Summary of the characteristics of the subjects included in the training and validation cohort.
\r\n\tFrom practice to a mathematical and technological application, scheduling has become another form of art: an algorithmic art, declined in as many OS and hardware constraints, from embedded systems onboard an aircraft or a spacecraft to databases in all financial and Internet servers.
\r\n\tThey have become ubiquitous so that a large part of our civilisational development is supported by their reliability, redundancy, and optimisation capacity. Like all of our civilisational assets, they are benefiting from scientific breakthrough in computational sciences such as evolutionary algorithms, Artificial Intelligence, and quantum computing. If not by using it, by being in need of adapting to the next generation of computing. Space development is also bringing new challenges, especially in redundancy and reliability.
Metabolomics, or metabolite profiling, comprises the study of the entire spectrum of low-molecular weight metabolites and their cellular processes in a biological system [1, 2, 3, 4]. Next to a large number of studies exploring the use of metabolomics in the field of disease diagnosis and prognosis, its application is also extended to other research areas such as toxicology [5], nutrition [6], microbiology [7], and drug discovery [8]. Together with high prevalence diseases such as diabetes [9], obesity [10, 11, 12], and neurological and cardiovascular disorders [13, 14], different types of malignant diseases including breast [15, 16], colorectal [17, 18], and lung cancer [19, 20, 21, 22, 23, 24] are being extensively examined by using a metabolomics approach.
Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), which can possibly be connected to a gas- or liquid chromatography system (GC-MS/LC-MS), are the analytical techniques that are primarily used in the field of metabolomics [25, 26, 27]. While 13C nuclei can be very useful in contribution to metabolite identification by NMR, the proton (1H) nucleus is mostly studied in metabolomics NMR experiments [28]. The 1H nucleus is omnipresent in metabolites, shows the highest relative sensitivity, and has a natural abundancy of 99.98%. 1H-NMR spectroscopy is a noninvasive technique that needs no sample extractions and that enables the identification and quantification of metabolites in biofluids as well as in tissues and therefore is becoming widely used in the field of metabolomics [29]. Despite that 1H-NMR is less sensitive compared to MS, it has many advantages: nondestructive, easy quantification, low cost per sample, minimal sample preparation requirements resulting subsequently in an excellent reproducibility and rapid high-throughput data acquirement [30]. In a single run of a few minutes, the 1H-spectrum from one sample provides information regarding the relative concentrations of all present metabolites. The metabolic phenotype provides a representative snapshot of an individual’s metabolic state and therefore enables the determination of cellular processes altered by disease [2].
Metabolites from a number of different diagnostic biofluids are already examined in multiple studies, mostly involving human blood plasma, serum, or urine [1, 22, 31, 32]. In parallel with biofluids, intact tumor tissues are frequently evaluated since intra-tumor heterogeneity is currently one of the major causes of treatment failure [33, 34]. To that end, high-resolution magic angle spinning NMR (HR-MAS NMR) as an analytical approach is gaining great attention [35, 36, 37, 38].
This review intends to point out the results of 1H-NMR metabolic profiling of lung cancer patients acquired by our research group and further explores the benefits which this method might deliver to contribute to an optimal treatment for lung cancer patients.
Experimental design focused on the analysis of fasting venous blood samples from lung cancer patients. Importantly, exclusion criteria were (i) not fasted for at least 6 h; (ii) fasting blood glucose concentration ≥ 200 mg/dl; (iii) medication intake in the morning of blood sampling, and (iv) treatment or history of cancer in the past 5 years, as described in the study of Louis et al. [20]. The blood samples were collected in lithium-heparin tubes and stored at 4°C within 5 min. Plasma aliquots were obtained after centrifugation at 1600 g for 15 min within 8 h after collection. Plasma sample preparation included a centrifugation step at 13,000 g for 4 min at 4°C and dilution of 200 μl of the supernatant with 600 μl deuterium oxide (D2O) containing 0.3 μg/μl trimethylsilyl-2,2,3,3-tetradeuteropropionic acid (TSP) as a chemical shift reference of the spectra. After presaturation for water suppression, the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence was used to acquire slightly T2-weighted spectra on a 400 MHz (9.4 Tesla) NMR spectrometer [1].
Before applying multivariate statistics, the data acquired by 1H-NMR analysis should be preprocessed. Preprocessing of data usually includes phasing, baseline correction, alignment, and normalization. In addition, the spectrum has to be divided into regions of which the integration value (i.e., area under the peak) can be used as a variable for the statistical analysis. Binning or bucketing is a commonly used technique to produce such a reduced set of variables by segregating the spectrum [39]. In point-wise binning, the spectrum is divided into so-called equally-sized bins. An important limitation of this method is the possible splitting of peaks, resulting in a loss of differentiating power and possibly data misinterpretation. To overcome this, another methodology based on spiking of the plasma with known metabolites is proposed. This approach describes how the 1H-NMR spectrum is divided into well-defined variable-sized integrations regions, being the variables for multivariate statistical analysis [40].
To obtain a correct signal assignment, 1H-NMR spectra of reference plasma samples to which a known metabolite was spiked, were acquired. Hereto, stock solutions were prepared by dissolving a relevant concentration of a known metabolite in a reference plasma sample. Reference plasma can be obtained by pooling the plasma of several blood samples from a healthy person. Next, a small amount of stock solution can be added to a reference plasma NMR sample (e.g., 10 μl stock solution to 200 μl reference plasma and 600 μl D2O containing the TSP reference). This procedure can be repeated for all metabolites of interest, using a fresh reference sample for each metabolite. The outcome of these spiking experiments allows an accurate identification of the chemical shifts and J-coupling patterns. On our 400 MHz (9.4 Tesla) NMR spectrometer, the described spiking method led to a segmentation of the spectra in 110 well-defined integration regions [40]. After integration and normalization (relative to the total integrated area, with exclusion of the contributions of TSP and water), these integration regions could be used as variables for multivariate statistical analyses.
The statistics were carried out by using supervised orthogonal partial least squares discriminant analysis (OPLS-DA) to train and validate a classification model which enables optimal discrimination between lung cancer patients and a control population. The statistical classifier was constructed after detection and removal of outliers in the training data set via unsupervised principle component analysis (PCA). In addition, PCA was also conducted to visualize significant intrinsic clusters in the case–control data set upon which identification of possible confounders was based.
Model characteristics such as the total explained intra- (R2X(Cum)) and intergroup (R2Y(Cum)) variation were examined together with sensitivity and specificity values in order to evaluate strength performance of the OPLS-DA classifier. Predictive ability (Q2(Cum)) of the model was demonstrated by cross-validation of the training set as well as by application of the model to an independent validation cohort.
The assigned and normalized integration regions of the 1H-NMR spectrum reflect the relative metabolite concentrations and thus represent the metabolic phenotype. Therefore, they can be used as variables for multivariate OPLS-DA statistics in order to discriminate between lung cancer patients and healthy controls. By applying this methodology on lung cancer plasma samples, a classification model that enables discrimination between those two groups was trained. Hereto, a large training cohort consisting out of 233 lung cancer patients and 226 controls was used. Characteristics of the subjects included in the training and validation cohort are summarized in Table 1. The trained OPLS-DA classifier resulted in a correct classification of 78% of the lung cancer patients and 92% of the control group (Figure 1A) [19]. To affirm that the discrimination was purely due to differences in plasma metabolite concentrations, PCA was conducted to exclude possible confounders. By means of PCA score plots, it was confirmed that gender, smoking status, disease, and chronic obstructive pulmonary disease (COPD) are no confounders [19].
