\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"3474",leadTitle:null,fullTitle:"Future Aspects of Tumor Suppressor Gene",title:"Future Aspects of Tumor Suppressor Gene",subtitle:null,reviewType:"peer-reviewed",abstract:'Tumor suppressor genes (TSGs) and their signaling networks are fast growing areas in current biomedical science. 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Single-wall carbon nanotubes (SWCNTs) are one of the most promising materials for future nano-electronics, because of their unique quasi-one-dimensional structures and excellent electric and mechanical properties. They also have very high chemical stability, owing to their robust sp2-bonding carbon network (graphene) with no dangling bonds. Because of the structural robustness, low-energy (typically 10 eV-20 keV) electron and photon irradiation in a vacuum had been generally assumed not to cause damage to SWCNTs when the energy is smaller than the knock-on threshold. In fact, analytical tools that use low-energy electrons or photons, such as scanning electron microscopy (SEM), had been commonly used for characterization of SWCNTs without serious concerns.
In 2004, however, we reported that electron irradiation in a SEM caused severe damage (low-energy irradiation damage) in SWCNTs produced by both thermal chemical vapor deposition and laser ablation methods (Suzuki et al., 2004b). Other techniques using low-energy electrons and vacuum-ultraviolet (VUV) light or soft x-rays (especially high-brilliance synchrotron radiation light), such as low-energy electron microscopy (LEEM) and photoemission spectroscopy, also inevitably damage SWCNTs. Therefore, paying attention to the low-energy irradiation damage is practically important for those who study SWCNTs. For example, when we measure the Raman and photoluminescence (PL) spectra and electric properties and take SEM images of the same SWCNTs, the SEM observations should be done last. Doing the high-resolution SEM observation first would inevitably cause severe damage and tremendously affects the following measurements.
The low-energy irradiation damage and its defect characteristics are also physically interesting. In this chapter, we will review the physical and chemical property changes induced by the damage, and the defect properties, which are significantly different from those of other types of damage. We will examine the defect-induced metal-semiconductor transition of the room-temperature electric properties and discuss its mechanism. We will also summarize other types of damage, which are often confused with the low-energy irradiation damage, focusing on the differences between them.
Before continuing to the main text, I must briefly explain how I compare spectra obtained form the same SWCNT sample. In many studies of the physical or chemical treatment of SWCNTs and graphene, spectra are often normalized to the maximum peak height. In contrast, when I show irradiation- and annealing-induced changes of Raman and PL spectra, the spectra are never normalized. That is, I obtain the spectra under the same condition to the best of my ability and directly compare the raw spectra. This methodology has been applied in all of our related reports, unless otherwise mentioned. With arbitrary spectral normalization, we would no longer be able to discuss the reversibility of the damage and recovery, which is a very important characteristic of low-energy irradiation damage.
We define low-energy irradiation damage as damage solely caused by irradiation of low-energy particles, where low-energy means that the energy is much smaller than the threshold energy of knock-on damage. Thus, the mechanism of the damage is completely different from knock-on damage. Moreover, we discriminate low-energy irradiation damage and secondary damage caused by the irradiation, such as damage by radicals. Irradiation by both electrons and photons irradiation was found to damage SWCNTs. However, other particles, such as atoms and ions, or quasi-particles such as plasmons, may also cause the damage.
In a Raman spectrum, a SWCNT shows the so-called G band (tangential mode) and disorder-induced D band, which are characteristic of a graphene sheet. The D band is ideally inactive and its appearance is evidence of symmetry breaking. The intensity ratio of the G and D bands is often utilized as an indicator of the degree of crystallinity. Another very important mode of SWCNTs is the radial breathing mode (RBM), which is often used for diameter evaluation. For a general review of Raman spectroscopy of CNTs, see (Dresselhaus et al., 2005), for example. Like other types of damage, low-energy irradiation damage generally decreases the G band and RBM intensities (There are some exceptions at the edges of the resonance window, as discussed below) and the G/D intensity ratio and increases the D band intensity, as shown in Figs. 1(a) and (b). Generally, the decrease of intensity is more prominent for the RBM than for the G band. Considering that the detectable Raman intensity from individual SWCNTs is owing to the resonance enhancement effect, the disappearance of Raman spectra is probably due to a reduction of the resonance enhancement. The initially divergent joint density of states, which is a characteristic of one-dimensional systems, would be considerably broadened by the formation of defects. Low-energy irradiation damage causes almost no broadening or almost no shift of the Raman peaks including the D band (Suzuki et al., 2010), although significant D band broadening due to gas-phase reaction has been observed (Yang et al., 2006. Zhang et al., 2006).
When SWCNTs are moderately damaged (or considerably recover from severe damage), originally hidden non-resonant RBM peaks sometimes appear. At the excitation wavelength of 785 nm, metallic and semiconducting SWCNTs are usually observed at about 150-160 and 200-240 cm-1, respectively. In Fig. 2(a), however, the moderately damaged (partially recovered) SWCNTs show a sharp peak at 182 cm-1 in the off-resonance region. The metallic SWCNTs at 156 cm-1, which were initially not strongly excited in this sample, also became more prominent in the moderately damaged sample. Further damage extinguishes these peaks again, as also shown in the figure. Similar off-resonant RBM peaks are also often observed in doped SWCNTs grown from boron- and nitrogen-containing feedstocks, as shown in Fig. 2(b) (Suzuki & Hibino, 2011). I think that the defects slightly shift the absorption energy or broaden the absorption edge and this makes the originally off-resonant peak resonant. Similarly, complicated behavior of the RBM intensity with increasing damage is observed at the edge of the resonance window (Suzuki & Kobayashi, 2007a).
a) G and D band, and (b) RBM regions of Raman spectra, and (c) PL spectra of unirradiated SWCNTs and of SWCNTs irradiated at 250 and 22º C. The irradiated electron energy and dose were 20 keV and 5.7×1016 cm-2. The excitation wavelength was 785 nm.
These results mean that the Kataura plot is modified by the defects.
The PL peak intensity of suspended semiconducting SWCNTs is more sensitively decreased than the Raman peak intensity, as shown in Fig. 1(c). In addition, broad spectral intensity newly appears at the longer wavelength side when the extent of the damage is moderate.
Severe damage finally extinguishes all spectral intensities in Raman (including the D band (Suzuki et al., 2005a)) and PL spectra (Suzuki & Kobayashi, 2007b). However, note that, in marked contrast to the damage caused by knock-on collisions and by radicals, the low-energy irradiation damage itself never eliminates a SWCNT.
a) RBM spectra of unirradiated and electron-irradiated SWCNTs and partially recovered SWCNTs. The electron energy and irradiation dose were 20 keV and 6.3×1016 cm-2, respectively. The irradiated and considerably damaged SWCNTs were partially recovered by annealing in Ar atmosphere at 350º C. The wavenuber range of 160-200 cm-1 is the off-resonance region and a peak is rarely observed there, initially. (b) RBM spectra of undoped and BN-doped SWCNTs. The doped SWCNTs also often exhibit peaks in the off-resonance region. The excitation wavelength was 785 nm.
a) SEM image of the SWNT sample after eliminating the electron-irradiated SWCNTs. The irradiation was done along the dashed line. The electron energy and the local dose were 1 keV, and 1.5×1019 cm-2, respectively. Note that the elimination was done by selective combustion in air, not by the irradiation itself. (b) Position dependence of the number of SWCNTs suspended between neighboring pillars in (a). Here, diagonally suspended SWCNTs were neglected.
The low-energy irradiation itself does not cut a SWCNT. However, the damage significantly decreases the chemical tolerance of SWCNTs, because the irradiation-induced defects make the sidewall chemically active. Therefore, we can selectively eliminate the irradiated SWCNTs by heating in air, as shown in Fig. 3 (Suzuki et al., 2005a). A part of the SWCNT sample was intensively irradiated in a SEM using the line scan mode along the dashed line. Then, the sample was heated in air at 420º C for 30 m. The irradiated SWCNTs were selectively eliminated by combustion due to the reduced chemical tolerance. Note that a irradiation dose that is too high often has an entirely opposite effect, because the irradiation-induced contaminants on the SWCNT surfaces protect the SWCNTs from oxygen. As shown in (b), the irradiation effects almost completely disappear about 600 nm from the irradiation line. Such a high spatial resolution can be easily obtained using a convergent electron beam.
There have been many attempts to functionalize SWCNTs by using other molecules or metal particles. In many cases, defects are intentionally created to functionalize the sidewall, which is originally inert (Yan et al., 2005). Low-energy irradiation damage could also be applied for spatially selective functionalization with electron beam lithography.
