Nominal chemical compositions of the used Al alloys (wt.%).
\r\n\t
",isbn:"978-1-80356-948-2",printIsbn:"978-1-80356-947-5",pdfIsbn:"978-1-80356-949-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"c0d1c1c93a36fd9d726445966316a373",bookSignature:"Dr. Sylvanus Gbendazhi Barnabas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11434.jpg",keywords:"Indigenous People, Natives, First People, Minorities, United Nations, UN Declaration, Indigenous People Rights, Self-Determination, States, Independence, Struggle for Rights, Contemporary Times",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2022",dateEndSecondStepPublish:"May 5th 2022",dateEndThirdStepPublish:"July 4th 2022",dateEndFourthStepPublish:"September 22nd 2022",dateEndFifthStepPublish:"November 21st 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Legal practitioner, consultant and a law academic with a diversity of interest in multi and intra-disciplinary scholarship on legal issues at national regional and international levels.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"293764",title:"Dr.",name:"Sylvanus",middleName:"Gbendazhi",surname:"Barnabas",slug:"sylvanus-barnabas",fullName:"Sylvanus Barnabas",profilePictureURL:"https://mts.intechopen.com/storage/users/293764/images/system/293764.jpg",biography:"Sylvanus Barnabas is a Senior Lecturer in Law at the Faculty of Law, Nile University of Nigeria where he teaches various subjects in law; he obtained the degree of Doctor of Philosophy in international human rights law from Northumbria University at Newcastle upon Tyne, United Kingdom; he has a Master of Laws degree obtained with distinction in Environmental Law and Policy from University of Kent at Canterbury, Kent, United Kingdom; he also holds a Bachelor of Laws degree from Ahmadu Bello University, Zaria, Nigeria; and he is also a qualified a barrister and solicitor of the Supreme Court of Nigeria.",institutionString:"Nigerian Turkish Nile University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Nigerian Turkish Nile University",institutionURL:null,country:{name:"Nigeria"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440204",firstName:"Ana",lastName:"Cink",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440204/images/20006_n.jpg",email:"ana.c@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6494",title:"Behavior Analysis",subtitle:null,isOpenForSubmission:!1,hash:"72a81a7163705b2765f9eb0b21dec70e",slug:"behavior-analysis",bookSignature:"Huei-Tse Hou and Carolyn S. Ryan",coverURL:"https://cdn.intechopen.com/books/images_new/6494.jpg",editedByType:"Edited by",editors:[{id:"96493",title:"Prof.",name:"Huei Tse",surname:"Hou",slug:"huei-tse-hou",fullName:"Huei Tse Hou"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9052",title:"Psychoanalysis",subtitle:"A New Overview",isOpenForSubmission:!1,hash:"69cc7a085f5417038f532cf11edee22f",slug:"psychoanalysis-a-new-overview",bookSignature:"Floriana Irtelli, Barbara Marchesi and Federico Durbano",coverURL:"https://cdn.intechopen.com/books/images_new/9052.jpg",editedByType:"Edited by",editors:[{id:"174641",title:"Dr.",name:"Floriana",surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10981",title:"Sport Psychology in Sports, Exercise and Physical Activity",subtitle:null,isOpenForSubmission:!1,hash:"5214c44bdc42978449de0751ca364684",slug:"sport-psychology-in-sports-exercise-and-physical-activity",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/10981.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde Dorthea Grindvik",surname:"Nielsen",slug:"hilde-dorthea-grindvik-nielsen",fullName:"Hilde Dorthea Grindvik Nielsen"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10211",title:"The Science of Emotional Intelligence",subtitle:null,isOpenForSubmission:!1,hash:"447fc7884303a10093bc189f4c82dd47",slug:"the-science-of-emotional-intelligence",bookSignature:"Simon George Taukeni",coverURL:"https://cdn.intechopen.com/books/images_new/10211.jpg",editedByType:"Edited by",editors:[{id:"202046",title:"Dr.",name:"Simon George",surname:"Taukeni",slug:"simon-george-taukeni",fullName:"Simon George Taukeni"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7811",title:"Beauty",subtitle:"Cosmetic Science, Cultural Issues and Creative Developments",isOpenForSubmission:!1,hash:"5f6fd59694706550db8dd1082a8e457b",slug:"beauty-cosmetic-science-cultural-issues-and-creative-developments",bookSignature:"Martha Peaslee Levine and Júlia Scherer Santos",coverURL:"https://cdn.intechopen.com/books/images_new/7811.jpg",editedByType:"Edited by",editors:[{id:"186919",title:"Dr.",name:"Martha",surname:"Peaslee Levine",slug:"martha-peaslee-levine",fullName:"Martha Peaslee Levine"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"63746",title:"Wetting of Al Alloys for Hot Dipping Coating Process",doi:"10.5772/intechopen.81282",slug:"wetting-of-al-alloys-for-hot-dipping-coating-process",body:'At high temperatures, wetting of a solid (metal or ceramic) by the molten metallurgical melts is of great technological importance in a variety of metallurgical processes, e.g, hot dipping coating process, brazing process, casting process and sintering process. Each process has the different optimal wetting condition. For the hot dipping coating process, the perfect wettability of base materials by liquid metal is demanded. Two key issues for wetting at high temperatures include the spreading dynamics (wetting behavior) and the final wettability (the degree of wettability). For the former issue, it determined the technological parameters in process; for the latter issue, it would be one of the critical evaluation bases for whether the process can be carried out or not.
The description of wettability since from 1805 in Young’s work [1], has been well developed, as following,
where θ is contact angle for a liquid equilibrium with ideal solid at the point of triple line, σ
The coating process by using a hot dipping method, although a traditional technology with relatively high energy consumption, is also a reliable technology with high efficiency. The quality of coating directly depends on the wetting of base metal by the coating metal. The performance of coating as well as the technological parameters in the coating process is also affected by the trace addition in the alloys which may act on the solid/liquid interface and(or) the liquid/vapor interface. In this chapter, based on the effect of trace elements on the wetting behaviors and the interfacial structures, the wetting mechanism of base metals (steel, Ti6Al4V (TC4) alloy, pure Ti (TA2)) by Al alloys (4043 alloy and 6061 alloy) as well as the formation of precursor film in these systems would be presented in Section 3.
This chapter presents an overview of wetting parameters at high temperatures, wetting mechanism in the isothermal spreading, the effect of trace elements on the formation of interface and the possibility of designed interfacial structures.
At high temperatures, one needs to be careful in the characterization of the wetting of molten metal on the surface of materials (ceramics or metals) with relatively high melting pointing under the quasi-ideal condition.
First, the basic condition is the homogeneous temperature field for wetting should be established.
Second, the average roughness (Ra) of substrate should be obtained before wetting test. Usually, Ra for the metallic substrates after polishing and the monocrystal ceramic substrates are in the range of dozens of nanometers over a distance of 2 mm, Ra for the polycrystal ceramic substrates after polishing are in the range of hundreds of nanometers which depends on the relative density of the polycrystal ceramic substrates.
Third, due to the high sensitivity of metal to oxygen, the oxygen partial pressure in the atmosphere should be controlled, usually in a vacuum of ~10−4 Pa or a dried-deoxidized Ar atmosphere, the oxygen partial pressure was estimated to be lower than 10−14 Pa [2] in such a high vacuum, and the oxygen partial pressure was estimated to be lower than 10−8 Pa [2] in a dried-deoxidized Ar atmosphere.
Once the above conditions were confirmed, and then the various methods for the testing should be considered.
Several methods for the testing at room temperatures, such as sessile drop method, wetting balance method, vertical rod method, tilted plate method, capillary rise method, etc., but the sessile drop method based on the complicated calculation is usually adopted due to the good feasibility. One also should note that the sessile drop method used in more than 90% of wetting studies at high temperatures [3]. The size of drop for testing should refer to its capillary length (i.e., 2σlv/(ρg)1/2, where ρ is the density of liquid and g is the acceleration due to gravity), and thus a drop of volume ~5 μl with a spherical diameter of ~2 mm will be suitable for obtaining of the contact angle. Advancing contact angle is the parameter which the engineers mostly care about, and thus the study of wetting behavior used the advancing contact angle.
To acquire wetting parameters under the quasi-ideal condition, a specific wetting furnace is necessary, as be shown in Figure 1. The whole device mainly includes the controlled heat system, the vacuum system, the inertia gas flow system, the water-cooling system, and the image acquisition and data processing system. The details of this device were shown in Figure 1(a), W, Ta or Mo was used as a heater, and two typical drop transfer modes were used, the modified sessile drop method and the improved sessile drop method.
(a) Schematic diagram for wetting furnace and (b) the designed wetting furnace.
Comparing to the traditional sessile drop method (substrate and metal were heated together), the mentioned two sessile drop methods have a distinct advantage in measurement of initial contact angle and spreading dynamics, particularly for the system with a chemical reaction at elevated temperatures.
To acquire the wetting parameters accurately, a laser backlight source (650 nm in wavelength and 10 mW in power) together with the band-pass filter is necessary for an image acquisition and data processing system. To insure the reliability of obtained data, the drop profiles were captured in two axes, as shown in Figure 1(b). The typical side view of captured drop profile was shown in Figure 2. Before the calculation of contact angle, every pixel in the image was defined as a coordinate value (x and y coordinates), and then the program can seek the boundary between drop and backlight, and thus the pixel coordinate function of drop profile can be extracted. The function was further fitted by several models, i.e., Young-Laplace model, conic model, circle model. The choice of fitting model depends on the symmetry of captured drop profile or the contact angle. If the drop profile is almost axisymmetric, Young-Laplace model is the first choice. If the profile deviates axis symmetry, conic model is the first choice. If the contact angle is less than 5°, conic model or circle model is the first choice. Based on the results of calculation, the detailed wetting parameters can be obtained, i.e., the contact angle, the base diameter, the density, volume and surface tension of liquid.
Typical captured drop profile.
The chemical compositions of the used materials were shown in Tables 1 and 2.
Si | Fe | Cu | Mn | Mg | Zn | Ti | Al | |
---|---|---|---|---|---|---|---|---|
Al 6061 | 0.60 | 0.90 | — | — | 0.90 | 0.25 | 0.15 | Bal. |
Al 4043 | 4.5–6.0 | 0.80 | 0.30 | 0.05 | 0.50 | 0.10 | 0.20 | Bal. |
Nominal chemical compositions of the used Al alloys (wt.%).
Steel | C | Si | Mn | P | S | Fe | |
---|---|---|---|---|---|---|---|
Q235 | 0.12–0.2 | ≤0.3 | 0.3–0.7 | ≤0.045 | ≤0.045 | Bal. | |
Ti alloy | Ti | Fe | Si | C | Al | V | O |
TC4 | Bal. | 0.3 | — | 0.1 | 5.6–5.8 | 3.5–4.5 | 0.2 |
Pure Ti | Ti | Fe | Si | C | N | H | O |
TA2 | Bal. | 0.3 | 0.15 | 0.1 | 0.05 | 0.015 | 0.2 |
Nominal chemical compositions of the used substrates (wt.%).
Based on the wetting characterization, to establish the relationship of wetting behavior and surface/interface evolution, further reveal the wetting mechanism, some necessary micro-analysis were also carried out.
Trace elements in Al alloys, which may act on the surface of drop and/or the solid/liquid interface, and thus the industrial grade Al 4043 alloy and Al 6061 alloy were selected in this work which are of Si addition (~5 wt.%) and of Mg addition (~1 wt.%), respectively. The Si addition may both act on the surface of drop and solid/liquid interface, and the Mg addition may act on the surface of the drop mainly. The metallic substrates were selected as a reactive wetting system, i.e., Al/steel (low-carbon steel), Al/TC4 (Ti6Al4V) and Al/TA2 (TA2 grade pure Ti) systems.
The melting points of Al 4043 alloy and Al 6061 alloy were confirmed by DTA method (STA449-C, NETZSCH, and Germany), are 586 and 582°C, respectively, and thus the isothermal wetting experiments were carried out in a high vacuum (~10−4 Pa) by using improved sessile drop method at the range from 600 to 700°C.
The variations in the contact angle and the normalized contact radius (
Variation in contact angle and normalized contact radius with time, (a) and (b) for 4043 Al/steel, (c) and (d) for 6061 Al/TC4, respectively.
Variation in contact angle and normalized contact radius with time, (a) and (b) for 4043 Al/TC4, (c) and (d) for 6061 Al/TC4, (e) and (f) for 4043 Al/TA2, (g) and (h) for 6061 Al/TA2, respectively.
During spreading, the precursor film (diffusion bond or so called “wetting halo”) was formed at the latter stage of spreading in some specific samples. As shown in Figure 5(a)–(c) are the top-views for the samples after isothermal wetting at 650, 700 and 750°C for Al 4043/steel, and the top-views of (a-1) to (c-1) for Al 6061/steel samples after isothermal wetting at 600, 650 and 700°C. As a consensus, the formation of the precursor film always accompanies the good final wettability, and the larger width of the precursor and the better final wettability. Therefore, the final wettability of Al 6061/steel is better than Al 4043/steel at the same experimental temperature, although the latter has some precursor film at 650 and 700°C, the width of them is very limited (~500–1000 μm). Such a congruent relationship is also suitable for the wetting of metal/ceramic systems [4]. Also, in all Al/TC4 and Al/TA2 (except for Al 6061/TA2 at 600°C which is nonwetting at the final state), the precursor film can be found at the final state after wetting, also can be seen in Hg/Ag system [5] in the study by Be’er et al. However, the formation mechanism is so different from the evaporation-condensation mechanism (suggested by de Gennes [6]) and the surface diffusion mechanism (suggested by Li et al. [7]). Further, the precursor film, in a metal/ceramic system, especially for the melt contain some concentration of the active element, is an adsorbed film. The formation of the film should satisfy some specific conditions, as we reviewed before [4].
Top-view of some typical sessile drop samples of Al/steel after the wetting experiments in vacuum: (a)–(c) for Al 4043 sample at 650, 700 and 750°C; (a-1)–(c-1) for Al 6061 sample at 600, 650 and 700°C.
