\\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
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Sohel Murshed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"93483",title:"Dr.",name:"Salim Newaz",middleName:null,surname:"Kazi",fullName:"Salim Newaz Kazi",slug:"salim-newaz-kazi",email:"salimnewaz@um.edu.my",position:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},{id:"187135",title:"Ph.D.",name:"Kah Hou",middleName:null,surname:"Teng",fullName:"Kah Hou Teng",slug:"kah-hou-teng",email:"alex_teng1989@hotmail.com",position:null,institution:{name:"Liverpool John Moores University",institutionURL:null,country:{name:"United Kingdom"}}},{id:"194347",title:"Prof.",name:"Abu Bakar",middleName:null,surname:"Mahat",fullName:"Abu Bakar Mahat",slug:"abu-bakar-mahat",email:"ir_abakar@um.edu.my",position:null,institution:null},{id:"194348",title:"Dr.",name:"Bee Teng",middleName:null,surname:"Chew",fullName:"Bee Teng Chew",slug:"bee-teng-chew",email:"chewbeeteng@um.edu.my",position:null,institution:null},{id:"194349",title:"Prof.",name:"Ahmed",middleName:null,surname:"Al-Shamma'A",fullName:"Ahmed Al-Shamma'A",slug:"ahmed-al-shamma'a",email:"A.Al-Shamma'a@ljmu.ac.uk",position:null,institution:null},{id:"194350",title:"Prof.",name:"Andy",middleName:null,surname:"Shaw",fullName:"Andy Shaw",slug:"andy-shaw",email:"A.Shaw@ljmu.ac.uk",position:null,institution:null}]},book:{id:"6080",title:"Heat Exchangers",subtitle:"Advanced Features and Applications",fullTitle:"Heat Exchangers - Advanced Features and Applications",slug:"heat-exchangers-advanced-features-and-applications",publishedDate:"April 26th 2017",bookSignature:"S M Sohel Murshed and Manuel Matos Lopes",coverURL:"https://cdn.intechopen.com/books/images_new/6080.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"24904",title:"Prof.",name:"S. M. Sohel",middleName:null,surname:"Murshed",slug:"s.-m.-sohel-murshed",fullName:"S. M. Sohel Murshed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"8640",leadTitle:null,title:"Cancer Chemoresistance",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tNeoplasia is considered to be the result of aberrations in the homeostatic mechanisms regulating cell turnover. This may be due to a combination of genetic, epigenetic and stochastic factors. Drug resistance is one of the major reasons for treatment failure and tumor relapse. Hence, an improved understanding of the mechanisms of neoplastic growth is possible based on systematic cataloging of the druggable targets for each of the major hallmarks of cancer. This approach can also aid in the refinement and validation of the in vitro and in vivo models, as well as provide pointers for the development of novel systems. Genomic instability and mutation, as well as tumor-promoting inflammation should be included as underlying factors influencing the process of neoplasia along with factors dysregulating energetics. The focus of this book is to update the reader on an integrated perspective including epigenetics data and corroborative mechanistic evidence from multiple model systems including humans. This will enable the reader to better comprehend the current scenario in terms of the pharmacological aspects pertaining to cancer chemoresistance. Also, the challenges for the molecular oncology will be discussed as well as probable strategies and a road-map for cancer chemotherapeutic drug development.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"2a80fe34c552bb6ca76ef9cd8f21e377",bookSignature:"Dr. Suresh P.K.",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8640.jpg",keywords:"Molecular Mechanisms of Aberrations, Proliferation Mechanisms, Types of Cell Death, Signal Transduction Pathways, Angiogenesis in Cancer, Angiogenesis in Wound Healing, Molecular Mechanisms of Invasion, Molecular Mechanisms of Metastasis, Telomeres, Stem Cells, Delivery Challenges, Evasion Mechanisms",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 5th 2018",dateEndSecondStepPublish:"November 26th 2018",dateEndThirdStepPublish:"January 25th 2019",dateEndFourthStepPublish:"April 15th 2019",dateEndFifthStepPublish:"June 14th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"190244",title:"Dr.",name:"Suresh",middleName:null,surname:"P.K.",slug:"suresh-p.k.",fullName:"Suresh P.K.",profilePictureURL:"https://mts.intechopen.com/storage/users/190244/images/system/190244.jpeg",biography:"P.K. Suresh is a Professor at the School of Biosciences & Technology, VIT, Vellore (2009 to date). He has approximately 18.5 years of teaching, research and administrative experience in Biotechnology & Industrial Biotechnology and allied disciplines. He had also headed Biotechnology & Industrial Biotechnology departments and has handled a wide variety of theory papers. He has 45 research publications in SCOPUS-indexed journals and has completed 3 funded projects as the Principal Investigator. He has made several presentations at International conferences. He has guided 5 doctoral students (2 as co-guide) and is currently guiding 5 students in the doctoral program. He has organized and participated actively in several Faculty Development Programs in areas as diverse as Stem Cells, Bio-inspired Design and Pharmacokinetics and was also a resource person in these events.",institutionString:"School of Biosciences & Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Vellore Institute of Technology University",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"177731",firstName:"Dajana",lastName:"Pemac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/177731/images/4726_n.jpg",email:"dajana@intechopen.com",biography:"As a Commissioning Editor at IntechOpen, I work closely with our collaborators in the selection of book topics for the yearly publishing plan and in preparing new book catalogues for each season. This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"18657",title:"The Potential of Genetically Engineered Magnetic Particles in Biomedical Applications",doi:"10.5772/22750",slug:"the-potential-of-genetically-engineered-magnetic-particles-in-biomedical-applications",body:'Magnetic particles are currently one of the most important materials in the industrial sector, where they have been widely used for biotechnological and biomedical applications such as carriers for recovery and for detection of DNA, proteins, viruses, and cells (Perez et al., 2002; Kramer et al., 2004; Gonzales and Krishnan, 2005). The major advantage of magnetic particles is that they can be easily manipulated by magnetic force, which enables rapid and easy separation of target molecules bound to the particles from reaction mixtures (Mirzabekov et al., 2000; Gu et al., 2003; Kuhara et al., 2004; Xu et al., 2004). Use of magnetic particles is beneficial for complete automation of steps, resulting in minimal manual labor and providing more precise results (Sawakami-Kobayashi et al., 2003). Biomolecules such as DNA, biotin, and antibodies have been assembled onto magnetic particles and used as recognition materials for target recovery, separation, or detection.
The method chosen for biomolecule assembly is determined by the surface properties of the magnetic particles. Various methods of assembly onto magnetic particles have been reported such as electrostatic assembly (Goldman et al., 2002), covalent cross-linking (Grubisha et al., 2003; Gao et al., 2004) avidin-biotin technology (Gref et al., 2003), membrane integration (Mirzabekov et al., 2000; Tanaka et al., 2004), and gene fusion techniques (Nakamura et al., 1995b; Yoshino et al., 2004; Yoshino and Matsunaga, 2006). The amount and stability of assembled biomolecules and the percentage of active biomolecules among assembled molecules are dependent on the method used for coupling. However, the fabrication techniques have not been standardized. As applications for magnetic particles in the biotechnology field increase, magnetic particles with greater functionality and novel methods for their production are in demand.
Magnetotactic bacteria synthesize uniform, nano-sized magnetite (Fe3O4) particles, which are referred to as “bacterial magnetic particles” (BacMPs). A thin lipid bilayer membrane envelops the individual BacMP, which confers high and even dispersion in aqueous solutions as compared to artificial magnetic particles, making them ideal biotechnological materials (Matsunaga et al., 2003). To use these particles for biotechnological applications, it is important to attach functional molecules such as proteins, antibodies, peptides, or DNA. BacMP-specific proteins have been used as anchor proteins, which facilitate efficient localization and appropriate orientation of various functional proteins attached to BacMPs. We have developed several methods for modification and assembly of these functional organic molecules over the surface of BacMPs using chemical and genetic techniques. In this chapter, we describe advanced magnetic particles used in biomedical applications and the methods for bioengineering of these particles. Specific focus is given to the creation of functional BacMPs by magnetotactic bacteria and their applications.
