Characterizations of clinical imaging modalities (adapted from [9]).
\r\n\t
",isbn:"978-1-80356-477-7",printIsbn:"978-1-80356-476-0",pdfIsbn:"978-1-80356-478-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"b306ce94998737c764d08736e76d60e1",bookSignature:"Dr. Alyssa A Brewer and Dr. Brian Barton",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11636.jpg",keywords:"Mammalian, Primate, Human, Genetics and Epigenetics, Individual Variability, Adaptation, Cortical Reorganization, Cortical Recovery, Visual Field Map, Sensorimotor Maps, Bottom-Up Sensory Processing, Top-Down Visual Attention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 3rd 2022",dateEndSecondStepPublish:"May 4th 2022",dateEndThirdStepPublish:"July 3rd 2022",dateEndFourthStepPublish:"September 21st 2022",dateEndFifthStepPublish:"November 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Brewer is a Stanford-trained physician-scientist, tenured Associate Professor at UC Irvine, and Director of the mind space Lab, who uses cutting-edge computational neuroimaging to study the organization and plasticity of the human sensory cortex.",coeditorOneBiosketch:"Dr. Barton is a UCI-trained cognitive scientist who has pioneered the study of auditory field maps in the human cortex and currently focuses his research on computational neuroimaging measurements of audiovisual cortical processing and organization.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"115304",title:"Dr.",name:"Alyssa",middleName:"A",surname:"Brewer",slug:"alyssa-brewer",fullName:"Alyssa Brewer",profilePictureURL:"https://mts.intechopen.com/storage/users/115304/images/system/115304.jpg",biography:"Dr. Alyssa A. Brewer completed her undergraduate degrees at Stanford University, with a B.S. with Honors in Biological Sciences and an A.B. in Comparative Literature with interdisciplinary Honors in Humanities. She continued on at Stanford in a dual-degree graduate program, graduating with an M.D. and a Ph.D. in Neuroscience in 2007. Her work in graduate school with Brian Wandell, Ph.D., focused on computational neuroimaging measurements of visual cortex organization and plasticity in humans and macaque. She now is an Associate Professor in the Departments of Cognitive Sciences and Language Science, by courtesy, at the University of California, Irvine. Dr. Brewer’s research focuses on visual, auditory, and multi-sensory neuroscience, using behavioral, genetic, and high-resolution neuroimaging techniques to investigate questions ranging from the fundamental organization of human visual and auditory cortex to plasticity in visual, auditory, and sensorimotor regions.",institutionString:"University of California, Irvine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of California, Irvine",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"149246",title:"Dr.",name:"Brian",middleName:null,surname:"Barton",slug:"brian-barton",fullName:"Brian Barton",profilePictureURL:"https://mts.intechopen.com/storage/users/149246/images/system/149246.jpeg",biography:"Dr. Brian Barton received his B.S. in Psychology at the University of Oregon, where he studied visual attention and working memory with Edward Awh, Ph.D., and Edward Vogel, Ph.D. Dr. Barton then earned his Ph.D. in Psychology with a Concentration in Cognitive Neuroscience in 2013 at the University of California, Irvine (UCI), where he expanded his research into functional MRI measurements of visual cortex organization and plasticity with Alyssa A. Brewer, M.D., Ph.D. He continued on at UCI as a post-doctoral scholar for three years with Drs. Brewer, Greg Hickok, Ph.D., and Kourosh Saberi, Ph.D., applying his vision work to measurements of the organization of human auditory cortex. 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This novel approach is at the doorstep to its clinical application. Nevertheless, there is still a lack of consistent and unbiased data on the survival, distribution and safety of implanted cells. The tight collaboration between pharmacology, chemistry, biology and physics expanded the collection of methods for
Organ transplantation still remains the gold standard for the treatment of terminally damaged organs. This method brings along a collection of drawbacks like the shortage of available donor organs and the high morbidity of immunosuppressive therapy. Regenerative medicine offers an alternative for the replacement of organs and tissues overcoming pitfalls and proposing a therapy with patient’s own cells. The discovery of the self-renewal and differentiation capacities of stem cells accelerated the development of regenerative medicine and inspired researchers and clinicians to search for novel treatment options for the improvement of the quality of life of patients [1]. The tremendous success in medical sciences and biotechnology allowed the development of many ideas, some of which are now being approved by clinical trials. Nearly 26’000 studies utilizing cell therapy are currently ongoing [2] trying to establish the safety and effectiveness of this new method for applications in neurology, cardiology or oncology. Autologous stem cell therapy is a novel promising approach with increasing impact on regenerative medicine. Preliminary data of many preclinical studies on different human disorders showed a beneficial effect of this treatment [3]. The usage of the patient’s own cells to rebuild tissues and regain functionality after trauma is currently investigated, as it may have a profound influence on many human diseases once its application is approved. Several hurdles are yet to be overcome before the safety of this method is guaranteed. One possibility to avoid the post mortem read-out of a study or the invasiveness of a biopsy is the use of
In the past two decades many researchers concentrated on developing new modalities for better visualization on the cellular and molecular level. As none of the available imaging systems fulfils all needs, many efforts have been put into expanding the potential of the available methods by testing the application of a variety of vectors, genes, proteins and cells for precise read-outs. The visualization techniques relevant to clinical cell tracking include positron emission tomography (PET), single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) [4]. Hybridizations of computed tomography (CT) and MRI with PET and SPECT allow simultaneous acquisition of anatomical information and reveal new state-of-the-art modalities for successful molecular imaging (SPECT/CT, PET/CT, PET/MRI) [5]. Generally, the utilization of radioactive tracers provides high sensitivity and requires short image acquisition time. Nevertheless, the production of the radioactive isotopes is very expensive and its application comes along with radiation exposure for the patient. Therefore, MRI seems to be an attractive alternative devoid of harmful radiation. This modality has spectacular image resolution and anatomical read-out capabilities [6]. However, it is more time-consuming and lacks the high sensitivity of PET and SPECT [7] (see Table 1). There are also a few optical imaging modalities using bioluminescence (BLI) or fluorescence (FI), which have been widely utilized in small animal models [8]. These are cost-saving methods (using fluorescent proteins or luciferase activity) which allow for very rapid result obtainment. Nevertheless, their spatial resolution is low and decreases with depth, which is the main reason why they are not applicable for life cell imaging in humans.