The sectional views of interfacial structures for Al 6061/steel and Al 4043/steel samples are obviously different after isothermal wetting at the same temperature (at 650°C), as shown in Figures 6(a) and 7(a). Although two types of Fe-Al intermetallics can be found in all the samples (bottom: the continuous Fe2Al5 layer, upper: discontinued FeAl3), the effect of trace elements on the interfacial structures is obvious. In Al 4043/steel, the addition of Si segregated at solid/liquid interface which enhanced the interfacial reaction, so that the barrier of interdiffusion was established. Both Si element distribution map (Figure 6(c)) and the elements line distributions for the corresponding position of Figure 6(b) show Si is incline to segregate at solid/liquid interface rather than surface of liquid. Also, the segregation of Si induced the brittleness of the compact Fe2Al5 layer [8], which induced some continuous and propagating cracks. Actually, some Si was dissolved into the Fe2Al5 phase as a solid solution due to the Si segregation, which can be rewritten as Fe2(Al1−xSix)5, where x is in the range of 0.0625–0.104, as reported by Gupta [9]. Comparing with Al 4043/steel, in the interface of Al 6061/steel, no Mg segregation (even no trace of Mg) can be found in the interface or the bulk of drop due to the high volatility of Mg under the vacuum condition, as shown in Figure 7(a)–(c). The Fe2Al5 reaction layer on steel side is irregular and stretches into the steel side, which is one of the main differences from Al 4043/steel interface. Without the barrier of interdiffusion, the grain boundary as a short-circuit diffused path, Al element prefers to diffuse into the grain boundary, and then reacted with Fe. The X-Ray micro-Diffraction (micro-XRD) pattern of the phases at the surface of the precursor film for Al 6061 sample after isothermal wetting at 700°C in Figure 7(d) shows the precursor film contains Fe2Al5, i.e., the extended reaction layer.
Cross-sectional views of interface structures (Al 4043/steel): (a) at the close of triple line, (b) the central position at interface, (c) Si element distribution map corresponding to the purple rectangle in (b).
Cross-sectional views of interface structures (Al 6061/steel): (a) at the close of triple line, (b) the central position at interface, (c) the typical energy spectrum for the position of yellow cross in (b) and (d) the XRD pattern for the surface of precursor film.
Understanding the reasons caused the wetting, is the benefit of further controlling the manufactured process, which is the prime concern of engineering. In a metallic system, the first obstacle for wetting is the oxide film on the surface of substrate. Protsenko et al. [10] considered the effect of the formation of intermetallic compounds in the wetting with the metallic substrate covered by oxide film. By the formation of IMC by diffusion of reacting components through the thin oxide layer, the oxide film can be disrupted and then in situ a clean surface of intermetallic for wetting can be created. Also, as suggested by Durandet et al. [11], the precipitation of Fe-Al intermetallics is so fast even the contact time of liquid Al and steel as short as 20 ms. Further, the thickness of the IMC layer in this work is larger than the oxide film (in nanoscale), and thus the precipitation of IMC may be a factor for improving wettability. However, the time for spreading cannot correspond to the fast reaction.
The dynamic of IMC precipitation should not be the limited factor for spreading. Although the nonwettable Fe—O oxide film would block wetting, a reduction reaction 2yAl + 3FexOy = yAl2O3 + 3xFe can take place based on the thermodynamic consideration [12], and then Al melts can further react with the fresh surface of Fe. As known, the whole process is limited by the slowest step, and thus the reduction step may be the limited factor for spreading. In Al 6061/steel, although no trace of Mg was observed, the volatilization of Mg cannot be neglected. As suggested by Miller and Pa [13], Mg vapor as a gas flux can reduce Al2O3 in the brazing process of Al alloys. Here, the Fe—O oxide film also can be reduced by Mg vapor due to the more positive formation of Gibbs free energy of Fe—O compounds [12] under the same thermodynamic condition. Based on the result of microstructures, although the precursor film for Al 4043/steel also can be found, it only appears at high experimental temperature with very limited width due to the slight volatility of Al. All the interfacial structures indicate that the formation of the precursor film is related to the volatility of the active element in the specific system. However, the formation mechanism is not the evaporation-condensation mechanism. When the base metal was covered by the thin oxide film, the molten metal would infiltrate under the covered oxide film and then trigger the moving of triple line, and thus the spreading in this stage is also called secondary spreading or wetting, i.e., the formation of precursor film satisfies the subcutaneous infiltration mechanism (as proposed by Zhuang and Lugscheider [14]).
Based on the final wetting states, i.e., nonwetting and wetting states, the typical interfacial structures were selected, as shown in Figures 8, 9, 10. In Figure 8(a) and (b), the precursor with width of several millimeters as well as some Al-Ti intermetallics in the precursor film can be found. The obvious precursor film in Al/TC4 and Al/TA2 (except for the Al/TC4 and Al/TA2 at 600°C which are nonwetting) has the same formation mechanism i.e., so-called “subcutaneous infiltration”. The final wettability was less affected by the oxide film but was determined by the reaction products at the liquid/solid interface. As known, although some residual oxygen in the vacuum chamber could dissolve into Ti due to the high affinity of Ti to oxygen, and then inducing oxidation, however, the diffusion rate for oxygen into the interior of Ti is faster than the oxidation rate so that the oxide film would be thinned or even removed. In Al/TC4 and Al/TA2 systems, both the temperatures and the alloying elements (Si and Mg) caused the different interfacial structures and are responsible for the different final wettability. In Figure 8(d)–(f), the typical cross-sectional view of Al 6061/TC4 after isothermal wetting at 600°C shows the chemical compositions of the granular phase distributed above the reaction layer are closed to Al3Ti. The original concentration of Si in the bulk Al 6061 alloys is only 0.6 at.%, but the concentration of Si in the continuous reaction layer is far beyond that value, as shown in Figure 8(e). The distinct segregation of Si in the reaction layer was formed during wetting. For the nonwetting sample of Al 4043/TC4 (after wetting at 600°C), as shown in Figure 9(a) and (b), the interfacial structures with the virgate phase but no granular phase near triple line and the virgate phase together with granular phase at the center position can be found. Si concentration in the virgate phase is extremely high comparing with the original concentration in bulk Al 4043 alloy, as shown in Figures 9(c)–(e).
(a) Top-view of the microstructures around the triple line for Al 6061/TC4 after isothermal wetting at 600°C; (b) detail of the black rectangle area in (a); cross-sectional view of Al 6061/TC4 (c) near the triple line and (d) at central position of the interfacial microstructures with the elemental line distribution results; (e) and (f) EDS results for the corresponding colored crosses in (d), respectively.
Cross-sectional views for Al 4043/TC4 after isothermal wetting at 600°C: (a) at the triple line; (b) at the center of the interface; (c)–(e) the EDS results for the corresponding cross, circle and triangle in (b).
(a) Top-view of the microstructures at the triple line for Al 4043/TC4 after isothermal wetting at 650°C; (b) detail of the black rectangle area in (a); cross-sectional view of Al 4043/TC4 (c) at the triple line, and (d) at center of the interfacial microstructures with the elemental line distribution results; (e) and (f) EDS results for the corresponding colored crosses in (d), respectively.
For the wetting sample of Al 4043/TC4 which is similar to the interfacial structures in Al 6061/TC4, a precursor film with width of several millimeters was formed. However, such a precursor film contains two layers, as be shown in Figure 10(a) and (b). From the cross-sectional view of the film (Figure 10(c)), the upper layer is the residual Al, which was attracted by the capillary force from the loose reaction layer. At the central position of the interface (Figure 10(d)), the loose continuous layer also can be found, but the virgate phase almost disappeared and only can be found sporadically above the loose layer. Based on the EDS results (Figure 10(e) and (f)), the loose layer may be a continuous Al3Ti layer dissolved with Si as a solid solution. For the sample of Al 4043/TC4 after isothermal wetting at 650°C, the solidified Al was removed by NaOH aqueous solution (1 mol/L), and the macroscopical appearance of the sample and the details for the corresponding positions were shown in Figure 11. The granular phase in Figure 11(b) is corresponding to the loose continuous reaction layer, and the lamellate phase is corresponding to virgate phase in the cross-sectional view of the interface. Further, as shown in Figure 12, the XRD of the phases at the corresponding surface confirmed the granular phase (the loose continuous reaction layer) is Al3Ti, and the lamellate phase is Ti7Al5Si12 (τ1, a solid solution of Al in the TiSi2 phase [15]).
(a) Solidified Al for the sample of Al 4043/TC4 after isothermal wetting at 650°C was removed by NaOH aqueous solution (1 mol/L); (b) and (c) the microstructures for the corresponding positions in (a).
XRD patterns of the phases at the precursor films: for (a) Al 6061 and (b) Al 4043 samples after isothermal wetting at 700°C; (c) the exposed interface of Al 4043/TC4 after isothermal wetting at 650°C through removing of the solidified Al drop using NaOH aqueous solution, and (d) the original surface of TC4.
The formed Ti7Al5Si12 is a metastable phase, once the temperature was above 579°C, a decomposed reaction of Ti7Al5Si12 would take place, i.e.,
Al-Ti-Si partial isothermal section at 700°C for Al rich corner [
Si addition in Al alloys, as known, is a surface-active agent which can decrease the surface tension of the liquid and increase the flowability. However, in Al-Si/steel or Al-Si/Ti system, the interfacial microstructures confirm the affinity of Si to Fe (or Ti) is relatively higher than that of Si to the Al matrix. The Si segregation at the liquid/solid interface satisfies the thermodynamic condition. Such a thermodynamic model also can be used for predicting the segregation of alloying element at the liquid/solid interface. The adsorption energy based on the affinities, which can be described as following [3],
where
where
The calculated
B-M/A | Mg-Al/Fe | Mg-Al/Ti | Mg-Zn/Fe | Mg-Si/Fe | Mg-Cu/Fe | Mg-Ni/Fe | Mg-Si/Ti | Mg-Al/Cu | Mg-Si/Cu | Al-Si/Fe |
---|---|---|---|---|---|---|---|---|---|---|
−149 | −212 | −73 | −133 | 6 | −35 | −249 | −17 | 21 | −20 | |
B-M/A | Al-Zn/Fe | Al-Si/Ti | Al-Si/Cu | Cu-Ag/Si | Ni-Zn/Fe | Al-Cu/Fe | Cu-Si/Fe | Cu-Zn/Fe | Mg-Zn/Ti | Al-Mg/Ti |
43 | −73 | 1.8 | 21 | 70 | 181 | −118 | −42 | −137 | 221 |
All the variation in spreading of Al/steel and Al/Ti indicated the characteristics of reactive wetting, i.e., the typical linear spreading as well as the interfacial reaction. Reaction-limited models of linear spreading and nonlinear spreading for the description of the wetting behavior, as proposed by Eustathopoulos group, were expressed as following,
where
Arrhenius plot of the kinetic constants
Deduced activation energies from the slopes in Figure 14.
The average activation energy of linear stage and nonlinear stage.
In Al/steel system, two types of spreading mode, i.e., the linear spreading in Al 4043/steel and nonlinear spreading in Al 6061/steel, can be found. The activation energy for Al 4043/steel can be deduced from the slopes, is 8 kJ/mol for Al 4043. Also, the activation energy for Al 6061 can be deduced from the fitting result of Eq. (5), is 86 kJ/mol. In the work of wetting and spreading of molten pure Al on the surface of mild steel, studied by Ishida [17], the linear kinetics were also observed, and the activation energy is 21.8 kJ/mol. Obviously, the trace elements in the systems influenced the spreading dynamics, and caused the different activation energies. In Al 4043/steel, the segregation of Si at liquid/solid interface enhanced the reactivity, and then might lead to relatively small activation energy. In Al 6061/steel, the liquid Mg in molten Al 6061 alloy does not react with Fe directly. The moving of the triple depends on the removing of oxide film on the surface of substrate. The reduction of Fe—O oxide film by the Mg in Al 6061 and the formation of Fe-Al intermetallics play a combined action in the removing of oxide film, which can induce the spreading. Two spreading stages for Al 6061 at 700°C also indicate these two reaction mechanisms. Especially for the latter stage, the reduction reaction mechanism may play a major role on the moving of the triple line corresponding to the prolonged precursor film in this stage. Therefore, the apparent activation energy in Al 6061 is so different from Al 4043 and almost an order of magnitude larger.
In Al/TC4 system, such apparent activation energies should relate to the energy change of reaction. As suggested by Chen et al. [18], Gibbs energy changes of reaction per mole of reactants for the formation of Ti7Al5Si12 and Al3Ti in the range of 600–750°C are ~− 48 kJ/mol and ~− 30 kJ/mol, respectively. For the nonlinear stage, Ti7Al5Si12 decomposition may play a dominant role in the change of interface tension corresponding to the apparent activation energy of 10–38 kJ/mol; for the linear stage, the decomposition of Ti7Al5Si12 and the formation of Al3Ti may play the role for the change of interface tension corresponding to the apparent activation energy of 62 kJ/mol. The relatively higher activity of Si in Al 4043 (due to the higher concentration) may slow down the decomposition of Ti7Al5Si12, and then decrease the apparent activation energy. Further, the residual Ti7Al5Si12 beneath the drop and above on Al3Ti reaction layer at the close of the triple line (Figure 11(c)) should be one of the indicators that two reaction mechanisms together played a role on change of interface tension. Also, in Al/TA2 system, the apparent activation energies indicated that the whole wetting process is controlled by the above mechanism. Therefore, the activation energies (47–84 kJ/mol) may be also corresponding to the decomposition of Ti7Al5Si12 and the formation of Al3Ti.
