or the other wires. The maximum of the field gradient is about 1.4 mT/μm in the vicinity of the current-carrying wire.
\nThe individual control of electric current (hence magnetic field) in the two contours allows for a variety of experiments to be conducted on biological cell manipulation. This application shows that the biological cell manipulation is possible due to the presence of magnetic nanoparticles. To support this statement, some studies performed control experiments with RBC samples without adding magnetic nanoparticles [34]. It is shown that applying a magnetic field without nanoparticles initiates a slight motion of RBCs away from the field source which is attributed to local heating and the expanding solution. However, when the study is conducted by adding 1.1% magnetic nanoparticles, applying the magnetic field results in the cells focusing near the field source. The focusing is attributed to the drag effect, where a flow of magnetic nanoparticles drags the cells in the same direction. The potential application of this is that with time-varying magnetic field one can move RBCs towards or away from the specific region. This technique can be further evolved for precise controlling of cellular motion and drug-carrying cells. There are many questions related to the mechanism of magnetic nanoparticles interaction with living cells which deserve separate studies and it is out of the scope of this chapter. Nanoparticle manipulation using magnetic field potentially may be useful in various areas including molecular biology, medicine, gene engineering, and drug delivery technology.
\nMHD plays an important role in biomedical imaging, ranging from magnetic resonance imaging (MRI) that employs the endogenous magnetization contrast of water in tissue to magnetofluids acting as contrast agents in a number of imaging modalities. These contrast agents enhance the ability to detect tumors, infection, inflammation, infarction or lesions in the body. This section highlights the role of magnetic fluids as contrast enhancing agents in MRI, X-ray computed tomography (CT) and optical coherence tomography (OCT) imaging.
\nMRI is one of the major biomedical applications of MHD. MRI is a non-invasive tomographic medical imaging technique based on nuclear magnetic resonance (NMR) that provides high-resolution images of soft anatomical structures such as brain, heart, ligaments, and eyes [35, 36, 37, 38, 39, 40, 41]. This information is vital in delineating healthy from diseased tissues or organs. MRI takes advantage of the inherent magnetic dipole moments of the atomic nuclei in our bodies, specifically hydrogen nuclei contained in water—that makes about 70% of our body mass. Three magnetic fields comprising of a static magnetic field (SMF), a time-varying gradient magnetic fields (GMF) and a pulsed radiofrequency field (RF) are used to probe the magnetization/demagnetization map of the body. The water molecules that occupies most of the tissue in the body consist of hydrogen atoms with nuclei that possesses a quantum-mechanical spin. The hydrogen nucleus spin is associated to a magnetic dipole moment (Figure 5(A)) that gets aligned to a strong magnetic field
(A) The hydrogen nucleus possesses a quantum-mechanical spin (angular momentum) that is associated with a magnetic dipole moment. (B) When the body is placed in a strong magnetic field B0, the hydrogen nuclei dipoles get aligned with the field B0 with a net magnetization vector MZ0. The dipoles precess around the axis of the magnetic field with an angular frequency that follows Larmor equation
(A) When a 90° RF pulse is applied to the aligned magnetic dipoles, the net magnetization gets tipped to the transverse xy-plane. Dephasing of the spins results in a quick decrease of the net magnetization in the xy-plane MT. The dephasing occurs exponentially and characterized by T2. (B) After the pulsed magnetic field is removed, the longitudinal magnetic field MZ begins to grow exponentially to a maximum of MZ0; this growth is characterized by a parameter called T1, which the time it takes for the net magnetization along B0 to grow to 63% of the maximum value MZ0.
Tissue/organ contrasts in MRI arises from differences in mainly these two basic physical parameters: the difference in the spin-relaxation time
(A) The T1 relaxation time, known as the spin-lattice relaxation time, is the measure of how fast the net magnetization vector (NMV) occurs along the SMF. Different tissue in the body possesses different T1 relaxation times (a) which act as a contrast for the different tissue and even of diseased tissues such as tumors. (B) T2 relaxation refers to the progressive dephasing of spinning dipoles following the 90° pulse as seen in a spin-echo sequence due to tissue-particular characteristics (b).
