\r\n\tOver the past few decades, there has been a rationalization for better classification of dystonia and paying more attention to understanding the different causes of dystonic movements from the advanced study of genetics, neurophysiology, and functional imaging in various forms of dystonia.
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\n\t\t\t
1. Introduction
\n\t\t\t
Ionic liquids have proved to be one of the most impressive classes of fluids, due to their properties and applications to chemistry and engineering. One of the most recent applications of complex systems of ionic liquids and nanomaterials are IoNanofluids, from heat transfer to catalysis, solar absorbing panels, lubricants or luminescent materials. These novel materials belong to the class of nanofluids proposed in the last years and are a mixture of ionic liquid and nanomaterial, in the form of nanoparticle dispersion, and have already resulted in a number of publications in chemical and physical journals.
\n\t\t\t
There are several reasons to study these new materials/fluids, rather complex in structure. The most important property is their enhanced thermal properties, like thermal conductivity and heat capacity, heat transfer and heat storage. The complex interactions existing between the anion/cation of the ionic liquid and the nanomaterial surface create nano-regions that can enhance reactivity and selectivity of chemical reactions. As the physiochemical properties of ionic liquids themselves can be tailored to the desired application employing an ionic liquid as a base fluid means IoNanofluids can also be designed to meet any specific application or task requirement. They also are non-flammable and non-volatile at ambient conditions and can, therefore, be considered as “green” fluids.
\n\t\t\t
The possible scientific, technical and economic success of IoNanofluids open new markets, as new products for engineering fluids, heat insulators, catalysts, etc., can be envisaged. In addition, the replacement of environmentally aggressive chemicals, foams, solid composites are in daily order, imposed by regulations or social responsibility. These new challenges open new jobs for chemists, material scientists and engineers.
\n\t\t\t
The precursors of the IoNanofluids are nanofluids. Their impact in the scientific/ technical literature is very big. A total of 1575 nanofluids related publications, which include journal and conference articles, patent, news, letter and other, have appeared over the past 11 years.\n\t\t\t\t\t
\n\t\t\t\t In Figure 1 it can be seen an exponential growthof the total number of these items published per year since 2002. It is also believed that there are more than 300 research groups and companies worldwide involved in nanofluids research, a hot topic in an interdisciplinary field. Several spin-off companies have originated from nanofluids research and the number continues to increase.
\n\t\t\t
Figure 1.
Web of Knowledge record of nanofluids related publications
\n\t\t\t
The current review, which focuses the syntheses of ionic liquids, the preparation of IoNanofluids, their properties, experimental measurements, processes requirements and economic impact, pretends to contribute to clarify the overall question, always present in the appearance of a new field, which crosses several minds: Will IoNanofluids be useful to our society?
\n\t\t\t
Comparison between the IoNanofluids properties and those of the base ionic liquids will be the key for understanding the role of the interface between the ionic liquid and the nanomaterial in the determination of physical properties. The unexpected behavior observed in some IoNanofluids and the difference observed regarding the base fluid is, in our view, the most important aspect in this review.
\n\t\t
\n\t\t
\n\t\t\t
2. Ionic Liquids
\n\t\t\t
Ionic liquids (ILs) are materials composed entirely of ions, which have melting points below 100 ºC [1]. Such liquids are an elaborate network of ions which are governed by electrostatic charges and hydrogen bonding [2]. More recently room temperature ionic liquids (RTILs) have moved to the forefront of IL research due to their melting temperatures being below 30°C. Generally the asymmetric form of the ions (usually the cation) reduces the Coulombic interactions which results in a lowering of the melting points, see figure 2. These liquids exhibit favourable properties for solvent use due to the formation of air and moisture stable, low-volatile liquids, low flammability [3] under ambient conditions high ionic conductivity which also maintains their thermal and electrical stability over a large temperature range [4,5]. With judicious tailoring of the cation-anion structure a range of ILs can be synthesised with various pre-chosen physiochemical properties. This has resulted in them being applied in a multitude of techniques including catalysis [6], elemental analysis [7], synthesis [8], solar absorbing panels [9], lubricants [10], luminescent materials [11] and supercritical fluids [12,13]. Ionic liquids also provide very different solvent−solute interactions which can give rise to distinct chemistries compared with molecular solvent systems [14]. In addition to this, the use of ILs acting as both the solvent system and reactant/catalyst in a reaction process [15] makes them a “hot topic” for researchers. They have also been shown to immobilize and stabilize catalytic complexes or even act as modifiers that accelerate the reaction [16]. These IL-catalyst systems can be recycled potentially reducing chemical waste and increasing the lifetime of the catalyst, further adding to the ‘green’ aspects of ionic liquids [17]. More recent understanding and analysis of catalytic reactions show that even so called benign ILs are now not considered chemically passive and are capable of modifying the catalyst resulting in differing chemistries [18].
\n\t\t\t
Pioneering physical and chemical research in ILs where usually focused on imidazolium based cations with the corresponding tetrafluoroborate ([BF4]-) or hexafluorophosphate ([PF6]-) anions. These were initially chosen due to their ease of synthesis and purification. However, these ILs have been found to be of lower thermal stability and undergo hydrolysis reactions resulting in the production of HF and BF3 [19]. Recently, hydrophilic fluorine based anions such as bis(trifluorosulfonyl)imide ([NTf2]-) and the tris(perfluoroalkyl)trifluorophosphate ([FAP]-) have been developed. The stability of these anions is well established and has found many applications in the fields of catalysis [20]. Other halide free anions include alklysulfate, alkylphosphate and alklycarbonate molecules.
\n\t\t\t
The synthesis of all ionic liquids starts with the ’neutralisation’ of a Lewis base, typically alkylimidazoles, trialkylamines including pyrolles and piperidines, trialkylphopshines and pyridines are the most frequently used. For the synthesis of protic ILs, the Lewis base (represented as methylimidazole) can be neutralised directly by the addition of a Brönsted acid, see Figure 3, step 1. However, some of these salts are generally thermally unstable or exist in equilibrium with the free acid and base thus limiting their applications [21].
\n\t\t\t
Figure 2.
Common cations and anions used in air and moisture stable RTILs
\n\t\t\t
For many ILs the preparation is strongly associated with the considerations about the required purity of the ILs post synthesis. For example in the synthesis of imidazolium ILs, the most common synthetic strategy involves the synthesis of the corresponding commercially available alkylimidazolium halide (Cl- or Br-) followed by anion metathesis to the desired IL, see Figure 3, steps 2 and 3. For hydrophobic ILs such as those containing the [NTf2]- and [PF6]- anions, this can be achieved by anion exchange of the imidazolium halide with the corresponding Li+, Na+ or NH4\n\t\t\t\t+ salt. Therein, the IL forms a separate phase which can be further purified by washing with water to remove any remaining halide. The water solubility of the ILs is very dependent on both the anion and cation present, and in general will decrease with increasing organic character (alkyl chain length) of the cation and decrease with increasing fluorinated character in the anion. For hydrophilic ILs such as those containing the, [RSO4]- [CF3SO2]-, [BF4]- or [N(CN)2]- anions the corresponding Ag+ salt is used to precipitate out Ag halide salt which can be removed by filtration.
\n\t\t\t
Impurities in ILs such as water, halides, starting materials and organic solvents not only have a profound effect on their physical properties [22] but have also resulted in significant changes in reaction chemistry [23-27]. Within both these areas significant steps have been made in the creation of cleaner and more economic routes to the preparation of ILs [28,29].
\n\t\t\t
Other so halide free synthetic pathways involve direct alklylation to form the corresponding, alkylsulphate ([RSO4]-), alkylcarbonate ([RCO3]-) and trilfate ([CF3SO2]-) ILs, see Figure 3, step 4. The alkylsulphate [30] or alkylcarbonate [31] ILs which have found applications in their own right can be further reacted to form the corresponding halide free hydrophilic ILs.
\n\t\t\t
Figure 3.
General synthesis of air stable, metal free Ionic liquids
\n\t\t
\n\t\t
\n\t\t\t
3. IoNanofluids
\n\t\t\t
IoNanofluids are complex systems of nanofluids with nanomaterials. Before we deal directly with these systems, a brief digression in the field of nanofluids will help to clarify the properties and these especial fluids. The origin of the nanofluids is linked to the current challenges faced by many high-tech industries and thermal management systems for cooling of smaller features of microelectronic and more power output-based devices. The conventional method to increase the cooling rate is to use extended heat transfer surfaces but this approach requires an undesirable increase in the size of the thermal management systems. This fact, added to the thermophysical properties of the traditionally heat transfer fluids (HTFs) used in industry, such as water, ethylene glycol (EG) or engine oil (EO) greatly limit the cooling performance. This situation was partially overcome by the use of materials with high thermal conductivity, such as nanomaterials suspended or dispersed in this type of base fluids. Choi [32] at Argonne National Laboratory of USA coined the concept of “nanofluids” to meet the aforementioned cooling challenges facing many advanced industries and devices. This new class of heat transfer fluids is engineered by dispersing nanometer-sized solid particles, rods or tubes in traditional heat transfer fluids and they were found to exhibit significantly higher thermophysical properties, particularly thermal conductivity and thermal diffusivity than those of base fluids (BFs) [33-38].
\n\t\t\t
From practical application-based studies such as convective and boiling heat transfer characteristics [39-45], nanofluids (NFs) were also found to be even more promising as their convective heat transfer coefficient and critical heat flux were reported to be substantially higher as compared to those of their base fluids. In particular, nanofluids containing high thermal conductive materials such as carbon nanotubes (CNTs) shows anomalously enhanced thermal performance [45-47]. This is justified by the great difference between thethermal conductivity of CNTs (between 2000 and 3000 Wm-1K-1) and that of the base fluid (0.6 Wm-1K-1 for water).\n\t\t\t\t\t
The thermal conductivity of molecular, organic and inorganic liquids, with the exception of molten metals, ranges from 0.1 to 0.6 Wm-1K-1.
\n\t\t\t\t\n\t\t\t
\n\t\t\t
The concept of “IoNanofluids” was recently proposed by Nieto de Castro and co-workers [48] and it represents a very new class of heat transfer fluids where nanomaterials (particles, tubes and rods) are dispersed in ionic liquids only [49]. Since IoNanofluids are a specific type of nanofluids i.e., ionic liquids-based nanofluids, they are expected to have similar thermal properties than nanofluids, a fact that was proved recently by the authors [50]. The term IoNanofluids is therefore a new term in multidisciplinary fields such as nanoscience, nanotechnology, thermofluidity, chemical and mechanical engineering.The discovery that carbon nanotubes (CNT) and RTILs can be blended to form gels termed as “Bucky gels” which can potentially be used in many engineering or chemical processing such as making novel electronic devices, coating materials, and antistatic materials and thus, it opens a completely new field [51,52]. The “Bucky gels” are blends or emulsions of ILs with nanomaterials, mostly nanocarbons (tubes, fullerenes, and spheres) and they are actually CNT laden IoNanofluids. The possibility of using ionic liquids containing dispersed nanoparticles with specific functionalization such as functionalized single-walled nanotubes (SWCNT), multi-walled nanotubes (MWCNT) and fullerenes (C60, C80 etc.) opens the door to many applications. In recent reviews the authors have shown the properties of the IoNanofluids and nanofluids and highlighted their possible applications in different areas [9,53-55].
\n\t\t\t
\n\t\t\t\t
3.1. Manufacture of IoNanofluids
\n\t\t\t\t
Although significant progress has been made in the last years, variability in the heat transfer characteristics of the nanofluids so far reported is presented, with very different thermal conductivity enhancements for the same systems. This variability may be the result of the various synthetic techniques employed, and the purity of the starting materials. The manufacture of nanofluids is delicate, as it does not mean necessarily a simple mixture of solid particles and a liquid, in the thermodynamic definition, and the techniques used by different authors are sometimes ill-defined [37,56].