The electric properties are much more sensitively changed by low-energy irradiation damage than Raman and PL spectra. Moderate irradiation can convert a metallic field effect transistor (FET) into semiconducting. I will discuss this remarkable phenomenon in sec. 5. Here, I focus on the intensive irradiation effects I have studied by in-situ electric measurements during electron irradiation in a SEM equipped with piezo-actuated micro-probes for electric measurements (Suzuki, 2011). The device used here consists of two SWCNTs (A branch is seen between the electrodes) suspended between the drain and source electrodes (height: 300 nm), as shown in Fig. 4(a). The high-magnification SEM image was taken after all experiments had been completed. Otherwise, the conductivity of the SWCNTs would almost vanish. Fig. 4(b) shows the results of in-situ electric measurements during irradiation. The whole SWCNTs were first irradiated by an electron beam using the normal SEM observation mode. The SEM observation gradually decreased the conductivity.
Then, at ~42.76 s, they were intensively irradiated by using the line scan mode. This irradiation decreased the conductivity by two orders of magnitude in only a few seconds. As shown in Fig. 4(c), a very abrupt current decrease occurred at least within the initial 44 ms, which is the time resolution of the measurements. The gate voltage characteristics of the device before and after the irradiation are shown in Fig. 4(d). The irradiation decreased the two-probe conductivity by four to five orders of magnitude in the whole gate voltage range. Considering that the initial resistivity of the device would be dominated by the contact resistance between the SWNTs and electrodes, the intrinsic conductivity decrease would be much larger. Thus, intensive irradiation finally makes a SWCNT almost insulating. Similar results had been observed in previous works by another group (Marquardt et al., 2008. and Vijayaraghavan et al., 2010) and in our early work (Suzuki and Kobayashi., 2005), in which conventional on-substrate SWCNT devices were used. Here, I would like to get remind the readers again that even intensive irradiation does not cut a SWCNT. In fact, a SWCNT can be completely recovered by annealing, as shown later in sec. 4.2.
a) SEM image of a suspended SWNT device obtained after experiments. The substrate acts as a back-gate electrode. Scale bar: 200 nm. (b) Drain current during SEM observation and line scans. The drain voltage was set to 0.1 V, and the substrate (back-gate) was grounded. The electron energy was 1 keV. During the SEM observation, the irradiation dose rate was 1.2×1013 cm-2s-1 on average in the observation area. The dose rate during the lines scan was ~6×1016 cm-2s-1. (c) Time evolution of the drain current just before and after the line scan. The data collection was done using the sampling mode of a semiconductor parameter analyzer (Agilent 4156º C) and the time interval is not always the same. (d) Gate characteristics of the device before and after the electron irradiation. The drain voltage was 0.1 eV.
The low-energy irradiation damage has been observed in an energy range of several electron-volts to 25 keV. One important characteristic of the damage is that, in general, a lower energy is more destructive than a higher energy (Suzuki et al., 2004b), as shown in Fig. 5(a) (except for the energies below ~20 eV, where the optical absorption and electron energy loss spectra strongly reflect the specific electronic density of states of graphene). This can be well understood by the fact that the interaction (the cross section of electronic excitation) between a SWCNT and an incident electron (photon) is generally larger at a
a) G and D band spectra of pristine and electron-irradiated SWCNTs, showing the acceleration voltage dependence of electron irradiation damage. The irradiation dose was 2.7×1018 cm-2. (b) RBM spectra of pristine SWCNTs (black lines) and SWCNTs illuminated by 6-10 eV photons (red). Because the spectra were originally slightly sample-dependent, spectra before and after the irradiation are shown for each photon energy. (c) G/D area ratio of pristine SWCNTs and SWCNTs irradiated at various photon energies. In (b) and (c), the photon dose was 5×1017 cm-2 except for *2 and *3 in (c). The excitation wavelength was 785 nm. *1) higher order light cut by a pyrex window. *2) very intense unmonochromatized light through a pyrex window (hν≤3.5 eV). *3) The photon dose was 2.5×1017 cm-2.
smaller energy. A high-energy electron or photon easily penetrates a SWCNT without any electric excitation. An exception is when the photon energy is tuned to near the C 1s absorption edge, for which severer damage was observed than at the energy below the absorption threshold. However, the resonance effect does not seem to be very prominent, as will be shown in Fig. 11(b).
The existence of the threshold energy is also expected for the low-energy irradiation damage. As seen in the RBM spectra shown in Fig. 5(b), distinct spectral intensity decreases are observed at ~6 eV or larger for semiconducting SWCNTs with diameters of about 1.2-1.0 nm at 200-240 cm-1 (Suzuki & Kobayashi, 2008). Decreases in the G/D ratio are also clearly observed at 6 eV or higher, as shown in Fig. 5(c). Notably, the damage in metallic SWCNTs with diameters of ~1.6 nm at 140-160 cm-1 is not clear up to 8 eV. This is because of the diameter dependence of low-energy irradiation damage, as discussed in sec. 4.3. In electron (hole) tunneling injection studies using a scanning tunneling microscope (STM), slightly lower threshold energy of ~ 4 eV has been observed (Yamada et a., 2009). The reason for the discrepancy may be that the threshold energy depends on the diameter, chirality, or detailed defect structures. Anyway the threshold energy of the low-energy irradiation damage seems to be several electron volts.
a) G and D band, and (b) RBM spectra of unirradiated, photon-irradiated, and annealed SWCNTs. The SWCNTs were irradiated by unmonochromatized synchrotron radiation light (hν≤1 keV) up to a dose of 8×1020 cm-2. The excitation wavelength for the Raman measurements was 633 nm.
Probably the most important characteristic of the low-energy irradiation damage is the reversibility of the damage and recovery. Figure 6 shows Raman spectra of SWCNTs before and after VUV light irradiation and of SWCNTs annealed at 300º, 600º, 800º, 900º C. The irradiation caused severe damage and drastically decreased the G/D ratio and the RBM intensities. All the RBM peaks above 200 cm-1 corresponding to a diameter less than ~1.2 nm almost completely disappeared. However, the annealing at 300º, 600º, and 800º C gradually recovered the spectra, and at 900º C, all the peaks including the once disappeared peaks are almost fully recovered. I would like to point out once again that the spectra were not normalized at all. Thus, the results reveal that not only the spectral shape but also the spectral intensity itself is almost fully recovers by annealing.
The reversible damage and recovery is also observed in the electric properties. As mentioned in sec. 3.3, the low-energy irradiation damage almost extinguishes the electric conductivity. However, the extinguished conductivity is also fully recoverd by annealing, as shown in Fig. 7(a). An originally metallic SWCNT device was intensively irradiated in a SEM using the line scan mode. The irradiation extinguished the conductivity and made the SWCNT almost insulating. However, the conductivity was fully recovered by annealing in a vacuum at 300º C. Moreover, the reversibility can be observed repeatedly, as shown in Fig. 7(b). The complete reversibility of the electric properties has also been observed by another group, although they attribute the conductivity decrease and recovery to substrate charging and its release (Marquardt et al., 2008. and Vijayaraghavan et al., 2010). I will discuss this issue later in sec. 7.4.
a) Electric properties of a SWCNT device before and after the first electron irradiation and after annealing. The SWCNT was intensively irradiated by electrons of 20 keV up to a dose of 1×1020 cm-2. Then, the irradiated device was annealed at 300º C in Ar atmosphere for 30 min. (b) The electric properties of the same SWCNT device before and after the second irradiation and after the second annealing. The SWCNT was intensively irradiated again by 20-keV electrons up to a dose of 1.7×1020 cm-2. After the irradiation, the SWCNT was annealed at 300º C for 30 min and fully recovered again.
The reversibility of the damage and recovery indicates that the damage is not accompanied by a reduction of carbon atoms and that the number of carbon atoms is preserved. Recently, Mera et al. directly measured ion desorption from SWCNTs under soft X-ray illumination (Mera et al, 2010). They also excluded emission of carbon atoms from the SWCNTs.
Another important characteristic of the low-energy irradiation damage is that strong diameter dependence is observed when the irradiation is done at room temperature or above (Suzuki and Kobayashi, 2006). For example, in the RBM and PL spectra shown in Figs. 1, 2, 5, and 6, we can clearly see the diameter dependence of the damage; that is, thinner SWCNTs are more severely damaged. Especially, in Fig. 1(c), we can see a large difference in the extent of the damage due to very small diameter difference. The SWNTs observed at about 1151 and 1172 nm can be assigned to (12,1) and (11,3) tubes having diameters of 0.995 and 1.014 nm, respectively. These two peaks were considerably weakened by the photon irradiation at 250º C. On the other hand, the occurrence of the damage was not obvious for thicker SWNTs after the same irradiation dose at 250º C. The peaks at 1224 nm is assigned to (10,5) tubes having a diameter of 1.050 nm. The diameter difference between the considerably damaged (11,3) and hardly damaged (10,5) tubes is only 0.037 nm. It is very interesting that such a small diameter difference results in the distinctly different sensitivity to the irradiation.
a) G and D band and (b) RBM spectra of pristine, irradiated, and partially recovered SWCNTs. The SWCNTs were irradiated by 1-keV electrons up to a dose of 8×1017 cm-2. Then, the damaged SWCNTs were partially recovered by annealing at 400º C in Ar atmosphere for 30 min. The excitation wavelength was 785 nm. In (b), the hump at ~300 cm-1 is from the Si substrate.