Currently, magnetic particles offer vast potential for ushering in new techniques, especially in biomedical applications, as they can be easily manipulated by magnetic force. The important characteristics of these particles include (1) immobilization of higher numbers of probes onto magnetic particles because particle surfaces are wider than those of a flat surface, (2) reduction of reaction times because of good dispersion properties that increase reaction efficiency, (3) facilitation of the bound/free separation step with a magnet, without centrifugation or filtration, and (4) the use of automated robotic systems for all reaction steps. These characteristics offer great benefits for biomedical applications such as rapid and precise measurements or separations of bio-targets. Here, the methods for production of functional magnetic particles are introduced.
Commercialized magnetic particles are usually composed of superparamagnetic iron oxide nanoparticles (Fe3O4 or Fe2O3), which exhibit magnetic properties only in the presence of external magnetic fields. These particles are embedded in polymers such as polysaccharides, polystyrene, silica, or agarose. Micro-sized magnetic particles can be easily removed from suspension with magnets and easily suspended into homogeneous mixtures in the absence of an external magnetic field (Ugelstad et al., 1988). Furthermore, functional groups or biomolecules for the recognition of targets are conjugated to the polymer surfaces of magnetic particles (Fig. 1), and targets can be collected, separated, or detected by the magnetic particles.
Use of general magnetic particles
Biotin or streptavidin-assembled magnetic particles, on which complementary nucleic acid strands are immobilized, are widely used for the recovery or extraction of specific nucleic acids and are marketed worldwide. Moreover, magnetic particles can be used as supports for separation or detection of proteins or cells. For example, protein A- or protein G-assembled magnetic particles are suitable for antibody purification and are more efficient than column-purification techniques.
Currently, polymer magnetic particles marketed as Dynabeads (Invitrogen, co.) are one of the most widely used magnetic particles for biotechnology applications (Sawakami-Kobayashi et al., 2003; Prasad et al., 2003). These particles are prepared from mono-sized macroporous polystyrene particles that are magnetized by an in situ formation of ferromagnetic materials inside the pores. Dynabeads with diameters of 2.8 m or 4.5 m are the most widely used magnetic particles by scientists around the world, particularly in the fields of immunology, cellular biology, molecular biology, HLA diagnostics, and microbiology.
Antibody-immobilized magnetic particles have been used preferentially in target-cell separation of leukocytes (Stampfli et al., 1994; Schratzberger et al., 1997; Schwalbe et al., 2006; Nakamura et al., 2001) for in vitro diagnosis because of the simpler and more rapid methodology as compared to cell sorting using a flow cytometer. These commercially available magnetic particles are chemically synthesized compounds of micrometer and nanometer sizes. Several cell separation systems using nano-sized magnetic particles, such as 50-nm iron oxide particles with polysaccharide- (Miltenyi Biotech, co.) or dextran- (StemCell Technologies Inc.) coated superparamagnetic nanoparticles, are commercially available (Miltenyi, 1995; Wright, 1952). Because these particles are superparamagnetic and are preferred for high-gradient magnetic separation, specially-designed magnetic columns that produce high magnetic field gradients are required for cell separation (Miltenyi, 1995). Nano-sized magnetic particles are advantageous for assay sensitivity, rapidity, and precision. However, it remains difficult to synthesize nano-sized magnetic particles with uniform size and shape that adequately disperse in aqueous solutions. Consequently, advanced techniques and high costs are required for the production of nano-sized magnetic particles.
Magnetic particles are widely used not only as carriers for recovery or detections of bio-molecules, but also used as probes for magnetic detections, or agent for magnetic-field-induced heating. Especially, magnetic particles that have high saturation magnetization are ideal candidates for MRI contrast agents, and various kinds of magnetic particles have been developed and used for diagnoses. Recently, Mulder et. al. developed the paramagnetic quantum dots (pQDs) coated with paramagnetic and pegylated lipids which had a high relaxivity. The high relaxivity makes the pQDs contrast agent an attractive candidate for molecular MRI purposes. This nanoparticulate probe makes it detectable by both MRI and fluorescence microscopy (Mulder et al., 2006). It was successful that the synthesis of quantum dots with a water-soluble and paramagnetic micellular coating were used as a molecular imaging probe for both fluorescence microscopy and MRI. The present study uses magnetic nanoparticles as bimodal tools and combines magnetically induced cell labelling and magnetic heating. The particles are used in hyperthermia agents, where the magnetic particles are heated selectively by application of an high frequency magnetic field (Mulder et al., 2006). These magnetic heating treatments using superparamagnetic iron oxide nanoparticles continue to be an active area of cancer research. The research aimed to assess if a selective and higher magnetic nanoparticles accumulation within tumor cells is due to magnetic labeling and consequently a larger heating effect occurs after exposure to an alternating magnetic field in order to eliminate labeled tumor cells effectively (Kettering et al., 2007). Moreover, in recent years magnetic devised like giant magnetoresistive (GMR) sensors have shown a great potential as sensing elements for biomolecule detection (Baselt et al., 1998; Edelstein et al., 2000; Schotter et al., 2004). The GMR biochip based on spin valve sensor array and magnetic nanoparticle probes was developed for inexpensive, sensitive and reliable DNA detection using plasmid-derived samples (Xu et al., 2008). The applications of magnetic particles as probes are increasingly advanced in biomolecule quantitative analysis.
Magnetotactic bacteria synthesize nano-sized biomagnetites, otherwise known as bacterial magnetic particles (BacMPs), that are enveloped individually by a lipid bilayer membrane (Blakemore, 1983). BacMPs are ultrafine magnetite crystals (50-100 nm in diameter) with uniform morphology produced by Magnetospirillum magneticum AMB-1 (Fig. 2).
Transmission electron microscopic (TEM) image and schematic diagram of Magnetospirillum magneticum AMB-1 (A), bacterial magnetic particles (BacMPs, B) and schematic diagram of proteins on the BacMPs surface (C).
The molecular mechanism of BacMP synthesis involves a multiple-step process that includes vesicle formation, iron transport, and magnetite crystallization. This mechanism has been studied using genomic, proteomic, and bioinformatic approaches (Matsunaga et al., 2005; Nakamura et al., 1995a; Arakaki et al., 2003; Amemiya et al., 2007), and a comprehensive analysis provided a clear view of the elaborate regulation of BacMP synthesis.
Techniques for the mass cultivation of magnetotactic bacteria have been developed, allowing for a steady supply of BacMPs for industrial applications. Based on the molecular mechanism of BacMP formation in M. magneticum AMB-1, designed functional nanomaterials have also been developed. Through genetic engineering, functional proteins such as enzymes, antibodies, and receptors have been displayed on the surface of BacMPs.
The display of proteins on BacMPs was achieved using a fusion technique involving anchor proteins isolated from magnetotactic bacteria (Nakamura et al., 1995b). Figure 3A shows the procedure for producing functional magnetic particles through genetic engineering of these bacteria. Several proteins involved in the magnetic biosynthetic mechanism are embedded in the BacMP membrane. In M. magneticum AMB-1, MagA (46.8 kDa), Mms16 (16 kDa), and Mms13 (13 kDa) proteins have been used as anchor molecules for displaying functional proteins (Nakamura et al., 1995b; Yoshino et al., 2004; Matsunaga et al., 2005; Matsunaga et al., 1999; Matsunaga et al., 2000).
Preparation of BacMPs displaying functional proteins.(A) The functional protein gene is fused to an anchor gene for display of a functional protein on BacMPs. A plasmid harboring the fusion gene is introduced into M. Magneticum AMB-1. (B) TEMs of BacMPs displaying protein A which were treated with rabbit IgG after addition of gold nanoparticle (5 nm)-labeled anti-rabbit IgG antibodies (1) or anti-human IgG antibodies (2).