\n\t\t\t\t
Thus the synthesis of IoNanofluids can be a delicate operation. There are two main techniques used with normal solvents, the two-step process and the direct evaporation technique or single step. Most researchers use the two-step process, by dispersing commercial or self-produced nanoparticles in the liquid, a technique that can create large particle agglomerates, which can be destroyed by adding surfactants or using mechanical or ultrasound dispersion techniques.However the synthesis in situ seems to be the most efficient to produce very homogeneous particles, with a narrow size distribution, originating long period stability, especially for metal nanoparticles [57,58]. Aida and co-workers found that imidazolium-cation-based ionic liquids were excellent dispersants for CNT’s, forming physical gels, that could be reproduced using sonication or by grinding the suspension in an agate mortar with a pestle. These techniques were followed by the current authors groups, to obtain very stable emulsions, without surfactants, with 0-3% (w/w) loading of MWCNTs (Multi-walled carbon nanotubes) in a range of imidazolium and pyrrolidinium ILs.
\n\t\t\t\t
The importance of the purity of both starting materials and the technique used for manufacturing the dispersed nanomaterial is very important. In first place, the ionic liquid must be as pure as possible, as small quantities of water can affect its properties [59], and subsequently those of the Ionanofluid. Although the preparation of the dispersions is made open to atmosphere and therefore capable of introducing water in the samples, these were monitored by Karl-Fisher Coulometric analysis, and the amount of water in the pure ionic liquids never exceeded 400 ppm before the measurements and 800 ppm after the measurements, values that do not affect the thermal conductivity measurements [60].
\n\t\t\t\t
The properties and characteristics of the nanomaterials are an extremely important issue. Most of the nanomaterials are spherical, rod or oblong in shape. Current manufacturing procedures can result in batch to batch variability as the degree of outer shell nanomaterial functionalization caused during manufacture and geometries of the nanomaterials can change\n\t\t\t\t\t\t
In a majority, the producers of nanoparticles do not disclose the real structure of the particles, the presence of polymer coatings or oxidative type reactions
\n\t\t\t\t\t. One such example is in the case for silver nanoparticles, where 80% of the manufacturers use polymer coatings of non-disclosed thickness and properties. These coatings determine completely the heat transfer properties of the nanomaterials, and if we want to use silver nanoparticles they have to be chemically treated to eliminate them. Many publications on nanofluids systems previously reported were probably not aware of these problems and therefore those results have to be confirmed.
\n\t\t\t\t
Our current experience in Ionanofluid manufacture is based on MWCNTs, and therefore we restrict our analysis to IoNanofluids based on these nanomaterials. However several studies are currently in progress using TiO2 and Ag spherical particles, as well as nanomaterials delivered from nature [9,61-63].
\n\t\t\t\t
The IoNanofluids based on MWCNTs must obey the following conditions: homogeneous dispersion, stable over a great period of time (not producing phase separation, even at a micro scale), and be free of additives, such as surfactants or salts. In addition, one of envisaged applications involves their use as heat transfer fluids, a control of viscosity is crucial, in order to create fluids with sensible heat transfer coefficients in dynamic regime (good fluidity). The preparation procedure involves weighing the nanomaterial, addition to the ionic liquid and introduction into the sonicator cell. Optimization of the time and sonication energy, visual observation for phase separation of the IL from the Ionanofluid is crucial\n\t\t\t\t\t\t
The dispersion is black, as shown in \n\t\t\t\t\t\t\t\tFigure 4\n\t\t\t\t\t\t\t. Therefore a great care as to be taken in the observation, helped by reflected light analysis through the suspensions
\n\t\t\t\t\t. Excessive time and high energy can result in the break-up of the Ionanofluid and breakage of tube walls. Moreover, impurities in the glass cells can lixiviate them and introduce further elements into the dispersion. The IoNanofluids dispersions produced are then allowed to settle several hours before the thermophysical properties measurements. The existence in microphase separation is controlled by measuring the properties of the dispersion, in several occasions. As an example, for thermal conductivity, dispersions in [C2mim][dca], were measured within an interval of one year and their values did not differ by more than 2%, well within the uncertainty of the measurements [60]. Figure 4 illustrates the main steps for the preparation, starting with the ionic liquid, adding the carbon nanotubes, using the sonicator probe and finally the dispersion.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
3.2. Experimental properties and their impact on process equipment design
\n\t\t\t\t
As described above, the most important thermophysical properties for heat exchange equipment design are thermal conductivity, heat capacity, density and viscosity. They control the dynamics of heat transfer, namely the heat transfer coefficients and the heat transfer areas of the exchangers. In order to decide if any fluid can be used as an alternative to current engineering fluid, there are two essential questions to answer:
\n\t\t\t\t
Are the properties of the fluid adequate to the process(es) where it will be used?
If the answer to the first technical question is affirmative, is the fluid economic competitive?
\n\t\t\t\t
The answer to the first question raises another two problems: a) how accurate the thermophysical property data available is and b) what is the sensitivity of the main design parameters in heat exchange (heat transfer area, flow rates, pressure drops) are affected by the uncertainty of those properties. These factors will be discussed in detail below.
\n\t\t\t\t
Figure 4.
Main steps for the preparation of IoNanofluids with MWCNTs.
\n\t\t\t\t
The determination of experimental values of the thermophysical properties of ionic liquids has been discussed in two recent reports, regarding the methods of measuring (existing and foreseen new developments) and how important is to characterize the samples in order to trust the measurements made with the highest accuracy available [59,64].This fact, using ionic liquids as base fluids for the nanofluids, is very important as they can absorb water from the environment. As an example, Table 1 shows the results obtained for 3 ionic liquids in our laboratory, which were used for IoNanofluids preparation [60]. The ILs were obtained from Io-Li-Tec, DE, dried under vacuum for several days at approximately 60ºC and the water content was determined with a Karl-Fisher Coulometer.
\n\t\t\t\t
The effect on the measured values of the properties depends on these, being more significant for viscosity [65,66]. For thermal conductivity an effect of 1000 ppm (0.02 in the molar fraction of the mixture), the maximum effect at 70ºC\n\t\t\t\t\t\t
The effect decreases the value of the thermal conductivity and increases with temperature
\n\t\t\t\t\t is 0.2% (much smaller than measurement uncertainty). These results show that it is very important to characterize the samples, determining its water content, before and after the measurements, a fact that has not been recognized so far by many authors and journal editors.
\n\t\t\t\t
The methods used to measure the thermophysical properties have also to be well characterized: many deviations between data obtained by different methods and different laboratories are caused by ill-defined measuring methods [59,64]. It is not the purpose of this review to describe the best experimental systems, as a full discussion was presented before [64]. However the readers should be attentive to this problem. It is very tempting for some research group that enters the field of ionic liquids to use equipments already available, using measuring cells that sometimes are not adequate. In addition the availability on the market of reliable measuring instruments also creates an opportunity for “fast” data production.
\n\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\tIonic Liquid
\n\t\t\t\t\t\t\t
ManufacturerPurity / %
\n\t\t\t\t\t\t\t
ManufacturerH2O / ppm
\n\t\t\t\t\t\t\t
After DryingH2O / ppm
\n\t\t\t\t\t\t\t
After MeasurementsH2O / ppm
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[C2mim][dca]
\n\t\t\t\t\t\t\t
>98
\n\t\t\t\t\t\t\t
1850
\n\t\t\t\t\t\t\t
234.7 ± 48.6
\n\t\t\t\t\t\t\t
488.9 ± 58.6
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[C4mim][dca]
\n\t\t\t\t\t\t\t
>98
\n\t\t\t\t\t\t\t
1480
\n\t\t\t\t\t\t\t
324.9 ± 86.4
\n\t\t\t\t\t\t\t
683.6 ± 41.7
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[C4mpyr][dca]
\n\t\t\t\t\t\t\t
>98
\n\t\t\t\t\t\t\t
1710
\n\t\t\t\t\t\t\t
349.6 ± 47.9
\n\t\t\t\t\t\t\t
637.0 ± 57.0
\n\t\t\t\t\t\t
\n\t\t\t\t\t
Table 1.
Water content of 3 ionic liquids, before and after the thermal conductivity measurements
\n\t\t\t\t
Other factors are known to affect the determination of experimental values, not strictly dependent of the instrumental methods used. For example the compatibility of ILs with seals, gaskets and metals contained in the measuring cell is very important. Ionic liquids anions and cations can be very different in size and to date most of the existing information has been obtained for imidazolium cations, making it difficult to generalize for other non-imidazolium ionic liquids. These ions are not mutual independent, can form aggregates and complicate structures in the liquid phase. In addition the viscosity is moderate to high, the liquids are electrical conducting and the heat capacity per unit volume is rather high. All these factors condition heat and mass transfer in the transport properties determination and must be known “a priori” to avoid systematic errors.
\n\t\t\t\t
An example selected from reference [64] is sufficient to illustrate the point about “bad” and good” measurements. Figure 5 shows the heat capacity of [C4mim][BF4], obtained using DSC [67-73]. A wide variation between the datasets of up to 20 % at room temperature is observed. This situation is very uncommon in calorimetry; however it is known that, apart from differences in sample purity, the DSC used must be well calibrated before use, a fact which could also help to explain the scatter of data. However, it can be seen [50] that 5 sets of data agree within 2%, within their mutual uncertainties [50,67,68,72,73], a result that would be considered excellent for DSC data, the most popular measuring method, due to its speed and excellent repeatability. Bearing in mind that handling and measuring ILs physical properties is not trivial, the authors would like to recommend a careful analysis of all these aspects prior to making measurements and reporting data.
\n\t\t\t\t
The second point to analyze is how the sensitivity of the main design parameters in heat exchange (heat transfer area, flow rates, pressure drops) are affected by the uncertainty of those properties. This was the subject of many publications in the past, and recently we have applied this to ionic liquids. Using the same methodology [74], analyzing the effect of the uncertainty of thermophysical data of ionic liquids (density, heat capacity, thermal conductivity and viscosity) in the design of some current equipment, used in processes as solvents or heat transfer fluids. Data has been collected from IL Thermo database [75] for alkylmethylimidazolium, [Cnmim]- liquids, with [BF4]- and [PF6]- anions. This was justified by the fact that the thermophysical properties of ionic liquids, measured in different laboratories and by different methods do not agree within their mutual uncertainties. This was probably caused by incorrect methods of measurement and/or purity problems, as stated above. Results obtained show that the influence of actual errors in the thermophysical properties of ionic liquids can render any future design of chemical plant equipment as not working or excessively costing. Although the actual cost of ionic liquids is higher than conventional heat transfer fluids, the future production of higher quantities can make their use competitive, especially if a target price of 25US$/kg is achieved.
\n\t\t\t\t
The heat storage capacities of [BF4]- and [PF6]- and other ionic liquids, containing anions like [C2H5SO4], [(CF3SO2)2N], [CF3SO3] and [C8H17SO4], which can be considered as possible replacements of current heat transfer fluids, have been analyzed. A comparison with the properties of synthetic compounds (based on hydrocarbons, polyaromatics and siloxanes), showed that common imidazolium IL systems have higher heat capacities per unit volume than high performance commercial thermal fluids, such as Paratherm HE(a registered mark of Paratherm Corporation) and Syltherm 800™, Syltherm HF™ Dowtherm A™ and Dowtherm MX™ (trademarks of Dow Chemical Company, USA) [75]. Details of the methodology application can be found in this reference. The analysis was limited to study the effect of the uncertainty in the properties in the major design parameter, the heat transfer area, in a preselected heat transfer equipment, a shell and tube heat exchanger, as it reflects the changes in the design arising from the changes in the thermophysical properties of the ionic liquid process stream. This also permits a more facile estimation of the economic consequences of these changes in the design.
\n\t\t\t\t
Figure 5.