Aluminizing of steel or Ti alloys can increase the ability of anti-corrosion, the service time and the working temperature, significantly. The wetting of Al alloys plays an important role in the aluminizing process, and thus studied in this work. The following conclusions can be drawn:
In Al/steel, the wettability was improved by intermetallic formation which would lead to the replacement of the oxidized surface by a clean surface of an intermetallic compound, also due to the reduction by Al with oxide film; However, the final wettability of pure Ti (TA2) and Ti alloys (TC4) by Al was less affected by the oxide film, but was determined by the reaction products at the liquid/solid interface. Enhanced peritectic reaction of Ti7Al5Si12 caused the different interfacial structures of TA2 and TC4.
The alloying elements in Al 6061 alloy (with Mg addition) and Al 4043 alloy (with Si addition) resulted in distinctly different interfacial structures, the formation of precursor film and spreading dynamics. Mg played a role like gas flux and reduced the oxide film on the surface of substrate. Si segregated at solid/liquid interface which satisfied the thermodynamic model. Such a thermodynamic model also can be used for predicting the element segregation at the interface.
The precursor film in these reactive wetting systems is an extended reaction layer. The formation of it satisfies subcutaneous infiltration mechanism.
The spreading dynamics of these systems can be described by RPC model, and the activation energies are related to the removing of oxide film covered the substrate or the reaction at interface.
This work is supported by National Natural Science Foundation of China (no. 51665031), “Kaiwu” Innovation Team Support Project of Lanzhou Institute of Technology (no. 2018KW-05).
We have no conflicts of interest to declare.
Cardiac transplantation is the gold standard therapy for end-stage heart failure. The perfection of surgical interventions, development of modern immunosuppressive therapies, and implementation of rigorous transplant care protocols have contributed to better outcomes over the last several years [1, 2]. However, cardiac transplantation is limited by the number of available donor hearts, primary graft dysfunction (PGD), rejection of the heart, as well as by the side effects caused by immunosuppression therapy [3]. Gene therapy is an advanced treatment intervention that can potentially bridge the gap to overcome these common post-transplantation complications. The success of commercially available gene therapy interventions, such as Zolgensma for spinal muscular atrophy and Luxturna for Leber congenital amaurosis, demonstrates that gene therapy provides a viable treatment option for people who would otherwise suffer from diseases that have traditionally been thought of as impossible to treat.
Gene therapy works by altering the genetic composition of cells to confer therapeutic protein or RNA expression to the target organ. To date, it has been commercially used to treat spinal muscular atrophy, Duchenne muscular dystrophy, and for various types of ocular disorders [4]. There are currently many gene therapy clinical trials underway and growing in number (clinicaltrials.gov). Gene therapy based interventions have been studied for various cardiovascular diseases, such as coronary artery disease (CAD), heart failure (HF), and myocardial ischemia (MI) [5]. However, no intervention has yet been able to attain robust or long-term transgene expression in the heart in clinical practice. One promising intervention for HF was the AAV1-SERCA2a therapeutic which was evaluated in human clinical trials (CUPID, AGENT-HF, SERCA-LVAD). The trials, unfortunately, failed to demonstrate that the intervention led to a statistically significant difference in the primary endpoint of time to recurrent HF and secondary endpoint of time to first terminal events [6, 7, 8].
The heart is a complex target for gene therapy interventions due to its location in the body, the mechanical force of blood flow, endothelial barriers, cellular barriers, and the body’s immune response [9]. A cardiac graft being treated prior to transplantation is uniquely amenable to gene therapy as most of these traditional barriers of gene delivery to the heart can be overcome. Through gene therapy, a cardiac allograft can be engineered to express selected therapeutic genes that could prevent the onset of post-transplantation complications and potentially minimize or eliminate the need for traditional systemic immunosuppression medications [10, 11]. Gene therapy for heart transplantation, though attractive, has not been translated clinically.
There are major challenges that need to be overcome for gene therapy to be able to be applied for cardiac transplantation. One of them is that, despite major advances in the understanding of transplant immunology, there remains an incomplete understanding of the mechanisms of both rejection and tolerance. This includes the understanding of the details of regulatory cytokine networks, MHC-antigen interactions during the rejection process, and a complete understanding of co-stimulatory factors and their functions [12]. Another challenge is that most current gene delivery mechanisms confer a transient, low level of gene expression [13]. With the current understanding of gene therapy in the context, it also is unclear what is the optimal dose of the therapeutic transgene needed to confer an appreciable clinical effect. However, recent investigations describe methods of robust and global gene delivery to cardiac grafts that offer promise to overcome this challenge. Similarly, viral vector delivery systems pose risks to the host and allograft via eliciting undesired immune reactions, off-target gene delivery, and genome integration. With the recent success and clinical adoption of
To achieve a successful gene therapy intervention for cardiac transplantation, several components need to be addressed: disease or indication and therapeutic target, use of an appropriate animal to test the therapeutic, selection of the vector for gene delivery, and method for vector delivery. Here we review select post-transplantation complications and potential targets where gene therapy can be implemented to prevent them. We will also review translational animal models that have been developed for investigating gene therapeutic targets. Finally, we will discuss the different viral and non-viral vectors that can be used for gene delivery, the selection of promoters, and the different modalities that have been investigated for the delivery of vectors to cardiac grafts.
There are various insults that a cardiac graft experiences prior to, during, and after transplantation. Early damage to the cardiac graft can happen during the brain or cardiac death of the donor, organ procurement, organ preservation time, the implantation procedure, or as a result of reperfusion injury. These points of insult to the cardiac graft can trigger both innate and adaptive immune responses that result in injury. Common complications that occur following transplantation include primary graft dysfunction (PGD), coronary allograft vasculopathy (CAV), and rejection.
PGD is a leading cause of early mortality post-transplantation [14]. The diagnosis of PGD occurs in the first 24 hours following heart transplantation. It presents as severe ventricular dysfunction of the cardiac graft in the immediate post-transplant period, resulting in low cardiac output and hypotension despite the presence of adequate filling pressures [15]. Either the left, right, or both ventricles can be involved, and the severity of the dysfunction can range from mild to moderate to severe depending on the extent of circulatory support that is needed to maintain hemodynamic stability [16].
Numerous causative factors, starting from donor death to weaning the heart from cardiopulmonary bypass in the recipient, have been identified that contribute to the cause of PGD [17]. These factors relate to ischemic and ischemic-reperfusion injury of the cardiac graft. Additionally, the onset of systemic inflammatory response syndrome and the development of vasoplegic syndrome in the recipient have also been identified as significant causes [18]. Finally, the use of extended criteria donors, such as donation after cardiac death (DCD), has also been identified as a significant risk factor for PGD [19].
The treatment of PGD is primarily through supportive care. It is typically initially managed with the use of inotropic support using catecholamines and phosphodiesterase inhibitors. The next escalation in care is typically the use of an intra-aortic balloon pump, followed by the initiation of advanced mechanical support using extracorporeal membranous oxygenation.
Cardiac allograft vasculopathy (CAV) is a major cause of late heart graft failure [20]. It is characterized by diffuse and concentric narrowing of large epicardial and small intramyocardial arteries due to intimal fibromuscular hyperplasia, atherosclerosis, and vasculitis. As a result, the transplant recipient develops pathological changes within the donor blood vessels leading to a spectrum of diseases ranging from MI to HF. CAV is often unable to be diagnosed by coronary angiography and requires intravascular ultrasound for diagnosis.
The main driver of CAV is believed to be the immune system of the host. The intimal thickening seen in CAV results from an accumulation of smooth muscle cells (SMC) accompanied by the infiltration of T cells and macrophages which further contribute to intimal expansion [21, 22]. Yet CAV lesions characteristically stop at the suture line between the donor and the recipient. The endothelial lining of the vessels remains intact in CAV lesions suggesting that SMC injury may result from sterile inflammation as is seen during cold and warm ischemia effects and ischemia–reperfusion injuries [23].
Current treatments are based on vascular risk factor management and the use of statins and mTOR inhibitors (sirolimus and everolimus) to reduce the development of the disease. Percutaneous revascularization is used to treat focal obstructive coronary stenosis but repeat revascularization rates are high due to restenosis and disease progression [24]. However, patients who go on to develop allograft dysfunction require re-transplantation [25, 26].
Cardiac allograft rejection is among the most common causes of death in heart transplant recipients [1]. Acute rejection is categorized into hyperacute rejection acute cellular rejection (ACR), and antibody mediated rejection (AMR). Currently, recipients undergo routine screening for rejection with endomyocardial biopsies obtained by a bioptome. Hyperacute rejection is due to the presence of preformed host antibodies against the graft and portends an inevitable immediate immune rejection resulting in death [27]. ACR and AMR take longer to manifest and are thus amenable to potential gene therapy intervention and we will focus our discussion on these forms of rejection. To prevent rejection of the cardiac allograft, patients are treated with systemic multidrug immunotherapies. Multidrug immunosuppressive regimens currently used in human transplant recipients are associated with an increased risk of malignancy and opportunistic infections, a metabolic syndrome characterized by insulin resistance and dyslipidemia, and drug-specific toxicity [11].
An understanding of the different insults that the cardiac graft experiences during the different steps of transplantation helps to identify potential targets for gene therapy for cardiac transplantation. The cardiac graft endothelium is vulnerable to ischemic reperfusion injury. In this setting, leukocytes adhere to the activated endothelium. The complement system becomes activated, neutrophils migrate into the cardiac graft, subsequently followed by natural killer cells and macrophage infiltration. These early non-specific inflammatory reactions are then followed by alloimmune reactions that result in massive graft infiltration by dendritic cells, T-cells, B-cells, and macrophages. Donor-derived dendritic cells leave the cardiac graft and migrate to recipient lymph nodes and the spleen. There they present donor antigen to recipient T cells directly and trigger acute rejection.
Many candidate genes that interfere with one of these inflammatory mechanisms have been investigated in the context of cardiac transplantation. One such gene is endothelial nitric oxide synthase (eNOS). eNOS produces nitric oxide which is vasoprotective. Delivery of eNOS into the donor heart attenuated ischemic reperfusion injury, leukocyte infiltration, and cardiac graft rejection in a rabbit model [28]. Similarly, superoxide dismutase (SOD) gene delivery into a donor heart attenuated ischemic reperfusion injury after organ preservation and transplantation in a rabbit model [29]. SOD functions as a free radical scavenger that neutralizes reactive oxygen species generated during ischemic reperfusion injuries. Another target, nuclear factor-kappa B (NFkB), is a transcription factor involved in the up-regulation of pro-inflammatory gene products. One possible therapeutic intervention is to block NFkB in endothelial cells to attenuate ischemia–reperfusion injury in the myocardium. Sakaguchi et al. blocked NFkB by using double-stranded oligodeoxynucleotides with a specific affinity for NFkB (NFkB decoy group) to transduce rat hearts utilizing HVJ envelope [30]. The hearts were then preserved for 16 hours in hypothermic preservation solution before being heterotopically transplanted into a recipient rat. What they found is that the intervention attenuated ischemic reperfusion injury after prolonged heart preservation in hypothermic solution. Another protein that is up-regulated during inflammation and serves as a potential target for gene therapy is heat shock protein-70 (HSP-70). It has an essential role in protein folding and translocation and as chaperones for intracellular proteins. HSP-70 has particularly been shown to be associated with protection against ischemia–reperfusion injury. Jayakumar et al. infused rat hearts using 1 mL of the gene vector solution then incubated the hearts on ice for 10 minutes before heterotopically transplanting them into a recipient rat [31]. 4 days after the intervention, the hearts were perfused on a Langendorff apparatus for 45 minutes followed by reperfusion for 1 hour. They found that post-ischemic recovery of mechanical function was greater in the treatment arm versus control, recovery of coronary flow was greater as well. The conclusion was that HSP-70 gene transduction protects both the mechanical and endothelial function of the cardiac graft.
The most direct and immediate barrier to the success of cardiac transplantation is the recipient immune response. Currently, the most effective clinical therapy is lifetime immunosuppressive therapy. Knowledge about the immune response in transplantation has grown tremendously in recent years such that gene therapy can be used to intervene on different targets of the immune response. Both cell and antibody mediated effector mechanisms are responsible for acute rejection [32]. A strategy to protect the cardiac graft from recipient immune responses is through the delivery of genes that confer proteins to the graft that modulate host immune responses. These would include cytokines or soluble ligands. Qin et al. utilized a retrovirus and a plasmid delivery system to transfer genes that encode transforming growth factor beta-1 (TGF-β and interleukin 10 (IL-10) to a mouse myoblast and non-vascularized cardiac graft [33]. Grafts transduced with either of these genes had significantly prolonged survival when compared with the vector alone (39 days with IL-10 vs. 26 days with TGF-β vs. 12 days with vector alone). The therapeutic effect of transduced IL-10 and TGF-β1 has been demonstrated in follow-up investigations using different types of vectors [34, 35, 36].
Another point of gene intervention would be at the point of T-cell costimulatory activation. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a protein that modulates T-cell costimulatory activation. It becomes upregulated on T-cells upon T-cell activation. Gene delivery of a soluble CTLA-4 immunoglobulin fusion protein (CTLA4Ig) into the donor heart was associated with detectable CTLA4Ig serum levels 120 days after transplantation as well as long-term cardiac graft survival, >100 days in a rat model [37]. However, the expression of CTLA4Ig did enter systemic circulation causing some systemic immunosuppression in the rats. Another similar target is the programmed death-1 (PD-1) gene. It is expressed on activated T-cells, B-cells, and myeloid cells. When PD-1 binds one of its ligands, PD-L1 or PD-L2, it leads to the inhibition of activated T-cells. PD-L1 and PD-1 play an important role in both acute and chronic rejection of transplanted hearts in animal studies [38, 39, 40]. In rejecting human transplanted hearts, PD-L1 expression is decreased relative to PD-1 expression [41]. Gene delivery of soluble PDL1Ig fusion protein into the donor heart moderately prolonged cardiac graft survival in rats [42].
