Process parameters for IPA-based and additive-based alkaline texturing of mono-crystalline wafers.
\r\n\t
",isbn:"978-1-83968-930-7",printIsbn:"978-1-83968-929-1",pdfIsbn:"978-1-83968-931-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"f159c09dab49a9bc6239b42660d8e8ec",bookSignature:"Dr. Yongxia Zhou",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10310.jpg",keywords:"Brain Science, Brain-Computer Interface, Imaging of Neural Networks, Brain Networks, Brain Function, Molecular Imaging, Brain and Mind, Functional Imaging, Multimodal Imaging, Neuroplasticity Enhancement, Learning, Memory",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 28th 2020",dateEndSecondStepPublish:"October 26th 2020",dateEndThirdStepPublish:"December 25th 2020",dateEndFourthStepPublish:"March 15th 2021",dateEndFifthStepPublish:"May 14th 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Yongxia Zhou had completed her Ph.D. from the University of Southern California in Biomedical imaging (2004) and had been trained and worked as a neuroimaging scientist in several prestigious institutes including Columbia University, New York University, University of Pennsylvania. Her research interest is focused on neuroimaging and neuroscience applications.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou",profilePictureURL:"https://mts.intechopen.com/storage/users/259308/images/system/259308.jpeg",biography:"Yongxia Zhou obtained a PhD from the University of Southern California in Biomedical Imaging in 2004. Her main research interest is in radiology and neuroscience applications. She had been trained and worked as a medical imaging scientist at several prestigious institutes including Columbia University, University of Pennsylvania, and the National Institutes of Health (NIH). Her research focuses on multimodal neuroimaging integration including MRI/PET and EEG/MEG instrumentation that makes the best use of multiple modalities to help interpret underlying disease mechanisms. She has authored six monograph books, and edited several books for well-known publishers including IntechOpen and Nova Science. She has published more than 100 papers and presentations in many reputed international journals and conferences, and served as reviewer and editor for several well-known associations.",institutionString:"University of Southern California",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of Southern California",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@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:"9347",title:"Neuroimaging",subtitle:"Neurobiology, Multimodal and Network Applications",isOpenForSubmission:!1,hash:"a3479e76c6ac538aac76409c9efb7e41",slug:"neuroimaging-neurobiology-multimodal-and-network-applications",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9347.jpg",editedByType:"Edited by",editors:[{id:"259308",title:"Dr.",name:"Yongxia",surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8125",title:"Medical Imaging",subtitle:"Principles and Applications",isOpenForSubmission:!1,hash:"e0fa3875d6f66d5ccd8cd3f1444c3fb9",slug:"medical-imaging-principles-and-applications",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/8125.jpg",editedByType:"Edited by",editors:[{id:"259308",title:"Dr.",name:"Yongxia",surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7862",title:"Traumatic Brain Injury",subtitle:"Neurobiology, Diagnosis and Treatment",isOpenForSubmission:!1,hash:"247618f9fcfd8e9054e1202968e3387b",slug:"traumatic-brain-injury-neurobiology-diagnosis-and-treatment",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/7862.jpg",editedByType:"Edited by",editors:[{id:"259308",title:"Dr.",name:"Yongxia",surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"René Mauricio",surname:"Barría",slug:"rene-mauricio-barria",fullName:"René Mauricio Barría"}],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:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],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:"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:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"67140",title:"Industrial Silicon Solar Cells",doi:"10.5772/intechopen.84817",slug:"industrial-silicon-solar-cells",body:'Photovoltaics are an important renewable energy source which has grown rapidly from 8 GW in 2007 to 400 GW in 2017 [1]. Along with the increasing demand, the PV system costing has also dropped significantly from 35.7 $/Wp in 1980 to 0.34 $/Wp in 2017 accelerating its adoption [2]. Silicon (Si) which is an important material of the microelectronics industry has also been the widely used bulk material of solar cells since the 1950s with a market share of >90% [2]. The chapter will introduce the typical steps for manufacturing commercial silicon solar cells. A brief history of solar cells and over-view of the type of silicon substrates along with the different solar cell architecture will be introduced in Sections 2 and 3. Subsequently, the wet-chemistry and high temperature steps used in fabrication will be described in Sections 4 and 5. Section 6 will discuss about the metallization process along with typical characterization parameters for commercial solar cells. Finally, future roadmap and expected trends will be discussed in the concluding section.
The ‘photovoltaic effect’ literally means generation of a voltage upon exposure to light. The phenomenon was first observed by the French physicist Edmund Becquerel on an electrochemical cell in 1839, while it was observed by British scientists W.G. Adams and R.E. Day on a solid-state device made of selenium in 1876 [3]. From the 1950s onwards, there was rapid progress in the performance of commercial solar cells from <1% to >23% [2] and silicon has been the ‘work-horse’ of the photovoltaic industry since then. The evolution of silicon solar cells is shown in Figure 1.
Evolution of silicon solar cells. (a) 1941: Solar cell reported with grown-in junction, (b) 1954: Solar cell p-n junction formed with dopant diffusion, (c) 1970: Violet cell with Aluminum back-surface field, (d) 1974: Black cell with chemically textured surface [3].
The first silicon solar cells demonstrated by Russell Ohl of Bell Laboratories during 1940s were based on natural junctions formed from impurity segregation during the recrystallization process [3]. The cells had an efficiency of <1% due to lack of control over the junction location and the quality of the silicon material. The nomenclature for naming the regions (p-type: side which is illumination and n-type: other side) given by Ohl are since then being used for the solar cell naming conventions.
During the 1950s, there was rapid development in the high-temperature diffusion process for dopants in silicon. Person, Fuller and Chaplin of Bell Laboratories demonstrated a 4.5% efficient solar cell with lithium-based doping, which improved to 6% with boron diffusion. The solar cell had a ‘wrap-up’ around structure (Figure 1(b)) with both contacts on back side to avoid shading losses, but led to higher resistive losses due to the wrap-around structure. By 1960, the cell structure evolved to as shown in Figure 1(c). Since the application was for space explorations, high resistivity substrate of 10 Ω cm was used to have maximum radiation resistance. Vacuum evaporated contacts were used on both sides, while a silicon monoxide coating was used as an anti-reflective coating (ARC) on the front-side (FS) [3].
In early 1970s it was found that having sintered aluminum on the rear-side improved the cell performance by forming a heavily doped interface known as the ‘back-surface field (Al-BSF)’ and gettering of the impurities [3]. The Al-BSF reduces recombination of the carriers on the rear-side and hence improves the voltage and the long-wavelength spectral response. Implementation of finer and closely spaced fingers reduced the requirement on the junction doping and eliminated the dead layer. An ARC of titanium dioxide (TiOx) was used and its thickness was selected to reduce the reflection for shorter wavelengths and gave a violet appearance to the solar cells. Further improvement was made by texturing the wafers using anisotropic etching of (100) wafers to expose the (111) surfaces. The texturing led to improved light-trapping and gave the cells a dark velvet appearance. The improved cell architecture is shown in Figure 1(d). In 1976, Rittner and Arndt demonstrated terrestrial solar cells with efficiencies approaching 17% [3].
The passivated emitter solar cell (PESC) achieved a milestone of 20% efficiency in 1984–1986. The metal/silicon contact area was only 0.3% in PESC cells, while a double layer ARC of ZnS/MgF2 was used in both cell structures. In 1994, passivated emitter rear locally diffused (PERL) cell with an efficiency of 24% were demonstrated [3]. As compared to the PESC cell, the PERL cell had inverted pyramids on FS for better light-trapping and oxide-based passivation on both sides. Oxide passivation layer on the rear-side also improved the internal reflectance of the long wavelength and hence the spectrum response.
In addition to the evolving solar cell architectures, there has also been continuous development in the manufacturing domain in terms of increased throughput, improved process-steps and reduced costs. A brief over-view of the manufacturing of Si substrates and various types of solar cells is given in the next section.
Si is the second most abundant material on earth after oxygen and has been widely used in the semiconductor industry. Metallurgical grade silicon (Mg-Si) of 98% purity is obtained by heating quartz (SiO2) with carbon at high temperatures of 1,500-2,000 [4]. Mg-Si is further purified to obtain solar grade silicon chunks of 99.99% purity. The refined solar grade Si chunks are then processed further to obtain mono-crystalline and multi-crystalline forms of Si ingots, which are a large mass of silicon. In mono-crystalline Si, the atoms are arranged in the same crystal orientation throughout the material. For solar cells, (100) orientation is preferred as it can be easily textured to reduce the surface reflection [5]. Multi-crystalline Si, as the name suggest has multiple grains of Si material with different orientations, unlike the mono-crystalline substrates. Mono-crystalline material have higher minority carrier lifetime compared to multi-crystalline Si and hence higher solar cell efficiencies for a given solar cell technology.
The Czochralski (Cz) method for making mono-crystalline Si ingots is illustrated in Figure 2(a). High purity molten silicon with dopant is maintained above the melting point and then a seed crystal is pulled at a very slow rate to obtain an ingot of as large as 300 mm in diameter and 2 m in length [6]. The molten silicon can be doped with either p-type or n-type dopants to obtain the specific type of mono-crystalline Si ingot of up to 200 kg [2]. Wafers sawn from the ingots have circular edges and hence the shape is called a ‘psuedo square’. Multi-crystalline silicon ingots are made by melting high purity Si and crystallizing them in a large crucible by directional solidification process [7] as demonstrated in Figure 2(b). The process does not have a reference crystal orientation like the Cz process and hence forms silicon material of different orientations. Currently the multi-crystalline Si ingots weigh >800 kg [2] which are then cut into bricks and wafers are sawn further. Current size of mono-crystalline and multi-crystalline wafers for solar cell fabrication is 6 inch × 6 inch. The area of the mono-crystalline wafers will be little less due to the pseudo-square shape. The most widely used base material for making solar cells is boron doped p-type Si substrates. N-type Si substrates for also used for making high efficiency solar cells, but have additional technical challenges like obtaining uniform doping along the ingot compared to p-type substrates.
Illustration of (a) Cz process for mono-crystalline ingots and (b) directional solidification process for multi-crystalline ingots.
A broad classification of different types of solar cells along with efficiency ranges is shown in Figure 3. The standard aluminum back-surface field (Al-BSF) technology is one of the most common solar cell technology given its relatively simple manufacturing process. It is based on full rear-side (RS) Al deposition by screen-printing process and formation of a p+ BSF which helps repel the electrons from the rear-side of p-type substrate and improve the cell performance. The manufacturing flow for Al-BSF solar cells is shown in Figure 4. The standard design of commercial solar cells is with grid-pattern FS and full area RS contacts.
Broad classification of different types of solar cell.
Manufacturing flow of Al-BSF solar cells.
The passivated emitter rear contact (PERC) solar cell improves on the Al-BSF architecture by addition of rear-side passivation layer to improve rear-side passivation and internal reflection. Aluminum-oxide is a suitable material for RS passivation with average solar cell efficiencies nearing 21% obtained in production [8]. An existing Al-BSF solar cell line can be upgraded to PERC process by two additional tools (RS passivation layer deposition and laser for localized contact opening on the RS).
The remaining three cell architectures are mainly higher efficiency technologies based on n-type Si substrates. The a-Si heterojunction solar cell has a-Si layers on the FS and RS of n-type Si substrate to form ‘heterojunctions’ unlike the conventional high temperature diffusion-based p-n junction. Such technology allows processing at lower temperatures, but is very sensitive to the quality of the surface interfaces. a-Si-based heterojunction solar cell was commercially manufactured by Sanyo Electric, which is now taken over by Panasonic [9]. In the interdigitated back contact (IBC) solar cell design, both contacts are present on the rear-side eliminating the FS contact shading losses. Typically for IBC solar cells, the junction will also be located on the rear-side. One of the early manufacturers of the high efficiency n-type IBC solar cell is SunPower Corporation [10]. Bifacial cells, as the name suggests can capture light from both sides of the solar cells. This entails that the rear-side also has a grid-pattern contacts to enable light collection. An example of the bifacial technology is the BiSON solar cell developed and commercialized by ISC, Konstanz [11]. It should be noted that the indicated classification is not an exhaustive list of various other types of solar cell architectures which are in R&D phase, close to commercialization or already being manufactured. The subsequent sections will give an over-view of the process steps for manufacturing of Al-BSF solar cells.
Wet-chemistry-based treatment is an important step in solar cell processing for saw damage removal (SDR) for the as-cut wafers, texturing of the surface to increase the absorption of incoming solar radiation and edge isolation after the diffusion process. As discussed in the previous section, there are mainly mono-crystalline and multi-crystalline silicon wafers used for fabrication of solar cells. The wet-chemistry-based processing for the respective types of wafers will be discussed ahead.
As indicated in Section 2, the development of solar cells started primarily with mono-crystalline wafers and hence employed well-established methods from the domain of microelectronics. Alkaline anisotropic etching based on KOH/NaOH is used for pyramidal texturing of mono-crystalline wafers. An as-cut mono-crystalline wafer has a weighted average reflectance of >30% (over wavelength of 300–1,200 nm) which reduces to 11–12% after the texturing process. Typical morphology of an alkaline textured surface is shown in Figure 5. The anisotropic etching solution etches the (100) surface of the wafers to expose the (111) faces which have a higher density of silicon atoms and hence a slower etch rate compared to the (100) faces. This results in formation of random pyramid structures which form an angle of 54.7° with respect to the wafer surface.