MagA was one of the first proteins experimentally demonstrated to be localized on the surface of BacMPs (Nakamura et al., 1995a; Nakamura et al., 1993). MagA is a transmembrane protein identified from a M. magneticum AMB-1 mutant strain generated by transposon mutagenesis (Nakamura et al., 1995a). As proof of localization, luciferase (61 kDa) was fused to the C-terminus of MagA (Nakamura et al., 1995b). This was the first report of protein display on BacMPs using gene fusion techniques. However, the efficiency and stability of proteins displayed on BacMPs were limited, and only a few molecules were displayed on a single BacMP.
As research in this field progressed, a more effective and stable method for protein display was developed. To establish high levels of expressed proteins displayed on BacMPs, strong promoters and stable anchor proteins were identified using M. magneticum AMB-1 genome and proteome analysis (Yoshino and Matsunaga, 2005).
An integral BacMP membrane protein, Mms13, was isolated as a stable anchor molecule, and its anchoring properties were confirmed by luciferase fusion studies. The C-terminus of Mms13 was expressed on the surface of BacMPs, and Mms13 was tightly bound to the magnetite directly, permitting stable localization of luciferase on BacMPs. Consequently, the luminescence intensity obtained from BacMPs using Mms13 as an anchor molecule was more than 1,000-times greater than when MagA was used. Furthermore, the IgG-binding domain of protein A was displayed uniformly on BacMPs using Mms13 (Fig. 3B).
Strong promoters and stable anchor proteins allowed efficient display of functional proteins on BacMPs. However, the display of particular proteins remained a technical challenge due to the cytotoxic effects of the proteins when they were overexpressed in bacterial cells. Specifically, transmembrane proteins such as G-protein coupled receptors were still difficult to express in magnetotactic bacteria. An inducible protein expression system is often used to control the expression dose and timing of transmembrane proteins. Recently, we developed a tetracycline-inducible protein expression system in M. magneticum AMB-1 to prevent the toxic effects of transmembrane protein expression (Yoshino et al., 2010). This system was implemented to obtain the expression of tetraspanin CD81, where the truncated form of CD81, including the ligand binding site, was successfully expressed on the surface of BacMPs using Mms13 as an anchor protein and the tetracycline-inducible protein expression system. These results suggest that the inducible expression system will be a useful tool for the expression and display of transmembrane and other potentially cytotoxic proteins on the membranes of BacMPs.
Currently, many types of functional proteins can be displayed at high levels on magnetic particles due to the modifications described above. Generally, immobilization of proteins onto magnetic particles is performed by chemical cross-linking; however, this can hinder the activity of some proteins. Because the amine-reactive cross-linker can bind to proteins in a random manner, the target proteins may become inactivated. Furthermore, protein orientation on the solid phase is difficult to control during chemical conjugation. To overcome these difficulties, protein display on magnetic particles produced by magnetotactic bacteria through gene fusion is a promising approach, and the techniques have expanded the number of applications.
Magnetic iron oxide particles, such as magnetite (Fe3O4) and maghemite (γ-Fe2O3), are widely used in medical and diagnostic applications such as magnetic resonance imaging (Gleich and Weizenecker, 2005), cell separation (Miltenyi et al., 1990), drug delivery (Plank et al., 2003), and hyperthermia (Pardoe et al., 2003). To use these particles for biotechnological applications, the surface modification of the magnetic particle with functional molecules such as proteins, peptides, or DNA must be considered. Previously, only DNA- or antibody-immobilized magnetic particles were marketed and used in biotechnology; it was suggested that the techniques for the immobilization of enzymes or receptors were more complicated and time consuming. However, as the methods for assembling functional proteins onto magnetic particles have become simpler and more efficient, the applications of magnetic particles have expanded. Here, the applications of BacMPs displaying functional proteins such as antibody, enzyme, or receptor are described.
Magnetic particles have been widely used as carriers of antibodies for immunoassay, cell separation, and tissue typing (Herr et al., 2006; Tiwari et al., 2003; Weissleder et al., 2005). The use of magnetic particles is advantageous for full automation, minimizing manual labor and providing more precise results (Sawakami-Kobayashi et al., 2003; Tanaka and Matsunaga, 2000). In particular, immunomagnetic particles have been used preferentially in target cell separation from leukocytes (Stampfli et al., 1994; Schratzberger et al., 1997) for in vitro diagnosis, as this provides a more rapid and simple methodology compared with cell sorting using a flow cytometer.
To immobilize antibody, protein A, which is the antibody-binding protein derived from Staphylococcus aureus (Deisenhofer, 1981), has been immobilized on magnetic particles using the sequence of the Z-domain, a synthetic analogue of the IgG-binding B-domain. Staphylococcus protein A consists of a cell wall binding region and five domains, termed C, B, A, D, and E, with C next to the cell wall. The molecular interaction of protein A with IgG is well understood, and the binding sites on the Fc domain of IgG1, -2, and -4 have been characterized. X-ray analysis has revealed that the B-domain of protein A has two contact sites that interact with the Fc domain of IgG (Eliasson and Kogelschatz, 1988). Based on this knowledge, a synthetic Z-domain, which consists of 58 amino acids and is capable of binding the Fc domain, has been constructed (Lowenadler et al., 1987). IgG can bind the Z-domain on magnetic particles with uniform orientation.
Z-domain was displayed on bacterial magnetic particles using gene fusion techniques and was used to detect human insulin from whole blood by sandwich enzyme immunoassays. The experimental procedure was fully automated using a pipetting robot bearing a magnet (Tanaka and Matsunaga, 2000).
Antibody-conjugated BacMPs also can be utilized for cell separation. In general, nano-sized magnetic particles, rather than micro-sized particles, are preferred for cell separation because separated cells with nano-sized magnetic particles on their surfaces can be used in subsequent flow cytometric analysis (Graepler et al., 1998). Additionally, micro-sized magnetic particles are more likely to have inhibitory effects on cell growth and differentiation after magnetic separation.
Magnetic separation permits target cells to be isolated directly from crude samples such as blood, bone marrow, tissue homogenates, or cultivation media. Compared to other more conventional methods of cell separation, magnetic separation may be considered a sample enrichment step for further chromatographic and electromigratory analysis. To enrich for target cells, cell surface antigens, such as cluster of differentiation (CD) antigens, were used as markers. CD8, CD14, CD19, CD20, and CD34 positive cells were efficiently enriched from peripheral blood (Kuhara et al., 2004; Matsunaga et al., 2006). The separated CD34 positive cells retained the capability of forming colonies as hematopoietic stem cells.
Schematic illustration of cell separation procedures. (A) The initial separation of peripheral blood mononuclear cells (PBMCs) from whole blood and the subsequent magnetic separation of target cells from PBMCs using magnetic particles followed the common procedure. (B) Target cells were separated directly from whole blood using magnetic particles in the procedure for direct magnetic cell separation.
Protein G from Streptococcus sp (Gronenborn et al., 1991) was also displayed on BacMPs, resulting in the expansion of IgG-binding diversity. Direct magnetic separation of immune cells from whole blood using protein G-BacMPs binding anti-CD monoclonal antibodies was demonstrated (Fig. 4). Using this technique, B lymphocytes (CD19+ cells) or T lymphocytes (CD3+ cells) were successfully separated at a high purity.
To increase cell separation efficiency, a novel functional polypeptide, which functions to minimize nonspecific adsorption of magnetic particles to cells, was developed for surface modification of BacMPs (Takahashi et al., 2010). Previous reports had shown that the hydrophilicity or neutral charge of the particle surface was important for the reduction of nonspecific interactions between the nanoparticle and the cell surface (Fang et al., 2009; Patil et al., 2007). The designed polypeptide was composed of multiple units consisting of four asparagines (N) and one serine (S) residue and was referred to as the NS polypeptide. Modification of the surface of a magnetic particle with the NS polypeptide resulted in reduction of non-specific particle-particle and particle-cell interactions. NS polypeptides on magnetic nanoparticle surfaces function as a barrier to block particle aggregation and minimize nonspecific adsorption of cells to the nanoparticles; they also add the ability to recognize and bind to target cells by working as a linker to display protein G on the nanoparticles (Fig. 5). When the NS polypeptide is used in a single fusion protein as a linker to display protein G on magnetic particles, the particle acquires the capacity to specifically bind target cells and to avoid nonspecific adsorption of non-target cells. CD19+ cells represent 4.1% of leukocytes and in peripheral blood were calculated to be less than 0.004% of the total cells. Analysis of magnetically separated cells using flow cytometry revealed that CD19+ cells were separated directly from peripheral blood with greater than 95% purity using protein G-displaying BacMPs bound to anti-CD19 monoclonal antibodies with the NS polypeptide. Purities were approximately 82% when the NS polypeptide was not present.