An additional example of gene therapy applied to treat cardiac disease involves targeting angiogenic gene therapy that facilitates neovascularization to augment blood flow in ischemic myocardium. These include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). In particular, these targets have been assessed for treating ischemic disease caused by MI or congestive heart failure. Rosengart et al. delivered 4 x 108 to 4 x 1010 particle units of an adenoviral vector encoding the VEGF gene to individuals undergoing bypass graft surgery and as the sole therapy to the experimental group via mini-thoracotomy. The intervention demonstrated no adverse events and there was symptomatic improvement in both groups [43].
The Angiogenic Gene Therapy (AGENT) clinical trials were the first randomized control trial studies investigating the benefits of stimulating coronary angiogenesis with gene therapy using FGF-4 [44]. FGF-4 was delivered using adenovirus administered by infusion into the coronary arteries of patients with chronic stable angina. AGENT evaluated incremental doses of 3 x 108 to 1 x 1011 particle units. The overall improvement in exercise treadmill time was similar for those in the treatment and the control arms. However, post-hoc analysis showed that when baseline neutralizing antibody titer was controlled for, patients with titers less than 1:100, 44% had increased their exercise treadmill time by more than 30%. In patients with titers greater than 1:100, only 7% had increased their exercise treadmill time by more than 30%. AGENT 2 investigated whether FGF-4 improved myocardial perfusion compared with placebo. A significant decrease in ischemic defect size was observed in the treatment arm (21% relative decrease) that was not observed in the placebo group. AGENT 3 and 4 were planned to determine the efficacy and safety of FGF-4 in the larger population, however, an interim review of the data demonstrated no differences in exercise treadmill time and therefore recruitment was stopped.
HGF as a therapeutic target has been evaluated in numerous studies. In the context of therapy for MI, Jin et al. investigated the long-term effects of HGF in a rat MI model [45]. Utilizing an adenoviral vector for delivery of HGR, the vector was injected directly into the infarct border zone immediately after permanent coronary ligation. 10 weeks post-intervention, there was no significant difference in the left ventricular ejection fraction, but capillary density was significantly higher in the treatment groups, whereas arteriole density was unchanged. Masahiro et al. describe the use of recombinant HGF delivered by HVJ envelope for prolonged cardiac graft preservation in rats during hypothermic storage [46]. The rationale for this choice is that HGF functions as an antiapoptotic factor in the heart. They concluded that the administration of HGF prevented myocardial apoptosis and improved cardiac function after prolonged myocardial preservation in hypothermic solution.
Selection of an appropriate animal model for heart transplantation is critical to be able to translate a potential gene therapy intervention from the laboratory bench to the patient bedside. Numerous small animal models using rodents have been described where the heart is transplanted either heterotopically or orthotopically in the recipient animal. Similarly, there have been numerous large animal models described using pigs, sheep, and non-human primates (NHP). We will discuss examples of different types of small and large animal models in heart transplantation and in what instances an investigator may choose one over the other.
Heterotopic heart transplantation (HHT) is when the transplanted heart is placed in an ectopic position inside of the recipient without the removal of the recipient’s native heart. Intra-abdominal HHT is primarily used to investigate transplantation biology and is also suitable for studying unloading induced changes in the heart [47]. The heart of a donor animal is explanted and subsequently transplanted into the abdomen of a recipient animal. To accomplish this the donor ascending aorta is anastomosed to the recipient infrarenal aorta and the donor pulmonary aorta is anastomosed to the recipient inferior vena cava. The result of this configuration is that the graft beats with reduced left ventricular filling while coronary perfusion is preserved. It offers several advantages over orthotopic transplantation in research applications such as technical simplicity, better accessibility for biopsies, and survival of the recipient even in cases of graft rejection [48].
The first heterotopic abdominal heart transplantation was published using rats by Abbott et al. [49] in 1964 and subsequently modified by Ono et al. [50]. The technique of the latter has been widely adopted as the standard HHT rodent model. Heterotopic heart transplantation in mice is more challenging than in rats, however, testing mechanistic hypotheses is more practical in mice given the greater diversity of genetic modifications available in mice. The advantage of using a small animal model is that they are less costly when compared to the cost of a large animal. A larger number of small animals can be used to assess and describe the effects of a therapeutic transgene. It also allows for several transgenes to be tested in parallel to study the differences in efficacy between them. The main challenge in using small animals is that the micro-surgical implantation technique is very challenging given their smaller size. Another aspect that makes this surgery more challenging to do in smaller animals is that they have a lower tolerance for blood loss. Because of this, it is especially important that there be minimal blood loss during the procedure and that the anastomoses be hemostatic at the time of procedure completion.
The advantage of large animals is that the results of the gene therapy intervention are able to be translated more quickly into clinical practice than are the results obtained from small animal studies. However, large animals are very costly to acquire and maintain in comparison to small models. In the setting of small primates, Minanov et al. positioned NHP hearts into the iliac fossa of primate recipients [51]. More recently this transplant configuration has been used to investigate interventions in xenotransplantation using a porcine heart transplanted into a baboon [52, 53, 54]. Porcine to porcine heart transplantation is also used in the research setting to investigate the immune system effects of cardiac transplantation as well as gene therapy interventions (Figure 1) [55, 56, 57]. This surgical research model is also amenable for modeling post-cardiac transplantation complications, such as CAV and rejection, without subjecting the animal to a high risk of morbidity or mortality [55, 58]. The recent success of a porcine to human xenotransplantation using genetically modified pigs to minimize rejection by the human immune system of the xenograft stresses the importance of the selection of the appropriate animal model. After procuring the heart, the xenograft was preserved utilizing an
Heterotopic heart transplantation in the intra-abdominal position in a large animal porcine model. The donor aorta is anastomosed to the recipient infrarenal aorta and the donor pulmonary artery is anastomosed to the recipient inferior vena cava.
Orthotopic heart transplantation is when the transplanted heart is placed in the position of the recipient’s native heart. As such, the cardiac graft takes over providing the cardiovascular support of the recipient. This transplant configuration in research is most useful to investigate the cardiac graft’s overall ability to support the recipient following an administration of a new intervention. The pros of this design are that it most closely reflects clinical practice so one can investigate beyond the immunopathologic changes the heart undergoes after transplantation. This approach allows the investigator to determine whether an intervention permits the transplanted heart to perform its intended function to support the recipient’s cardiovascular system. This has been successfully described in porcine to porcine models, as well as in pig to baboon xenotransplantation models [60, 61, 62].
Vectors for gene delivery comprise viral and non-viral vectors. Viral vectors are the more efficient of the two but are also associated with more side effects than non-viral vectors. Each type of viral vector confers different gene expression characteristics, such as the length of time for transgene expression and the intensity of transgene expression (Table 1). Additionally, when constructing the optimal vector for cardiac gene delivery consideration must be given to the selection of promoter. Constitutively active promoters, such as CMV or RSV promoters, confer broad tissue tropism and strong expression. However, cardiac-specific promoters, such as myosin heavy chain promoter, myosin light chain promoter, and troponin T promoter have been used to restrict transgene expression in the heart [63]. While the cardiac-specific promoters focus gene delivery to cardiac tissue, they confer weaker expression when compared with constitutively active promoters (Table 2).
Viral vector | Genetic material | Capacity | Transduction ability | Peak gene expression | Main advantages | Characteristics |
---|---|---|---|---|---|---|
Adenovirus | dsDNA | 4.5–36 kb | Transduces both dividing and non-dividing cells. | 1–7 days | Efficiently delivers genes to most tissues. | Short-term but highly efficient gene delivery. Can elicit a strong inflammatory response. |
Adeno-associated virus | ssDNA | 4.7 kb | Transduces both dividing and non-dividing cells. | 2–4 weeks | Low immunogenicity. Broad but specific tropism. | Long-term gene expression. Low immunogenicity. |
Lentivirus | RNA | 8 kb | Transduces both dividing and non-dividing cells. | 4–6 days | Can carry multiple transgenes. Persistent gene transfer in dividing cells. | Persistent gene expression in dividing cells. Low but potential risk of mutagenesis. |
Summary of common viral vectors used in gene therapy.
Reference | Transduced gene | Therapeutic mechanism | Transduction method | Key findings/conclusions |
---|---|---|---|---|
Iwata et al. [28] | eNOS | Attenuation of ischemia–reperfusion injury | Lipid/DNA complex via intra-op coronary infusion | Allogeneic rabbit heart transplant model demonstrated that intramyocardial neutrophil and T-cell populations were halved in eNOS transduced hearts. NF-kB activation in microvascular endothelial cells and cardiomyocytes was significantly reduced. |
Abunasra et al. [29] | SOD | Attenuation of ischemia–reperfusion injury | Ad via | Heterotopic heart transplant model in rats demonstrated positive immunoreactivity for SOD and 86.8% +/− recovery of pre-ischemic left ventricular pressure. |
Jayakumar et al. [31] | HSP-70 | Attenuation of ischemia–reperfusion injury | HVJ envelope via | Heterotopic heart transplant model in rats demonstrated greater post-ischemic recovery of mechanical function and greater recovery of coronary flow in HSP-70 treated mice. |
Sakaguchi et al. [30] | NF-kB decoy | Attenuation of ischemia–reperfusion injury | HVJ envelope via | Heterotopic heart transplant model in rats demonstrated introduction of NF-kB decoy into the nuclei of endothelial cells and cardiomyocytes. After 1 hour of reperfusion the NF-kB decoy group showed significantly higher degrees of recovery of left ventricular function. |
Guillot et al. [37] | CTLA4Ig | Attenuation of T-cell costimulatory pathway | Ad via intramyocardial injection | Heterotopic heart transplant model in rats demonstrated indefinite graft survival (>100 days) and could be detected in the graft at least 1 year after gene transfer. Evident suppression of antibody production against donor alloantigens up to at least 120 days after gene transfer. |
Dudler et al. [42] | PD-L1Ig | Attenuation of T-cell costimulatory pathway | Ad via | Heterotopic heart transplant model in rats demonstrated a prolonged median survival time (17 days vs. 11 days). Also demonstrated a decreased number of CD4 cells and monocytes/macrophages infiltrating the graft. |
Grines et al. [44] | FGF | Angiogenic therapy | Ad via intracoronary infusion | Randomized controlled trial that enrolled patients with chronic stable angina demonstrated improved exercise time on a treadmill for those treated with intervention and had a baseline time < or equal to 10 minutes. Intervention decreased the ischemic defect size. Larger efficacy studies failed to demonstrate significant differences in exercise time on a treadmill so the trial was stopped. |
Rosengart et al. [43] | VEGF | Angiogenic therapy | Ad via intramyocardial injection | Phase I clinical study that enrolled patients with clinically significant coronary artery disease. There were no systemic or cardiac related adverse events related to vector administration. Coronary angiography and stress sestamibi scan showed improvement in the treated area. All patients reported improvement in angina class after therapy. |
Jin et al. [45] | HGF | Angiogenic therapy | Ad via intramyocardial injection | Myocardial infarction model in rats demonstrated no significant difference in the left ventricular ejection fraction. It did observe increased capillary density in the treatment group. |
Ryugo et al. [46] | HGF | Angiogenic therapy/Antiapoptosis | HVJ via cold static storage | Cardiac grafts procured from rats demonstrated that HGF treated hearts had a significantly higher recovery rate of left ventricular developed pressure. c-MET/HGF receptor expression was stronger in the treatment group. |
Summary of investigations of gene therapy for cardiac transplantation.
Adenovirus (Ad) vectors have high transduction efficiency. They are able to transduce both quiescent and dividing cells and maintain epichromosomal persistence in the host cell [64]. Ad vectors also have a broad tropism profile and large packaging capacity (4.5-36 kb). They offer efficient transduction of cardiomyocytes. However, gene expression is transient, peaking 1–7 days after delivery and then diminishing until it ceases at about 2–3 weeks after transduction [65]. They carry double-stranded DNA. Their main disadvantage is the widely pre-existing viral immunity among the general population. Since Ad is strongly immunogenic it causes undesired immune responses in treated subjects [66]. In order to overcome this and improve their capacity, Ad vectors have undergone several generations of engineering.
The first generation of Ad vectors was designed by removing the E1A gene which makes it so the recombinant Ad is unable to replicate within the host cell [67]. With the deletion of this gene, complementary cell lines, such as HEK293, had to be designed to express E1A and E1B in order to produce the viral vector. The main disadvantages of the first generation of Ad were that de novo expression of Ad proteins could activate the host immune response and there was still the possibility of spontaneous homologous recombination between the vector and engineered E1 region from HEK293 that could generate replication-competent adenovirus [68].
In the second generation of Ad vectors, further early gene regions (E2a, E2b, or E4) of the vector were deleted to permit additional space for the transgenes. As in the first generation, the deleted genes needed to be complemented by engineered production cell lines. However, the deletion of these genes led to inefficient complementation of E2/4 with engineered cell lines thus negatively affecting viral vector amplification, resulting in lower titers. Another disadvantage was that the native Ad late genes that were still retained within the viral genome could trigger host immunogenicity and cellular toxicity [69].
Finally, the third generation of Ad vectors have all Ad viral sequences deleted except for the inverted terminal repeat sequences and packaging signal. As such, these are referred to as “gutless” or “high capacity” Ad vectors (HCAd). The production of HCAds in cell culture requires an adenoviral helper virus similar to the first-generation Ad vectors. Compared with the previous Ad vector generations, HCAds have reduced immunogenicity, prolonged transduction in the host cell, and a significantly larger transgene capacity [64]. Their large transgene capacity makes it so that multiple transgenes could be delivered. The main disadvantage of HCAds is the challenge of ensuring that the helper virus is eliminated from the final vector preparation.
Adeno-associated viral (AAV) vectors were discovered as a contaminant of Ad preparations in 1965 [70]. They lack essential genes needed for replication and expression of their own genome. They are not known to cause any human diseases. AAV vector was first used in humans in 1995 to deliver the cystic fibrosis transmembrane regulator (CFTR) gene into a patient with cystic fibrosis using the AAV2 capsid [71]. Today, recombinant AAVs are the leading vectors for the delivery of gene therapies. The first recombinant AAV gene therapy product, Glybera, was approved by the European Medicines Agency to treat lipoprotein lipase deficiency in 2012. Five years later, Luxturna was approved as the first recombinant AAV gene therapy product in the United States [72, 73].