Existing values of the heat capacity for [C4mim][BF4] as a function of temperature (2010). - Nieto de Castro et al. [50]; - Van Valkenburg et al. [67]; - Rebelo et al.[68]; - Kim et al.[69]; - Fredlake et al. [70]; - Waliszewski et al. [71]; - Garcia-Miaja et al. [72]; - Garcia-Miaja et al. [73].
\n\t\t\t\t
The equipment chosen is one modern solar power plant that uses a molten salt receiver as thermal energy storage system, which captures the sun\'s energy and stores it in hot molten sodium nitrate or molten nitrates mixtures, so that power can be generated when needed, not just when the sun is shining. The heat transfer unit uses a molten salt through oil to salt heat exchanger [76,77]. The molten salt mixture used was replaced by a ionic liquid, one set of reference conditions for the operation were chosen based on a given set of values of the thermophysical properties and then the assigned values were perturbed about their reference values, within ranges commensurate with the actual stage of experimental uncertainty reported in IL Thermo database [75]. The effect of the uncertainties of the thermophysical properties of the ionic liquids can be calculated by calculating the new heat transfer area A\n\t\t\t\t\t0 and its variation A as a function of the variation in percentage of the thermophysical properties, ,Δρ ,Δη ,Δλ and ΔCP. Figure 6 shows in a 3D plot the effect of ΔCP and Δλ in ΔA for [C2mim][BF4], using again the viscosity uncertainty, Δη as a parameter for the surfaces. The density is not shown, as this is the property known with less uncertainty. Not using extreme values, whereby the area can be overestimated by 50 %, an error of + 20 % in viscosity, - 20 % in thermal conductivity and -10 % in heat capacity generates an error of + 20 % in the area of the heat exchanger.
\n\t\t\t\t
From the results presented we can conclude that the effects of the uncertainty in the thermophysical properties of RTIL’s are high and that the heat transfer areas (see Table 2) are higher than those obtained with the used heat transfer oils. The exception to this is [C2mim][BF4]. These effects can render equipment obsolete and/or induce additional operational costs, well above of those estimated by design. When a heat exchanger is built, its cost will be weakly dependent on the size/length of the pipes, but highly dependent on the heat transfer area and the operational costs will increase significantly with size. However, to increase the capacity of the unit after having been built would represent an additional cost, possibly smaller than replacing it with a new unit. Therefore, the wise approach would be to obtain good experimental measurements of the heat transfer used, as described above.
\n\t\t\t\t
Figure 6.
3D plot of the effect of uncertainty of heat capacity (CP ) and thermal conductivity () for [C2mim][BF4] on the area (A) of a shell and tubes heat exchanger,using viscosity uncertainty, , as a parameter for the surfaces (upper, + 20 %; lower, - 20 %); the lines in the planes represent the maximum and minimum values of the area variation for ± 20 %, , and ± 30 %, ---, in Δλ and ΔCP. Adapted from [74].
\n\t\t\t\t
In order to determine whether ionic liquids are economic as practical heat transfer fluids the costs of heat transfer equipment need to be examined. Details of the cost estimation of the heat exchanger can be found in [75]. The total cost required for a new design can be broken in five parts [84], the battery limits investment, the utility investment, the off-site investment, the engineering fees and the working capital. From these, we were concerned first with the battery limit investment, which is the cost of individual plant items and their installation to form the working process. The cost of the heat exchanger will be a function of its size (were the type of heat exchanger and the heat transfer area are critical), the materials of its construction (materials compatibility between metal parts and heat transfer fluids), design pressure and temperature, and it can be given by:
where CE represents the cost of the equipment with a given capacity X (here the heat transfer area, A0), CB the base cost of a reference equipment with a capacity XB, and m a constant depending of the equipment type (m=0.68 for a shell and tube heat exchanger). The base cost of a carbon steel shell and tube heat exchanger, with a heat transfer area of 80 m2 would be 3.28104 US$. fM is the correction factor for materials of construction different from carbon steel, fP the correction factor for design pressure and fT the correction factor for design temperature. Values used for these factors can be found in references [74, 84].
\n\t\t\t\t
The results obtained for the estimated costs for the shell and tube heat exchangers using the different heat transfer fluids are shown also in Table 2. Keeping other factors constant the heat exchangers for the [PF6]- based RTIL’s are significantly more expensive that the conventional fluids. However [C2mim][BF4] IL is only moderately more expensive. Depending on the process, it may be possible to obtain savings in the ILs equipment, either by changing other design variables (De, Di, pressure drops, materials, temperatures of the cold and hot streams, etc.,) or, by using other ionic liquids than the ones tested, especially those ILs with lower viscosity values. In addition, the cost of ionic liquids, which is currently in the order of 100-500 US$/kg for research due to high value of the personnel costs involved at this scale, are now evolving for industrial production to targeted prices of 25 US$/kg [85], a value which makes them valuable alternative heat transfer fluids, from the economic side. For example, the ionic liquid [C2mim][EtSO4] is now available on an tonne scale, from Solvent Innovation GmbH, Cologne (www.solventinnovation.de) or BASF AG (www.basionics.de).
Values of Heat Transfer Liquids Properties, Reference Area A0and Estimated Costs for the Shell and Tube Heat Exchanger
\n\t\t\t\t
For IoNanofluids, there is only one study, still unpublished, performed in Lisbon laboratory [86], with [C4mim][NTf2] and [C2mim][EtSO4] and MWCNTs. As no data is available for the heat capacity and viscosity enhancements\n\t\t\t\t\t\t
Measurements are under progress
\n\t\t\t\t\t, we have assumed for the corresponding enhancements E\n\t\t\t\t\t\tλ\n\t\t\t\t\t = E\n\t\t\t\t\t\tη\n\t\t\t\t\t, E\n\t\t\t\t\t\tCp = 1.5; 2; 5 % and E\n\t\t\t\t\t\tρ\n\t\t\t\t\t = 0. Figure 7 shows the variation in the area A of the same heat exchanger as a function of the volume fraction of the Ionanofluid\n\t\t\t\t\t\t
As the densities of the carbon nanotubes are much smaller than those of the base fluids, the volume fraction is much greater than the weight fraction (0.5, 1, 3%)
\n\t\t\t\t\t. The data points are labeled to show the values of the areas obtained. The maximum enhancements in the thermal conductivity were found for the 3% w/w IoNanofluids, around 25% for [C4mim][NTf2]. The effect, only of the thermal conductivity enhancement can be as much as 20% decrease in the area, and therefore in the cost of the heat exchanger, saving about US$ 20 mfor a 20% volume fraction of MWCNT (3% w/w), a value very significant. Progress in the experimental measurement of density, heat capacity and viscosity of these IoNanofluids will be reported soon.
\n\t\t\t\t
Figure 7.
AovsCNT for ionic liquids and IoNanofluids. - fluids based on [C4mim][NTf2]; - fluids based on [C2mim][EtSO4]. Close to each data point is the cost of the heat exchanger, in US$.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
3.3. Other process requirements
\n\t\t\t\t
There are a number of factors that have to be considered to make the possible the use of these IoNanofluids in industry. We restrict the discussion associated with the analysis of thermal stability and toxicity.
\n\t\t\t\t
\n\t\t\t\t\t
3.3.1. Thermal stability
\n\t\t\t\t\t
The thermal stability of the IoNanofluids has two major components: the thermal stability of the ionic liquid base fluid and the thermal stability of the dispersion, on a long term. These are facts that have to be studied. In the case of ionic liquids there is already a substantial amount of information that allow us to be confident that it is easy to target an operational value of 200ºC\n\t\t\t\t\t\t\t
In a great majority of chemical processes, temperatures for heat transfer above 200ºC are not used, for energy cost reasons
\n\t\t\t\t\t\t, especially for the liquids mentioned in this review. However, ionic liquids have the tremendous advantage of being target designed, so there will be always the possibility of synthesizing a new high temperature ionic liquid. However the thermal stability of the IoNanofluids is a totally different game, as the homogeneous system can be transformed in a heterogeneous phase, with micro phase equilibria, promoting aggregation of the nanomaterials and/or phase separation, at a micro or macroscopic level. In principle, the increase in temperature will facilitate the homogeneous system, due to the increase in entropy of the base fluid. No data is yet available for temperatures above 70ºC, so any further conclusion will be premature. New studies in this area are needed.
\n\t\t\t\t
\n\t\t\t\t
\n\t\t\t\t\t
3.3.2. Toxicity of ionic liquids, nanomaterials and IoNanofluids
\n\t\t\t\t\t
Regarding toxicity, there are not any studies for IoNanofluids, and none to date for nanofluids. In the absence of any additional effect, the toxicity of an Ionanofluid will be a sum of the toxicity of the base ionic liquid and that of the nanomaterial used. For ionic liquids, our current knowledge is still scarce, and without long term consequences, but some conclusions can already been suggested [87,88]. Following the extensive review by Petkovic et al. [87], “it is clear that the numerous formulations of ionic liquids available provide a great pool of, and impetus for, many commercial applications, but not without significant toxicological and environmental concerns. The vast majority of toxicological studies on ionic liquids, available up to the present date, have focused on imidazolium ionic liquids. In addition, frequently, the ionic liquids ‘‘selected’’ for study tackled under a common assay were randomly chosen. Despite the scientific weight of these studies, the lack of systematisation (e.g. monitoring the effect of defined structural alterations in a specific head group) means that it is impossible at the moment to achieve a holistic analysis, which weakens conclusions and devalues the predictive algorithms under development.”(citation) Some problems regarding the selection of the bioassay, namely subjectivity and regional–orientation restrict generalizations. Legislation demands and standardised tests should be kept as a priority, engaging models of different complexity. The environmental persistence of any chemical should be taken as one of the most critical ecotoxicological parameters [88].
\n\t\t\t\t\t
The European Community regulation on chemicals and their safe use—REACH (Registration, Evaluation, Authorisation and Restriction of CHemical substances)—[89] aims to increase the awareness of the industry on hazards and risk management. REACH registration, in force since 2007, is mandatory for any chemical produced in the quantity over one tonne per year. Although it is being criticised for itsever-increasing cost and the number of animals employed intesting, [90] REACH undoubtedly provides a meaningful, and necessary, framework to raise human and environmental safety. Currently, only the ionic liquids which have already found application on industrial scale are undergoing REACH registration. As an example, as [C2mim][X] (X=Cl-, [C2SO4]-, [C1SO3]-,[O2CMe]- and [NTf2]-) and [C4mim][Cl] [91], but there are nodoubts that this number will continuously increase.It appears, however that the cytotoxicity of ionic liquids cannot be systematically estimated by a summation of the independent effects of the cation and anion [92, 93]. Moreover, mixtures (binary or ternary) of ionic liquids have been rarely investigated [94].
\n\t\t\t\t\t
The next components of IoNanofluids to be analysed are the nanomaterials used. However the toxicity of nanomaterials, although present in small mass content in the IoNanofluids, raises several problems and requires certain rules to be obeyed.
\n\t\t\t\t\t
First, the nanomaterials dispersed in the IL have different chemical and physical properties than those of bulk materials of identical composition. It is then reasonable to expect that the biological properties of nanomaterials are different as that of bulk materials. Secondly, nanomaterials may be unique in environmental or biological systems. The properties of a nanoparticle in nonpolar solvents change when extracted into the aqueous phase; furthermore, nanoparticles in biological fluids (buffered solutions, cell culture media, or blood) may behave differently, as well. The nanoparticle surface is the part of the nanoparticle system that will have direct interactions with the biological entity (as with the ionic liquid); therefore, the surface of the nanoparticle will influence the biological response. Finally, a full characterization profile of the nanoparticles system being tested in biology must be reported [95].
\n\t\t\t\t\t
The identity of the nanoparticle sample must be known in order to accurately report the positive, negative, or neutral effects of nanoparticles in vitro or in vivo. National and international standards committees (such as International Organization for Standardization, American Society for Testing and Materials, and International Council on Nanotechnology) have begun to establish recommendations for adequate nanomaterial physicochemical characterization data relevant to toxicology. These recommendations come from the literature of a variety of disciplines, including biological, environmental, and material sciences [96-98].