Training cohort | Validation cohort | |||
---|---|---|---|---|
C | LC | C | LC | |
Number of subjects, | 226 | 233 | 89 | 98 |
Gender, | ||||
Male | 119 (53) | 160 (69) | 44 (49) | 66 (67) |
Female | 107 (47) | 73 (31) | 45 (51) | 32 (33) |
Age, yrs. (range) | 67 ± 11 (38–88) | 68 ± 10 (36–88) | 69 ± 10 (47–89) | 64 ± 9 (45–83) |
BMI, kg/m2 (range) | 28.3 ± 5.0 (18.7–46.7) | 25.8 ± 4.5 (17.5–41.8) | 28.4 ± 5.7 (16.2–52.0) | 26.2 ± 4.7 (16.8–38.5) |
COPD, | 39 (17) | 119 (51) | 9 (10) | 35 (36) |
Taking lipid-lowering medication, | 124 (55) | 122 (52) | 56 (63) | 39 (40) |
Diabetes, | 23 (10) | 40 (17) | 20 (22) | 12 (12) |
Smoker, | 47 (21) | 113 (49) | 15 (17) | 48 (49) |
Ex-smoker, | 102 (45) | 110 (47) | 36 (40) | 46 (47) |
Non-smoker, | 77 (34) | 10 (4) | 38 (43) | 4 (4) |
Pack years (range) | 16 ± 24 (0–175) | 33 ± 21 (0–125) | 13 ± 18 (0–60) | 38 ± 21 (0–150) |
Left, | 103 (44) | 40 (41) | ||
Right, | 119 (51) | 54 (55) | ||
Bilateral, | 6 (3) | 4 (4) | ||
Unknown, | 5 (2) | 0 (0) | ||
Amount of tumors, | 239 | 102 | ||
NSCLC-Adenocarcinoma, | 91 (38) | 46 (45) | ||
NSCLC-Squamous carcinoma, | 66 (28) | 29 (28) | ||
NSCLC-Adenosquamous carcinoma, | 5 (2) | 1 (1) | ||
NSCLC-Carcinoid, | 5 (2) | 0 (0) | ||
NSCLC-NOS, | 8 (3) | 6 (6) | ||
SCLC, | 30 (13) | 15 (15) | ||
Unknown, | 34 (14) | 5 (5) | ||
IA, | 55 (23) | 12 (12) | ||
IB, | 21 (9) | 5 (5) | ||
IIA, | 11 (5) | 7 (7) | ||
IIB, | 15 (6) | 4 (4) | ||
IIIA, | 48 (20) | 17 (16) | ||
IIIB, | 26 (11) | 12 (12) | ||
IV, | 63 (26) | 45 (44) |
Summary of the characteristics of the subjects included in the training and validation cohort.
BMI: Body mass index; C: controls; COPD: chronic obstructive pulmonary disease; LC: lung cancer patients; NOS: not otherwise specified; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; and TNM: tumor, node, metastasis.
OPLS-DA score plots, resulting from the classification of the training cohort of 233 lung cancer patients and 226 controls (A) and the independent validation cohort of 98 lung cancer patients and 89 controls (C). The AUC of ROC curves confirms the predictive ability of the classification model by cross-validation of the training cohort and an independent validation model (B). AUC: Area under the curve; C: controls; CV: cross-validation; LC: lung cancer patients; PS: predicted scores; and ROC: receiver operating characteristic.
While these results definitely support the applicability of this methodology for the detection of lung cancer, no clear differentiation between tumor stages or histological subtypes could be detected yet, that is, none of the trained OPLS-DA models already showed significant clustering of different tumor stages or histological subtypes. This probably is due to the limited number of lung cancer patients in the subgroups and the diffuse character of the subgroups formed on the basis of histology and clinical tumor stage. However, the ability of a constructed OPLS-DA model to discriminate between 76 stage I lung cancer patients and 76 randomly selected controls with 74% sensitivity and 78% specificity strongly suggests that plasma metabolite phenotyping reveals the presence of lung cancer already during early stadia of tumor development (Figure 2) [19].
OPLS-DA score plot, resulting from the classification of 76 stage-I lung cancer patients and 76 randomly selected controls of the training cohort. C: Controls.
Importantly, after training of a promising classification model, confirmation of the validity of the model needs to be considered. When the metabolic fingerprint of a large cohort of patients and controls is available, this can be realized by applying the model on an independent validation cohort consisting out of an independent group of both lung cancer patients and controls. In this study, an independent cohort of 98 patients with lung cancer and 89 controls was used for validation of the trained model classifier. The trained model shows a high predictive accuracy with a sensitivity of 71% and a specificity of 81% (Figure 1B and C) [19].
To further illustrate the potential of the methodology described above, the following paragraph demonstrates that different cancer types are characterized by a specific metabolite profile. Hereto, the same workflow was applied on a data set of 54 lung cancer patients and 80 breast cancer patients. Again, the segmentation of the spectrum was based on metabolite spiking and OPLS-DA statistics were used to train a classification model, this time in discriminating lung cancer from breast cancer. The resulting model allows a correct classification of both cancer types with a sensitivity of 93% (93% of the 54 lung cancer patients were correctly classified) and a specificity of 99% (99% of the 80 breast cancer patients were correctly classified) (Figure 3A). Validation of the model by applying it on an independent cohort of 81 lung cancer patients and 60 breast cancer patients confirmed these findings and shows a sensitivity of 89% and a specificity of 82% (Figure 3B and C) [20]. Another recent study explored these promising results by establishing an OPLS-DA classification model that allows discrimination between three different types of cancers, that is, lung, breast, and colorectal cancers. After 1H-NMR measurements of 37 plasma samples of each patient group, multivariate statistics revealed that each type of cancer was represented by a specific metabolic signature (Figure 4) [41]. Since the metabolic phenotype allows a clear differentiation between different cancer types, it can be assumed that the metabolic profile should not be considered as a general cancer marker but rather as a distinguishing characteristic of a specific cancer type.
OPLS-DA score plots, resulting from the classification of the training cohort of 54 lung cancer patients and 80 breast cancer patients (A) and the independent validation cohort of 81 lung cancer patients and 60 breast cancer patients (C). The AUC of ROC curves confirms the predictive ability of the classification model by cross-validation of the training cohort and an independent validation model (B). AUC: Area under the curve; BC: breast cancer patients; LC: Lung cancer patients; PS: predicted scores; and ROC: receiver operating characteristic.
OPLS-DA score plot, resulting from the classification of a population of lung-, breast- and colorectal cancer patients, each group consisting of 37 individuals. CRC: Colorectal cancer patients; BC: breast cancer patients; and LC: lung cancer patients.
The metabolites that contributed the most to the differentiation between lung cancer patients and healthy controls were identified and selected based on their variable importance for projection (VIP) value by means of an S-plot. The variables on the wings of the S-plot are the ones with the strongest contribution to the model and the highest statistical reliability [42]. Metabolic phenotyping of blood plasma shows that lung cancer patients are characterized by elevated glucose and decreased lactate levels, which implies an increased gluconeogenesis. This enhanced gluconeogenesis reflects the reaction of the human body to the Warburg effect or aerobic glycolysis in which, even in normoxic conditions, cancer cells rely on fermentation, that is, glycolysis leading to lactate production via fermentation of pyruvate. The Warburg effect, which takes place in cancer cells, can be observed in tumor tissue by means of 1H-NMR as shown by Rocha et al. They demonstrated that lung tumors of different histological subtypes are all characterized by lowered glucose whereas lactate levels are increased, which is supported by the significantly enhanced glycolytic activity of cancer cells compared to normal cells [23]. Moreover, lung cancer patients show decreased phospholipid plasma levels, pointing to an increased lipogenesis and enhanced membrane synthesis, which is correlated with increased proliferation of cancer cells [43, 44, 45, 46]. Other metabolites with an increased concentration in lung cancer patients compared to controls are N-acetylated glycoproteins, β-hydroxybutyrate, leucine, lysine, tyrosine, threonine, glutamine, valine, and aspartate. Contrarily, metabolites showing a decreased concentration in lung cancer patients are alanine, sphingomyelin, citrate, chlorinated phospholipids (e.g., phosphatidylcholine), and other phospholipids [19].
Evaluation of the advantages versus limitations of NMR spectrometers with higher magnetic field strength was accomplished by comparing the results obtained for the same plasma samples on both a medium-field (9.4 Tesla; 400 MHz) and high-field (21.1 Tesla; 900 MHz) NMR spectrometer. For a 900 MHz spectrum, an improved resolution as well as a higher signal to noise (S/N) ratio is observed as compared to a 400 MHz spectrum (Figure 5) [47]. Because of these improved characteristics, measurements with a high-field spectrometer enable to define the integration regions more accurately using spiking experiments, resulting in less signal overlap and therefore in a larger number of integration regions that are representative for a single metabolite. Yet, discriminative power of both high- and medium-field spectra is rather comparable. These findings are in line with the study of Bertram et al., who demonstrated that the prediction performance and thus obtained information out of the spectra meant for diagnosis strongly increases when shifting the magnetic field strength from 250 to 500 MHz, whereas the effect of further increasing the magnetic field strength from 500 to 800 MHz appeared less strong when group discrimination is concerned [48]. However, analysis with a high-field spectrometer can be the preferred choice for the detection and identification of new, low-concentration metabolites and therefore can contribute to a better understanding of the underlying disturbed biochemical pathways of disease [47]. A drawback is the high cost of high-field spectrometers, which raises strongly with the magnetic field strength. By comparison, the cost of a 400 MHz spectrometer is in the order of €300,000 while a 900 MHz spectrometer can reach the cost of €2,750,000. The need of a supplementary cryoprobe can raise these estimated amounts even more with €200,000 [47]. In addition, such instruments demand for an isolated building for its housing, which is less practical in a clinical setting. Taken all into account, medium-field (400–600 MHz) spectrometers will probably become the preferred instruments for future application in clinical metabolomics.