AAVs carry single-stranded DNA (ssDNA). However, the efficiency of AAVs are limited by ssDNA in that it needs to be converted to double-stranded DNA (dsDNA) prior to expression. This step is circumvented through the use of self-complementary vectors which package an inverted repeat genome that can fold into dsDNA without the requirement for DNA synthesis or base-pairing between multiple vector genomes [74]. Transgene expression peaks at around 2–4 weeks after delivery. AAVs can carry transgenes up to 4.7 kb in size.
There are 13 natural AAV serotypes. These have been isolated from laboratory Ad stocks and mostly from human or non-human primate origin [75]. Engineering or recombinant AAV capsids confer the vector the capability to transduce multiple tissue types. Recombinant AAVs are composed of the same capsid sequence and structure as found in wild-type AAVs. Recombinant AAVs encapsidate genomes that are devoid of all AAV protein-coding sequences and that have therapeutic genes designed in their place. The complete removal of viral coding sequences maximizes the packaging capacity of these AAVs and contributes to their low immunogenicity and cytotoxicity [73].
Capsid development approaches are based on rational design and directed evolution. The rational design was among the first approaches to improve vector capsids. This entailed adding peptide sequences onto the surface of the capsid to direct the tropism of the vector and deter immunological recognition [76]. While rational design allowed for the early development of specialized AAVs, a major limitation of that approach is that there oftentimes is insufficient knowledge regarding AAV cell surface binding, internalization, trafficking, uncoating, and gene expression. The basis of directed evolution is in the simulation of natural evolution. Capsid libraries are placed under selective pressure to yield genetic variants with specific biological properties and advantageous characteristics. This way directed evolution of the capsid does not require a prior understanding of the molecular mechanisms involved in the selection criteria [73].
Cell-type specific transgene expression, however, is conferred at the level of gene transcription by the promoters used in AAV vectors. The serotype AAV9 has been shown to have the highest cardiac gene transduction efficacy in mice and rats with either systemic or direct cardiac injection [77, 78]. Meanwhile, the serotype AAV6 has proven to be a more effective vector when injected into the myocardium of pigs and non-human primates [79, 80]. Piacentino et al. described a recombinant AAV serotype engineered via rational design, termed SASTG, which has extremely high-level cardiac transduction and tropism [81]. A challenge for AAV-mediated gene therapy is overcoming the negative effect that innate immunity has on transgene expression. Yet adaptive immunity to the capsid and the foreign transgene is the main factor for decreased efficacy. Notwithstanding, recombinant AAVs are accepted as the least immunogenic when compared to other viral vectors. Patients that have been exposed to AAV serotypes that gene therapy is based on will have a high chance of forming antibodies against the vector capsid [82]. One plausible way of removing these anti-AAV antibodies from the bloodstream is by using plasmapheresis [83]. Another described pre-treatment is the use of IgG-cleaving endopeptidases which reduce IgG antibodies from the serum [84]. Besides removing the neutralizing antibodies, investigators have also utilized rational design and directed evolution to develop AAV capsids that evade neutralizing antibodies [85, 86, 87, 88].
Lentiviral vectors constitute a genus of the retrovirus family. They permit long-term transgene expression by integrating the delivered genes into the host genome and can carry transgenes up to 8 kb in size [89]. They can deliver single-stranded RNA to both dividing and non-dividing cells and display robust transduction efficiency [90]. A unique advantage of lentiviral vectors is the ability to express multiple genes from a single vector [91, 92]. Transgene expression peaks after 4–6 days. The immune response to lentiviral vectors is low but concerns remain about potential insertional mutagenesis and off-target gene expression [93]. They have a preference for targeting the coding regions of genes, carrying the risk of insertional oncogenesis [94]. Additionally, the vector lacks tropism for the heart, making it unideal for heart-specific delivery through
Naked nucleic acids allow for the delivery of large genes in high quantities. These include DNAs, mRNAs, micro RNAs, and siRNAs. However, the lack of protection from endonuclease degradation makes them unreliable with low cellular internalization of the transgene [97]. Additionally, naked nucleic acids have an uncondensed shape and polyanionic charge that does not allow for their efficient uptake into cells. The half-life of plasmid DNA is about 10 minutes following systemic injection into mice [98].
Nanoparticles have been developed to interact with nucleic acids to protect them from degradation and condense them into nano-sized complexes that can be internalized by cells. Two main types of nanoparticles being used in investigations are lipid-based and cationic polymer-based. Another modification that is being used to improve the uptake of naked nucleic acids by cells is through chemical modification to mRNA to reduce the activation of the immune system and improve the stability of the RNA. These modified mRNAs are attractive agents for short-term gene delivery to the myocardium [99].
Wild-type hemagglutinating virus of Japan (HVJ) was discovered in 1953 and is a member of the paramyxovirus family. The envelope of HVJ is composed of a lipid bilayer and two integral membrane glycoproteins, F and HN, that project from the viral surface [100, 101]. HVJ envelope vector is constructed by incorporation of plasmid DNA into inactivated HVJ-containing liposomes [102]. During the preparation of the envelope vector, HN and F are retained but all the genome inside of HVJ is removed. It has high efficacy to induce a molecule into a target cell by the strong action of fusing cells on its membrane. Additionally, the removal of all the virus genomes confers low immunogenicity to the vector and eliminates replication and viral gene expression in cells. It is in essence a “viral, non-viral hybrid vector” [101]. HVJ can be used to deliver DNA, RNA, and oligonucleotides efficiently both
Gene delivery to any organ is a challenging feat. Gene delivery to the whole cardiac allograft is an especially challenging task given numerous obstacles.
Direct intramyocardial injection of the vector into the myocardium is one such technique for vector delivery. It is easy to perform the injections and could theoretically be performed during graft procurement or after cardiac transplantation. Guzman et al. described the use of this technique for the delivery of adenovirus injected through a 25-gauge needle into the cardiac apex [103]. The intramyocardial injection has also been described in a clinical trial where subjects underwent a thoracotomy with the injection of vascular endothelial growth factor-2 naked deoxyribonucleic acid. They found that the procedure is well tolerated and reported few major adverse cardiac events at 1 year [104]. The major limitation of this technique for cardiac transplantation is that it only allows for limited focal delivery and the inability to target deeper muscular structures of the heart, such as the septum. Additionally, it is challenging to keep all of the injected material inside of the myocardium, leading to leakage from the needle holes and causing injury to the heart [105].
Intracoronary infusion of the vector is another described technique. By this method, the vectors are infused directly into the coronary arteries and reach the target cells for transduction by transit through the coronary arterial tree. Intracoronary infusion can be achieved by several methods: coronary catheterization prior to procurement,
Catheterization of the coronary arteries for delivery and infusion through the cardioplegia catheter at the time of the graft procurement allows for a more dispersed and homogenous distribution of transgene delivery than is achieved through intramyocardial injections. Generally, transgene expression is able to be observed along with the distribution of the coronary arteries [2]. Several disadvantages exist with these delivery techniques. One is the negative effect pre-existing coronary artery disease has on the ability of vectors to reach their cellular target. Another is that since the infusion of the vector is based on a single bolus delivery when using a catheter-based approach, there is a large amount of vector that is lost to the systemic circulation resulting in poor transduction efficacy of the heart and a significant amount of off-target transduction. Finally, transduction efficacy is hampered by the presence of circulating neutralizing antibodies in the recipient against viral vectors. Vector particles containing proteins that are similar to antigens that humans are exposed to following natural infection may be neutralized by antibodies upon injection in some humans because of pre-existing immunity [106].
Administration of the vectors during cardiopulmonary bypass featuring complete heart isolation and continuous cardiac perfusion addresses the issues associated with the catheter-based intracoronary infusion. The technique for achieving this was described by Katz et al. using separate pumps for the systemic and cardiac circuits permitting continuous isolated arrested heart perfusion [8]. This allows for the vectors to be recirculated through the coronary circulation of the heart, allowing for additional opportunities for the vectors to attach to cells and achieve entry. However, cardioplegia arrest requires for the heart and circulation to be maintained at a cold temperature (4°C) which is not favorable for vector attachment and entry into the target cells [107].
The procedure for cardiac transplantation offers a unique opportunity for gene delivery that does not exist for other indications for therapeutic intervention for heart disease. The cardiac graft is removed from the recipient and preserved for a period of time
Gene delivery to a whole cardiac graft has been described in both small and large animal models utilizing
Schematic for delivery of viral vectors to a cardiac allograft using normothermic, sanguinous
There are several advantages that make ex vivo normothermic, sanguinous perfusion the ideal platform for translating gene therapy into clinical practice. The ability to recirculate the perfusate through the coronary arteries multiple times over a prolonged period of time optimizes the chances the delivery vectors attach to the target cells and enter. Normothermic perfusion provides a favorable environment for viral vectors to be able to efficiently transduce cells, enabling receptor-mediated vector entry and optimizing the downstream processes of transductions [107]. The main obstacle to overcome with this vector delivery modality is the use of whole blood from the donor to make the circulating perfusate. The presence of preformed antibodies to different viral vectors could effectively neutralize the ability of the viral vectors to achieve cellular attachment. One successful intervention to overcome this is the addition of a blood washing step prior to adding the donor blood to the perfusion device and this way remove any neutralizing blood components [56].
Gene therapy for cardiac transplantation promises to transform clinical practice in the near future with cardiac grafts that are more robust and lasting than ever. However, in order to achieve its widespread adoption, there are various factors that need to be taken into consideration for how to achieve successful vector delivery and transgene expression to the cardiac graft. Here, we discussed several considerations such as choice of vector, choice of the therapeutic gene, and choice of vector delivery mechanism. Just as important is the selection of the appropriate animal model for determining the efficacy and therapeutic effect of a gene therapy construct. The successful translation of gene therapy interventions for cardiac transplantation can potentially minimize or eliminate the incidence of post-transplantation complications and the need for systemic immunosuppression therapy.
All Works published by IntechOpen prior to October 2011 are licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported license (CC BY-BC-SA 3.0). Works published after October 2011 are licensed under a Creative Commons Attribution 3.0 Unported license (CC BY 3.0), the latter allowing for the broadest possible reuse of published material.
",metaTitle:"Translation Policy",metaDescription:"Translation of Works - Book Chapters",metaKeywords:null,canonicalURL:"/page/translation-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"All Works licensed under CC BY-BC-SA 3.0 can be freely translated and used for non-commercial purposes. Works licensed under CC BY 3.0 license can be freely translated and used for both commercial and non-commercial purposes.
\\n\\nAll translated Chapters have to be properly attributed in accordance with the requirements included in IntechOpen's Attribution Policy. Besides proper attribution translated sections of Works must include the following sentence: "This is an unofficial translation of a work published by IntechOpen. The publisher has not endorsed this translation".
\\n\\nAll rights to Books and other compilations are reserved by IntechOpen. The copyright to Books and other compilations is subject to a Copyright separate from any that exists in the included Works.
\\n\\nA Book in its entirety, or a significant part of a Book, cannot be translated freely without specific written consent by the publisher. Requests for permission can be made at permissions@intechopen.com.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:'All Works licensed under CC BY-BC-SA 3.0 can be freely translated and used for non-commercial purposes. Works licensed under CC BY 3.0 license can be freely translated and used for both commercial and non-commercial purposes.
\n\nAll translated Chapters have to be properly attributed in accordance with the requirements included in IntechOpen's Attribution Policy. Besides proper attribution translated sections of Works must include the following sentence: "This is an unofficial translation of a work published by IntechOpen. The publisher has not endorsed this translation".
\n\nAll rights to Books and other compilations are reserved by IntechOpen. The copyright to Books and other compilations is subject to a Copyright separate from any that exists in the included Works.
\n\nA Book in its entirety, or a significant part of a Book, cannot be translated freely without specific written consent by the publisher. Requests for permission can be made at permissions@intechopen.com.