\n\t\t\t\t\t
There are a few key points that the growing body of nanotoxiciology literature has taught us. First, morphological characterization, such as particle size and shape, should be measured in the most dispersed state achievable. Second, ideally, particle characterization data should be measured under conditions as close to the point application as possible a property should be measured using more than one method. The successful development of safe nanomaterials requires a strong collaborative effort between toxicologists, physical scientists and engineers. All characterization data should be validated using multiple techniques. Scientists from chemistry, biology, and engineering backgrounds must work together to address issues related to the potential impacts of nanomaterials, nanocomposites, and nanoparticle-containing consumer and medicinal products on the environment, human health, and even the synthesis and manufacture of nanomaterials. The ultimate goal of this collaborative effort is to determine the effects of nanomaterials in environmental and biological systems [95].
\n\t\t\t\t\t
One key property essential to an understanding of the responses between nanomaterials and biological systems is the interaction between cells and the surface of the nanoparticle.
\n\t\t\t\t\t
Primary characterization is performed on particles as-synthesized or as-received: in its dry native state. Secondary characterization is performed on particles in the wet phase as a solution or suspension in aqueous media. This media could be in ultrapure water, vehicle solution, or cell culture media (prokaryotic or eukaryotic). Physical and chemical characterization relevant to toxicity testing includes size and size distribution (including aggregation/agglomeration/coagulation state), concentration and purity, surface activity/reactivity, particle composition of surface coatings. Tertiary characterizations are performed on particles following interactions with cells under in vivo or in vitro conditions, and imaging the nano–bio interface. Characterization data and functionality information of nanoparticles suspended in serum, media, buffers, or other biological fluids may be different than data gathered in water. Determining the toxic effect of a nanomaterial is a challenging endeavour because each study requires a comprehensive material characterization component (which includes both physical and chemical properties) and adequate toxicological evaluation (relevant to the hypothesized route of exposure and eventual biological fate) [99].
\n\t\t\t\t\t
It is difficult to produce nanomaterials on a large scale, because the mass of material produced is very small. One gram of nanoparticles is approximately equivalent to one billion particles. The immediate challenge of toxicological studies of nanoparticles is not only producing enough material for a complete in vivo study, but to also produce enough material for characterization purposes. Therefore, both new toxicological testing and characterization methods are needed when tackling this problem. New methodologies, as well as, standardization of common techniques are needed within the realm of determining the safety of nanomaterials [95,100].
\n\t\t\t\t\t
Finally this problem must be tackled as a logical sequence from laboratory synthesis to industrial production. The priority aspects will be the ecological, human health, and waste elimination besides the costs of the full operation, as the functionalities of IoNanofluids are many and extremely varied. The most important parameter to be considered is the interference parameter for the mixtures (interfacial behaviour), a logic consequence of the primordial role of the nanomaterial – IL interaction [96]. A wide range of physicochemical properties are relevant to toxicology, like particle size distribution, morphology, chemical composition, solubility and surface chemistry and reactivity [95]. Not a single method can be used, but combinations of standard tests have to devise.
\n\t\t\t\t\t
Some authors state that the surfactant may cause physical and/or chemical instability problems. The use of surfactants or any other additives to stabilize the microemulsions of the nanofluids can be worse than the nanomaterials and ionic liquids [99,100].
\n\t\t\t\t\t
A new network of existing infrastructures to ensure a cost-effective and time-efficient examination of health, safety, and environmental aspects of nanomaterials throughout Europe and linking effectively with other international related activities is urgently needed, through European Chemical Agency, ECHA [101].
\n\t\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
4. Theoretical Modelling of Nano and IoNanofluids
\n\t\t\t
Since nanofluids were found to exhibit anomalously high thermal conductivity which cannot be predicted by the existing classical models, based on macro and nanoscale mechanisms numerous theoretical models for nanofluids have been developed over the last decade [37]. However, most of these models are neither validated with wide ranges of nanofluids systems nor accepted widely. On the other hand, no theoretical model so far is available (to the best of our knowledge) for the prediction of thermal conductivity of this newly emerged IoNanofluids. Thus, in an attempt to predict the effective thermal conductivity of IoNanofluids, representative classical model as well as recent models are used here.
\n\t\t\t
The effective thermal conductivity of suspensions of milli- or micro-sized solid particles can be predicted by numerous classical models like the most popular Maxwell [102] and Hamilton-Crosser [103] models. The Maxwell model for the effective thermal conductivity (λeff) of suspensions of spherical inclusions can be expressed as [102]:
where ϕp is the particle volume fraction, and f and p are the thermal conductivities of the base fluid and particle, respectively.
\n\t\t\t
The Maxwell model [102] was later modified by Hamilton and Crosser [103] for the effective thermal conductivity of both the spherical and non-spherical particles by using a shape factor. Their model is a function of the thermal conductivities of both solid and liquid phases, volume fraction, and the shape of the disperse particles. The Hamilton-Crosser model [103] has the form:
where the shape factor n = 3 for spherical particles and n = 6 for cylindrical particles. For spherical particles, Eq.(3) reduces to Eq.(2).
\n\t\t\t
Most of the researchers working on nanofluids [37] found these classical models are unable to predict the anomalous thermal conductivity of nanofluids. Therefore, many theoretical studies have been carried out to understand the heat transfer mechanism and to develop models for predicting the effective thermal conductivity of nanofluids [37]. Among a handful of efforts, by taking into account the effects of particle size, concentration, and interfacial nanolayer two models for the prediction of thermal conductivity of nanofluids (λeff-nf) containing spherical and cylindrical nanoparticles were developed by Murshed et al. [36]. The model for suspensions of spherical nanoparticles is expressed as [36]:
where\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\tω\n\t\t\t\t\t\t=\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tλ\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tl\n\t\t\t\t\t\t\t\t\t\tr\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t/\n\t\t\t\t\t\t\t\tλ\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tf\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t,\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\tγ\n\t\t\t\t\t\t=\n\t\t\t\t\t\t1\n\t\t\t\t\t\t+\n\t\t\t\t\t\tt\n\t\t\t\t\t\t/\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tr\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tp\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t ,\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tγ\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t1\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t=\n\t\t\t\t\t\t1\n\t\t\t\t\t\t+\n\t\t\t\t\t\tt\n\t\t\t\t\t\t/\n\t\t\t\t\t\t(\n\t\t\t\t\t\t2\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tr\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tp\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t)\n\t\t\t\t\t\n\t\t\t\t ,r\n\t\t\t\t\tp\n\t\t\t\t is the radius of the particle, t and λlrare the thickness and the thermal conductivity of interfacial nanolayer, respectively. On the other hand, model for the cylindrical nanoparticles has the form [36]:
Although the thickness of nanolayer (t)is considered to be 1 nm [36], the thermal conductivity of a nanolayer still cannot be determined by experimental or theoretical means. However, the orderness and orientation of fluid molecules absorbed on a nanoparticle surface result in an intermediate value of thermal conductivity of nanolayer i.e., λf<λlr<λp. Hence, the thermal conductivity nanolayer is given by\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tλ\n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t1r\n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t=\n\t\t\t\t\t\t\tω\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tλ\n\t\t\t\t\t\t\t\tf\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t, where ω>1 is an empirical parameter which depends on the orderness of fluid molecules in the interface as well as the nature and surface chemistry of nanoparticle. In this study, t = 1 nm and ω=1.2 were used.
\n\t\t\t
The measured and predicted thermal conductivity of nanofluids and IoNanofluids were compared in our previous study [104] and it has been depicted here. It can be seen from Figure 8that while the recent model by Murshed et al. [36] (i.e., Eq.(4)) shows fairly good prediction of the effective thermal conductivity of [C4mim][NTf2]-based Ionanofluid at low concentration of multi-wall carbon nanotubes (MWCNT), classical Hamilton-Crosser model [103] severely over-predicts the results. It is noted that the weight concentrations of MWCNT were converted to corresponding volumetric concentrations for the predictions by both models. Due to almost identical thermal conductivity values of both base ionic liquids i.e., [C4mim][NTf2] and [C2mim][EtSO4], both models give similar predictions for [C2mim][EtSO4]-based Ionanofluid [104]. However, at a high MWCNT concentration of 3 wt % (equivalent to 19.3 volume %) it is anticipated that the increase in thermal conductivity will not be as high as for the low concentration and any classical or recent model can easily over-predict the thermal conductivity at such a high concentration. This is mainly due to absence of dynamic mechanism for such high concentration.
\n\t\t\t
Figure 8.
Comparison between predicted and measured thermal conductivity of nanofluids and IoNanofluids as a function of MWCNTconcentration [104]. - [C4mim][NTf2] + MWCNT; - [C2mim][EtSO4] + MWCNT; - water + MWCNT;- - - Eq. (3) for [C4mim][NTf2] + MWCNT;Eq. (5) for [C4mim][NTf2] + MWCNT.
\n\t\t\t
Although by adjusting fitting parameters nanofluids´ thermal conductivity models [36] can be used for IoNanofluids, it is important to understand the underlying mechanisms and to develop model for thermal conductivity and other thermo-physical properties of IoNanofluids by taking into account electrochemical factors and molecular level structuring and interactions of both the base ionic liquids and the dispersed nanoparticles.
\n\t\t
\n\t\t
\n\t\t\t
5. Conclusions and Looking Forward
\n\t\t\t
IoNanofluids are shown to be a very interesting class of nanofluids for many engineering applications, namely in heat transfer and storage. Although there are still a short number of publications with IoNanofluids, the number is definitely increasing, as a very recent paper with grapheme shows [105]. Regardless of the small current industrial production of ionic liquids, the base fluids, it is expected to increase in a short term, because the properties of ionic liquids are very attractive as green solvents and reactants. The evolution of their chemistry has been tremendous and therefore, the price of their production will decrease to levels that will make them competitive with current fluids used in industry.
\n\t\t\t
The manufacture, handling and characterization of IoNanofluids is still in development, but it is thought that significant progress will be made in a near future, namely in the nanoparticles and emulsions characterization. Further fundamental and applied studies are needed.
\n\t\t\t
One special topic of concern is the toxicity of IoNanofluids, a reflex not only of the toxicity of the base ionic liquids but also of the constituent nanomaterials. Depending on the ionic liquids used, the systems can be toxic and all the users must be aware of it. However those IoNanofluids based on hydrophilic ionic liquids are a safe choice. In addition, there is also a risk with the nanomaterials used, and there is a wide awareness of how important is to study their effect in vitro and in vivo systems. A wide range of physicochemical properties are relevant to toxicology, like particle size distribution, morphology, chemical composition, solubility and surface chemistry and reactivity. The specific interactions of the ionic liquids with the nanomaterials can alter the individual toxicity of them. Many studies are still necessary to reach all the necessary conclusions and compliance with existing legislation, namely in Europe.
\n\t\t\t
The application of existing models to predict the behaviour of the IoNanofluids, namely the enhancement in the thermal conductivity, showed that it is fundamental to understand better the mechanism of heat transfer in these systems, namely the role played by the interface ionic liquid (cation and anion)-nanoparticle, whatever shape they have. This needs theoretical developments and molecular simulation studies that will give the insight for developing new heat transfer models.
\n\t\t
\n\t
Acknowledgments
\n\t\t\t
This research was partially funded by FCT- Fundação para a Ciência e a Tecnologia, Portugal, through Centro de Ciências Moleculares e Materiais, PEst-OE/QUI/UI0536/2011 and PDCT/QUE-FTT/104614/2008.
School of Chemistry and Chemical Engineering/QUILL, Queen’s University, U. K.
