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1. Introduction
Ceramic materials with high thermal conductivity are of great interest in the thermal management of integrated electronic device packaging such as high-power light emitting devices (LEDs), power semiconductor modules, micro and nano fluidics, thermoelectrics, solar cells, and wireless communication devices. These electronic devices and packages generate more heat than before as the system design goes into more integrated, miniaturized, and increasing data communication due to the multifunctional requirement in wireless communication and the Internet of things (IOT) environment. Moreover, a global movement for a clean environment has shifted the public interest from conventional cars with combustion engines to electric vehicles (EVs) and hybrid electric vehicles (HEVs), thus drastically increasing the use of integrated power modules with increased powers and operation frequencies. In this regard, the development of high thermal conductivity ceramics for packaging substrate and filler materials for composites is of great importance. This chapter briefly examines recent trends, development, and technical issues of selected high thermal conductivity ceramic materials and their composites.
2. High thermal conductivity ceramics and their composites
2.1. Aluminum nitride (AlN) base ceramics and composites
2.1.1. AlN ceramics with sintering additives
Aluminum nitride (AlN) has a highly covalent bonded wurtzite structure with a high thermal conductivity and a low thermal expansion coefficient (CTE) of 4.5 ppm/°C that matches well with silicon devices. Typical thermal conductivity of AlN is 140–180 W/mK but varies in the range 18–285 W/mK in polycrystalline AlN ceramics depending on the process condition, purity of starting materials, and microstructures [1]. AlN is stable at 700–1000°C in an oxygen atmosphere. It also has excellent dielectric properties: low dielectric constant (εr) = 9 and low loss (tan δ) = 0.0003 at 1 MHz. With these outstanding physical and thermal properties, AlN ceramic is frequently selected as a candidate material for insulating substrate (direct band gap energy ~6.015 eV) for power electronics device and package. However, sintering of AlN with high density for effective heat transfer and high mechanical strength is challenging due to its highly covalent and low diffusive nature that requires very high sintering temperatures over 1900°C in a reducing atmosphere with applied pressure even though it is stable near 1000°C in air. Also, degradation of thermal conductivity due to oxygen inclusion is another confronting issue in high thermal conductivity AlN substrate fabrication.
Many works to promote the densification of AlN ceramic bodies using different kinds of sintering additives such as CeO, Sm2O3, Y2O3, CaO, CaZrO3, and their multiple co-additions have been investigated [2, 3, 4, 5]. Some of the recent results showing the thermal conductivities obtained in polycrystalline bodies are 90–156 W/mK as summarized in Table 1, which is far below the theoretical value and has a wide span from each other. Ceria (CeO) doped AlN exhibited a stiff increase in thermal conductivity and decent increase in mechanical strength with a small amount of addition (~1.5 wt%), compared to the yttria (Y2O3) addition [2]. High energy sintering method like spark plasma sintering (SPS) was applied [3, 4] as well as conventional solid state reaction (SSR) method [2] for effective low temperature densification process. The two-step sintering technique was also conducted using different temperatures to minimize grain growth and purification of AlN grains [5] (Figure 1).
Physical properties of AlN ceramics with the addition of sintering additives and densification methods.
Figure 1.
Effect of Ce and Y doping on the thermal conductivity and hardness of AlN ceramics [2].
2.1.2. AlN composites with GNP/GNS/rGO: electrically conducting
Carbon based nanostructured materials such as graphene nanoplatelets (GNP) or nanosheets (GNS) were added to AlN matrix to improve physical properties (Table 2). The electrical conductivity was increased with the addition of multilayer graphene as expected but the thermal conductivity was decreased with the addition in both in-plane and through-plane direction, which is adverse to other ceramic/graphene composites data. This sharp decline of thermal conductivity in both directions seems attributed to the large thermal resistance at the thin interaction zone existing in the interface between AlN and GNP [6]. The high directionality in the in-plane and through-plane of AlN/GNP composites, 74 W/mK for in-plane and 37 W/mK for through-plane, is ascribed to the thermal contact resistance existing in both phase interfaces that are severe in the perpendicular heat transfer direction of graphene nanoplatelets [7]. This strong directionality in heat transfer, thermal conductivity, can be easily found in the boron nitride (BN)/polymer composite system, in which 2D morphology BN filler materials are used [9, 10, 11, 12, 13, 14, 15, 16]. In case of reduced graphene oxide (rGO) added AlN, the thermal conductivity decreased sharply from 92.5 to 37.4 W/mK when 2 wt% of rGO was added, though there are minor increases in flexural strength and fracture toughness at ≤1 wt% of rGO, which is due to the low crystallinity, high vacancy defects in rGO, and increased interfacial thermal resistance [8]. The declining thermal conductivity behaviors of AlN composites with these three carbon based 2D fillers exhibited almost similar results as GNP, GNS, and rGO basically had the same morphology and physical properties. High thermal conductivity materials with high directionality in heat transfer can be used in specific directional heat dissipation applications as thermal interface materials (TIM) (Figures 2 and 3).
AC electric conductivity (a) and thermal conductivity data (b) with GNP content in the AlN composites [6].
Figure 3.
Fracture toughness and flexural strength of AlN/GNS composites [7].
2.1.3. Si3N4 base ceramics
Silicon nitride (Si3N4) ceramics has been drawing a lot of interest as a high thermal conductivity dielectric material used in insulated metal substrate (IMS) for power electronic circuit modules. Si3N4 have several benefits: high mechanical properties (flexural strength >800 MPa, Vickers’ hardness >10 GPa), high electrical resistivity, and excellent thermal properties with thermal resistance, high thermal conductivity 70–180 W/mK. However, in reality, fabrication of Si3N4 with high thermal conductivity and high mechanical strength is not easy due to difficulties in densification and morphological control in microstructure. Typical approaches to get such a high performance Si3N4 are: (i) using raw materials with low oxygen to remove Si vacancies that cause phonon scattering, (ii) fabrication of Si3N4 ceramics with textured microstructure to utilize thermal anisotropy in Si3N4 crystals, (iii) using non-oxide sintering additives with low oxygen content to avoid oxygen content from the oxide phase, and (iv) selecting optimal additives that can minimize the Si vacancies [9]. Some of selected results based on these approaches are summarized in Table 4. When non-oxide additives like YF3 was added to Si3N4 with MgO instead of Y2O3, the mechanical strength and thermal conductivities were improved from 40 to 52; it was further increased to 75 W/mK after the annealing treatment at 1850°C. However, Vickers’ hardness was decreased slightly due to larger particle sizes than with the Y2O3 addition [9]. The thermal conductivity of Si3N4 increased up to 100 W/mK when Yb2O3/SiO2 was added and the dielectric loss was decreased from 11.5 × 10−4 to 1.4 × 10−4 (2 GHz) by adjusting the ratio from 0.33 to 1.3 [10]. The influence of nitration and sintering conditions on the mechanical and thermal properties of the sintered reaction bonded Si3N4 (SRBSN) with Y2O3-MgO additives, and the coarsening of grain size and aspect ratio decreased the hardness and fracture toughness while increasing the thermal conductivity. Vickers’ hardness of 17.32 GPa, fracture toughness of 8.36 MPa·m1/2, and thermal conductivity of 98.52 W/m·K were obtained by adjusting nitration and gas pressure sintering (GPS) [11]. A comparative study of the effects of oxide and non-oxide additives on the microstructure, lattice oxygen content, and thermal conductivity of Si3N4 ceramic was investigated. Non-oxide additives such as MgSiN2, YF3, YbF3 induced a decrease in the amount of secondary phases and lattice oxygen contents, thus increasing thermal conductivity from 65 to 101.5 W/mK, while the flexural strength was not affected significantly [12].
Physical properties of Si3N4 ceramics with the addition of sintering additives and densification methods.
2.1.4. AlN-BN base composites: electrically insulating
Boron nitride (BN) was introduced in the AlN matrix to realize low dielectric constant and moderate thermal conductivity [17]. Boron nitride (h-BN) has a hexagonal structure with good thermal shock resistance and high thermal conductivity together with directional preference in heat transfer, i.e., anisotropy in thermal conductivities at in-plane and through-plane of the substrate due to the 2D shape of the BN flake or BN nanosheet. The in-plane and through-plane thermal conductivities are about 300 and 30 W/mK, and the average apparent value is 33 W/mK. The h-BN has low dielectric constant and loss tangent, εr = 4–4.6, tan δ = 0.0012–0.0017 at 8.8 GHz, and dielectric strength at AC = 67–95 kV, which varies depending on the purity. BN has been used in many applications due to these excellent properties, for example, in microelectronic packaging especially in thermal management parts such as heat sinks and power electronic substrates, etc. The addition of BN to AlN also can improve chemical resistance and moisture resistance since the AlN can be hydrolyzed slowly in water (Table 3).
In the AlN–BN composites with 8 wt% Sm2O3-CaF2 as sintering aid, the highest thermal conductivity of 85 W/mK and lowest loss tangent of 4 × 10−3 were achieved at the sintering temperature of 1800°C by the SPS method. The obtained thermal conductivity was lower than that of pure AlN because the platelet BN particles randomly distributed along the AlN matrix hinders direct contact of AlN so that phonon scattering is inhibited [17]. When yttrium oxide (Y2O3) from 3 to 8 wt% is added to the AlN–15%BN composites, the thermal conductivity was increased from 110 to 140 W/mK, which is attributed to the significant decrease in residual grain boundary phase containing yttrium by using SPS method [18]. The addition of CaF2 and increasing temperature also improved the densification, thermal conductivity, and grain boundary purification at the AlN–BN system. As a result, high thermal conductivity of 110 W/mK was obtained when 3 wt% of CaF2 was added and sintered at 1850°C [19]. In the aluminum oxynitride (γ-AlON)–BN system that was prepared by the self-propagating high-temperature synthesis (SHS) process, platelet shaped h-BN grains are re-oriented during the hot-pressing process resulting in the anisotropy of thermal conductivities. The thermal conductivity of (γ-AlON)–BN composites were 14 W/mK for through-plane direction of BN grains and 42.5 W/mK for in-plane direction which is perpendicular to the hot-pressing force [20] (Figure 4).
Figure 4.
Compositional dependence of thermal conductivity of the composites in the (γ-AlON)–BN system determined in (a) perpendicular and (b) parallel to the pressing force [20].
2.2. Polymer matrix composites with high thermal conductivity ceramic fillers
Polymer matrix composites for thermal management packaging are usually filled with high thermal conductivity ceramics such as AlN, h-BN, and carbon based fillers like carbon nano fibers (CNTs), graphite or graphene nanosheets (GNSs), and reduced graphene oxide (rGO). Polymers with AlN and h-BN ceramic filler systems are mostly preferred for high thermal conductivity with electrically insulating heat transfer substrates or thermal interface materials (TIM) due to the high thermal conductivity, low dielectric constant and low loss characteristics of AlN and BN ceramics. On the other hand, carbon based fillers are preferred in TIMs where electrically conducting characteristics are allowed.
2.2.1. Polymer: BN composites
In the hexagonal-boron nitride (h-BN) filled polymer composites, the major issues to enhance heat transfer property are surface treatment of h-BN platelet particles to improve the dispersion of the filler particles in the polymer matrix; to lower the interface thermal resistance; and to increase the alignment of h-BN particles to the preferred orientation in order to achieve high directional thermal conductivity in composites. Table 5 summarizes several technical efforts to enhance the heat transfer properties of polymer–BN composites [13, 14, 15, 16, 21, 22, 23, 24].
Examples of thermal conductivities of polymer–BN composites.
A combined technique that uses mechanical vibration and rotating magnetic field induced high degree of alignment of 10% filler loaded composite exhibited 74% improvement in thermal conductivity compared to the unaligned sample by the formation of conductive network and the reduction of the thermal boundary resistance. The reduction in the thermal boundary resistance between h-BN and bisphenol-A based resin was induced by a high degree of alignment of h-BN platelets via the combined process [13].
The effect of AC and DC electric fields on the anisotropically aligned microstructure in the h-BN filled silicone rubber composites was studied. It was found that the degree of re-orientation of h-BN was more effective under the AC than the DC field during the curing process of the h-BN-silicone composite (Figure 5), and the thermal conductivity of the e-field assisted curing composite was about 250% higher than that cured without E-field [14]. In a recent study, the largest total number of linear densely packed BN nanosheets (LDPBNs) was formed by applying AC field, and thickening of LDPBNs and narrowing of interparticle gaps were achieved by applying a switching DC field (Figure 6). As a result, the thermal conductivity was increased four times that of the composite without LDPBN structure [15].
Figure 5.