\n\nPolicy last updated: 2016-06-09
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. In the Engineering side, Digital Signal Processing, Computer Architecture, Electronics Devices, Digital Filtering and Engineering Management.\nApart from his Academic Interest and activities he loves sport especially, Cricket, Football, Snooker and Squash. He plays cricket for Esbjerg city in the second division team as an opener wicket keeper batsman. He is a very good player of squash but has not played squash since his arrival in Denmark.",institutionString:null,institution:null},{id:"611",title:"Prof.",name:"T",middleName:null,surname:"Nagarajan",slug:"t-nagarajan",fullName:"T Nagarajan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universiti Teknologi Petronas",country:{name:"Malaysia"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:6669},{group:"region",caption:"Middle and South America",value:2,count:5955},{group:"region",caption:"Africa",value:3,count:2457},{group:"region",caption:"Asia",value:4,count:12710},{group:"region",caption:"Australia and Oceania",value:5,count:1016},{group:"region",caption:"Europe",value:6,count:17716}],offset:12,limit:12,total:134176},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{},books:[{type:"book",id:"9985",title:"Geostatistics",subtitle:null,isOpenForSubmission:!0,hash:"423cb3896195a618c4acb493ce4fd23d",slug:null,bookSignature:"Prof. Jeffrey M. Yarus, Dr. Marko Maucec, Dr. Timothy C. Coburn and Associate Prof. Michael Pyrcz",coverURL:"https://cdn.intechopen.com/books/images_new/9985.jpg",editedByType:null,editors:[{id:"78011",title:"Prof.",name:"Jeffrey M.",surname:"Yarus",slug:"jeffrey-m.-yarus",fullName:"Jeffrey M. Yarus"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10845",title:"Marine Ecosystems - Biodiversity, Ecosystem Services and Human Impacts",subtitle:null,isOpenForSubmission:!0,hash:"727e7eb3d4ba529ec5eb4f150e078523",slug:null,bookSignature:"Dr. Ana M.M. Marta Gonçalves",coverURL:"https://cdn.intechopen.com/books/images_new/10845.jpg",editedByType:null,editors:[{id:"320124",title:"Dr.",name:"Ana M.M.",surname:"Gonçalves",slug:"ana-m.m.-goncalves",fullName:"Ana M.M. Gonçalves"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11027",title:"Basics of Hypoglycemia",subtitle:null,isOpenForSubmission:!0,hash:"98ebc1e36d02be82c204b8fd5d24f97a",slug:null,bookSignature:"Dr. Alok Raghav",coverURL:"https://cdn.intechopen.com/books/images_new/11027.jpg",editedByType:null,editors:[{id:"334465",title:"Dr.",name:"Alok",surname:"Raghav",slug:"alok-raghav",fullName:"Alok Raghav"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11124",title:"Next-Generation Textiles",subtitle:null,isOpenForSubmission:!0,hash:"093f9e26bb829b8d414d13626aea1086",slug:null,bookSignature:"Dr. Hassan Ibrahim",coverURL:"https://cdn.intechopen.com/books/images_new/11124.jpg",editedByType:null,editors:[{id:"90645",title:"Dr.",name:"Hassan",surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11168",title:"Sulfur Industry",subtitle:null,isOpenForSubmission:!0,hash:"39d4f4522a9f465bfe15ec2d85ef8861",slug:null,bookSignature:"Dr. Enos Wamalwa Wambu and Dr. Esther Nthiga",coverURL:"https://cdn.intechopen.com/books/images_new/11168.jpg",editedByType:null,editors:[{id:"187655",title:"Dr.",name:"Enos",surname:"Wambu",slug:"enos-wambu",fullName:"Enos Wambu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11254",title:"Optical Coherence Tomography",subtitle:null,isOpenForSubmission:!0,hash:"a958c09ceaab1fc44c1dd0a817f48c92",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/11254.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11273",title:"Ankylosing Spondylitis",subtitle:null,isOpenForSubmission:!0,hash:"e07e8cf78550507643fbcf71a6a9d48b",slug:null,bookSignature:"Dr. Jacome Bruges Armas",coverURL:"https://cdn.intechopen.com/books/images_new/11273.jpg",editedByType:null,editors:[{id:"70522",title:"Dr.",name:"Jacome",surname:"Bruges Armas",slug:"jacome-bruges-armas",fullName:"Jacome Bruges Armas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11369",title:"RNA Viruses",subtitle:null,isOpenForSubmission:!0,hash:"52f8a3a1486912beae40b34ac557fed3",slug:null,bookSignature:"Ph.D. Yogendra Shah",coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",editedByType:null,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11433",title:"Human Migration in the Last Three Centuries",subtitle:null,isOpenForSubmission:!0,hash:"9836df9e82aa9f82e3852a60204909a8",slug:null,bookSignature:"Dr. Ingrid Muenstermann",coverURL:"https://cdn.intechopen.com/books/images_new/11433.jpg",editedByType:null,editors:[{id:"77112",title:"Dr.",name:"Ingrid",surname:"Muenstermann",slug:"ingrid-muenstermann",fullName:"Ingrid Muenstermann"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11434",title:"Indigenous Populations - Perspectives From Scholars and Practitioners in Contemporary Times",subtitle:null,isOpenForSubmission:!0,hash:"c0d1c1c93a36fd9d726445966316a373",slug:null,bookSignature:"Dr. Sylvanus Gbendazhi Barnabas",coverURL:"https://cdn.intechopen.com/books/images_new/11434.jpg",editedByType:null,editors:[{id:"293764",title:"Dr.",name:"Sylvanus",surname:"Barnabas",slug:"sylvanus-barnabas",fullName:"Sylvanus Barnabas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11436",title:"Beauty - Evolutionary, Social and Cultural Perspectives on Attractiveness",subtitle:null,isOpenForSubmission:!0,hash:"8f2773e5d4ffe767f38dd15712258e8c",slug:null,bookSignature:"Dr. Farid Pazhoohi",coverURL:"https://cdn.intechopen.com/books/images_new/11436.jpg",editedByType:null,editors:[{id:"470837",title:"Dr.",name:"Farid",surname:"Pazhoohi",slug:"farid-pazhoohi",fullName:"Farid Pazhoohi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11437",title:"Social Media - Risks and Opportunities",subtitle:null,isOpenForSubmission:!0,hash:"000e31f2e2f7295805e9a3864158ad63",slug:null,bookSignature:"Dr. Shafizan Mohamed and Dr. Shazleen Mohamed",coverURL:"https://cdn.intechopen.com/books/images_new/11437.jpg",editedByType:null,editors:[{id:"302450",title:"Associate Prof.",name:"Shafizan",surname:"Mohamed",slug:"shafizan-mohamed",fullName:"Shafizan Mohamed"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:38},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:13},{group:"topic",caption:"Business, Management and Economics",value:7,count:7},{group:"topic",caption:"Chemistry",value:8,count:23},{group:"topic",caption:"Computer and Information Science",value:9,count:24},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:15},{group:"topic",caption:"Engineering",value:11,count:65},{group:"topic",caption:"Environmental Sciences",value:12,count:10},{group:"topic",caption:"Immunology and Microbiology",value:13,count:16},{group:"topic",caption:"Materials Science",value:14,count:25},{group:"topic",caption:"Mathematics",value:15,count:11},{group:"topic",caption:"Medicine",value:16,count:116},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:6},{group:"topic",caption:"Neuroscience",value:18,count:4},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:9},{group:"topic",caption:"Physics",value:20,count:9},{group:"topic",caption:"Psychology",value:21,count:10},{group:"topic",caption:"Robotics",value:22,count:2},{group:"topic",caption:"Social Sciences",value:23,count:9},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:4}],offset:12,limit:12,total:667},popularBooks:{featuredBooks:[{type:"book",id:"10858",title:"MOOC (Massive Open Online Courses)",subtitle:null,isOpenForSubmission:!1,hash:"d32f86793bc72dde32532f509b1ec5b0",slug:"mooc-massive-open-online-courses-",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/10858.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10195",title:"Serotonin and the CNS",subtitle:"New Developments in Pharmacology and Therapeutics",isOpenForSubmission:!1,hash:"7ed9d96da98233a885bd2869a8056c36",slug:"serotonin-and-the-cns-new-developments-in-pharmacology-and-therapeutics",bookSignature:"Berend Olivier",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg",editors:[{id:"71579",title:"Prof.",name:"Berend",middleName:null,surname:"Olivier",slug:"berend-olivier",fullName:"Berend Olivier"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10755",title:"Corporate Governance",subtitle:"Recent Advances and Perspectives",isOpenForSubmission:!1,hash:"ffe06d1d5c4bf0fc2e63511825fe1257",slug:"corporate-governance-recent-advances-and-perspectives",bookSignature:"Okechukwu Lawrence Emeagwali and Feyza Bhatti",coverURL:"https://cdn.intechopen.com/books/images_new/10755.jpg",editors:[{id:"196317",title:"Associate Prof.",name:"Okechukwu Lawrence",middleName:null,surname:"Emeagwali",slug:"okechukwu-lawrence-emeagwali",fullName:"Okechukwu Lawrence Emeagwali"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11120",title:"Environmental Impact and Remediation of Heavy Metals",subtitle:null,isOpenForSubmission:!1,hash:"9e77514288e7394f1e6cd13481af3509",slug:"environmental-impact-and-remediation-of-heavy-metals",bookSignature:"Hosam M. Saleh and Amal I. Hassan",coverURL:"https://cdn.intechopen.com/books/images_new/11120.jpg",editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:null,surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10901",title:"Grapes and Wine",subtitle:null,isOpenForSubmission:!1,hash:"5d7f2aa74874444bc6986e613ccebd7c",slug:"grapes-and-wine",bookSignature:"Antonio Morata, Iris Loira and Carmen González",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg",editors:[{id:"180952",title:"Prof.",name:"Antonio",middleName:null,surname:"Morata",slug:"antonio-morata",fullName:"Antonio Morata"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11080",title:"Engineering Principles",subtitle:"Welding and Residual Stresses",isOpenForSubmission:!1,hash:"6c07a13a113bce94174b40096f30fb5e",slug:"engineering-principles-welding-and-residual-stresses",bookSignature:"Kavian Omar Cooke and Ronaldo Câmara Cozza",coverURL:"https://cdn.intechopen.com/books/images_new/11080.jpg",editors:[{id:"138778",title:"Dr.",name:"Kavian",middleName:"Omar",surname:"Cooke",slug:"kavian-cooke",fullName:"Kavian Cooke"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11332",title:"Essential Oils",subtitle:"Advances in Extractions and Biological Applications",isOpenForSubmission:!1,hash:"742e6cae3a35686f975edc8d7f9afa94",slug:"essential-oils-advances-in-extractions-and-biological-applications",bookSignature:"Mozaniel Santana de Oliveira and Eloisa Helena de Aguiar Andrade",coverURL:"https://cdn.intechopen.com/books/images_new/11332.jpg",editors:[{id:"195290",title:"Ph.D.",name:"Mozaniel",middleName:null,surname:"Santana De Oliveira",slug:"mozaniel-santana-de-oliveira",fullName:"Mozaniel Santana De Oliveira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11029",title:"Hepatitis B",subtitle:null,isOpenForSubmission:!1,hash:"609701f502efc3538c112ff47a2c2119",slug:"hepatitis-b",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/11029.jpg",editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9537",title:"Human Rights in the Contemporary World",subtitle:null,isOpenForSubmission:!1,hash:"54f05b93812fd434f3962956d6413a6b",slug:"human-rights-in-the-contemporary-world",bookSignature:"Trudy Corrigan",coverURL:"https://cdn.intechopen.com/books/images_new/9537.jpg",editors:[{id:"197557",title:"Dr.",name:"Trudy",middleName:null,surname:"Corrigan",slug:"trudy-corrigan",fullName:"Trudy Corrigan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11371",title:"Cerebral Circulation",subtitle:"Updates on Models, Diagnostics and Treatments of Related Diseases",isOpenForSubmission:!1,hash:"e2d3335445d2852d0b906bb9750e939f",slug:"cerebral-circulation-updates-on-models-diagnostics-and-treatments-of-related-diseases",bookSignature:"Alba Scerrati, Luca Ricciardi and Flavia Dones",coverURL:"https://cdn.intechopen.com/books/images_new/11371.jpg",editors:[{id:"182614",title:"Dr.",name:"Alba",middleName:null,surname:"Scerrati",slug:"alba-scerrati",fullName:"Alba Scerrati"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11012",title:"Radiopharmaceuticals",subtitle:"Current Research for Better Diagnosis and Therapy",isOpenForSubmission:!1,hash:"f9046d6f96148b285e776f384991120d",slug:"radiopharmaceuticals-current-research-for-better-diagnosis-and-therapy",bookSignature:"Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/11012.jpg",editors:[{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9974",title:"E-Learning and Digital Education in the Twenty-First Century",subtitle:null,isOpenForSubmission:!1,hash:"88b58d66e975df20425fc1dfd22d53aa",slug:"e-learning-and-digital-education-in-the-twenty-first-century",bookSignature:"M. Mahruf C. Shohel",coverURL:"https://cdn.intechopen.com/books/images_new/9974.jpg",editors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:4428},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"10858",title:"MOOC (Massive Open Online Courses)",subtitle:null,isOpenForSubmission:!1,hash:"d32f86793bc72dde32532f509b1ec5b0",slug:"mooc-massive-open-online-courses-",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/10858.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:1677,editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10195",title:"Serotonin and the CNS",subtitle:"New Developments in Pharmacology and Therapeutics",isOpenForSubmission:!1,hash:"7ed9d96da98233a885bd2869a8056c36",slug:"serotonin-and-the-cns-new-developments-in-pharmacology-and-therapeutics",bookSignature:"Berend Olivier",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:1337,editors:[{id:"71579",title:"Prof.",name:"Berend",middleName:null,surname:"Olivier",slug:"berend-olivier",fullName:"Berend Olivier"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10755",title:"Corporate Governance",subtitle:"Recent Advances and Perspectives",isOpenForSubmission:!1,hash:"ffe06d1d5c4bf0fc2e63511825fe1257",slug:"corporate-governance-recent-advances-and-perspectives",bookSignature:"Okechukwu Lawrence Emeagwali and Feyza Bhatti",coverURL:"https://cdn.intechopen.com/books/images_new/10755.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:1309,editors:[{id:"196317",title:"Associate Prof.",name:"Okechukwu Lawrence",middleName:null,surname:"Emeagwali",slug:"okechukwu-lawrence-emeagwali",fullName:"Okechukwu Lawrence Emeagwali"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11120",title:"Environmental Impact and Remediation of Heavy Metals",subtitle:null,isOpenForSubmission:!1,hash:"9e77514288e7394f1e6cd13481af3509",slug:"environmental-impact-and-remediation-of-heavy-metals",bookSignature:"Hosam M. Saleh and Amal I. Hassan",coverURL:"https://cdn.intechopen.com/books/images_new/11120.