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Lajunen",authors:[{id:"18856",title:"Prof.",name:"Konstantin",middleName:null,surname:"Popov",fullName:"Konstantin Popov",slug:"konstantin-popov"},{id:"18860",title:"Prof.",name:"Marja",middleName:null,surname:"Lajunen",fullName:"Marja Lajunen",slug:"marja-lajunen"}]},{id:"13931",title:"The Design of Nanoscale Inorganic Materials with Controlled Size and Morphology by Ionic Liquids",slug:"the-design-of-nanoscale-inorganic-materials-with-controlled-size-and-morphology-by-ionic-liquids",signatures:"Elaheh Kowsari",authors:[{id:"16210",title:"Dr.",name:"Elaheh",middleName:null,surname:"Kowsari",fullName:"Elaheh Kowsari",slug:"elaheh-kowsari"}]},{id:"13932",title:"Synthesis of Novel Nanoparticle - Nanocarbon Conjugates Using Plasma in Ionic Liquid",slug:"synthesis-of-novel-nanoparticle-nanocarbon-conjugates-using-plasma-in-ionic-liquid",signatures:"Toshiro Kaneko and Rikizo Hatakeyama",authors:[{id:"19594",title:"Prof.",name:"Toshiro",middleName:null,surname:"Kaneko",fullName:"Toshiro Kaneko",slug:"toshiro-kaneko"},{id:"19595",title:"Prof.",name:"Rikizo",middleName:null,surname:"Hatakeyama",fullName:"Rikizo Hatakeyama",slug:"rikizo-hatakeyama"}]},{id:"13933",title:"Nanoparticle Preparation in Room-Temperature Ionic Liquid under Vacuum Condition",slug:"nanoparticle-preparation-in-room-temperature-ionic-liquid-under-vacuum-condition",signatures:"Tetsuya Tsuda, Akihito Imanishi, Tsukasa Torimoto and Susumu Kuwabata",authors:[{id:"18431",title:"Dr.",name:"Tetsuya",middleName:null,surname:"Tsuda",fullName:"Tetsuya Tsuda",slug:"tetsuya-tsuda"},{id:"20450",title:"Prof.",name:"Tsukasa",middleName:null,surname:"Torimoto",fullName:"Tsukasa Torimoto",slug:"tsukasa-torimoto"},{id:"20451",title:"Prof.",name:"Susumu",middleName:null,surname:"Kuwabata",fullName:"Susumu Kuwabata",slug:"susumu-kuwabata"},{id:"20467",title:"Prof.",name:"Akihito",middleName:null,surname:"Imanishi",fullName:"Akihito Imanishi",slug:"akihito-imanishi"}]},{id:"13934",title:"Perspectives of Ionic Liquids Applications for Clean Oilfield Technologies",slug:"perspectives-of-ionic-liquids-applications-for-clean-oilfield-technologies",signatures:"Rafael Martínez-Palou and Patricia Flores Sánche",authors:[{id:"18064",title:"Dr.",name:"Rafael",middleName:null,surname:"Martínez Palou",fullName:"Rafael Martínez Palou",slug:"rafael-martinez-palou"},{id:"24168",title:"Dr.",name:"Patricia",middleName:null,surname:"Flores Sánchez",fullName:"Patricia Flores Sánchez",slug:"patricia-flores-sanchez"}]},{id:"13935",title:"Ionic Liquid Based Electrolytes for Dye-Sensitized Solar Cells",slug:"ionic-liquid-based-electrolytes-for-dye-sensitized-solar-cells",signatures:"Chuan-Pei Lee, Po-Yen Chen and Kuo-Chuan Ho",authors:[{id:"5989",title:"Prof.",name:"Kuo-Chuan",middleName:null,surname:"Ho",fullName:"Kuo-Chuan Ho",slug:"kuo-chuan-ho"},{id:"30213",title:"Dr.",name:"Chuan-Pei",middleName:null,surname:"Lee",fullName:"Chuan-Pei Lee",slug:"chuan-pei-lee"},{id:"30223",title:"BSc.",name:"Po-Yen",middleName:null,surname:"Chen",fullName:"Po-Yen Chen",slug:"po-yen-chen"}]},{id:"13936",title:"Quaternary Ammonium and Phosphonium Ionic Liquids in Chemical and Environmental Engineering",slug:"quaternary-ammonium-and-phosphonium-ionic-liquids-in-chemical-and-environmental-engineering",signatures:"Anja Stojanovic, Cornelia Morgenbesser, Daniel Kogelnig, Regina Krachler and Bernhard K. Keppler",authors:[{id:"17516",title:"Dr.",name:"Daniel",middleName:null,surname:"Kogelnig",fullName:"Daniel Kogelnig",slug:"daniel-kogelnig"},{id:"20872",title:"Dr.",name:"Anja",middleName:null,surname:"Stojanovic",fullName:"Anja Stojanovic",slug:"anja-stojanovic"},{id:"20873",title:"Dr.",name:"Regina",middleName:null,surname:"Krachler",fullName:"Regina Krachler",slug:"regina-krachler"},{id:"20874",title:"Dr.",name:"Bernhard K.",middleName:null,surname:"Keppler",fullName:"Bernhard K. Keppler",slug:"bernhard-k.-keppler"},{id:"24420",title:"MSc.",name:"Cornelia",middleName:null,surname:"Morgenbesser",fullName:"Cornelia Morgenbesser",slug:"cornelia-morgenbesser"}]},{id:"13937",title:"Ionic Liquids within Microfluidic Devices",slug:"ionic-liquids-within-microfluidic-devices",signatures:"Marina Cvjetko and Polona Žnidaršič-Plazl",authors:[{id:"18755",title:"Dr.",name:"Polona",middleName:null,surname:"Žnidaršič-Plazl",fullName:"Polona Žnidaršič-Plazl",slug:"polona-znidarsic-plazl"},{id:"23486",title:"Ms.",name:"Marina",middleName:null,surname:"Cvjetko Bubalo",fullName:"Marina Cvjetko Bubalo",slug:"marina-cvjetko-bubalo"}]},{id:"13938",title:"Ionic Liquids: Methods of Degradation and Recovery",slug:"ionic-liquids-methods-of-degradation-and-recovery",signatures:"E.M. Siedlecka, M. Czerwicka, J.Neumann, P. Stepnowski, J.F Fernández and J. 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1. Introduction
It is quite well-known that classical 2D cell lines and in vivo models have been used near universally to investigate biological mechanisms and assess novel therapies across a large range of clinical problems [1]. Nevertheless, the results from these experiments are critically limited by a systemic lack of translational power for the response, efficacy, safety, and toxicity in humans despite its primary benefits in clinical research [2, 3]. Cell lines generically display insufficiency and inaccuracy in modeling the immune system, stromal components, and organ-specific functions after multiple passages [4]. Leaving aside animal welfare arguments, species-specific variations in organ development and pathogenesis are a long-standing bottleneck due to which animal models cannot mimic a given human disease that is polymorphic, to begin with [5]. Therefore, to define and treat disease pathology seamlessly, biologists exploited the critical features of stem-cell and came up with three-dimensional (3-D) or organotypic cultures or organoids from human samples that could successfully phenocopy cell-type composition, architecture, and to some extent, functionality (e.g., contraction, filtration, excretion, neural activity, etc.) of their natural counterparts [6, 7, 8].
Organoids, a term coined for referring to ‘mini organs’, [9] are best described as in vitro three dimensional (3D) cellular clusters exclusively derived from healthy cells – like primary tissue, embryonic stem cells, or induced pluripotent stem cells (iPSCs) [10] or even tumor cells [11]. Since these cells are capable of self-renewal and self-organization, organoids portray outstanding similarity to organ functionality as the tissue of origin compared to other conventional routes [2, 12]. The sole purpose of developing organoids is to recreate and miniaturize the multicellular structure of organs while retaining the 3-dimensional construct indefinitely.
It can now be commented that the development of organoid technology has generated a robust new methodology to zoom into the physiological events ex vivo, and this fact can be explained. Firstly, scientists have a wider domain of cell types to choose from, some of which were historically hard-to-access; secondly, organoids contain multiple differentiated cell types; and thirdly, organoids are genetically stable [13]. The intrinsic nature of this innovative near-physiological technology has created a paradigm shift in our understanding of basic developmental biology or stem cell research directed to a host-pathogen relationship in infectious diseases, degenerative conditions, genetic disorders, oncology, genome engineering, biobanking, and regenerative and personalized medicine [14, 15]. Through a complete visualization of spatiotemporal cellular interactions, organoid modeling reflects the predominant structural and functional properties of essential organs like kidneys [16], lungs [17, 18, 19, 20], gut [21], brain [22], prostate [23], heart [24] and retina [25].
Human organoids are intrinsically human-derived, rapid-to-set-up, robust in scaling up, and ideal for genetic manipulation and personalization [26]. In simple terms, the organoid is an attractive strategy for clinical applications and bridges the gap between basic research and clinical practice. Along these lines, biomedical and pharmaceutical investigations on particularly relevant, rigorously designed, well-characterized, and controlled organotypic models will travel a long way in redefining fundamental discoveries, testing novel hypotheses at the 3D level and for the validation of critical data without sacrificing the integrity of any living being in the name of science. It should also be kept in mind that this technology is still in its infancy; much of the current hype originates from its enormous potential rather than a finite number of real-life scientific advancements. Hence, COVID-19 researchers use bronchial, respiratory, liver, kidney, intestine, and brain organoids to study the pathogenesis of SARS-CoV-2 and virus-specific cellular reaction on various organ systems.
In this chapter, we aim to answer a plethora of scientific questions related to the situation around the SARS-CoV-2 battle in the light of organoid technology, emphasizing key findings in therapeutic interventions meant to prevent and cure the serious medical threats imposed by SARS-CoV-2. We will highlight the state-of-the-art tools and methodologies available for human organoid lines and deep-dive into the case studies of fantastic in vitro organ models that well-known research groups have employed for understanding the root cause of COVID-19 devastation.
2. Virology and organoid
It is well-known that immortalized cell lines and animal models have paved the way for identifying the pathobiology of obligate intracellular parasites or viruses. Despite their paramount role in this field, none can adequately reproduce human disease pathology or exactly recapitulate the homeostatic functions of a normal cell. Therefore, virologists have moved on from carrying out investigations on non-natural hosts to patient-derived organoid models to address the unmet need for human model systems in studying virology and its therapeutic interventions [27]. Organoid technology, a human-based model technique, has broadened the scope for studying viral infections by enhancing the translatability of results from in vitro cell cultures or ex vivo animal systems to a more human in vivo mimicking condition. Since the route of host-pathogen interactions largely varies based on virus nature and its host type, including age, sex demographic profile, and genetic constitution of the hosts, it is crucial to have an accurate prototype of its natural host to conduct the experiments.
2.1 Culturing the unculturable
At almost all stages of replication, viruses associate closely with the host cell, and therefore the cell model used to research virus infection is crucial. Primary cells better represent the phenotype of healthy cells in vivo but have a short lifetime, are difficult to culture, and are heterogeneous and thereby renders manipulating them difficult. The widespread use of immortalized cell lines for culturing diverse virus strains is a common practice, but the induction of interferon-stimulated genes and other antiviral defenses is defective in many tumor-derived and artificially immortalized cell lines. These flaws can interfere with virus replication, particularly when cells are infected at lower, more physiologically important multiplicities. Moreover, there are some challenging cases where the virus fails to adapt in man-made culture conditions, like, norovirus or other enteric viruses, which remain unculturable to date in any kind of cell line system. Luckily for us, stem-cell-derived human intestinal organoids have successfully grown and studied these viral cultures up to one round of infection [28]. Similarly, respiratory viruses which are challenging to grow in cell lines like human coronavirus HKU1, human bocavirus, and human rhinovirus C could be successfully isolated from clinical specimens using Human airway epithelial (HAE) cultures [29, 30, 31]. These data prove that there is room for discovering unknown viruses and their mechanism of infection, pathogenesis, and immune escape through the fine-tuning of crucial features of the organoid platform [32].