Many cells are potentially accessible by imaging and developments in this field already support the diagnosis and therapy of several human diseases. However, a feasible technique for non-invasive monitoring of the tissue engineering process is still missing. A variety of cells was shown to be applicable for tissue and organ restoration, but yet little is known about the safety, viability, functionality and migration of these cells
\n\t\t\t\t \n\t\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t50-200 µm (preclinical) 0.5-1 mm (clinical) | \n\t\t\tminutes | \n\t\t\tnot defined | \n\t\t\tIonizing radiation | \n\t\t\tYes | \n\t\t\t$$ | \n\t\t
\n\t\t\t\t | \n\t\t\t25-100 µm (preclinical) ~1 mm (clinical) | \n\t\t\tminutes-hours | \n\t\t\t10-3 – 10-5M poor | \n\t\t\tNo ionizing radiation | \n\t\t\tYes | \n\t\t\t$$$ | \n\t\t
\n\t\t\t\t | \n\t\t\t1-2 mm (preclinical) 5-7mm (clinical) \n\t\t\t | \n\t\t\tseconds-minutes | \n\t\t\t10-11 – 10-12M excellent | \n\t\t\tIonizing radiation | \n\t\t\tYes | \n\t\t\t$$$ | \n\t\t
\n\t\t\t\t | \n\t\t\t1-2 mm (preclinical) 8-10 mm (clinical) | \n\t\t\tminutes | \n\t\t\t10-10 – 10-11M excellent | \n\t\t\tIonizing radiation | \n\t\t\tYes | \n\t\t\t$$ | \n\t\t
Characterizations of clinical imaging modalities (adapted from [9]).
The phenomenon of Magnetic Resonance Imaging (MRI) was discovered observing the reaction of certain nuclei, mostly 1H in the body, when placed in a strong magnetic field (B0) [10]. Within a magnetic field, the sum of spins is a net magnetization aligned with the applied field. The macroscopic magnetization is an effect of a slight excess of spins in “low energy” state, in parallel to the B0 direction. The precession frequency of each atom with magnetic moment is directly proportional to the strength of the magnetic field. After applying a radiofrequency (RF) pulse which matches the precession frequency, some of the “excess” atoms absorb energy and flip, thereby changing the direction of the net magnetization vector. The flip angle depends on the intensity, waveform and duration of the RF pulse [11]. These atoms then re-emit the energy during transition to their original orientation (relaxation) (Figure 1).
MRI scanner uses radiowaves and strong magnetic fields to obtain anatomical and functional body images. 1) Atoms spin in random directions. 2) Applying a magnetic field makes atoms line up either in the direction of B0, or in the opposite direction. The distribution is not exactly equal, as more atoms prefer to turn in “low energy” state, thereby creating a net magnetization parallel to B0. 3) Introducing a RF pulse makes half of the “excess” atoms change the direction of their magnetization moment-to the “high energy” state. 4) Turning the RF off makes these atoms turn back to their “low energy” position (relaxation), thereby emitting energy.
As already shown, MRI is based on a unique combination of radio waves and strong magnetic fields, which allows the generation of cross-sectional images of the body in any plane. Depending on the relaxation time after the RF pulse, one can distinguish between T1-and T2-weighted images.
MRI is an imaging modality, which uses non-ionizing electromagnetic radiation and is thus not harmful for patients. This is one of the strongest advantages of this technology over the other methods described in this chapter.
One of the biggest advantages of MRI is its high soft tissue contrast. This allows for very precise images and simultaneous detection of functional, molecular and anatomical data. The tight collaboration of science and medicine led to the clinical implementation of the MRI modality for various diseases. Nevertheless, most of its potential remains at the pre-clinical state, as the application safety of many methods is still under investigation. Cerebral perfusion imaging, MR angiography flow imaging, cardiac MRI, functional MRI and MR spectroscopy are just a few of the MRI sub-groups. However, up-to-date, MR is clinically mainly used for the imaging of soft tissues.
A clinical trial study with patients suffering from acute myocardial infarction showed successful implementation of MRI. Intracoronary infusions of bone marrow-derived stem cells at different time points helped with cardio regeneration, which could be visualized by this technique [12]. Another study is on its doorstep to clinics, gathering breast cancer patients for breast restoration. The aim is to use MRI of autologous adipose-derived stem cells to visualize the engraftment into the host tissue. The outcome of this study may have a great impact on the utilization of MRI for cell tracking as a novel tool for breast tissue regeneration [13]. A further example for the implementation of MRI for cell therapy studies was the evaluation in a multiple sclerosis clinical trial. In this case, adult bone marrow derived stromal cells were intravenously administered to the patients and MRI scans were performed to follow the occurring changes. The main objective was to evaluate the effect of mesenchymal stem cell transplantation on the number of Gadolinium (Gd)-positive lesions [14]. Another way of addressing the safety and efficacy of using autologous mesenchymal stem cells as a possible therapy for multiple sclerosis is being proposed by a group, using MR imaging for the assessment of the therapeutic effect of the cell treatment [15]. All in all, MRI seems to be a promising tool for monitoring therapy and diagnostic outcomes. Nevertheless, most of the clinical studies using stem cell therapy in combination with MRI are focused on the visualization of the regenerating soft tissue, rather than on the transplanted stem cells, their localization, viability and safety.
Further efforts have been put into the development of strategies for bone and cartilage regeneration. Recent studies are concentrating on developing a MRI-based method for visualization of knee osteoarthritis by assessing the number and location of lesions, cartilage thickness, and subchondral bone alteration at different time points [16]. Others went further by using autologous adipose tissue derived mesenchymal stem cells (AD MSCs) as the most hopeful candidate progenitor cell source for cartilage tissue engineering in patients with degenerative arthritis. Promising results showed improved knee functions and reduced pain without any adverse events. The cartilage regeneration process was captured by MRI at different time points, showing decreased size of cartilage defect, while the volume of cartilage increased over time in the high-dose patients (Figure 2) [17]. This depicts an excellent example of the gradual morphologic regeneration process, visualized by means of MRI.