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:847,editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:null,surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10901",title:"Grapes and Wine",subtitle:null,isOpenForSubmission:!1,hash:"5d7f2aa74874444bc6986e613ccebd7c",slug:"grapes-and-wine",bookSignature:"Antonio Morata, Iris Loira and Carmen González",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg",publishedDate:"June 15th 2022",numberOfDownloads:2273,editors:[{id:"180952",title:"Prof.",name:"Antonio",middleName:null,surname:"Morata",slug:"antonio-morata",fullName:"Antonio Morata"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11080",title:"Engineering Principles",subtitle:"Welding and Residual Stresses",isOpenForSubmission:!1,hash:"6c07a13a113bce94174b40096f30fb5e",slug:"engineering-principles-welding-and-residual-stresses",bookSignature:"Kavian Omar Cooke and Ronaldo Câmara Cozza",coverURL:"https://cdn.intechopen.com/books/images_new/11080.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:591,editors:[{id:"138778",title:"Dr.",name:"Kavian",middleName:"Omar",surname:"Cooke",slug:"kavian-cooke",fullName:"Kavian Cooke"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11332",title:"Essential Oils",subtitle:"Advances in Extractions and Biological Applications",isOpenForSubmission:!1,hash:"742e6cae3a35686f975edc8d7f9afa94",slug:"essential-oils-advances-in-extractions-and-biological-applications",bookSignature:"Mozaniel Santana de Oliveira and Eloisa Helena de Aguiar Andrade",coverURL:"https://cdn.intechopen.com/books/images_new/11332.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:515,editors:[{id:"195290",title:"Ph.D.",name:"Mozaniel",middleName:null,surname:"Santana De Oliveira",slug:"mozaniel-santana-de-oliveira",fullName:"Mozaniel Santana De Oliveira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11029",title:"Hepatitis B",subtitle:null,isOpenForSubmission:!1,hash:"609701f502efc3538c112ff47a2c2119",slug:"hepatitis-b",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/11029.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:413,editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9537",title:"Human Rights in the Contemporary World",subtitle:null,isOpenForSubmission:!1,hash:"54f05b93812fd434f3962956d6413a6b",slug:"human-rights-in-the-contemporary-world",bookSignature:"Trudy Corrigan",coverURL:"https://cdn.intechopen.com/books/images_new/9537.jpg",publishedDate:"June 8th 2022",numberOfDownloads:2194,editors:[{id:"197557",title:"Dr.",name:"Trudy",middleName:null,surname:"Corrigan",slug:"trudy-corrigan",fullName:"Trudy Corrigan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11371",title:"Cerebral Circulation",subtitle:"Updates on Models, Diagnostics and Treatments of Related Diseases",isOpenForSubmission:!1,hash:"e2d3335445d2852d0b906bb9750e939f",slug:"cerebral-circulation-updates-on-models-diagnostics-and-treatments-of-related-diseases",bookSignature:"Alba Scerrati, Luca Ricciardi and Flavia Dones",coverURL:"https://cdn.intechopen.com/books/images_new/11371.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:341,editors:[{id:"182614",title:"Dr.",name:"Alba",middleName:null,surname:"Scerrati",slug:"alba-scerrati",fullName:"Alba Scerrati"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"11043",title:"Endometriosis",subtitle:"Recent Advances, New Perspectives and Treatments",isOpenForSubmission:!1,hash:"7baf1c70b11d41400bb9302ae9411ca4",slug:"endometriosis-recent-advances-new-perspectives-and-treatments",bookSignature:"Giovana Ap. Gonçalves",coverURL:"https://cdn.intechopen.com/books/images_new/11043.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"185930",title:"Associate Prof.",name:"Giovana",middleName:null,surname:"Gonçalves",slug:"giovana-goncalves",fullName:"Giovana Gonçalves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10536",title:"Campylobacter",subtitle:null,isOpenForSubmission:!1,hash:"c4b132b741dd0a2ed539b824ab63965f",slug:"campylobacter",bookSignature:"Guillermo Tellez-Isaias and Saeed El-Ashram",coverURL:"https://cdn.intechopen.com/books/images_new/10536.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"73465",title:"Dr.",name:"Guillermo",middleName:null,surname:"Téllez",slug:"guillermo-tellez",fullName:"Guillermo Téllez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10798",title:"Starch",subtitle:"Evolution and Recent Advances",isOpenForSubmission:!1,hash:"f197f6062c1574a9a90e50a369271bcf",slug:"starch-evolution-and-recent-advances",bookSignature:"Martins Ochubiojo Emeje",coverURL:"https://cdn.intechopen.com/books/images_new/10798.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11083",title:"Hazardous Waste Management",subtitle:null,isOpenForSubmission:!1,hash:"d553bd4f6f1c4b115ca69bd19faac7dc",slug:"hazardous-waste-management",bookSignature:"Rajesh Banu Jeyakumar, Kavitha Sankarapandian and Yukesh Kannah Ravi",coverURL:"https://cdn.intechopen.com/books/images_new/11083.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"218539",title:"Dr.",name:"Rajesh Banu",middleName:null,surname:"Jeyakumar",slug:"rajesh-banu-jeyakumar",fullName:"Rajesh Banu Jeyakumar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10848",title:"Tribology of Machine Elements",subtitle:"Fundamentals and Applications",isOpenForSubmission:!1,hash:"3c4ca4c4692ca8d4fa749b4ae81ec1fa",slug:"tribology-of-machine-elements-fundamentals-and-applications",bookSignature:"Giuseppe Pintaude, Tiago Cousseau and Anna Rudawska",coverURL:"https://cdn.intechopen.com/books/images_new/10848.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"18347",title:"Prof.",name:"Giuseppe",middleName:null,surname:"Pintaude",slug:"giuseppe-pintaude",fullName:"Giuseppe Pintaude"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10856",title:"Crude Oil",subtitle:"New Technologies and Recent Approaches",isOpenForSubmission:!1,hash:"8d0a7ca35b3de95b295dc4eab39a087e",slug:"crude-oil-new-technologies-and-recent-approaches",bookSignature:"Manar Elsayed Abdel-Raouf and Mohamed Hasan El-Keshawy",coverURL:"https://cdn.intechopen.com/books/images_new/10856.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"102626",title:"Prof.",name:"Manar",middleName:null,surname:"Elsayed Abdel-Raouf",slug:"manar-elsayed-abdel-raouf",fullName:"Manar Elsayed Abdel-Raouf"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9625",title:"Spinocerebellar Ataxia",subtitle:"Concepts, Particularities and Generalities",isOpenForSubmission:!1,hash:"365a7025fd46eb45de2549bdd9d50b98",slug:"spinocerebellar-ataxia-concepts-particularities-and-generalities",bookSignature:"Patricia Bozzetto Ambrosi",coverURL:"https://cdn.intechopen.com/books/images_new/9625.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"221787",title:"Dr.",name:"Patricia",middleName:null,surname:"Bozzetto Ambrosi",slug:"patricia-bozzetto-ambrosi",fullName:"Patricia Bozzetto Ambrosi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10905",title:"Plant Defense Mechanisms",subtitle:null,isOpenForSubmission:!1,hash:"84ad5b27dde5f01dc76087d0fd6fa834",slug:"plant-defense-mechanisms",bookSignature:"Josphert Ngui Kimatu",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"224171",title:"Prof.",name:"Josphert N.",middleName:null,surname:"Kimatu",slug:"josphert-n.-kimatu",fullName:"Josphert N. Kimatu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10686",title:"Natural Gas",subtitle:"New Perspectives and Future Developments",isOpenForSubmission:!1,hash:"581763788a6a59e653a9d1d9b5a42d79",slug:"natural-gas-new-perspectives-and-future-developments",bookSignature:"Maryam Takht Ravanchi",coverURL:"https://cdn.intechopen.com/books/images_new/10686.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"2416",title:"Dr.",name:"Maryam",middleName:null,surname:"Takht Ravanchi",slug:"maryam-takht-ravanchi",fullName:"Maryam Takht Ravanchi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10988",title:"Railway Transport Planning and Manageme",subtitle:null,isOpenForSubmission:!1,hash:"5cb54cc53caedad9ec78372563c82e2c",slug:"railway-transport-planning-and-management",bookSignature:"Stefano de Luca, Roberta Di Pace and Chiara Fiori",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"271061",title:"Prof.",name:"Stefano",middleName:null,surname:"de Luca",slug:"stefano-de-luca",fullName:"Stefano de Luca"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"299",title:"Cynology",slug:"cynology",parent:{id:"25",title:"Veterinary Medicine and Science",slug:"veterinary-medicine-and-science"},numberOfBooks:5,numberOfSeries:0,numberOfAuthorsAndEditors:166,numberOfWosCitations:147,numberOfCrossrefCitations:104,numberOfDimensionsCitations:213,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"299",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10497",title:"Canine Genetics, Health and Medicine",subtitle:null,isOpenForSubmission:!1,hash:"b91512e31ce34032e560362e6cbccc1c",slug:"canine-genetics-health-and-medicine",bookSignature:"Catrin Rutland",coverURL:"https://cdn.intechopen.com/books/images_new/10497.jpg",editedByType:"Edited by",editors:[{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8793",title:"Owls",subtitle:null,isOpenForSubmission:!1,hash:"8df7a192b3300e2640a0e1c530f4e259",slug:"owls",bookSignature:"Heimo Mikkola",coverURL:"https://cdn.intechopen.com/books/images_new/8793.jpg",editedByType:"Edited by",editors:[{id:"144330",title:"Dr.",name:"Heimo",middleName:"Juhani",surname:"Mikkola",slug:"heimo-mikkola",fullName:"Heimo Mikkola"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5469",title:"Canine Medicine",subtitle:"Recent Topics and Advanced Research",isOpenForSubmission:!1,hash:"a7e798d88413dd09f8a4af2b2e325b82",slug:"canine-medicine-recent-topics-and-advanced-research",bookSignature:"Hussein Abdelhay Elsayed Kaoud",coverURL:"https://cdn.intechopen.com/books/images_new/5469.jpg",editedByType:"Edited by",editors:[{id:"265070",title:"Dr.",name:"Hussein Abdelhay",middleName:null,surname:"Essayed Kaoud",slug:"hussein-abdelhay-essayed-kaoud",fullName:"Hussein Abdelhay Essayed Kaoud"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3423",title:"Insights from Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"8712769decefe74bd752ce339f476964",slug:"insights-from-veterinary-medicine",bookSignature:"Rita Payan-Carreira",coverURL:"https://cdn.intechopen.com/books/images_new/3423.jpg",editedByType:"Edited by",editors:[{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1667",title:"A Bird's-Eye View of Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"7be827d70aa0311258d658f729670887",slug:"a-bird-s-eye-view-of-veterinary-medicine",bookSignature:"Carlos C. Perez-Marin",coverURL:"https://cdn.intechopen.com/books/images_new/1667.jpg",editedByType:"Edited by",editors:[{id:"25632",title:"Dr.",name:"Carlos C.",middleName:null,surname:"Perez-Marin",slug:"carlos-c.-perez-marin",fullName:"Carlos C. Perez-Marin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:5,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"28679",doi:"10.5772/32100",title:"Values of Blood Variables in Calves",slug:"values-of-blood-variables-in-calves",totalDownloads:9601,totalCrossrefCites:16,totalDimensionsCites:36,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Martina Klinkon and Jožica Ježek",authors:[{id:"90171",title:"Prof.",name:"Martina",middleName:null,surname:"Klinkon",slug:"martina-klinkon",fullName:"Martina Klinkon"}]},{id:"28666",doi:"10.5772/25785",title:"Steroid Hormones in Food Producing Animals:",slug:"steroid-hormones-in-food-producing-animals-",totalDownloads:8258,totalCrossrefCites:11,totalDimensionsCites:16,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Annamaria Passantino",authors:[{id:"64540",title:"Prof.",name:"Annamaria",middleName:null,surname:"Passantino",slug:"annamaria-passantino",fullName:"Annamaria Passantino"}]},{id:"28681",doi:"10.5772/31374",title:"Clinical Approach to the Repeat Breeder Cow Syndrome",slug:"clinical-approach-to-the-repeat-breeder-cow-syndrome",totalDownloads:11046,totalCrossrefCites:4,totalDimensionsCites:12,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Carlos C. Perez-Marin, Laura Molina Moreno and Guillermo Vizuete Calero",authors:[{id:"25632",title:"Dr.",name:"Carlos C.",middleName:null,surname:"Perez-Marin",slug:"carlos-c.