Typical surface morphology of an alkaline textured mono-crystalline wafer.
Typical parameters for the alkaline texturing process are shown in Table 1. It should be noted that the values of various parameters are indicative and are not to be taken as absolute as there are a variety of additive manufacturers in the market. Isopropyl alcohol (IPA) was initially used as an additive in the texturing solution, which is not involved in the etching reaction, but acts as a wetting agent to improve the homogeneity of texturing process by preventing the H2 bubbles (generated during the reaction) adhering to the silicon surface [12]. However by 2010, IPA was gradually replaced with alternative additives due to drawbacks like unstable concentration as the bath temperature is close to the boiling point of IPA (82.4°C), high costs, high consumption, health hazards and explosiveness [12]. Many groups have published development work to replace IPA with alternate additives to overcome the disadvantages of IPA, increase the process window and reduce the surface reflectance [12, 13, 14, 15, 16]. Additives also reduce the processing time to <10 minutes and increases the bath life to >100 runs.
Process | KOH/IPA | KOH/additive |
---|---|---|
KOH (%) | 3 | <3 |
IPA (%) | 6 | — |
Additive (%) | — | <2 |
Process temperature [°C] | >80 | 70–100 |
Pyramid size [μm] | 5–12 | 2–7 |
Process time [min] | 30–40 | 5–10 |
Organic content [wt%] | 4–10 | <1.0 |
Boiling point [°C] | 83 | >100 |
Bath lifetimes | <15 | >100 |
Process parameters for IPA-based and additive-based alkaline texturing of mono-crystalline wafers.
The texturing process of the mono-crystalline wafers is typically performed in a ‘batch’ which implies that the wafers are loaded in a carrier with slots to hold the wafers (100 slots in a carrier) and then the batch is processed sequentially in baths for texturing, cleaning, treatment steps to remove the organic residue and metal contamination and drying the processed wafers. The carriers are typically coated with PVDF which has very good resistance to various chemicals, abrasion and mechanical wear and tear. Typical carrier for mono-crystalline wafers handling is shown in Figure 6. The batch texturing tool has dedicated baths for each step with dosing tanks for chemicals used in the bath. The tool processes many carriers simultaneously and can reach a throughput of >6,000 wafers/h with processing of four carriers at the same time.
Carriers for loading wafers in the batch tool. Source: RCT solutions GmbH.
Multi-crystalline wafers offer a cost advantage compared to the mono-crystalline wafers and hence have been more widely adopted. However, the alkaline chemistry used for texturing mono-crystalline wafers does not work well for multi-crystalline wafers due to the presence of different grain orientations. An alternative acidic chemistry based on HF and HNO3 was developed to remove the saw damage and texture the multi-crystalline wafers simultaneously [17, 18]. The acidic solution-based texturing operates at temperatures below room temperature and hence leads to reduced reaction gas emission, little heat generation, higher stability of the etching solution and better control of the etch rate [18]. A comparison of alkaline texturing and acidic texturing process for multi-crystalline wafers is shown in Figure 7.
Comparison of alkaline and acidic texturing for multi-crystalline wafers. Reflectance curves after deposition of SiNx:H are also showed for comparison [17].
The acidic texturing process of multi-crystalline wafer can be done in significantly reduced time compared to the alkaline texturing process and hence can be implemented in an ‘inline’ configuration where the wafers are passed through rollers immersed in the etching bath. A representative image of an inline process along with the typical acidic texturing process is shown in Figure 8. For a five lane configuration, the inline tool can have a throughput of up to 4,000 wafers/h. It is important to note that the wafer surface facing down in the etching solution is textured better than the top-side and is the ‘sunny-side’ for further processing. The acidic texturing process leads to formation of porous silicon on the textured surface which absorbs light and also increases the surface recombination [18]. Hence the porous silicon is removed using a dilute alkaline solution. Subsequently, an acidic clean (HF + HCl) is performed to remove oxides and metal contamination from the wafer surfaces.
(a) Representative inline process with five lanes and (b) acidic texturing process flow for multi-crystalline wafers.
It is important to note that the acidic texturing process discussed above is suitable for the slurry-wire sawn (SWS) multi-crystalline wafers. In the past few years, diamond-wire sawing (DWS) process has replaced the slurry-wire-based cutting due to process and economic advantages [19]. The saw damage of the SWS multi-crystalline wafers is more than the DWS wafers, which have deep straight grooves and a much more smoother surface than the slurry-wire sawn wafers [19]. The saw damage for the SWS wafers plays an important role for initiating the texturing process, which does not occur for the DWS wafers.
Various methods have been proposed to texture DWS multi-crystalline wafers and are summarized in Table 2 [20]. By tuning the various methods, reflectance of close to 0% can be obtained and hence the term ‘black silicon’ has been used for the texturing process of DWS multi-crystalline wafers. RIE was the first method for making black silicon and uses sulfur hexaflouride (SF6) to react with Si and gases like Cl2 and O2 for passivating and limiting the reaction [20]. Recently, commercial multi PERC solar cells with average efficiency of 21.3% have been demonstrated with RIE-based texturing process [21]. However, since RIE is a vacuum-based process the throughput is low as compared to a typical inline process and also additional pre-processing and post-processing is required to remove the saw damage and damage due to ion-bombardment, respectively. A variant of the RIE method which does not require vacuum or plasma has been implemented in a commercial tool [22].
Method | Reagents | Mask | Catalyst | Minimum reflectance (%) |
---|---|---|---|---|
Reactive ion etching (RIE) | SF6/O2, SF6/Cl2/O2, SF6/O2/CH4 | None | None | 4.0 |
Plasma immersion ion implantation (PIII) | SF6/O2 | None | None | 1.8 |
Laser irradiation | CCl4, C2Cl3F3, SF6, Cl2, N2, air | None | None | 2.5 |
Plasma etching | SF6 | Ag nano particles | None | 4.2 |
Metal-assisted chemical etching (MACE) | AgNO3/HF/HNO3 | None | Ag, Au | 0.3 |
Electrochemical etching | HF, EtOH,H2O | None | None | <5.0 |
Various methods for texturing diamond-wire sawn multi-crystalline wafers [20].
One of the approaches for texturing DWS multi-crystalline wafers is to upgrade the existing acidic texturing-based chemistry with additives [23, 24, 25]. Such an approach can potentially have a lower CoO compared to the MACE-based approach [23]. Reflectance of such an additive-based approach has been demonstrated to be similar to the conventional isotexturing solution with solar cell efficiency of 18.7% for the Al-BSF-based structure [24].
MACE-based texturing is similar to the conventional acidic etching method with an additional step of catalytic metal deposition. The process flow consists of SDR, catalyst metal deposition, chemical etching and post-treatment. Efficiencies of 19.2% have been obtained for commercial multi Al-BSF cells using batch-type MACE texturing process [26]. Inline-type MACE-based commercial tool has been demonstrated with the possibility to tune the reflectance in the range of 12–23% and obtain average efficiency for Al-BSF and PERC structure of 18.8 and 20.2%, respectively [27]. Representative images of textured surface based on MACE process are shown in Figure 9. The cost of ownership (CoO) of the inline MACE process is potentially lower compared to the batch-based MACE process with scope to reduce it further by recycling Ag from the texturing bath [27].
MACE textured DWS multi wafers, (a) surface with Ravg = 12% and (b) surface with Ravg = 22% [27].
The emitter region in a solar cell is fabricated by a high temperature diffusion process (to be discussed in sections ahead). During the diffusion process, phosphor silicate glass (PSG) is deposited on the wafer which should be removed before deposition of the ARC layer. As depicted in Figure 10, after the diffusion step, the n-type region is also present on the edges and the rear-side of the wafer. The n-type layer on edges and the rear-side will short-circuit the emitter with the base substrate and hence it is important to etch these regions and isolate the emitter on the FS from the base substrate as depicted in Figure 10(c).
Processing of silicon wafer after diffusion and edge isolation (a) Textured silicon wafer, (b) Diffused silicon wafer, (c) Diffused silicon wafer after edge-isolation.
The edge isolation process can be performed in an inline manner similar to the texturing process discussed in the previous section. The exception in this case is that the chemical should etch only the rear-side and edges without interacting with the FS. A representative image of the edge isolation process is shown in Figure 11. It is important to note that the rollers are present only on the bottom-side to avoid any contact of the etching solution with the front-side. The subsequent steps after the RS etching are similar to those in the inline texturing machine.
Representative image of solar cell in an inline edge-isolation bath.
High temperature processes form a vital part of solar cell fabrication. Examples of such processes are forming the p-n junction by diffusion, firing of screen-printed contacts, activating surface passivation layers or annealing process induced defects. The section glimpses the basic physics of emitter diffusion process and plasma enhanced chemical vapor deposition (PECVD).
Emitter diffusion is one of the crucial thermal steps in the industrial solar cell fabrication. The n-type emitter of the crystalline p-type silicon solar cells is formed by phosphorus (P) diffusion. In the diffusion process, the Si wafers are sent in a furnace and exposed at 800–900°C to phosphoryl chloride (POCl3) and O2 which results in PSG deposition on the Si wafer surfaces. This step is called as pre-deposition, where the PSG [28] acts as a source of phosphorus (P) dopants to diffuse into the Si wafer. The next step is drive-in, where the supply of dopant gases is disconnected and P from the PSG layer diffuses further into the Si wafer. Hannes et al. [29] illustrates for the optimum process feasibility for photovoltaic applications, three different effects have to be considered. Firstly, the in-diffusion of P from the PSG and its presence in electrically active and inactive states in the Si wafer, which increases Shockley-Read-Hall (SRH) recombination. Secondly, the gettering of impurities into the Si layer towards the PSG layer. Finally, the metal contact formation with the P-doped Si emitter draws out the generated power.
The diffusion process is quantified by sheet resistance which depends on the depth of p-n junction and P concentration profile. The sheet resistance has units of Ω/cm (commonly measured as Ω/□) and is measured using a four-point probe system. The definition of sheet resistance is illustrated in Eq. (1).
where R = resistance of a rectangular section (Ω); ρ = resistivity (Ω cm); l = length of the rectangular section (cm); A = area of the rectangular section (cm2); W = width of the rectangular section (cm); D = depth of the rectangular section (cm) and ρsheet = resistance for given depth (D) when l = W (Ω/□).
The earlier values of emitter sheet resistance were 30–60 Ω/□ with p-n junction depths of >400 nm and high P surface concentration. With improvements in the front-side silver (Ag) contacting paste, the emitter sheet resistance is now in the range of 90–110 Ω/□ with junction depth of around 300 nm and lower P surface concentration. Shifting to larger sheet-resistance allows to capture more light in the UV and blue spectrum, while also reducing the surface recombination to improve the Voc. It should be noted that the diffusion process occurs on the FS (directly exposed to the gases) and also on the edges and RS. If the edge isolation process is not carried out (as discussed in Section 4.3), the emitter will be short-circuited with the substrate.
Figure 12 shows the POCl3 diffusion process in a closed quartz-tube system.POCl3 is a liquid source supplied to the process tube by bubbling it with a carrier gas N2. By mixing
(a) Schematic representation of the batch-type diffusion process and (b) representative image of a batch-type diffusion equipment. Source: centrotherm GmbH.
At the Si surface,
Chlorine which is a by-product during the pre-deposition cleans the wafers and quartz-tube by forming complexes with metals. PSG is used as source for driving in the P atoms into Si surface. During the drive-in process, POCl3 is switched off and only O2 is added to build up a thin oxide layer beneath the PSG to enhance the diffusion of P atoms into Si surface.
Inside the diffusion tube there are five heating zones as illustrated in Figure 13. The zones are:
Loading zone (LZ)—area from where the wafers are loaded into the tube.
Center loading zone (CLZ)—area between the loading zone and centre zone.
Center zone (CZ)—center area of the tube.
Center gas zone (CGZ)—area between the centre zone and gas zone.
Gas zone (GZ)—area from where the gases move out through the exhaust.
Heating zones inside the diffusion tube.
Typically the temperatures of each heating zone are adjusted to obtain equal emitter sheet resistance for all wafers across the boat.
Environment of diffusion process should be very clean and hence quartz material is used for the tubes. Cleanliness of the tubes and loading-area maintenance also affects the process results. Since in gas-phase diffusion there is no residue in the tube, it results in a cleaner process. By half pitch loading in the low pressure (LP) conditions [31], the throughput can be increased. Commonly 1,000 wafers are loaded in a single tube and with five diffusion tubes in a batch-type diffusion system, a throughput of up to 3,800 wafers/h can be achieved for solar cell manufacturing.
An inline diffusion system where the wafers are transported on a belt with phosphoric acid as the source of P dopants was also used in commercial production [32]. However, compared to the inline process, the batch process is more clean, effective and efficient. For n-type solar cells or advanced solar cells concepts like PERT, the p-type batch diffusion is based on boron (B) dopant sources like boron tribromide (BBr3) [33, 34].