MRI evaluation of articular cartilage regeneration in the medial and femoral condyles after intra-articular injection of autologous AD MSCs. Sagittal and coronal MRIs before, 3, and 6 months after AD MSCs injection depicted the beneficial effect of the high-dose stem cell therapy upon cartilage regeneration by visualizing increase in thickness, and significantly decreased defect size. (Reprinted from [
Besides its tremendous spatial resolution for visualization of soft tissues, MRI has proven successful in the imaging of the spinal cord and column. There are several clinical studies concentrating on the regeneration of this region using mesenchymal stem cell (MSC) transplants after injury. One group is trying to evaluate the change of MSC-treated spinal cord injury using MRI. Scans will be performed at 3 and 6 months after transplantation in order to track the effects of the possible cell treatment and the different ways of application (intravenous, intrathecal, into the spinal cord) [18]. The outcome of this trial will allow suggesting the most beneficial cell delivery method for further studies. Another project was concentrating on the visualization of spinal cord lesions inducing limb paralysis. The proposed treatment strategy included injections of bone marrow derived stem cells. Again, the preferred non-invasive imaging method for localization of the injuries was MRI [19]. It seems that MRI is a suitable imaging tool to assess spinal cord lesions and their repair by stem cells. One group addressed the safety and efficacy of autologous MSC injections in patients with chronic spinal cord injury. The outcome of this study revealed changes in MRI such as decreased cavity size and the appearance of fiber-like low signal intensity streaks [20]. An increasing amount of research is concentrating on the transplantation of stem cells as a therapeutic tool, but still, most of the data derives from pre-clinical models. Nevertheless, promising studies in humans reveal new possible solutions for many disorders.
The implementation of contrast agents for enhancement of MRI offers higher contrast and resolution. Gadolinium (Gd) and superparamagnetic iron-oxide (SPIO) are most commonly used for direct stem cell labeling in clinical and preclinical trials, with SPIO particles offering the highest sensitivity amongst all MR contrast agents. Despite initial reports that SPIO labeling of stem cells is safe and does not affect cell biology, recent studies indicate certain metabolic and functional changes. Therefore, some essential issues need to be considered before accepting such agents for clinical trials. A recent study [21] used Gd-or SPIO-labeled mesenchymal stem cells, transduced with a luciferase vector to monitor their viability via BLI. The outcome showed a distinction between viable and non-viable Gd cells, correlating with the luciferase signal. However, dead SPIO-cells indicated a persistent signal void
Safety and efficacy of autologous stem cell therapies remains a big issue and a non-invasive visualization tool like MRI is facilitating the refinement of the procedures. Since MRI provides more biological and functional data than CT-without radiation-the system provides a huge advantage for pediatric patients as well as patients needing multiple scans. This makes it a superior imaging modality in many clinical studies and encourages more patients to sign up for the trials, as the risk for unwanted complications is decreased. However, MRI does not come with excellent sensitivity and abundant molecular probes compared to other techniques, following in this chapter.
Radionuclide-based positron emission tomography (PET) is one of the most sensitive molecular imaging techniques. Contrary to MRI, this technique uses radiation. The agents used for the visualization are labeled with a positron emitting radionuclide (11C, 13N, 15O, 18F etc.) which decays by emitting a positively charged particle (β+). A positron is a particle with the same mass as an electron, but with an opposite charge. Every positron-emitting radionuclide has its own positron range (traveling distance), depending on the energy of its β+-particle. The higher the energy, the longer the distance and, therefore, the larger the loss of spatial resolution. Once most of its energy is lost, the positron eventually annihilates with an electron from the surrounding tissue, whereby their mass is converted into electromagnetic energy in the form of high-energy photons [24]. The PET Imaging technique is based on the coincidence detection of two 511 keV photons emitted simultaneously in opposite directions (180o apart). They are collected by a ring system of photon-sensitive detectors (scintillation crystals), surrounding the object of interest (Figure 3). Although the exact location of a single annihilation is unknown, the acquisition of a large number of coincidence events over many angles can provide enough information to reconstruct an image of the spatial distribution of radioactivity as a function of time [5].
PET scanner detects coincidence of two 511 keV photons emitted in opposite directions after annihilation of a positron (β+) with an electron (e-) in the surrounding media. The signals are captured by scintillation crystals and amplified by photomultipliers. These events are then collected to construct images depicting the activity distribution.
The idea for the development of the PET technique was developed in the 1950s and was introduced only a few decades later [25] as a clinical device for neurology and cardiology. Later, the need of precise anatomic localization and metabolic readout led to the invention of new imaging strategies. Combining two complementary modalities can add anatomical and/or physiological information to molecular imaging studies using software fusion of data. This technology is most successful for studies of organs and tissues that do not move with time, e.g. the brain [26]. Another approach allowing for simultaneous and/or sequential obtainment of data by a single device is the fusion of PET with CT or MRI. The immense value of combining the benefits of two imaging modalities in one instrument in order to assess molecular as well as morphologic information is of major interest nowadays. These devices allow for more exact attribution of the radioactivity to a specific anatomic site within the patient. Another great impact on the expansion of possible PET applications is the increasing availability of PET radiopharmaceuticals. Many researchers are working towards the development of novel radiotracers for diagnosis and/or therapy of various diseases. Combinations of new technologies and radioligands have already been applied in diverse studies and thus provided many insights for the further development of personalized medicine.
Great improvements have been made towards the diagnosis and the therapy monitoring of cancer, brain and heart diseases, as well as for a variety of malignancies and organ/tissue restorations. [18F]fluorodeoxyglucose ([18F]FDG) is the most widely used PET radiopharmaceutical. It is a metabolic tracer and the mechanism of uptake is based on phosphorylation to [18F]FDG-6-phosphate, which is not further metabolized. [18F]FDG has a wide range of applications in oncology, neurology, cardiology and inflammation imaging.