The diameter dependence is observed in the recovery process, as shown in Fig. 8. The electron irradiation largely decreased the G/D ratio (a) and once almost completely extinguished all of the RBM peaks (b). The sample was partially recovered by annealing at 400º C. Then, only the peak at about 205 cm-1, corresponding to the thickest SWNTs among the initially observed ones, significantly recovered.
The diameter dependence of damage is more or less also observed in knock-on damage (Krasheninnikov & Nordlund, 2010) and damage by radicals (Yang et al., 2006, Zhang et al., 2006b). However, the diameter dependence of low-energy irradiation damage is more prominent, as mentioned above. The damage caused by knock-on collision and radicals also occurs in thick MWCNTs and graphite, but the low-energy irradiation damage has not. Also noteworthy is that the diameter dependence is not prominent when SWCNTs are irradiated at low temperature, as shown in the next section.
Severer damage is observed at lower temperatures (Suzuki & Kobayashi, 2007a). As shown in Fig. 1, the irradiation at 250º C results in much less damage than at 22º C. The temperature dependence is seen at lower temperatures, and less damage is observed at -27º C than at -267º C (6 K), as shown in Fig. 9. These results suggest that low-energy irradiation-induced defects can be healed even at -27º C. In fact, the electric conductivity of irradiated SWCNTs gradually recovers at room temperature, as shown in Fig. 10 (Suzuki & Kobayashi, 2007). The temperature dependence of the damage is completely opposite to that observed in gas phase reactions (An et al., 2002, Zhang et al., 2006a).
a) G and D band, (b) RBM, and (c) PL spectra of pristine SWCNTs and of SWCNTs irradiated at -27º, and -267º C. The SWCNTs were irradiated by 40-eV photons up to a dose of 7.2×1017 cm-2. The excitation wavelength was 785 nm. In (b), the hump at ~300 cm-1 is from the Si substrate.
Fig. 9(b) also shows that the diameter dependence of the damage is less prominent at -27º C, meaning that the recovery of all the observed SWCNTs is almost completely forbidden at this temperature, regardless of the diameter. In other words, the less damage in a thicker SWCNT observed at room temperature and above is a consequence of the fact that a defect created in the thicker SWCNT can be more quickly healed by the thermal energy at the irradiation temperature. The diameter dependence can mainly be ascribed to the diameter dependence of the defect healing rather than to that of defect creation.
The recovery of the damage at room temperature or below suggests that the activation energy of the defect healing is quite small. We have proposed a simple method for determining the activation energy of defect healing in SWCNTs (Suzuki et al., 2010). For example, recovery curves of the G/D ratio can be used for the analysis. In Fig. 11(a), we show Raman spectra of SWCNTs before and after irradiation and after 2, 14, and 64 min annealing at 240º C. The annealing gradually recovered the irradiated SWCNTs. From these measurements, we obtained recovery curves of the G/D ratio at several temperatures, as shown in Fig. 11(b). The reason for the relatively small values of the G/D ratio is that we adopted the area ratio rather than the peak height ratio, in order to decrease static errors.
a) Current-voltage characteristics of a SWCNT device before and just after electron irradiation and 13, 36, 136 min after the irradiation. The electron energy and irradiation dose were 20 keV and 1.8×1015 cm-2,respectively. (b) Time evolution of the irradiation-induced resistance (ΔR) at 22º C. The initial value of the irradiation-induced resistance (ΔRo) was 19.8 kΩ.
The activation energy
where
Interestingly, although a partial recovery of low-energy irradiation damage at room temperature is easily observed in the electric properties (Fig. 10), it has not been observed in Raman spectra. Once we obtain the activation energy value, we can estimate the recovery curve at a given temperature
a) Raman spectra of SWCNTs before and after electron irradiation and after annealing at 240º C. The electron energy and dose were 20 keV, and 8×1016 cm-2, respectively. The excitation wavelength was 785 nm. (b) Recovery curves of the G/D area ratio otbained at several annealing temperatures. (c) Activation energy of the defect healing obtained from the recovery curves at 140º and 120º C. (d) Simulated recovery curves of the G/D ratio at room temperature (20º C) obtained from the recovery curves at 120º and 140º C in (b), respectively.
Fig. 11(d) shows the recovery curves at 20º C simulated from the experimental recovery curves at 140º and 120º C and eq. (2). The two independently obtained curves are almost consistent. Note that the unit of the horizontal axes is “year”. Recovery of the G/D ratio from 2.8 to 3.0 at 20º C would take about 230 years. Similarly, the recovery from 6.0 to 6.5 at 20º C was estimated to take about 7 years (Suzuki et al., 2010). Thus, the recovery would be much too slow to observe at room temperature in usual experiments. The very long recovery time at room temperature is a consequence of the relatively slow recovery at elevated temperatures in Raman spectra. On the other hand, the recovery of the electric properties is much more rapid. Annealing at 300º C for 30 min often results in recovery of conductivity of several orders of magnitude, as already shown in Fig. 7.
a) LEEM image of suspended SWNTs on a patterned Si substrate. (b) G and D band Raman spectra of unirradiated and soft X-ray-illuminated (280. 0 and 285.5 eV) SWCNTs and electron-irradiated (~20 eV) SWCNTs. The excitation wavelength was 785 nm. The soft X-ray illumination was done at BL-27SU at SPring-8, Hyogo, Japan. The electron irradiation was a consequence of LEEM observation. The soft X-ray and electron irradiations were done after thorough degassing.
Though we evaluate the activation energy from the G/D ratio here, any other quantity that is a monotonic function of the defect density can basically be used for the analyses. This method can also be used to analyze other kinds of defects and desorption barriers of chemisorbed atoms or molecules on SWCNTs.
As I mentioned in sec. 2, the low-energy irradiation damage is caused by the irradiation itself. We found that the damage does not depend on the remnant gas pressure at ~10-4 Pa or below (Suzuki et al., 2008). The low-energy irradiation damage has been observed in a surface-science-grade ultra-high vacuum (UHV) of ~1×10-8 Pa by VUV light illumination (Suzuki & Kobayashi, 2006a. Suzuki & Kobayashi, 2007a, Mera et al., 2009. Mera et al., 2010.), electron beam irradiation (Arima et al., 2009.), and electron (hole) injection from a STM tip (Berthe et al., 2007. Yamada et al., 2009). The damage occurs as ever when SWCNTs are thoroughly degassed in a UHV before irradiation. Other examples of occurrence of the damages in UHV surface analysis systems are shown in Fig. 12(b). The SWCNTs were irradiated by electrons during LEEM observation [Fig. 12(a)] or by soft X-rays at a photoemission spectroscopy beamline attached to a synchrotron radiation ring. The damage to SWCNTs is especially severe in LEEM observation using very low-energy electrons of several tens electron volts, due to the energy dependence of the damage (sec. 4.1). In an UHV, no irradiation-induced change is observed even in high-energy-resolution photoemission spectroscopy (Suzuki et al., 2004a), indicating that chemical reactions with gas molecules are negligible. Nevertheless, very severe damage is observed in Raman spectra.
A low-energy electron and photon can easily dissociate a small molecule (for example, photodissociation). On the other hand, such low-energy irradiation damage (or structural change) is not commonly observed inside the bulk of a metal or semiconductor. Actually, it has not been reported for graphite. Very interestingly, even among CNTs, the damage has been reported for SWCNTs but not for MWCNTs. An electron irradiation experiment in an SEM has shown that the irradiation causes no reduction of the conductivity of MWCNTs with a diameter of ~10 nm (Bachtold et al., 1998. Hobara et al., 2004). The irradiation conditions used in those studies (4 C cm-2 of 20-keV and 20 C cm-2 of 10-keV electrons) roughly correspond to 10 to 1000 fold of a value that can cause a SWCNT conductivity decrease of a few orders of magnitude (Suzuki, 2011). Thus, the damage seems to be specific to SWCNTs or thin CNTs with a diameter of ~1 nm. Even among SWCNTs, the extent of the damage strongly depends on the diameter: Thinner SWCNTs are more severely damaged, as discussed in section 4.3.
The diameter dependence of the damage may explain the occurrence of the damage in SWCNTs and its absence in MWCNTs and graphite. Considering that the damage strongly depends on the diameter among SWCNTs, it would be possible that a MWCNT of 10-nm diameter is no longer damaged by low-energy irradiation at room temperature. If the occurrence and the absence of the damage originate in the diameter difference, we can expect that strain in the sidewall plays an essential role in the defect formation or its stabilization. Alternatively, it is interesting to view the occurrence and absence of the damage in terms of dimensionality. Graphite, in which the damage does not occur, is a three-dimensional material, and a SWCNT, in which the damage occurs, is a one-dimensional material. Notably, it has been well established that structural changes occur in zero-dimensional fullerenes by photon and electron irradiation (Zhao et al., 1994. Onoe et al., 2003). This is generally described as “polymerization” instead of damage, because the irradiation causes chemical bonds to form between neighboring fullerenes. The structural change can be reversibly restored by annealing, exactly like the low-energy irradiation damage of a SWCNT. The electronic states, which spread in the whole crystal in a bulk material, should be localized in low-dimensional materials or nanomaterials, and the degrees of freedom of atomic movement should become larger. Thus, in low-dimensional materials or nanomaterials, local structural change would easily occur with low-energy irradiation and the defect structure would be stabilized (See also sec. 6).