Thermal conductivity of BN/silicone composites at different volume fractions [14].
Figure 6.
Schematic model of the generation of higher conduction routes through LDPBNs using various applications of electric fields [15].
A flexible h-BN/poly(vinyl alcohol) composite tape was fabricated by the infiltration of poly(vinyl alcohol) (PVA) solution into the h-BN stack with vacuum filtration to reduce the gap between the h-BN particles and to increase the degree of alignment of h-BN platelets. The in-plane and through-plane thermal conductivities of h-BN/PVA composites thus obtained were 1.63 and 8.44 W/mK, respectively [16]. In the same h-BN/PVA system, the degree of the orientation of h-BN platelet particles can be improved by pressure assisted casting [24], where the degree of orientation of the h-BN particle can be observed by the characteristic peaks in the X-ray diffraction (XRD) data. In order to boost the alignment of h-BN particles, the coating of electric or magnetic field sensitive materials such as TiO2 or Fe3O4 ceramics on to the h-BN particles are also explored to enhance the thermal conductivity [21, 23]. The h-BN particles coated with TiO2 by the sol–gel process were aligned in a vertical direction to the applied field such that the through-plane thermal conductivity of h-BN/polyurethane acrylate (PUA) composite was increased by 190%, while the in-plane thermal conductivity of the composite was decreased by 72% compared to the untreated h-BN composite [21]. High dielectric constant and high thermal conductivity h-BN/poly(arylene ether nitrile) (PEN) composites were developed by magnetic alignment of h-BN through the coating of magnetic Fe3O4 particles together with an additional surface modification by polydopamine (PDA) and functional monomer KH550: (3-aminopropyl) triethoxy-silan). These surface modifications improved the dispersion of h-BN fillers in PEN matrix and the interfacial adhesion. In the BN/Fe3O4/PDA + KH550/PEN composite system, both dielectric constant and loss tangent were increased significantly with the amount of BN/Fe3O4/PDA + KH550, and the thermal conductivity was increased by 140% compared to the neat PEN film [22]. The enhancement of thermal conductivity in h-BN/epoxy composites through the surface modification of h-BN particles via silane coupling agents with different carbon chain has been investigated. The thermal conductivity of h-BN/epoxy composite was improved by 45.4% due to better dispersion of h-BN in epoxy resin than untreated h-BN, which attributed to the higher interfacial affinity of the composite obtained by using longer carbon chain of silane on the h-BN surface [23] (Figures 7, 8, and 9).
Figure 7.
Thermal conductivity of h-BN/PUA composite and TiO2 coated h-BN/PUA composite before and after electric field alignment: (a) through-plane and (b) in-plane thermal conductivity [21].
Figure 8.
Thermal conductivities of neat PEN and BN/Fe3O4/PDA + KH550/PEN composite films with various amounts of filler loading content [22].
Figure 9.
Thermal conductivities of h-BN/epoxy composites with untreated BN, MPCB (Al2O3/epoxy), silane (C3)/BN, and silane (C16)/BN [23].
The effects of h-BN particle sizes, exfoliation of BN particles, and compression of h-BN/PVA composites on the thermal conductivity behavior were investigated [24]. Figure 10(a) shows that the thermal conductivity of h-BN/PVA composites was increased to almost two times when the as-received h-BN flakes are exfoliated into a thin h-BN nanosheet. Also, h-BN particles with smaller size exhibited a higher thermal conductivity in the h-BN/PVA composites, as shown in Figure 10(b). Further increase in the thermal conductivity of h-BN/PVA composites were realized by uniaxial thermal compression after solution casting of h-BN/PVA composite film at 90°C which is above the glass transition temperature of the PVA polymer. Figure 11 shows FE-SEM micrographs of the cross-sectional views of 30 vol% h-BN/PVA composites before (a) and after compression, which clearly show the h-BN particles alignment perpendicular to the pressing direction (b). The through (transverse)-plane and in-plane thermal conductivities measured by laser flash method are plotted together with theoretical modeling in Figure 12. Two models, arithmetic and Wiener models are used for the calculation of the two-phase composite system with the following equations.
Figure 10.
Effect of mechanical exfoliation (a) and h-BN particle sizes (b) on the through-plane thermal conductivities of h-BN/PVA composites [24].
Figure 11.
Cross-sectional views of 30 vol% h-BN/PVA composite films observed by FE-SEM: (a) uncompressed and (b) compressed [24].
Figure 12.
Effect of uniaxial compression on the transverse and in-plane mode thermal conductivities of h-BN/PVA composite films: (a) uncompressed and (b) compressed samples [24].
Arithmetic model:
λ=cλ1+1−cλ2E1
where, c = proportion of component 1.
1–c = proportion of component 2
λ1, λ2 = thermal conductivity of component 1, 2.
Wiener model:
λ/λ2=1−c1−λ1/λ2/1+αλ1/λ2/1+αc1−λ1/λ2/1+αλ1/λ2E2
where, α = 0.5 for dispersion model, λ1 < λ2.
In this calculation, the thermal conductivity of PVA and h-BN was assigned as 0.2 and 33 W/mK, respectively. The in-plane, perpendicular to the compressing direction, thermal conductivities were 5 times higher than those of through-plane at the un-compressed samples, and had 10 times higher values at the compressed samples. The highest thermal conductivity obtained at 50 vol% h-BN loaded PVA composite was 13 W/mK in the in-plane mode, while that of through-plane mode was about 1.1 W/mK, which is lower than that the uncompressed sample [24]. The decrease in the through-plane mode thermal conductivity at the h-BN/PVA composites is due to the reduction in through-plane particle contact by the alignment of h-BN platelets parallel to the in-plane direction, which results in the increasing in-plane thermal conducting paths and decreasing through-plane thermal conducting paths. The Wiener model seems more close to the experimental data than the arithmetic model but the gap between these theoretical and experimental data is wide indicating that there still remain many factors that should be improved to reach an optimum condition in the fabrication of polymer/ceramic composites with high thermal conductivity.
In summary, several methods were explored to increase the thermal conductivity of h-BN/polymer composites. Examples are (i) surface modification of h-BN particles with functional organics to improve the affinity and dispersion of the h-BN/PVA solution, (ii) coating dielectric and ferrous ceramic materials on the h-BN particle to increase the alignment performance with the application of electric and magnetic field, (iii) exfoliation of h-BN flakes into thin h-BN nanosheets for better particle connection in a given filler loading, and (iv) mechanical compressing to promote particle alignment and inter-particle contact.
2.2.2. Polymer: AlN composites
Aluminum nitride (AlN) is a priority choice for filler material in high thermal conductivity polymer/ceramic composites since it has high thermal conductivity (320 W/mK, theoretical), good insulating (electrical resistivity > 1014 Ω·cm) characteristic, low dielectric constant (2.2–3.7 at 1 MHz), and low CTE (4.4 ppm/°C) which is close to silicon. In hot-pressed AlN/PMMA (polymethyl methacrylate) composites, thermal conductivity of 1.87 W/mK was obtained at 70 vol% AlN loaded composite which is about 10 times higher than the PMMA resin (0.18 W/mK) as shown in Figure 13(a). The dielectric constant and loss of the composite were 4.4 (Figure 13(b)) and0.017 at 1 MHz [25]. In the polypropylene (PP)/AlN composites with 3-D segregated structure made by mechanical grinding of PP and AlN mixture followed by hot-pressing at 190°C, core–shell structured PP/AlN composites were obtained. The comparative results of this 3D core–shell structure composite with conventional solution and melt mixed composites revealed that this mechanically ground composite with 10 vol% AlN showed 23% higher thermal conductivity than the others [26]. Thermal conductivity of aluminum nitride loaded poly(propylene glycol) (PPG) fluidic solution was also studied and the results have shown that the thermal conductivities of AlN/PPG fluids were dependent on the AlN solid loading and molecular weight of PPG [27].
Figure 13.
Experimental and calculated thermal conductivities data of PMMA/AlN composites with variation of AlN fillers [25].
In summary, in spite of efforts to increase thermal conductivity in polymer/ceramic composites, the thermal conductivities obtained in polymer matrix ceramic filled composites are still far below that of the fully ceramic base materials due to the low thermal conductivities in the polymer matrix which is limited in improving thermal conductivity when they are electrically insulating. So, further elaboration is needed in the development of high thermal conductivity polymers with electrical insulation to get the utmost high thermal conductivity in polymer/ceramic composites, since the thermal conductivities of filler ceramics are more likely to depend on their own intrinsic nature and are hardly changed by material science and engineering manipulation.
2.3. LTCC ceramics with high thermal conductivity
Low temperature co-fired ceramics (LTCC) have several benefits in microelectronic packaging. Typical sintering temperature of LTCC is below 1000°C, so they can be co-fired with highly conductive electrodes such as silver (Ag) or copper (Cu) metal. Most of the current LTCC materials are composed of low temperature melting glass matrix and ceramic fillers for functional adjustment such as electrical, mechanical, and thermal properties depending on the requirement of the application. Hence, LTCC is sometimes called glass–ceramics but technically, LTCC is part of glass–ceramic composites. For example, in the field of high frequency (RF, microwave, and mm wave) devices and packaging substrates, low loss and low dielectric constant ceramic powder such as alumina (Al2O3) powder is added to the low loss glass matrix. As a result, secondary phases are evolved during the heat treatment process due to part of the alumina filler particles being subjected to react with glass matrix. Interestingly, these secondary phases contribute to the improvement of dielectric properties and mechanical strength when proper filler particle and matrix composition are selected. LTCC has been used for many applications due to energy saving in the low temperature sintering process, excellent dielectric properties, and ease in 3D integration and miniaturization. Examples are radio frequency-system in-a-package (RF-SiP) module, LED packages, high temperature sensors, microelectromechanical system (MEMS) package, micro-heaters, microfluidics etc. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38].
2.3.1. Glass-ceramic base LTCC system
Recently, the use of high thermal conductivity with insulating ceramic substrate is rapidly increasing to enhance the heat transfer property of integrated electronic device and package. Since the conventional LTCCs are based on the glass matrix ceramic composite (GMC) system with low thermal conductivity of the glass phase (1–2 W/mK), the thermal conductivity of most LTCCs are as low as 2–5 W/mK as shown in Table 6 [38, 39, 40, 41, 42, 43, 44], which is still higher than FR-4 (typically 0.1–0.2 W/mK) substrate but far lower than high thermal conductivity bulk ceramics such as alumina, AlN, or Si3N4.
Increasing the thermal conductivity in the glass–ceramic system can be realized by recrystallization, addition of high thermal conductivity fillers such as Al2O3, AlN, BN, and Si3N4 particles. Various types of filler particle morphologies such as platelet, fibrous types are addressed to improve the inter-particle contact to lower interfacial heat resistance and tailor heat transfer directionality in the substrate. Microstructural manipulations such as filler particle re-orientation, low thermal conductivity, secondary phase removal, and grain boundary control are also explored. Among them, some of key research works are summarized in Table 6 [33, 45, 46, 47, 48, 49, 50, 51, 52, 53].
In the alumina (Al2O3) filled glass–ceramic system, MgO–CaO–Al2O3–SiO2, the addition of alumina decreased the thermal conductivity of the glass–ceramic, where diopside or anorthite phase is a major re-crystallized secondary phase as shown in Figure 14. The thermal conductivities of diopside-based and anorthite-based glass–ceramics that sintered at <1000°C are 2.37 and 2.35 W/mK, respectively. It was found that the crystallinity is a more important factor than the ratio of dioposide and anorthite such that the highest bending strength and thermal conductivity were obtained at the samples with high crystallinity, since the main peak intensities in the XRD patterns of glass–ceramics is linearly proportional [33, 45]. In the 40 wt% alumina–60 wt% BSSZ (Bi2O3–ZnO–B2O3–SiO2) glass system [46], the reported thermal conductivity of 7.2 W/mK is unusually high compared to that of previously known glass–ceramics [38, 39, 40, 41, 42, 43, 44] with a high dielectric constant of 10.9 and low loss of 0.009 at the sintered tape.
Figure 14.
Dependences of thermal conductivity for MgO–CaO–SiO2–Al2O3 glass–ceramic system on Al2O3 additions [33, 45].
Aluminoborosilicate (ABS) glass-ceramics containing ≤15 wt% of multiwalled carbon nanotubes (MWCNTs) exhibited an improvement of electrical conductivity by ~106 and a thermal conductivity by ~70%. The maximum electrical conductivity of 2.1 S/cm was obtained when 15 wt% MWCNTs was added to an ABS base LTCC, while that of pure ABS was only ~10−6 S/cm. The percolation threshold exists at the 2.5–5 wt% MWCNTs added region owing to the uniform dispersion of MWCNTs up to 10 wt%, which is a relatively higher loading rate than others [48] (Figure 15).