In the past few years many researchers concentrated on cell-based therapies for the restoration of damaged myocardium showing the involvement of different cell types in this process such as: skeletal myoblasts, embryonic stem cells, bone-marrow derived stem cells, cardiac resident cells, mesenchymal stem cells, and circulating progenitor cells. [27]. The introduction of cells into the damaged myocardium seems to be a promising technique and therefore several tools for assessing the viability, localization and metabolism of the injected cells have been evaluated [28]. The implanted cells should be suitably labeled for detection via imaging, in order to be distinguishable from the surrounding cells and structures. This can be achieved by PET imaging using [18F]FDG. It was already shown to be feasible for dynamic tracking of [18F]FDG-labeled progenitor cells during intracoronary injection after acute myocardial infarction [29]. One of the main glucose uptake sites in the body are skeletal muscles. Using PET imaging of this glucose derivate allows for longitudinal assessment of skeletal muscle regeneration and degeneration [30]. This allows for easy visualization by [18F]FDG uptake in response to physical exercise, thus making muscle cells a good diagnostic tool for therapy of muscle disorders [31]. Whether this technology is suitable for regenerative medicine purposes has to be further evaluated.
Another application of this tracer was shown in a clinical study using bone marrow cells for autologous stem cell therapy after myocardial infarction. They included the PET modality in their experimental design and investigated the myocardial flow ([13N]NH3) and perfusion/metabolism mismatch ([18F]FDG) [32]. The usage of PET for tracking
Another possibility for PET application is the utilization of reporter-gene systems (e.g. Herpes Simplex Virus type 1 thymidine kinase (HSV1-tk)) [34]. The main advantage of this method is that the obtained signal is specific only to viable cells, as they are able to express the reporters. This allows not only for visualization of acute cell retention, but also for viability read-outs [7]. HSV1-tk is currently the most investigated enzyme reporter gene for long term
PET/CT has also become an essential tool for assessing prognosis and establishing treatment decisions in oncology. This system found broad application, mainly in defining different stages/locations of metastatic cancer. In this case PET is used for visualizing the increased metabolic activity of the tumor and the addition of CT provides anatomical information on its exact location in the body [41]. This helped immensely in the management of a broad spectrum of malignancies, their diagnosis, staging and therapy-response-assessment. The most commonly used radiopharmaceutical in clinics [18F]FDG was shown to be essential to the treatment of a great range of pathologies. This can significantly contribute to precise therapy response assessment possibly influencing the therapeutic management and treatment planning [42]. Another study revealed a promising application of fluorine-18 labeled amino acid-based radiotracers for small cell lung cancer detection via PET imaging [43]. Furthermore, a recently developed categorization method for differentiation of osteosarcoma phenotypes by comparing SUV values of PET radioligands for glucose metabolism ([18F]FDG), hypoxia ([18F]FMISO) and bone remodelling ([18F]fluoride) showed promising results. These findings can improve the future evaluation of the treatment strategy depending on the specificity of the malignancy [44]. These tracers can be applicable also for regenerative purposes, studying the healing process of e.g. bones. A current clinical study for bone reconstruction of the skull is examining the regeneration after introducing an implant using PET/CT via [18F]fluoride. Succeeding in this would help out many patients with cranial defects and significantly improve their quality of life [45].
Cardiology also gained immense benefits from the development of the hybrid imaging systems (e.g. correction of attenuation and evaluation of coronary classifications), CT for coronary angiography, and acquisition of 3-D hybrid images for the definition of heart viability and diagnosis of cardiac inflammations and infections [46]. Recent advances in stem cell therapy show promising results for myocardium restoration, neovascularization and enhancement of perfusion [47-50].
Research on the central nervous system (CNS) mainly emphasized on mapping different aspects of neurotransmitter activity, e.g. dopaminergic, cholinergic, serotonergic and glutamatergic systems as well as beta-amyloid visualization for Alzheimer’s disease (AD) [5, 51, 52]. PET Imaging has been applied widely to detect and quantify subtle abnormalities in CNS diseases. Therefore, this technology is also immensely popular as a modeling tool in CNS drug discovery and development. It is used for evaluation of drug deposition, as well as for studying disease biomarkers to monitor drug effects on brain pathologies [24]. Another CNS utilization of this modality was shown in a promising study regarding spinal cord injury [53]. The combined efforts of stem cell and neuroscience researchers made it possible to visualize the spinal cord regeneration process on the cellular and molecular level. In order to explore the effect of
After the successful introduction of the PET/CT system to the clinics, the integration of PET with MRI was the next step. This new hybrid technique allows for simultaneous functional PET imaging combined with soft tissue morphological MR images. The novel approach brings better contrast among soft tissues as well as functional imaging capabilities, when compared to PET/CT. Nevertheless, this technology is still not clinically mature at this point. Technically, the implementation of PET/MR faces three major issues: 1. The photomultiplier-based PET scanners do not work in the proximity of the magnetic field of the MR scanner; 2. Metallic objects (e.g. surface coils used to get the best MR quality images) interfere with gamma rays from PET, resulting in unwanted attenuation; 3. MR data cannot be used for attenuation correction, as CT data, which is a limiting factor for the use of PET in therapy response monitoring [56].
As PET signal processing might disturb the high-frequency signals of MRI, and conventional PET electronics fail in an even weak magnetic field, it soon became clear that new solutions had to be found to circumvent the joint interferences. One possibility would be to leave just the PET crystals in the MR field, whereas the PMTs are positioned outside and connected to the crystals by optical fibres. Another approach to avoid the disturbance would be to place the PET and MR scanners remote to each other, but still linked by a common bed, so that the patient does not move between the two scans. Last, but not least, the PMTs could be replaced by solid state electronics which are not disturbed by the MR field [57]. Hence, various approaches were developed during the last fifteen years for application in small animal studies, where the usage of more PET tracers is allowed and where use is not as legally restricted, as in human studies. For a review, see Herzog, 2012 [57]. Improvements in pre-clinical study design enable smooth transfer of knowledge and molecular measurements between species thereby facilitating clinical translation. Recently, PET/MRI for human imaging became available as well, towing to support form the industry. Siemens Healthcare first designed prototypes of a BrainPET/MRI device and the first reports of patients have been communicated [58, 59]. This opened new possibilities in the field of molecular imaging and prepared the development of an integrated whole-body PET/MRI scanner. A recent study compared the performance of whole-body PET/MRI to PET/CT of breast cancer patients and claimed that PET/MRI is a feasible technique for usage in clinics, forgoing gamma radiation for high quality imaging with short examination time [60]. Another example for implementation of this new technique was shown in a sarcoma patient, who underwent chemotherapy and autologous stem cell injection. MRI showed lesions in the upper and lower leg, whereas PET revealed high [18F]FDG uptake only in one of the lesions (Figure 4). This case illustrates the benefit of combining different imaging modalities in order to get more precise outcomes, thereby improving the application fields of personalized medicine. This methodology might also be useful for the investigation of regenerative processes in damaged organs or tissues, for example after autologous stem cell therapy for boosting the healing progression.
