Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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This achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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We are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
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Thank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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\r\n\tThe topology is known as ‘Analysis Situs’, which explore the properties and relations between geometrical (or with certain set properties) objects in an ambient space or intrinsically to each space when the set-theoretic space in question has properties that affect the relations with another space, or the continuous transformation of self-space. The properties called topological invariants are of big importance to the topology, since much of these characterize geometrical spaces, dynamical systems, defines metrizability in spaces, the dimension as the concept of dimensional invariants of topological spaces as can be the algebraic varieties studied in algebraic geometry, etcetera. In this book, we consider several topics of the topology and their different areas as are the algebraic topology, differential topology, symplectic topology, topological spaces and manifolds, dimension theory, and the general study of topology, which is very rough as a mathematics study area.
\r\n
\r\n\tThe modern topology developments are focused now on items and contents as the homotopy, cohomology, non-commutative rings, Cobordisms, Lindelöf Spaces, Projective Manifolds, Connectivity, Topos, and Singular Manifolds, which in much go directed to the development of the different string theories and the development of the topology of quantum field theories to the conceptual precision and understanding of the Universe. Also in artificial intelligence and numerical simulation, the topology is fundamental to define spaces with adequate metrizability in the dynamical systems and the design of the artificial intelligence units of advanced automatons and approach of androids to human behavior.
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\n
1. Introduction
\n
Since its discovery 100 years ago by Sir J.J. Thompson for the quantitative measurement of the mass and charge of cathode rays, mass spectrometer eventually evolved as a reliable analytical platform aimed at the analysis of small and large molecules [1]. While hyphenation of mass spectrometry with gas chromatography achieved its early success, however, liquid chromatography could not due to indigent mass spec interfaces. This is given the inability of interfaces to handle higher flow rates of liquid sample. Additionally, ionization techniques such as chemical and electron impact ionization did not suit for thermolabile and high molecular weight compounds [2, 3]. Advancement in ionization techniques such as fast atom bombardment that suited for analysis of large molecules, thermospray and particle beam ionization which were efficient for small molecules enabled the fruitful hyphenation of liquid chromatography with mass spectrometry [4, 5, 6, 7]. Thermospray in general forms ammonium adducts, while particle beam generated electron impact spectra. Within a few years thermospray was succeeded by atmospheric pressure ionization techniques such electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), atmospheric pressure photoionization (APPI) and atmospheric pressure matrix assisted laser desorption ionization (AP-MALDI). Mass spectrometer operates on the principle of ionization of analytes followed by their separation based on their mass-to-charge ratio [8]. Various mass spectrometer analyzers ranging from linear trap, ion trap, triple quadrupole, time of flight and orbitrap have specific applications for sample analysis in preclinical drug discovery and development.
\n
Medicinal chemistry efforts in drug discovery is majorly focused on understanding the right combination of new chemical entity (NCE) properties that helps in cherry-picking the compounds with promising properties to progress from discovery to development phase. In the process of lead optimization, NCE’s are subjected to a series of drug metabolism and pharmacokinetic assays to assess the druggable properties and mitigate late stage failures. Almost 40% of failures in development phase were due to poor pharmacokinetic properties of NCE’s [9]. However, this percentage had gradually decreased to 10% as major pharmaceutical companies incorporated drug metabolism and pharmacokinetic screening (DMPK) in lead optimization phase of drug discovery. In this view, compounds must pass through a series of screens that scrutinize the problematic compounds until a small number have been selected for more rigorous testing in the development phase. Hence, lead optimization typically is an iterative process that uses the DMPK data to optimize the druggable properties of NCE’s. Regardless of the screening panel, qualitative and quantitative analytical results to understand absorption, distribution, metabolism and excretion (ADME) properties were generated using liquid chromatography–tandem mass spectrometry (LC–MS/MS) [10, 11, 12, 13, 14, 15, 16, 17]. In this chapter, we have briefly discussed on various atmospheric pressure ionization techniques/mass analyzers, and applications of mass spectrometer in drug discovery with special emphasis on drug metabolism and pharmacokinetic assays.
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2. Atmospheric pressure ionization
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Ionization in atmospheric ionization sources occur at atmospheric pressure and ions then gets transferred into the vacuum. As the liquid completely converts in to gas phase in the ionization source, those ionization techniques that use atmospheric pressure ionization are more convenient to hyphenate with liquid chromatography. These ionization techniques include electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI) and are most widely used. Additionally, MALDI that also uses atmospheric pressure ionization is getting popular with its unique feature in performing mass spectrometry imaging (MSI) and analysis of large molecules [18]. Also, other ionization techniques such as desorption electrospray (DESI) or direct analysis in real time (DART) are becoming popular for the analysis of surface or solid samples [19, 20]. However, their applications in the field of drug metabolism and pharmacokinetics are very limited.