Figure 15.
Thermal and electrical conductivity with MWCNT content for the ABS–MWCNT nanocomposites [48].
In the calcium aluminosilicate (CAS) glass system, the thermal conductivity was increased from 1.6 to 7.9 W/mK when 35 vol% of β-Si3N4 whiskers added to CAS–Si3N4 composites were sintered at 775–850°C in air (Figure 16). This thermal conductivity is much higher than other LTCC systems reported [38, 39, 40, 41, 42, 43, 44, 46, 47, 50]. However, the thermal conductivity was decreased when the β-Si3N4 whiskers loading exceed 35 wt%. The dielectric constant and loss measured at 1 MHz were 7.1 and 0.006, respectively [49].
Figure 16.
Experimental data and theoretical curve of the thermal conductivity of CAS–Si3N4 composites as a function of β-Si3N4 whisker contents [49].
The Li2ZnTi3O8 (LZT) system with 1 wt% of LMZBS (Li2O: MgO: ZnO: B2O3: SiO2 = 1: 1: 1: 1: 1) as a sintering aid, thermal conductivity of 5.8 W/mK, and CTE of 11.97 ppm/°C were obtained at samples sintered at 875°C. High dielectric constant and loss of the LZT–LMZBS system at 1 MHz were 24.14 and 5.1 × 10−4, respectively. Microwave dielectric properties of the sintered tape measured by split post dielectric resonator (SPDR) technique were εr = 21.9, tan δ = 6 × 10−4 at 5 GHz, and τε of −29 ppm/°C [50] (Figure 17).
Figure 17.
Thermal conductivity measurement data of LZT + LMZBS bulk sintered at 900°C [50].
Glass–ceramics filled with 3–40 μm size monocrystal diamond particles were studied, and the results showed highest thermal conductivity at the glass–diamond composites with 30 μm size diamonds that sintered at 750°C and revealed the lowest CTE, the highest thermal conductivity and bending strength: 4.35 ppm/°C, 9.01 W/mK, and 108.25 MPa [51] (Figure 18).
Figure 18.
Thermal conductivity (a), CTE (b), and bending strength (c) of glass–diamond LTCCs sintered at 750°C [51].
The addition of 1D materials such as AlN whiskers, carbon fibers, and copper fibers to the alumina/30 vol% glass composites was studied. The addition of AlN whiskers did not improve the thermal conductivity compared with AlN powder addition and fibrous fillers was more effective in increasing thermal conductivity of the composites. The highest thermal conductivity obtained in these composites was Al2O3/glass with 30 vol% copper fibers that sintered at 850°C as shown in Figure 19 [52]. The specific resistivity of Al2O3/30% glass and Al2O3/30% glass/30%AlN-whiskers are 2.0–2.1 × 1012 Ω·cm while those of 30% carbon fiber and 30% copper fiber added composites were 8.7 × 10−3 and 3.4 × 10−6 Ω cm, respectively. Therefore, these two electrically conductive composites are not applicable to electrically insulating thermal management material, or they can be coated with a insulating glass layer on the surface to improve electrical resistivity [52].
Figure 19.
Variation of thermal conductivities of Al2O3/glass composites with the addition of 1D filler content [52].
In the borosilicate glass–AlN composite LTCC, the thermal conductivity was increased from 11.9 to 18.8 W/mK by the addition of 14 vol% β-Si3N4 whiskers as shown in Figure 20. This enhanced thermal conductivity may be due to the formation of a thermal conducting path by bridging the isolated AlN particles through β-Si3N4 whiskers. The dielectric properties of this composites are εr = 6.5 and tan δ = 0.0016 at 1 MHz, and the values are not significantly changed with the amount of whiskers due to their similarity in dielectric properties between AlN and Si3N4 [53].
Figure 20.
(a) Experimental data and theoretical curve of the thermal conductivity of the CMBS–AlN–Si3N4 ceramic composites as a function of β-Si3N4 whisker volume fraction and (b) relative dielectric constant and dielectric loss of CMBS–AlN–Si3N4 ceramic composites as a function of β-Si3N4 whisker volume fraction [53].
2.3.2. Glass-free LTCC system
Glass-free or non-glass base LTCC systems have been investigated to reduce the complexity of the LTCC systems due to the multiple phases included such as glass, filler particles, and additional sintering additives. Due to their complexity, several problems occurred during the preparation of LTCC circuits and devices in the integrated electronic module. To overcome this complexity in chemical interaction and inhomogeneous dielectric properties and difficulties in slurry dispersion, LTCC systems with simple phase components were developed [54, 55, 56, 57, 58, 59, 60] (Table 7).
Compositions and physical properties of glass-free LTCC systems.
In a conventional LTCC system, glass was used as a matrix phase to lower the sintering temperatures below 1000°C because the functional dielectric ceramic materials were mostly fully densified at the high sintering temperatures, over 1200°C, where high electrically conductive metals such as Ag or Cu cannot be used as a matching electrode. LTCCs containing glass phase matrix generally exhibited low thermal conductivity as we have seen in Table 6. In the glass-free LTCCs, lowering the sintering temperature below 1000°C is a primary requirement without introducing secondary phases except the minor content of the sintering agent. Finding a low temperature synthesis and low temperature melting crystalline phase ceramic compound is a crucial point to develop glass-free LTCCs. Glass-free LTCC compositions applicable in the industry with proven mechanical properties and reliabilities are hardly found, even though several primary research results showing excellent dielectric properties were reported [54, 55, 56, 57, 58, 59, 60]. The substantial problems exposed in the previous glass-free LTCC systems are weak mechanical strength, reactive with matching electrode materials during heat treatment, and vulnerable in moisture environment.
In the calcium germinates and silicates system, the dielectric constants were 6.5–10.8, quality factor (Q × f) = 16,000–39,000 (@10 GHz), temperature coefficients of dielectric constant were 70–140 ppm/°C for samples sintered at 1180–1200°C, which are slightly higher temperatures for LTCC processing. These systems did not show any chemical reaction with Ag electrode. On the other hand, in the calcium tellurates system, the dielectric constants were 15.5–23.6, Q × f = 13,400–49,300 (~10 GHz), temperature coefficients of dielectric constant were 130–140 ppm/°C for samples sintered at 780–840°C; but this system was vulnerable at Ag electrode. The high temperature coefficients of dielectric constant were suppressed by the addition of 10 mol% of CaTiO3 [54].
For an AMP2O7 (A = Ca, Sr.; B = Zn, Cu) system, all of the compounds reacted with Ag but can be co-fired with Cu under reduced atmosphere. Among them, SrZnP2O7 sintered at 950°C exhibited a dielectric constant of 7.06, Q × f = 52,781 GHz, and temperature coefficient of resonance frequency (τf) = −70 ppm/°C; therefore, this compound can be modified into a temperature stable composition if a proper counter dielectric material with negative temperature coefficient is mixed with it. The thermal conductivity of this system was not provided [55].
In the LiMgPO4 tape sintered at 950°C, the microwave dielectric properties were, εr = 6.4, tan δ = 0.0002, CTE = 10.5 ppm/°C, and the thermal conductivity was 7.1 W/mK, which is twice as high as that of conventional glass–ceramic base LTCCs. The microwave dielectric properties of sintered tape were measured by using split post dielectric resonator (SPDR) method connected with a vector network analyzer [56].
Bi4(SiO4)3 glass-free LTCC tape system has shown dielectric constant of 13.3, loss (tan δ) of 0.0007 at 15GHz, and thermal conductivity of 2.82 W/mK [57]. The Li2MgTi3O8 glass-free ceramics sintered at 925°C exhibited a dielectric constant of 27, Q × f value of 58,480 GHz (@5.8 GHz), and very stable temperature coefficient of resonance frequency τf = 0.45 ppm/°C. This system is compatible with silver electrode [58]. Another Li-base glass-free LTCC is Li2.08 TiO3–LiF system, where the microwave dielectric properties of εr = 22.4, Q × f = 35,490 GHz were obtained at the 900°C sintered tape. The CTE and thermal conductivity of the system were 22.4 ppm/°C and 4.75 W/mK, respectively. The system also is compatible with silver electrode and has a high insulating rate of 50 kV/mm that has a potential in high power application. For the aforementioned glass-free system, the thermal conductivities obtained are 2.28–7.1 W/mK, which is well above that of the most of conventional glass–ceramic base LTCCs [59]. Zinc molybdate with 1% B2O3 that sintered at 850–900°C exhibited a dielectric constant of 11.1 CTE of 4.7 ppm/°C, and a break down voltage of 17.6 kV/mm. However, the thermal conductivity was relatively low, 1.4 W/mK, compared to the other glass-free LTCCs. This system may be applicable to high temperature insulating dielectrics due to low CTE and high break down voltage [60].
However, regardless of excellent dielectric and thermal properties, some of the glass-free LTCC compounds containing lithium element have a water soluble problem that limits the application. Therefore, they might need a protective layer coating to resist under weathering conditions.
3. Summary and future prospects
In this chapter, recent research and development works on high thermal conductivity ceramics and their composites for thermal management of integrated electronic packages are briefly explored. Key lessons drawn from these prior works can be summarized as follows:
3.1. High thermal conductivity bulk ceramics
Most frequently found HTCC base high thermal conductivity ceramics are alumina and nitride ceramics such as AlN, BN, and Si3N4 materials. Among them, silicon nitride ceramic seems the most frequently used in the power electronic applications these days. In nitrides and nitride based ceramic matrix composites, key parameters that control the thermal property are densification including pore removal, grain size and grain boundary control, impurity, and secondary phase control. Among them, densification is the primary factor to achieve high thermal conductivity due to high thermal resistance of pores. These nitride ceramics are difficult to sinter with high density so that spark plasma sintering and two-step sintering methods together with the addition of small amount of sintering aids should be applied to realize high densification. In nitride ceramics, controlling the oxygen content is a very important factor in addition to the parameters required in oxide materials.
In the LTCC-base materials, there are many research works on the development of high mechanical strength LTCC materials but few works are found in the improvement of thermal conductivity of LTCCs. Some works found in the literature are mainly on re-crystallization and phase control in the matrix and show only minor improvement in thermal properties compared with the noticeable enhancement in mechanical properties. The main reason for this minor change in thermal property in the conventional glass–ceramic type LTCC comes from the glass matrix which comprises more than half the volume of the sintered body. The volume fraction of newly evolved nano-crystalline phases through heat treatment process are so small that the overall apparent thermal conductivity might not change significantly while the mechanical strength can be easily boosted by the inclusion of the nano-crystalline phase in the matrix.
In thermally conductive and electrically conducting ceramics composites, the electrical conductivity was improved with the addition of 2D carbon allotropes like graphene nano sheet/platelet; however, the thermal conductivity was decreased with the involvement of graphene in the AlN matrix, which may be due to the thin interaction layer at the AlN–GNS/GNP interface that would cause thermal resistance. Large difference was observed between the in-plane and through-plane thermal conductivity of the composites as can be observed in the polymer/graphene composites.
3.2. Polymer matrix composites with high thermal conductivity
Polymer matrix composites with high thermal conductivity and electrically insulating ceramic filler materials are mostly used for dielectric insulation layers in LED packaging substrate for effective heat dissipation to the metallic heat spreading panels. Most frequently used insulating ceramic filler materials are alumina, BN, and AlN powders. Among them, BN platelet powders are preferred due to the anisotropic thermal conductivity behavior in the 2D structure of the BN crystal. Lots of researches have been focused on the tailored re-orientation of BN nanosheets in the BN/polymer solution into in-plane or through-plane of the BN/polymer composite tape using magnetic and electric field during casting process. Also, there are some efforts to coat ferrous or dielectric nano particles on BN platelet particles to promote the easy alignment of BN platelet particles into the intended direction. Surface modification of BN particles with functional organics such as silane coupling agent, dopamine, and secondary functional monomers are applied to enhance the thermal conductivity of the composites by improving the BN/polymer affinity and interfacial adhesion, thereby lowering interfacial heat resistance.
Polymer matrix composites with high thermal conductivity inorganic fillers such as CNT, graphite flake, and graphene nanosheets exhibited a great improvement in thermal conductivity with a little amount of additions. However, they are mostly electrically conducting so that they cannot be used for electrical circuit substrates. Instead, these composites are mainly used for thermal interface materials. These polymer/carbon allotropes base composites can also be used for flexible device application as well as rigid substrates since the morphology of carbonates filler particles are 1D or 2D.