In terms of the relation between the damage and structure, it is very interesting to explore whether the damage occurs in graphene, which is a two-dimensional material and can be considered to be a SWCNT of infinite diameter. Zhou et al. reported that soft x-ray illumination damages graphene, on the basis of their C 1s x-ray absorption and Raman spectroscopy results (Zhou et al., 2009). Very interestingly, the illumination effects increased with a decreasing number of layers of exfoliated graphene and were negligible even for monolayer epitaxial graphene on SiC, which has a relatively strong interaction with the substrate. These results suggest that low dimensionality is strongly related to the low-energy irradiation damage.
a) Room-temperature gate voltage characteristics of a SWCNT device before and after electron irardiation. The SWCNT was once scanned by an electron beam of 100 pA. The electron energy and scan speed were 20 keV and 400 nm/s, respectively. (b) Room-temperature Coulomb diamond characteristics of a SWCNT device before and after electron irradiation. The SWCNT was once scanned by an electron beam of 500 pA. The electron energy and scan speed were 20 keV and 400 nm/s, respectively. (c) Schematic explanations of the defect-induced semiconductng properites. (d) Schematic explanations of the defect-induced Coulomb oscillation properites.
As mentioned in sec. 3.3, intensive irradiation finally makes a SWCNT almost insulating. However, when the damage is moderate, a metal-semiconductor transition of the electric properties is often observed. In our early study, we irradiated the whole device in a SEM and observed the conversion of the electric properties at 28 K (Vijayaraghavan et al., 2005). Further irradiation caused an increase of the nominal band gap observed in the low-temperature electric properties. More recently, we succeeded in converting the room-temperature device characteristics from metallic to semiconducting by local irradiation using an electron beam lithography system (Suzuki et al., 2008). Before the irradiation, the device characteristics were almost gate-independent, which is a common feature of a metallic SWCNT. A part of a metallic SWCNT was once scanned by an electron beam. Then, the room-temperature gate characteristics of the device were converted to semiconducting, as shown in Fig. 12(a). After the irradiation, ambipolar semiconducting gate characteristics were clearly observed.
Room-temperature Coulomb oscillations have been observed when defects form a small dot in a SWCNT channel (Matsumoto et al., 2003). The low-energy irradiation damage can also be used to fabricate such small dots intentionally. As shown in Fig. 12(b), after irradiation, multi-dot Coulomb oscillation properties are sometimes observed at room temperature.
A schematic model of a possible mechanism for the irradiation-induced semiconducting properties is shown in Fig. 12(c) (Kanzaki et al., 2007. Suzuki et al., 2008). The temperature dependence of device characteristics after irradiation shows that an energy barrier for carriers is formed in the SWCNT channel. The barrier height observed in the electric properties reaches about 0.6 eV, when irradiation-induced semiconducting properties are observed at room temperature. Recently, a STM study more directly showed that a local band gap is actually formed in a metallic SWCNT by a carrier injection-induced defect (Yamada et al., 2009). This suggests that the defect-induced local band gap opening is the origin of the barrier. The carrier transport is inhibited by the barrier at the gate voltage of around 0 V. The device still turns on at large gate voltage. This can be reasonably explained in terms of gate-induced band bending in a metallic SWCNT. The density of states near the Fermi level of a metallic SWCNT is very small. Owing to the small density of states near the Fermi level, we can bend the band by applying gate voltage and reduce the effective barrier height for an electron. At sufficiently large gate voltage, the device will turn on. Thus, the metal-semiconductor transition is explained by the defect-induced barrier formation and gate-induced band bending. When Coulomb oscillation is observed, the defects seem to act as tunneling barriers, as schematically shown in Fig. 12(d). In this case, tiny multi-dots divided by the defects seem to be formed in the vicinity of the irradiated part.
The defect-induced conversion of the electric properties seems to be caused by defects formed by other methods. In fact, conversion of the electric properties from metallic to semiconducting also occurs when defects are induced by plasma treatment of metallic SWCNT-FETs. More interestingly, the defect-induced semiconducting electric properties well explain the fact that the ratio of “semiconducting” SWCNTs that act as FETs has been reported to strongly depend on the growth method (Suzuki et al., 2008, Mizutani et al., 2009). The plasma-enhanced CVD method has been reported to produce preferentially semiconducting SWCNTs, and the ratio of semiconducting SWCNTs has been reported to reach about 90 % (Li et al., 2004. Ohnaka et al., 2006) or even 97 % (Mizutani et al., 2009). On the other hand, for the laser ablation method, which generally produces high-quality SWCNTs, the semiconducting SWCNT ratio was evaluated to be quite small, about 30 % (Li et al., 2004). I think that the growth method dependence of the ‘‘semiconducting’’ SWCNT ratio is mainly due to the growth method dependence of defect density. Distinguishing whether the electronic structure is metallic or semiconducting by electric measurements may be inconclusive, especially when the SWCNT shows “semiconducting” properties.
The low-energy irradiation damage can be caused by 10-eV photons, which have very small momentum. This indicates that the momentum of an incident particle would have no essential role in the damage, which is in remarkable contrast to knock-on damage. Thus, the defect formation would be due to bond breaking, which follows an electronic excitation by the energy of the incident particle. An energy of ~10 eV is still high enough to cut C-C bonds. Thus, it is reasonable that low-energy irradiation creates a defect with finite probability if the defect structure is stable and the lifetime is long enough. A simple example of this kind of structural change is photodissociation of a molecule. A bond breaking following electronic excitation can easily dissociate a small molecule In a bulk crystal, on the other hand, even the breaking of several bonds would result in immediate re-bonding without any structural change because an atom has very little freedom of displacement due to the existence of surrounding atoms. The situation in a SWCNT is one between a molecule and bulk. More than one bond breaking would be necessary to stabilize the defect. Among related carbon materials, low-energy electron and photon irradiation-induced structural change (polymerization) is known to occur for fullerenes. On the other hand, the damage has not been reported for graphite or MWCNTs, as discussed in sec. 4.7.
Interestingly, Yamada et al. (Yamada et al., 2009) have proposed, on the basis of thier STM results, that carrier injection first creates primary defects whose lifetime is very short (<50 ms). Most of them are quickly annihilated and the structure is restored. However, in rare cases, a primary defect fails to recover and a stable defect is created. The quantum efficiency of the primary defect formation was evaluated to be 2×10-10 at a bias voltage of 3.5 V near the defect creation threshold.
The detailed atomic structure of a low-energy irradiation-induced defect is not clear at present. A detectable change has not been observed even with microscopy techniques, such as SEM. This is one of the main reasons that the low-energy irradiation had not been recognized for such a long time, although SEM had been commonly used for characterizing SWCNTs since their discovery. Our previous TEM observation showed that the tube wall is not clearly destroyed regardless of severe damage (Suzuki et al., 2005b). The Stone-Wales defect, which is formed by a C-C bond rotation, is consistent with the conservation of the number of carbon atoms. However, the stable structure seems to contradict the relatively small activation energy and healing at a moderate temperature or even at room temperature or below. Another possible defect is a vacancy in the tube wall with a migratory C adatom on the surface. The observed activation energies (0.7-1.4 eV, sec. 4.5) are very close to the C adatom migration energies, which are theoretically predicted to depend on the SWCNT diameter and to be 0.6 to 1.3 eV (Krasheninnikov et al., 2004). However, a high-resolution TEM observation has shown that annihilation of the vacancy and migratory adatom is governed by the recombination barrier rather than by the adatom migration barrier itself (Hashimoto et al., 2004). The existence of such a vacancy-adatom defect (with the adatom bounded in the vicinity of the vacancy) was also strongly suggested by a scanning tunneling microscopy study (Lee et al., 2005). The vacancy-adatom defect is simply formed by breaking two bonds of a C atom. The recombination barrier of the vacancy-adatom defect in SWCNTs has been calculated to be ~1-2 eV (Okada, 2007), which is rather close to the observed activation energies. Determining the presice defect structure is a future issue.
The low-energy irradiation damage is often confused with other types of damage and irradiation-induced phenomena. Here, I would like to summarize differences in the defect characteristics of low-energy irradiation damage and other damages.
Knock-on damage is caused by ballistic ejection of an atom from a solid by an incident particle. Thus, the damage is accompanied by a loss of SWCNT mass. The displacement energy (kinetic energy at which an atom can escape from the solid.) in a SWCNT is considered to depend on the diameter and to be 15-20 eV. However, when the incident particle is an electron whose mass is much smaller than a carbon atom, the threshold energy becomes ~80 keV from the energy and momentum conservation laws. The threshold energy for a photon will be much larger. Thus, the energy at which knock-on damage is observed is much larger than that at which the low-energy irradiation damage is normally observed. Knock-on damage occurs in MWCNTs and graphite. For a recent review focusing on carbon and other nanomaterials, see (Krasheninnikov, 2010).