Effect of NS polypeptide on cell separation.(A) Schematic diagram of expression vectors for fusion proteins, Mms13-protein G (1), Mms13-(N4S)10–protein G (2), and Mms13-(N4S)20-protein G (3). (B) Correlation between the display of NS polypeptide on BacMPs and nonspecific binding of BacMPs to the cell surface. The number of RAW 264.7 cells separated using BacMPs displaying protein G (○), BacMPs displaying (N4S)10-protein G (×), or BacMPs displaying (N4S)20-protein G (△) were counted, and the ratio of nonspecifically separated cells was calculated. (C) Direct magnetic separation of CD19+ cells from whole blood using BacMPs displaying (N4S)20-proteins bound to PE-labeled anti-CD19 mAbs.
Display of fusion proteins (protein G and NS polypeptide) on BacMPs significantly improved recognition of and binding to target cells, and minimized adsorption of non-target cells. These promising results demonstrated that NS polypeptides may be a powerful and valuable tool in various cell associated applications.
Enzymes can catalyze various biochemical reactions with high efficiency and specificity and are therefore used in industrial production (Patil et al., 2007). However, the production and purification of recombinant enzymes can be quite time and cost consuming. If enzymes could be immobilized on magnetic particles, they could be reused following magnetic recovery from the reaction mixture. Enzymes and antibodies immobilized on BacMPs using bifunctional reagents and glutaraldehyde have been found to have higher activities than those immobilized on artificial magnetic particles (Matsunaga and Kamiya, 1987). The luciferase gene (luc) was cloned downstream of the MagA promoter and the effect of iron on the regulation of MagA expression was investigated; transcription of MagA was found to be enhanced by low concentrations of iron. As an initial proof-of-concept experiment for the recovery of enzyme-displaying BacMPs, luciferase was assembled onto BacMPs (Nakamura et al., 1995b). The genes for acetate kinase and liciferase were fused to the N- and C-terminus of the MagA anchor protein for simultaneous display of two different enzymes (Matsunaga et al., 2000). Acetate kinase catalyzes the phosphorylation of acetate by ATP. Therefore, this reversible reaction generates ATP in the presence of ADP and acetyl phosphate. The results presented in Fig. 6 are consistent with the hypothesis that ATP is generated in situ by acetate kinase present on BacMPs through phosphorylation of ADP to ATP (Fig. 6). Thus, protein-BacMPs complexes were constructed by joining the luciferase gene to the N- or the C-terminal domains of MagA, and also constructed bifunctional active fusion proteins on BacMPs using MagA as an anchor with acetate kinase and luciferase.
Simultaneous display of two different enzymes, acetate kinase (ackA) and luciferase (luc), onto BacMPs. (A) Schematic diagram of fusion genes, and (B) luciferase activity on BacMPs
A highly thermostable enzyme, pyruvate phosphate dikinase (PPDK), which converts pyrophosphate PPi to ATP, was also expressed on BacMPs. Pyrosequencing relies on the incorporation of nucleotides by DNA polymerase, which results in the release of PPi. The ATP produced by PPDK-displaying BacMPs can be used by luciferase in a luminescent reaction (Fig. 7). PPDK-displaying BacMPs were employed in a pyrosequencing reaction and a target oligonucleotide was successfully sequenced (Yoshino et al., 2009). The PPDK enzyme was recyclable in each sequence reaction as it was immobilized onto BacMPs which could be manipulated by a magnet. These results illustrate the advantages of using enzyme-displaying BacMPs as biocatalysts for repeat usage. Nano-sized PPDK-displaying BacMPs are useful for the scale-down of pyrosequencing reaction volumes, thus permitting high-throughput data acquisition.
Schematic diagram of the principle of pyrosequencing using PPDK-BacMPs. PEP: phosphoenolpyruvate, PPi: pyrophosphate, Pi: phosphate, PPDK: Pyruvate phosphate dikinase. PEP : phosphoenolpyruvate, PPi : pyrophosphate, Pi : phosphate, PPDK : Pyruvate phosphate dikinase
Along with immunoassays and cell separations, ligand-binding assays to study receptor proteins are highly desired applications for magnetic particles. Receptor proteins play critical roles in gene expression, cellular metabolism, signal transduction, and intercellular communication. In particular, nuclear receptors and transmembrane receptors can be major pharmacological targets. These types of receptors have been assembled onto BacMPs.
The estrogen receptor is a nuclear receptor serving as a ligand-inducible transcriptional regulator. In recent decades, it has been suggested that natural and synthetic compounds can act as steroid hormones and adversely affect humans and wildlife through interactions with the endocrine system. These compounds have been broadly referred to as environmental endocrine disrupting chemicals (EDCs). Several chemicals, such as plastic softeners (bisphenol A) or detergents (4-nonylphenol), were originally considered harmless, but now are suspected of having estrogenic effects. It is probable that many unidentified chemical compounds are potential EDCs.
To evaluate and detect these chemical compounds, estrogen receptor ligand-binding domain (ERLBD) was displayed on BacMPs (Yoshino et al., 2005). ERLBD-BacMP complexes can be used for assays based on the competitive binding of alkaline phosphatase conjugated 17β-estradiol (ALP-E2) as a tracer. The dissociation constant of the receptor was 2.3 nM. Inhibition curves were evaluated by the decrease in luminescence intensity resulting from the enzymatic reaction of alkaline phosphatase. The overall simplicity of this receptor binding assay resulted in a method that could be easily adapted to a high-throughput format.
Subsequent-generation evaluation systems for EDCs can distinguish between agonists and antagonists (Yoshino et al., 2008). In one system, ERLBD-displaying BacMPs and green fluorescent protein (GFP)-fused coactivator proteins were used in combination, and ERLBD-displaying BacMPs were incubated with ligands and GFP-coactivators. Binding of the agonist to ERLBD induced a conformational change of ERLBD and promoted binding of the GFP-coactivator to an ERLBD dimer on the BacMP. Binding of the antagonist to ERLBD prevented the GFP-coactivator from binding to the ERLBD-BacMPs. Ligand-dependent recruitment assays of GFP-labeled coactivators to ERLBD-BacMPs were performed by measuring the fluorescence intensity (Fig. 8A). This method was used to evaluate 17-estradiol (E2) and estriol (E3) as full agonists, octylphenol (OP) as a partial agonist, and ICI 182,780 (ICI) as an antagonist (Fig. 8B). The full agonists showed dose-dependent increases in fluorescence. Octylphenol had lower fluorescence intensity than E2, and ICI 182,780 did not produce fluorescence. The method developed in this study can be used to evaluate the estrogenic potential of chemicals by discriminating whether a chemical is an ER full agonist, a partial agonist, or an antagonist. This novel method has important potential for screening for new EDC candidates and their effects in the environment.
Schematic diagram of the GFP-coactivator recruitment assay (A) and the assay results (B). Estrogen receptor ligand binding domain (ERLBD)-BacMPs were incubated with ligand and GFP-coactivator. Binding of agonist to ERLBD induced conformation change of ERLBD and promoted binding of GFP-coactivator to ERLBD dimmer on BacMPs. Binding of antagonist to ERLBD prevented GFP-coactivator binding to ERLBD-BacMPs. E2:17βEstradiol, E3:Estriol, OP:Octylphenol, ICI:ICI 182780
G protein-coupled receptors (GPCRs) play a central role in a wide range of biological processes and are prime targets for drug discovery. GPCRs have large hydrophobic domains, and therefore, purification of GPCRs from cells is frequently time-consuming and typically results in loss of the native conformation. The D1 dopamine receptor, which is a GPCR, was successfully assembled into the lipid membrane of BacMPs (Yoshino et al., 2004). D1 dopamine receptor-displaying BacMPs were simply extracted by magnetic separation from ruptured AMB-1 transformants. This system conveniently retains the native conformation of GPCRs without the need for detergent solubilization, purification, and reconstitution after cell disruption.