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2.1 Electrospray ionization (ESI)
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In ESI, analytes initially get charged with the assistance of electrical energy and charged ions transfer from solution to gaseous phase, before subjecting to mass spectrometric analysis. Ionic species in solution can be analyzed as such, whereas neutral compounds can be converted to ionic species and studied by ESI-MS. Electrospray ionization occurs in four stages: 1) charging of analytes in the capillary tube 2) formation of fine spray of charged droplets 3) solvent evaporation 4) columbic explosion/Rayleigh scattering of ions from the droplet (Figure 1). The liquid effluent moves from liquid chromatography to the mass spectrometer through a fused silica capillary maintained at voltage of 2.5–6.0 KV. In negative mode, to avoid discharge the range is lower (3–4 KV) than positive mode. ESI is a condensed phase ionization process and the ions have to be already present in solution. To generate ions, the pH has to be adjusted in such a way that ionizable groups are either protonated or deprotonated. In some cases, neutral molecules can be analyzed by the formation of adducts with ions such as ammonium, sodium, potassium, acetate or silver. Charged droplets undergo nebulization in the presence of nebulizer gas. After nebulization, charged droplets further reduce in size with the assistance of heat and breakdown in to minute droplets. Finally, as the droplets grow smaller and smaller, ions get released in to gaseous phase by a mechanism called rayleigh scattering/columbic explosion. The emitted ions are sampled by a sampling skimmer cone and are then accelerated into the mass analyzer for subsequent measurement of molecular mass and ion intensity [21, 22, 23, 24]. An important characteristic of ESI-MS is it works as a concentration-dependent detector, which means MS response is directly proportional to concentration of analyte. Hence, irrespective of flow rate of mobile phase post column to the ionization source, response remains the same as long as the source-gas conditions are optimal for the flow rate. ESI technique is suitable for the analysis of polar to moderately polar molecules.
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Figure 1.
Mechanism of electrospray ionization process.
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Mode
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Q0
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Q1
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Q2
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Q3
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Analysis type
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Full scan mode (Q1 MS)
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RF only
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RF/DC
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RF only
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RF only
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Qualitative
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Full scan mode (Q3 MS)
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RF only
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RF only
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RF only
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RF/DC
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Qualitative
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Product ion scan (PI)
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RF only
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RF/DC
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RF only
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RF only
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Qualitative
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Precursor ion scan (PC)
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RF only
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RF only
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RF only
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RF/DC
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Qualitative
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Multiple reaction monitoring (MRM)
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RF only
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RF/DC
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RF only
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RF/DC
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Quantitative
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Table 1.
Modes of triple quadrupole operation and analytical requirements.
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2.2 Atmospheric pressure chemical ionization (APCI)
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In atmospheric pressure chemical ionization, unlike ESI, sample evaporation occurs first, followed by ionization in gas phase through corona discharge needle (Figure 2) [25]. The ionization principle is mostly similar to chemical ionization; however, it occurs at atmospheric pressure. APCI-MS can also be called as mass-sensitive detector, as the higher flow that goes in to ionization source, the higher will be the peak response. One important requirement in APCI for optimal sensitivity is the sample has to be completely evaporated, before subjecting to ionization. First an aerosol of mobile phase is formed with the assistance of nebulizer gas. This aerosol is further subjected to heating at 200–550°C in a ceramic tube enabling complete evaporation. Even though higher temperatures are employed, the actual temperature felt by analyte molecules is way lesser due to a phenomenon called evaporative cooling effect/evaporation enthalpy. Next, analyte molecules in gas phases were bombarded with electrons formed from corona discharge needle [26, 27]. In positive mode primary ions such as N2+ are formed by electron impact. These ions further react with water in several steps by charge transfer to form H3O+. Ionization of the analytes occurs then by proton transfer from H3O+. In negative mode ions are formed either by: (i) resonance capture (AB to AB−), (ii) dissociative capture (AB to B−) or (iii) ion–molecule reaction (BH to B−). One disadvantage with APCI when compared to ESI is, APCI is not suitable for thermolabile compounds as typical temperatures experienced by the analyte molecules are ~150°C. However, in case of ESI, molecules encounter temperatures ~40°C in the process of evaporation.
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Figure 2.
Mechanism of atmospheric pressure chemical ionization process.
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2.3 Atmospheric pressure photo ionization (APPI)
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APPI by design is similar to APCI, with only difference being the replacement of corona discharge needle with gas discharge krypton lamp (10.0 eV) that produces ultraviolet photons [28, 29, 30]. Evaporation of liquid phase happens in pneumatic nebulizer. While ionization potential for most of the analytes is less than 10 eV; mobile phase constituents such as water, acetonitrile and methanol has higher potential requirements. Presence of dopants such as toluene or acetone will help in enhancing the sensitivity of analyte ions. Dopant molecules absorb photon energy and eject an electron, resulting in the formation of radical cation. Ionization of analytes can happen by two processes: 1) Charge transfer between analyte and radical cations generated from dopant molecules. 2) Charge transfer between dopant molecules and mobile phase components and finally from mobile phase components to analytes (Figure 3). Similar to other atmospheric pressure ionization techniques, APPI is also suitable for negative mode of ionization. Sensitivity of APPI is flow rate dependent and better sensitivities have been reported at low flow rates. When compared to APCI, APPI offers lesser matrix effects and minimal source contamination. Success of APPI as an ionization technique was reported in the analysis of steroids and quinones [31, 32, 33].