Magnetic fluids play an important role as contrast enhancing agents in MRI. These contrast agents serve to shorten the relaxation time of the water molecules surrounding the tissue or organs with the contrast agent molecules, which then increases the signal intensity detected and thereby providing a positive contrast. The contrast agents used in MRI can broadly be divided into two major categories: the
Compounds | \nTrade name | \nTarget organs and tissue | \nReference | \n
---|---|---|---|
\n | \n|||
Gadopentetate dimeglumine (Gd-DTPA) | \nMagnevist®\n | \nGlioma | \n[46, 47] | \n
Gadoterate meglumine (Gd-DOTA) | \nDotarem®\n | \nBrain and spine | \n[48] | \n
Polyamidoamine | \nDendrimer®\n | \nAngiography and tumor differentiation | \n[49] | \n
Gadoxetate disodium (Gd-EOB-DTPA) | \nPrimovist®\n | \nLiver | \n[50] | \n
Gadodiamide (Gd-DTPA-BMA) | \nOmniscan®\n | \nBlood vessels | \n[51] | \n
Gadobenate dimeglumine (Gd-BOPTA) | \nMultiHance®\n | \nLiver | \n[52] | \n
Gadoteridol (GD-HP-DO3A) | \nProHance®\n | \nBrain and spine | \n[53] | \n
Gadoversetamide (C20H34GdN5O10) | \nOptiMARK®\n | \nBrain, spine, and liver | \n[54] | \n
Gadobutrol (Gd-BT-DO3A) | \nGadovist®/Gadavist®\n | \nAngiography | \n[55] | \n
Gadocoletic acid trisodium | \nGadocoletic acid | \nAngiography | \n[56] | \n
Gadomelitol | \nVistarem® (Gadomelitol) | \nAngiography | \n[57] | \n
Gadoteric acid (Gd-DOTA) | \nClariscanTM | \nBrain and spine | \n[58] | \n
\n | \n\n | ||
Ferumoxide (AMI-25) (Fe3O4·γFe2O3) | \nFeridex®\n | \nLiver, spleen, Bone marrow | \n[59, 60] | \n
Ferumoxsil (AMI-121) (Fe3O4·γFe2O3) | \nLumirem®\n | \nLiver, spleen, gastrointestinal tract | \n[61] | \n
Ferumoxtran (Fe3O4·γFe2O3) | \nSinerem®\n | \nLymph nodes, blood | \n[62] | \n
Ferrixan (Fe3O4) | \nResovist®\n | \nLiver | \n[63] | \n
Commonly used MRI contrast agents for medical diagnosis.
Computed tomography (CT) is a powerful non-invasive diagnostic imaging technique [64]. CT can be employed for imaging hard organs or tissues (e.g., bones) or soft ones such as the gastrointestinal (GI) tract, the cardiovascular system, renal tract, liver, lungs, cartilage, and tumorous tissue with the aid of contrast agents. A CT image is obtained by rotating an X-ray source(s) (or detector/detector array) around an object or vise verse, with a detector(s) positioned directly opposite the radiation source(s). Generally, X-ray scans are taken at small angular increments during rotation around the object over 360° or 180° [65]. An X-ray attenuation (or phase or scattering) map or projections are thus obtained. The projections are then processed mathematically to create a 3D rendering of the scanned object.
\nAnother diagnostic imaging method related to CT is X-ray fluoroscopy—form of a projection imaging with contrast agent. Fluoroscopy allows for the acquisition of real-time, continuous images of the internal organs. Like in MRI, imaging contrast agents are often used in X-ray imaging for better contrast resolution. Usually, small iodinated agents are injected into blood vessels for use in fluoroscopic angiography, allowing for the evaluation of blood flow and visualization of the vasculature system, while barium contrast media are introduced orally or with an enema to investigate the anatomy (and pathology) of the gastrointestinal tract. The X-ray absorption coefficient \n
Compound | \nTrade name | \nTarget organ | \nReference | \n
---|---|---|---|
1. Gadopentate dimeglumine (Gd-DTPA) | \nMagnevist®\n | \nUrinary tract, aorta, blood vessels in cranium | \n[68, 69] | \n
2. Gadodiamide (Gd-DTPA-BMA) | \nOmniscan®\n | \nArterial angiography, | \n[70] | \n
3. Gadoteridol (Gd-HP-DO3A) | \nProHance®\n | \nAorta, brain tumors, | \n[71] | \n
4. Gadobutrol (Gd-BT-DO3A) | \nGadovist®\n | \nAlternative to iodinated agents | \n[72] | \n
5. Gadoxetate disodium (Gd-EOB-DTPA) | \nPrimovist®\n | \nLiver, spleen, urinary tract | \n[73] | \n
Lanthanide-based contrast agents for CT and X-ray.
where \n
While lanthanide-based contrast agents are a common stay in MRI, their application in CT as contrast agents is being explored based on their high atomic numbers [64]. The two major reasons motivating the investigation of gadolinium-based compounds as CT contrast agents include use in patients who are contraindicated for iodinated agents based on allergic reactions or renal insufficiency and the fact that
OCT is non-invasive cross-sectional imaging modality that uses light to interrogate tissue providing a 3D rendering of the tissue under investigation [74]. Figure 8 depicts the principle of OCT. A low-coherence light from a laser source is split into two halves, with one half guided to a mirror (reference arm) and the other half used to illuminate the tissue under investigation (sample arm). The reflections from the reference arm and from the tissue are recombined by beam combiner and detected. The electrical signal from the photodetector is bandpass digitized and demodulated before being stored on a computer. The low-coherence in the light being used allows for interference between the two arms to occur only when the two optical path lengths are equal. Therefore, fine scanning of the reference arm mirror allows for interference to occur with light originating from the different depths of the tissue. Transverse scanning of the optical beam then allows for a 3D imaging of the tissue [75].