Comparison of the 1H-NMR spectra of human blood plasma acquired at a high-field (900 MHz) (top) and medium-field (400 MHz) (bottom) spectrometer. Both spectra are zoomed-in between 0.80 and 1.10 ppm. The top spectrum shows an increased resolution and improved S/N ratio. The paired labeled peaks each represent a methyl group of the amino acid valine. ppm: Parts per million.
The contribution of metabolic phenotyping toward the clinical environment, often referred to as pharmacometabolomics, can encompass the entire patient journey, starting from an improved screening selection and earlier diagnosis to a follow-up for treatment response prediction and enhanced personalized choice of therapy [49]. Despite several challenges that accompany the implementation of such a unique innovative technique, for example, biomarker validation and cost-effectiveness [49, 50], the authors are highly convinced that metabolism-based biomarkers carry the potential to significantly contribute to future daily standard clinical practice.
For lung cancer, metabolic phenotyping by means of 1H-NMR can further be useful in preceding low-dose computed tomography (LDCT) scanning as a tool to deliver additional and complementary risk factors for a better selection of high-risk individuals. Currently, selection of those individuals is primarily based on age and smoking status/history [51]. As an outcome of the National Lung Screening Trial, it is stated that mortality is significantly reduced when screening with LDCT occurs [52]. Although sensitivity levels of LDCT screening are high and the number of diagnoses in early stadia increases, the positive predictive value of LDCT is currently still low [53]. Other drawbacks of LDCT screening are the high rate of false positive results, the high risk of overdiagnosis and consequently additional radiation exposure due to avoidable diagnostic tests [54]. In order to meet with the raising interest in improving the accuracy of risk prediction, promising clinically relevant diagnostic biomarkers which can add predictive value to existing models are indispensable [55, 56]. Therefore, a noninvasive blood-based screening test in complement with LDCT would be a valuable tool to reduce the number of individuals undergoing unnecessary and sometimes harmful follow-up treatments. Likewise, in a next phase, identification of prognostic biomarkers could assist in the tracing of early-stage lung cancer patients who would most likely benefit from current therapies, for example, surgery with curative intent or adjuvant chemotherapy [57].
Next to the discovery of diagnostic and prognostic biomarkers, metabolic profiling is being extensively examined for its use in prediction of individual therapy response [58, 59, 60, 61]. Personalized treatment will contribute to a reduction of adverse reactions by (i) prediction of the patient’s response and (ii) administration of the most efficient drug dose. Moreover, longitudinal monitoring of patients allows to track post-interventional outcome or deviations in response and therefore can assist in paving the way toward long-term personalized health [49].
Analysis of metabolic changes in blood plasma by 1H-NMR spectroscopy allows to significantly discriminate between lung cancer patients and healthy controls. Additionally, metabolic phenotyping supports detection of lung cancer in all stages and enables differentiation between different cancer types such as breast and lung cancers. This indicates that a metabolomics approach can actively contribute to lung cancer diagnosis, even in early stages of tumor development. For daily clinical practice, where the main goal is to correctly classify patients, a medium-field (400–600 MHz) NMR spectrometer can provide sufficient discriminative power to perform clinical metabolomics. For research purposes, on the other hand, where disease-related disturbed pathways deserve a more extensive analysis, high-field NMR (e.g., 900 MHz) spectra are preferred. The ability of high-field NMR to observe a larger number of metabolites that are represented by a nonoverlapping signal, permits a deeper look into the underlying affected metabolic pathways. We show that increased glucose levels are observed while lactate levels are decreased in blood plasma of lung cancer patients. These aberrant metabolite concentrations indicate an increased gluconeogenesis as counteraction of the body to the Warburg effect in the cancer cells. Moreover, the fact that cancer cells manage an enhanced membrane synthesis can be confirmed by the lowered plasma levels of phospholipids.
Encouraged by all these promising results, the authors strongly believe that 1H-NMR-based metabolic fingerprinting will become widely clinically implemented by serving as (i) an additional screening tool for lung cancer, (ii) a procedure to define complementary risk factors for current risk models toward an improved selection of lung cancer patients eligible for LDCT, and (iii) an innovative method to better characterize lung cancer patients in order to provide them with the best treatment strategies available.
This study is part of the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa and supported by Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society. The authors like to thank Prof. Dr. Eric de Jonge and Prof. Dr. Philip Caenepeel for their support in sample recruitment.
The authors declare that they have no conflict of interest.
Cells are pre-programmed to carry out certain functions – this represents their potential. At the same time, they are sensitive to physical or biological changes in their surrounding environment and will modify their function accordingly – and this becomes their constantly changing actuality. Cells
In the early days of cell culture in the 1950’s the focus was to get cells to propagate rapidly and reliably in flasks, facilitated by the destruction of their ECM. With the realisation that cells grown in 3D conditions are more mimetic of human cell biology, the focus has changed away from getting the cells to propagate to getting the cells to function (physiologically). These two conditions mark the extremes in a spectrum of cellular activity [1].
Bearing this in mind, there are a number of factors that should be considered when changing this focus and transitioning from the classical 2D cell culture to 3D cell culture. These factors not only indicate which 3D culture systems could be expected to be advantageous over others but also indicate which should generate data that is more representative of the
Perhaps, the most significant difference between 2D and 3D culture is the establishment of longer diffusion gradients for the majority of cells and thus the cells will experience significantly different levels of oxygen, CO₂, nutrients and waste products.
Related to the diffusion gradients is the amounts of various compounds in the environment around cells: cells in 2D are typically exposed to levels of for example O₂ and glucose which are not seen in the intact, healthy organism.
Another very significant difference will be the establishment of channels of communication between cells that are not only juxtapositioned but also further away. In 2D, immortal cells are typically passaged roughly every week (and shorter for faster growing cells). At the end of this cycle, cells are usually treated with enzymes or cocktails (containing trypsin, collagenases or other compounds) that damage proteins protruding from the plasma membrane and which dissolve or fragment the ECM. Similar cocktails may be used to produce cell suspensions from tissue biopsies, or these biopsies may be pressed through a mesh to ‘liberate’ cells. All these treatments release proapoptotic factors, damage cells and have a significant impact on gene expression. Cells will attempt to repair this damage and recover, but need time to do so. So, the final factor to consider is time.
While there are numerous publications illustrating that 3D cell culture can mimic functionalities of human tissues, perhaps one of the most graphic is shown in Figure 1 where a freshly extirpated human liver biopsy and 29 day old C3A spheroids have been biosynthetically labelled with [35S]-methionine and their proteins extracted and run on high resolution two-dimensional gels (IPG-SDS). Notice that, not only are the proteins expressed in very similar amounts, but also that their post-translationally modifications are very similar.
Human biopsy tissue (ca. 0.5 mm3) and spheroids (29 day-old, ca. 1 mm3) were biosynthetically labelled for 20 hrs with [35S]-methionine. Some of the proteins are named for reference: ACTB, Actin beta; ALBU, Albumin; ALDH2, Aldehyde dehydrogenase 2; APE, Apolipoprotein E; CCND1, Cyclin D; HSPA8, Heat shock protein 8; HSPH1, Heat shock protein H1; HYOU1, Hypoxia up-regulated protein 1; PSMA5, Proteasome subunit alpha type-5; SAHH, S-adenosyl-L-homocysteine hydrolase; TUBB5, Tubulin beta chain 5; VCL, Vinculin; YWHAH, 14–3-3 protein eta.
For many purposes in medical research, what is needed is a model system that accurately reflects what happens in the living organism - more often than not a human being – to shed light on many different processes, whether normal physiology or what goes wrong in disease, or infections by microorganisms, or the effects of compounds during treatment or poisoning.
3D cell culture promises to offer what is needed, but the field is still relatively new and many of the products used are small modifications of existing products that have been available for many years and as such, many have not been ideally suited to the purpose.
For these reasons, when we started to design some equipment specifically designed to support 3D cell culture. In doing so, we used four aims to guide the process. These were:
Use
Allow the cells to do what they want. Do not provide unnecessary compounds and do not stress them in any unphysiological way.
Keep the culture conditions as close to that seen
Keep it simple (both for the cells and the user).
The main requirements that we addressed were: diffusion gradients, shear stress and time.