Additionally, display of the tetraspanin CD81 was demonstrated using the inducible expression system (Yoshino et al., 2010) described above. CD81 is utilized when hepatitis C virus (HCV) infects hepatocytes and B lymphocytes. Therefore an inhibitor of the human CD81-HCV E2 interaction could possibly prevent HCV infection (Pileri et al., 1998). This interaction was the motivation behind efforts to produce CD81-displaying BacMPs. Consequently, the interaction between BacMPs displaying truncated CD81 and the HCV E2 envelope were detected, suggesting that CD81-displaying BacMPs could be effectively applied to identify inhibitors of the CD81-E2 interaction.
Transmembrane receptors constitute the most prominent family of validated pharmacological targets in biomedicine. Receptor-displaying BacMPs were readily extracted from ruptured AMB-1 transformants by magnetic separation, and after several washings were ready for analysis. Moreover, BacMPs are well-suited for use in a fully automated ligand-screening system that employs magnetic separation. This type of system facilitates rapid buffer exchange and stringent washing, and reduces nonspecific binding.
The suitability of magnetic particles for use in fully-automated systems is an important advantage in solid phases of bioassays. Automated robots bearing magnets permit rapid and precise handling of magnetic particles leading to high-throughput analysis. Different types of fully-automated systems have been developed to handle the magnetic particles and to apply them to nucleotide extraction, gene analysis, and immunoassays.
Figures 9-11 show the layout of an automated workstation with which magnetic particles are collected at the bottom of microtiter plates (Maruyama et al., 2004; Tanaka et al., 2003). For fluid handling, the processor is equipped with an automated pipetter (1) that moves in the vertical and horizontal directions. The platform contains a disposable tip rack station (2), a reagent station (3) that serves as reservoirs for wash buffers, and a reaction station (4) for a 96-well microtiter plate, where a magnetic field can be applied using a neodymium iron boron sintered (Nd-Fe-B) magnet on its underside. One pole of the Nd-Fe-B magnet applies a magnetic field to one well (Matsunaga, 2003). Eight poles of the Nd-Fe-B magnet are aligned on iron rods, and 12 rods are set on the back side of the microtiter plate to apply magnetic fields to the 96 wells. The magnetic field can be switched on (magnetic flux density: 318 mT) and off (magnetic flux density: <10 mT) by rotating the rods 180°. The reaction station is combined with a heat block with a range of 4–99°C and is configured to perform the hybridization step. Heating and magnetic separation can be performed simultaneously in one well. This precise thermal control unit is suitable for DNA handling and has been used for DNA extraction, SNP detection in the genes for aldehyde dehydrogenase 2 (ALDH2) (Maruyama et al., 2004) and transforming growth factor (TGF) (Yoshino et al., 2010), detection of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), and determination of microsatellite repeats in the human thyroid peroxidase (TPOX) gene (Nakagawa et al., 2007).
Automated magnetic separation system, and magnetic separation is achieved in the bottom of microtiter plates.
Figure 10 shows the layout of an automated workstation with which magnetic particles can be separated on the inner surface of pipette tips. The automated system consists of an automated eight-way pipette bearing a retractable magnet mounted close to the pipette tips (1) a tip rack, (2) a reaction station for a 96-well microtiter plate, and (3) a luminescence detection unit. One rack can hold 8 × 3 tips for reactions. For automated magnetic separation, the suspension of magnetic particles is aspirated and dispersed using an automated pipette bearing a magnet. The automated pipette can move horizontally, and magnetic particles collected on the inner surface of pipette tips can be resuspended in the subsequent wells by the pipetting action (Matsunaga et al., 2007). As an advantage, this system can eliminate the carry-over of reaction mixtures to the following reaction steps. Due to precise liquid handling, this workstation is mainly used for highly-sensitive immunoassays, though its throughput capacity is less than the above system. Using this workstation, a fully-automated immunoassay was developed to detect EDCs (Matsunaga et al., 2003; Yoshino et al., 2008), human insulin (Tanaka and Matsunaga, 2000), and a prostate cancer marker (prostate specific antigen).
Automated magnetic separation system, and magnetic separation is achieved on the inner surface of pipette tips.
Figure 11 shows the layout of an automated workstation with which magnetic particles can be collected onto a magnetic rod (Ota et al., 2006). This workstation is equipped with eight automated pestle units and a spectrophotometer that is interfaced with a photosensor amplifier. The magnetic rod that moves in both vertical and horizontal directions is composed of a neodymium–iron–boron (Nd–Fe–B) magnet pole and a covering sheath. DNA concentrations and purities are measured in the cuvette using an absorbance spectrometer that is integrated with the workstation. Light traverses the solution in the cuvette from bottom to top. When magnetic particles are collected from the reaction mixture, the core magnetic pole is sheathed, and then magnetic particles are suspended in the following step by stirring of the sheath without the core rod. The sheath is used as a pestle to gently mix the suspension of magnetic particles and solid samples. Using this system, DNA was directly extracted from dried maize powder using aminosilane-modified BacMPs. Furthermore, the quantitative detection of genetically-modified maize genes was examined by real-time PCR. This system offers rapid assay completion with high DNA yields and qualities comparable to those of conventional detergent-based methods.
Automated magnetic separation system, and magnetic separation is achieved onto a magnetic rod.
Magnetic particles have been utilized as biomolecule carriers since the 1970s when applied research examined bioreactors using enzyme-immobilized magnetic particles. Since then, various types of synthetic and bioengineered magnetic particles have been produced, modified, and enhanced. These magnetic particles have been widely used in place of centrifugation, filter, and chromatography separations, and applied to purifications of biological matter including target cells, proteins, and nucleic acids. More recent advances in the bioengineering of magnetic particles produced by magnetotactic bacteria have resulted in powerful tools for medical applications as well as basic research. This review focused on the applications of BacMPs for recovery or detections of bio-molecule. BacMPs are also available for other applications such as MRI contrast agents, and carriers for drug delivery systems, and so on. High potential magnetic particles will be developed combining with genetic engineering, and especially it is quite easy to control the kinds and numbers of proteins-displayed on BacMPs. Furthermore, it is possible to display artificially designed proteins or polypeptides onto BacMPs by the same methods. These approaches provide a new innovation in material science. Elucidation of the mechanism of magnetic particle formation in M. magneticum AMB-1 has provided a roadmap for designing novel biomaterials useful in multidisciplinary fields.
The finite element method (F.E.M.) is a numerical procedure that can be applied to solve various problems in engineering and science. In general, this method is used to solve steady, transient, linear, and nonlinear problems in electromagnetics, structural analysis, and fluid dynamics [1]. The finite element method has the main advantage of being able to handle all kinds of geometries and non-homogeneous materials without the need to change computer code formulations. The idea of this method is to break the problem into a large number of areas, each with simple geometry to facilitate problem-solving. As a result, the domain breaks down into a number of small elements, and the problem goes from small but challenging to solve into large and relatively easy to solve. Through the process of discretization, linear algebra problems are formed with many unknowns. In the case of electromagnetics, a discretization scheme, as implied by F.E.M., which implicitly combines most of the theoretical features of the problem analyzed is the best solution for obtaining accurate results in problems with complex, nonlinear geometries, etc. [2, 3]. This method can also be used for complex differential equations that are very difficult to solve. In the case of electromagnetic or magnetic fields, the finite element method is also known as FEMM.