3.3. High thermal conductivity ceramics for LED and IGBT packages
Ceramic materials used for applications in LED packages are typically of two types: dielectric insulating substrates for circuit forming bed and high thermal conductivity fillers for thermal interface material. The insulating ceramic substrates for IGBT modules mostly use alumina, AlN ceramics, but recent development moves to Si3N4 and LTCC for high power device due to reliability or low cost.
3.4. Future prospects
Regardless of the aforementioned progresses in the development and commercialization of ceramics, there are several challenges in the high thermal conductivity ceramic based heat transfer materials:
Continuous efforts in lowering costs and cost-effective processing of high temperature sintering HTCCs with high thermal conductivity are required in materials chemistry and innovative processing techniques. Compared to the HTCC based high thermal conductivity ceramics, LTCCs still require further enhancement in both thermal and mechanical characteristics in order to be adopted in thermal management applications. Since the major part of the conventional LTCC formulation consists of glass, the utmost thermal conductivity of the glass–ceramic filler composites thus obtained is limited and far below that of HTCC based high thermal conductivity ceramics. Therefore, first, we need to investigate ways to improve thermal conductivity of the glass phase itself as it is done in many polymer matrix composites. Second, the mechanical strength of LTCC should be further improved even though some results demonstrated enhanced mechanical strength via recrystallization process through the interfacial reaction and nucleation between glass phase and crystalline filler phase. Other challenges in high thermal conductivity LTCCs may be the development of non-glass base LTCCs, which have already been attempted earlier as applications in RF and microwave dielectric materials. The non-glass based LTCCs are exempted from the usage of low thermal conductivity glass matrix phase; they will exhibit higher thermal conductivity than the conventional type.
There are many reports that state the achievement of high thermal conductivities in polymer matrix composites using high thermal conductivity ceramic fillers. As a practical point of view, however, simply increasing thermal conductivity of ceramic filled polymer composites does not ensure the potential use in thermal management application, especially when they are used as thermal interface materials. Other factors, such as adhesion strength to the substrates or heat sink materials for TIM application and tensile strength of thermal tapes or flexible device substrates, also should be considered in addition to thermal and electrical properties since the more filler loading, the less adhesion and tensile strength is provided.
For insulated metal substrates (IMS) using high thermal conductivity ceramics, a reliable solution for CTE mismatch between ceramic and metal joining inducing delamination and crack generation failure in harsh conditions such as cyclic temperature environment is still required. In addition, for highly effective heat transfer performance IMS, we may need an ultra-thin insulation layer with high dielectric breakdown voltage together with high mechanical strength, which enables both low thermal resistance and low package profile of high power device and module.
Acknowledgments
This work was supported by the R&D convergence program of MSIP (Ministry of Science, ICT and Future Planning) and NST (National Research Council of Science & Technology) of the Republic of Korea (Grant No. CAP-13-02-ETRI).
Conflict of interest
None.
\n',keywords:"thermal conductivity, ceramics, composites, electronic, packaging",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/60539.pdf",chapterXML:"https://mts.intechopen.com/source/xml/60539.xml",downloadPdfUrl:"/chapter/pdf-download/60539",previewPdfUrl:"/chapter/pdf-preview/60539",totalDownloads:2326,totalViews:1926,totalCrossrefCites:2,totalDimensionsCites:6,totalAltmetricsMentions:0,introChapter:null,impactScore:2,impactScorePercentile:80,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"November 15th 2017",dateReviewed:"February 21st 2018",datePrePublished:null,datePublished:"June 27th 2018",dateFinished:"April 6th 2018",readingETA:"0",abstract:"Recently, ceramic substrates have been of great interest for use in light emitting diode (LED) packaging materials because of their excellent heat transfer capability. The thermal conductivities of ceramic-based substrates are usually one or two orders of magnitude higher than those of conventional epoxy-based substrates. The demand for ceramic substrates with high mechanical strength and thermal conductivity is also growing due to their use in thin and high-power device packaging substrates. Examples are direct bonded copper or aluminum or direct plated copper substrates for insulated gate bipolar transistors; thin and robust ceramic packages for image sensor modules that are used in mobile smart phones; ceramic packages for miniaturized chip-type supercapacitors; and high-power LED packages. This chapter will cover the development and application of ceramics and ceramic composites with high thermal conductivity for the thermal management of integrated electronic packaging substrates such as high-power LED packaging, power device packaging, etc.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/60539",risUrl:"/chapter/ris/60539",book:{id:"6631",slug:"heat-transfer-models-methods-and-applications"},signatures:"Hyo Tae Kim",authors:[{id:"234425",title:"Dr.",name:"Hyo Tae",middleName:null,surname:"Kim",fullName:"Hyo Tae Kim",slug:"hyo-tae-kim",email:"hytek@kicet.re.kr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Korea Institute of Ceramic Engineering and Technology",institutionURL:null,country:{name:"Korea, South"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. High thermal conductivity ceramics and their composites",level:"1"},{id:"sec_2_2",title:"2.1. Aluminum nitride (AlN) base ceramics and composites",level:"2"},{id:"sec_2_3",title:"Table 1.",level:"3"},{id:"sec_3_3",title:"Table 2.",level:"3"},{id:"sec_4_3",title:"Table 3.",level:"3"},{id:"sec_5_3",title:"2.1.4. AlN-BN base composites: electrically insulating",level:"3"},{id:"sec_7_2",title:"2.2. Polymer matrix composites with high thermal conductivity ceramic fillers",level:"2"},{id:"sec_7_3",title:"Table 5.",level:"3"},{id:"sec_8_3",title:"2.2.2. Polymer: AlN composites",level:"3"},{id:"sec_10_2",title:"2.3. LTCC ceramics with high thermal conductivity",level:"2"},{id:"sec_10_3",title:"Table 6.",level:"3"},{id:"sec_11_3",title:"Table 7.",level:"3"},{id:"sec_14",title:"3. Summary and future prospects",level:"1"},{id:"sec_14_2",title:"3.1. High thermal conductivity bulk ceramics",level:"2"},{id:"sec_15_2",title:"3.2. Polymer matrix composites with high thermal conductivity",level:"2"},{id:"sec_16_2",title:"3.3. High thermal conductivity ceramics for LED and IGBT packages",level:"2"},{id:"sec_17_2",title:"3.4. Future prospects",level:"2"},{id:"sec_19",title:"Acknowledgments",level:"1"},{id:"sec_22",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Franco Júnior A, Shanafield DJ. Thermal conductivity of polycrystalline aluminum nitride (AlN) ceramics. Cerâmica. 2004;50(315). DOI: 10.1590/S0366-69132004000300012'},{id:"B2",body:'Choi HS, Im HN, Kim YM, Chavan A, Song SJ. Structural, thermal and mechanical properties of aluminum nitride ceramics with CeO2 as as sintering aid. Ceramics International. 2016;42:11519-11524. DOI: 10.1016/j.ceramint.2016.04.028'},{id:"B3",body:'He X, Yea F, Zhanga H, Liu L. Effect of Sm2O3 content on microstructure and thermal conductivity of spark plasma sintered AlN ceramics. Journal of Alloys and Compounds. 2009;482:345-348. DOI: 10.1016/j.jallcom.2009.04.013'},{id:"B4",body:'Kobayashi R, Ohishi K, Tu R, Goto T. 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Low-temperature sintering and microwave dielectric propertiesof zinc metatitanate-rutile mixtures using boron. The Journal of the American Ceramic Society. 1999;82(11):3043-3048. DOI: 10.1111/j.1151-2916.1999.tb02200.x'},{id:"B48",body:'Mukhopadhyay A, Otieno G, Chu BTT, Wallwork A, Green MLH, Todd RI. Thermal and electrical properties of aluminoborosilicate glass–ceramics containing multiwalled carbon nanotubes. Scripta Materialia. 2011;65:408-411. DOI: 10.1016/j.scriptamat.2011.05.023'},{id:"B49",body:'Ma M, Liu Z, Li Y, Zeng Y, Yao D. Thermal conductivity of low-temperature sintered calcium aluminosilicate glass–silicon nitride whisker composites. Ceramics International. 2013;39:4683-4687. DOI: 10.1016/j.ceramint.2012.11.056'},{id:"B50",body:'Arun S, Sebastian MT, Surendran KP. Li2ZnTi3O8 based high κ LTCC tapes for improved thermal management in hybrid circuit applications. Ceramics International. 2017;43:5509-5516. DOI: 10.106/j.ceramint.2017.01.073'},{id:"B51",body:'Feng D, Li Z, Zhu Y, Ji H. Influence of diamond particle size on the thermal and mechanical properties of glass-diamond composites. Materials Science and Engineering B. 2018;227:122-128. DOI: 10.1016/j.mseb.2017.10.017'},{id:"B52",body:'Wang S, Zhang D, Ouyang X, Wang Y, Liu G. Effect of one-dimensional materials on the thermal conductivity of Al2O3/glass composite. Journal of Alloys and Compounds. 2016;667:23-28. DOI: 10.1016/j.jallcom.2016.01.120'},{id:"B53",body:'Ma M, Liu Z, Li Y, Zeng Y, Yao D. Enhanced thermal conductivity of low-temperature sintered borosilicate glass–AlN composites with β-Si3N4 whiskers. Journal of the European Ceramic Society. 2013;33:833-839. DOI: 10.1016/j.jeurceramsoc.2012.09.030'},{id:"B54",body:'Valant M, Suvorov D. Glass-free low-temperature cofired ceramics: Calcium germanates, silicates and tellurates. Journal of the European Ceramic Society. 2004;24:1715-1719. DOI: 10.1016/S0955-2219(03)00483-7'},{id:"B55",body:'Bian JJ, Kim DW, Hong KS. Glass-free LTCC microwave dielectric ceramics. Materials Research Bulletin. 2005;40:2120-2129. DOI: 10.1016/j. materresbull.2005.07.003'},{id:"B56",body:'Thomas D, Abhilash P, Sebastian MT. Casting and characterization of LiMgPO4 glass free LTCC tape for microwave applications. Journal of the European Ceramic Society. 2013;33:87-93. DOI: 10.1016/j.jeurceramsoc.2012.08.002'},{id:"B57",body:'Abhilash P, Sebastian MT, Surendran KP. Glass free, non-aqueous LTCC tapes of Bi4(SiO4)3 with high solid loading. Journal of the European Ceramic Society. 2015;35:2313-2320. DOI: 10.106/j.jeurceramsoc.2015.02.002'},{id:"B58",body:'Zhou H, Wang N, Gong J, Fan G, Chen X. Processing of low-fired glass-free Li2MgTi3O8 microwave dielectric ceramics. Journal of Alloys and Compounds. 2016;688:8-13. DOI: 10.1016/j.jallcom.2016.07.214'},{id:"B59",body:'Bian JJ, Yu Q, He JJ. 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1. Introduction
Immunisation, a key primary healthcare component and an indisputable human right, is a public health achievement of the 20th century saving millions of lives every year. Vaccines and immunisation programmes currently prevent 3.5 to 5 million deaths every year from diseases like diphtheria, tetanus, pertussis, influenza, and measles. Also, they have prevented major epidemics of life-threatening diseases since the beginning of their widespread use in the 1900s underpinning global health security. Vaccines are now available to prevent more than 20 life-threatening diseases and are a vital tool in the battle against antimicrobial resistance.
The history of public concerns about and questioning vaccines, however, is as old as vaccines themselves. Modern communication systems have only accelerated anxieties about vaccine safety and its regulation. This has resulted in pockets of people who are reluctant or refuse recommended vaccination(s), or who chose to delay some vaccines. The SAGE Working Group on Vaccine Hesitancy documented that any delay in acceptance or refusal of vaccination despite the availability of vaccination services is vaccine hesitancy. It is complex and context-specific, varying across time, place, and vaccines. Interestingly, the Working Group retained the term ‘vaccine’ rather than ‘vaccination’ hesitancy, although the latter more correctly implies the broader range of immunisation concerns [1].
It is important to monitor the reasons why a substantial number of people hesitate to receive recommended vaccinations. This allows identification of important trends over time and designing and evaluation strategies to address vaccine hesitancy and thereby increase vaccine uptake. Empirical and theoretical frameworks that assess vaccine hesitancy focus primarily on confidence in vaccines and the system that delivers them. It is essential to acknowledge that confidence covers trust in vaccines including concerns about vaccine safety, trust in healthcare workers delivering the vaccine, and in those making the decisions to approve of vaccines for a population. Vaccination behaviour can be explained by complacency (not perceiving diseases as high risk), constraints (structural and psychological barriers), the calculation (engagement in extensive information searching), and aspects pertaining to collective responsibility (willingness to protect others). These are the five main personal determinants for vaccine hesitancy [2]. To add to it would be vaccination convenience. The physical availability of vaccines, geographical accessibility, affordability and willingness-to-pay, ability to understand or comprehend that is, language and health literacy and ability of the immunisation services to appeal may affect vaccine uptake. In addition, the actual or perceived quality of the service and the degree to which vaccination services are delivered at a time and place within a cultural context that is convenient and comfortable may also affect the decision to be vaccinated and could lead to vaccine hesitancy.