Simultaneous whole-body PET/MRI acquired with a molecular MR (mMR) scanner in a 13-year old boy with a Ewing sarcoma known for six years. The patient underwent standard chemotherapy together with autologous stem cell transplantation. After
The clinical application of the PET/MRI technique has to be further established. Nevertheless, if MRI can replace CT for anatomical screening, it adds value as well as decreases radiation exposure, which would be of great benefit for the patients. However, the ongoing question of choosing the best suitable visualization method remains unanswered, as there is still insufficient knowledge about which PET/MRI applications are superior to the well-known PET/CT for a variety of clinical cases.
Unlike PET, single photon emission computer tomography (SPECT) uses radiopharmaceuticals labeled with gamma emitters instead of positron emitters. The concept of transmission and emission tomography, later developed into SPECT, was first introduced in the late 1950s. This period is associated with phenomenal growth of Nuclear Medicine, when some of the most prominent gamma-radiation emitting radionuclides (131I and 99mTc) were produced [61]. While the primary use of 131I was dedicated to thyroid cancer treatment, its use was later expanded for imaging of the thyroid gland itself, its function and the therapy of hyperthyroidism. The development of a generator system for 99mTc (1960s) was an important breakthrough and today it is the most utilized element in the field of Nuclear medicine. Other typical gamma emitting radionuclides utilized in SPECT are 123I, 67Ga and 111In. The most common SPECT systems consist of a gamma camera with rotating NaI(Tl) detector modules located between the photomultipliers and collimators (Pb) (Figure 5), an on-line computer for acquisition and processing of data and a display system [62]. Generally, a target-specific SPECT radiopharmaceutical consists of two parts: a gamma-emitting radionuclide and a targeting biomolecule (e.g. peptide, antibody fragment) [63]. Similar to PET, SPECT also enables 3-D imaging and hybrid systems (SPECT/CT) are available as well.
Underlying principle of SPECT: (1) A radioisotope decays by emitting gamma rays. (2) A rotating gamma-sensitive detector with a collimator in front indicates the scintillation site where gamma rays are parallel to the collimator pinholes. (3) The collected data is then transferred to photomultipliers and finally to a computer for analysis.
Various stem cells hold promise for the treatment of many human diseases. However, little is known about the exact function, location and survival of the transplanted cells. The usage of the SPECT imaging modality to answer these questions revealed promising results. Clinical studies with SPECT indicated evidence for efficacious imaging of transplanted radiolabeled cells in cardiac disease. Encouraging results were obtained from studies using [99mTc]hexamethylpropylenamineoxine (HMPAO)-labeled stem cells. Comparison of intracoronary (IC) and transendocardial (TE) delivery of the cells to the heart showed more intense retention signal 18h after cell injection in the TE patients [64]. Another study could illustrate homing of bone marrow mononuclear cells TE injection after acute myocardial infarction. Cell retention was successfully visualized in the damaged heart tissue [65]. Similar results were obtained by a group showing homing of bone marrow progenitor cells after intracoronary transfer using the same radiotracer [66]. Controversially, further experiments investigating the homing of the same cells after myocardial infarction indicated very heterogeneous uptake of the 99mTc-labeled cells, but for all patients there was lack of or decreased uptake of cells in walls with perfusion defects. The perfusion imaging was performed with thallium (201Tl) [67]. Although the safety of autologous stem cell transplantation to the heart after infarction has been shown, it is still not known how many of these cells actually remain in the damaged site, or in near proximity to it. To address their homing and apoptotic rate, autologous bone marrow cells were labeled with [111In]oxine and injected
Further investigations were made to detect angiogenesis after myocardial infarction utilizing SPECT. This was assessed using a novel radiolabelled peptide ([99mTc]NC100692, Maraciclatide), which has high affinity to an angiogenesis-related integrin (αvβ3) [71] (Figure 6). The successful implementation of this tracer led to a follow-up study, addressing the effect of bone marrow stem cells transplantation on angiogenesis in chronic ischaemic heart failure patients [72]. The patients underwent SPECT imaging using the same [99mTc]RGD imaging peptide. This new imaging tracer was shown to be feasible in patients with heart failure. However, the changes with stem cell therapy did not reach statistical significance.
Illustration of localized angiogenesis-tracer uptake (Maraciclatide:top) in a region of perfusion deficit (MIBI: bottom). A: short axis slice; B: long axis slice. Figure was provided by courtesy of Prof. Brian Hutton.