\nSchematic illustrating the concept of low coherence interferometry. Using a short coherence length light source and a Michelson-type interferometer, interference fringes are observed only when the path lengths of the two interferometer arms are matched to within the coherence length (lc) of the light source (adapted from [
The ability of a tissue to be magnetized is quantified as magnetic susceptibility \n
where
As shown in Figure 9, when the magnetic nanoparticles get laterally displaced by the magnetic force, the OCT the increase in the light scattered back also gets shifted laterally. Figure 9(B–D) shows the variation in the OCT signal variation that follow changes in the nanoparticles position arising from the magnetic force.
\nMagnetomotive OCT tissue configuration. (A) A sample is doped with magnetic microparticles, placed in a magnetic field and shone with an optical imaging beam. The contrast mechanisms illustrated by two states of a magnetic microparticle (filled and dash-outlined shapes, respectively) within the imaging focal volume and the associated (A–D).
As it was initially assumed by Widder et al. in 1978 [78], magnetic constructs can target specific locations, such as tumor sites, holding enormous potential for site-specific drug delivery, see Figure 10. This subchapter discusses a clinically driven application of MHD focusing on magnetic drug targeting. MHD drug targeting refers to the magnetically targeted and/or triggered therapeutic agent delivery method that augments the concentration of the agent in the target area. In the first part, drug-loaded magnetic constructs are discussed as individual intra-vascular vehicles for site-specific drug delivery. In the second part, magnetohydrodynamic (micro) pumps for controlling magnetic nanoparticles dispersed in a base fluid are discussed. These are reviewed and summarized separately based on the knowledge already available in literature.
\nMagnetic constructs (A) or constructs with evenly distributed magnetic material (B) applied parenterally (intravenously or intra-arterially), can be used as intravascular vehicles for targeted drug delivery if drug-loaded (C) or -coated (D).
Due to their superior properties such as biocompatibility, biodegradability, large loading capacity, and controlled release ability, magnetic constructs have attracted a lot of attention. They offer mean to remotely direct therapeutic agents to well-localized sites of interest, improving control on dosing, reducing the concentration requirements up to 20% [79], associated toxicity, and fluctuation in circulating drug levels [80, 81, 82]. While drug release usually occurs by passive diffusion, triggering via enzymatic activity, physiological conditions [83] or magnetically [84, 85, 86], see Figure 11, can be performed. On-site controlled drug release is another important factor for effective therapeutics. For example, when the magnetic construct is exposed to an alternating magnetic field, drug release can occur. Via facilitated drug release, collateral tissue damage and toxic side effects may be further decreased or fully eliminated [87, 88]. This is important for applications balancing between efficacy and toxicity, e.g., chemotherapies [89].
\nTargeted drug release.
The use of magnetic constructs as therapeutic agents has increased exponentially since the earliest studies by Senyei et al. [90] and magnetic carriers of increased sophistication have been developed [91]. While nanoparticles are the simplest magnetic constructs, currently, there are many different types of carriers for magnetic targeting. Generally, any biocompatible magnetic materials, magnetic materials coated by a biocompatible polymer or inorganic material, or magnetic materials precipitated inside the pores of a biocompatible polymer or inorganic material can be used. While the use of iron oxide particles in the form of magnetite (Fe3O4) or maghemite (γ-Fe2O3) predominates, any metal, e.g., cobalt or nickel, or metal derivatives, e.g., μ-oxo N,N′-bis(salicylidene)ethylenediamine iron-Fe(salen) [92, 93, 94], are used. Magnetic constructs can be porous or hollow single magnetic nano/microparticles encapsulating the drug in pores and cavities [95], non-magnetic polymeric or inorganic nano/microparticles encapsulating both magnetic material and drug [96], magnetosomes [97], micelles [98] or liposomes, micro/nanoswimmers or micro/nanomotors prepared by layer-by-layer deposition [99] or 3D-printing [100], nanoparticle clusters [96, 101].
\nThe basic principle of magnetically targeted drug delivery is based on the physical phenomenon of the translational motion of a magnetic construct when a magnetic field gradient is applied. Magnetic construct with a therapeutic agent encapsulated into the construct and/or conjugated on its surface is injected systemically (or delivered locally via catheter) and transported by the blood circulation to the target location. While intravenous injection is associated with higher clearance from the bloodstream, it is being used more frequently when compared to the intra-arterial routes. A strong, high-gradient magnetic field is then applied to allow translating magnetic constructs to the target location and capturing them. Literature suggests that flux density at the target location must be of the order of a few hundred millitesla with a few teslas per meter field gradient for slow blood flow arteries and up to a few hundred for fast blood flow arteries.