A bare Si surface reflects >30% of the light incident. As discussed in Section 4, the texturing process improves the light-capturing. It is desirable to reduce the reflectance further which is obtained by depositing an ARC layer. TiOx was one of the earliest material to be used as an ARC layer for solar cells, however since it could not provide adequate surface passivation it was eventually replaces by SiNx:H [37]. Thermally grown silicon oxide (SiO2) was also employed as the passivating material in the record breaking passivated emitter rear locally diffused (PERL) cells [37]. High thermal budget and long process time made SiO2-based passivation unsuitable for mass-production of solar cells [37]. A comprehensive review of various ARC and passivating material for solar cell applications is discussed in [37].
The plasma enhanced chemical vapour deposition (PECVD) process is suitable for depositing an ARC layer of SiNx:H which not only reduces the reflection but also passivates the front-side n-type emitter and the bulk thus improving the solar cell efficiency [36, 37]. A schematic of a batch-type PECVD system is shown in Figure 14. The wafers are loaded in a graphite boat with the front-sides facing each other. An RF plasma based on process gases ammonia (NH3) and silane (SiH4) operating at a temperature of 400–450°C deposit the hydrogenated SiNx:H layer as per Eq. (4) [35]. The hydrogen incorporated in the SiNx:H film diffuses into the bulk during the firing step (discussed in next section) and passivates the dangling bonds to improve the solar cell performance [36, 37].
(a) Schematic diagram of batch-type PECVD process for SiNx:H deposition and (b) graphite boat for loading Si wafers in the PECVD furnace.
The refractive index (RI) of the SiNx:H film is controlled by the ratio of SiH4/NH3 gas, while the thickness depends on the deposition duration. The SiNx:H-based ARC can minimize the reflection for a single wavelength and the wavelength-thickness is given by [38],
where t = thickness of the SiNx:H ARC layer, λ0 = wavelength of incoming light and n1 = refractive index of the SiNx:H layer.
Based on the relationship, the ARC is also called as a ‘quarter wavelength ARC’. For solar cells, the RI and thickness are selected to minimize the reflection at a wavelength of 600 nm as it is the peak of the solar spectrum. The thickness and RI of the ARC is selected to be the geometric mean of materials on either side, i.e., glass/air and Si. The typical thickness of the SiNx:H ARC is 80–85 nm with RI of 2.0–2.1 giving the solar cell a color of blue to violet blue. A representative image of textured multi-crystalline solar cell deposited with SiNx:H is shown in Figure 15(a), while the variation of SiNx:H color based on its thickness is shown in Figure 15(b). It is important to note that there is a dependence on the surface texture and ARC color for given deposition parameters. There is a variety of solar modules where the color of the solar cells is darker unlike the typical blue color. A typical ARC deposition stage in a solar cell manufacturing line consists of two PECVD systems, each with four tubes and a throughput of up to 3,500 wafers/h.
(a) Representative image of SiNx:H coated multi-crystalline solar cell, (b) variation of SiNx:H layer based on its thickness.
SiNx:H is not suitable for passivating p-type Si and hence dielectrics like Al2O3 are used for RS passivation for cell architecture like PERC cells [8] or for p-type emitters in n-type solar cells. For PERC solar cells, the Al2O3 passivating layer is capped by a SiNx:H to protect it from the Al-paste during the firing process and also serve as an internal reflector for the long wavelength light. Commercial PECVD and atomic layer deposition (ALD)-based systems are available for depositing Al2O3 with throughput of up to 4,800 wafers/h [39].
The last processing step for solar cell fabrication is the FS and RS metallization to draw out the power with minimum resistive losses. Ag is a good contact material for the n-type emitter, while Al makes a very good contact with the p-type substrate. A combination of Ag/Al paste is used to print pads on the RS to facilitate interconnection of solar cells in a module. Screen-printing is a simple, fast and continuously evolving process for solar cell metallization.
A schematic representation of the screen-printing process is shown in Figure 16. The screens have an emulsion coated stainless steel mesh with openings as per the desired metallization pattern as illustrated in Figure 17(a). The metal paste is spread over the screen via the flood and the squeegee movement that deposits the paste on the solar cell based on the screen-pattern. Snap-off is the distance the screen and the solar cell. The squeegee pressure and the snap-off distance are the critical parameters that determine the paste lay down and geometry of the Ag FS fingers.
Illustration of the screen-printing process for solar cell metallization.
(a) Mesh-emulsion screen with finger opening for FS Ag printing [40] and (b) representative FS metallization pattern.
Typical paste lay down for Ag/Al RS pads, RS Al and FS Ag are 35–45 mg, 1.1–1.4 g and 100–120 mg, respectively for a 6 inch Al-BSF multi-crystalline solar cell. An illustrative Ag FS metallization pattern is shown in Figure 17(b). The Ag finger opening has reduced to below 30 μm, while application of 5 bus-bar is being increasingly adopted now. With such screen parameter and good paste lay down, consistent FF of >80% should be obtained for the Al-BSF solar cells with an optical shading loss of <6%.
The metallization pastes consist of metal powder, solvents and organic binders. In case of FS Ag paste, the paste also contains glass-frit while etches the SiNx:H layer and makes contact with the n-type emitter [41]. The metal pastes are dried after printing and finally they are sent through a fast-firing furnace for sintering and form the RS Al-BSF and FS Ag contact. An example of such a fast-firing furnace with the temperature profile is shown in Figure 18. The FS Ag finger sintering process is illustrated in Figure 19. When the solar cell passes through the fast-firing furnace, the organic binders are burnt, followed by melting of the glass frit and finally formation of Ag crystallites contacting the n-type emitter. The firing profile needs to be tuned based on the specific types of metallization pastes and emitter diffusion profile. As an example, the firing peak temperature could be low to not form a good ohmic contact on the FS, while a too high temperature can lead to diffusion of Ag through the junction and shunting of the p-n junction. Image of a complete multi-crystalline Al-BSF solar cell is shown in Figure 20.
(a) Example of a firing furnace for sintering metal contacts and (b) illustrative temperature profile of a firing furnace. Source: centrotherm GmbH.
Illustration of the firing process. (a) Burning out of the organic binders, (b) melting of glass frit which etches the SiNx:H and (c) Ag crystallite formation at the emitter interface.
(a) FS of a complete solar cell and (b) RS of a complete solar cell.
The costing of various factors in solar cell processing have decreased over the years, while the contribution of front Ag is still the most significant [42]. Significant amount of work has been done to replace Ag by alternate metal like copper (Cu) which has a conductivity value of very close to that of Ag and also offers a potential significant cost advantage [43, 44]. Cu has high diffusivity and solubility in Si and hence a barrier-layer like nickel (Ni) is deposited on Si prior to Cu plating [42]. Light-induced plating (LIP) which is derived from conventional plating utilizes the photovoltaic effect of light to plate the desired metal and has many advantages compared to conventional plating [43, 44].
Ni-Cu-based front-side metallization requires an additional front-side ARC patterning step unlike the Ag paste-based metallization and in most cases also an additional Ni sintering step to reduce the contact resistance and have good adhesion of the metal stack [42]. Commercial DWS cut mc-Si solar cells based on Ni-Cu-Ag plated stack have been demonstrated with finger width of 22 μm, aspect-ratio of close to 0.5 and similar efficiency as that of reference screen-printed Ag-based solar cells [45].
Continuous improvement in the Ag FS pastes along with simplicity, reliability and high throughput of the screen-printing process has made it difficult for Ni-Cu-based metallization to compete with Ag-based FS metallization. However, high solar cell efficiency concepts like bifacial heterojunction solar cells, where Cu can be directly plated onto the transparent conducting oxide, the plating process is simplified and requires only a single tool [39]. Similarly, high efficiency concepts which require reduced amount of metal can achieve the same using plating-based metallization [42, 46].
The final step is I-V testing of the complete solar-cells as per the standard test conditions (STC), i.e., AM 1.5G, 1000 W/m2 with a Class AAA solar simulator. An example of FS probing of solar cell is shown in Figure 21. The typical parameters obtained from the I-V tester are indicated in Table 3. I-V testers have many characterization parameters which can be helpful for diagnosis of solar cell defects. Representative electroluminescence (EL) and thermal IR image of a solar cell with some defects are shown in Figures 22(a)–(c). An EL image of a good solar cell with uniform intensity is shown in Figure 22(a), while for a solar cell in which the FS fingers are not printed uniformly, a darker contrast can be seen in Figure 22(b). Figure 22(c) shows a thermal IR image of a solar cell with a localized shunt which has been formed during one of the processing steps. In the end, the solar cells are sorted in different efficiency bins based on the selected classification.
I-V measurement FS probing for solar cell characterization.
Parameter | Comments |
---|---|
Voc (V) | Good mc-Si Al-BSF solar cells have a value of >0.635 V |
Isc (A) | Good mc-Si Al-BSF solar cells have a value of >9.0 A |
FF (%) | Good mc-Si Al-BSF solar cells have a value of >80% |
Efficiency (%) | Good mc-Si Al-BSF solar cells have a value of >18.6% |
Vmpp (V) | Corresponding voltage at the maximum power point |
Impp (A) | Corresponding current at the maximum power point |
Rs (Ω) | Good mc-Si Al-BSF solar cells have a value of <1.5 mΩ |
Rsh (Ω) | Good mc-Si Al-BSF solar cells have a value of >100 Ω |
Irev (A) | Reverse current at a voltage of −12 V should be <0.5 A for good solar cells |
FS BB-BB resistance (Ω) | Resistance measured between the BB’s on the FS |
RS BB-BB resistance (Ω) | Resistance measured between the BB’s on the RS |
Parameters for characterization of a solar cell obtained from I-V measurement.
(a) EL image of a good solar cell, (b) EL image of a solar cell with non-uniformity in Ag finger printing and (c) thermal IR image of a solar cell indicating presence of localized shunts.
DWS has become the standard for mono-crystalline wafers, while it is expected to have a market share of >80% by 2022 for multi-crystalline wafers [2]. SWS for multi-crystalline wafers is expected to phase-out by that time. With DWS, the kerf loss would also become <80 μm by 2022, which would in turn reduce the poly-Si consumption per wafer below 15 g. 3BB design for front-contacts are expected to phase-out by 2020 with 50% share for 5BB design. With continuous improvements in Ag pastes and screens, the FS finger width is projected to reduce to 30 μm by 2022. Wet-chemical processing tools have crossed throughput of 8,000 wafers/h in 2018 and would touch 9,000 wafers/h by 2020. Thermal processing equipments have reached throughput of 5000 wafers/h in 2018 and expected to cross 7,000 wafers/h by 2020. The metallization and I-V testing/sorting section is expected to have a throughput of >7,000 wafers/h by 2022.
Al-BSF-based cell technology which has a market share of >60% in 2018 is expected to reduce to <20% by 2025. With more emphasis on high efficiency solar cells concepts, share of PERC technology is expected to be >50% by 2022. Production efficiency of Mono PERC is expected to be >22% by 2022, while for multi PERC it should touch 21% by the same time. An important aspect related to multi-PERC is the mitigation of LeTID-based problem to minimize the loss of efficiency after installations of the modules in the field. Si HJ cells with efficiencies of >22% in 2018 after expected to reach stable efficiency of 23% by 2020, with a market share of around 10% by 2022. High efficiency bifacial cells with an additional advantage of tapping the solar radiation from the rear-side is expected to have a market share of 20% by 2022. N-type back contact solar cells are expected to cross 24% efficiency by 2020.
Si solar cells have become an important part of the renewable energy domain over past decades with matured manufacturing technologies. P-type multi-crystalline wafers have become the main-stay for solar cell production. However, with higher efficiency and decreasing production costs, mono-crystalline solar cells have also gained a significant share and are expected to compete closely with multi-crystalline wafers in the near future. For standard Al-BSF technology, 19 and 20% has become the bench-mark for multi-crystalline and mono-crystalline solar cells, respectively. Mono-PERC and multi-PERC cells have reached stabilized efficiencies of 21.5 and 20%, respectively. In addition, PERC also provides a simpler approach for bifacial solar cells by having a grid pattern on the RS instead of the full area contact. High efficiency n-type and bifacial solar cells have a market-share of <10% which is expected to increase in the future. The manufacturing technologies have matured considerably over the past few years with further improvements to increase the throughput.
The authors would like to thank the colleagues from RCT Solutions GmbH from whom some of the contents for the chapter have been taken. Mehul C. Raval would like to thank colleague Jim Zhou for the discussions regarding black silicon texturing.
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States and worldwide [1, 2, 3, 4]. TBI results from an injury to the brain following exposure to external physical forces including falls, car accidents, explosive blasts, and assault [5, 6]. These injuries often have long-term consequences to the health of injured individuals, and few effective treatments are currently available [6]. The pathophysiology is characterized by damage to the neuronal and glial cells of the brain as well as the associated vasculature [6], and the role of inflammation as a causative agent of tissue injury has emerged as a focus of TBI research [7]. Preclinical research focusing on the mechanisms underlying secondary inflammation and treatment of TBI employs various animal models [8]. This review will discuss TBI as a public health problem, the pathology of TBI and the significance of the peripheral immune response in the outcome of TBI in human and animal models.