Despite the immense progress in the field of stem cell imaging research, the pre-labeling approach for cell visualization remains challenging for now. Most of the stem cell clinical trials tend to utilize techniques for following the regenerative process (e.g. tissue growth, vascularization and functional recovery), rather than direct tracking of the injected cells [73]. The use of autologous stem cell therapy for heart regeneration is of high importance for cardiomyopathy patients and is showing promising results. However, the therapeutic effect is by now mostly measured by an enhancement of the heart regional and global contractility as a cell treatment outcome [73]. One other factor, often taken into consideration when testing a new approach for cardio-regeneration, is the heart perfusion efficacy. This could be measured by
Another possibility to assess the regeneration process is by using direct labeling of certain proteins, known to be connected to basic organ functions. This method was performed to estimate the liver self-regeneration after hepatectomy via 99mTc-labeled galactosyl-human-serum-albumin. The liver uptake value could be calculated from SPECT/CT images of patients at different time points after surgery [75]. An additional visualization possibility for the hepatic function was shown by [99mTc]phytate colloid uptake by the liver. As colloid uptake by perfused Kupffer cells is proportional to perfused hepatocyte mass, this could be used for direct quantification of perfused liver mass by quantitative SPECT in cirrhotic patients [76]. Although the liver is well-known for its self-regeneration capacity, stem cell therapy seems to boost this capacity. Several studies addressed the therapeutic effect of autologous stem cells for liver regeneration [77-79]. Nevertheless, none of them assessed the fate of these cells
There is no perfect imaging modality for non-invasive cell tracking in clinics. The research findings of the last few decades on the arena of imaging have prompted an intense interest of many investors, who facilitated the translation of these ideas into clinics. Nevertheless, to date no state-of-the-art imaging tool is capable of delivering an all-in-one solution. Many factors have to be considered before choosing the proper visualization modality, depending on the question to be addressed. There is emerging need for versatile imaging methods capable of monitoring the autologous stem cells
Despite the immense progress in the field of personalized medicine, there are still many black boxes, on which non-invasive imaging is beginning to shed light. One can observe an increased awareness of the importance of these imaging modalities and their significant impact on diagnosis and management of human disorders are being recognized. Brilliant ideas and developments in this field are catalyzing the design of new strategies every day, giving rise to possible solutions. A summary of the characteristics of the “perfect clinical imaging modality” for stem cell tracking is given in Table 2. Nevertheless, such an all-in-one technique is not available yet, but the development of hybrid imaging devices for multimodal imaging was a big step towards the ideal system.
1. Safe, non-toxic and biocompatible | \n\t\t
2. Single-cell detection at any anatomic location | \n\t\t
3. Limitless depth of penetration | \n\t\t
4. High spatial and temporal resolution, excellent molecular sensitivity | \n\t\t
5. No genetic modifications of the stem cells | \n\t\t
6. Insignificant/no dilution with cell division | \n\t\t
7. Possible quantification of cell number and viability | \n\t\t
8. Serial and long term monitoring in patients up to several months/years | \n\t\t
9. Insignificant/no uptake of tracer by non-target cells | \n\t\t
10.Multimodality-based approach | \n\t\t
11.Low costs | \n\t\t
Requirements for the design of the “perfect clinical imaging modality” for stem cell tracking
The techniques of SPECT/CT, PET/CT and PET/MRI are the state-of-the-art modalities for successful biomedical molecular imaging. Various diseases related to metabolism, apoptosis, tumors, genetics, and stem cells have been identified by these systems [62]. The same approaches are already being successfully transferred in numerous clinical studies using autologous stem cells for organ and tissue restoration. Nevertheless, the selection of a given visualization technique depends on its strengths and weaknesses with respect to the intended use. All currently developed molecular imaging techniques for stem cell tracking have inherent limitations. For imaging of delivery and short-term homing of the injected stem cells in different organs, a direct labelling approach may be the answer (iron oxide or [18F]FDG), even though any potential toxicity must be taken into account. MRI offers the highest spatial resolution and near real-time image guidance for cell delivery, although with significantly lower molecular sensitivity than other modalities, such as PET or SPECT. For long-term cell monitoring, reporter gene imaging, using PET or SPECT, appears to be a better choice. Ultimately, finding the most suitable system or combination of systems for proper diagnosis and/or treatment remains the essence of health care and personalized medicine.
The authors would like to thank Arch. Teofana Haralampieva for the great support in the visualization of the different imaging modalities and Damina Balmer for her editorial assistance in the preparation of this manuscript. A special thank you goes to the team members of the Laboratory for Urologic Tissue Engineering and Stem Cell Therapy at USZ.
The very low frequency (VLF) waves, namely, the radio waves whose wavelengths are between 10 and 100 km and operate at the frequencies ranging from 3 to 30 kHz, are usually used for long-distance propagations. In this frequency band, both the ground medium (occupied by land, lake, or seawater) and the ionosphere (the sky region of the height over 60–90 km distinct from daytime to nighttime states) are strongly reflecting for the excited waves, so that the VLF waves are conducted to propagate in free space between the two parallel reflecting walls. This is the so-called terrestrial waveguide. Generally, a vertical electric dipole antenna, polarized in perpendicular to the ground interface, can be idealized to generate these guiding waves in transverse magnetic (TM) modes, whereas the transverse electric (TE) modes generated by a horizontally polarized electric dipole antenna would not propagate along the radial direction. Assuming that the spherical coordinate system has been established, “the ground-ionosphere waveguide” is formed by the two concentric spherical shells.
Along a great propagation path across two states of the daytime and nighttime sections, the resulted cycle clips by interferences would be observed in phase for VLF radio waves [1, 2, 3, 4, 5, 6, 7]. Most of the early explanations of this phenomenon [8, 9, 10] were based on the ray-optic model; however, it seems unlikely to be accountable correctly for the mentioned matter for a long-distance propagation. That is because, on the one hand, it would be required to include lots of ray paths in explaining the VLF wave propagation at great distances, yet only a few low-order modes are necessary; and on the other hand, there should be consideration of including the diffraction corrections for using ray-optic models over a curved earth.
For a better knowledge of diurnal behaviors as phase and amplitude variations for VLF radio waves, extensive studies had been developed over the years by researchers. In the 1960s, the effect of multimode interferences had been addressed by Wait [11, 12] for VLF radio waves in the presence of a nonuniform earth-ionosphere waveguide. Later, the study had been extended by Bahar in the 1970s [13, 14, 15, 16] where the inhomogeneous waveguide was assumed to be represented by successive cascaded earth-ionosphere waveguides, for which the height variations were accounted for the day-to-night transition. In these analyses, the mode-conversion coefficients had been formulated by employing the orthogonal properties of basis functions. Consequently, the resulted coefficients could be utilized to derive a set of coupled first-order differential equations for the forward and backward wave amplitudes in the transition region, to extend the study into a more general case with arbitrarily varying effective height. However, it should be pointed out that these computational schemes by previous treatments had neglected the influence of the geomagnetic field. In the study by Galejs [17, 18], the transition geometry of waveguide with an abrupt height change of d
The analytical formulas for mode-conversion coefficients have been derived in the circadian transitional period by Pan et al. [19, 20, 21] applied in ELF/SLF electromagnetic wave propagation in earth-ionosphere waveguide due to sunrise and sunset. Apart from its simplicity, the proposed computations are also feasible for studying the influence of the anisotropic behavior from the ionosphere, including reflection characteristics of the transitional daytime and nighttime sections. The study leads us to treat the ionosphere as anisotropic plasma medium and derive the mode-conversion coefficients resulted from the daytime and nighttime transitions for VLF waves.