Low-energy irradiation often causes hydrocarbon contaminants to adhere to the sample surface. The contaminant adhesion is prominent in a conventional SEM, in which a UHV is usually unavailable. At the electron energy where severe damage is observed (1 keV or smaller), severe contaminant adhesion is also observed. This is because the interaction both between electrons and a SWCNT and between electron and hydrocarbon gases are strong at such a low energy. However, effects caused by the damage and by the contaminant adhesion can be easily distinguished by annealing. The contaminants do not sublimate even at ~900º C, whereas the low-energy irradiation damage can be recovered by annealing at moderate temperatures, as discussed in sec. 4. In our experiments, it is rather difficult to detect contaminant effects because the spectra or electric properties of pristine SWCNTs and SWCNTs recovered from the damage are almost identical (see Figs. 6 and 7), although I do not deny that the contaminants cause some so-called environmental effects (Ohno, 2010).
Irradiation in remnant gases can also cause radical-induced etching, which is the opposite of the contaminant adhesion. For example, the cutting of MWCNTs has been clearly demonstrated under gas atmosphere formed by intentional gas bleeding (Yuzvinsky et al., 2005). In this way, the damage by radicals is generally accompanied by etching, which eventually cuts and eliminates CNTs. Thus, this damage can not be fully recovered. In some literatures, reversible chemisorption and desorption on SWCNT or graphene has been suggested. However, spectra before chemisorption and after desorption by annealing are often compared after arbitrary normalization. This damage also occurs in thick MWCNTs and graphite, although some diameter dependence of the damage is observed (Yang et al., 2006, Zhang et al., 2006b). Metallic SWCNTs are preferentially damaged by radicals (Yang et al., 2006. Zhang et al., 2006b), although such preference has not been observed for low-energy irradiation damage. Moreover, severer damage is observed at higher temperatures due to more activated chemical reactions (An et al., 2002. Zhang, 2006a). This is entirely opposite to the low-energy irradiation damage (sec. 4.4). Of course, the radical effect becomes severer at higher pressures and negligible in a UHV. Reader should recall that low-energy irradiation damage occurs in a UHV after thorough degassing, although no indication of chemical reaction is observed (sec. 4.6).
In a standard SEM in which the adhesion of contaminants occurs, the radical effects seem to be less important. Otherwise, the contaminants would not adhere due to etching. According to my experience, intensive irradiation in a conventional SEM can not cut or eliminate even a SWCNT (Fig. 7). I suppose that the radical effects are largely suppressed due to the adhesion of contaminants, which would protect the sample surface (sec. 3.2).
There has been an attempt to explain the electric property changes by irradiation-induced charging of the substrate (back-gate dielectric) just under the SWCNT (Marquardt et al., 2008. Vijayaraghavan et al., 2010). They observed a large conductivity decrease of on-substrate SWCNT devices by electron irradiation in a SEM. Furthermore, they reversibly and repeatedly recovered the electric properties by applying a high bias voltage (~10 V) to the SWCNT. The phenomena they observed seem to be essentially the same as ours. However, they ascribed the conductivity decrease to a local band gap opening caused by irradiation-induced charging of the dielectric SiO2 layer just under the SWCNT. Actually, theoretical calculations predict that a uniform (Li et al., 2003) or inhomogeneous (Rotkin & Hess, 2004) electric field can open a gap in a metallic SWCNT of specific chiralities. Marquardt et al. (Marquardt et al., 2008) and Vijayaraghavan et al. (Vijayaraghavan et al., 2010) think that electron irradiation in a SEM causes such local and inhomogeneous charging of the dielectric. In their model, the recovery is explained by a release of trapped charges in the vicinity of the SWCNT caused by the high-bias voltage applied to the drain electrodes. In a conventional on-substrate device, a large electric field may be produced by irradiation-induced charging, considering that the field strength is inversely proportional to the square of the distance.
However, the substrate charging model does not at all explain the fact that the irradiation-induced conductivity decrease is as ever observed for suspended SWCNTs, as shown in Fig. 4. The theoretical calculations have predicted that an extraoridinarily high electric field of ~1 Vnm-1 barely opens a band gap of several ten milli-electron volts. It is very unlikely that such a high electric field is formed at SWCNTs suspended 300 nm above the substrate. In fact, a simulation has been performed under a condition where the gate voltage was applied from a metal tip located only 0.5 nm from a SWCNT (Rotkin & Hess, 2004). Similarly, this model cannot explain the degradation of Raman and PL spectra of suspended SWCNTs (Figs. 1 and 9). Moreover, electron (hole) injection-induced band gap opening has been observed for a metallic SWCNT lying on a metal substrate, which does not have charge trap sites (Yamada et al., 2009). This model does not explain the observed band gap value, either. The calculations show that the maximum value of the field-induced band gap is at most ~0.1 eV, which is not sufficient to explain the almost insulating properties observed at room temperature. In fact, an energy barrier of ~0.6 eV was observed for a SWCNT whose room-temperature electric properties were converted from metallic to semiconducting by irradiation (sec. 5). Finally, it should be noted that the irradiation-induced conductivity decrease has been observed in all measured SWCNTs, whereas, in the theoretical calculations, band gaps open only in SWCNTs having certain chiralities. Considering that the irradiation-induced physical property changes can recover at a moderate temperature (~300º C [Fig. 7]), the high bias-induced recovery observed in refs. 7 and 8 seems to be due to annealing by Joule heating. I do not deny an electric field-induced band gap opening in a metallic SWNT. However, I do not think that such a high or inhomogeneous electric field is produced by simple SEM observation or line scans.
Low-energy electron and photon irradiation may increase the temperature of the irradiated SWCNTs. However, the heating effect itself does not explain the low-energy irradiation damage at all because less damage is observed at higher temperatures, as shown in Fig. 1. Originally, SWCNTs are thermally very stable materials. Thus, at least under usual conditions, irradiation-induced heating itself would not damage the SWCNTs in a vacuum, if ever. In practice, damage is often observed during Raman measurements in air when the excitation laser power is too large. However, this is not low-energy irradiation damage, but instead would be combustion, because this damage is not observed in a vacuum or an inert gas atmosphere.
I have shown that low-energy electron and photon irradiation solely damages SWCNTs. The low-energy irradiation damage extinguishes the characteristic optical and electric properties and reduces chemical tolerance. Thus, we have to pay attention to the damage when we use analytical tools that use low-energy electrons (SEM, LEEM etc.) and VUV light or soft X-rays (photoemission spectroscopy using bright light). The defects have some unique properties. The damage and recovery are reversible, indicating that the number of carbon atoms is preserved. The damage strongly depends on diameter. That is, thinner SWCNTs are more severely damaged. The damage has been observed in SWCNTs but not in MWCNTs, suggesting that it is characteristic of low-dimensional structures or nanostructures. The activation energy of the defect healing depends on the extent of the damage and was evaluated to be about 0.7 to 1.4 eV. Because of the relatively small activation energy, the defects can be healed even at room temperature or below, and less damage occurs at higher temperatures. I also showed that the irradiation-induced defects can convert the room temperature electric properties of a metallic SWCNT to semiconducting. The conversion can be explained by the local band gap opening caused by the defect and gate-voltage-induced band bending in the metallic SWCNT. Energetically, the low-energy is still sufficiently larger than the C-C bond energy and can therefore break the bonds. Future studies should address the detailed defect structure.
This work has been done through cooperation of many coworkers. I thank all of my coworkers for their cooperation and assistance in this work.
Chronic pain (CP) is one of the most leading causes of disabilities affecting more than 30% of people worldwide [1, 2, 3]. It is a disease in its own right [4]. Individuals with moderate to severe pain experience a marked decrease in the physical, psychological, and social well-being. It further affects the quality of life, reduces the ability to perform routine activities, and leads to work absenteeism. Economic costs associated with the management of chronic pain in United States include direct healthcare costs ranging from $260 to $330 billion and indirect cost ranging from $300 to $350 billion per annum [5]. The leading causes of year lost to disability worldwide in 2013 include low back pain, neck pain, migraine, and musculoskeletal disorders [6].
Management of CP is often based on trial-and-error approach with tricyclic antidepressants, anticonvulsants, and narcotics. Many studies have also suggested that combination of drugs is superior to single agent for CP management [7]. Recent advances in understanding the pain mechanism have favored the use of ketamine as a rescue agent in refractory chronic pain syndromes [8]. The most recent definition of neuropathic pain by International Association for the Study for Pain (IASP) excludes the pain states characterized by central sensitization in the absence of a discrete nerve injury such as CRPS-1 and fibromyalgia [8]. Further the new pain descriptor nociplastic pain includes the condition associated with altered processing of pain that does not fit into nociceptive category such as fibromyalgia, CRPS-1, nonspecific chronic back pain, irritable bowel syndrome, and other functional visceral pain disorders [9]. Drugs used to be effective for one type of pain have been shown in various studies to be effective for other type of pain also [10, 11]. Even though the preclinical studies supported the antinociceptive effect of ketamine against central and peripheral neuropathic pain states, there is growing evidence suggesting its analgesic effect in inflammatory and non-neuropathic pain conditions also [12, 13, 14]. Hence the present topic focuses specifically on the effect of ketamine on non-neuropathic pain conditions.