\nTraumatic brain injury is a major cause of death and disability in the United States and worldwide [1, 2, 3, 4]. An estimated 69 million people sustain a TBI each year around the world [9]. In the United States, incidence of TBI has risen steadily over recent years. An average of 1.7 million TBIs occurred per year from 2002 to 2006 [1], but an estimated 2.8 million TBIs occurred in 2013 [4]. There is a gender disparity in groups most affected by TBI—in the United States, males are more commonly affected than females. Age group differences are also evident in TBI prevalence, with young children, young adults, and the elderly most frequently suffering from TBI. The specific age groups that most commonly sustain TBIs are ages 0–4 years, 15–24 years, and 75 years and older [4]. Traumatic brain injuries arise from a variety of causes including traffic accidents, falls, abuse, sports injuries, and traumatic impact with an object [4, 5]. The most prevalent causes of injury vary predictably with patient age. Injuries in younger patients are most commonly associated with sports activities or high-risk behaviors such as distracted driving, while injury in the older population of patients is more frequently associated with falls [5]. These events cause injuries of a range of clinical severities including mild, moderate, and severe TBI. In the clinical setting, these injuries are most frequently classified using the Glasgow Coma Score (GCS) [10]. The GCS assesses overall consciousness of the patient and classifies injury severity based on eye, motor, and verbal responses to stimuli [5, 10]. Scores range from 3 to 15. Higher scores correlate with decreased injury severity—for clinical classification purposes, a GCS range of 13–15 has been used to demarcate mild injury, 9–12 for moderate injury, and 8 or less to indicate severe TBI [5]. Imaging modalities including CT and MRI are also used to further assess the severity of TBI and inform prognosis [10].
\nA traumatic brain injury may be defined as an injury to brain tissue caused by direct external force [10]. The physical impact of TBI initiates a plethora of downstream processes with deleterious effects on neuronal and glial tissue. Overall, the pathophysiology of a TBI can be divided into primary and secondary phases of injury [5, 10, 11, 12]. The primary phase of injury includes the cellular damage caused at the instant of injury by the direct mechanical impact of trauma. Primary injury can manifest as cell death, hemorrhage, and/or diffuse axonal injury. First, neurons and supporting vasculature can be directly torn by the shear forces of injury. This damage to the neurovascular network results in intracranial hemorrhage, which can lead to increased intracranial pressure as blood builds up inside the skull. Intracranial bleeding can also generate hematomas. Both increased intracranial pressure and hematoma formation have negative impacts on neural recovery [11, 13]. Primary injury can also encompass diffuse axonal injury. Diffuse axonal injury is damage to neurons going beyond the initial lesion area, caused by dynamic forces spreading through the brain from the primary impact [11]. These physical forces resulting from traumatic brain injury can be either linear accelerational forces or rotational forces. Since neural tissue is elastic and does not have a strong internal structure, the brain has little tolerance for this disruption and is very susceptible to injury from these forces [12]. Primary injury also disturbs autoregulation of cerebral blood flow and cellular metabolism. Normal control mechanisms for blood flow and metabolism fail due to the cellular damage of TBI, resulting in cellular effects similar to those seen in ischemic stroke. As the massive damage overwhelms cellular metabolism, ATP production cannot match demand, and neuronal and glial supplies of ATP become inadequate to fuel cellular ion pumps. The resulting dysregulation of ion flow initiates various downstream pathways leading to necrosis, apoptosis, and oxidative damage [14]. Additional mechanisms of secondary injury have been described and include the long-term changes resulting from the physiological processes triggered by the primary phase of injury [12].
\nNeuroinflammation plays a major role in the secondary phase of injury. While all resident brain cells are involved in some way in the response to TBI, the role of microglia, the resident immune cells of the brain, in neuroinflammation has been particularly well-studied. When brain injury occurs, cells damaged in the primary phase of injury release cell signals known as damage-associated molecular patterns (DAMPs). In the early stages of injury, resident microglial cells are activated by these DAMPs and migrate to the injury site [7, 15]. These cells have a profound effect on both acute and chronic injury processes as they secrete both pro- and anti-inflammatory cytokines and can remain activated for up to 18 years after TBI [7, 16]. Cytokines released by microglia have a plethora of effects including alteration of local blood flow and modification of the blood-brain barrier (BBB) [15]. Microglia also assist in walling off the injured area in a protective effort to prevent the spread of bleeding and cellular damage. However, these cells can also generate additional reactive oxygen species (ROS) with damaging effects on cells [17]. While glial cell activation is a key part of the secondary phase of TBI, there is also an important role for the peripheral immune system in TBI recovery. The central nervous system is typically viewed as an immune-privileged site, with few or no peripheral-derived immune cells present. However, following TBI, the blood-brain barrier is damaged, allowing infiltration of peripheral-derived circulating immune cells including neutrophils, macrophages, and lymphocytes [17]. Glutamate excitotoxicity, oxidative stress, and neuroinflammation all contribute to the cellular damage observed in the secondary phase of injury, and the long-term damage resulting from these processes can be extensive. This secondary phase of injury is the primary target for TBI therapeutics—while efforts can be made to reduce TBI incidence, once a TBI has occurred nothing can be done to treat primary injury. Therefore, potential TBI treatments are aimed at reducing damage from the secondary phase of injury [14].
\nMultiple rodent models have been used to study the role of inflammation in TBI. Due to the variety of injury causes and individual patient health effects, human TBI exhibits multifaceted disease processes, and different animal models are used to recapitulate different aspects of human injury. Here, we discuss three common mouse models of TBI: weight drop, fluid percussion injury (FPI), and controlled cortical impact (CCI). All three of these models generate TBI by direct impact, either applied directly to the brain through a craniectomy or applied to the intact skull. While each of these models replicate certain features of human TBI, no one model fully expresses the varied picture of clinical TBI.
Weight drop and fluid percussion injury are both used to produce diffuse injury in rodent models of TBI. Weight drop injury relies on gravity-driven fall of the weight to generate injury. Injury severity can be controlled by adjusting both the height of the drop and the mass of the weight used. Modification of injury severity allows this model to reproduce features of mild, moderate, or severe TBI. Weight drop injury results in cortical cell death, cerebral edema, neuroinflammation, and blood-brain barrier compromise, and this method of injury is relatively time-efficient to perform [18, 19]. In addition, weight drop injury results in demonstrable cognitive deficits, which may reproduce features of human TBI [20].
FPI can also reproduce certain histological features of human TBI and can be modified to generate different severities of injury. The FPI method is one of the most commonly used models of experimental TBI and can be adjusted to generate mild, moderate, or severe TBI [21]. Fluid percussion injury is performed using the injection of fluid into the cranial cavity, generating injury as a pressure wave spreads through the fluid applied to the brain [8, 22]. This model results in cortical contusion, hemorrhage, inflammation, diffuse axonal injury, and gliosis, with accompanying memory and motor deficits [21, 23, 24]. Application of FPI causes both focal and diffuse damage to the brain and has been used to assess multiple prospective TBI therapeutics [25].
CCI generates injury by application of a mechanical focal impact to the brain using a controlled piston. This technique was initially developed to replicate features of injuries caused by automobile accidents but is now commonly used to study multiple aspects of focal TBI pathology [26]. Controlled cortical impact machines allow modification of the depth, velocity, dwell time, and angle of the impact, as well as variation of the size and shape of the impactor tip. These highly reproducible features make the CCI model especially well-suited to induce a wide range of injury severities, and the tight control of injury parameters is an important advantage of this model [26, 27]. The CCI method of experimental TBI typically includes a craniotomy before impact to the intact dura mater, although this method can also be used to produce closed-head injury [27]. Injury induced by CCI replicates many histopathological changes seen in human TBI, including cortical contusion, blood-brain barrier compromise, inflammation, and oxidative stress [26]. Corresponding to the histological features observed in this model, CCI results in functional deficits, including memory, learning, and motor deficits similar to those observed in human TBI patients [26]. These deficits are observed in both the acute and chronic periods, while other models including FPI less frequently report the chronic persistence of cognitive deficits [27]. The CCI model also has an overall higher survival rate compared to the fluid percussion model [26]. The reproducibility, tight control of experimental parameters, persistence of cognitive deficits, and high survival rate induced by CCI make it an excellent model for TBI research. For these reasons, the work outlined in this dissertation takes advantage of the CCI model.
The peripheral-derived immune cell response is a key feature of the physiologic response to traumatic brain injury, which can have both positive and negative effects. The central nervous system is typically regarded as an immune-privileged site due to the action of the blood-brain barrier (BBB), which prevents peripheral immune cells from readily entering CNS tissue [7, 15]. However, following TBI, the integrity of the blood-brain barrier is compromised by a variety of mechanisms, allowing infiltration of peripheral-derived immune cells into brain parenchyma [28]. Various immune cells including neutrophils, macrophages, and lymphocytes have been shown to infiltrate the lesion area following injury, releasing cytokines that influence recovery [17]. These peripheral immune cells have a profound effect on injury recovery—impact of these infiltrating cells can be either beneficial or deleterious to recovery depending on the specific cells and mechanisms involved. While all of these cell types may affect TBI recovery, macrophages in particular have been a focus of TBI research [29]. This review will discuss the general mechanisms of blood-brain barrier compromise after TBI and survey the effects of peripheral immune cell infiltration, with a focus on macrophages.
\nThe blood-brain barrier (BBB) forms a protective layer separating the CNS from the surrounding environment, including circulating peripheral immune cells. The brain is typically regarded as an immune-privileged site due to the operation of the BBB—under normal physiologic conditions, peripheral immune cells in the vasculature cannot enter CNS tissue [7, 15]. The healthy brain exists in a tightly regulated system, and proper operation of the BBB is critical in maintenance of the correct microenvironment for healthy neural function [30]. Multiple cell types including brain endothelial cells, astrocytes, and pericytes compose the BBB [30]. Traumatic brain injury compromises the BBB by direct damage to the cells composing this barrier. The direct damage to cerebral vasculature and disruption of endothelial tight junctions allows entry of immune cells and proteins from the vasculature into cerebral tissue [28, 31]. Rising calcium concentrations activate caspases in endothelial cells, initiating apoptosis of brain endothelial cells and resulting in additional damage to the BBB [28]. The glutamate excitotoxicity observed in TBI also has been shown to increase production of reactive oxygen and nitrogen species (known as oxidative stress), causing further apoptosis of brain endothelial cells [31]. Reactive oxygen species can also increase migration of peripheral monocytes through up-regulation of cellular adhesion molecules [31]. The physical damage to brain endothelial and glial cells combined with the activation of apoptotic and stress-related pathways in the endothelium that disrupt tight junctions can increase BBB permeability, allowing circulating peripheral immune cells to enter the brain. Massive influx of peripheral immune cells, induced by brain-derived cytokine release (IL-6, TNF, IL-1β, etc.) at the lesion area over time, further contributes to BBB damage. Additional cytokine, matrix metallopeptidase (MMP), and reactive oxygen species (ROS) released by activated neutrophils and monocyte/macrophages further disrupt the BBB via down-regulation of tight junction proteins as well as through recruitment of additional inflammatory cells [28, 31, 32, 33, 34]. An overview of the major peripheral immune cell response is depicted in Figure 1.
\nOverview of major peripheral immune cell response to TBI.
\nNeutrophils: Neutrophils arrive at the lesion area in the early stages of injury—these cells migrate to the area of injury and infiltrate damaged brain tissue within the first 24 hours postinjury [33]. These cells are recruited by the release of IL-8, a chemoattractant cytokine known to be generated in the early stage of TBI [35]. Numbers of circulating neutrophils rise significantly in the acute phase of TBI. One study found that neutrophils present following TBI appear to be less susceptible to apoptosis than neutrophils in uninjured patients, which may contribute to the increased numbers observed [36]. In contrast to the few studies implicating a positive role for neutrophils in TBI recovery [33, 37], numerous show deleterious effects. One study, using the CCI model, found that neutrophil depletion improved tissue recovery. Neutrophil-depleted mice in this study showed decreased cell death and tissue loss following TBI [38]. Another study assessed the effects of decreased immune cell infiltration following TBI via administration of anti-intercellular adhesion molecule 1 (ICAM1) antibody in a fluid percussion model of rat TBI. Rats given anti-ICAM1 showed decreased neutrophil infiltration following injury 26 hours following TBI, which correlated with increased motor recovery [39]. Several mechanisms have been suggested to explain these negative effects. Some studies have indicated that neutrophils bind endothelial cells and platelets after TBI, decreasing blood flow and promoting ischemia [33]. As previously mentioned, neutrophils can also damage the BBB through release of MMPs and reactive oxygen and nitrogen species [33]. In addition, many of the cytokines generated by neutrophils following TBI have been shown to have negative effects on neural recovery. These cytokines include IL-9, IL-12, CXCL5, and TNFα. IL-9 can increase the damage caused by excitotoxicity following TBI, and high levels of IL-12 have been correlated with poor postinjury outcome (Figure 1). CXCL5 contributes to BBB compromise, and TNFα plays a role in neurotoxicity [33]. However, other studies have found that infiltration of peripheral cells in the acute stage of injury has little effect on recovery, suggesting instead that infiltration of peripheral-derived monocytes in the later stages of injury (greater than 48 hours after injury) has the greatest influence on injury progression [7].