Atmospheric oxygen (21%) provides a partial pressure (pO₂) of about 145 mm Hg (ca. 190 μM) to cells grown in 2D cultures. This is considerably more than the partial pressure of oxygen measured in tissues (11% to 0.1%) which should be considered as normoxic for cell culture [3]. Thus, cells grown in 2D cultures are exposed to unphysiological, hyperoxic conditions.
In the human body cells are usually located within 200 μm of a capillary [4] (corresponding to only 10 to 40 cell layers thick). Because cells are actively consuming oxygen, there will be a diffusion gradient into the cell. This is not problematic in 2D because the cultures are typically only one cell layer thick, but it becomes a challenge in 3D because there the spheroids can become tens or hundreds of cell layers thick. Despite that there may be a preferential transport of oxygen through cells and tissues by hydrophobic channelling within membranes, suggesting that oxygen diffusion within cells and tissues may be faster than through water, there will clearly be a limit [5].
In seminal work, Sutherlands group clearly demonstrated that the pO₂ in the centre of a spheroid fell to 0% when the radius was greater than 250 μm, corresponding quite well with the
A flow of media past a spheroid significantly reduced this zone and had a very significant effect on the oxygenation of the spheroid. This allowed the spheroids to become larger before their cores reached anoxia. The beneficial effect of flow was almost completely negated if the spheroid was resting on a gas impermeable surface (e.g. glass or a gas-impermeable membrane) [6]. Spheroids appear to have a large capacity to adapt and significantly reduce their consumption when the supply of either O₂ or glucose or both is restricted [7, 8, 9].
Interestingly, hepatocytes, (which express haemoglobin
Exactly the same arguments apply to CO₂: it has been demonstrated that CO₂ (as HCO3−) diffuses through spheroids of many cell types essentially as if the cells are not there [11]. Cells in clusters increase their aerobic respiration and decrease oxidative phosphorylation as they reprogram to a more anabolic based metabolism. This reduces their need for O₂ and their production of CO₂. Although this was first noted by Warburg in relation to cancer [12], it probably more strongly reflects the effects of ‘mis-culture’ of tumour cells in 2D rather than a metabolic style reflective of tumours
Interestingly the rate of glucose diffusivity through spheroids of different cell types has been shown to differ by a factor of up to 4. The diffusion into a spheroid is quite rapid and an equilibrium is established after about 1 hour (single cells reach this equilibrium within a minute) [13]. These differences may be correlated to how tightly connected the cells become. C3A spheroids have been shown to rapidly deplete normoglycaemic media (5.5 mM) of glucose within 8 hours, converting much of it to glycogen. The cells were then able to reconvert the glycogen to glucose and survive for the next 40 (or 64 hrs) hrs until the next media exchange [9].
Diffusion gradients will also apply to nutrients and waste products. For example, NH3 is produced by transamination followed by deamination, from biogenic amines and purine and pyrimidine bases. NH3 (as NH4OH) is a smaller and less lipophilic molecule and thus its diffusivity five times slower than CO₂ through cells than through pure water at 37 °C making it more difficult to ‘escape’ [11].
The conclusions are clear for 3D cell culture: without a vasculature, cell clusters should not be too big in order to avoid anoxia (and ensuing necrosis) and should be irrigated on all sides to diminish the depletion zone and accelerate gas, substrate and metabolite exchange.
There is a growing appreciation that the mechanical properties and cell mechanics, play an important role in gene expression and cell development. The concept that is emerging is that cell types which experience shear stress
Thus, in some cases shear stress is positive: see-saw shaking of induced pluripotent stem cell (iPSC) constructs for 17 days promoted cell aggregation, and induced significantly higher expression of chondrogenic-related marker genes than observed in static cultures [15]. A platform rocking at 7 ° with a 3 second cycle results in an average shear stress of about 0.01 Pascal [16]. These shear forces are however distributed unevenly – both spatially and temporally during the motion of the container (bag, or flask) [17]. A similar, ultra-low shear stress is also seen in clinostat cultures. In this case though, the shear stress is distributed essentially homogeneously spatially and temporarily throughout the culture [9].
Fluid-induced shear stress (ca. 0.02–0.06 Pa) in microfluidic devices
Stirred tank suspension bioreactors and orbital shakers are used widely [21, 22, 23] but both result in significantly higher shear forces (0.3–0.66 Pa and 0.6–1.6 Pa respectively) and are considered to be in the critical/lethal range for mammalian cells [24].
Since most cells are found in tissues which experience very little shear stress, equipment that is designed to cultivate cells from these tissues should expose cell clusters to as little shear stress as possible. It is easier to reintroduce shear stress if needed, than to struggle to remove it from a system not designed to be shear stress free.
As mentioned above, enzymatic treatment of tissues or cells in 2D damages both the ECM and surface located proteins (including their modifications). This raises a number of questions.
The first is as to whether this damage can be repaired, i.e. can the 3D cultures recover the metabolic or physiological properties that they exhibited
If the damage cannot be repaired, then the question raised is whether this failure is due to a limitation of the cells used, whether several cell types are needed, whether the procedures used prevent the recovery, or whether it is a true limitation that the performance cannot be replicated
If it can, the next question is how long do cells need to repair this damage?
A final question is that if the damage can be repaired, then once the cells have recovered, how stable is the 3D culture, i.e. for how long can the 3D culture be used?
The answer to these questions depends very much on the origin of the cells. For immortal cells, there are now numerous publications suggesting that these cells need to grow as spheroids for at least 2 weeks to recover their
One observation that appears to be true for the majority of cells, irrespective of their origin, is that they grow considerably much slower as spheroids or organoids as they do in 2D cultures. Thus, doubling times in 3D may be as long as every 50 or 100 days rather than the 1 to 2 days seen in 2D [32, 33]. This makes sense: tissues and tumours
Starting with isolated cells in culture, it is necessary therefore to anticipate that the cells need to re-adapt to being in clusters once again. There is a lot that needs to occur in such a readaptation process: for example, isolated cells do not have tight junctions and so their import and export pumps will have mixed: and need to be ‘re-deployed’ to different regions of the plasma membrane once tight junction has been re-established [36]. While this is critically important for most cells, the specialisation of pumps in the liver cells is exquisite and intricate [37]. Redeployment of pumps might not be an active process – the cell after all was not designed to work in 2D cultures. Hence, the cell may have to rely on protein turnover to degrade the misplaced pumps and on membrane delivery processes to establish the pumps on the correct sides of the tight junctions. And there are innumerable other redeployments (changes to the cytoskeleton [1], organelle organisation, gene and protein expression, epigenetic marking [38], post-translational modifications and metabolic reprogramming [8, 9]) to complete.
The take home message here is that researchers have to be much more patient and expect that they will need to maintain 3D cultures for extended periods of time (weeks or months). With this in mind, these extended periods will place a premium on cultures that are highly reproducible and preferably also high yield. Cultures that reach and maintain a dynamic equilibrium for weeks or months will be advantageous in that they will mimic the homeostasis seen in tissues and will provide a large window of utility. Within this window, it will be possible to for example collect multiple samples from the same culture (like collecting biopsies from the same animal at different times) or perform repeated treatment studies [39]. These samples could be used for the same assay at different times or multiple different assays at the same time, or both if there is sufficient biomass available. But the stability of the biological process needs to be documented throughout this window before perturbation experiments can be initiated [32, 40].
Maintaining cultures for extended times greatly increases the risk of infections, and thus requires great care. This can be facilitated if all aspects of a 3D culture system have to be considered so that the culture is well protected from external contamination.
So – what does a cell culture system that addresses all of these issues look like?
First it is a CO₂ incubator. The incubator constructed can maintain a steady temperature both over time and within its volume. The inclusion of a powerful fan to mix the air within the incubator ensures no differences in temperature or gas partial pressures (and speed temperature recovery after the door has been opened). Measurements show that the difference in temperature between the top of the chamber and the bottom are less than 0.2 °C.
Figure 2 illustrates that the incubator quickly reaches running conditions after about 15 minutes when it is first switched on and that it can maintain a steady temperature and CO₂ % (in the figure, over 12 hrs).
% CO₂
When the door is opened, the controlling software switches off the fan, heaters and the UV-C lamp (if active) and closes the CO₂ valve. Closing the door reactivates these functions. Figure 3 illustrates the effect of opening the door wide open (90 °) for respectively either 30 seconds or two minutes showing that running conditions are re-established by about 4 or 6 minutes.
The effect on CO₂ %
Note that the internal temperature in the culture vessel falls by a maximum of only 0.1 °C while the door is open illustrating that the cultures are not exposed to any cold shock which would affect their gene expression.