-perez-marin",fullName:"Carlos C. Perez-Marin"},{id:"89533",title:"Mr.",name:"Guillermo",middleName:null,surname:"Vizuete",slug:"guillermo-vizuete",fullName:"Guillermo Vizuete"},{id:"89535",title:"Mrs.",name:"Laura",middleName:null,surname:"Molina",slug:"laura-molina",fullName:"Laura Molina"}]},{id:"28685",doi:"10.5772/31721",title:"Pharmacokinetic – Pharmacodynamic Considerations for Bovine Mastitis Treatment",slug:"pharmacokinetic-pharmacodynamic-considerations-for-bovine-mastitis-treatment",totalDownloads:7499,totalCrossrefCites:6,totalDimensionsCites:12,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Nora Mestorino and Jorge O. Errecalde",authors:[{id:"88409",title:"Dr.",name:"Nora",middleName:null,surname:"Mestorino",slug:"nora-mestorino",fullName:"Nora Mestorino"},{id:"125928",title:"Prof.",name:"Jorge",middleName:null,surname:"Errecalde",slug:"jorge-errecalde",fullName:"Jorge Errecalde"}]},{id:"43196",doi:"10.5772/55550",title:"Feline Mammary Fibroepithelial Hyperplasia: A Clinical Approach",slug:"feline-mammary-fibroepithelial-hyperplasia-a-clinical-approach",totalDownloads:4670,totalCrossrefCites:5,totalDimensionsCites:11,abstract:null,book:{id:"3423",slug:"insights-from-veterinary-medicine",title:"Insights from Veterinary Medicine",fullTitle:"Insights from Veterinary Medicine"},signatures:"Rita Payan-Carreira",authors:[{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira"}]}],mostDownloadedChaptersLast30Days:[{id:"43169",title:"Dermatology in Dogs and Cats",slug:"dermatology-in-dogs-and-cats",totalDownloads:10261,totalCrossrefCites:2,totalDimensionsCites:4,abstract:null,book:{id:"3423",slug:"insights-from-veterinary-medicine",title:"Insights from Veterinary Medicine",fullTitle:"Insights from Veterinary Medicine"},signatures:"Elisa Bourguignon, Luciana Diegues Guimarães, Tássia Sell Ferreira and Evandro Silva Favarato",authors:[{id:"124361",title:"Mrs.",name:"Elisa",middleName:null,surname:"Bourguignon",slug:"elisa-bourguignon",fullName:"Elisa Bourguignon"}]},{id:"52760",title:"Canine Parvovirus Type 2",slug:"canine-parvovirus-type-2",totalDownloads:3023,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Canine parvovirus (CPV) enteritis is characterized by intestinal hemorrhage with severe bloody diarrhea. The causative agent, CPV‐2, was first identified in the late 1970s. CPV is a nonenveloped, linear, single‐stranded DNA virus with a genome of approximately 5 kb, and it belongs to the genus Parvovirus, together with feline panleukopenia virus, mink enteritis virus, raccoon parvovirus, and porcine parvovirus. An antigenic variant, CPV‐2a, identified within a few years after the emergence of CPV‐2, and another variant, CPV‐2b, began appearing in the canine population in 1984. In 2000, a novel antigenic variant, CPV‐2c, was first detected in Italy. This chapter focuses on the history, viral evolution, epidemiology, pathogenesis, clinical signs, diagnosis, vaccination, and prevention of CPV‐2.",book:{id:"5469",slug:"canine-medicine-recent-topics-and-advanced-research",title:"Canine Medicine",fullTitle:"Canine Medicine - Recent Topics and Advanced Research"},signatures:"Chao-Nan Lin and Shu-Yun Chiang",authors:[{id:"190874",title:"Associate Prof.",name:"Chao-Nan",middleName:null,surname:"Lin",slug:"chao-nan-lin",fullName:"Chao-Nan Lin"},{id:"194988",title:"Dr.",name:"Shu-Yun",middleName:null,surname:"Chiang",slug:"shu-yun-chiang",fullName:"Shu-Yun Chiang"}]},{id:"52705",title:"Chronic Mitral Valve Insufficiency in Dogs: Recent Advances in Diagnosis and Treatment",slug:"chronic-mitral-valve-insufficiency-in-dogs-recent-advances-in-diagnosis-and-treatment",totalDownloads:3815,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Chronic mitral valvular insufficiency (CMVI) is the most common acquired heart disease in dogs and is characterized by degenerative valvular changes causing progressive thickening of mitral leaflets and incomplete closure of mitral valve. As the disease progresses, it causes congestive heart failure (CHF) and pulmonary edema if the LA dilation cannot accommodate the volume overload by mitral regurgitation. Therefore, it is the most common cause of cardiac mortality in dogs. This chapter discusses general features of CMVI in dogs focusing on recent advances in diagnosis and treatment.",book:{id:"5469",slug:"canine-medicine-recent-topics-and-advanced-research",title:"Canine Medicine",fullTitle:"Canine Medicine - Recent Topics and Advanced Research"},signatures:"Sang-II Suh, Dong-Hyun Han, Seung-Gon Lee, Yong-Wei Hung, Ran\nChoi and Changbaig Hyun",authors:[{id:"13534",title:"Prof.",name:"Changbaig",middleName:null,surname:"Hyun",slug:"changbaig-hyun",fullName:"Changbaig Hyun"},{id:"371146",title:"Dr.",name:"Sang-II",middleName:null,surname:"Suh",slug:"sang-ii-suh",fullName:"Sang-II Suh"},{id:"371147",title:"Dr.",name:"Dong-Hyun",middleName:null,surname:"Han",slug:"dong-hyun-han",fullName:"Dong-Hyun Han"},{id:"371148",title:"Dr.",name:"Seung-Gon",middleName:null,surname:"Lee",slug:"seung-gon-lee",fullName:"Seung-Gon Lee"},{id:"371149",title:"Dr.",name:"Yong-Wei",middleName:null,surname:"Hung",slug:"yong-wei-hung",fullName:"Yong-Wei Hung"},{id:"371150",title:"Dr.",name:"Ran",middleName:null,surname:"Choi",slug:"ran-choi",fullName:"Ran Choi"}]},{id:"52484",title:"Infectious Causes of Abortion, Stillbirth and Neonatal Death in Bitches",slug:"infectious-causes-of-abortion-stillbirth-and-neonatal-death-in-bitches",totalDownloads:2793,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Problems in gestational development in dogs can be determined by infectious and non‐infectious causes. Among the non‐infectious causes, trauma during pregnancy, genetic characteristics of the animal, deficit nutrition, thyroid dysfunction, maternal problems and hormonal disorders are found. The majority of the cases are in relation to infectious diseases, one should consider viral, bacterial, fungal and protozoal, which can interfere directly or indirectly in the foetal development. The progression of foetal development may be affected by the direct action of the microorganisms to overcome the placenta, but they are also able to affect pregnancy and release placental toxins by inflammatory processes and, may still cause maternal pathologies, which entail problems such as hyperthermia, hypoxia and endotoxemia, which can result in abortion. Several diseases can trigger pregnancy loss in dogs. This action can be direct by microorganisms, as well as indirectly triggering other problems that lead to abortion. This chapter discusses the infectious aetiologies of reproductive failures (abortion, stillbirth and neonatal death) in bitches.",book:{id:"5469",slug:"canine-medicine-recent-topics-and-advanced-research",title:"Canine Medicine",fullTitle:"Canine Medicine - Recent Topics and Advanced Research"},signatures:"João Marcelo Azevedo de Paula Antunes, Débora Alves de Carvalho\nFreire, Ilanna Vanessa Pristo de Medeiros Oliveira, Gabriela Hémylin\nFerreira Moura, Larissa de Castro Demoner and Heider Irinaldo\nPereira Ferreira",authors:[{id:"191197",title:"Ph.D.",name:"João",middleName:null,surname:"Antunes",slug:"joao-antunes",fullName:"João Antunes"},{id:"191203",title:"MSc.",name:"Débora Alves",middleName:null,surname:"De Carvalho Freire",slug:"debora-alves-de-carvalho-freire",fullName:"Débora Alves De Carvalho Freire"},{id:"191204",title:"MSc.",name:"Ilanna Vanessa",middleName:null,surname:"Pristo De Medeiros Oliveira",slug:"ilanna-vanessa-pristo-de-medeiros-oliveira",fullName:"Ilanna Vanessa Pristo De Medeiros Oliveira"},{id:"191205",title:"BSc.",name:"Gabriela Hémylin",middleName:null,surname:"Ferreira Moura",slug:"gabriela-hemylin-ferreira-moura",fullName:"Gabriela Hémylin Ferreira Moura"},{id:"191207",title:"Dr.",name:"Larissa",middleName:null,surname:"De Castro Demoner",slug:"larissa-de-castro-demoner",fullName:"Larissa De Castro Demoner"},{id:"194801",title:"MSc.",name:"Heider Irinaldo Pereira",middleName:null,surname:"Ferreira",slug:"heider-irinaldo-pereira-ferreira",fullName:"Heider Irinaldo Pereira Ferreira"}]},{id:"28674",title:"Atresia Ani in Dogs and Cats",slug:"atresia-ani-in-dogs-and-cats",totalDownloads:15460,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Lysimachos G. Papazoglou and Gary W. Ellison",authors:[{id:"85124",title:"Prof.",name:"Lysimachos",middleName:null,surname:"Papazoglou",slug:"lysimachos-papazoglou",fullName:"Lysimachos Papazoglou"},{id:"91413",title:"Prof.",name:"Gary",middleName:null,surname:"Ellison",slug:"gary-ellison",fullName:"Gary Ellison"}]}],onlineFirstChaptersFilter:{topicId:"299",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"\r\n\tGlobally, the ecological footprint is growing at a faster rate than GDP. This phenomenon has been studied by scientists for many years. However, clear strategies and actions are needed now more than ever. Every day, humanity, from individuals to businesses (public and private) and governments, are called to change their mindset in order to pursue a virtuous combination for sustainable development. Reasoning in a sustainable way entails, first and foremost, managing the available resources efficiently and strategically, whether they are natural, financial, human or relational. In this way, value is generated by contributing to the growth, improvement and socio-economic development of the communities and of all the players that make up its value chain. In the coming decades, we will need to be able to transition from a society in which economic well-being and health are measured by the growth of production and material consumption, to a society in which we live better while consuming less. In this context, digitization has the potential to disrupt processes, with significant implications for the environment and sustainable development. There are numerous challenges associated with sustainability and digitization, the need to consider new business models capable of extracting value, data ownership and sharing and integration, as well as collaboration across the entire supply chain of a product. In order to generate value, effectively developing a complex system based on sustainability principles is a challenge that requires a deep commitment to both technological factors, such as data and platforms, and human dimensions, such as trust and collaboration. Regular study, research and implementation must be part of the road to sustainable solutions. Consequently, this topic will analyze growth models and techniques aimed at achieving intergenerational equity in terms of economic, social and environmental well-being. It will also cover various subjects, including risk assessment in the context of sustainable economy and a just society.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",hasOnlineFirst:!0,hasPublishedBooks:!1,annualVolume:11975,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. She serves as an Associate Editor for the International Journal of the Analytic Hierarchy Process. She is a member of AHP Academy and a member of several editorial boards. She has over 160 Scientific Publications in International Journals and Conferences and she is the author of 5 books on Innovation and Decision Making in Industrial Applications and Engineering.",institutionString:null,institution:{name:"Parthenope University of Naples",institutionURL:null,country:{name:"Italy"}}},editorTwo:null,editorThree:null,series:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null},editorialBoard:[{id:"179628",title:"Prof.",name:"Dima",middleName:null,surname:"Jamali",slug:"dima-jamali",fullName:"Dima Jamali",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSAIlQAO/Profile_Picture_2022-03-07T08:52:23.jpg",institutionString:null,institution:{name:"University of Sharjah",institutionURL:null,country:{name:"United Arab Emirates"}}},{id:"170206",title:"Prof.",name:"Dr. Orhan",middleName:null,surname:"Özçatalbaş",slug:"dr.-orhan-ozcatalbas",fullName:"Dr. Orhan Özçatalbaş",profilePictureURL:"https://mts.intechopen.com/storage/users/170206/images/system/170206.png",institutionString:null,institution:{name:"Akdeniz University",institutionURL:null,country:{name:"Turkey"}}},{id:"250347",title:"Associate Prof.",name:"Isaac",middleName:null,surname:"Oluwatayo",slug:"isaac-oluwatayo",fullName:"Isaac Oluwatayo",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVIVQA4/Profile_Picture_2022-03-17T13:25:32.jpg",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},{id:"141386",title:"Prof.",name:"Jesús",middleName:null,surname:"López-Rodríguez",slug:"jesus-lopez-rodriguez",fullName:"Jesús López-Rodríguez",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRBNIQA4/Profile_Picture_2022-03-21T08:24:16.jpg",institutionString:null,institution:{name:"University of A Coruña",institutionURL:null,country:{name:"Spain"}}},{id:"208657",title:"Dr.",name:"Mara",middleName:null,surname:"Del Baldo",slug:"mara-del-baldo",fullName:"Mara Del Baldo",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLMUQA4/Profile_Picture_2022-05-18T08:19:24.png",institutionString:"University of Urbino Carlo Bo",institution:null}]},onlineFirstChapters:{paginationCount:2,paginationItems:[{id:"82392",title:"Nanomaterials as Novel Biomarkers for Cancer Nanotheranostics: State of the Art",doi:"10.5772/intechopen.105700",signatures:"Hao Yu, Zhihai Han, Cunrong Chen and Leisheng Zhang",slug:"nanomaterials-as-novel-biomarkers-for-cancer-nanotheranostics-state-of-the-art",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11405.jpg",subseries:{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering"}}},{id:"81778",title:"Influence of Mechanical Properties of Biomaterials on the Reconstruction of Biomedical Parts via Additive Manufacturing Techniques: An Overview",doi:"10.5772/intechopen.104465",signatures:"Babatunde Olamide Omiyale, Akeem Abiodun Rasheed, Robinson Omoboyode Akinnusi and Temitope Olumide Olugbade",slug:"influence-of-mechanical-properties-of-biomaterials-on-the-reconstruction-of-biomedical-parts-via-add",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11405.jpg",subseries:{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering"}}}]},publishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"7437",title:"Nanomedicines",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7437.jpg",slug:"nanomedicines",publishedDate:"February 13th 2019",editedByType:"Edited by",bookSignature:"Muhammad Akhyar Farrukh",hash:"0e1f5f6258f074c533976c4f4d248568",volumeInSeries:5,fullTitle:"Nanomedicines",editors:[{id:"63182",title:"Dr.",name:"Muhammad Akhyar",middleName:null,surname:"Farrukh",slug:"muhammad-akhyar-farrukh",fullName:"Muhammad Akhyar Farrukh",profilePictureURL:"https://mts.intechopen.com/storage/users/63182/images/system/63182.png",institutionString:"Forman Christian College",institution:{name:"Forman Christian College",institutionURL:null,country:{name:"Pakistan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},testimonialsList:[{id:"27",text:"The opportunity to work with a prestigious publisher allows for the possibility to collaborate with more research groups interested in animal nutrition, leading to the development of new feeding strategies and food valuation while being more sustainable with the environment, allowing more readers to learn about the subject.",author:{id:"175967",name:"Manuel",surname:"Gonzalez Ronquillo",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",slug:"manuel-gonzalez-ronquillo",institution:{id:"6221",name:"Universidad Autónoma del Estado de México",country:{id:null,name:"Mexico"}}}},{id:"18",text:"It was great publishing with IntechOpen, the process was straightforward and I had support all along.",author:{id:"71579",name:"Berend",surname:"Olivier",institutionString:"Utrecht University",profilePictureURL:"https://mts.intechopen.com/storage/users/71579/images/system/71579.png",slug:"berend-olivier",institution:{id:"253",name:"Utrecht University",country:{id:null,name:"Netherlands"}}}},{id:"8",text:"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality.",author:{id:"202192",name:"Catrin",surname:"Rutland",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",slug:"catrin-rutland",institution:{id:"134",name:"University of Nottingham",country:{id:null,name:"United Kingdom"}}}}]},submityourwork:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],subseriesList:[],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:318,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/176142",hash:"",query:{},params:{id:"176142"},fullPath:"/profiles/176142",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()