2.2 Reproducing the natural virus host environment
Viruses isolated from patient samples like feces, blood, or nasopharyngeal swabs infested with a particular infection, can be grown on organoids without any imposed mutation or adaption. These cultures will now exactly recapitulate the fundamental features and infectivity profiles of the natural host cell [33, 34]. Therefore, conclusions drawn on the various aspects of organotropism, receptor usage, innate immunity induction, etc., is now even more reliable than laboratory-adapted or ATCC strains. The readouts used for post-infection analysis may differ in cell lines vs. organoids based on the culture environment and discussed in the following sections.
2.3 Provide new insights
Data from cell lines have earlier shown that the small open reading frame upstream of the main polyprotein ORF which is also present in the 5’UTR genomic region in enteroviruses, cannot be utilized for the initiation of translation [35]. Lulla et al. had reported for the first time that the small protein encoded by this uORF is crucial for virus release in human intestinal organoids [36]. The viruses lacking this uORF are therefore attenuated in this model. Later on, other publications on intestinal organoids have reiterated that different enteroviruses infect different cell types and induce an antiviral response characteristic of a particular cell type [37, 38].
To assess the influence of host conditions such as age and comorbidities on the progress and severity of viral infections, cross-interactions between co-detected pathogens in a single host can be studied closely with organoids. This was never feasible with cell lines because different viruses are often not culturable on the same cell line. For example, respiratory viruses are well-known for causing asthma and pathologies like cystic fibrosis or chronic obstructive pulmonary disease. HAE infection samples collected from healthy and asthmatic donors with rhinovirus have shown a unique airway epithelial structure with inflammatory signaling in asthmatic patients [39, 40].
2.4 Utilization in fighting the SARS-CoV-2 pandemic
Multiple types of organoid models were used to study the detrimental effect of SARS-CoV-2 infection on human hosts and its potential therapeutic interventions [41]. To begin with, HAE cultures served as faithful models for the lungs where efficient replication occurred through the infection of ciliated cells in the airway [42]. Therapeutic investigations on organoid models showed the repurposed drug remdesivir and remdesivir–diltiazem to be functional in resisting further SARS-CoV-2 infection [43]. Lamers et al. had proved for the first time that the human gut epithelium is the second major replication site of the virus [44]. Combined with the novel insights from other organoid research groups, it was proved that the SARS-CoV-2 genome is detectable in feces even after the virus is absent from oropharyngeal swabs, which explains the outcome of intestinal infection and potential fecal transmission [45].
These findings were closely followed by the observation of increased efficiency to infect secondary tissue by the virus. In terms of relative importance, the next area of investigation using organoids has been establishing the neuro-invasive aspect of SARS-CoV-2 by using brain organoid models [46]. Epidemiological studies showed the direct contribution of SARS-CoV-2 infection to neurological complications like headaches, ischemic stroke, and encephalitis, including cranial nerve-related complications such as anosmia and hyposmia, and ageusia [47, 48]. Recently, Pellegrini et al. utilized choroid plexus organoids to demonstrate the potential viral tropism for choroid plexus epithelial cells that affect the epithelium [49]. Damage to this barrier is suspected as a possible entry route for the virus into the cerebrospinal fluid and the brain.
2.5 Extensive research in Zika virus pandemic
Zika virus, a mosquito-borne flavivirus, is reportedly the causative agent for the infection known as ZIKV. Although adult victims show mild symptoms, newborns are marked with microcephaly, a condition in which infants are born with an abnormally small head. Being spread in over 70 countries and territories globally, [50] ZIKV is declared a global health emergency by WHO whereby microcephalic fetal tissues have shown traces of ZIKV in damaged fetal brains [51]. Due to accessibility challenges with live infected human fetal samples and postmortem tissues showing a diverse range of quality and genetic history, clinical examinations are replaced for good by brain organoid model studies. These focus on cellular tropism and pathogenesis mechanisms of ZIKV in controlled settings [52].
In 2016, the first study on brain organoid models was published by Tang et al., where they used monolayer cultures of forebrain-specific neural progenitor cell (NPCs) to model ZIKV infection during human brain development [53]. These were the initial results towards projecting that ZIKV more efficiently infects NPCs layers over human pluripotent stem cells (hPSCs) or immature neurons. Infection of cerebral organoids and human neurospheres with ZIKV and dengue virus 2 (DENV2) has proved that only ZIKV attenuates NPC growth, suggesting that the extreme aftereffect of ZIKV infection as an exceptional feature of the flavivirus family [54]. Later on, studies using brain organoids derived from hPSCs have also led to a significant understanding of various other aspects of ZIKV infection on fetal brain development [52].
Due to the limited accessibility of organoid methodologies to virology research groups and the delay in the pace of commercialization of this technology, the majority of the published work so far has been a result of cross-functional collaborative efforts [55]. This challenge is closely followed by complications arising from heterogeneity inherent to the structural complexity and cell-type diversity in brain organoid models compared to simpler analogs such as neurospheres [56]. Moreover, the low-throughput nature of culturing and analyzing organoids creates a significant obstacle in drug screening which usually needs a high-throughput styled experimental protocol. We anticipate the evolution of more sophisticated brain organoids in the future that involves the co-culturing of endothelial cells or microglial cells to enhance the physiological relevance of modeling ZIKV infection during fetal human brain development.
2.6 Technical challenges
The classical nature of 3D organoid models was closed round structures embedded in Matrigel, challenging to infect with viruses as receptors needed for infection are always located deep inside. This shortcoming was overcome in HAE cultures where cells are grown on a Transwell. Therefore, round gut organoids can be easily transformed into an open organoid model where they are accessible from the upper and lower sides simultaneously to establish the desired infection [28, 57, 58]. This model system is technically advantageous for infectious disease studies and drug-testing in antimicrobial therapy.
The next significant challenge worth consideration is readouts used for analysis after infection. Due to the release of viral particles in a nonlytic manner, virus cultures in primary cellular models do not result in plaque-like cytopathic effect (CPE) most of the time, for example, in the case of enterovirus A71. Huang et al. have shown using human intestinal organoids that are infected with enterovirus A71 that viral release happens through exosomes instead of a lytic process characteristic of a classical RD cell line [59]. This production is quantified through back titration or plaque assays using cell lines. The aforementioned protocol of measurement of the number of viral particles is a matter of concern in the case of primary cultures, which calls for more suitable evaluation methods.
3. COVID-19 and organoid
The severe acute respiratory syndrome coronavirus (SARS-CoV) first emerged in the human population in November 2002. Phylogenetic analysis of this viral isolate indicated that it has a zoonotic origin, and horseshoe bats (R. sinicus) seem to be its natural reservoir. With local travel restrictions and a wildlife trade ban, there were no further naturally acquired human cases of SARS in Guangdong, China. In late 2019, a novel coronavirus, SARS-CoV-2, again crossed the animal-to-human interspecies barrier to infect humans [60]. Palm civets and other mammals acted as their amplification hosts, which resulted in a super-transmissible form that could effectively spread from human to human at an unprecedented rate. This rapid propagation happened by the deposition of infected droplets or aerosols on the respiratory epithelium. This led to a pneumonia outbreak in Wuhan, China [61] which causes coronavirus disease-19 (COVID-19) marked by symptoms like fever, cough, shortness of breath, myalgia, fatigue, and sometimes gastrointestinal symptoms such as nausea, vomiting, and diarrhea [62]. Viral RNA was detected in patients’ respiratory, stool and urine specimens. This condition can extend to severe lung injury and multi-organ failure, eventually leading to death in senile and comorbid patients.
In a few months, the virus had disseminated globally and sustained its pathogenicity irrespective of external factors. After WHO declared this a public health emergency of pandemic proportions, there were several lockdowns, social distancing protocols, hygienic measures, strict travel bans, strategic medical care, and vaccination programs to control the obnoxity of this outbreak. Even after one year of a relentless pandemic situation, the world is trying hard to combat the collateral damage to the global economy, public health, and civil life.
Genomic analyses of SARS-CoV-2 prove ~96% identity to the bat coronavirus BatCoV RaTG13 and 88% identity to two other bats SARSr-CoVs [61, 63, 64]. Sharing multiple similarities with SARS-CoV [65], phylogenetic analysis of SARS-CoV-2 shows that it belongs to lineage B of the beta-coronavirus genus in the family Coronaviridae [63] and has a possible common host cell receptor due to similarity in the receptor-binding domain. Animal model studies further confirmed that Angiotensin-converting enzyme 2 (ACE2)-dependent viral entry into cells is a critical step [66]. The evolution of different mutants is another concern, and quick studies can help understand the infectivity, pathogenesis, and targeting better. The B.1.1.7 variants in England, B.1.351 mutant in South Africa, P.1 in Brazil, B.1.427 in California, and now B.1.617, a “double mutant” common in India, have caused havoc on life and the economy.
Like SARS and MERS, pathobiology of the recently emerged COVID-19 is not limited to the respiratory tract because the damage has been observed and confirmed repeatedly in multiple organs [65], albeit the lungs are the main site of the infection. To investigate the rationale behind the organotropism of SARS-CoV-2, we need 3D model systems that mimic the physiological conditions at their best. Herein, organoid technology comes in as the basic framework of COVID-19 research with a much higher impact than animal models and cellular studies. Fortunately, the past decade has witnessed a revolutionary breakthrough in the generation of organoids for almost every human organ, including intricate systems like the heart, intestine, brain, and lung organoids. In the following sub-sections, we will discuss the constitution, contribution, limitations, and future applications of organoid technology in understanding the mechanism of organotropism by SARS-CoV-2 (Section 3.1-3.4), which influences and, in most cases, aggravates comorbid conditions in COVID-19 patients.
The first step in the pipeline of using 2D and 3D models for COVID-19 studies in vitro starts with tissue dissociation from different organs and is followed by stem/ progenitor cell isolation using popular sorting methods like fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) (Figure 1). Sorted stem/progenitor cells are cultured in a 3D organoid culture system and subjected to SARS-CoV-2, which mimics the organ-specific infection. Different aspects of the post-infection studies like infection rate, gene expression analysis, infection mechanism, immune-response, inflammatory response, and histology can be studied. The 3D-organoid models can then be subjected to drug screening, drug repurposing, and vaccine development-related studies (Figure 1). Figure 1 provides a layout of the COVID-19 research platform.
Figure 1.
The COVID-19 research platform’s layout using 3D organoids. Tissue dissociation from various organs is the first step in the pipeline for using 2D and 3D models for Covid-19 studies in vitro. Isolated stem/progenitor cells by fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) cells are grown in 3D using extracellular matrix mimetics and nourished with niche-specific culture medium. Stem/progenitor cells derived from various tissues self-organize into tissue-specific organoids. 3D organoid cultures are infected with SARS-CoV-2. Various aspects of post-infection studies can be conducted as shown.
3.1 Lung organoid
Dan et al. described an approach to synthesizing patient-specific lung tissue in a modular method to model relevant human lung disease, as well as for high-throughput drug screening to detect targeted therapies [67]. The first development of long-term differentiated human airway organoid cultures, which can morphologically and functionally simulate human airway epithelium, was done by Z. Zhou et al. to predict the infectivity of influenza viruses [68]. Optimized to contain the four major airway epithelial cell types- ciliated, goblet, club, and basal cells, these organoids were exposed to two ‘pairs’ of already studied viruses. Resultantly, the pair of humans-infective virus replicated more robustly than the pair of matched viruses poorly infective in humans.