In order to reduce the diffusion depleted zone to a minimum, we have adopted the clinostat technology. Introduced for cell culture more than 20 years ago, this technology has been used to culture hundreds of different types of cells and tissues (cell lines, stem cells, primary cells) as well as bacteria and viruses and produced some excellent research. The major limitation of the initial equipment was that it was difficult to use (for example the culture chamber could not be opened but had to be accessed via luer lock ports).
Basically, a clinostat keeps cell clusters in suspension by rotating the culture vessel in a vertical direction (like a wheel). At the right speed, the uplift caused by the effect of liquid viscosity between the vessel and the clusters is balanced by the effect of gravity (these systems are often referred to as ‘simulated microgravity’ because the clusters appear to float or be maintained in a ‘stationary orbit’ (relative to the culture vessel)). Thus, the incubator that has been built has been equipped with clinostat motors. These have to run very smoothly so that there is no vibration (which would otherwise shake the clusters apart). Figure 4 A) would reveal 50/60 Hz mains ‘noise’ effects while B) would reveal high frequency noise.
Variations in the rotational speed of a clinostat motor. (A) Long term variations during 1 second: RPM (± STD) 5.03 ± 0.210; 10.03 ± 0.277; 30.21 ± 0.278; 100.38 ± 0.224. (B) Sort term variations during one thousandth of a second. RPM (± STD) 5.12 ± 0.002; 9.82 ± 0.004; 30.13 ± 0.008; 100.66 ± 0.007.
To retain ‘continuity’ with previously published data, we have maintained the basic geometry of the culture chamber.
The next requirement is to be able to open the culture vessel easily for the purpose of introducing or removing cell clusters, for changing the media, or adding compounds or collecting samples.
Figure 5 illustrates a culture vessel with a top access port for media exchange, a front access port for collecting individual cell clusters, and front window that can be removed to reveal a petri-dish like 10 mL culture chamber.
A culture vessel designed to provide easy access to the culture chamber. (A) Exploded view of parts. (B) Front view showing spheroids in the culture chamber (white spots).
Changing the growth media is illustrated in the video (https://bit.ly/2PkiE9m). The culture chamber is removed from the incubator and the spheroids are allowed to sink to the bottom. The top port plug is removed and 90–95% of the media is sucked away using a sterile syringe and long needle. Fresh media is introduced in the same way, making sure to overfill the growth chamber so that any bubbles are driven into the ‘drip-cup’ around the top port. The plug is then replaced, the drip cup emptied, washed with 70% ethanol for sterility and the culture vessel replaced in the clinostat incubator. The whole procedure takes less than 40 seconds, resulting in minimal stress for the cell clusters (a video of this can be seen on CelVivo’s website). Small samples of the media can be collected at any time using the same approach.
In this design (Figure 5), the gas exchange membrane has been moved from its ‘cylinder end’ position to a circumferential ‘side’ position whilst still retaining essentially the same area to allow rapid gas exchange between the culture chamber and the humidification chamber. Relocating the gas exchange membrane allows the culture chamber to be illuminated from the back and observed from the front (using the cameras), facilitating inspection of the clusters without disturbing the culture, or even opening the incubator door. This also helps to minimise infection risks.
Most incubators are humidified with water trays or tanks, which usually increase the relative humidity close to 100% to prevent cultures from losing water and concentrating the media. This is fortunate because CO₂ normally does not transverse dry membranes very readily. By hydrating the atmosphere, CO₂ can dissolve into the water vapour (giving H2CO3) and then diffuse easily across the membrane [41].
Unfortunately, the combination of high humidity and the warm temperatures inside an incubator are strongly conducive to infections and so regular thorough cleaning is necessary to prevent contamination of the cultures.
Microbial infection can be mitigated if the humidification of the incubator chamber can be reduced. For that reason, a culture vessel has been designed that can humidified itself. This permits the incubator to be run in a ‘dry state’ (i.e. with only ambient humidity). Assuming that the air around the incubator contains 40% relative humidity, (at 20 °C and normal pressure), then when this air enters the incubator and is warmed up to 37 °C, its relative humidity will fall to 13.9% making microorganism growth more difficult.
The culture vessel is humidified by placing water beads in a circumferential chamber around the gas exchange membrane and allowing air exchange into this chamber. In use, the hydrated beads release water linearly with time to the atmosphere (1 mL water gives about 1.67 L water vapour) and maintain a very high humidity close to the membrane and facilitating gas exchange (Figure 6).
Loss of water from water beads in a culture vessel in a clinostat incubator at 37 °C.
The circumferential position of the gas exchange membrane facilitates another feature of the culture chamber. Because there is nothing on either planar side of the vessel, it is possible to provide uniform illumination from one side and observe the culture from the other side. Fey
A clinostat incubator, containing 6 culture vessels (one back illuminated).
Even though most modern incubators have a double door, with the inner door made of glass, it is difficult to see the cell clusters clearly often because of poor illumination. The use of an integrated back-light and a camera to inspect the cultures brings yet another advantage: it is not necessary to open the incubator to see the cultures. If these shadow area measurements are repeated over time it becomes possible to follow the growth curve of the clusters. The only manipulation required is to change the media (typically this would be every 2–3 days). If the media is changed for example on a 2, 2 and 3 day (weekly) cycle, then the incubator will need to be opened only 10 times during a 21 day culture. Since a practiced person can change the media within 1 minute each time, this means that the cells need to be out of the incubator for less than 10 minutes in the 21 day period.
Thus, the construction using illumination and a camera for each cell culture vessel minimises the number of times that the incubator needs to be opened. This in turn further reduces the risk of infection, in addition to the effect gained by running the incubator ‘dry’.
An extra source of illumination has been included on the same side as the camera so that it is possible to see the clusters by direct inspection and not just their silhouettes.
All of the images are displayed on (and can be captured from) a tablet that also serves to regulate the temperature, CO₂ and rpm of the culture vessels (Figure 8).
The tablet display showing regulation of the rpm and set value (left panel), culture vessel (main panel), clinostat incubator number (A-1, main panel top left), actual rpm (top right), actual temperature and CO₂ (bottom left). The front access port plug can be seen at the bottom right of the culture vessel.
One final step has been taken to reduce the risk of microorganism contamination even further. A UV-C light has been built into the incubator. The UV-C LED source itself is behind the bowl of the incubator but the UV-C light is led out through a fused silica light guide which passes along the shaft of the fan. UV-C capture from the LED was calculated to be 88%. By terminating the light guide in an arrow shape (with angles of 52 and 56 °), the emitted UV-C sweeps the incubator as the fan rotates. Normally, UV-C light reflectance from stainless steel is usually about 5% but this has been increased to about 75% by using a special ePTFE coating. Thus, the UV-C irradiation is reflected in all directions and will reach all surfaces. All clinostat motors are activate during decontamination so that all sides of the culture vessel holder will also be irradiated. The inner surface of the glass door is assumed to be totally absorbing for the UV-C. According to the specifications of the LED lamp, the UV-C light emitted will provide a dose of at least 12 mJ/cm2 everywhere in the incubator after 2 hours. This results in a log4 reduction (99.99% reduction) in viable bacteria. A log6 reduction is normally defined as sterile for medical facilities (and therefore this is classified only as a decontamination).
One easy way to initiate spheroid cultures is to use embryoid body plates (Figure 9).
C3A spheroids at various times.
Here, cells are centrifuged into the bottom of inverted square-based pyramid micro-indentations in microtitre plate wells. Not surprisingly, the spheroids are somewhat squarish immediately after their release from the embryoid body plate and there is quite a lot of loose cells (seen most clearly in the ‘Day 0 and 2’ image in Figure 9).
These loose cells do not sediment down as quickly as the spheroids and thus are lost during successive media changes. The remaining spheroids become steadily rounder and more robust as they grow. Starting from a single embryoid body plate well, these procedures have been shown to produce large numbers of spheroids (about 1200) similar to those shown in Figure 9 after 21 days (these would normally be cultured in four culture vessels). At this stage, each spheroid contains about 82,300 cells and contains 12.31 μg protein (C3A spheroids). The standard deviation of their diameters is less than 21% (after 21 days in culture) and this approach thus provides large numbers of very reproducible spheroids for further experimentation [39, 43].
Once C3A spheroids have recovered, they reach a metabolic equilibrium, characterised by a constant production of ATP, cholesterol and urea for at least 24 days [32]. During this period, treatment of these spheroids with for example any one of six commonly used drugs (acetaminophen (APAP), amiodarone, diclofenac, metformin, phenformin and valproic acid) causes them to respond (as shown by the increase in ATP production) and then recover to the pre-treatment conditions [43]. This can be repeated multiple times and has been proposed to be useful for assessing repeated-dose drug toxicity [39].