In this chapter, the matter of VLF wave propagation is addressed in the presence of an earth-ionosphere cavity. Considering the diurnal behavior caused by sunrise and sunset transitions, the mode-conversion coefficients in an earth-ionosphere waveguide have been derived under an abrupt effective height change. The proposed computational scheme guarantees satisfactory accuracy of the electromagnetic field in the transition ranges and can be developed in the derivation of the coupled differential equations for the wave amplitudes in a transition section of gradually varying height. Additionally, the mode interference has been analyzed. The time dependence
In this section, the expressions of electromagnetic components have been addressed for VLF radio waves propagating in an anisotropic earth-ionosphere waveguide. The computations are based on an analysis of exploiting the concept that the VLF radio waves propagate in a spherical earth-ionosphere waveguide, with finite surface impedance boundaries. Wave components are formulated in the expression of Airy functions for the VLF radio waves in the context.
Assume that the strength of geomagnetic field
in which the constant
where the variable
In what follows, it is assumed that the characteristics of VLF radio waves are determined by propagation paths from the exciting source to the receiving field point, that is, the characteristics of propagation will not be affected by other propagation paths.
In an idealized geometry, the ionosphere layers are regarded as the anisotropic plasma, and the waveguide is occupied by free space, characterized by the permeability
in which the functions
in which
with
In the above formulas, the variable
The coupling impedance
and the
where the variable
In the evaluation of Eq. (8) to Eq. (9), the Airy functions have been employed. In order to clarify these special functions, the following expressions provided by the use of Bessel functions are defined as follows [23]:
in which the Airy functions are defined by the first- and second-kind Hankel functions of one third or two third order. In addition, the Wronskian equality for the Airy function is defined as follows:
In what follows, the propagation parameters are computed for VLF waves and quantitatively compared to the isotropic case to study the anisotropic ionosphere properties influenced by the geomagnetic fields.
To consider an anisotropic ground-ionosphere waveguide, the surface impedance matrix for the field components has been applied to terminate the source-free waveguide at the same altitude as in the region of the waveguide source. In Figures 1 and 2, the elements of impedance matrix have been computed at an operating frequency by
The amplitudes of elements of the ionospheric impedance matrix versus the propagation direction
The phases of elements of the ionospheric impedance matrix versus the propagation direction
The diagonal elements
At VLF radio frequencies, the surface impedance of the ground is much smaller than that of the ionosphere. This makes the change of the ground conductivity to have little effect on the phase velocity and attenuation rate of the waves [19]. In the following computations, the ground is assumed to be idealized to the sea surface. By the proposed formulas, we will compute the anisotropic ionosphere parameters. To begin with, the modal equation of VLF wave propagation can be solved readily by (8), so that the characteristic parameters are calculated correspondingly. In Figures 3(a) and 3(b), with the conductivity and the relative dielectric constant of sea water being
The attenuation rates versus the normalized frequency
As is depicted from Figure 3(a), the attenuation rates of lower modes are raised by increasing the operating frequencies. But for the higher modes, the attenuation rates decrease on the same condition. This is because the fundamental mode as the ground wave term cannot propagate at great propagation distances, whereas the high modes as sky waves, multi-reflected by the ground and ionosphere walls, will propagate through long path. Considering that both the radiating antenna and the receiving antenna are located in the same state of daytime or nighttime, the equivalent altitude of the ionosphere is quite different from each state along with propagation path. In Figure 3, it is shown that the attenuation rates of lower modes have different behaviors for daytime and nighttime [
As is shown in Figures 4(a) and 4(b), the relative phase velocities are evaluated, correspondingly, in variance of the normalized frequencies (with
The relative phase velocity versus the relative frequency
In conclusion, the attenuation rates and phase velocities of the ground wave mode are affected by strength and inclination angles of earth geomagnetic field. However, at a greater geomagnetic angle, the attenuation rate becomes larger, and the relative phase velocity decreases correspondingly. On the other hand, the influences of the attenuation rates and the phase velocities are weakened by propagating direction. For fundamental modes, there exist directional actions in attenuation rate and phase velocity. For example, the attenuation rate propagating westward will be greater than that propagating eastward, if the relative phase velocity propagating eastward is also smaller than that propagating westward [19].
In this section, the orthogonal properties of basis functions are considered at each side of daytime and nighttime waveguides, respectively, while the ionosphere layer has been treated as anisotropic plasma. The transmission and reflection coefficients are determined by the resulting linear equations from field matching. Thus, the mode-conversion coefficients are obtained for VLF waves propagating in the terrestrial waveguide during sunrise and sunset.
The idealized model representing the sunrise or sunset transition is depicted in Figure 5, where a cascading anisotropic waveguide is formed by two sections with different effective heights. Each section of the ionosphere layer is regarded as anisotropic plasma, and the waveguide is occupied by the free space, characterized by the permeability
Geometry of transitional regions in the nonuniform terrestrial waveguides with an abrupt effective height change of 20 km caused by sunset and sunrise, respectively. (a) Night-to-day transition; (b) day-to-night transition.
In region
In Eq. (16), the different phase velocities, attenuation rates, and height functions are taken into consideration for the incident wave and the reflected wave for each wave type, respectively. In region
in which
The superscript
At the junctions of day and night sections, the interferences of VLF radio waves occur due to discontinuity of abrupt effective heights. Assume that the electromagnetic waves are incident at the junction from port
The symbol
At the junction of the waveguide sections with
in which the column vectors
Taking into account the properties of height-gain functions, the row vectors
in which matrix
It yields
in which
Therefore, the reflection scattering matrix can be approximated by
with
where the elements of the matrices
and
where
in which
whose elements are
in which the delta function
It is noted that Eq. (37) and Eq. (38) define the reflection matrix
Due to the revolution of the earth, the boundary of daytime and nighttime regions is moving over time. Thus, in the period of the daytime and nighttime transitions, the received phase of VLF radio waves in a receiving antenna appears a regular fluctuation. This is called the transition period interfered by mode conversions.