Several in vitro models, such as Vero cells, Huh7 cells, and human airway epithelial cells, have been used early on in the COVID-19 pandemic to isolate and study the SARS-CoV-2 virus. These studies took a notch up when SARS-CoV-2 was isolated and propagated in TMPRSS2-expressing Vero E6 cells, thereby proving the indispensable role of TMPRSS2 serine protease in viral replication. Nevertheless, these models are limited by their poor representation of the histology, physiology, and pathology of the events occurring in our respiratory tract [69]. Y. Han et al. have developed a lung organoid model of alveolar type II cells using human pluripotent stem cells (hPSCs) that could be adapted for drug screens [70]. This organotypic culture was able to express ACE2 and are permissive to SARS-CoV-2 infection. High throughput screening experiments identified FDA-approved drug candidates, ima-tinib and mycophenolic acid, which are efficient inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids.
To test the validation of Remdesivir, a Covid-19 drug candidate, A. Mulay et al. successfully developed and infected differentiated air-liquid interface cultures of proximal airway epithelium and organoid cultures of alveolar epithelium by SARS-CoV-2 [71]. They displayed an epithelial cell-autonomous proinflammatory response that proved the relevance of this platform for studying COVID-19 pathobiology and rapid drug screening against SARS-CoV-2.
3.2 Brain organoid
While the Coronavirus disease 2019 manifests clinically acute respiratory symptoms along with fever [72], a large subset of patients, especially younger victims, develop complete or partial olfactory dysfunction (anosmia/hyposmia) during the course of infection [73]. This loss in olfaction occurred without (83%) associated rhinorrhea or nasal congestion at a median of 0.5 days after symptom onset [74]. While the majority of patients recovered within a couple of weeks from the onset of olfactory symptoms, few continued to have refractory and disabling anosmia [75]. Neurological symptoms like headache, dysgeusia, confusion, seizure, and viral encephalitis have been reported in 36.4% of 214 COVID-19 patients in Wuhan, China, where 45.5% of patients had severe SARS-CoV-2 infections [47, 76]. Similarly, France and Germany reported neurologic findings in 84.5% (49/58) and 36.4% (8/22) of COVID-19 patients, respectively, of which the latter studies had detected viral RNA in brain biopsies of patients who succumbed to the disease [77].
In 2016, D. Pamies et al. had put forward human mini-brains or BrainSpheres- an organotypic brain model derived from iPSC for the first time [78], comprising of different types of neurons, astrocytes, and oligodendrocytes. After its application on Zika, Dengue, HIV, and John Cunningham (JC) virus, they used this model to understand the extent of SARS-CoV-2 virus infection in human brain cells. Their results demonstrated that SARS-CoV-2 could infect and replicate in cells of neuronal origin, thereby proving the critically potential neurotropism of SARS-CoV-2. In yet another study, the same group had shown that SARS-CoV-2 could directly infect and effectively damage the olfactory sensory neurons of golden Syrian hamsters [75]. The entry receptor of the spike protein in SARS-CoV-2, ACE2, is widely detected in the brain, especially in the substantia nigra, middle temporal gyrus, and posterior cingulate cortex [79, 80]. Interestingly, serine protease TMPRSS2 expression was undetectable in the BrainSpheres, which suggests an alternative mechanism for spike (S) protein priming during viral entry. Together, these findings indicate that the human brain might be an extra-pulmonary target of SARS-CoV-2 infection.
Initially, it was proposed that anosmia and ageusia happen due to infection of non-neuronal cells in the olfactory system [81], which was busted by reports supporting the presence of viral particles in the CNS biofluid [82] and signs of neural damage biomarkers in the plasma of COVID-19 patients [83]. Taken together, a direct infection rather than a secondary immune response seems more accountable for neurological outcomes and predicted future neurodevelopmental disorders. Given that the human brain is arguably an extra-pulmonary target of SARS-CoV-2 infection, biologists and neuroscientists also need to figure out the impact of SARS-CoV-2 on a prototypical developing brain. Brain organoid research or the BrainSphere model is also limited by the absence of microglia or brain immune cells since they originate from the mesoderm germ layer and invade the developing brain from the blood, unlike neural precursor cells [84].
3.3 Gut organoid
While most COVID-19 patients suffer from mild to severe respiratory illnesses, >50% of patients manifest gastrointestinal disorders with prolonged symptoms like diarrhea, nausea, etc., which becomes severe to fatal when left unattended [85]. Although the virus has been detected in the upper respiratory tract of humans, proving the nasopharynx as a prominent site of replication, the highest expression of ACE2 occurs in the brush border of intestinal enterocytes [86]. Interestingly, when 53% of a cohort of 73 hospitalized patients had SARS-CoV-2 RNA in stool specimens, viral RNA was found in rectal swabs of 23% of patients even after negative nasopharyngeal testing, which implied fecal-oral transmission route leading to gastrointestinal infection or vice-versa [87, 88]. Of note, viral nucleoprotein-positive cells were found in the gastrointestinal epithelial cells from biopsy specimens [89] and pediatric patients [90]. Also, the SARS-CoV-2 receptor ACE2 is highly expressed on differentiated enterocytes suggesting that the intestine is a vital target organ for the pathogen. Therefore, models to understand the mechanism of SARS-CoV-2 and validate drug efficiency in the gut for COVID-19 patients are the need of the hour.
Based on the high homology of SARS-CoV-2 to SARS-related coronaviruses isolated from horseshoe bats, J. Zhou et al. established and characterized expandable intestinal organoids derived from Chinese horseshoe bats of the Rhinolophus sinicus species that can recapitulate bat intestinal epithelium [41]. These bat enteroids were readily infectable and could sustain SARS-CoV-2 replication. They also demonstrated active replication of SARS-CoV-2 in human intestinal organoids along with isolation of infectious virus from the stool specimen of diarrheal COVID-19 patients [91]. This again confirmed that the established culture conditions for human intestinal organoids could be extended to other members of the mammalian species.
This report, along with the work done by M. M. Lamers et al. [44] and R. Zang et al., unanimously reported that the intestine is a potential site of SARS-CoV-2 replication since enterocytes, the most common cell type of the intestinal epithelium, get readily infected [92]. M. M. Lamers et al. established human small intestinal organoids (hSIOs) from primary gut epithelial stem cells containing all proliferative and differentiated cell types of the in vivo epithelium [44]. Of note, hSIOs have been utilized for in vitro culturing of norovirus for the first time. The authors used confocal and electron microscopy to show that SARS-CoV and SARS-CoV-2 infect enterocyte lineage cells in an hSIO model. They reported similar infection rates of enterocyte precursors and enterocytes, whereas ACE2 expression increased ~1000-fold upon differentiation at the mRNA level. Therefore, while the infected enterocytes upregulated the viral response genes through cytoplasmic sensing of the viral RNA genome, the host-cell membrane-bound serine proteases TMPRSS2 and TMPRSS4 were found to cleave the SARS-CoV-2 spike protein to facilitate viral entry. They conclude the following facts from this study: (a) intestinal epithelium supports SARS-CoV-2 replication, (b) hSIOs serve as a faithful biological model for coronavirus infection, and (c) viral entry is supported even at low ACE2 concentrations.
Since organotypic cultures are derived from pluripotent or organ restricted stem cells having the ability to mimic a natural 3D environment, they need a cell source with excellent self-renewal ability. The gut is one such source that allows unlimited replenishments of a particular cell type or tissue. Single-layered human intestinal organoids (HIOs) derived from human adult gut stem cells contain only epithelial cell types [93]. Pluripotent stem cells derived from HIOs (PSC-HIOs) made of endodermal/mesodermal progeny [94], resembling epithelium and fibroblasts or gut capillaries, respectively [95]. While PSC-HIOs are not 100% mature, HIOs are architecturally too simple, resulting in lower in vivo transplantability and analytical access to intermediate developmental stages. Until further modifications are done on them, both models are comparable and complementary to each other with model-specific pros and cons. As per previous reports, HIOs express ACE2 and are susceptible to SARS-CoV-2 [44, 92].
Inspired by the prior human intestinal organoids derived from pluripotent stem cells (PSC-HIOs) for modeling of gastrointestinal infections, J. Kruger et al. used this organoid model to dissect SARS-CoV-2 pathogenesis and then study its inhibition by remdesivir and famotidine (histamine-2-blocker), a potential drug candidate for COVID-19 treatment [96]. Immunostaining for ACE2 and TMPRSS2 showed large expression in the gastrointestinal tract with maxima in the intestine. This ready infection of organoids with SARS-CoV-2 followed by the viral spread across entire PSC-HIOs subsequently led to organoid deterioration except goblet cells lacking ACE2 expression. The drug testing data showed that remdesivir and EK1 (but not famotidine) effectively inhibited SARS-CoV-2 infection in a dose-dependent manner at a low micromolar concentration which rescued the morphology of PSC-HIOs. This is a benchmark study that has established the applicability of PSC-HIOs in the field of organ-specific drug testing related to gut infection, like SARS-CoV-2, rotavirus, norovirus, enterovirus 71, and human adenovirus.
3.4 Human capillary organoids
Since ACE2 is the SARS-Cov-2 receptor, clinical-grade human recombinant soluble ACE2 (hrsACE2) has already undergone clinical phase 1 and phase 2 testing. hrsACE2 slowed or even stopped the virus’s systemic dissemination from the lungs to other tissues, including potentially reducing SARS-CoV-2 attacks on the endothelial cells of the blood vessel linings. hrsACE2 has shown promising therapeutic efficacy in treating severe COVID-19 [97]. To this end, V. Monteil et al. pursued the development of engineered human blood vessel organoids and human kidney organoids to get confirmatory evidence on the effect of hrsACE2 on SARS-CoV-2 infection in multiple human organoid models [98].
To begin with, they first isolated the SARS-CoV-2 from a nasopharyngeal sample of a patient in Sweden with confirmed COVID-19, cultured it on Vero E6 cells, and successfully isolated the virus for characterization by next-generation sequencing and electron microscopy. The cellular studies showed that hrsACE2 can reduce viral growth in Vero E6 cells by a factor of 1,000–5,000. Their data demonstrated that hrsACE-2 can inhibit in vitro SARS-CoV-2 infection in a dose-dependent manner, unlike mouse rsACE2 highlighting the specificity of hsrACE2 in blocking SARS-CoV-2 entry. With the in vitro evidence at hand, they moved on to the organoid model studies.
Before getting into the deeper details, let us have a look at the background for capillary organoid research in the light of SARS-CoV-2. It was already well-known during that time that viremia initiates during the course of COVID-19 despite the irregular observation of viral RNA in blood [88]. However, a viral size of 80–100 nm is suggestive of the fact that local tissue infections can only occur through the viremic invasion into vascular endothelial cells unless there is preexisting tissue damage. This hypothesis was tested by infecting iPSC-derived human capillary organoids, which resemble human capillaries with clear lumen, lined by CD31+ endothelial cells and PDGFR+ pericyte cells and basal membrane [99]. A qRT-PCR analysis of these organoids for the presence of viral RNA indicates a gradual rise in the levels of viral RNA from day 3 to 6 of infection, proving active replication and production of progeny virus. This was followed by a marked decrease in replication without any associated toxicity on adding hrsACE2 to the capillary organoid culture.
SARS-CoV-2 can directly infect blood vessel cells which can also shed progeny viruses. Most importantly, this can be significantly inhibited by hrsACE2 at the early stages of the infection. This is the underlying rationale behind the hope of using soluble ACE2 for protecting the host body from lung injury and block the virus from entering target cells. Having said that, no data on its impact during the advanced stage of COVID-19 is currently accessible [98].
3.5 Kidney organoids
Since renal organotropism was becoming increasingly prominent in SARS-CoV-2, M. Glatzel et al. did an in silico data analysis of single-cell RNA sequencing that was available in the public datasets. Their calculations revealed that RNA of genes (ACE2, TMPRSS2, CTSL) that help to promote the viral infection is enriched in multiple kidney-cell types from fetal development through adulthood. This corroborates previous reports stating that enrichment may facilitate SARS-CoV-2–associated kidney injury [77]. They also quantified the SARS-CoV-2 viral load in precisely defined kidney compartments obtained with the use of tissue microdissection from the samples of patients who underwent autopsy. The findings revealed that 50 percent of patients had observable SARS-CoV-2 viral loads in all kidney compartments tested, with glomerular cells being the most often infected [100].