\n\nMonocytes: The role of monocyte/macrophages has been particularly well-studied in regard to the effects of infiltrating peripheral-derived immune cells after TBI. Although a minority in terms of numbers of circulating immune cells, composing only 5–10% of the peripheral immune cell population, monocytes play an important role in TBI recovery [36]. Monocytes are the primary infiltrating immune cells observed at 3–5 days following injury [29]. While some studies have even argued that peripheral monocytes are the most prominent infiltrating immune cell at 24 hours postinjury as well [40]. Circulating monocytes can display pro- or anti-inflammatory properties. When monocytes migrate into affected tissue, they mature into macrophages with pro- or anti-inflammatory characteristics [36]. These cells can have a neuroprotective effect via phagocytosis of dead cell debris, release of growth factors, and production of anti-inflammatory cytokines. Monocyte/macrophages also release granulocyte-macrophage colony-stimulating factor (GM-CSF), which may have a neuroprotective effect through promotion of stem cell differentiation and suppression of apoptotic pathways [41]. However, monocyte/macrophages may have differing effects on TBI recovery depending on their inflammatory profile.
\nWhile monocyte/macrophages may be beneficial in some aspects of TBI recovery, other studies have found that these cells may also negatively affect neural recovery through different mechanisms. One study assessed the influence of macrophages on TBI recovery using a chemokine CC ligand-2 (CCL2) knockout mouse model. This study found increased levels of CCL2 following TBI in both human patients and in a murine weight drop injury model. CCL2 knockout mice showed decreased macrophage accumulation and smaller lesion volumes at 2 and 4 weeks after injury [42]. One study showed that depletion of monocytes using clodronate liposomes decreased neutrophil infiltration and edema and resulted in improved neurobehavioral recovery [43]. Several mechanisms have been suggested by which macrophages could exert neurotoxic effects. Infiltrating macrophages may release reactive oxygen and nitrogen species, increase additional recruitment of neutrophils and monocytes, and generate multiple pro-inflammatory cytokines including TNF, IL-1β, and IL-6 (Figure 1) [41]. The apparent discrepancy between the neurodegenerative and pro-resolving effects of macrophages following TBI is most likely due to the release of both pro- and anti-inflammatory signals from these cells, with corresponding positive or negative effects [29]. As previously mentioned, monocytes are capable of maturing into macrophages with either pro- or anti-inflammatory characteristics [36]. These two populations are traditionally defined as M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Although the overall balance between these phenotypes is driven by injury processes [44], their differential characteristics and the mechanisms underlying their fate choice remain under investigation.
\nMonocyte/macrophages display different phenotypes depending on the cellular microenvironment. Classical macrophages, called M1 macrophages, specialize in promoting inflammation and phagocytosing pathogens. The second class of macrophages, called M2 macrophages, serves to promote tissue recovery [45]. Macrophages are a critical part of the tissue repair process following injury, but these cells can be either helpful or damaging depending on M1/2 status. Following TBI, macrophage polarization toward the M1 phenotype has been associated with neurodegeneration, while polarization toward the M2 phenotype has been shown to reduce oxidative stress [46]. However, these classes are not absolute—macrophages respond to their cellular environment to become more or less M1/2, existing on a continuum with M1 and M2 subcharacteristics at either end [45]. The varied expression of M1 pro-inflammatory vs. M2 pro-recovery traits can be a critical factor in recovery during the peripheral-derived inflammatory response to TBI.
\nThe classically activated or M1 phenotype macrophages are known to function as pro-inflammatory cells. Early studies indicated that these cells become activated by a combination of IFNγ signaling and either direct TNF signaling or Toll-like receptor-induced production of TNF, usually triggered by lipopolysaccharide (LPS) [47]. In the typical response to wound healing outside the CNS, these cells are important in protection against bacterial infection. M1-polarized macrophages generate reactive oxygen species and also activate inducible nitric oxide synthase (iNOS) to generate nitric oxide as well as an array of pro-inflammatory cytokines including IL-12, TNFα, IL-6, IL-1β, and nitric oxide [47, 48]. Identification of M1 macrophages is typically done by measuring gene expression of characteristic markers including IL-12, IL-1β, iNOS, TNFα, and IL-6 [46]. High levels of CCR2 with low CX3CR1 expression have also been used as an indicator of pro-inflammatory status in macrophages [49]. Bystander tissue damage from M1 macrophages can be catastrophic in the normally immune-privileged setting of the CNS.
\nPeripheral-derived macrophages have been shown to rapidly infiltrate the injured brain within the first 1–3 days postinjury [46]. Although both M1 and M2 macrophages are likely present at this stage, early studies of macrophage polarization following TBI indicated that the M1 phenotype predominates in the initial response to brain trauma [48]. CCI-induced increase in expression of pro-inflammatory markers has been demonstrated as early as 6 hours following injury, suggesting that macrophages expressing M1 traits are a key part of the acute response to TBI [46]. One study found that increases in the number of IL-12-expressing macrophages/microglia were evident by 24 hours following CCI injury, and the number remained increased compared to sham controls out to 7 days postinjury [46]. Other work demonstrated that either macrophages polarized toward the M1 phenotype or a transitional phenotype between M1/2 (to be discussed later) become predominant over M2 phenotype by 7 days following CCI injury. This phenomenon correlates with neurodegeneration [46].
\nBased on these reports, macrophages seem to be skewed toward the M1 phenotype for an extended period following CNS injury, with corresponding negative effects on recovery. This contrasts with the typical immune response outside neural tissue, where an early increase in M1 macrophages gives way to pro-recovery M2 macrophages [46]. The neurotoxic effect of M1 macrophages is most likely mediated by pro-inflammatory cytokines. Levels of M1-associated pro-inflammatory cytokines transiently increase in brain tissue during the acute response to injury. Specifically, IL-1β, IL-6, and TNFα levels have been shown to significantly increase in brain tissue by 12 hours postinjury in a mouse model. These cytokines return to sham levels by 7 days postinjury [50]. Support for the importance of these cytokines as mediators of M1-induced secondary neural damage following TBI is provided by a study targeting these cytokines as a potential TBI therapeutic. For example, treatment with Minozac, an inhibitor of pro-inflammatory cytokines, ameliorated the TBI-induced increase of pro-inflammatory cytokines in cortex and hippocampus and resulted in decreased neuronal damage and improved neurocognitive function following TBI [50].
\nThe alternatively activated or M2 phenotypic macrophages are known to serve as pro-recovery or anti-inflammatory cells. These cells are activated by IL4 and serve an immunoregulatory function, in contrast to the microbe-killing function of their M1 counterparts [47]. Like M1 macrophages, identification of M2 macrophages employs gene expression levels of a wide array of characteristic markers. Markers commonly used for this purpose include CD206, Fizz1, Ym1, IL1-RN, Arg1, TGFβ, SOCS3, and IL4-RA [46]. Low levels of CCR2 with high CX3CR1 expression have also been used as a marker for pro-repair macrophages [49]. Studies using these markers have demonstrated an important role for M2-polarized macrophages at multiple time points following TBI. Increases in M2 markers have been shown as early as 6 hours following CCI injury [46]. The reported timeline of M2 influence varies depending on the specific markers assessed. For example, the number of TGFβ-expressing macrophages/microglia has been demonstrated to increase by 24 hours post-CCI injury and remain elevated compared to sham out to 7 days following injury [46]. Increase in expression of Arg1 has also been demonstrated in macrophages/microglia following CCI. Interestingly, the increase in Arg1 expression in macrophages/microglia, which first becomes evident at 24 hours post-CCI, continues to rise out to 7 days postinjury rather than decreasing back toward normal levels as was observed for TGFβ [46]. Expression of CD163, another marker of the pro-resolving M2 phenotype, has also been investigated following TBI. One study showed increased expression of CD163+ macrophages following weight-drop TBI in a rat model. This may have anti-inflammatory effects following TBI through suppression of the pro-inflammatory macrophage phenotype [51]. While timing of expression of specific markers can vary, these studies indicate that macrophages expressing M2 phenotypic traits are a significant factor in TBI recovery.
\nMacrophage polarization toward the alternatively activated or M2 phenotype has beneficial effects on recovery following TBI through a variety of mechanisms. M2-polarized macrophages are characterized by expression of multiple markers including arginase 1 (Arg1), CD206, CD301, resistin-like α, and PDL2 [48]. Alternatively activated macrophages have been shown to decrease T-cell proliferation, promote angiogenesis, assist in generation of extracellular matrix components, and benefit wound healing and tissue repair [47]. In addition, the anti-inflammatory cytokines TGFβ and IL10 secreted by alternatively activated macrophages help to decrease activation of classical macrophages, reducing bystander tissue damage [47]. One study demonstrated that experimentally altering macrophage/microglia phenotype to favor M2 polarization by inhibition of NOX2 results in decreased oxidative damage [46]. In another report, inhibition of high-mobility group box 1 (HMGB1) decreased M1 and increased M2 polarization of macrophages/microglia, which correlated with decreased lesion volume and improved recovery [52]. Moreover, activation of the cannabinoid receptor CB2R decreased M1 and promoted M2 macrophage polarization, accompanied by decreased edema and improved blood flow and behavioral recovery [53]. These studies employed different methods to influence macrophages toward the M2 phenotype with similar results—increased expression of M2 traits has a positive impact on TBI recovery. Additional studies are needed to confirm this beneficial role of M2 macrophages in TBI.
\nAs previously mentioned, macrophages in vivo do not always show a sharply demarcated M1 or M2 phenotype. Several studies have shown expression of both M1 and M2 traits in macrophages following TBI, while others have demonstrated that macrophages can switch between phenotypes [54, 55]. One study using the CCI model demonstrated co-expression of iNOS, a classical M1 marker, with Arg1, an M2 marker, in perilesional macrophages/microglia following injury [46]. Another study assessed expression of a wide array of pro-inflammatory (associated with M1) and anti-inflammatory (associated with M2) genes in mouse cortical tissue following CCI injury and found that both sets of genes are co-expressed at 1, 2, and 7 days postinjury. This study also showed that perilesional microglia/macrophages co-labeled with both M1 and M2 markers at all three time points [56]. A different study using flow cytometry to sort Arg1-positive and Arg1-negative brain macrophages following TBI demonstrated that neither Arg1+ or Arg1− cells displayed gene expression profiles consistent with the M1 or M2 patterns defined by in vitro studies, although two distinct populations of macrophages did seem to exist in this context [48]. These findings suggest that the classic M1 and M2 traits may actually coexist in the same macrophages following TBI. To confirm this at the level of the individual macrophage, one study employed single-cell RNA sequencing to assess the expression of classical and alternative markers in individual macrophages 1 day following TBI. This work demonstrated that traditional M1/2 markers are frequently co-expressed at high levels in the same cell [55]. This study also demonstrated that high expression of well-known M1 or M2 markers did not seem to down-regulate expression of markers of the opposite class. Some macrophages with high expression of Arg1, an established M2 marker, also displayed high expression of TNF and/or IL-1β, known M1 markers [55]. This type of M1/2 combination profile was displayed in a variety of genes, demonstrating that macrophage polarization in vivo can widely differ from the traditional M1/2 paradigm established primarily by in vitro studies [55]. Surprisingly, this study actually failed to find any macrophages that fit entirely within the M1 or M2 category, suggesting that all macrophages responding to TBI respond to injury stimuli along a continuum of expression [55]. Intermediate macrophage phenotypes with traits of both M1 and M2 have also been found in studies of spinal cord injury and Alzheimer’s disease [46]. The results of these studies indicate the existence of a continuum between M1 and M2 macrophages in the setting of brain injury and disease.
\nThe specific stimuli and mechanisms involved in the continuum of M1/2 expression are currently areas of active research. Some authors have suggested that dual expression of M1 and M2 characteristics is a necessary part of the macrophage response to TBI, as these cells must respond to both pro- and anti-inflammatory environmental signals simultaneously in the setting of brain trauma [54]. This concept is supported by the results of the previously mentioned study demonstrating concurrent expression of both pro- and anti-inflammatory gene signatures [56]. The function of infiltrating monocyte/macrophages, therefore, appears to depend more on the specific gene expression and cytokine profile than on overall classification as M1 or M2. These findings underscore the importance of improving our understanding of the pathways involved in regulation of expression on the M1/2 continuum. Data from multiple studies have indicated that the Tie2/Angiopoietin pathway is an important factor in the continuum of expression between M1 and M2 macrophages. In addition, data from our project, to be discussed in the following chapters, have specifically implicated this pathway in the context of M1/2 polarization after TBI.