In Figure 6, the geometries of the transition model are presented by cascaded terrestrial waveguides, respectively. These models are approximated by an inhomogeneous waveguide represented in Figure 7 with a varying height. The height function can be defined as follows:
Varying height profile in the transition region between the night and day paths with (a) planar model in abrupt discontinuity; (b) spherical model in discontinuity; (c) cascaded planar model in abrupt discontinuity; and (d) cascaded spherical model in discontinuity.
Gradually varying height profile in the transition region between the night and day paths with (i) nighttime section, (ii) transition section with varying ionospheric effective height, and (iii) daytime section.
in which
with
In this case, the scattered coefficients derived in Eq. (36) to Eq. (37) can be developed as follows:
So that, we have
and
in which
and
respectively.
In the following computations, numerical solutions are obtained by computer software, such as Matlab, to quantitatively evaluate the resulted formulas for mode-conversion coefficients of VLF radio waves due to sunrise and sunset.
During long-distance propagation across the transition regions, several modes contribute to the net fields. Based on the derived formulas, the vertical electric field component can be determined by the distance variations, so that the mode-conversion coefficients can be obtained, correspondingly. Consider that the altitude of the lower ionosphere is assumed to be at
Nth | Anisotropic ionosphere | |||
---|---|---|---|---|
Re ( | Im ( | Re ( | Im ( | |
1 | 1.0554 | 0.1188i | −1.5452 | −0.0717i |
2 | −0.5785 | −0.0165i | 0.4090 | 0.0143i |
3 | 0.2533 | 0.0071i | −0.1753 | −0.0061i |
4 | −0.1415 | −0.0039i | 0.0974 | 0.0034i |
5 | 0.0902 | 0.0025i | −0.0620 | −0.0022i |
The transmitted coefficients and scattered coefficients
Nth | Anisotropic ionosphere | |||
---|---|---|---|---|
Re ( | Im ( | Re ( | Im ( | |
1 | 0.9883 | 0.0014i | −0.0939 | −0.0372i |
2 | 0.0946 | 0.0080i | 0.1188 | 0.0074i |
3 | −0.0167 | −0.0038i | −0.0509 | −0.0032i |
4 | 0.0069 | 0.0021i | 0.0283 | 0.0018i |
5 | −0.0038 | −0.0014i | −0.0180 | −0.0011i |
6 | 0.0025 | 0.0009i | 0.0125 | 0.0008i |
7 | −0.0017 | −0.0007i | −0.0091 | −0.0006i |
8 | 0.0013 | 0.0005i | 0.0070 | 0.0004 |
The transmitted coefficients and scattered coefficients
Technically, the magnitudes of the first-second and second-first mode-conversion coefficients will affect more than the higher modes [19]. It is seen that more summation terms would be required to guarantee accuracies of calculations at high operating frequencies. In Tables 1 and 2, the determined elements of the reflected and transmitted scattering matrix are calculated by Eq. (36) and Eq. (37), respectively. The derived matrix is subjected to modal equations by Eq. (8). It is noted that for more complicated case of varying ionosphere heights, these coefficients can be derived by Eq. (42) and Eq. (43) which are not addressed in the illustrative example for simplicity.
For a better understanding of the interference pattern by the use of the obtained formulas, the following computations are developed when the ionosphere layer is composed of a succession of two bounded layers, each with a distinct character. Assuming that the transmitting antenna is placed on the sea surface in region
Illustrative example of mode interferences in N-to-D propagation path with spatial distributions of the field component
From Figure 8(c) and Figure 8(d), the distributions of the electromagnetic field strength for VLF waves due to sunrise are depicted at the operating frequency
In a similar manner, the wave components are evaluated through a D-to-N propagation path. Considering that all parameters are chosen as same as those in Figure 8, the spatial distribution of the scattered field is depicted in Figure 9(d) through a D-to-N propagation path. However, it is seen that the interference pattern is unlikely in agreement with reciprocity in which the section on the right side is subjected to different incident angles. This shall also be affected by the earth geomagnetic field inclination angle and the propagation angle. However, the proposed computational scheme is in advantage of providing a straightforward in calculation for nonreciprocal model. In Figure 9(e), the electromagnetic field in the transition region by corresponding formulas is plotted versus the propagation distance in the same figure at the operating frequency
Illustrative example of mode interferences in
The magnitudes of the field component
In Figure 10(a), the interfered electric field due to sunrise is computed as comparing with that for a homogeneous waveguide representing for daytime and nighttime, respectively. It is seen that the interference subjected to mode conversion is resulted from discontinuousness from distinct ionosphere boundaries due to day and night propagation paths.
In order to validate of the proposed computational scheme, the simulation has been compared with the experimental data addressed in a recent paper [25] in Figure 10(b). The radiation power is 250 kw, and the radiating device is chosen by un-directional antenna. The experimental data are measured at the operating frequency
It is shown from Figure 10(b) that the calculated result as synthetic field being interfered by multimode-conversion effect is closer to the experimental data measured on 4 o’clock and 5 o’clock than measured on 6, 7, and 8 o’clock data near the sunrise line. Additionally, the measured data after 6 o’clock does not change too much since process of sunrise passed. Taking into account that the difference between calculated data and the measured data is resulted from the applied models and specific measuring conditions, such as the time, locations, and propagation paths, the proposed computational scheme would be more helpful by adjusting it into more practical models than a simple structure with abrupt discontinuity in height boundaries.
In this chapter, the effect of multimode interferences is investigated for VLF radio waves due to sunrise and sunset based on an idealized cascaded anisotropic inhomogeneous terrestrial waveguide. The coefficients of mode conversion for scattered vectors and transmitted vectors are evaluated at the junction of abrupt discontinuity representing the nighttime and daytime transition. The treatment provided can be enhanced in the future by a more practical terrestrial waveguide with varying effective ionosphere height rather than the abrupt one. The study may provide with some help in the applications of long-distance communication and navigation.
The authors are grateful to all referees for their constructive comments and suggestions in improving the quality of this chapter. The authors thank all associate editors very much for their help and encouragements.
No potential conflict of interest was reported by the authors.
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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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