The liver is the primary source of many of the proteins found in the blood. To illustrate just how stable C3A spheroids are, they have been kept alive for 302 days. Even after this length of time C3A spheroids are quite capable of synthesising and post translationally modifying these blood proteins (Figure 10).
Proteins secreted from 302 day old C3A spheroids. Some of the proteins are named for reference: ACTB, actin beta; ALBU, albumen; APA4, apolipoprotein a I; APA4, apolipoprotein a IV; APOC3, apolipoprotein C III; APOE, apolipoprotein E, CO3 complement C3 alpha; CO4 complement C4; FETA Foetal albumen; FGL1, fibrinogen-like protein 1; FIBB, fibrinogen beta; FIBG, fibrinogen gamma; ITH4, inter alpha trypsin inhibitor heavy chain 4; MTN3, Matrilin3; PEDF, pigment epithelium derived factor; THRB, prothrombin; TRFE, Serotransferrin; TTHY, transthyretin.
Already 8 years ago, clinostat spheroids constructed from C3A cells were shown to be more effective of predicting drug toxicity than primary human hepatocytes
C3A spheroids have also been used to reveal novel signalling pathways involved in drug treatment (acetaminophen) [46].
Currently one of the major weakness of testing for genotoxicity is the inability of indicator cells to express metabolic enzymes needed for the activation and detoxification of genotoxic compounds
Herbal medicines are often assumed to be safe because they are ‘natural products’, despite the lack of data. To reduce the cost and accelerate their testing, a C3A 3D spheroid model has been developed and benchmarked against Sprague Dawley rats to test one of the most widely used extracts, (
Heteromeric proteins from spheroids even been used as an internal quality control for proteomic data [49].
Epigenetic marking and histone clipping have been shown to be recovered in spheroids [38] and this has been shown to occur during intestinal differentiation
Spheroids and organoids are being used to investigate the self-organisation of multicellular tissues [53]. Human induced pluripotent stem cells (hiPS cells) have been used to generate neural spheroids that contain oligodendrocytes, neurons and astrocytes [28] and to mimic the blood brain barrier [54]. Primary and stem cells have been used to recapitulate the intricate pattern and functionality of pancreatic islets, working towards regenerative medicine for diabetes [55]. Progress is also being made towards producing transplantable photoreceptor precursors using pluripotent stem cell-derived retinal organoids to treat retinal degeneration diseases [56].
Bacterial-host interactions during Salmonella infections are being studied using iPSCs organoids and stem cell enteroids to mimic the intestinal villus and crypt [57].
Multicellular, physiologically active organotypic cultures are being use to study a wide variety of human viral pathogens with a view to pre-clinical evaluation of vaccines, antivirals and therapeutics [58].
Clinostat cultures are also being used in bone research. Low dietary intake of both vitamin D and K is negatively associated with fracture risk, often seen in persons suffering from osteoporosis. Treatment of primary human osteoblasts (hOBs) 3D multicellular spheroids with a combination of vitamin D and K, enhanced gene expression of periostin and collagen (COL-1), as well as inducing extended osteoid formation. The two vitamins apparently affected bone mechanical properties differently: vitamin D enhancing stiffness and K2 conveying flexibility to bone. It is anticipated that the combination of these effects may translate to increased fracture resistance
Clinostat bioreactors systems clearly provide readily controllable 3D cell culture conditions, needing small amounts of cells, media or other compounds and provide sufficient cellular material for a wide variety of assays. The culture vessels and clinostat incubator described here, would be beneficial for many
The advantages of culture stability for months, its reproducibility and the possibility to treat and then see the response and recovery (if necessary, for multiple times on the same culture) offer a great potential for future research. The novel equipment described here, will facilitate this research.
Furthermore, the fact that the clinostat system does not require changes in media, the use of scaffolds or special growth factors will not only facilitate the transition from other systems to this clinostat approach but will also allow the cells to respond in their own natural pre-programmed manner.
Thanks to 3D cell culture, the border between basic research and clinical applications is dissolving – and this new era of self-assembling tissue mimetic structures requires a new range of purpose-built equipment.
The authors are all employees of CelVivo ApS.
The culture vessel and clinostat incubator illustrated in this chapter are sold under the ClinoReactor® and ClinoStar® trade names by CelVivo ApS.
Video materials referenced in the text are available at: https://bit.ly/2PkiE9m.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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Jovandaric"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:75,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"42000",doi:"10.5772/53159",title:"Valorisation of Cheese Whey, a By-Product from the Dairy Industry",slug:"valorisation-of-cheese-whey-a-by-product-from-the-dairy-industry",totalDownloads:7019,totalCrossrefCites:57,totalDimensionsCites:121,abstract:null,book:{id:"3424",slug:"food-industry",title:"Food Industry",fullTitle:"Food Industry"},signatures:"Chiara Mollea, Luca Marmo and Francesca Bosco",authors:[{id:"93865",title:"Dr.",name:"Francesca",middleName:null,surname:"Bosco",slug:"francesca-bosco",fullName:"Francesca Bosco"},{id:"96159",title:"Dr.",name:"Chiara",middleName:null,surname:"Mollea",slug:"chiara-mollea",fullName:"Chiara Mollea"},{id:"166295",title:"Prof.",name:"Luca",middleName:null,surname:"Marmo",slug:"luca-marmo",fullName:"Luca Marmo"}]},{id:"29151",doi:"10.5772/32358",title:"Hydrocolloids in Food Industry",slug:"hydrocolloids-in-food-industry",totalDownloads:30615,totalCrossrefCites:31,totalDimensionsCites:113,abstract:null,book:{id:"2082",slug:"food-industrial-processes-methods-and-equipment",title:"Food Industrial Processes",fullTitle:"Food Industrial Processes - Methods and Equipment"},signatures:"Jafar Milani and Gisoo Maleki",authors:[{id:"91158",title:"Associate Prof.",name:"Jafar",middleName:"Mohammadzadeh",surname:"Milani",slug:"jafar-milani",fullName:"Jafar Milani"},{id:"124058",title:"Ph.D. Student",name:"Gisoo",middleName:null,surname:"Maleki",slug:"gisoo-maleki",fullName:"Gisoo Maleki"}]},{id:"41694",doi:"10.5772/53172",title:"Seaweeds for Food and Industrial Applications",slug:"seaweeds-for-food-and-industrial-applications",totalDownloads:8297,totalCrossrefCites:31,totalDimensionsCites:98,abstract:null,book:{id:"3424",slug:"food-industry",title:"Food Industry",fullTitle:"Food Industry"},signatures:"Berna Kılınç, Semra Cirik, Gamze Turan, Hatice Tekogul and Edis Koru",authors:[{id:"88972",title:"Dr.",name:"Edis",middleName:null,surname:"Koru",slug:"edis-koru",fullName:"Edis Koru"},{id:"161688",title:"Dr.",name:"Berna",middleName:null,surname:"Kılınç",slug:"berna-kilinc",fullName:"Berna Kılınç"}]},{id:"40180",doi:"10.5772/50568",title:"Plant Tissue Culture: Current Status and Opportunities",slug:"plant-tissue-culture-current-status-and-opportunities",totalDownloads:66470,totalCrossrefCites:43,totalDimensionsCites:90,abstract:null,book:{id:"3568",slug:"recent-advances-in-plant-in-vitro-culture",title:"Recent Advances in Plant in vitro Culture",fullTitle:"Recent Advances in Plant in vitro Culture"},signatures:"Altaf Hussain, Iqbal Ahmed Qarshi, Hummera Nazir and Ikram Ullah",authors:[{id:"147617",title:"Dr.",name:"Altaf",middleName:null,surname:"Hussain",slug:"altaf-hussain",fullName:"Altaf Hussain"}]},{id:"53601",doi:"10.5772/66840",title:"Chitosan in Agriculture: A New Challenge for Managing Plant Disease",slug:"chitosan-in-agriculture-a-new-challenge-for-managing-plant-disease",totalDownloads:5680,totalCrossrefCites:31,totalDimensionsCites:67,abstract:"In recent years, environmental-friendly measures have been developed for managing crop diseases as alternative to chemical pesticides, including the use of natural compounds such as chitosan. In this chapter, the common uses of this natural product in agriculture and its potential uses in plant disease control are reviewed. The last advanced researches as seed coating, plant resistance elicitation and soil amendment applications are also described. Chitosan is a deacetylated derivative of chitin that is naturally present in the fungal cell wall and in crustacean shells from which it can be easily extracted. Chitosan has been reported to possess antifungal and antibacterial activity and it showed to be effective against seedborne pathogens when applied as seed treatment. It can form physical barriers (film) around the seed surface, and it can vehicular other antimicrobial compounds that could be added to the seed treatments. Chitosan behaves as a resistance elicitor inducing both local and systemic plant defence responses even when applied to the seeds. The chitosan used as soil amendment was