\nMagnetic constructs are driven by the magnetic force \n
where \n
In the case of supermagnetic constructs in a diamagnetic base solution, the magnetic moment
where \n
Under the assumption that magnetic constructs are very small and could be assumed to be point-like particles:
\nOn the one side, the magnetic force \n
In order to increase magnetic force up to several orders of magnitude further, magnetizable implant (biocompatible wire, needle, stent, filament or seed) creating a high-gradient magnetic field at the target location under the influence of an external magnetic field could be used, see Figure 12 [104]. While implant can solve problem of magnetic force strength and distance decay, as well as being successfully used at MRI facilities in applications related to cardiovascular, digestive and urinary systems under clinically feasible conditions, it makes the procedure of magnetic drug targeting minimally invasive. The concept has been successfully demonstrated
Implant-assisted magnetic drug targeting with the magnetic stent implanted in the vasculature.
Although magnetic drug targeting is appealing, most studies demonstrate only
The concept of MHD (micro)pump is relatively new and was developed by Jang and Lee [112] only in 1999 with an initial goal of applying in drug delivery applications. The working fluid of MHD (micro)pump is magnetic fluids. The term nanofluid was previously introduced by Choi and Eastman [113] in 1995 and describes colloidal suspensions of magnetic nanoparticles or nanotubes (dØ < 100 nm) in a based solution e.g., water, oil, ethylene glycol mixture etc. Magnetic fluids, also called ferro- or nano-fluids, simultaneously exhibit liquid and magnetic properties, leading to the possibility to control their flows with magnetic fields.
\nIn a typical setup, see Figure 13, a uniform magnetic field of strength
Schematic of MHD (micro)pump (A) and its simplification (B). When an electric potential difference V is applied between the electrodes, an electric current circulates through the electrically conducting magnetic fluid perpendicularly to the uniform magnetic field of strength B so that driving Lorentz force F is produced.
Magnetic separation. Left: while magnetically labeled objects (yellow) are attracted by the magnet, non-magnetic objects (gray) and base fluid can be filtered out. Right: after removing the magnetic force captured objects are recovered.
Schematic of the polydimethylsiloxane (PDMS)-glass microfluidic chip for the liquid-metal-based magnetohydrodynamic (MHD) micropump (adapted from [
Magnetic separation is being used in many biomedical applications, particularly cellular separation [121]. It is achieved via labeling the desired biological entity, e.g., red blood cells, with biocompatible magnetic nanoparticles. Labeled objects are separated from the base solution by passing the mixture through a high magnetic field gradient immobilizing the labeled entities via the magnetic force:
\nwhere \n
In this section, we describe some of the applications of MHD such as pumps, integrated fluidic networks, stirrer, and micro-coolers.
\nOne the best-known application of MHD is in the field of fluid pumping. The device consists of a conduit with two electrodes on either side. When a potential difference is applied across the electrodes, current flux
Below is an example of MHD-based micro-pumped on PDMS platform.
\nIn lab-on-chip applications, it is often necessary to transport fluids and reagents across networks of conduits. Controlling the flow usually requires the use of pumps and valves. It is hard to implement mechanical pumps and valve in a lab-on-chip setting. MHD provides a proper solution that does not require a mechanical component. The basic idea is to equip many of the network’s conduits, if not all, with individually controlled electrodes. By careful control of the electrode’s currents and in the presence of a magnetic field, it is possible to direct the fluid flow along any desired direction [123, 124].
\n\nFigure 16 shows a simple example of an MDH microfluidic network fabricated using low temperature co-fired ceramic tapes (LTCT). By programming, electrodes can circulate the fluid around the tours at any desired direction and even maintain their temperature allowing for various biological processes like thermal cycling and potentially polymerase chain reaction (PCR) for DNA amplification.
\nA prototype of an MHD microfluidic network. The conduits are labeled with numbers (adapted from [
Although the characteristic lengths associated with the microfluidic devices are small (e.g., in the order of 100 μm), diffusion alone does not allow sufficiently fast mixing. For example, at room temperature, myosin’s diffusion coefficient in water is about 10−11 m2/s, and the diffusion time along with a length of 100 μm is very large, about 103 s. Since Reynolds number (
MHD provides us with rather easy means for mixing and stirring. Two different types of MHD stirrers have been reported in the literature. One relies on altering the flow direction to enhance dispersion [126, 127], while another type induces secondary flows to improve the mixing. For more details, refer to [126, 127].
\nIn the current studies, it is shown that MHD is very suitable for providing better stirring in the microfluidic setting.
\nSince MHD can facilitate fluid circulation, it can be used to facilitate cooling. Liquid metals are particularly suitable for this purpose due to their high thermal conductivity, high boiling point temperature, ad large electric conductivity. Since MHD propulsion is easy to implement, miniaturize and does not require mechanical components, it is ideal for micro-cooling applications, such as those required in microelectronics. Although various patents address MHD micro-coolers, it is not known whether any products are in actual use.