FEMM is a suite of programs for solving low-frequency electromagnetic problems on two-dimensional planar and axisymmetric domains. The program currently addresses linear/nonlinear magnetostatic problems, linear/nonlinear time-harmonic magnetic problems, linear electrostatic problems, and steady-state heat flow problems. In the problem of this method, there are generally three parts to the problem [4].
Interactive shell program is a Multiple Document Interface pre-processor and a post-processor for various types of problems that are solved by FEMM. This case is a CAD-like interface for laying out the geometry of the problem to be solved and for defining material properties and boundary conditions [5]. The program also allows the user to inspect a field at specific points, as well as evaluate several different integrals and plot varying amounts of interest along with a user-defined contour [6]. Triangle breaks down the solution region into a large number of triangles, a vital part of the finite element process. Furthermore, Solvers, each solver takes a set of data files that describe problems and solves the relevant partial differential equations to obtain values for the desired field throughout the solution domain [7].
Finite Element Method Magnetics (FEMM) software has been developed for reasons of dealing with some of the limiting cases of Maxwell equations. The magnetic problem that is handled can be considered as a low frequency (L.F.) problem. In some cases, this problem can ignore displacement currents. This program discusses 2D planar and 3D axisymmetric linear and nonlinear harmonic magnetic, magnetostatic, and linear electrostatic problems [8].
Computer-assisted field distribution analysis for electromagnetic devices or component performance has become a simple, profitable, and fast method with good accuracy [9]. The magnetic field calculation problem aims to determine the value of one or more unknown functions, such as magnetic field intensity, magnetic flux density, scalar magnetic potential, and magnetic vector potential.
From a mathematical point of view, Maxwell equations can generally explain physical electromagnetic phenomena. Specifically, this point of view is a differential equation with specific boundary conditions. With this method, the correct solution to the problem is obtained. It is an analytical method that can be used to solve problems [10]. Analytical methods (method of appropriate representation, method of variable separation) are often applied to solve relatively simple problems. However, the problems that occur in practice are sometimes more complex regarding loading conditions, boundary conditions, geometric construction, and material heterogeneity, so that the integration of differential equations is challenging to solve by analytical methods. Therefore, the analytic solution can only be done by making a simplified model that allows the integration of the differential Equations [11]. Sometimes it is better to come up with a more realistic estimate of the value, rather than a precise solution from a simplified model. The approximate solution by the finite element method obtained by the numerical method reflects reality better than the exact solution of the simplified model [12].
Specific forms of electromagnetic field law for static magnetic fields are overcome by considering solving the magnetic problem through FEMM. Some of them are considering the model of the relationship between magnetic induction and the intensity of its magnetic field, the enunciation of static magnetic fields, passing conditions through discontinuity surfaces, enunciation of scalar magnetic potential - magnetostatic field problems and enunciation using magnetic vector potentials [13]. Some geometric configurations conform to the general formula for the unique conditions of a particular shape. The solution to this problem also depends on the relationship between magnetic intensity and magnetic field induction, the choice of material types such as linear and non-isotropic materials, linear and isotropic materials, nonlinear and non-isotropic materials with hysteresis, and nonlinear and isotropic materials, without permanent magnetization [14].
In other cases, such as in the development of magnetorheological devices (dampers, brakes, mounting, etc.), FEMM is used to solve the problem of magnetic flux density. Using the help of FEMM, solving magnetic problems can be solved quickly. The magnetic flux density, which is complex and challenging to be solved by numerical methods, can be determined by simulating the FEMM by using the material properties data to obtain the magnitude of the magnetic flux density. The simulation results are then used to determine the predicted values such as the pressure difference (in the case of the damper valve) using numerical or calculation methods [15].
The magnetorheology (M.R.) device is a device that implements intelligent materials as a working medium such as magnetorheological fluids (MRFs) and magnetorheological elastomers (M.R.E.s). M.R. devices are types of the controllable (semi-active) category. During its development, this device has been developed into a working medium such as M.R. damper, brake, and mounting for various applications. On the commercialization side, this device is not popular enough because of several things such as higher costs, more difficult production levels, and still under development. However, compared to other types of devices in its application (active and passive), M.R. devices have more advantages. MRFs and M.R.E.s are materials that are often used for research and development of M.R. devices.
As new technologies are developed, these materials have been discovered and developed in several applications. This material is unique because external stimuli can alter it. In this case, magnetorheological fluids are materials with properties that can be controlled by magnetic fields [16]. The MR fluids condition can be altered by using a varying magnitude of the magnetic field. This fluid is composed of magnetic particles that are pressed into a viscosity fluid. The absence of a magnetic field in this fluid causes its lower viscosity. These particles have a tiny size, ranging from 3 to 10 microns [17]. The magnetic particles of M.R. fluids are equipped with a special coating to weaken their magnetism and reduce the tendency to bond with each other between the particles. One of the weaknesses in M.R. fluid is the deposition, which occurs due to differences in density and gravitational force so that the fluid only focuses on the point where it is treated. Another disadvantage is the possibility of leakage into unwanted areas in the mechanism and thickening after long-term use, so component replacement is required. However, the application of M.R. fluid is extensive due to its precise control capabilities and dynamic response [17, 18]. The resulting output is relatively faster and more accurate because it uses an electric current as a conductor when compared to conventional mechanical mechanisms [19].
The structure and properties of the M.R. fluid outside or under the influence of the magnetic field are shown in Figure 1. The changes that occur when the M.R. fluid is under the influence of a magnetic field occurs in less than ten milliseconds. M.R. fluids regain their properties in the temperature range − 40 to 150 C, while the yield points of M.R. fluids range from 50 to 100 kPa [20].
Structures of M.R. fluid, ferromagnetic particles in silicon oil suspension: (a) without magnetic field effect, and (b) with magnetic field effect [17].
The particle chain blocks the flow and converts the liquid to a semi-solid state in milliseconds. This phenomenon develops yield stress which increases with the magnitude of the applied magnetic field [21]. M.R. devices typically consist of hydraulic cylinders containing micron-sized magnetically polarized particles suspended in the fluid [17, 18].
M.R. fluids work in several modes, including shear mode, valve mode, and squeeze mode [22]. MRF has been widely applied through shear mode and valve mode. Meanwhile, the application of MRFs which work with the new squeeze mode, has recently been developed. Also, MRFs can be operated in a combination of common MRFs working modes.
The shear mode is an operating mode in which the MRFs are influenced by a magnetic field between two parallel surfaces. One of the surfaces will move, and the other will be in a fixed condition. The shear mode is mostly applied to brakes and clutches. However, some dampers use a shear mode. The second is flow mode or valve mode; this mode is an operating mode in which the MRFs flow between two parallel surfaces that are at rest and simultaneously subjected to a magnetic field perpendicular to the direction of flow. Many applications of valve mode are found in dampers. Squeeze mode is an operational mode in which the MRFs flow-through two parallel surfaces and are subjected to a magnetic field that is perpendicular to the direction of flow. Squeeze mode is different from shear mode, the force exerted by one of the surfaces is the compression force, while in the shear mode it provides the shear force. Figure 2 shows an illustration of the working principle of each MRFs working mode.
MRFs working mode; (a) shear mode; (b) flow mode; (c) squeeze mode [23].
The commercialization of the use of MRFs technology was first used in 1995 for braking on stationary bicycles. MRFs technology tends to be cheaper and easier to use when compared to previous eddy-current-based braking technologies [24]. The world is full of potential applications for MRFs. Systems that require fluid motion control by changing viscosity, solutions based on MRFs technology may be applied to save functionality as well as costs. Simple and smart technology that can produce better products is the crucial factor of MRFs technology. Superior features such as fast response, simple application of electrical power input and mechanical power output, and controllability make MRFs technology the choice of many engineering technologies. The sliding mode (used in brake and clutch) and valve mode (used in shock breakers) have been thoroughly studied, and several products are already on the market [25].