Pain can be classified as nociceptive, neuropathic, and nociplastic in origin. Nociceptive pain results from stimulation of primary nociceptive nerve endings by actual or threatened tissue damage, while integrity of nerve fibers is preserved. In contrast to nociceptive pain, neuropathic pain results from direct injury or disease affecting somatosensory nervous system. Recently defined nociplastic pain is the pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory nervous system causing pain. Characterization of altered nociception is yet to be defined [15]. Another widely, used terminology is mixed pain. It is a complex overlap of various known pain types (nociceptive, neuropathic, and nociplastic) in any combination acting simultaneously and/or concurrently to cause pain in the same area [16].
Acute pain is reduced with the removal of painful stimulus, while chronic pain persists beyond the useful limit of pain signal and often extends beyond 3–6 months after the initial tissue injury has healed. IASP along with World Health Organization (WHO) proposed a new chronic pain classification for the 11th edition of International Classification of Diseases (ICD) as chronic primary pain and chronic secondary pain. Chronic primary pain is defined as the pain in one or more anatomical region that persists or recurs for longer than 3 months; it is associated with significant emotional stress and functional disability, and the symptoms are not better accounted for by another diagnosis. Chronic secondary pain is considered as a symptom of another condition, whereas in chronic primary pain, the pain itself is considered as a disease. These conditions often exhibit central sensitization along with psychological distress and pain catastrophizing. For example, chronic widespread pain, fibromyalgia (CRPS 1) temporomandibular disorder, irritable bowel syndrome, most back pain, and neck pain syndromes [17].
Approximately 30% of world’s population suffer from chronic pain, and it is more common in females and in old population [18, 19]. Other risk factors include low socioeconomic status, geographical and cultural factors, and psychological factors such as anxiety and depression. Increase in prevalence may negatively affect the global health status and overall economy of countries [20].
Even though the acute pain or traumatic injury may proceed the development of chronic pain, mechanism behind the chronic pain may differ from those implicated in acute pain [21]. In contrast to acute pain, the diagnosis of chronic pain is not often straightforward. It often involves biomedical and psychological factors. Standardized questionnaires such as LANSS, Pain DETECT, and DN4 are used to evaluate pain along with functional abilities and emotional distress in chronic pain patients. Detailed history, clinical examination and confirmatory tests are often necessary for presumption of diagnosis. Several studies have reported the successful short-term management of chronic nonmalignant pain with ketamine infusion.
Ketamine initially labeled as CI-581 is a phencyclidine derivative prepared by Professor Calvin from Parke Davis. After experimental studies on animals, first human trial was conducted on prisoners on August 3, 1964 by Dr. Domino and Dr. Corssen. They found that ketamine could rapidly produce analgesia with unique state of altered consciousness, which was later named as “dissociative anesthesia” by Toni, wife of Dr. Domino. Because of its sympathomimetic effects and wide safety margin, ketamine was used as war anesthetic to American soldiers in Vietnam war [22].
Ketamine [2-(2-chlorophenyl)-2-(methyalmino)-cyclohexanone ketamine] is a racemic mixture of two optical enantiomers [23]. S(+) ketamine is two times stronger than parent compound and four times stronger than R(−) ketamine. It has also anti-hyperalgesic effects [24]. R(−) ketamine has potent antidepressant effect [25]. Ketamine undergoes demethylation and hydroxylation and metabolites are conjugated and excreted in urine [26]. Nor ketamine is the main metabolite, and it is one-third to one-fifth as potent as its parent compound [27].
Ketamine can be safely administered through several routes with varying bioavailability: intravenous (100%), intramuscular (93%), oral (20%), nasal (50%), and rectal (20%) and even epidural [28]. FDA has approved the use of intranasal S (+) ketamine along with antidepressant in treatment-resistant depression [29].
Discovery of N-methyl-D-aspartate (NMDA) receptor and its noncompetitive inhibition by ketamine has revolutionized the use of ketamine as a potent anti-hyperalgesic drug in various painful states.
NMDA receptors are important for learning, memory, and synaptic plasticity, and it is also involved in amplification of pain signals and opioid intolerance. Non-competitive antagonism of NMDA receptor by ketamine occurs by two different mechanisms. It decreases the frequency of channel opening by allosteric mechanism and reduces the time spent in the acute open state [30]. Ketamine equally binds to NMDA subtypes 2A to 2D and results in favorable effect compared with other subtype selective NMDA antagonists [31]. It inhibits NMDA-mediated responses both in spinal cord and thalamus. Its non-competitive antagonism allows the endogenous agonist glutamate to continue to binding to these sites. Ketamine at lower concentration blocks closed channels, while higher concentration blocks both open and closed channels [32]. Ketamine can also interact with NMDA receptors present at periphery [33].
Ketamine also binds to μ, κ, and δ receptors; however, this interaction is not responsible for its analgesic effect as their block is not antagonized by naloxone [34, 35, 36]. At high doses it also produces local anesthetic effect by blockade of sodium channel receptors [37].
Ketamine’s interaction with monoaminergic system is significant with the stimulation of non-adrenergic neurons and inhibition of catecholamine uptake, and it provokes hyperadrenergic condition (norepinephrine, dopamine, serotonin) [38]. R(−) isomer inhibits only neuronal uptake while S(+) isomer inhibits extra neuronal uptake also [22]. Ketamine also has a direct inhibitory effect on nicotinic and muscarinic receptors [39].
Ketamine also acts on other non-NMDA pathways that play significant role in pain and mood regulation including the blockade of Na-K channel (hyperpolarization-activated cyclic nucleotide gated (HCN), activation of high affinity D2 receptors and L-type voltage-gated calcium channels, facilitation of gamma aminobutyric acid A (GABA-A) signaling, and enhancement of descending inhibitory pathways [32, 40, 41].
Ketamine can also block large conductance Kca channels (BK channel) and preferentially suppresses spinal microglia hyperactivation after nerve injury, which may explain its potent effect against neuropathic pain [42]. Direct inhibition of nitric oxide synthase could also contribute to its analgesic and anesthetic properties [43].
Over the past few years, the use of ketamine infusion for the management of CP had increased dramatically but with wide variation in dose, monitoring, and selection of patients. This has led to the creation of consensus Guidelines to start ketamine infusion for CP by American Society of Regional Anesthesia and Pain Medicine along with American Academy of Pain Medicine and American Society of Anesthesiologists [44].
Ideally treatment session should be carried out in inpatient settings under the care of anesthetists, nurse anesthetists, or emergency physicians experienced in ketamine administration and trained in advanced cardiac life support. Availability of personnel and equipment for resuscitation at all times is mandatory (Grade A recommendation).
There is a grade B recommendation for the use of ketamine infusion for (CRPS) and Grade D recommendation against fibromyalgia, ischemic limb pain, migraine headache, and low back pain.
There is moderate evidence to support the use of higher dosage of ketamine over longer periods for chronic pain conditions.
Prior to infusion of ketamine base line ECG should be considered for individuals at high risk of cardiovascular events. Baseline and post infusion liver function tests should be considered for individuals with baseline liver dysfunction (alcohol abusers, chronic hepatitis) or for patients who also are expected to receive high doses of ketamine at frequent intervals (Grade C evidence).
Ketamine should not be used in patients with poorly controlled cardiovascular disease and poorly controlled psychosis (Grade B). It should be avoided in patients with severe hepatic impairment, but may be administered judiciously with proper monitoring in patients with moderate disease (Grade C). Basic monitoring such as hemodynamic and respiratory parameters, sedation levels using a validated scale same as individuals receiving ketamine in a non-chronic treatment regime irrespective of the dose and route of administration are essential.
There is limited direct evidence to support the preemptive use of benzodiazepines and α2 agonists, and there is no evidence to support antidepressant, antihistaminic, or anticholinergic medications prior to start of ketamine infusion at sub-anesthetic doses for CP treatment.
There is moderate evidence to support intranasal ketamine for breakthrough pain and low-level evidence for use of oral ketamine and other NMDA antagonists as follow-up therapy after infusion.
Given the refractory nature of patients who receive ketamine infusion, the positive outcome could be considered as 30% pain relief or greater in conjunction with patient satisfaction and/or more objective indicators of meaningful benefit such as 12.8% improvement in Oswestry disability index score in a patient with back pain or 20% or greater reduction in opioid use.
Complex regional pain syndrome (CRPS) was recognized as a distinct pain condition during American civil war in 1864 by Mitchell [45], and it had been described by various names since that time.
It is a chronic pain condition characterized by autonomic and inflammatory features, and it is most often followed by fracture, soft tissue injury, or any surgical procedure, which is often disproportionate in magnitude or duration to the normal course of pain after similar tissue trauma. In 10% of the cases, no inciting cause can be identified [46].