Vaccine hesitancy is a continuum with those who accept all with no doubts and refuse all vaccines with no doubts as extremes (Figure 1). This may include a proportion who accept or completely refuse vaccines but are unsure. Between the extremes are those vaccine-hesitant individuals who accept some, delay or refuse some vaccines. While high levels of hesitancy lead to low vaccine demand, low levels of hesitancy do not necessarily mean high vaccine demand [3].
Figure 1.
Vaccine hesitancy continuum.
2. Determinants of vaccine hesitancy
Provided that vaccine hesitancy is complex and context-specific it may be influenced by historic, socio-cultural, psychosocial, family, environmental, health system or institutional, economic, or political factors. Apart from these contextual factors, individual or group and vaccine or vaccination-specific concerns may also determine vaccine hesitancy. Taking about individual and group influences, they may arise from personal or social or peer perceptions of the vaccine (Table 1) [3].
Contextual factors
Communication and media environment (including social media)
Influential leaders (local or central), immunisation programme gatekeepers and anti- or pro-vaccination lobbies
Historical influences
Religion/culture/gender/socio-economic
Socio-cultural/psychosocial
Family
Perception of the pharmaceutical industry
Politics
Health and other related policies
Geographic barriers
Individual and group factors
Personal, family and/or community members’ experience with vaccination (ranging from local pain or swelling to high grade fever, to anaphylaxis)
Knowledge and/or awareness
Beliefs and attitudes in relation to health and disease prevention
Perceived or heuristic risks and benefits
Health system and healthcare providers – trust and personal experience
Immunisation as a social norm versus not needed or harmful
Vaccine and vaccination-related factors
Epidemiological and scientific evidence in relation to risks and benefits
Organisation structure of the vaccination programme and its mode of delivery (for example, routine programme or mass vaccination campaign)
Introduction of a new vaccine or new formulation or a new recommendation for an existing vaccine
Vaccination schedule
Mode of administration (for example, oral or intramuscular injection)
Reliability and/or source of supply of vaccine and/or vaccination equipment
The strength of the recommendation and/or knowledge base and/or attitude of healthcare professionals
Direct and indirect costs
Table 1.
Determinants of vaccine hesitancy.
3. COVID-19 vaccine hesitancy
COVID-19 vaccine hesitancy is real. In a meta-analysis that computed the overall COVID-19 vaccine acceptance rate across the US, the vaccine acceptance was as low as 12% and higher up to 91% [4]. Similarly, in a community-based sample of the American adult population, it was found that the likelihood of getting a COVID-19 immunisation was 52% very likely and 22% not likely or not, with individuals having lower education, income, or perceived threat of getting infected being more likely to report that they were not likely to not going to get COVID-19 vaccine (that is, vaccine hesitancy) [5]. A multi-country study of six Southeast Asian countries showed that the majority (84%) would accept COVID-19 vaccines. However, the variation between countries was significant with the lowest rates reported in Vietnam (27%) and the highest rates reported in Russia (72%) [6]. The disparities in inter-regional and inter-country (even within countries) COVID-19 vaccine hesitancy has been well documented. In a global cross-sectional study that included participants from seventeen countries across regions, it was found that participants from China (95.3%), Australia (96.4%), and Norway (95.3%) were most likely to get COVID-19 vaccination. However, participants from United States (29.4%), Japan (34.6%), and Iran (27.9%) were least likely to get vaccinated or in other words likely to be vaccine hesitant [7]. In a nationwide survey reported from India, only 30% of adults had no issue with the COVID-19 vaccine or vaccination [8]. This finding corroborates with the neighbouring nation Bangladesh where the reported prevalence of vaccine hesitancy was 46.2% [9]. The overall prevalence of COVID-19 vaccine hesitancy among Chinese adults was modest at 8.4% (95% CI, 8.09 to 8.72) for primary vaccination and 8.4% (95% CI, 8.07 to 8.70) for booster vaccination [10]. COVID-19 vaccine hesitancy has been particularly higher among older people (27.0%, 95% CI 15.1 to 38.9) [11].
3.1 Quantifying COVID-19 vaccine hesitancy
A literature search revealed few efforts aimed at quantifying vaccine hesitancy in the population [12, 13]. Firstly, the vaccine hesitancy index (VHI) was constructed using population characteristics aligned with factors identified by an Office for National Statistics (ONS) survey analysis; the factors included in the index were population under fifty, the proportion of Black or African or Caribbean ethnic population, children under five, population with less than degree level qualification and rental housing (social or private as a proportion of the total population) [14]. This was an improved version of the earlier published COVID-19 vulnerability index (VI) that considered income domain indicators and long-term illness [15].
3.2 Predictors of COVID-19 vaccine hesitancy
The data relating to the safety and efficacy of vaccines against COVID-19 are largely from high-income countries. In addition, the rapid pace of vaccine development has been highlighted in the literature as the primary reason for COVID-19 vaccine hesitancy. A COVID-19 vaccination acceptance and hesitancy survey including data from 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa, South America, Russia (an upper-middle-income country) and the United States reported that there was considerably higher willingness to take a COVID-19 vaccine in LMIC samples (mean 80.3%; median 78%; range 30.1%) compared with the United States (mean 64.6%) and Russia (mean 30.4%). The primary reason for acceptance was explained by interest in personal protection against COVID-19, whereas concerns in relation to side effects resulted in hesitancy [16]. It is, however, important to note that reported intentions may not always translate into vaccine uptake [17]. These findings corroborate a study conducted by Africa Centres for Disease Control and Prevention, in partnership with the London School of Hygiene and Tropical Medicine, in 15 African nations. More than three-fourths (79%) of respondents in Africa would be vaccinated against COVID-19 if it were deemed safe and effective. This may be explained based on lived experience in LMICs, where many vaccine-preventable infectious diseases are still a leading cause of morbidity and mortality, resulting in a higher perceived need for or value of vaccines [18]. However, in contrast, many people including medical professionals from high-income countries have not seen the devastating effects of these diseases in their respective countries. This is because they have successfully eliminated or eradicated numerous vaccine-preventable diseases. As a consequence resulting in altered risk calculations, complacency and limited collective responsibility about vaccination decision-making [18, 19]. In a survey among the United Kingdom (UK) adults that assessed their religious and political beliefs as well as their eagerness, willingness, and hesitance to take various global COVID-19 vaccines it was found that social media use does have an effect on perceived knowledge about vaccines as well as on vaccine hesitancy (especially Twitter!). People also express concerns over the trustworthiness of foreign vaccine production and testing protocols [20].
Evidence shows that 38%, 21%, 13%, and 11% variance in COVID-19 vaccine hesitancy can be explained by vaccine confidence, vaccine complacency, sociodemographic, and other psychological factors respectively [21]. Right-wing political affiliation, higher risk propensity, and less negative mental health effects of the COVID-19 pandemic were the principal sociodemographic and psychological determinants of COVID-19 vaccine hesitancy. Other sociodemographic determinants include younger age, women, race, and employment status. However, this particular study failed to examine the variance explained by vaccine convenience factors like availability, accessibility, affordability, willingness to pay, language, and health literacy [21]. Similarly, the willingness to vaccinate among Chinese adults was associated with gender (being women), higher levels of education, married residents, increased washing hands, never smoking, a higher score of health condition, increased wearing masks, higher level of convenient vaccination, increased social distance, disease risks outweigh vaccine risk, lower level of vaccine conspiracy beliefs, and a higher level of trust in doctor and developer [10].
In a study that assessed the intention to vaccinate for different effectiveness scenarios and side effects using the health belief model, it was found that the probability of rejecting a vaccine or indecision in relation to vaccine uptake were associated with the severity of COVID-19. This includes, but not limited to, adverse side effects and effectiveness of the vaccine; decreased fear of contagion, perceived benefits including immunity, and the protection of oneself and the social environment; available information, specialists’ recommendations; action signals, such as responses from ones’ family and the government; and susceptibility, including the contagion rate per 1000 population. The vaccine scenarios used in the study revealed that the individuals preferred less risky vaccines in terms of fewer side effects, rather than effectiveness [22].
In a cross-sectional study that aimed at determining the predictors of COVID-19 vaccine hesitancy among pregnant women it was found that, vaccine hesitant women are younger and further along in pregnancy. COVID-19 vaccine hesitant pregnant women also reported hesitancy for influenza and Tdap vaccines. Vaccine hesitancy was associated with lack of information to take an informed decision, personal long term side effects, short and long term side effects on the pregnancy, and harmful ingredients in the vaccine [23].
In a qualitative analysis that explored the intention to receive or not receive COVID-19 vaccine among Malaysians using an integrated framework of theory of reasoned action and health belief model, it was found that the predictors of vaccine hesitancy were age, religious beliefs, subjective norms, susceptibility, attitude, and vaccine confidence or trust [24]. In contrast to the findings of a global survey from seventeen countries which reported increasing vaccine hesitancy with increase in age [7], this study reported that the vaccine hesitancy was higher among those young, primarily driven by perceived (low) risk of COVID-19. The study also stressed the importance of social influence; an individual is more likely to get vaccinated if one or the other in his/her closest circle is either vaccinated or intend to get vaccinated [24].
A population based cross-sectional study from Germany reported predictors of COVID-19 vaccine hesitancy among adults more than or equal to 18 years of age. Regression analysis showed that the odds of willingness to get vaccinated were lower for females in comparison to males; however, participants of older age group, higher education, health literacy, and adherence to preventive measures increased the odds of willingness to get vaccinated [25].
Vaccine hesitancy or say vaccine acceptance, be in at individual level or societal level is driven by complex factors. The Royal Society of Canada Framework (an adapted version of Hasnan and Tan framework) discusses COVID-19 vaccine acceptance as shown in Figure 2. The four major domains of factors that influence vaccine acceptance are immunisation knowledge (highlighting the importance of vaccine related reliable information, that is, easily accessible, up-to-date, and accurate tailored for each target group), healthcare workers, people in place (in accordance with the goal of the World Health Organisation Immunisation Agenda 2030) and the health care system (highlighting the role of immunisation programmes, health legislations and policies) [26]. Each of these major domains influence each other and none of these stand alone; the intersections are highlighted in white boxes. The blue circle illustrate the broader context under which each of the major domain is influenced, which includes, but not limited to, education, control of infection, communication, and communities [27, 28].
Figure 2.
Framework of factors that influence vaccine acceptance.
4. Implications for routine immunisation
The implications of the COVID-19 pandemic and its vaccine hesitancy against routine immunisation is multi-modal – one, the pandemic and related movement restrictions or other mitigation measures, partial or complete suspension of vaccination clinics or fear of COVID-19, stress, anxiety, and depression may have limited parents access to avail routine immunisation vaccines for their children [29, 30]. In a data triangulated from global, country-based, and individual-reported sources during the pandemic period, it was found that there was a decline in the number of administered doses of diphtheria pertussis tetanus-containing vaccine (DTP3) (33% fewer doses in April 2020) and the first dose of measles-containing vaccine (MCV1) (9–57% fewer doses) in the early part of 2020 [31]. The primary reason reported by WHO regional offices were substantial disruption to routine vaccination sessions, and in particular, related to interrupted vaccination demand and supply, including reduced availability of the health workforce. Similarly, a systematic review reported a decline or delay in vaccination at the time of the COVID-19 pandemic, highlighting the need for a sustained catch-up program, especially in low- and middle-income countries [32].
Secondly, the impact of COVID-19 vaccine hesitancy is not limited to pandemic vaccines but may continue to extend to routinely recommended vaccines. Though certain studies found increased vaccine confidence in parents for routine childhood vaccines as compared to the COVID-19 vaccine, certain studies highlight the concern of COVID-19 vaccine hesitancy rubbing off on routine immunisation vaccine hesitancy [33, 34, 35, 36]. In a study that attempted to understand the impact of the pandemic on routine childhood vaccine hesitancy, it was found that the routine childhood vaccine hesitancy increased during the COVID-19 pandemic, mainly due to increased risk perception [37, 38].