\nIn summary, this chapter covers important aspects of the MHD applied in the biomedical field. A new MFDM with the two-layer layout is proposed to improve the correction performance of the DM for full-order aberrations. The results showed the effectiveness of the method to correct full-order aberrations for adaptive optics systems. Furthermore, RBC manipulation by the magnetic field is demonstrated via an external magnetic field produced by a system of two current-carrying wires. It is shown that cell motion towards and away from the wires, as well as periodic motion in the region between the wires. This approach will likely have application in various fields including molecular biology, medicine, gene engineering, and drug delivery technology.
\nMHD plays an integral part in biomedical imaging, ranging from the endogenous magnetization properties of tissue that play an important role in MRI imaging to the ferromagnetic/superparamagnetic fluids that act as contrast enhancing agent in several imaging techniques such as MTI, CT/X-ray and OCT imaging. Several commercial contrast agents are in clinical use today. Research continues to be undertaken on new contrast agents and on the utility of MRI contrast agents in areas such as CT/X-ray and OCT imaging.
\nMoreover, the same magnetic constructs allow for a combination of enhanced diagnostic imaging (MRI, CT, OCT) and therapeutics (targeted drug delivery). While some technical challenges remain, several drug delivery systems have been successfully developed for treatment of pulmonary disorders, cancer, and cardiovascular diseases. At the end, we briefed current MHD-based devices with potential biomedical applications. MHD-based microfluidics operates at low voltages, can direct the liquid to flow along any desired path without a need for valves and pumps, and continuously circulate the sample in a closed loop, and furthermore can chaotically stir the sample without moving part.
\nAuthors do not have a conflict of interest.
We are witnessing a new era in the treatment of HCV infection due to the development of DAAs that allows to cure a chronic disease without an effective vaccine. The therapy with pegylated interferon and ribavirin is no longer the standard of care. Unfortunately, there is a gap between these advances and the real access to treatment for patients in low- and middle-income countries (LMIC). In Latin America, the main identified barrier to access to hepatitis C treatment was for long a time the high price of these DAAs. While this issue has not yet been fully resolved, it has become evident that there are other gaps that need to be attended in order to undertake a comprehensive viral hepatitis elimination effort [1]. In this chapter, we propose to portray the main challenges that have not allowed fulfilling this purpose and present new strategies that could contribute toward addressing this health challenge.
\nChronic HCV infection is a health problem that affects more than 71 million people worldwide. HCV is associated with several hepatic pathologies, including cirrhosis and hepatocellular carcinoma as well as many other extrahepatic manifestations that are a major cause of global health burden [2].
\nThe real incidence of hepatitis C and cirrhosis in Latin America is unknown. It has been estimated that at least 10 million Latin Americans may be infected with HCV [3, 4]. In some Latin American countries that provided national data, cirrhosis death rates were between 5 and 17/100,000 for men and 3 and 5/100,000 for women [5].
\nLiver cirrhosis mortality trends vary widely among countries in Latin America. Mortality rates increased in Costa Rica, Guatemala, Honduras, and Paraguay, but fell in Chile, Mexico, and Argentina. In 1980, age-standardized cirrhosis mortality rates in Chile and Mexico were, respectively, 53.4 (43.6–67.9) per 100,000 and 45.9 (35.6–57.0) per 100,000, the highest in the region. In 2010, Mexico remained the country with the highest cirrhosis mortality rate in the region, at 38.3 (30.7–47.5) per 100,000. Liver cirrhosis was the fourth leading cause of death in Mexico in 2010, accounting for 18% of deaths in males aged 40–49 years [6]. Disability, quality of life, and social aspects should be considered when assessing the impact of the disease.
\nOverall updated population-based epidemiological studies of viral hepatitis in most Latin American countries are still a significant challenge. This barrier is crucial to define health policies in the region [7]. There is a paucity of epidemiological data from rural areas where a significant percentage of the population resides. Most data are focused on seroprevalence of the disease, and studies are typically cross-sectional in design. Most of the studies have been conducted in select populations and do not allow to gain the real prevalence and incidence of HCV infection.
\nEfforts have been made to model the disease in some countries of the region, such as Mexico, Brazil, Argentina, and Chile. All of them indicate that if the number of patients identified and treated do not increase over the years, HCV-related morbidity and mortality are expected to increase, and the impact on the development of liver cirrhosis and hepatocarcinoma may be overwhelming [8].
\nIn Mexico, for example, with the majority of cases arising from transfusion prior to the implementation of blood screening protocol, the annual number of HCV infection was estimated to peak in the mid-1990s. The annual number of new cases was estimated at 5620 new cases in 2013 [9].
\nIn 2013, the total number of viremic infections was estimated at 560,700 (326, 900–605,200), and it was forecasted to decrease to 406,100 viremic infections in 2030. The number of HCC cases in 2013 was estimated at 2660 cases, and it was forecasted to increase by 55% by 2030. The number of liver-related deaths will increase by 55% from a base of 2370, while decompensated cirrhosis and compensated cirrhosis infections will increase 55 and 40% from a base of 6750 and 54,460 in 2013 [9].