CRPS is subdivided into type 1 and type 2 on the basis of absence or presence of major peripheral nerve injury. The diagnostic features are almost similar in both subtypes although there is difference in etiology, which contributes to uncertainty about the role of neuropathic mechanism [46].
Incidence is found to be greater in females compared with males, and many patients recover within a year, but smaller group may progress to CP. Possible contributing mechanisms include peripheral and central sensitization, autonomic changes and sympathetic afferent coupling, inflammatory and immune alterations in higher centers along with genetic and psychological factors [46]. So effective management of chronic form is often difficult. CRPS causes significant morbidity, and 80% of patients with CRPS are severely disabled [47]. So it needs multidisciplinary care aimed at attaining adequate pain relief, functional restoration, and psychological improvement. Many patients are poorly responsive to regular therapeutic approaches, and ketamine has been shown to decrease pain levels in refractory cases of CRPS in several studies.
Various routes of application of ketamine for CRPS had been explained in several studies. Topical application of ketamine in inflammatory and neuropathic pain conditions resulted in reduction of pain by downregulation of NMDA, α-3-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainite receptors [48]. It had been evidenced that application of 10% ketamine cream reduced tactile allodynia and pain scores within 30 min in CRPS patients. Systemic level of ketamine remained undetectable in the study, which suggested the peripherally mediated effect [49]. Another study showed that topical application of ketamine (0.25–1.5%) to the affected areas of limbs relieved pain and swelling in the early dystrophic stage of CRPS 1. This could be due to the local analgesic effect or peripherally mediated NMDA antagonistic effect of ketamine [50, 51].
Similarly early stage of CRPS was treated with very low dose of epidural ketamine for 10 days in a patient to get prolonged pain relief up to 8 months, which suggested the role of ketamine on NMDA receptors on dorsal horn neurons [52].
Kirkpatrick in his study found that patients with lower limb CRPS responded better than upper limb CRPS for graded dose of ketamine for 5 days [53]. However, the study on mouse model of CRPS showed that subcutaneous ketamine reduces the nociceptive sensitization better in chronic stage than in acute stage [54].
A randomized controlled trial on 60 CRPS1 patients had shown that duration of disease did not affect the response of ketamine in sub-anesthetic dose. The study group received a continuous sub-anesthetic titrated dose of S(+) ketamine ranging from (1.2–7.2% μg/kg/m) for 4.2 days. S(+) ketamine is 2–4 times more potent than racemic ketamine and required less dose for the same analgesic effects with minimal side effects. Recovery is also quicker with S(+) ketamine due to its rapid clearance compared with R(−) ketamine. Median duration of illness was 7.4 years (0.1–31.9 years). ketamine was found to produce significant reduction in pain scores for 10–12 weeks compared with placebo [55].
Pharmacokinetic-pharmacodynamic study on these patients had shown that concentration of ketamine reduced rapidly on the termination of infusion, but analgesic effect outlasts the treatment period by 10 weeks [56]. This is in contrast with the effect of S (+) ketamine in acute experimental pain where the analgesic effect correlates with its plasma concentration [57]. Prolonged effect of sub-anesthetic dose of ketamine could be due to the long-term desensitization of NMDA receptors in spinal cord or restoration of inhibitory sensory control in the brain [58].
Another low-dose ketamine (0.35 mg/kg/min not to exceed 25 mg/h) study on 19 out patients over 4 h for 10 days showed significant reduction (50%) in affective component of pain. Activity watch scores were significantly reduced. Low dose infusion can be done in outpatient basis and is cost-effective also. However, study was stopped halfway by stressing that higher ketamine dose provided much greater pain relief for prolonged period without any complication [59].
This was also suggested by Goldberg, who studied effect of ketamine infusion at two different doses for two different time periods. In his first study with low-dose ketamine for 10 days in 40 CRPS patients, he found significant reduction in pain scores, with increased ability to initiate movement and tendency to decreased autonomic regulation. A total of 36 patients had pain relief for 2 weeks, while eight patients had pain relief for 12 weeks similar to Sigterman’s study [55], but here they have used racemic ketamine [60].
In his second study on 16 patients with moderate-dose ketamine for 5 days, he found significant reduction in pain scores compared with 10 days regime at the end of infusion (2.8 ± 0.65
In refractory and generalized CRPS patients, the anesthetic dose of ketamine in range of (3–7 mg/kg/h) produced significant reduction in pain. As ketamine’s analgesic potency and duration of clinical effect are dose-dependent, author had evaluated anesthetic dose of ketamine in these refractory patients along with midazolam and clonidine. Significant pain relief was observed at 1, 3, 5, 6 months. Quality of life and ability to perform work are significantly improved in many of the patients at 3 and 6 months. Ten out of 20 patients were completely pain free for 5–11 years, and they had not taken any pain medication further [63]. On the first day of infusion, mobilization of neurogenic edema fluid occurs, later on third day, venous tone returns to the affected extremity [64]. Few patients experienced muscle weakness and weight loss. No neurocognitive adverse effects were observed at 6 weeks after anesthetic infusion of ketamine in another study. It could also be due to reduction in pain and pain medicine uptake [65]. However, in 20% of patients, nosocomial, urinary, and pulmonary complications have occurred. No long-term psychiatric impairments have been seen in any of these 20 CRPS patients [63].
Although there is a grade D recommendation for the use of ketamine in fibromyalgia, cancer pain, ischemic pain, and migraine headache [44], various studies have demonstrated its beneficial effects in alleviating pain in fibromyalgia, phantom limb pain, ischemic limb pain, and headache [66, 67, 68, 69].
Fibromyalgia, a functional pain syndrome, is characterized by widespread musculoskeletal pain, fatigue, sleep abnormality, and somatic hyperalgesia. Mean estimated global prevalence of fibromyalgia is 2.7% with female preponderance. Patients often experience pain from head to toe; cognitive dysfunction and memory deficit are common severe symptoms of fibromyalgia. Autonomic disturbances manifest in all areas of body, which correlate with severity of fibromyalgia. It is associated with many of the features of central sensitization including hyperalgesia, allodynia, and temporal summation [70].
Diffuse pain processing in the brain is altered, and it correlates with fibromyalgic nociplastic pain. Increased substance P in cerebrospinal fluid, decreased μ opioid receptor availability along with high level of opioids in cerebrospinal fluid, and reduced levels of noradrenaline, serotonin neurotransmitters are seen compared with healthy individuals [71, 72, 73]. It is often difficult to identify the cause of the nociplastic alteration as it may not be caused by single etiology. Evaluation should be holistic including all symptoms experienced by the patients along with aggravating factors and functional capabilities of the patients. Integrated multidisciplinary approach including patient education, fitness, medical management, and psychotherapy is often needed [70].
Sorenson had found that ketamine produced significant reduction in pain scores and increased endurance in fibromyalgia patients compared with morphine and lidocaine [66]. Graven-Nielsen had also demonstrated that ketamine reduced referred pain, temporal summation, and muscular hyperalgesia in fibromyalgia patients [11]. However, Noppers had reported only short-term benefits after (0.5 mg/kg) of S(+) ketamine corresponding to its plasma concentration in 24 fibromyalgia patients. It is in contrast with the prolonged benefits of long-term infusion of ketamine in CRPS patients, which suggested that duration of infusion is critical rather than the dose of ketamine [74]. Other studies had also proved that long-term infusion produces cascade of molecular changes both at spinal and supraspinal sites [58].
This large inter-patient variability in response to ketamine infusion may occur from a dosing effect, duration of treatment, individual differences in metabolic degradation, genetic variation of NMDA receptors [64]. This variability in response was also reported by Rabben in trigeminal neuropathic patients with 0.4 mg/kg of intramuscular ketamine [75]. Another possibility of varied response in patients could be heterogeneity in pathophysiology of fibromyalgia [71]. Guedj had demonstrated distinct brain function single- photo emission computed tomography (SPECT) pattern in responders and non-responders to ketamine [76].
In refractory cases of migraine, titrated doses of ketamine had reduced pain severity in acute states [69]. A randomized controlled trial has reported that 25 mg of intranasal ketamine reduced the severity of aura in migraine patients [77]. Combination of ketamine (0.5 mg/kg in 2 h) and magnesium sulfate (3000 mg in 30 min) had demonstrated immediate pain relief in two cluster headache patients. It also produced reduction in pain intensity and attack frequency for up to 6 weeks along with reduction in suicidal tendencies [78]. Previous studies on effectiveness of memantine against refractory migraine had further suggested the role of NMDA antagonists against headache [79].
Preclinical studies on ketamine in rats have shown to reverse sensitization in visceral pain syndromes, which provides a good rationale for using ketamine in irritable bowel syndrome [80, 81]. Non-responding refractory pancreatic pain in a pediatric patient has shown reduction in pain scores and morphine requirement after sub-anesthetic infusion of ketamine [82].