\nThe Tie2/Angiopoietin signaling axis was first identified for its key role in the regulation of angiogenic pathways, but this receptor complex is also gaining increasing recognition for its importance in peripheral immune cells. The receptor tyrosine kinase Tie2 (also known as Tek) interacts with its ligands, the angiopoietin family of proteins, to influence vascular development [57]. Studies in endothelial cells have shown that Tie2 is differentially regulated by its ligands Angiopoietin 1 (Angpt1) and Angiopoietin 2 (Angpt2). Angpt1 typically acts as an agonist for Tie2, while Angpt2 serves as an antagonist with several exceptions [58, 59]. Although Tie2/Angiopoietin signaling has been most studied for its role in regulation of vascular function, Tie2 is also expressed in a subpopulation of monocyte/macrophages called Tie2-expressing monocytes (TEMs) implicated in tumor formation and inflammation [60]. This review will discuss the mechanisms involved in the Tie2/Angiopoietin signaling axis and investigate the function of TEMs in various cellular contexts.
\nTie2 is a receptor tyrosine kinase first identified on vascular endothelial cells [61]. There are multiple components to the Tie2 signaling pathway where the angiopoietin ligands serve as binding partners [59]. In addition to its expression on endothelial cells, Tie2 is expressed in TEMs, hematopoietic stem cells, neutrophils, eosinophils, and some muscle satellite cells [59, 62]. Angiopoietin 1 (Angpt1) is primarily expressed in platelets and perivascular cells, while Angiopoietin 2 (Angpt2) is expressed in endothelial cells [63]. Expression of both Angiopoietins has also been demonstrated in hematopoietic stem cells and some immune cell types including monocyte/macrophages [64, 65]. Angpt1 serves as a Tie2 agonist, activating this receptor and increasing endothelial vessel stability [59]. However, the function of Angiopoietin 2 (Angpt2) is more variable. Some studies have shown that Angpt2 can act as either an agonist or antagonist of Tie2 depending on cellular context, and increased expression of Angpt2 has been demonstrated in multiple disease states [59]. Angpt2 has been found to act as a Tie2 agonist in the context of decreased Angpt1 signaling, absence of Tie1/Tie2 heterocomplexes, or inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP) in the endothelium [59, 66, 67]. However, the dominant role of Angpt2 and/or these co-complexes in TBI has not been established. This ligand has repeatedly been shown to act as an antagonist in the setting of inflammation [68]. Although less studied than its counterpart, Tie1 has also been found to interact with Tie2 to promote Tie2/Angiopoietin interactions in vascular remodeling [59, 69]. The interactions between Tie2, Tie1, Angpt1, and Angpt2 have a profound influence on cell survival and vascular permeability [59, 61].
\nThe downstream cellular effects of Tie2 binding with an Angiopoietin ligand can vary widely with cellular context. This is partially due to the differing effects of Angpt1 vs. Angpt2—Angpt1 binding has been shown to oppose the effects of inflammatory cytokines and decrease vascular permeability, while Angpt2 has been found to increase vascular permeability in a number of inflammatory models [59]. Binding patterns of these two ligands with Tie2 are distinct from each other, which may contribute to their differing effects. The fibrinogen-like domain of Angpt1 binds an immunoglobulin domain of Tie2, which may help Angpt1 increase cluster formation and cross-phosphorylation of Tie2 upon binding [68]. In contrast, Angpt2 has a slightly different amino acid sequence in the fibrinogen-like domain and is also more likely to form dimers than oligomers. These structural differences may contribute to the different effects of the two ligands [68]. The central importance of clustering in Tie2 activation is confirmed by the results of one study that used an anti-Angpt2 antibody to cluster Angpt2. The clustering of Angpt2 caused it to act as an agonist to Tie2 rather than an antagonist, resulting in decreased vascular permeability and increased organ protection in the setting of sepsis [70]. Once Tie2 is activated, multiple downstream signaling pathways could be involved as effectors. Specifically, the Akt/PI3K (phosphatidylinositol 3 kinase) pathway has been implicated as a downstream effector of Tie2. This pathway is critical for cell survival and M2 macrophage polarization [61, 71, 72]. In the context of inflammation, Tie2 activation is decreased by a variety of mechanisms, (1) Angpt2 can be released from endothelial cells and competitively inhibits Angpt1/Tie2 binding, (2) overall expression of Tie2 and Angpt1 may be decreased, or (3) the extracellular domain of Tie2 can be cleaved [68]. The decrease in Tie2-Akt/PI3K signaling up-regulates Angpt2. This creates a feedback loop that further decreases Tie2 signaling [68]. The overall effect of the increasing endothelial-derived Angpt2 signaling is an increase in vascular permeability and amplification of inflammatory processes; however, these effects in the brain have not been established following TBI-induced neuroinflammation [63].
\nWhile expression of Tie2 has been most studied in endothelial cells, Tie2 has also been shown to be expressed in hematopoietic cell types. The role of Tie2 has been studied in hematopoietic stem cells and a subset of monocytes in addition to vascular and lymphatic endothelial cells [59]. Interestingly, Tie2 expression has also been demonstrated on neutrophils—Angiopoietin 1 has been shown to interact with Tie2 on neutrophils to promote neutrophil migration [73]. The role of Tie2 in macrophages has been increasingly recognized for its importance in tumorigenesis and inflammation. This critical function of Tie2 signaling will be discussed in the following sections of this review.
\nTie2 has been shown to play an important role in a subset of monocyte/macrophages known as Tie2-expressing monocytes or macrophages (TEMs). TEMs have been most studied in the setting of tumorigenesis and have been found to promote tumor development through a variety of mechanisms. In addition to potentiating overall tumor growth and metastasis, TEMs have been demonstrated to directly promote tumor angiogenesis [74]. Other research has shown that TEMs not only promote tumorigenesis but are necessary for tumor angiogenesis and tumor recurrence following chemotherapy [75]. Several mechanisms have been proposed as effectors of this process. The interaction of Angpt2 with Tie2 in TEMs has been implicated in the pro-angiogenic effect of TEMs as well as in metastasis. One study found that inhibition of Angpt2 blocked the pro-angiogenic function of TEMs in tumors, and another study suggested that inhibition of Angpt2 could help to limit metastasis [59]. Tumor-associated expression of Angpt2 has also been shown to increase expression of pro-angiogenic factors in TEMs [76]. In addition, TEMs in tumors display increased expression of the anti-inflammatory cytokine IL-10. Stimulation of these cells by Angpt2 can work through IL-10 to influence activity of T cells by decreasing T-cell proliferation and increasing regulatory T cells for an overall immunosuppressive effect [77]. Angpt1-Tie2 interaction may also influence tumor development. TEMs are known to express Angpt1 [78], indicating that they may be able to activate Tie2 through autocrine signaling. Angpt1 expression in tumor-infiltrating TEMs has been suggested as a mechanism of increasing tumor angiogenesis through interaction with endothelial cells [78]. While both Angpt1 and Angpt2 may influence the tumor-promoting activity of TEMs, studies agree that the protumorigenic activity of these cells is under control of Tie2/Angiopoietin signaling. This discovery has established the Tie2/Angiopoietin signaling axis as a target of interest in tumor therapeutic research. Several treatments aimed at blocking Tie2/Angiopoietin signaling are currently in development, with three Tie2/Angiopoietin inhibitors currently in clinical trials as cancer therapeutics [79]. No trials are currently underway for brain injury.
\nThe origin and M1/2 polarization status of TEMS is currently under active investigation. Some studies have found that these cells seem to be polarized toward the M2 phenotype [80]. TEMs have been shown to display increased expression of arginase 1 (Arg1) and scavenger receptors accompanied by decreased expression of pro-inflammatory and anti-angiogenic mediators compared to tumor-associated macrophages that lack Tie2 expression. This expression pattern is consistent with an M2 polarization state [78]. In addition, TEMs exert an anti-inflammatory effect in the context of tumorigenesis. These cells release IL-10 and VEGF, decrease T-cell proliferation, inhibit antigen presentation by dendritic cells, and promote T-cell conversion to regulatory T cells [80]. However, TEMs may also play important roles in a variety of disease settings aside from tumorigenesis. Specifically, many studies have implicated TEMs as key regulators of inflammation.
\nAn influential role of TEMs under inflammatory conditions remains under investigation. In the setting of inflammation, Tie2 expression may influence macrophage phenotype on the M1/2 continuum [45]. While TEMs have been shown to favor the M2 phenotype in the context of tumor infiltration, Tie2 expression has been demonstrated in monocytes polarized to both M1 and M2 phenotypes [60, 78]. Investigations of whether Tie2 expression in inflammatory disease correlates with M1 or M2 phenotype have shown conflicting results. One study showed Tie2 activation in synovial macrophages of human patients with autoimmune rheumatoid arthritis. In this study, Angpt2/Tie2 signaling interacted with TNF to up-regulate IL-6 and macrophage inflammatory protein 1α (MIP-1α), and antagonizing this pathway reduced synovial inflammation in a mouse model of disease [81]. Exogenous Angpt1 application to human monocyte cultures has been shown to up-regulate TNF and possibly regulate their polarization state [45]. Another study found that Angiopoietin binding works synergistically with TNF to drive expression of pro-inflammatory cytokines in human-cultured monocytes under several polarized conditions [60]. In contrast, previous studies showed anti-inflammatory effects of Angpt1 binding in TEMs and found that Angpt1 blocks LPS-induced TEM migration and ameliorates LPS-induced TNF expression via NF-ΚB [82]. Angpt2 has also been shown to augment immunosuppressive cytokines and T-reg chemokines expressed by TEMS in vitro [77]. These conflicting results suggest that Tie2 signaling may serve differential functions depending on acute and chronic conditions and may be dependent upon the activation state of the cells. Furthermore, the role of clustering and oligomerization of angiopoietin molecules on Tie2 binding and activation [83] raises the possibility that Tie2 may be differentially regulated under these conditions, although individual studies failed to confirm p-Tie2 states directly. Therefore, the role of Tie2 activation in the M1/M2 continuum remains unclear. While Tie2 signaling has been implicated in promoting injury-induced and tumor-promoting vascular health in numerous non-CNS models [59, 74, 75], its role in regulating monocyte/macrophage polarization in CNS inflammation remains unexplored. Furthermore, limited data exist regarding novel pathways that may regulate Tie2 function in TBI-induced peripheral immune response.
\nMany cell-to-cell interactions become key in the regulation of inflammation following TBI. As previously mentioned, one of the most detrimental results of TBI is the breakdown of the BBB. Adhesion molecules contribute to cell-cell and cell-extracellular matrix (ECM) interactions that mediate inflammation by promoting peripheral leukocyte infiltration across the BBB and aggregation to the site of injury. This represents the initiation of the inflammatory response [84]. After tissue injury, circulating immune cells will recognize signals released from injured tissue, will stop on the luminal surface of blood vessels, transmigrate paracellularly across the endothelial layer, and enter the injured milieu [85, 86]. This process is referred to as the leukocyte adhesion cascade, which involves tethering, rolling, activation, firm adhesion, and transmigration. Numerous preclinical models have determined the detrimental role of leukocyte migration and accumulation during neuroinflammation in TBI [39, 87].
\nAdhesion molecules involved in these processes include three major families: selectins, integrins, and immunoglobulins. Selectins are a group of transmembrane glycoproteins expressed on the surface of leukocytes, which express L-selectin, and endothelial cells, which express P- and E-selectins following activation [88]. These glycoproteins mediate the initial tethering of leukocytes to the vessel wall by binding to counter-receptors and rolling within moments of tissue injury [89]. Integrins are a family of adhesion molecules broken into subclassifications of α and β subunits that are responsible for cellular attachment to the ECM and leukocyte-endothelial cell adhesion and are denominated by the β subunit CD18. These molecules include CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD11c/CD18, and CD11d/CD18 [90, 91]. Immunoglobulins are a superfamily in which some members are glycoprotein adhesion molecules that regulate the adhesion and migration between leukocytes and endothelial cells during the inflammatory process. These molecules include ICAM-1, ICAM-2, VCAM-1, and PECAM-1 [92]. Key adhesion molecules involved in TBI inflammatory response are summarized in Table 1. Eph receptors and their ephrin ligands have also been implicated in the migration step of leukocyte infiltration into injured tissue and subsequent inflammation and will be discussed further.