V. Monteil et al. adapted their previously published procedure [97] to produce kidney organoids from human embryonic stem cells into 3D suspension culture to assess if SARS-CoV-2 would directly invade human tubular kidney cells [101]. Kidney organoids showed conspicuous tubular-like shapes, as observed by Lotus tetraglobus lectin (LTL), a standard marker of proximal tubular epithelial cells. Similar to their human capillary organoid study, infections of kidney organoids were monitored for at least six days post-infection, and their qRT-PCR data were analyzed for the presence of viral RNA. The team used Vero E6 cells to determine the virus’s progeny. SARS-CoV-2 reproduced in kidney organoids, as predicted in cells and tissues that express ACE2. The engineered kidney organoids developed infectious progeny virus, as shown by the ability of supernatant from infected kidney organoids to infect Vero E6 cells on day six post-infection. hrsACE2 significantly decreased SARS-CoV-2 infections in a dose-dependent way in the human kidney organoids, with no evidence of toxicity. In summary, engineered human kidney organoids can also be infected with SARS-CoV-2, and this infection can be inhibited by hrsACE2, similar to blood vessel organoids.
Taken together, renal tropism explains the major clinical signs of kidney injury in patients with COVID-19 having mild or severe symptoms. These studies also predict that SARS-CoV-2 infection can potentially aggravate any preexisting renal conditions. The coronavirus receptor ACE2 is expressed in kidney organoids, which may help researchers further understand the disease’s systemic effects, and multiple questions regarding the pathogenesis can be answered. Thus, the development of multi-organ organoids can address the multi-organ dysfunction, a symptom of COVID-19 illness.
4. Future directions and conclusion
After SARS-CoV and MERS-CoV, SARS-CoV-2 is the third coronavirus in terms of pathogenicity to jump to humans within two decades. This suggests that similar zoonotic coronavirus spillovers can happen again in the near future. Nevertheless, the events relating to coronavirus pathogenesis and transmission are not completely known yet. There is a lack of efficient in vitro systems to accurately model host tissues. As conventional animal models, like mice, are not natural hosts to SARS-CoV-2 infection, there is a surge in the development of alternate pre-clinical models to recapitulate the targeted human organs.
Herein, organoid technology used to model human organ development and various human pathologies in a petri dish has played a significant role in understanding SARS-CoV-2 infection and replication. For drug response studies, drug screening, and repurposing, organoids, especially patient-derived organoids, have become popular. Organoid-based studies are leading to personalizing drugs, formulating regenerative medicine, and establishing gene therapy. In comparison to age-old animal models and cell lines, there has been a noticeable improvement in the reproducibility of results and statistical power of experiments. From all previous data, human organoids of lung, gut, kidney, brain, and blood vessels represent excellent experimental models to study the biology of SARS-CoV-2 [44].
Having said that, researchers working in this field are still trying to identify and troubleshoot the inherent challenges in various aspects of handling organoids, including the maintenance costs, cross-technique artifacts, and interpretation of data [26]. It is now well known that the generation and handling of organoids are way more tedious than two-dimensional cell culture protocols. Moreover, the essential growth factors being more expensive and not explicitly tested for applications in the organoid system, one has to prepare them in-house. With the emergence of various commercial sources for reagents tailored to the organoid culture, there is reason to believe that this problem will be fixed quickly. Moreover, the range of cellular heterogeneity for a particular organoid system needs to be improved. Also, mimicking the native micro-and matrix-environment encountered by cells within organoids remains a challenge. Reverse engineering methodologies are only in their infancy as it comes to developing rigorous protocols for the in vitro maturation of organoids that are largely fetal-like in cultures [102]. Advances in stem cell, progenitor cell, and pluripotent stem cell handling and directed differentiation techniques will soon help create more physiologically relevant organoids.
In combination with genome editing techniques for manipulating 3D models, organoid technology will be implemented at a large scale in basic and clinical research in the forthcoming era [14]. Progress with other technologies, such as microRNA switches and potentially CRISPR–Cas9, 3D bioprinting, and 3D organoids, will further advance the fast-developing multi-organ disease modeling COVID-19 and its associated therapeutic build-up. Though organoid technology suffers from multiple lacunae but COVID-19 has shown the feasibility and practicality of the organoid platform, suggesting further investment to create an in vitro organ mimicking reliable system for successful and effective discovery of therapeutics.
\n',keywords:"COVID-19, Organoids, Infection, ACE2, Challenges, Gut, Lung, Brain",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/77234.pdf",chapterXML:"https://mts.intechopen.com/source/xml/77234.xml",downloadPdfUrl:"/chapter/pdf-download/77234",previewPdfUrl:"/chapter/pdf-preview/77234",totalDownloads:166,totalViews:0,totalCrossrefCites:2,dateSubmitted:"April 28th 2021",dateReviewed:"May 24th 2021",datePrePublished:"June 24th 2021",datePublished:"December 1st 2021",dateFinished:"June 17th 2021",readingETA:"0",abstract:"COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and has emerged as a devastating pandemic. SARS-CoV-2 not only causes respiratory illness but also leads to impairment of multi-organ function. Scientists are racing to evaluate a range of experimental therapeutics to target COVID-19 systemically. The World Health Organization (WHO) and the Center for Disease Control and Prevention (CDC) are accelerating global research priorities to mobilize innovation towards diagnostics, treatments, and vaccines against COVID-19. In this scenario, information about appropriate organ-specific physiologically relevant models is critical to generate knowledge about the pathophysiology and therapeutic targeting of COVID-19. Human and animal organoids are providing a unique platform, demonstrating their applicability for experimental virology. This review provides a brief analysis of the available organoid models used to study and device strategies to combat COVID-19.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/77234",risUrl:"/chapter/ris/77234",signatures:"Ria Sanyal and Manash K. Paul",book:{id:"10535",type:"book",title:"SARS-CoV-2 Origin and COVID-19 Pandemic Across the Globe",subtitle:null,fullTitle:"SARS-CoV-2 Origin and COVID-19 Pandemic Across the Globe",slug:"sars-cov-2-origin-and-covid-19-pandemic-across-the-globe",publishedDate:"December 1st 2021",bookSignature:"Vijay Kumar",coverURL:"https://cdn.intechopen.com/books/images_new/10535.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-756-3",printIsbn:"978-1-83968-755-6",pdfIsbn:"978-1-83968-757-0",isAvailableForWebshopOrdering:!0,editors:[{id:"63844",title:"Dr.",name:"Vijay",middleName:null,surname:"Kumar",slug:"vijay-kumar",fullName:"Vijay Kumar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",fullName:"Manash K. Paul",slug:"manash-k.-paul",email:"paul_cancerbiotech@yahoo.co.in",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",institution:{name:"University of California Los Angeles",institutionURL:null,country:{name:"United States of America"}}},{id:"416519",title:"Dr.",name:"Ria",middleName:null,surname:"Sanyal",fullName:"Ria Sanyal",slug:"ria-sanyal",email:"sanyalria2021@gmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/416519/images/16709_n.jpg",institution:{name:"University of Minnesota",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Virology and organoid",level:"1"},{id:"sec_2_2",title:"2.1 Culturing the unculturable",level:"2"},{id:"sec_3_2",title:"2.2 Reproducing the natural virus host environment",level:"2"},{id:"sec_4_2",title:"2.3 Provide new insights",level:"2"},{id:"sec_5_2",title:"2.4 Utilization in fighting the SARS-CoV-2 pandemic",level:"2"},{id:"sec_6_2",title:"2.5 Extensive research in Zika virus pandemic",level:"2"},{id:"sec_7_2",title:"2.6 Technical challenges",level:"2"},{id:"sec_9",title:"3. COVID-19 and organoid",level:"1"},{id:"sec_9_2",title:"3.1 Lung organoid",level:"2"},{id:"sec_10_2",title:"3.2 Brain organoid",level:"2"},{id:"sec_11_2",title:"3.3 Gut organoid",level:"2"},{id:"sec_12_2",title:"3.4 Human capillary organoids",level:"2"},{id:"sec_13_2",title:"3.5 Kidney organoids",level:"2"},{id:"sec_15",title:"4. 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Altex, 2017: p. 362-376'},{id:"B79",body:'Chen, R., et al., 2020'},{id:"B80",body:'Hoffmann, M., et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 2020. 181(2): p. 271-280.e8'},{id:"B81",body:'Brann, D.H., et al., Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Science Advances, 2020. 6(31)'},{id:"B82",body:'Zhou, H., et al., A Novel Bat Coronavirus Closely Related to SARS-CoV-2 Contains Natural Insertions at the S1/S2 Cleavage Site of the Spike Protein. Current Biology, 2020. 30(11): p. 2196-2203.e3'},{id:"B83",body:'Kanberg, N., et al., Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology, 2020. 95(12): p. e1754-e1759'},{id:"B84",body:'Bullen, C.K., Infectability of Human BrainSphere Neurons Suggests Neurotropism of SARS-CoV-2*. Altex, 2020'},{id:"B85",body:'Wei, X.-S., et al., Diarrhea Is Associated With Prolonged Symptoms and Viral Carriage in Corona Virus Disease 2019. Clinical Gastroenterology and Hepatology, 2020. 18(8): p. 1753-1759.e2'},{id:"B86",body:'Hikmet, F., et al., The protein expression profile of ACE2 in human tissues. Molecular Systems Biology, 2020. 16(7)'},{id:"B87",body:'Xiao, F., et al., Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology, 2020. 158(6): p. 1831-1833.e3'},{id:"B88",body:'Wang, W., et al., Detection of SARS-CoV-2 in Different Types of Clinical Specimens. Jama, 2020'},{id:"B89",body:'Xiao, F., et al., Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology, 2020. 158(6): p. 1831-1833 e3'},{id:"B90",body:'Xu, Y., et al., Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med, 2020. 26(4): p. 502-505'},{id:"B91",body:'Zhou, J., et al., Infection of bat and human intestinal organoids by SARS-CoV-2. Nature Medicine, 2020. 26(7): p. 1077-1083'},{id:"B92",body:'Zang, R., et al., TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol, 2020. 5(47)'},{id:"B93",body:'Sato, T., et al., Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 2009. 459(7244): p. 262-5'},{id:"B94",body:'Spence, J.R., et al., Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature, 2010. 470(7332): p. 105-109'},{id:"B95",body:'Holloway, E.M., et al., Differentiation of Human Intestinal Organoids with Endogenous Vascular Endothelial Cells. Developmental Cell, 2020. 54(4): p. 516-528.e7'},{id:"B96",body:'Krüger, J., et al., Drug Inhibition of SARS-CoV-2 Replication in Human Pluripotent Stem Cell–Derived Intestinal Organoids. Cellular and Molecular Gastroenterology and Hepatology, 2021. 11(4): p. 935-948'},{id:"B97",body:'Zhang, H., et al., Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine, 2020. 46(4): p. 586-590'},{id:"B98",body:'Monteil, V., et al., Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell, 2020. 181(4): p. 905-913.e7'},{id:"B99",body:'Wimmer, R.A., et al., Human blood vessel organoids as a model of diabetic vasculopathy. Nature, 2019. 565(7740): p. 505-510'},{id:"B100",body:'Pei, G., et al., Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia. J Am Soc Nephrol, 2020. 31(6): p. 1157-1165'},{id:"B101",body:'Garreta, E., et al., Fine tuning the extracellular environment accelerates the derivation of kidney organoids from human pluripotent stem cells. 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Department of Chemistry, University of Minnesota, USA
'},{corresp:"yes",contributorFullName:"Manash K. Paul",address:"paul_cancerbiotech@yahoo.co.in",affiliation:'
Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), USA
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)