It is the need of the hour to leverage COVID-19 vaccination awareness campaigns to include routine immunisation call-to-action messages [39]. Clear communication between public health authorities, providers, and the general public, and from providers to parents or caregivers on the value, safety, and necessity of routine immunisation will remain a critical piece to help alleviate concerns and address vaccine hesitancy. Engaging local leaders in the community may help resonate with public health messages related to the importance of routine vaccines, especially when the discussion around public health becomes tainted with political and/or non-medical aspects. In this process of communication, it is important to maintain a delicate balance between what is known and acknowledging the uncertainties that remain. Easing societal restrictions where possible, taking the necessary steps to reach standard marketing authorization, offering a fixed monetary reward as an incentive, involving physicians in the vaccination campaign, and focusing on vaccine effectiveness while communicating risks clearly and transparently are recommended as measures to reduce vaccine hesitancy [40].
Overall, the strategies include offering pre-structured, pre-tested communication from community trusted sources such as healthcare providers, local representatives, and authorities. It should be ensured that they are culturally relevant, accessible and in multiple languages. It is important to improve the accessibility of population to vaccines and vaccine related information. This should be made possible through adoption of flexible, context specific delivery models. The success of these strategies are rested with training and education of those involved and community engagement. It is necessary to involve youth ambassadors, healthcare workers, community champions and faith leaders to raise knowledge and awareness on vaccinations. Vaccination of friends, relatives and household members should be celebrated; an approach of community immunity should be fostered; aided by locally developed action plans with a continuous, open, and transparent dialogue [41].
5. Conclusion
The implications of contextual factors, individual and group factors, vaccine, and vaccination related factors on vaccine hesitancy is long recognised. However, the additive or multiplicative, multi-modal implications of COVID-19 vaccine hesitancy on routine immunisation is less recognised. It is the need of the hour to leverage COVID-19 vaccination awareness campaigns to include routine immunisation call-to-action messages with effective monitoring and evaluation aided by implementation research strategies. The areas that should be strengthened to restore and maintain vaccine confidence includes trust in health care provider–patient encounters, public health messaging, vaccine mandates, diversity, inclusion, and representation in health sectors, and industry influence on health care.
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We also discuss the multimodal nature of the COVID-19 pandemic and its vaccine hesitancy-related implications on routine immunisation. The pandemic and related movement restrictions or other mitigation measures, partial or complete suspension of vaccination clinics or fear of COVID-19, stress, anxiety, and depression may have limited parents’ access to avail routine immunisation vaccines for their children. Also, the impact of COVID-19 vaccine hesitancy is not limited to pandemic vaccines but may continue to extend to routinely recommended vaccines.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82919",risUrl:"/chapter/ris/82919",signatures:"Mohan Kumar and V.L. Surya",book:{id:"11724",type:"book",title:"COVID-19 Vaccines - Current State and Perspectives",subtitle:null,fullTitle:"COVID-19 Vaccines - Current State and Perspectives",slug:null,publishedDate:null,bookSignature:"Prof. Ibrokhim Y. 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Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Shen SC, Dubey V. Addressing vaccine hesitancy: Clinical guidance for primary care physicians working with parents. Canadian Family Physician. 2019;65(3):175-181'},{id:"B2",body:'Betsch C, Schmid P, Heinemeier D, Korn L, Holtmann C, Böhm R. Beyond confidence: Development of a measure assessing the 5C psychological antecedents of vaccination. PLoS One. 2018;13(12):e0208601. DOI: 10.1371/journal.pone.0208601'},{id:"B3",body:'Mac Donald NE. Vaccine hesitancy: Definition, scope and determinants. Vaccine. 2015;33(34):4161-4164. DOI: 10.1016/j.vaccine.2015.04.036'},{id:"B4",body:'Yasmin F et al. COVID-19 vaccine hesitancy in the United States: A systematic review. Frontiers in Public Health Systematic Review. 2021;9:770985. DOI: 10.3389/fpubh.2021.770985'},{id:"B5",body:'Khubchandani J, Sharma S, Price JH, Wiblishauser MJ, Sharma M, Webb FJ. COVID-19 vaccination hesitancy in the United States: A rapid national assessment. Journal of Community Health. 2021;46(2):270-277. DOI: 10.1007/s10900-020-00958-x'},{id:"B6",body:'Marzo RR et al. Hesitancy in COVID-19 vaccine uptake and its associated factors among the general adult population: A cross-sectional study in six southeast Asian countries. Tropical Medicine and Health. 2022;50(1):4. DOI: 10.1186/s41182-021-00393-1'},{id:"B7",body:'Wong LP et al. COVID-19 vaccination intention and vaccine characteristics influencing vaccination acceptance: A global survey of 17 countries. Infectious Diseases of Poverty. 2021;10(1):122. DOI: 10.1186/s40249-021-00900-w'},{id:"B8",body:'Chandani S et al. COVID-19 vaccination hesitancy in India: State of the nation and priorities for research. Brain Behaviour, & Immunity Health. 2021;18:100375-100375. DOI: 10.1016/j.bbih.2021.100375'},{id:"B9",body:'Hossain MB et al. COVID-19 vaccine hesitancy among the adult population in Bangladesh: A nationwide cross-sectional survey. PLoS One. 2021;16(12):e0260821. DOI: 10.1371/journal.pone.0260821'},{id:"B10",body:'Wu J et al. COVID-19 vaccine hesitancy among Chinese population: A large-scale national study. Frontiers in Immunology Original Research. 2021;12:781161. DOI: 10.3389/fimmu.2021.781161'},{id:"B11",body:'Veronese N et al. Prevalence of unwillingness and uncertainty to vaccinate against COVID-19 in older people: A systematic review and meta-analysis. Ageing Research Reviews. 2021;72:101489. DOI: 10.1016/j.arr.2021.101489'},{id:"B12",body:'Acharya R, Porwal A. "a vulnerability index for the management of and response to the COVID-19 epidemic in India: An ecological study," the lancet. Globalization and Health. 2020;8(9):e1142-e1151. DOI: 10.1016/S2214-109X(20)30300-4'},{id:"B13",body:'Macharia PM, Joseph NK, Okiro EA. A vulnerability index for COVID-19: Spatial analysis at the subnational level in Kenya. BMJ Global Health. 2020;5(8):e003014. DOI: 10.1136/bmjgh-2020-003014'},{id:"B14",body:'Daras K, Alexiou A, Rose TC, Buchan I, Taylor-Robinson D, Barr B. How does vulnerability to COVID-19 vary between communities in England? Developing a small area vulnerability index (SAVI). Journal of Epidemiology and Community Health. 2021;75(8):729-734'},{id:"B15",body:'Welsh CE, Sinclair DR, Matthews FE. Static socio-ecological COVID-19 vulnerability index and vaccine hesitancy index for England. The Lancet Regional Health – Europe. 2022;14:100296. DOI: 10.1016/j.lanepe.2021.100296'},{id:"B16",body:'Solís Arce JS et al. COVID-19 vaccine acceptance and hesitancy in low- and middle-income countries. Nature Medicine. 2021;27(8):1385-1394. DOI: 10.1038/s41591-021-01454-y'},{id:"B17",body:'McEachan RRC, Conner M, Taylor NJ, Lawton RJ. Prospective prediction of health-related behaviours with the theory of planned behaviour: A meta-analysis. Health Psychology Review. 2011;5(2):97-144. DOI: 10.1080/17437199.2010.521684'},{id:"B18",body:'"COVID 19 Vaccine Perceptions: A 15 country study." Avaialble from: https://africacdc.org/download/covid-19-vaccine-perceptions-a-15-country-study/. [Accessed: June11, 2022].'},{id:"B19",body:'Machingaidze S, Wiysonge CS. Understanding COVID-19 vaccine hesitancy. Nature Medicine. 2021;27(8):1338-1339. DOI: 10.1038/s41591-021-01459-7'},{id:"B20",body:'Bullock J, Lane JE, Shults FL. What causes COVID-19 vaccine hesitancy? Ignorance and the lack of bliss in the United Kingdom. Humanities and Social Sciences Communications. 2022;9(1):87. DOI: 10.1057/s41599-022-01092-w'},{id:"B21",body:'Gerretsen P et al. Individual determinants of COVID-19 vaccine hesitancy. PLoS One. 2021;16(11):e0258462-e0258462. DOI: 10.1371/journal.pone.0258462'},{id:"B22",body:'Cerda AA, García LY. Hesitation and refusal factors in Individuals\' decision-making processes regarding a coronavirus disease 2019 vaccination. Frontiers in Public Health, Original Research. 2021;9:626852. DOI: 10.3389/fpubh.2021.626852'},{id:"B23",body:'Sutanto M, Hosek MG, Stumpff S, Ramsey PS, Boyd A, Neuhoff BK. Predictors of COVID-19 vaccine hesitancy and top concerns in pregnant women at a South Texas clinic [A128]. Obstetrics & Gynecology. 2022;139:37S-38S'},{id:"B24",body:'Ng JWJ, Vaithilingam S, Nair M, Hwang L-A, Musa KI. Key predictors of COVID-19 vaccine hesitancy in Malaysia: An integrated framework. PLoS One. 2022;17(5):e0268926. DOI: 10.1371/journal.pone.0268926'},{id:"B25",body:'Umakanthan S, Lawrence S. Predictors of COVID-19 vaccine hesitancy in Germany: A cross-sectional, population-based study. Postgraduate Medical Journal. 2022. DOI: 10.1136/postgradmedj-2021-141365. Available from: https://pmj.bmj.com/content/early/2022/02/02/postgradmedj-2021-141365'},{id:"B26",body:'Dubé E, MacDonald NE. COVID-19 vaccine hesitancy. Nature Reviews Nephrology. 2022;18(7):409-410. DOI: 10.1038/s41581-022-00571-2'},{id:"B27",body:'Hasnan S, Tan NC. Multi-domain narrative review of vaccine hesitancy in childhood. Vaccine. 2021;39, 1(14):1910-1920. DOI: 10.1016/j.vaccine.2021.02.057'},{id:"B28",body:'MacDonald NE et al. Royal society of Canada COVID-19 report: Enhancing COVID-19 vaccine acceptance in Canada. FACETS. 2021;6:1184-1246. DOI: 10.1139/facets-2021-0037'},{id:"B29",body:'Mansour Z et al. Impact of COVID-19 pandemic on the utilization of routine immunization services in Lebanon. PLoS One. 2021;16(2):e0246951. DOI: 10.1371/journal.pone.0246951'},{id:"B30",body:'Rodríguez-Hidalgo AJ, Pantaleón Y, Dios I, Falla D. Fear of COVID-19, stress, and anxiety in university undergraduate students: A predictive model for depression. Frontiers in Psychology, Original Research. 2020;11:591797. DOI: 10.3389/fpsyg.2020.591797'},{id:"B31",body:'Shet A et al. Impact of the SARS-CoV-2 pandemic on routine immunisation services: Evidence of disruption and recovery from 170 countries and territories. The Lancet Global Health. 2022;10(2):e186-e194. DOI: 10.1016/S2214-109X(21)00512-X'},{id:"B32",body:'SeyedAlinaghi S et al. Impact of COVID-19 pandemic on routine vaccination coverage of children and adolescents: A systematic review. Health Science Reports. 2022;5(2):e00516. DOI: 10.1002/hsr2.516'},{id:"B33",body:'Temsah M-H et al. Parental attitudes and hesitancy about COVID-19 vs. routine childhood vaccinations: A National Survey. Frontiers in Public Health Original Research. 2021;9:752323. DOI: 10.3389/fpubh.2021.752323'},{id:"B34",body:'Badur S, Ota M, Öztürk S, Adegbola R, Dutta A. Vaccine confidence: The keys to restoring trust. Human Vaccines & Immunotherapeutics. 2020;16(5):1007-1017. DOI: 10.1080/21645515.2020.1740559'},{id:"B35",body:'Olusanya OA, Bednarczyk RA, Davis RL, Shaban-Nejad A. Addressing parental vaccine hesitancy and other barriers to childhood/adolescent vaccination uptake during the coronavirus (COVID-19) pandemic. Frontiers in Immunology. 2021;12:663074. DOI: 10.3389/fimmu.2021.663074'},{id:"B36",body:'Saurish SMVA, Amoghashree MR, Narayanamurthy, Gopi A. “Did this pandemic trigger a spike in mothers′ hesitancy over their children’s routine immunizations? -A cross sectional study.” Clinical Epidemiology and Global Health. 2022;15:101023. DOI: 10.1016/j.cegh.2022.101023'},{id:"B37",body:'He K, Mack WJ, Neely M, Lewis L, Anand V. Parental perspectives on immunizations: Impact of the COVID-19 pandemic on childhood vaccine hesitancy. Journal of Community Health. 2022;47(1):39-52. DOI: 10.1007/s10900-021-01017-9'},{id:"B38",body:'Karafillakis E, Van Damme P, Hendrickx G, Larson HJ. COVID-19 in Europe: New challenges for addressing vaccine hesitancy. The Lancet. 2022;399(10326):699-701. DOI: 10.1016/S0140-6736(22)00150-7'},{id:"B39",body:'MOC Ota, Badur S, Romano- Mazzotti L, Friedland LR. “impact of COVID-19 pandemic on routine immunization,” (in eng). Annals of Medicine. Dec 2021;53(1):2286-2297. DOI: 10.1080/07853890.2021.2009128'},{id:"B40",body:'Stamm TA, Partheymüller J, Mosor E, Ritschl V, Kritzinger S, Eberl J-M. Coronavirus vaccine hesitancy among unvaccinated Austrians: Assessing underlying motivations and the effectiveness of interventions based on a cross-sectional survey with two embedded conjoint experiments. The Lancet Regional Health – Europe. 2022;17:100389. DOI: 10.1016/j.lanepe.2022.100389'},{id:"B41",body:'Razai MS, Chaudhry UAR, Doerholt K, Bauld L, Majeed A. Covid-19 vaccination hesitancy. BMJ. 2021;373:n1138. DOI: 10.1136/bmj.n1138'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mohan Kumar",address:"kumar.mohan324@gmail.com",affiliation:'