Besides MRFs, magnetorheological elastomers (M.R.E.s) are also intelligent materials that are currently a topic of development. In the last 20 years, the number of publications related to the creation, characterization, and application of M.R.E. has increased significantly. This significant increase occurred after 1995 regarding the viscoelasticity properties of M.R.E. initiated by Rigby and Jilken in their 1983 publication [26] when it is compared with the number of publications in the field of MRF and MRF applications.
The development of intelligent components based on M.R.E.s must pay attention to the composition of M.R.E.s because it can be formed with a variety of fill materials. The characteristics of the pre-blended matrix greatly influence the physical properties of M.R.E.s, which can make M.R.E.s solid or hollow. However, in general, M.R.E.s use a non-hollow matrix. To obtain a non-hollow matrix, the degassing method can be used to remove air bubbles or voids in the matrix. The magnetizable particles have an essential role in the magnetic induction properties of M.R.E.s. Much research has focused on these magnetized particles to achieve better rheological properties. Particles that are generally used are iron particles because they have a high permeability value and can be magnetized well [27]. M.R. effect is greatest due to the relationship between iron particles, this property can be achieved with high permeability and particle saturation. However, high saturation is also followed by an increase in the residual magnetic field that appears [28]. Therefore, the use of alloy particles in M.R.E.s, such as iron and cobalt or nickel alloys, is not as widely used as the use of C.I.P. The residual magnetic field in the particles will remain after the magnetic field has been lost so that the M.R. properties cannot return to their original state [29]. The size of the particles must be considered because it affects the properties of M.R.E. in receiving several magnetic domains.
Magnetic reluctance, or magnetic resistance, is a concept used in the analysis of magnetic circuits. It is defined as the ratio of magnetomotive force (mmf) to magnetic flux. It represents the opposition to magnetic flux and depends on the geometry and composition of an object.
Magnetic reluctance in a magnetic circuit is analogous to electrical resistance in an electrical circuit in that resistance is a measure of the opposition to the electric current. The definition of magnetic reluctance is analogous to Ohm law in this respect. However, the magnetic flux passing through a reluctance does not give rise to the dissipation of heat as it does for current through a resistance. Thus, the analogy cannot be used for modeling energy flow in systems where energy crosses between the magnetic and electrical domains. An alternative analogy to the reluctance model, which correctly represents energy flows is the gyrator–capacitor model. The magnetic circuit is derived using Kirchoff law, as illustrated in Figure 3 [30, 31].
Illustration of reluctance circuit on M.R. device.
The symbols 1 dan Mrfluid are used to illustrate the reluctance of the design. So that it can be obtained as in the Eq. (1):
where L is the effective distance that magnetic flux passes in each slice, μ is the magnetization property, and A is the effective area of the magnetic flux. Eq. 2 shows the total magnetomotive force generated from the sum of the magnetomotive force on all parts contained in one loop. So that we get the direct magnetomotive force for magnetic flux and reluctance as illustrated below,
Magnetic flux depends on a large number of copper coils and the current flowing in the coil so that Eq. (2) can be rewritten as Eq. (3),
where N and I are the numbers of copper turns on the coil and the current flowing in the coil.
The dimensions of the M.R. device depend on the target performance required, the function, and the space to be used. Dimensions determine the level of difficulty or ease in the M.R. device manufacturing process. Besides, according to the control classification of M.R. devices, dimensions will affect the value of pressure drop and damping force as well as the appearance of the device. One example is the configuration of a geometric arrangement that relies on the length of the fluid flow path in the equation to determine the predicted value for pressure drop.
In this case, suppose that the target to be achieved is the pressure drop and damping force. The target pressure drop and damping force should be considered according to the needs and functions of the device. The milestones are related to the dimensions of the devices that have been designed. It is the determination of the number of devices that must be used with the available space and the targets that must be achieved.
FEMM can be simulated with some software. In general, all simulation procedures in some software are almost the same, such as FEMM and Ansoft Maxwell. The simulation process starts by making a design that will be simulated in a two-dimensional sketch. However, to perform a FEMM simulation, in general, the design to be simulated is made in two dimensions. Next is the material selection stage, coil configuration, meshing, and simulating as described below:
The initial settings made in the FEMM software are problem settings to be simulated. In this case, the problem to be simulated is a magnetic problem with axisymmetric.
After making the initial setup and exporting the 2D design, then select the material according to the design that has been made. Material selection can be done by taking the existing software library or creating materials that have not been provided by FEMM by inputting all material property data to be used. Material selection can be seen in Figure 4 above:
Material selection.
The coil that will be used is inserted when performing the magnetic simulation with the FEMM software. In determining the coil, it is needed to input the type of wire, the number of turns, and the current that will be used.
This process is an essential part of the simulation. The meshing process is a process of dividing an area which is divided into several areas to simplify the simulation process. Figure 5 shows the results of the FEMM simulation meshing.
Meshing result.
The simulation software used is the Finite Element Method Magnetics (FEMM). The software is used to simulate the magnetic valve design that has been made. 2D designs that have been created are then exported to FEMM. Next, the problem setting to be simulated is determined, namely the magnetic problem with the symmetrical type. After the basic settings for the simulation are carried out, then adjust the material selection and coil selection according to the design that has been made.
The materials selection in the valve circuit is considered to get optimal results. Material selection is based on a predetermined valve design. Thus the direction of magnetic flux can be bent by nonmagnetic materials and produce a magnetic flux direction that is perpendicular to the direction of fluid flow. This is under the coil configuration, and the fluid flow path geometry arrangement used to obtain the magnetic flux direction perpendicular to the fluid direction.
After all the parameters have been adjusted, proceed with the meshing process and simulate to get the magnetic flux density (B) results, as shown in Figure 6.
(a) Magnetic flux density results from the FEMM simulation; (b) magnetic flux density plot.
This study describes a 3D magnetic simulation design of a magnetorheological multi-coil brake (M.R.B.). The design used in this study is an axial M.R.B. design with a configuration of more than one coil that is placed outside the casing. The placement of the device aims to simplify the brake maintenance process. Figure 7 shows the multi-coil M.R. brake design in vertical and horizontal views. The simulation process is only carried out on a pair of coils that represent the entire coil and can distribute the magnetic flux to the entire electromagnetic part. The purpose of this simulation is to determine the results of the magnetic flux on the surface of the disc brake rotor. This simulation uses the FEMM modeling approach assisted by Ansoft Maxwell software.
Multi-coil MR brake design; (a) vertical view; (b) horizontal view.
The result is that the magnetic flux value of M.R.B. with a multi-coil configuration is higher than the magnetic flux value in conventional M.R.B. which only uses one coil with a larger size. Furthermore, the simulation results that have been obtained are used to determine the effect of different fluids on each variation. This study used several types of magnetorheological fluids (MRFs), MRF-122EG, MRF-132DG, and MRF-140CG, which were injected into each device design. Variations in the electric current input of 0.25 amperes, 0.50 amperes, 0.75 amperes, and 1.00 amperes are given in the simulation process. The results of magnetic flux distribution for MRF-132DG with the difference in current input can be seen in Figure 8 below:
Comparison of magnetic flux distribution to variation of MRFs; (a) 0.5 amperes; (b) 0.75 amperes; (c) 1 ampere.
The resulting magnetic flux values were obtained from the FEMM simulation. The simulation is carried out by taking several variations of the electric current input and the difference in the fluid flow gap given to the device. The results show an increase in magnetic flux with each increase in electric current input and an increase with each narrower gap. As an example is the MRF-132DG design simulation for the MRF-132DG type, as shown in Figure 9 below:
FEMM simulation results for magnetic flux.
In this study, silicone R.T.V. based anisotropic magnetorheological elastomer with 70% weight fraction of iron particle were fabricated using a validated mold and capable of aligning the particle in several angles (0°, 45°, dan 90°). This study begins with the fabrication of anisotropic M.R.E. curing mold, which covers the stage of design, simulation, prototype fabrication, and validation. Anisotropic M.R.E. mold was designed using Autodesk Fusion 360. To determine the value of magnetic flux density and distribution throughout the print, it was examined using simulations on Ansoft Maxwell. The simulation results show that the best magnetic flux density value on the mold is 0.3 T to form a good particle alignment in the matrix. At the same time, the magnetic flux density value of 0.3 T can be achieved by providing an electric current input of 0.2, 0.1, and 1 ampere respectively for the mold angles of 0°, 45°, and 90° during the curing chamber. This curing process is carried out for three hours under a magnetic field and left for one day before the sample is taken.