\nIn Argentina, there were an estimated 342,300 (155,000–537,000) infected individuals in 2013. Prevalence is estimated to have peaked at 382,700 patients in 2002 and to decline to 237,000 by 2030. There will be 62,630 compensated cirrhotic patients in 2030 as compared to 37,110 in 2013. In addition, there will be 3510 cases of HCC, and 8470 patients will be progressing to decompensated cirrhosis by 2030. Liver-related deaths in 2030 will number 3060 as compared to 1550 deaths in 2013. In 2013, 13% of viremic cases are estimated to have compensated cirrhosis or more advanced liver disease (decompensated cirrhosis, HCC, or transplant), while this proportion will increase to 32% in 2030 [9].
\nThis type of epidemiological pattern is most likely to occur in the different countries through Latin America unless diagnostic and treatment rates of the HCV infection are increased.
\nWorldwide, the number of people that are aware of the diagnosis of hepatitis C is low. One of the challenges with diagnosing HCV infection is that it is often asymptomatic and that individuals seek medical attention only when they develop symptoms or signs of liver disease. In Mexico, for example, the average age at diagnosis of hepatitis C is 60.7 years, and 44% of them have liver cirrhosis, indicating that patients are arriving late for diagnosis and treatment [10, 11, 12].
\nScreening for HCV infection is central for identifying unknown cases. The early diagnosis of HCV infection can help to reduce the burden of disease and limit transmission to those at risk of infection or reinfection. Screening is critical to achieving the WHO targets by 2030 [13].
\nA high percentage of HCV-infected people lives in countries with limited resources to screen and treat hepatitis C. Latin America needs to overcome numerous challenges such as the lack of awareness among health professionals and the public in general. Each country in the region needs to plan its public health policy and screening strategy, but overall linkage to care remains an important hurdle.
\nPolitical interest around the issue of hepatitis C treatment is uneven in the Latin American region. While affordability of DAAs has improved significantly in some countries such as Brazil, Mexico, Colombia, and Argentina, through strategies such as facilitating and speeding up the registration of the new DAAs, negotiating prices, compulsory licensing or generic competition, and exploring financial means by governments, insurance companies, or patients remain a significant task to undertake [14].
\nAccess to treatment in different countries of Latin America is not systematic as they organize their healthcare in diverse ways so that eligibility and availability criteria vary significantly. Furthermore, specific guidance about health care entitlement is either not available, unclear, or not followed by medical professionals involved in diagnosing and treating hepatitis C.
\nAnother important barrier restricting access to treatment in Latin America, particularly for the inhabitants with the lowest resources, is the limitations of providers of care. As a result, the number of patients referred for subspecialist evaluation remains low, and even when it occurs, patients may face long-distance travel, extended waiting time, and a lack of scheduling flexibility [15].
\nAmong primary care provider’s risk factors for HCV infection are not regularly sought, and deficiencies in HCV testing represent an additional barrier. Knowledge of HCV is generally inadequate.
\nLimited liver specialist availability through the region further contributes to the restriction of widespread opportunity of receiving treatment.
\nRisk factors for hepatitis C have changed over the years. A lack of knowledge regarding risk factors and treatment may contribute to low cure rates [16]. As blood bank screening has become almost universal, prevention and control of HCV should focus on recognizing high-risk population. In addition, rural populations, especially in areas with lower economic provision, should be under more attention. Evidence reported that intravenous or intranasal drug use and incarceration as well as the presence of hepatitis C in special populations such as patients with chronic renal failure in pre-dialysis, those in hemodialysis or co-infected individuals with HIV/hepatitis B are independent indicators of risk for past or present HCV infection [17]. The evolution of these risk factors will provide insights into understanding the future burden of hepatitis C.
\nAnother important issue is the recognition that people remain at risk of reinfection with hepatitis C virus (HCV), even after clearance of the primary infection [18]. A significant issue is the recognition of cofactors that can accelerate progression of hepatic fibrosis in patients with HCV, such as obesity, diabetes mellitus, co-infection with HIV or hepatitis B, and alcohol consumption [19].
\nIn order to achieve the continuum of care, identification of challenges in the region becomes very important. Special attention must be given at individual countries as their challenges may differ in their impact and significance (Figure 1).
\nChallenges to effectively treat HCV infection in Latin America.
A social communication strategy is required to increase the perception that hepatitis C is a preventable and curable disease. It is necessary to educate the population about the risk factors and easy access to screening, utilizing massive ways of communication such as newspaper, magazine, book publishing, as well as radio, television, internet, film, and social media. It is important to make sure that messages are backed up by data in order to avoid confusion and being visionary to provide a good reason to attend the message. The inclusion of the rapid test should be recommended as part of routine test in medical examinations of high-risk individuals. This test allows point-of-care testing that can take place outside the clinical laboratory and can be administered and interpreted by nonspecialists, the results are available in 5–10 min, and its sensibility is 95–99% and specificity 99–100% [20]. In those cases with a positive test, it is necessary to determine a viral load to detect viremic cases and guarantee access to treatment.