Department of Community Medicine, KMCH Institute of Health Sciences and Research, India
Department of Microbiology, Coimbatore Medical College and Hospital, India
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As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Waisundara and Miljana Z. Jovandaric",coverURL:"https://cdn.intechopen.com/books/images_new/10111.jpg",editedByType:"Edited by",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:27,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"38573",doi:"10.5772/51687",title:"Food Phenolic Compounds: Main Classes, Sources and Their Antioxidant Power",slug:"food-phenolic-compounds-main-classes-sources-and-their-antioxidant-power",totalDownloads:10269,totalCrossrefCites:42,totalDimensionsCites:115,abstract:null,book:{id:"3203",slug:"oxidative-stress-and-chronic-degenerative-diseases-a-role-for-antioxidants",title:"Oxidative Stress and Chronic Degenerative Diseases",fullTitle:"Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants"},signatures:"Maria de Lourdes Reis Giada",authors:[{id:"153687",title:"Associate Prof.",name:"Maria De Lourdes",middleName:"Reis",surname:"Giada",slug:"maria-de-lourdes-giada",fullName:"Maria De Lourdes Giada"}]},{id:"39159",doi:"10.5772/51788",title:"Oxidative Stress in Diabetes Mellitus and the Role Of Vitamins with Antioxidant Actions",slug:"oxidative-stress-in-diabetes-mellitus-and-the-role-of-vitamins-with-antioxidant-actions",totalDownloads:6348,totalCrossrefCites:19,totalDimensionsCites:40,abstract:null,book:{id:"3203",slug:"oxidative-stress-and-chronic-degenerative-diseases-a-role-for-antioxidants",title:"Oxidative Stress and Chronic Degenerative Diseases",fullTitle:"Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants"},signatures:"Maria-Luisa Lazo-de-la-Vega-Monroy and Cristina Fernández-Mejía",authors:[{id:"46162",title:"Dr.",name:"Maria-Luisa",middleName:null,surname:"Lazo-De-La-Vega-Monroy",slug:"maria-luisa-lazo-de-la-vega-monroy",fullName:"Maria-Luisa Lazo-De-La-Vega-Monroy"}]},{id:"66369",doi:"10.5772/intechopen.84255",title:"General Perception of Liposomes: Formation, Manufacturing and Applications",slug:"general-perception-of-liposomes-formation-manufacturing-and-applications",totalDownloads:3320,totalCrossrefCites:17,totalDimensionsCites:40,abstract:"Liposomes are currently part of the most reputed carriers for various molecular species, from small and simple to large and complex molecules. Since their discovery, liposomes have been subject to extensive evolution, in terms of composition, manufacturing and applications, which led to several openings in both basic and applied life sciences. However, most of the advances in liposome research have been more devoted to launching new developments than improving the existing technology for potential implementation. For instance, the evolution of the conventional lipid hydration methods to novel microfluidic technologies has permitted upscale production, but with increase in manufacturing cost and persistent use of organic solvents. This chapter intends to present general concepts in liposome technology, highlighting some longstanding bottlenecks that remain challenging to the preparation, characterization and applications of liposomal systems. This would enhance the understanding of the gaps in the field and, hence, provide directions for future research and developments.",book:{id:"8095",slug:"liposomes-advances-and-perspectives",title:"Liposomes",fullTitle:"Liposomes - Advances and Perspectives"},signatures:"Christian Isalomboto Nkanga, Alain Murhimalika Bapolisi, Nnamdi Ikemefuna Okafor and Rui Werner Maçedo Krause",authors:[{id:"284670",title:"Prof.",name:"Rui",middleName:null,surname:"Krause",slug:"rui-krause",fullName:"Rui Krause"},{id:"284672",title:"Mr.",name:"Alain",middleName:null,surname:"Bapolisi",slug:"alain-bapolisi",fullName:"Alain Bapolisi"},{id:"284673",title:"MSc.",name:"Christian",middleName:null,surname:"Nkanga",slug:"christian-nkanga",fullName:"Christian Nkanga"},{id:"284675",title:"Mr.",name:"Okafor",middleName:null,surname:"Nnamdi",slug:"okafor-nnamdi",fullName:"Okafor Nnamdi"}]},{id:"52680",doi:"10.5772/65715",title:"Endogenous Antioxidants: A Review of their Role in Oxidative Stress",slug:"endogenous-antioxidants-a-review-of-their-role-in-oxidative-stress",totalDownloads:4096,totalCrossrefCites:14,totalDimensionsCites:33,abstract:"Oxidative stress (OxS) constitutes a disturbance caused by an imbalance between the generation of free radicals and antioxidant system, which causes damage to biomolecules. This, in turn, may lead the body to the occurrence of many chronic degenerative diseases. Therefore, it is very important to know the functioning of those endogenous (and exogenous) antioxidants systems to prevent such diseases. Due to evolutionary conditions in living beings, among other functions have been developed and selected defense systems against the deleterious action of free radicals. Such systems are intrinsic in cells (at level intracellular and extracellular) and act together with the dietary exogenous antioxidants. All these antioxidant systems have very important role in preserving the oxide/reduction equilibrium in the cell. To understand the role of the transcription factor Nrf2 in regulating the processes of antioxidant defense, it must also know the role of many of the endogenous antioxidants that occur because of its activation. Therefore, this chapter makes a literature review of the most important general aspects of endogenous antioxidant systems, which will provide another point of view from which to approach the study and treatment of many chronic degenerative diseases, such as diabetes, hypertension, and Parkinson.",book:{id:"5407",slug:"a-master-regulator-of-oxidative-stress-the-transcription-factor-nrf2",title:"The Transcription Factor Nrf2",fullTitle:"A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2"},signatures:"Tomás Alejandro Fregoso Aguilar, Brenda Carolina Hernández\nNavarro and Jorge Alberto Mendoza Pérez",authors:[{id:"154732",title:"Dr.",name:"Jorge A.",middleName:null,surname:"Mendoza-Pérez",slug:"jorge-a.-mendoza-perez",fullName:"Jorge A. Mendoza-Pérez"},{id:"154908",title:"Dr.",name:"Tomás A.",middleName:null,surname:"Fregoso-Aguilar",slug:"tomas-a.-fregoso-aguilar",fullName:"Tomás A. Fregoso-Aguilar"},{id:"194794",title:"Dr.",name:"Brenda Carolina",middleName:"Carolina",surname:"Hernandez Navarro",slug:"brenda-carolina-hernandez-navarro",fullName:"Brenda Carolina Hernandez Navarro"}]},{id:"59054",doi:"10.5772/intechopen.72898",title:"Has Molecular Docking Ever Brought us a Medicine?",slug:"has-molecular-docking-ever-brought-us-a-medicine-",totalDownloads:3151,totalCrossrefCites:17,totalDimensionsCites:25,abstract:"Molecular docking has been developed and improving for many years, but its ability to bring a medicine to the drug market effectively is still generally questioned. In this chapter, we introduce several successful cases including drugs for treatment of HIV, cancers, and other prevalent diseases. The technical details such as docking software, protein data bank (PDB) structures, and other computational methods employed are also collected and displayed. In most of the cases, the structures of drugs or drug candidates and the interacting residues on the target proteins are also presented. In addition, a few successful examples of drug repurposing using molecular docking are mentioned in this chapter. It should provide us with confidence that the docking will be extensively employed in the industry and basic research. Moreover, we should actively apply molecular docking and related technology to create new therapies for diseases.",book:{id:"6365",slug:"molecular-docking",title:"Molecular Docking",fullTitle:"Molecular Docking"},signatures:"Mark Andrew Phillips, Marisa A. Stewart, Darby L. Woodling and\nZhong-Ru Xie",authors:[{id:"214567",title:"Prof.",name:"Zhong-Ru",middleName:null,surname:"Xie",slug:"zhong-ru-xie",fullName:"Zhong-Ru Xie"},{id:"223007",title:"Ms.",name:"Marisa A.",middleName:null,surname:"Stewart",slug:"marisa-a.-stewart",fullName:"Marisa A. Stewart"},{id:"223009",title:"Mr.",name:"Darby L.",middleName:null,surname:"Woodling",slug:"darby-l.-woodling",fullName:"Darby L. Woodling"},{id:"223013",title:"Mr.",name:"Mark Andrew",middleName:null,surname:"Phillips",slug:"mark-andrew-phillips",fullName:"Mark Andrew Phillips"}]}],mostDownloadedChaptersLast30Days:[{id:"69775",title:"Principles of Chromatography Method Development",slug:"principles-of-chromatography-method-development",totalDownloads:4294,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"This chapter aims to explain the key parameters of analytical method development using the chromatography techniques which are used for the identification, separation, purification, and quantitative estimation of complex mixtures of organic compounds. Mainly, the versatile techniques of ultra−/high-performance liquid chromatography (UPLC/HPLC) are in use for the analysis of assay and organic impurities/related substances/degradation products of a drug substance or drug product or intermediate or raw material of pharmaceuticals. A suitable analytical method is developed only after evaluating the major and critical separation parameters of chromatography (examples for UPLC/HPLC are selection of diluent, wavelength, detector, stationary phase, column temperature, flow rate, solvent system, elution mode, and injection volume, etc.). The analytical method development is a process of proving the developed analytical method is suitable for its intended use for the quantitative estimation of the targeted analyte present in pharmaceutical drugs. And it mostly plays a vital role in the development and manufacture of pharmaceuticals drugs.",book:{id:"8912",slug:"biochemical-analysis-tools-methods-for-bio-molecules-studies",title:"Biochemical Analysis Tools",fullTitle:"Biochemical Analysis Tools - Methods for Bio-Molecules Studies"},signatures:"Narasimha S. Lakka and Chandrasekar Kuppan",authors:[{id:"304950",title:"Prof.",name:"Chandrasekar",middleName:null,surname:"Kuppan",slug:"chandrasekar-kuppan",fullName:"Chandrasekar Kuppan"},{id:"309984",title:"Mr.",name:"Narasimha S",middleName:null,surname:"Lakka",slug:"narasimha-s-lakka",fullName:"Narasimha S Lakka"}]},{id:"72074",title:"The Chemistry Behind Plant DNA Isolation Protocols",slug:"the-chemistry-behind-plant-dna-isolation-protocols",totalDownloads:3797,totalCrossrefCites:4,totalDimensionsCites:7,abstract:"Various plant species are biochemically heterogeneous in nature, a single deoxyribose nucleic acid (DNA) isolation protocol may not be suitable. There have been continuous modification and standardization in DNA isolation protocols. Most of the plant DNA isolation protocols used today are modified versions of hexadecyltrimethyl-ammonium bromide (CTAB) extraction procedure. Modification is usually performed in the concentration of chemicals used during the extraction procedure according to the plant species and plant part used. Thus, understanding the role of each chemical (viz. CTAB, NaCl, PVP, ethanol, and isopropanol) used during the DNA extraction procedure will benefit to set or modify protocols for more precisions. A review of the chemicals used in the CTAB method of DNA extraction and their probable functions on the highly evolved yet complex to students and researchers has been summarized.",book:{id:"8912",slug:"biochemical-analysis-tools-methods-for-bio-molecules-studies",title:"Biochemical Analysis Tools",fullTitle:"Biochemical Analysis Tools - Methods for Bio-Molecules Studies"},signatures:"Jina Heikrujam, Rajkumar Kishor and Pranab Behari Mazumder",authors:[{id:"74521",title:"Dr.",name:"Rajkumar",middleName:null,surname:"Kishor",slug:"rajkumar-kishor",fullName:"Rajkumar Kishor"},{id:"309357",title:"Prof.",name:"Pranab Behari",middleName:null,surname:"Mazumder",slug:"pranab-behari-mazumder",fullName:"Pranab Behari Mazumder"},{id:"318351",title:"Ph.D. Student",name:"Jina",middleName:null,surname:"Heikrujam",slug:"jina-heikrujam",fullName:"Jina Heikrujam"}]},{id:"64549",title:"Plant Lipid Metabolism",slug:"plant-lipid-metabolism",totalDownloads:2677,totalCrossrefCites:8,totalDimensionsCites:14,abstract:"In plants, the synthesis of fatty acids takes place in the chloroplast and the fatty acid synthase is prokaryotic type. In plants, the structure of membrane lipids is different from that of eukaryotic cells. The membranes of the chloroplasts are essentially formed of galatolipids. This chapter will also focus on the structure and biosynthesis of fatty acids and membrane lipids in plants. Lipids of seeds are essentially composed of TAG; it would be interesting to describe