\nAdhesion molecule family | \nMolecule | \nInvolvement/association with TBI | \nExpression | \nMediates | \n
---|---|---|---|---|
Selectin | \nE-selectin (CD62E, ELAM-1) | \nUp-regulated 2–24 hrs in percussion model of TBI in rats, activated by IL-1 and TNFα [93]. | \nActivated endothelial cells | \nSlow leukocyte rolling | \n
\n | P-selectin (CD62P) | \nIncreased CSF levels in children with severe TBI and associated with poor outcome [94]. Stimulated by TNFα and IL-1 [95]. | \nSecretory granules of platelets and endothelial cells | \nLeukocyte rolling | \n
Integrins | \nCD11b | \nDepletion of CD11b macrophages in diphtheria toxin receptor mice increased inflammatory signaling during TBI [96]. This may be due to critical mechanisms for TBI recovery being impaired. | \nMacrophages and microglia | \nPathogen and DAMP recognition, phagocytosis, and cell survival [97] | \n
\n | CD18/CD11b (Mac-1) | \nBlockade attenuates neutrophil accumulation following TBI in rats [98]. | \nNeutrophils, monocytes/macrophages, and NK cells | \nFirm adhesion during transmigration of leukocytes | \n
\n | CD18/CD11d | \nBlockade reduces lesion volume and macrophage infiltration 3 d post-TBI in rats [99]. | \nNeutrophils and monocyte/macrophages | \nAdhesion of leukocytes | \n
Immunoglobulin | \nICAM-1 | \nIncreased significantly in TBI up to 72 hours postinjury, and blockade reduced leukocyte accumulation and improved neurological function following TBI [100, 101]. Soluble ICAM-1 in CSF was found in patients with severe cerebral injuries and BBB impairment [102]. Stimulated by IL-8, IL-1, and TNFα. | \nEndothelial cells | \nLeukocyte passage across vascular endothelial cell layer to injured tissue. Promotes leukocyte adhesion and migration [103] | \n
\n | VCAM-1 | \nSignificantly decreased in children suffering from inflicted TBI [104]. | \nActivated endothelial cells [105] | \nPromotes leukocyte adhesion through VLA-4 receptor [106] | \n
Adhesion molecules involved in TBI inflammatory response.
Eph receptors tyrosine kinases and their membrane-bound ephrin ligands function as mediators of cell migration and a wide-range of cellular functions across different cell types. Eph receptors are the largest family of receptor tyrosine kinases that are activated following cell-to-cell contact [107]. The Eph receptors are classified as either EphA or EphB receptors based on ligand binding. EphB receptors typically bind to transmembrane ephrin B ligands [107, 108, 109], while some Eph receptors, such as EphA4, can bind to both A and B ephrins [110]. Eph receptors play critical roles in axon guidance, synaptogenesis, neuromuscular junctions, and vascular remodeling among other roles [107, 109, 111]. Importantly, multiple Eph receptors and ephrins play a critical role in inflammation [111]. Ephrin A1 in endothelial cells responds to TNF stimulation, and multiple Eph receptors and ephrins respond to LPS [111]. EphA4 has been demonstrated to influence both spinal cord injury and TBI [111, 112].
\nEph/ephrin signaling contributes to immune cell function. For example, EphA4 expression influences multiple different immune cell types including T cells, B cells, platelets, monocyte/macrophages, and dendritic cells [113, 114, 115]. Both CD4+ and CD8+ T cells have been shown to express EphA4 [116], and EphA4 expression in CD4+ T cells has been implicated in T-cell migration [117, 118]. EphA4 is also critical in migration of memory T cells in response to ephrin A1 stimulation [116]. EphA4 expression in monocyte/macrophages effects their polarization status by mediating their pro-inflammatory (M1-like) state [115]. Moreover, ephrin A1 stimulation increased monocyte adhesion in a cell culture model through interaction with EphA4 on endothelial cells [119]. While these studies highlight that Eph/ephrin signaling is important in peripheral-derived immune cells, a significant research gap exists concerning the specific mechanisms involved in bi-direction signaling and its role in the function of peripheral immune cells following TBI.
\nUnderstanding the role of the peripheral-derived immune response to TBI is an important unmet need in TBI research. TBI is a leading cause of death and disability worldwide, and the secondary phase of injury is a critical target for therapeutics. Infiltration of peripheral immune cells through the compromised blood-brain barrier forms a major component of this phase, which can have both beneficial and deleterious effects. Monocyte/macrophages impact the response to TBI by a variety of mechanisms. These cells can cause tissue damage through pro-inflammatory traits or exert pro-recovery effects through anti-inflammatory traits, and the continuum of M1/2 expression is a growing research focus. Tie2 and cell-to-cell contact signaling is gaining attention for its role in peripheral immune cells, which provides additional opportunity for developing novel therapeutic treatments following TBI.
\nWe recognize the Institute for Critical Technology and Science, Virginia Tech (JFA award, MHT; Fellowship support AH), and the Center for Engineered Health, VT. This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, R01NS096281 (MHT).
\nThe authors declare no conflict of interest.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"160349",title:null,name:null,middleName:null,surname:null,slug:"",fullName:null,position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"25887",title:"Dr.",name:null,middleName:null,surname:"Abbasi",slug:"abbasi",fullName:"Abbasi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"161332",title:"Dr",name:null,middleName:null,surname:"Abu-El Hassan",slug:"abu-el-hassan",fullName:"Abu-El Hassan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"212347",title:"Dr.",name:null,middleName:null,surname:"Abubakar",slug:"abubakar",fullName:"Abubakar",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"93806",title:"Dr",name:null,middleName:null,surname:"Adani",slug:"adani",fullName:"Adani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"158756",title:"Dr",name:null,middleName:null,surname:"Adler",slug:"adler",fullName:"Adler",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"63002",title:"Dr.",name:null,middleName:null,surname:"Agius",slug:"agius",fullName:"Agius",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"34637",title:"Dr.",name:null,middleName:null,surname:"Ahmed",slug:"ahmed",fullName:"Ahmed",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"118228",title:"Dr",name:null,middleName:null,surname:"Ahmed",slug:"ahmed",fullName:"Ahmed",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"89784",title:"Dr",name:null,middleName:null,surname:"Ai",slug:"ai",fullName:"Ai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"158339",title:"Dr",name:null,middleName:null,surname:"Akahoshi",slug:"akahoshi",fullName:"Akahoshi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"158540",title:"Dr",name:null,middleName:null,surname:"Al-Jumaily",slug:"al-jumaily",fullName:"Al-Jumaily",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5682},{group:"region",caption:"Middle and South America",value:2,count:5165},{group:"region",caption:"Africa",value:3,count:1682},{group:"region",caption:"Asia",value:4,count:10206},{group:"region",caption:"Australia and Oceania",value:5,count:886},{group:"region",caption:"Europe",value:6,count:15610}],offset:12,limit:12,total:117097},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{sort:"dateEndThirdStepPublish",topicId:"11"},books:[{type:"book",id:"10446",title:"Water Quality",subtitle:null,isOpenForSubmission:!0,hash:"add02f40c29f68a0848e95f7256aa648",slug:null,bookSignature:"Dr. J. Kevin Summers",coverURL:"https://cdn.intechopen.com/books/images_new/10446.jpg",editedByType:null,editors:[{id:"197485",title:"Dr.",name:"J. Kevin",surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10679",title:"Mass Production",subtitle:null,isOpenForSubmission:!0,hash:"2dae91102099b1a07be1a36a68852829",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10679.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10689",title:"Risk Management in Construction",subtitle:null,isOpenForSubmission:!0,hash:"e3805b3d2fceb9d33e1fa805687cd296",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10689.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10686",title:"Natural Gas",subtitle:null,isOpenForSubmission:!0,hash:"00c048ae4d953f71babbd835498ff081",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10686.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10680",title:"Product Life Cycle",subtitle:null,isOpenForSubmission:!0,hash:"da71e53ace2603746e0f4e351d5cc140",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10680.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10690",title:"Air Traffic",subtitle:null,isOpenForSubmission:!0,hash:"92f4b965eba992071bb91df88b00d10d",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10690.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10688",title:"Roof Engineering",subtitle:null,isOpenForSubmission:!0,hash:"ef37aca9bed84fff5b9c8220949d655d",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10688.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10684",title:"Biorefineries",subtitle:null,isOpenForSubmission:!0,hash:"23962c6b77348bcbf247c673d34562f6",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10684.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10775",title:"Hypersonic Vehicles",subtitle:null,isOpenForSubmission:!0,hash:"daf80a5a7593c0dd419516cbd4b1f0a3",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10775.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10013",title:"Geothermal Energy",subtitle:null,isOpenForSubmission:!0,hash:"a5f5277a1c0616ce6b35f4b44a4cac7a",slug:null,bookSignature:"Dr. Basel I. Ismail",coverURL:"https://cdn.intechopen.com/books/images_new/10013.jpg",editedByType:null,editors:[{id:"62122",title:"Dr.",name:"Basel",surname:"Ismail",slug:"basel-ismail",fullName:"Basel Ismail"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10374",title:"Advances in Micro- and Nanofluidics",subtitle:null,isOpenForSubmission:!0,hash:"b7ba9cab862a9bca2fc9f9ee72ba5eec",slug:null,bookSignature:"Prof. S. M. Sohel Murshed",coverURL:"https://cdn.intechopen.com/books/images_new/10374.jpg",editedByType:null,editors:[{id:"24904",title:"Prof.",name:"S. M. Sohel",surname:"Murshed",slug:"s.-m.-sohel-murshed",fullName:"S. M. Sohel Murshed"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10491",title:"Anaerobic Digestion in Natural and Built Environments",subtitle:null,isOpenForSubmission:!0,hash:"082ec753a05d6c7ed8cc5559e7dac432",slug:null,bookSignature:"Dr. Anna Sikora and Dr. Anna Detman",coverURL:"https://cdn.intechopen.com/books/images_new/10491.jpg",editedByType:null,editors:[{id:"146985",title:"Dr.",name:"Anna",surname:"Sikora",slug:"anna-sikora",fullName:"Anna Sikora"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:9},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:18},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:7},{group:"topic",caption:"Computer and Information Science",value:9,count:10},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:5},{group:"topic",caption:"Engineering",value:11,count:15},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:5},{group:"topic",caption:"Materials Science",value:14,count:4},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:60},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:1},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:6},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:3},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:27},popularBooks:{featuredBooks:[{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.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:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8468",title:"Sheep Farming",subtitle:"An Approach to Feed, Growth and Sanity",isOpenForSubmission:!1,hash:"838f08594850bc04aa14ec873ed1b96f",slug:"sheep-farming-an-approach-to-feed-growth-and-sanity",bookSignature:"António Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/8468.jpg",editors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8816",title:"Financial Crises",subtitle:"A Selection of Readings",isOpenForSubmission:!1,hash:"6f2f49fb903656e4e54280c79fabd10c",slug:"financial-crises-a-selection-of-readings",bookSignature:"Stelios Markoulis",coverURL:"https://cdn.intechopen.com/books/images_new/8816.jpg",editors:[{id:"237863",title:"Dr.",name:"Stelios",middleName:null,surname:"Markoulis",slug:"stelios-markoulis",fullName:"Stelios Markoulis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9376",title:"Contemporary Developments and Perspectives in International Health Security",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"b9a00b84cd04aae458fb1d6c65795601",slug:"contemporary-developments-and-perspectives-in-international-health-security-volume-1",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, Sagar C. Galwankar, Ricardo Izurieta and Thomas Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/9376.jpg",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7769",title:"Medical Isotopes",subtitle:null,isOpenForSubmission:!1,hash:"f8d3c5a6c9a42398e56b4e82264753f7",slug:"medical-isotopes",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9279",title:"Concepts, Applications and Emerging Opportunities in Industrial Engineering",subtitle:null,isOpenForSubmission:!1,hash:"9bfa87f9b627a5468b7c1e30b0eea07a",slug:"concepts-applications-and-emerging-opportunities-in-industrial-engineering",bookSignature:"Gary Moynihan",coverURL:"https://cdn.intechopen.com/books/images_new/9279.jpg",editors:[{id:"16974",title:"Dr.",name:"Gary",middleName:null,surname:"Moynihan",slug:"gary-moynihan",fullName:"Gary Moynihan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7807",title:"A Closer Look at Organizational Culture in Action",subtitle:null,isOpenForSubmission:!1,hash:"05c608b9271cc2bc711f4b28748b247b",slug:"a-closer-look-at-organizational-culture-in-action",bookSignature:"Süleyman Davut Göker",coverURL:"https://cdn.intechopen.com/books/images_new/7807.jpg",editors:[{id:"190035",title:"Associate Prof.",name:"Süleyman Davut",middleName:null,surname:"Göker",slug:"suleyman-davut-goker",fullName:"Süleyman Davut Göker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5128},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.