\nIt is recommendable to expand the number of health care professionals who can diagnose and administer DAAs, especially in rural areas fostering engagement in the continuum of care. Primary care physicians are in an ideal position to offer screening and diagnosis. Patients with advanced liver disease or complicated cases should be referred to the gastroenterologist, infectious disease specialist, or hepatologist. Nurses are at the forefront of providing information about the spread and diagnosis and treatment options available [21].
\nTo pursue this goal, we propose to connect health teams from remote areas with specialists in medical centers in order to promote the continuity of patient care.
\nThe training course includes:
Epidemiology of HCV infection.
Transmission of HCV infection.
Detection of HCV infection in risk groups.
Treatment of HCV infection.
Strategies for the prevention of hepatitis C.
The Extension for Community Healthcare Outcomes (ECHO) model by the University of New Mexico Health Sciences Center (UNMHSC) has developed a platform to deliver complex specialty medical care to underserved populations through an innovative educational model of team-based interdisciplinary development. Using state-of-the-art telehealth technology, best practice protocols, and case-based learning, ECHO trains and supports primary care providers to develop knowledge and self-efficacy in hepatitis. ECHO has signed agreements in some Latin American countries which will contribute to advance the continuum of care for hepatitis C [22].
\nThese types of programs will increase the familiarization of hepatitis C among general practitioners and nurses. They can be implemented taking advantage of the structure of the available health subsystems in every Latin American country.
\nRural communities face barriers when accessing health services, including facilities to perform laboratory studies. Latin America is confirmed by a diverse group of countries with great urban and rural disparities. Their health systems are usually structured in three levels: national, state, and local or their equivalents for every nation. Since 1990 every country in the region has gone through a series of health sector reforms with the aim of increasing equity, effectiveness, and coverage of health systems; unfortunately, despite their positive results, they have not achieved the proposed goals.
\nAn important strategy would be the implementation of point-of-care testing in rural areas and instrument the structure to send blood samples to central laboratories when necessary. One of the primary goals of central laboratories is to achieve a 48-hour or less turnaround on the shipment of laboratory specimens from laboratory sites to the central lab location. These laboratories must have minimum levels of infrastructure, human resources, and quality standards to guarantee technical competence in the analytical framework. At the local level, this reference network could be established at health centers, hospitals, or other places defined by the state, with operational scope within a geographical area.
\nAmong these populations prevalence of hepatitis C is markedly increased and has been documented between 4 and 96% in several studies [23]. They are by far undiagnosed and unlinked to care. Very seldom do they seek medical attention unless they present overt clinical liver disease. As a preventive strategy, these patients should be screened actively, diagnosed, and be treated with DAAs. Treatment programs should include opiate substitution treatment and various harm reduction programs, including needle exchange programs. Ideally, these services should be delivered in the same place with an integrated approach [24, 25].
\nIn the annual budgets of the prisons, it is necessary to foresee human and material resources to ensure they have medical facilities that improve HCV screening by point-of-care testing, outreach methods with mobile teams, rapid tests, and FibroScan to allow them to offer access to DAAs. We must strengthen the system of general prevention of hepatitis among all inmates as well.
\nA micro-elimination strategy should be implemented at individual hospitals, screening, diagnosing, and treating high-risk population attending for medical care. These populations include patients with liver diseases, patients with chronic renal failure, patients in pre-dialysis, patients with solid organ transplants, hemophiliacs, diabetics, and immunosuppressed patients from different etiologies as well as those pursuing emergency care. The micro-elimination strategy at these places should include the medical and paramedical personnel.
\nAt the level of hospitals and health centers, an anonymous record of information on patients with hepatitis C should be implemented. This registry will provide epidemiological information on the route of acquisition of the disease, comorbidities and barriers to treatment access and document the response to DAAs and serve as an instrument that permits recording follow-up.
\nOften in Latin American countries, access to DAAs is mired in bureaucracy implying excessive requirements difficult to meet for both patient and doctors. It is necessary to speed up the process in order to reduce the long queue of medication assignment, awaiting approval response, and shorten the long queue of medications awaiting review. At the institutional level, the form of payment (refund) of the medication can take months or years, so this is another important issue to overcome in order to make DAAs easily accessible.
\nHigher rates of DAA treatment must be accompanied by efficient screening, increased awareness, and more prescribers. It is necessary to innovate in the screening process, uncovering previously unidentified cases and those in the greatest need of treatment or at a high risk of transmitting the infection.
\nUnderstanding the care cascade is vital for eliminating the virus. Reducing the HCV burden requires educational effort and scale-up of DAA therapies. The simplicity of oral regimens that are effective across HCV genotypes expands the number of physicians that can prescribe DAAs with scalable treatment models. Novel prescription systems are being developed, whereby internists and general practitioners may be eligible to prescribe DAAs in consultation with specialists (Figure 2).
\nStrategies for accessing HCV infection treatment.