their synthesis during the maturation of the seeds. Some plants contain in their reserve lipids unconventional fatty acids such as gamma linolenic acid in Borrago officinalis L., short-chain fatty acids C: 12 and C: 10, fatty acids with very long chains, and fatty acids that are cyclical. All of these fatty acids can have industrial and/or pharmaceutical applications.",book:{id:"7036",slug:"advances-in-lipid-metabolism",title:"Advances in Lipid Metabolism",fullTitle:"Advances in Lipid Metabolism"},signatures:"Fatiha AID",authors:[{id:"256576",title:"Prof.",name:"Fatiha",middleName:null,surname:"Aid",slug:"fatiha-aid",fullName:"Fatiha Aid"}]},{id:"66369",title:"General Perception of Liposomes: Formation, Manufacturing and Applications",slug:"general-perception-of-liposomes-formation-manufacturing-and-applications",totalDownloads:3320,totalCrossrefCites:17,totalDimensionsCites:40,abstract:"Liposomes are currently part of the most reputed carriers for various molecular species, from small and simple to large and complex molecules. Since their discovery, liposomes have been subject to extensive evolution, in terms of composition, manufacturing and applications, which led to several openings in both basic and applied life sciences. However, most of the advances in liposome research have been more devoted to launching new developments than improving the existing technology for potential implementation. For instance, the evolution of the conventional lipid hydration methods to novel microfluidic technologies has permitted upscale production, but with increase in manufacturing cost and persistent use of organic solvents. This chapter intends to present general concepts in liposome technology, highlighting some longstanding bottlenecks that remain challenging to the preparation, characterization and applications of liposomal systems. This would enhance the understanding of the gaps in the field and, hence, provide directions for future research and developments.",book:{id:"8095",slug:"liposomes-advances-and-perspectives",title:"Liposomes",fullTitle:"Liposomes - Advances and Perspectives"},signatures:"Christian Isalomboto Nkanga, Alain Murhimalika Bapolisi, Nnamdi Ikemefuna Okafor and Rui Werner Maçedo Krause",authors:[{id:"284670",title:"Prof.",name:"Rui",middleName:null,surname:"Krause",slug:"rui-krause",fullName:"Rui Krause"},{id:"284672",title:"Mr.",name:"Alain",middleName:null,surname:"Bapolisi",slug:"alain-bapolisi",fullName:"Alain Bapolisi"},{id:"284673",title:"MSc.",name:"Christian",middleName:null,surname:"Nkanga",slug:"christian-nkanga",fullName:"Christian Nkanga"},{id:"284675",title:"Mr.",name:"Okafor",middleName:null,surname:"Nnamdi",slug:"okafor-nnamdi",fullName:"Okafor Nnamdi"}]},{id:"61865",title:"A Click Chemistry Approach to Tetrazoles: Recent Advances",slug:"a-click-chemistry-approach-to-tetrazoles-recent-advances",totalDownloads:2687,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Introduction to tetrazole and click chemistry approaches was briefed in a concise way in order to help the readers have a basic understanding. Tetrazole and its derivatives play very important role in medicinal and pharmaceutical applications. The synthesis of tetrazole derivatives can be approached in ecofriendly approaches such as the use of water as solvent, moderate conditions, nontoxic, easy extractions, easy setup, low cost, etc. with good to excellent yields.",book:{id:"6365",slug:"molecular-docking",title:"Molecular Docking",fullTitle:"Molecular Docking"},signatures:"Ravi Varala and Bollikolla Hari Babu",authors:[{id:"212519",title:"Dr.",name:"Varala",middleName:null,surname:"Ravi",slug:"varala-ravi",fullName:"Varala Ravi"},{id:"221476",title:"Dr.",name:"Bollikolla",middleName:null,surname:"Hari Babu",slug:"bollikolla-hari-babu",fullName:"Bollikolla Hari Babu"}]}],onlineFirstChaptersFilter:{topicId:"43",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82531",title:"Abnormal Iron Metabolism and Its Effect on Dentistry",slug:"abnormal-iron-metabolism-and-its-effect-on-dentistry",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.104502",abstract:"Iron is a necessary micro-nutrient for proper functioning of the erythropoietic, oxidative and cellular metabolism. The iron balance in the body adversely affects the normal physiologic functioning of the body and structures in the oral cavity. Various abnormalities develop owing to improper iron metabolism in the body which reflects in the oral cavity. The toxicity of iron has to be well understood to immediately identify the hazardous effects which arise owing to it and to manage it. It has been very well mentioned in the chapter. The manifestations of defects of iron metabolism in the oral cavity should be carefully studied to improve the prognosis of the treatment of the same. Disorders related to iron metabolism should be managed for improvement in the quality of life of the patient.",book:{id:"10842",title:"Iron Metabolism - A Double-Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg"},signatures:"Chinmayee Dahihandekar and Sweta Kale Pisulkar"},{id:"82403",title:"Use of Plant Secondary Metabolites to Reduce Crop Biotic and Abiotic Stresses: A Review",slug:"use-of-plant-secondary-metabolites-to-reduce-crop-biotic-and-abiotic-stresses-a-review",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.104553",abstract:"Plant secondary metabolites (PSM) are small molecules of organic compounds produced in plant metabolism that have various ecological functions, such as defense against pathogens, herbivores, and neighboring plants. They can also help to reduce abiotic stresses, such as drought, salinity, temperature, and UV. This chapter reviewed the ecological functions of the PSM and how people utilize these metabolites to reduce crop biotic and abiotic stresses in agriculture. Specific topics covered in this review are (1) extraction of PSM from plant parts and its application on crops; (2) screening of crop/cover crop germplasms for high PSM content and with resistance to pathogens, herbivores, and/or neighboring plants; (3) regulation of PSM biosynthesis (including plant hormones and defense activators) to increase plant readiness for defense; (4) transcriptome and genome technology improvements in the last decade leading to valuable tools to characterize differential gene expression and gene composition in a genome, and lineage-specific gene family expansion and contraction. In addition, there is a critical need to understand how the biosynthesis and release of allelochemicals occur. Filling this knowledge gap will help us to improve and encourage sustainable weed control practices in agriculture.",book:{id:"11331",title:"Secondary Metabolites - Trends and Reviews",coverURL:"https://cdn.intechopen.com/books/images_new/11331.jpg"},signatures:"Ziming Yue, Varsha Singh, Josiane Argenta, Worlanyo Segbefia, Alyssa Miller and Te Ming Tseng"},{id:"81728",title:"Plant Secondary Metabolites: Therapeutic Potential and Pharmacological Properties",slug:"plant-secondary-metabolites-therapeutic-potential-and-pharmacological-properties",totalDownloads:30,totalDimensionsCites:0,doi:"10.5772/intechopen.103698",abstract:"Plants are an essential source for discovering novel medical compounds for drug development, and secondary metabolites are sources of medicines from plants. Secondary metabolites include alkaloids, flavonoids, terpenoids, tannins, coumarins, quinones, carotenoids, and steroids. Each year, several new secondary metabolites are extracted from plants, providing a source of possibilities to investigate against malignant illnesses, despite certain natural chemicals having distinct anticancer activities according to their physicochemical features. Secondary metabolites found in plants are frequently great leads for therapeutic development. However, changes in the molecular structure of these compounds are improving their anticancer activity and selectivity and their absorption, distribution, metabolism, and excretion capacities while minimizing their toxicity and side effects. In this section, we will discuss the most significant breakthroughs in the field of plant secondary metabolites, some of which are currently in clinical use and others that are in clinical trials as anticancer drugs. This study gives an up-to-date and thorough summary of secondary plant metabolites and their antioxidant, antibacterial, and anticancer effects. Furthermore, antioxidant and antibacterial, and anticancer effects of secondary metabolites are addressed. As a result, this article will serve as a thorough, quick reference for people interested in secondary metabolite antioxidants, anticancer, and antibacterial properties.",book:{id:"11331",title:"Secondary Metabolites - Trends and Reviews",coverURL:"https://cdn.intechopen.com/books/images_new/11331.jpg"},signatures:"Muhammad Zeeshan Bhatti, Hammad Ismail and Waqas Khan Kayani"},{id:"80495",title:"Iron in Cell Metabolism and Disease",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:22,totalDimensionsCites:0,doi:"10.5772/intechopen.101908",abstract:"Iron is the trace element. We get the iron from the dietary sources. The enterocytes lining the upper duodenal of the intestine absorb the dietary iron through a divalent metal transporter (DMT1). The absorbed ferrous iron is oxidized to ferric iron in the body. This ferric iron from the blood is carried to different tissues by an iron transporting protein, transferrin. The cells in the tissues take up this ferric form of iron by internalizing the apo transferrin with its receptors on them. The apo transferrin complex in the cells get dissociated resulting in the free iron in cell which is utilized for cellular purposes or stored in the bound form to an iron storage protein, ferritin. The physiological levels of iron are critical for the normal physiology and pathological outcomes, hence the iron I rightly called as double-edged sword. This chapter on iron introduces the readers basic information of iron, cellular uptake, metabolism, and its role cellular physiology and provides the readers with the scope and importance of research on iron that hold the great benefit for health care and personalized medicine or diseases specific treatment strategies, blood transfusions and considerations.",book:{id:"10842",title:"Iron Metabolism - A Double-Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg"},signatures:"Eeka Prabhakar"},{id:"81233",title:"Secondary Metabolites of Fruits and Vegetables with Antioxidant Potential",slug:"secondary-metabolites-of-fruits-and-vegetables-with-antioxidant-potential",totalDownloads:43,totalDimensionsCites:1,doi:"10.5772/intechopen.103707",abstract:"An antioxidant is of great interest among researchers, scientists, nutritionists, and the public because of its ability to prevent oxidative damage, as indicated by various studies. This chapter mainly focuses on the free radicals and their types; antioxidants and their mode of action against free radicals; fruits, vegetables, and their byproducts as a source of antioxidants; and various analytical methods employed for assessing antioxidant activity. Antioxidants discussed in this chapter are ascorbic acid, Vitamin E, carotenoids and polyphenols, and their mechanism of action. Different antioxidant activity assay techniques have been reported. Fruits and vegetables are abundant sources of these secondary metabolites. The waste generated during processing has many bioactive materials, which possibly be used in value-added by-products.",book:{id:"11331",title:"Secondary Metabolites - Trends and Reviews",coverURL:"https://cdn.intechopen.com/books/images_new/11331.jpg"},signatures:"Ravneet Kaur, Shubhra Shekhar and Kamlesh Prasad"},{id:"81044",title:"Metabolomics and Genetic Engineering for Secondary Metabolites Discovery",slug:"metabolomics-and-genetic-engineering-for-secondary-metabolites-discovery",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.102838",abstract:"Since 1940s, microbial secondary metabolites (SMs) have attracted the attention of the scientific community. As a result, intensive researches have been conducted in order to discover and identify novel microbial secondary metabolites. Since, the discovery of novel secondary metabolites has been decreasing significantly due to many factors such as 1) unculturable microbes 2) traditional detection techniques 3) not all SMs expressed in the lab. As a result, searching for new techniques which can overcome the previous challenges was one of the most priority objectives. Therefore, the development of omics-based techniques such as genomics and metabolomic have revealed the potential of discovering novel SMs which were coded in the microorganisms’ DNA but not expressed in the lab or might be produced in undetectable amount by detecting the biosynthesis gene clusters (BGCs) that are associated with the biosynthesis of secondary metabolites. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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