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:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8468",title:"Sheep Farming",subtitle:"An Approach to Feed, Growth and Sanity",isOpenForSubmission:!1,hash:"838f08594850bc04aa14ec873ed1b96f",slug:"sheep-farming-an-approach-to-feed-growth-and-sanity",bookSignature:"António Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/8468.jpg",editors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8816",title:"Financial Crises",subtitle:"A Selection of Readings",isOpenForSubmission:!1,hash:"6f2f49fb903656e4e54280c79fabd10c",slug:"financial-crises-a-selection-of-readings",bookSignature:"Stelios Markoulis",coverURL:"https://cdn.intechopen.com/books/images_new/8816.jpg",editors:[{id:"237863",title:"Dr.",name:"Stelios",middleName:null,surname:"Markoulis",slug:"stelios-markoulis",fullName:"Stelios Markoulis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9376",title:"Contemporary Developments and Perspectives in International Health Security",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"b9a00b84cd04aae458fb1d6c65795601",slug:"contemporary-developments-and-perspectives-in-international-health-security-volume-1",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, Sagar C. Galwankar, Ricardo Izurieta and Thomas Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/9376.jpg",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7769",title:"Medical Isotopes",subtitle:null,isOpenForSubmission:!1,hash:"f8d3c5a6c9a42398e56b4e82264753f7",slug:"medical-isotopes",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"8468",title:"Sheep Farming",subtitle:"An Approach to Feed, Growth and Health",isOpenForSubmission:!1,hash:"838f08594850bc04aa14ec873ed1b96f",slug:"sheep-farming-an-approach-to-feed-growth-and-health",bookSignature:"António Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/8468.jpg",editedByType:"Edited by",editors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9523",title:"Oral and Maxillofacial Surgery",subtitle:null,isOpenForSubmission:!1,hash:"5eb6ec2db961a6c8965d11180a58d5c1",slug:"oral-and-maxillofacial-surgery",bookSignature:"Gokul Sridharan",coverURL:"https://cdn.intechopen.com/books/images_new/9523.jpg",editedByType:"Edited by",editors:[{id:"82453",title:"Dr.",name:"Gokul",middleName:null,surname:"Sridharan",slug:"gokul-sridharan",fullName:"Gokul Sridharan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9018",title:"Some RNA Viruses",subtitle:null,isOpenForSubmission:!1,hash:"a5cae846dbe3692495fc4add2f60fd84",slug:"some-rna-viruses",bookSignature:"Yogendra Shah and Eltayb Abuelzein",coverURL:"https://cdn.intechopen.com/books/images_new/9018.jpg",editedByType:"Edited by",editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8816",title:"Financial Crises",subtitle:"A Selection of Readings",isOpenForSubmission:!1,hash:"6f2f49fb903656e4e54280c79fabd10c",slug:"financial-crises-a-selection-of-readings",bookSignature:"Stelios Markoulis",coverURL:"https://cdn.intechopen.com/books/images_new/8816.jpg",editedByType:"Edited by",editors:[{id:"237863",title:"Dr.",name:"Stelios",middleName:null,surname:"Markoulis",slug:"stelios-markoulis",fullName:"Stelios Markoulis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9585",title:"Advances in Complex Valvular Disease",subtitle:null,isOpenForSubmission:!1,hash:"ef64f11e211621ecfe69c46e60e7ca3d",slug:"advances-in-complex-valvular-disease",bookSignature:"Michael S. Firstenberg and Imran Khan",coverURL:"https://cdn.intechopen.com/books/images_new/9585.jpg",editedByType:"Edited by",editors:[{id:"64343",title:null,name:"Michael S.",middleName:"S",surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10150",title:"Smart Manufacturing",subtitle:"When Artificial Intelligence Meets the Internet of Things",isOpenForSubmission:!1,hash:"87004a19de13702d042f8ff96d454698",slug:"smart-manufacturing-when-artificial-intelligence-meets-the-internet-of-things",bookSignature:"Tan Yen Kheng",coverURL:"https://cdn.intechopen.com/books/images_new/10150.jpg",editedByType:"Edited by",editors:[{id:"78857",title:"Dr.",name:"Tan Yen",middleName:null,surname:"Kheng",slug:"tan-yen-kheng",fullName:"Tan Yen Kheng"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9386",title:"Direct Numerical Simulations",subtitle:"An Introduction and Applications",isOpenForSubmission:!1,hash:"158a3a0fdba295d21ff23326f5a072d5",slug:"direct-numerical-simulations-an-introduction-and-applications",bookSignature:"Srinivasa Rao",coverURL:"https://cdn.intechopen.com/books/images_new/9386.jpg",editedByType:"Edited by",editors:[{id:"6897",title:"Dr.",name:"Srinivasa",middleName:"P",surname:"Rao",slug:"srinivasa-rao",fullName:"Srinivasa Rao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editedByType:"Edited by",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editedByType:"Edited by",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"270",title:"Humanities",slug:"humanities",parent:{title:"Social Sciences",slug:"social-sciences"},numberOfBooks:3,numberOfAuthorsAndEditors:49,numberOfWosCitations:16,numberOfCrossrefCitations:8,numberOfDimensionsCitations:32,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"humanities",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"6944",title:"Heritage",subtitle:null,isOpenForSubmission:!1,hash:"80ee36ba67b1fe4ff971074f7ddc4d00",slug:"heritage",bookSignature:"Daniela Turcanu-Carutiu",coverURL:"https://cdn.intechopen.com/books/images_new/6944.jpg",editedByType:"Edited by",editors:[{id:"176482",title:"Prof.",name:"Daniela",middleName:null,surname:"Turcanu-Carutiu",slug:"daniela-turcanu-carutiu",fullName:"Daniela Turcanu-Carutiu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6169",title:"Culture and Identity",subtitle:null,isOpenForSubmission:!1,hash:"925cd8ebef5226a2fc3b36d060a27ecb",slug:"culture-and-identity",bookSignature:"Wilfred Isak April",coverURL:"https://cdn.intechopen.com/books/images_new/6169.jpg",editedByType:"Edited by",editors:[{id:"110034",title:"Dr.",name:"Wilfred",middleName:"Isak",surname:"April",slug:"wilfred-april",fullName:"Wilfred April"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2301",title:"Social Sciences and Cultural Studies",subtitle:"Issues of Language, Public Opinion, Education and Welfare",isOpenForSubmission:!1,hash:"d8b131a7ee5b8a5b952c49dc19c0cfe5",slug:"social-sciences-and-cultural-studies-issues-of-language-public-opinion-education-and-welfare",bookSignature:"Asuncion Lopez-Varela",coverURL:"https://cdn.intechopen.com/books/images_new/2301.jpg",editedByType:"Edited by",editors:[{id:"111237",title:"Dr.",name:"Asunción",middleName:null,surname:"Lopez-Varela Azcárate",slug:"asuncion-lopez-varela-azcarate",fullName:"Asunción Lopez-Varela Azcárate"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:3,mostCitedChapters:[{id:"39104",doi:"10.5772/37095",title:"Stress Management for Medical Students: A Systematic Review",slug:"stress-management-for-medical-students-a-systematic-review",totalDownloads:6083,totalCrossrefCites:2,totalDimensionsCites:15,book:{slug:"social-sciences-and-cultural-studies-issues-of-language-public-opinion-education-and-welfare",title:"Social Sciences and Cultural Studies",fullTitle:"Social Sciences and Cultural Studies - Issues of Language, Public Opinion, Education and Welfare"},signatures:"Muhamad Saiful Bahri Yusoff and Ab Rahman Esa",authors:[{id:"111238",title:"Dr.",name:"Muhamad Saiful Bahri",middleName:null,surname:"Yusoff",slug:"muhamad-saiful-bahri-yusoff",fullName:"Muhamad Saiful Bahri Yusoff"},{id:"121385",title:"Prof.",name:"Ab Rahman",middleName:null,surname:"Esa",slug:"ab-rahman-esa",fullName:"Ab Rahman Esa"}]},{id:"39097",doi:"10.5772/38617",title:"International Higher Education Rankings at a Glance: How to Valorise the Research in Social Sciences and Humanities?",slug:"international-higher-education-rankings-at-a-glance-how-to-valorise-the-research-in-social-scien",totalDownloads:1471,totalCrossrefCites:0,totalDimensionsCites:5,book:{slug:"social-sciences-and-cultural-studies-issues-of-language-public-opinion-education-and-welfare",title:"Social Sciences and Cultural Studies",fullTitle:"Social Sciences and Cultural Studies - Issues of Language, Public Opinion, Education and Welfare"},signatures:"José M. Gómez-Sancho and Carmen Pérez-Esparrells",authors:[{id:"118304",title:"Dr.",name:"Jose María",middleName:null,surname:"Gomez-Sancho",slug:"jose-maria-gomez-sancho",fullName:"Jose María Gomez-Sancho"},{id:"118305",title:"Dr.",name:"Carmen",middleName:null,surname:"Pérez-Esparrells",slug:"carmen-perez-esparrells",fullName:"Carmen Pérez-Esparrells"}]},{id:"39099",doi:"10.5772/38850",title:"Japan’s University Education in Social Sciences and Humanities Under Globalization",slug:"education-and-research-of-social-science-and-humanities-in-japan-under-globalization",totalDownloads:1427,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"social-sciences-and-cultural-studies-issues-of-language-public-opinion-education-and-welfare",title:"Social Sciences and Cultural Studies",fullTitle:"Social Sciences and Cultural Studies - Issues of Language, Public Opinion, Education and Welfare"},signatures:"Akiyoshi Yonezawa",authors:[{id:"120081",title:"Prof.",name:"Akiyoshi",middleName:null,surname:"Yonezawa",slug:"akiyoshi-yonezawa",fullName:"Akiyoshi Yonezawa"}]}],mostDownloadedChaptersLast30Days:[{id:"71421",title:"Cultural Heritage of a Three Centuries Old Wooden Church",slug:"cultural-heritage-of-a-three-centuries-old-wooden-church",totalDownloads:203,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Patricia Săsăran, Ancuța Țenter and Lorelay-Diana Jianu",authors:null},{id:"73006",title:"Ideological Interaction Theory in Critical Discourse Analysis",slug:"ideological-interaction-theory-in-critical-discourse-analysis",totalDownloads:200,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Yadu Prasad Gyawali",authors:null},{id:"70968",title:"Public Governance and Cultural Heritage: Exploring the Links between Culture and Social Indicators with the Principal Component Analysis",slug:"public-governance-and-cultural-heritage-exploring-the-links-between-culture-and-social-indicators-wi",totalDownloads:204,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Ionela Munteanu Florea, Marioara Mirea and Cosmin Susu",authors:null},{id:"72415",title:"China’s Use of Public Diplomacy in the United States: From World War II to the Twenty-First Century",slug:"china-s-use-of-public-diplomacy-in-the-united-states-from-world-war-ii-to-the-twenty-first-century",totalDownloads:194,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Sally Burt",authors:null},{id:"39090",title:"Cyberfeminist Theories and the Benefits of Teaching Cyberfeminist Literature",slug:"cyberfeminist-theories-and-the-benefits-of-teaching-cyberfeminist-literature",totalDownloads:2317,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"social-sciences-and-cultural-studies-issues-of-language-public-opinion-education-and-welfare",title:"Social Sciences and Cultural Studies",fullTitle:"Social Sciences and Cultural Studies - Issues of Language, Public Opinion, Education and Welfare"},signatures:"Maya Zalbidea Paniagua",authors:[{id:"146627",title:"Prof.",name:"Maya",middleName:null,surname:"Zalbidea",slug:"maya-zalbidea",fullName:"Maya Zalbidea"}]},{id:"72251",title:"Public Diplomacy: Functions, Functional Boundaries and Measurement Methods",slug:"public-diplomacy-functions-functional-boundaries-and-measurement-methods",totalDownloads:177,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Cao Wei",authors:null},{id:"39083",title:"Western and Eastern Ur-Topias: Communities and Nostalgia",slug:"western-and-eastern-ur-topias-communities-and-nostalgia",totalDownloads:1576,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"social-sciences-and-cultural-studies-issues-of-language-public-opinion-education-and-welfare",title:"Social Sciences and Cultural Studies",fullTitle:"Social Sciences and Cultural Studies - Issues of Language, Public Opinion, Education and Welfare"},signatures:"Anjan Sen and Asun López-Varela",authors:[{id:"111237",title:"Dr.",name:"Asunción",middleName:null,surname:"Lopez-Varela Azcárate",slug:"asuncion-lopez-varela-azcarate",fullName:"Asunción Lopez-Varela Azcárate"}]},{id:"71441",title:"Cultural Heritage Objects of Southern Benin: Plant Dyes and Exudates Used in Their Confection",slug:"cultural-heritage-objects-of-southern-benin-plant-dyes-and-exudates-used-in-their-confection",totalDownloads:173,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Louis Fagbohoun and Cathy Vieillescazes",authors:null},{id:"67101",title:"Thanking in Cameroon French",slug:"thanking-in-cameroon-french",totalDownloads:329,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Bernard Mulo Farenkia",authors:[{id:"283073",title:"Dr.",name:"Bernard",middleName:null,surname:"Mulo Farenkia",slug:"bernard-mulo-farenkia",fullName:"Bernard Mulo Farenkia"}]},{id:"58584",title:"Space and Time Travelers Exploring Cultural Identity of the City",slug:"space-and-time-travelers-exploring-cultural-identity-of-the-city",totalDownloads:605,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"culture-and-identity",title:"Culture and Identity",fullTitle:"Culture and Identity"},signatures:"Arzu Ispalar Çahantimur and Gözde Kırlı Özer",authors:[{id:"106544",title:"Associate Prof.",name:"Arzu",middleName:null,surname:"Ispalar Cahantimur",slug:"arzu-ispalar-cahantimur",fullName:"Arzu Ispalar Cahantimur"},{id:"228585",title:"MSc.",name:"Gözde",middleName:null,surname:"Kırlı Özer",slug:"gozde-kirli-ozer",fullName:"Gözde Kırlı Özer"}]}],onlineFirstChaptersFilter:{topicSlug:"humanities",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/202805/greanious-alfred-mavondo",hash:"",query:{},params:{id:"202805",slug:"greanious-alfred-mavondo"},fullPath:"/profiles/202805/greanious-alfred-mavondo",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)}()