shown to give many benefits to different plant species by reducing the pathogen attack and infection. Concluding, the chitosan is an active molecule that finds many possibilities for application in agriculture, including plant disease control.",book:{id:"5412",slug:"biological-activities-and-application-of-marine-polysaccharides",title:"Biological Activities and Application of Marine Polysaccharides",fullTitle:"Biological Activities and Application of Marine Polysaccharides"},signatures:"Laura Orzali, Beatrice Corsi, Cinzia Forni and Luca Riccioni",authors:[{id:"189361",title:"Ph.D.",name:"Laura",middleName:null,surname:"Orzali",slug:"laura-orzali",fullName:"Laura Orzali"},{id:"189612",title:"Dr.",name:"Luca",middleName:null,surname:"Riccioni",slug:"luca-riccioni",fullName:"Luca Riccioni"},{id:"189614",title:"Dr.",name:"Beatrice",middleName:null,surname:"Corsi",slug:"beatrice-corsi",fullName:"Beatrice Corsi"},{id:"189615",title:"Prof.",name:"Cinzia",middleName:null,surname:"Forni",slug:"cinzia-forni",fullName:"Cinzia Forni"}]}],mostDownloadedChaptersLast30Days:[{id:"64570",title:"Banana Pseudo-Stem Fiber: Preparation, Characteristics, and Applications",slug:"banana-pseudo-stem-fiber-preparation-characteristics-and-applications",totalDownloads:9428,totalCrossrefCites:15,totalDimensionsCites:18,abstract:"Banana is one of the most well-known and useful plants in the world. Almost all the parts of this plant, that are, fruit, leaves, flower bud, trunk, and pseudo-stem, can be utilized. This chapter deals with the fiber extracted from the pseudo-stem of the banana plant. It discusses the production of banana pseudo-stem fiber, which includes plantation and harvesting; extraction of banana pseudo-stem fiber; retting; and degumming of the fiber. It also deals with the characteristics of the banana pseudo-stem fiber, such as morphological, physical and mechanical, durability, degradability, thermal, chemical, and antibacterial properties. Several potential applications of this fiber are also mentioned, such as the use of this fiber to fabricate rope, place mats, paper cardboard, string thread, tea bags, high-quality textile materials, absorbent, polymer/fiber composites, etc.",book:{id:"7544",slug:"banana-nutrition-function-and-processing-kinetics",title:"Banana Nutrition",fullTitle:"Banana Nutrition - Function and Processing Kinetics"},signatures:"Asmanto Subagyo and Achmad Chafidz",authors:[{id:"257742",title:"M.Sc.",name:"Achmad",middleName:null,surname:"Chafidz",slug:"achmad-chafidz",fullName:"Achmad Chafidz"},{id:"268400",title:"Mr.",name:"Asmanto",middleName:null,surname:"Subagyo",slug:"asmanto-subagyo",fullName:"Asmanto Subagyo"}]},{id:"40180",title:"Plant Tissue Culture: Current Status and Opportunities",slug:"plant-tissue-culture-current-status-and-opportunities",totalDownloads:66453,totalCrossrefCites:43,totalDimensionsCites:89,abstract:null,book:{id:"3568",slug:"recent-advances-in-plant-in-vitro-culture",title:"Recent Advances in Plant in vitro Culture",fullTitle:"Recent Advances in Plant in vitro Culture"},signatures:"Altaf Hussain, Iqbal Ahmed Qarshi, Hummera Nazir and Ikram Ullah",authors:[{id:"147617",title:"Dr.",name:"Altaf",middleName:null,surname:"Hussain",slug:"altaf-hussain",fullName:"Altaf Hussain"}]},{id:"68437",title:"Chemical Properties of Starch and Its Application in the Food Industry",slug:"chemical-properties-of-starch-and-its-application-in-the-food-industry",totalDownloads:4743,totalCrossrefCites:19,totalDimensionsCites:48,abstract:"Starch is an important food product and a versatile biomaterial used world-wide for different purposes in many industrial sectors including foods, health, textile, chemical and engineering sector. Starch versatility in industrial applications is largely defined by its physicochemical properties and functionality. Starch in its native form has limited functionality and application. But advancements in biotechnology and chemical technological have led to wide-range modification of starch for different purposes. The objective of this chapter is to examine the different chemical reactions of starch and expose the food applications of the modification products. Several literatures on starch and reaction chemistry including online journals and books were analyzed, harmonized and rationalized. The reactions and mechanisms presented are explained based on the principles of reaction chemistry. Chemical modification of starch is based on the chemical reactivity of the constituent glucose monomers which are polyhydroxyl and can undergo several reactions. Starch can undergo reactions such as hydrolysis, esterification, etherification and oxidation. These reactions give modified starches which can be used in baked foods, confectionaries, soups and salad dressings. This chapter discusses the different chemical reactions of starch, the associated changes in functionality, as well as the applications of chemically modified starches in the food industry.",book:{id:"8170",slug:"chemical-properties-of-starch",title:"Chemical Properties of Starch",fullTitle:"Chemical Properties of Starch"},signatures:"Henry Omoregie Egharevba",authors:[{id:"300976",title:"Associate Prof.",name:"Henry",middleName:"Omoregie",surname:"O. Egharevba",slug:"henry-o.-egharevba",fullName:"Henry O. Egharevba"}]},{id:"63169",title:"The Dairy Industry: Process, Monitoring, Standards, and Quality",slug:"the-dairy-industry-process-monitoring-standards-and-quality",totalDownloads:9068,totalCrossrefCites:12,totalDimensionsCites:27,abstract:"Sampling and analysis occur along the milk processing train: from collection at farm level, to intake at the diary plant, the processing steps, and the end products. Milk has a short shelf life; however, products such as milk powders have allowed a global industry to be developed. Quality control tests are vital to support activities for hygiene and food standards to meet regulatory and customer demands. Multiples of chemical and microbiological contamination tests are undertaken. Hazard analysis testing strategies are necessary, but some tests may be redundant; it is therefore vital to identify product optimization quality control strategies. The time taken to undergo testing and turnaround time are rarely measured. The dairy industry is a traditional industry with a low margin commodity. Industry 4.0 vision for dairy manufacturing is to introduce the aspects of operational excellence and implementation of information and communications technologies. The dairy industries’ reply to Industry 4.0 is represented predominantly by proactive maintenance and optimization of production and logistical chains, such as robotic milking machines and processing and packaging line automation reinforced by sensors for rapid chemical and microbial analysis with improved and real-time data management. This chapter reviews the processing trains with suggestions for improved optimization.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Niamh Burke, Krzysztof A. Zacharski, Mark Southern, Paul Hogan,\nMichael P. Ryan and Catherine C. Adley",authors:[{id:"243276",title:"Dr.",name:"Michael P",middleName:null,surname:"Ryan",slug:"michael-p-ryan",fullName:"Michael P Ryan"},{id:"246153",title:"Prof.",name:"Catherine",middleName:null,surname:"Adley",slug:"catherine-adley",fullName:"Catherine Adley"},{id:"264302",title:"Ms.",name:"Niamh",middleName:null,surname:"Burke",slug:"niamh-burke",fullName:"Niamh Burke"},{id:"264304",title:"Mr.",name:"Krzysztof A",middleName:null,surname:"Zacharski",slug:"krzysztof-a-zacharski",fullName:"Krzysztof A Zacharski"},{id:"264305",title:"Mr.",name:"Paul",middleName:null,surname:"Hogan",slug:"paul-hogan",fullName:"Paul Hogan"},{id:"264306",title:"Dr.",name:"Mark",middleName:null,surname:"Southern",slug:"mark-southern",fullName:"Mark Southern"}]},{id:"40181",title:"Plant Tissue Culture Media",slug:"plant-tissue-culture-media",totalDownloads:105011,totalCrossrefCites:9,totalDimensionsCites:32,abstract:null,book:{id:"3568",slug:"recent-advances-in-plant-in-vitro-culture",title:"Recent Advances in Plant in vitro Culture",fullTitle:"Recent Advances in Plant in vitro Culture"},signatures:"Abobkar I.M. Saad and Ahmed M. Elshahed",authors:[{id:"144204",title:"Prof.",name:"Abobkar",middleName:null,surname:"Mohamed",slug:"abobkar-mohamed",fullName:"Abobkar Mohamed"}]}],onlineFirstChaptersFilter:{topicId:"33",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82066",title:"Chocolate: Health, Processing, and Food Safety",slug:"chocolate-health-processing-and-food-safety",totalDownloads:22,totalDimensionsCites:0,doi:"10.5772/intechopen.104819",abstract:"Chocolate is a popular food product internationally, and it is consumed daily. Consuming chocolate has been linked to many human health benefits such as lower cholesterol levels, but there are some negative impacts such as weight gain because of its sugar content. Moreover, food safety issues related to chocolate have existed, and it can be contaminated by any biological, chemical, or physical hazards, which lead to many health issues. Regarding that, this chapter will discuss the benefits and negative impacts of consuming chocolate and provide the process of manufacturing the product.",book:{id:"11025",title:"A