Magnetostatic simulation has a vital role in this research. The simulation process is carried out using Ansoft Maxwell software. This simulation is useful in estimating the magnetic flux density value in the curing chamber and knowing the direction of the magnetic field vector formed. The mold design that has been made will be simulated with various current values so that it can be seen as the current value needed to generate a magnetic flux density value of 0.3 T in the curing chamber. The magnetic properties data from V.S.M. are used to create new materials in the simulation. Thus, the material formed in the simulation is the same as the material used as the mold material. After the material in the simulation is the same as the actual condition, it is expected that the results of the simulation will not differ much from the measurement using a gauss-meter.
The simulation was carried out by providing variations in the angle of formation of M.R.E. with 0°, 45°, and 90°. One of the simulation results using an angle of 45° is shown in Figure 10 below:
Simulation results of a 45°: Vector magnetic (a) distribution of magnetic flux and (b) vector.
Figure 10 shows the distribution of the magnetic flux over a 45° curing space. The distribution of magnetic flux density in the curing chamber is marked in green color, which means that the value of the magnetic flux density in the area is medium. By changing the angle of the curing space by 45° relative to the direction of the magnetic field vector, anisotropic M.R.E. with a particle arrangement of 45° can be produced. After simulating several current values, the current required to produce 0.3 T in the curing chamber is 0.1 A. The graph in Figure 11 shows the low magnetic flux density values on the left and right of the graph. This is because the measuring line of the magnetic flux density value touches the wall of the curing chamber, which is made of nonmagnetic aluminum.
Magnetic flux density distribution values in a 45° curing chamber at a current of 0.1; 0.2; 0.3; 0.5; and 1 A.
In recent research, M.R.B. T-shaped usually used more than one wire coil electromagnetic to maximize magnetic flux reaching all Magnetorheological Fluids (MRFs) gap. This research was focused on the reduction of wire coil on Magnetorheological Brake (M.R.B.). Serpentine flux was used to maximize all MRFs gaps that only use a single coil. The research was begun by designing M.R.B. design, followed by magnetostatic simulation using Finite Element Method Magnetics, calculate braking torque based on simulation, prototyping M.R.B. to get real braking torque measurement, and the last was measure braking torque using a torque sensor with constant angular velocity. The result of magnetostatic simulation shows the magnetic flux that reaches all MRFs gap. The most excellent magnetic flux density was 0,45 T at 1 A current on the outer annular. This result was used to calculate shear stress based on Bingham Model that would generate braking torque. The braking torque generated on modeling torque and experiment was 1,51 Nm and 1,91 Nm at 1 A current with 20% difference, respectively. Figure 12 shows an exploded design of M.R. brake.
Exploded design of M.R. brake.
The use of an electric current greatly affects the magnetic flux density. The greater the electric current used, the greater the magnetic flux density produced. It can be illustrated in Figure 13. The results given show the change in the resulting magnetic flux density, which is marked in a darker color, accompanied by more flux lines produced. The change has a limit point due to the ability of the material [32] as well as the flux that attaches to a particular component.
Simulation results for magnetostatics: (a) 0.1 A; (b) 0.5 A and (c) 1 A.
Figure 14 shows the distribution of magnetic flux density along the MRF gap with different variations of electric current. At current 1 A, the greatest magnetic flux density value exceeds 0.45 T, which is in the outer annular part. The higher the current applied, the lower the increase in magnetic flux density. This is because the direction of the magnetic flux is getting closer to the wall so that the resulting flux is limited. The ability of the copper wire to distribute magnetic flux also affects the result.
Distribution of magnetic flux density along the MRF gap at variations of electric current 0.1–1 A.
The new concept of a magnetorheological (M.R.) damping device used in the seismic building is discussed in this paper. The damper is aimed to deliver a comparable damping performance with the existing semi-active seismic damper design but with lower M.R. fluids volume requirement. This capability is achieved through the improvement in the M.R. valve performance using a meandering flow structure which was placed in the bypass line. Figure 15 shows the sectional design of M.R. damper for seismic building and its valve.
M.R. damper for seismic building design.
This research is focused on the performance analysis of the M.R. valve pressure drop using an analytical approach. There are two main steps needed for the analytical approach, the magnetic field simulation, and the analytical pressure drop calculation. The simulation work of the M.R. valve magnetic circuit performance was carried out using finite element method magnetic (FEMM) software to calculate the distribution of magnetic flux density values. The simulated magnetic field density values would then be matched with the M.R. fluids characteristics data to predict the yield stress value of the fluids to be used in the pressure drop calculation. As a result, the M.R. valve is predicted to generate maximum off-state pressure drop of 5.35 MPa and a piston speed of 0.184 m/s. Meanwhile, at on-state condition (1.4 A), the valve is generating pressure drop up to 9.13 MPa at a piston speed of 0.184 m/s. The generated total pressure drop of the M.R. valve reaches 16.39 MPa. The MR fluids that are used in this design are only 1.5 x 10−4 m3. From the generated total pressure drop, the peak of the damping force is obtained with 1.4 A, which is 32.19 kN. Meanwhile, the calculation result of the seismic force is 125.3 kN. Thus, it can be concluded that with the peak generated damping force, this seismic damper design will be capable of providing a damping performance which is appropriate to the seismic force with four parallel devices.
In this study, the FEMM simulation was used to obtain the magnetic flux density value in the valve section. The magnetic flux density value is used to calculate the predicted yield stress value, which is then used to predict the value of the pressure drop and the damping force. Yield stress is obtained through magnetic simulation using FEMM software which aims to obtain a magnetic flux density graph. Then the resulting magnetic flux density value is included in the calculation to get the yield stress value. The simulation process used is a magnetic simulation of the working fluid with a viscosity of 0.112 Pa.s which is obtained from the MRF132-DG property data by Lord Corp [33]. Figure 16 shows the results of 2D magnetic simulations with FEMM and magnetic flux density graphs obtained through the simulation process.
Result of FEMM simulation.
Figure 17 above is obtained from a FEMM simulation based on a 2D design with an MRF132-DG working fluid and 900 coils. The wire used uses copper wire 28 A.W.G. with a diameter of 0.3211 mm with a resistance of 213 Ω/km. The graph shows the results of the magnetic flux density at the annular and radial channel against the variation of current input 0.5 A; 0.75 A; 1.0 A; 1.4 A.
Magnetic flux density result.
Finite element magnetic is a method that can be used to facilitate an intricate work or may not even be completed by other methods. In this case, the field of magnetorheology is an example of a problem by using the finite element method solution. The magnetorheological device is a device that uses iron particle materials whose working principle is to change its rheological properties due to the influence of a magnetic field. This magnetic field gives rise to a magnetic flux density in the device whose magnitude can be determined by solving the finite element method. To find out the magnitude of the magnetic flux density value, some finite element method magnetics software can be used, such as FEMM and Ansoft Maxwell. The solution to these problems can be resolved with the existence of boundary conditions and initial setups that are following the procedure, such as the type of problem, the use of materials, and a clear design configuration. Thus, problems requiring the finite element method can be resolved with good accuracy. Problem-solving with the finite element method simulation is considered more accurate than other methods. In the case of magnetorheological devices, magnetic simulation with the finite element method is very helpful to achieve the research objectives.
The authors gratefully thank the ministry of research and technology (RISTEK/BRIN) for the funding of Hibah World-Class Research 2020-2021.
The authors have no conflict of interest.
The authors thank Ariyo Nurachman Satiya Permata, Ilham Rizkia Nyaubit, Ilham Bagus Wiranto, and Rivananda Rama S that have been doing the simulations for finite element magnetic in magnetorheological devices so the authors could do this book chapter as well.
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