Randomized controlled trial on 35 patients with ischemic limb pain had shown that combination of low dose ketamine and opioid produced significant pain relief compared with opioid alone [68]. Animal studies had shown that ischemia can produce hyperalgesia and allodynia, hence the addition of low-dose ketamine along with opioid produced enhanced analgesic effect in these patients [68]. Ketamine also tends to reduce the pain in vasoocclusive crisis in sickle cell anemia patients [83].
Ketamine is associated with adverse psychomimetic, cardiovascular, and gastrointestinal effects resulting from its action on various receptors [84, 85, 86]. Double-blinded randomized controlled trial using midazolam and clonidine as premedication along with low-dose ketamine up to 5.2 μg/kg/min showed no psychomimetic and cardiovascular adverse effects [59]. However, another study calculated number needed to harm; “harm” defined as ketamine-induced psychomimetic adverse effects; where author found that number needed to harm for hallucination to be 21 when ketamine was used alone and number increased to 35 when used in combination with benzodiazepines suggesting that adjuvant may lessen but not eliminate psychomimetic effects [87]. Research is being conducted to develop wearable device to deliver low, non-dissociative dose of ketamine. Studies on animals and ketamine abusers raised the concern of hepatotoxicity and cystitis on prolonged use [88]. In humans, the incidence of hepatotoxicity and cystitis found to be increased with higher and frequent doses of ketamine; however, the liver enzyme levels were back to normal after withdrawing the drug [63].
Medicine is an art as well as science, and the evidence-based medicine not only relies on scientific literature but also the judgment of clinician and patient preferences and satisfaction. The use of ketamine infusion for chronic pain is an evolving treatment that shows great promise. Though the consensus guidelines for intravenous use of ketamine for chronic pain advocate the use of ketamine only for complex regional pain syndrome, various other clinical studies suggested its role in other chronic refractory painful conditions. Effect of ketamine on various receptors not only affects the sensory component but also the affective motivational component of pain. It decreases pain scores along with the reduction of analgesic medications, which further improves well-being and the quality of life. However, continuous refinement of treatment protocol is essential along with emphasis on both long-term safety and effectiveness.
IntechOpen publishes different types of publications
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Findings indicate that availability and accessibility of the communication channels, ICT infrastructure, affordability of communication tariffs and ownership of communication tools influenced the choice of communication channels. Likewise, membership in professional groups, accessibility of knowledge sources, affordability of tariffs for, access to agricultural extension services, availability of knowledge and ICT infrastructure influence the flow of agricultural knowledge. It is concluded that effective agricultural knowledge flow increases knowledge accessibility, usage and creation. It is recommended that each agricultural stakeholder should be involved in conducting relevant agricultural knowledge roles so as to enhance the accessibility, sharing, exchange, dissemination and usage of agricultural knowledge.",book:{id:"5844",slug:"ontology-in-information-science",title:"Ontology in Information Science",fullTitle:"Ontology in Information Science"},signatures:"Wulystan P. Mtega and Mpho Ngoepe",authors:[{id:"215179",title:"Dr.",name:"Wulystan",middleName:null,surname:"Mtega",slug:"wulystan-mtega",fullName:"Wulystan Mtega"},{id:"215180",title:"Prof.",name:"Mpho",middleName:null,surname:"Ngoepe",slug:"mpho-ngoepe",fullName:"Mpho Ngoepe"}]}],mostDownloadedChaptersLast30Days:[{id:"58727",title:"Ontology: Core Process Mining and Querying Enabling Tool",slug:"ontology-core-process-mining-and-querying-enabling-tool",totalDownloads:1647,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Ontology permits the addition of semantics to process models derived from mining the various data stored in many information systems. The ontological schema enables for automated querying and inference of useful knowledge from the different domain processes. Indeed, such conceptualization methods particularly ontologies for process management which is currently allied to semantic process mining trails to combine process models with ontologies, and are increasingly gaining attention in recent years. In view of that, this chapter introduces an ontology-based mining approach that makes use of concepts within the extracted event logs about domain processes to propose a method which allows for effective querying and improved analysis of the resulting models through semantic labelling (annotation), semantic representation (ontology) and semantic reasoning (reasoner). The proposed method is a semantic-based process mining approach that is able to induce new knowledge based on previously unobserved behaviours, and a more intuitive and easy way to represent and query the datasets and the discovered models compared to other standard logical procedures. To this end, the study claims that it is possible to apply effective reasoning methods to make inferences over a process knowledge-base (e.g. the learning process) that leads to automated discovery of learning patterns and/or behaviour.",book:{id:"5844",slug:"ontology-in-information-science",title:"Ontology in Information Science",fullTitle:"Ontology in Information Science"},signatures:"Kingsley Okoye, Syed Islam and Usman Naeem",authors:[{id:"219803",title:"Dr.",name:"Kingsley",middleName:null,surname:"Okoye",slug:"kingsley-okoye",fullName:"Kingsley Okoye"},{id:"219806",title:"Dr.",name:"Syed",middleName:null,surname:"Islam",slug:"syed-islam",fullName:"Syed Islam"},{id:"219807",title:"Dr.",name:"Usman",middleName:null,surname:"Naeem",slug:"usman-naeem",fullName:"Usman Naeem"}]},{id:"59449",title:"Examples of Ontology Model Usage in Engineering Fields",slug:"examples-of-ontology-model-usage-in-engineering-fields",totalDownloads:2137,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"The proposed research deals with the improvement of engineering knowledge classification and recognition by means of ontology usage. Ontology model allows structure information as well as to raises the effectiveness of search. Research describes the development of ontology models for engineering knowledge in Internet portal and modeling system for the classification and recognition of marine objects. The ontology model usage for the engineering knowledge portal development allows to systematize data and knowledge, to organize search and navigation, to describe informational and computational recourses according to the meta-notion standards. The description of modeling system subject domain is based on ontology that allows to realize the recognition of marine objects based on their parameters.",book:{id:"5844",slug:"ontology-in-information-science",title:"Ontology in Information Science",fullTitle:"Ontology in Information Science"},signatures:"Larysa Globa, Rina Novogrudska, Alexander Koval and Vyacheslav\nSenchenko",authors:[{id:"105085",title:"Prof.",name:"Larysa",middleName:null,surname:"Globa",slug:"larysa-globa",fullName:"Larysa Globa"},{id:"219895",title:"Dr.",name:"Rina",middleName:null,surname:"Novogrudska",slug:"rina-novogrudska",fullName:"Rina Novogrudska"},{id:"219896",title:"Prof.",name:"Alexander",middleName:null,surname:"Koval",slug:"alexander-koval",fullName:"Alexander Koval"},{id:"221967",title:"Dr.",name:"Vyacheslav",middleName:null,surname:"Senchenko",slug:"vyacheslav-senchenko",fullName:"Vyacheslav Senchenko"}]},{id:"58350",title:"Semantic Remote Sensing Scenes Interpretation and Change Interpretation",slug:"semantic-remote-sensing-scenes-interpretation-and-change-interpretation",totalDownloads:1403,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"A fundamental objective of remote sensing imagery is to spread out the knowledge about our environment and to facilitate the interpretation of different phenomena affecting the Earth’s surface. The main goal of this chapter is to understand and interpret possible changes in order to define subsequently strategies and adequate decision-making for a better soil management and protection. Consequently, the semantic interpretation of remote sensing data, which consists of extracting useful information from image date for attaching semantics to the observed phenomenon, allows easy understanding and interpretation of such occurring changes. However, performing change interpretation task is not only based on the perceptual information derived from data but also based on additional knowledge sources such as a prior and contextual. This knowledge needs to be encoded in an appropriate way for being used as a guide in the interpretation process. On the other hand, interpretation may take place at several levels of complexity from the simple recognition of objects on the analyzed scene to the inference of site conditions and to change interpretation. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}]},{type:"book",id:"7218",title:"OCT",subtitle:"Applications in Ophthalmology",coverURL:"https://cdn.intechopen.com/books/images_new/7218.jpg",slug:"oct-applications-in-ophthalmology",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Michele Lanza",hash:"e3a3430cdfd6999caccac933e4613885",volumeInSeries:2,fullTitle:"OCT - Applications in Ophthalmology",editors:[{id:"240088",title:"Prof.",name:"Michele",middleName:null,surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza",profilePictureURL:"https://mts.intechopen.com/storage/users/240088/images/system/240088.png",biography:"Michele Lanza is Associate Professor of Ophthalmology at Università della Campania, Luigi Vanvitelli, Napoli, Italy. His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. 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I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"117248",title:"Dr.",name:"Andrew",middleName:null,surname:"Macnab",slug:"andrew-macnab",fullName:"Andrew Macnab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. Gonzalez-Sanchez",slug:"juan-a.-gonzalez-sanchez",fullName:"Juan A. Gonzalez-Sanchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico System",country:{name:"United States of America"}}},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}}]}},subseries:{item:{id:"40",type:"subseries",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive Species, Destruction of Habitats, Overexploitation of Natural Resources, Pollution, Global Warming, Conservation of Natural Spaces, Bioremediation",scope:"