Hepatitis C in Latin America has now become an important health issue. Strategies to identify patients have changed over time, shifting from blood bank to occult patients in high-risk populations (Figure 3). Implementation of treatment access is the main objective in order to achieve the WHO strategy of elimination by 2030. The pathway toward this goal is flagged by several barriers, including simplified detection, drug costs, public and professional education, awareness, and government concern, so the majority of HCV-infected individuals can benefit from the new generation of HCV antivirals.
\nHepatitis C a Global Health issue.
Strategies to eliminate HCV infection must emphasize that this is a curable and preventable disease. As therapeutic regimens have become simpler and almost without side effects, the number of health care professionals who can diagnose and administer hepatitis C treatment is expanding the number of patients accessing treatment.
\nThe authors declare no conflict of interest.
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",metaTitle:"Waiver Policy",metaDescription:"We feel that financial barriers should never prevent researchers from publishing their research. With the need to make scientific research more publically available and support the benefits of Open Access, more institutions and funders have dedicated funds to assist their faculty members and researchers cover the APCs associated with publishing in Open Access. Below we have outlined several options available to secure financing for your Open Access publication.",metaKeywords:null,canonicalURL:"/page/waiver-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"At IntechOpen, the majority of OAPFs are paid by an Author’s institution or funding agency - Institutions (73%) vs. Authors (23%).
\\n\\nThe first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
\\n\\nHowever, as Open Access becomes a more commonly used publishing option for the dissemination of scientific and scholarly content, in addition to institutions, there are a growing number of funders who allow the use of grants for covering OA publication costs, or have established separate funds for the same purpose.
\\n\\nPlease consult our Open Access Funding page to explore some of these funding opportunities and learn more about how you could finance your IntechOpen publication. Keep in mind that this list is not definitive, and while we are constantly updating and informing our Authors of new funding opportunities, we recommend that you always check with your institution first.
\\n\\nFor Authors who are unable to obtain funding from their institution or research funding bodies and still need help in covering publication costs, IntechOpen offers the possibility of applying for a Waiver.
\\n\\nOur mission is to support Authors in publishing their research and making an impact within the scientific community. Currently, 14% of Authors receive full waivers and 6% receive partial waivers.
\\n\\nWhile providing support and advice to all our international Authors, waiver priority will be given to those Authors who reside in countries that are classified by the World Bank as low-income economies. In this way, we can help ensure that the scientific work being carried out can make an impact within the worldwide scientific community, no matter where an Author might live.
\\n\\nThe application process is open after your submitted manuscript has been accepted for publication. To apply, please fill out a Waiver Request Form and send it to your Author Service Manager. If you have an official letter from your university or institution showing that funds for your OA publication are unavailable, please attach that as well. The Waiver Request will normally be addressed within one week from the application date. All chapters that receive waivers or partial waivers will be designated as such online.
\\n\\nDownload Waiver Request Form
\\n\\nFeel free to contact us at oapf@intechopen.com if you have any questions about Funding options or our Waiver program. If you have already begun the process and require further assistance, please contact your Author Service Manager, who is there to assist you!
\\n\\nNote: All data represented above was collected by IntechOpen from 2013 to 2017.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'At IntechOpen, the majority of OAPFs are paid by an Author’s institution or funding agency - Institutions (73%) vs. Authors (23%).
\n\nThe first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
\n\nHowever, as Open Access becomes a more commonly used publishing option for the dissemination of scientific and scholarly content, in addition to institutions, there are a growing number of funders who allow the use of grants for covering OA publication costs, or have established separate funds for the same purpose.
\n\nPlease consult our Open Access Funding page to explore some of these funding opportunities and learn more about how you could finance your IntechOpen publication. Keep in mind that this list is not definitive, and while we are constantly updating and informing our Authors of new funding opportunities, we recommend that you always check with your institution first.
\n\nFor Authors who are unable to obtain funding from their institution or research funding bodies and still need help in covering publication costs, IntechOpen offers the possibility of applying for a Waiver.
\n\nOur mission is to support Authors in publishing their research and making an impact within the scientific community. Currently, 14% of Authors receive full waivers and 6% receive partial waivers.
\n\nWhile providing support and advice to all our international Authors, waiver priority will be given to those Authors who reside in countries that are classified by the World Bank as low-income economies. In this way, we can help ensure that the scientific work being carried out can make an impact within the worldwide scientific community, no matter where an Author might live.
\n\nThe application process is open after your submitted manuscript has been accepted for publication. To apply, please fill out a Waiver Request Form and send it to your Author Service Manager. If you have an official letter from your university or institution showing that funds for your OA publication are unavailable, please attach that as well. The Waiver Request will normally be addressed within one week from the application date. All chapters that receive waivers or partial waivers will be designated as such online.
\n\nDownload Waiver Request Form
\n\nFeel free to contact us at oapf@intechopen.com if you have any questions about Funding options or our Waiver program. If you have already begun the process and require further assistance, please contact your Author Service Manager, who is there to assist you!
\n\nNote: All data represented above was collected by IntechOpen from 2013 to 2017.
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