Glance at Food Processing Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11025.jpg"},signatures:"Ahmed Albandary, Fatemah Albandary and Amit K. Jaiswal"},{id:"78140",title:"Thoughts for Foods: Imaging Technology Opportunities for Monitoring and Measuring Food Quality",slug:"thoughts-for-foods-imaging-technology-opportunities-for-monitoring-and-measuring-food-quality",totalDownloads:216,totalDimensionsCites:1,doi:"10.5772/intechopen.99532",abstract:"In recent decades, the quality and safety of fruits, vegetables, cereals, meats, milk, and their derivatives from processed foods have become a serious issue for consumers in developed as well as developing countries. Undoubtedly, the traditional methods of inspecting and ensuring quality that depends on the human factor, some mechanical and chemical methods, have proven beyond any doubt their inability to achieve food quality and safety, and thus a failure to achieve food security. With growing attention on human health, the standards of food safety and quality are continuously being improved through advanced technology applications that depend on artificial intelligence tools to monitor the quality and safety of food. One of the most important of these applications is imaging technology. A brief discussion in this chapter on the utilize of multiple imaging systems based on all different bands of the electromagnetic spectrum as a principal source of various imaging systems. As well as methods of analyzing and reading images to build intelligence and non-destructive systems for monitoring and measuring the quality of foods.",book:{id:"11025",title:"A Glance at Food Processing Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11025.jpg"},signatures:"Ayman Eissa, Lajos Helyes, Elio Romano, Ahmed Albandary and Ayman Ibrahim"},{id:"78268",title:"Utilization of Agro-Industrial Wastes as Edible Coating and Films for Food Packaging Materials",slug:"utilization-of-agro-industrial-wastes-as-edible-coating-and-films-for-food-packaging-materials",totalDownloads:205,totalDimensionsCites:0,doi:"10.5772/intechopen.99786",abstract:"Mostly, food packaging employs synthetic materials obtained from nonrenewable sources. These packaging materials are based on petrochemicals and cause substantial environmental problems by producing massive amounts of non-biodegradable solid wastes. Edible coatings and films are considered as the potential solution to these problems of non-biodegradable packaging solid wastes for maintaining food-environment interactions, retaining food quality, and extending shelf life. In addition, edible coatings and films offer prevention from microbial spoilage of packed foods by controlling moisture and gas barrier characteristics. Increasing environmental concerns and consumer demands for high-quality eco-friendly packaging have fueled the advancement of innovative packaging technologies, for instance, the development of biodegradable films from renewable agricultural and food processing industry wastes. Therefore, the current chapter presents the application of edible coatings and films as an alternative to conventional packaging, emphasizing the fundamental characterization that these biodegradable packaging should hold for specific applications such as food preservation and shelf life enhancement. The primary employed components (e.g., biopolymers, bioactive, and additives components), manufacturing processes (for edible films or coatings), and their application to specific foods have all been given special consideration in this chapter. Besides, a future vision for the use of edible films and coatings as quality indicators for perishable foods is presented.",book:{id:"11025",title:"A Glance at Food Processing Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11025.jpg"},signatures:"Urmila Choudhary, Basant Kumar Bhinchhar, Vinod Kumar Paswan, Sheela Kharkwal, Satya Prakash Yadav and Prity Singh"},{id:"78863",title:"Effects of the Incorporation of Arabinoxylans Derived from Selected Cereals (Rice Bran and Corn Fibre) and Sugarcane Bagasse on the Quality of Baked Foods: A Systematic Review",slug:"effects-of-the-incorporation-of-arabinoxylans-derived-from-selected-cereals-rice-bran-and-corn-fibre",totalDownloads:97,totalDimensionsCites:0,doi:"10.5772/intechopen.99488",abstract:"The supplementation of baked foods, namely cookie/biscuits, bread and cakes with agricultural by-products from cereal based fibres (rice bran and corn fibre) and sugarcane bagasse at rates of 0% - 15%; 0% - 30% and 0% - 10% respectively can significantly improve its nutritive value and enhanced its physical and sensorial qualities. This chapter aims to review the role of dietary fibres derived from selected cereals (rice bran and corn fibre) and sugarcane bagasse in baked foods, namely cookies/biscuits, bread and cakes; evaluate their effects on the physical and sensory qualities of these baked food products and to critically assess their beneficial impacts in baked foods. These enriched food products can potentially be utilised in shaping health policies, contribute to the dietary fibre needs of consumers and facilitate the development of functional foods. Fibre enriched foods potentially can assist in improving various physiological functions of the human body. A Keyword-based search strategy was utilised to conduct a comprehensive search for articles catalogued in ScienceDirect, Web of Science, PubMed, Medline, CINAHL and Google Scholar that were published between January 1, 2010 and August 1, 2020. Applicable aspects of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines provided the framework of this review. Fourteen (14) studies met the inclusion/extraction criteria and was placed into sub-groups by food types and fibre used in supplementation. Only eleven (11) studies were suitable for statistical data analysis. The supplementation of sugarcane bagasse at both 5% and 10% and rice bran up to 15% into cookies/biscuits significantly undesirable acceptance (p < 0.05). Corn fibre enriched cookies/biscuits up to 20% showed a significantly (p < 0.05) favourable impact on the sensory qualities of the food product. The physical qualities of sugarcane bagasse supplemented cookies/biscuits were negatively affected. The incremental addition of sugarcane bagasse resulted in at 50% rise in the firmness of 10% enriched cookies/biscuits, from 5.7 ± 5.4 (Kg Force) to 13.0 ± 3.9 (Kg Force). Corn fibre cookies supplementation did not significantly affect its physical qualities. Rice bran incorporation of 15% in bread showed a significant (p < 0.05) undesirable effect on its sensory qualities. However, the was no significant adverse effect on its physical quality. Corn bran enriched cakes up to 20% fibre incorporation displayed a significant (p < 0.05) favourable effect on the sensory properties of cakes.",book:{id:"11025",title:"A Glance at Food Processing Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11025.jpg"},signatures:"Roy Orain Porter"},{id:"77920",title:"Honey Production Process",slug:"honey-production-process",totalDownloads:176,totalDimensionsCites:0,doi:"10.5772/intechopen.99439",abstract:"Honey has been considered as a very important and superior nutrient in human nutrition since ancient times due to its ability to be consumed by humans without processing, easy digestibility, nutritional properties and biological benefits. Although honey contains many desired bioactive and antibacterial substances, which may be sufficient for antimicrobial activity, it cannot be produced in sufficient quantities due to low water activity under normal conditions. This causes various food and bee-borne spores/non-spores pathogens going viral. Hence, it may cause the risk of parasitological and fungal agents to be found. In honey production, “Hazard Analysis Critical Control Point (HACCP)” must be applied meticulously and completely. Current technologies in honey production will be explained in this section.",book:{id:"11025",title:"A Glance at Food Processing Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11025.jpg"},signatures:"Emek Dümen, Nadide Gizem Tarakçı and Gözde Ekici"},{id:"78007",title:"Retracted: Applications of Phage-Based Biosensors in the Diagnosis of Infectious Diseases, Food Safety, and Environmental Monitoring",slug:"retracted-applications-of-phage-based-biosensors-in-the-diagnosis-of-infectious-diseases-food-safety",totalDownloads:73,totalDimensionsCites:0,doi:"10.5772/intechopen.99537",abstract:"Bacteriophages are interesting entities that parasite bacteria. After infection, they gain new properties such as selectively binding proteins, thanks to genetic manipulation capability. Owing to this, they may be applied as recognition elements in different types of biosensors. Combining bacteriophages with various transducers can then result in the construction of innovative sensor designs that could improve the quality of food safety and environmental monitoring services. Contamination of foods by bacterial pathogens, such as Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella typhimurium, results in human infection that can severely affect the immunocompromised, the elderly, and pregnant women. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"