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Figure 3.
Schematic representation of atmospheric pressure photo ionization process.
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In a nut shell, ESI is useful for the analysis of moderately polar to highly polar analytes; APCI covers moderately polar to non-polar analytes, whereas APPI suits for non-polar to moderately polar analytes.
MALDI operates on principle of ionization of analytes dissolved in a matrix consisting of organic compound (sinapinic acid, α-cyano-4-hydroxycinnamic acid, 2,5-dihydroxybenzoic acid) and evaporated to dryness on a target plate [34]. Matrix crystallizes up on drying and the analyte dissolved with in it also gets co-crystallized. Firstly, laser beam hits the dried sample and ionize organic compound, which later ionize the analyte molecules. Laser beam causes both desorption and ionization of analytes. Nitrogen laser emitting at 337 nm and Nd: YAG laser emitting at 355 nm are the most widely used ones (Figure 4). MALDI is considered as a very soft ionization technique that causes minimal fragmentation of the analyte ions and is also suitable for analysis of large molecules ranging from peptides to proteins, lipids and polymers [35, 36, 37, 38]. It is also amenable to high throughput and target sample plates can be readily stored for future use. One major advantage of MALDI-MS is chromatographic separation of analytes is not required. However, due to lack of separation, matrix interferences impact the analytical results [39, 40]. Additionally, MALDI is not suitable for low molecular weight compounds. Also, MALDI needs TOF as an analyzer to cover high mass range in a linear mode, whereas ESI can be coupled with any mass analyzer. Recently, MALDI has been coupled to triple quadrupole and successfully used for the analysis of small molecules [41, 42].
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Figure 4.
Mechanism of matrix assisted laser desorption ionization process.
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3. Mass analyzers
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3.1 Quadrupole analyzer
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Quadrupole mass analyzer consists of four hyperbolic or circular rods positioned in parallel and are located diagonally at identical distances from each other. The rods are diagonally connected. Positive direct current (DC; U) is applied to one pair of rods and negative potential is applied to the other pair of rods. Apart from direct current, alternating radiofrequency (RF; Vcos ωt) potential is also applied to these rods. The ion trajectory is affected in x and y directions by the total electric field composed by a quadrupolar alternating field and a constant field. Because there is only a two-dimensional quadrupole field the ions accelerated after ionization, maintain their velocity along the z axis.
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The motion of ions in the quadrupole can be best described by Mathieu Equations [43]. The ions supposedly travel in a stable trajectory and only those ions that travel in stable trajectory reaches detector. Mass spectrum is obtained by ramping RF and DC voltages in a constant ratio. When DC voltage is set to zero and RF voltage is maintained, all ions pass through quadrupole. It is the DC voltage that helps in filtering out the ions of interest and generate mass spectrum (Figure 5). Hence, the quadrupoles that apply only RF voltages just act as ion guides or collision cell. Mass resolution for typical quadrupole analyzers falls in the range 0.6–0.8 da units, which is defined to be a unit resolution. However, current generation high resolution mass spectrometers offer to determine masses within 5–10 ppm error.
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Figure 5.
Schematic diagram of operation of quadrupole mass analyzer.
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3.2 Triple quadrupole mass analyzer
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Triple quadrupole mass analyzer consists of two RF/DC mass analyzers and two RF only mass analyzers. Q0and Q2 (collision cell) were considered to be RF only quadrupoles, whereas Q1 and Q3 falls under RF/DC mass analyzers [44]. Hence, Q0 and Q2 acts as ion guides and Q1 and Q3 acts as mass filters. Q0 acts as an ion guide by focusing all the ions obtained from ionization source to Q1. Q1 even though a RF/DC mass analyzer, can also be operated in RF only quadrupole depending on the type of analysis. When it comes to qualitative analysis, Q1 acts as a RF only quadrupole, whereas in case of quantitative analysis it acts as RF/DC quadrupole. Similarly, Q3 also operates in both modes based on the analytical requirements. Q2 in addition being a RF only quadrupole, acts as a collision cell to fragment the ions and generate compound specific information, which enables the mass spec to be a more specific and selective detection system (Figure 6). Process of generation of fragment ions in the collision cell is termed as collision induced dissociation (CID), which happens with the assistance of neutral argon or nitrogen gas [45, 46].
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Figure 6.
Schematic diagram of triple quadrupole mass analyzer.
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Based on the modes in which the mass analyzers are operated and the analytical requirements, they can be briefly classified as below:
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While full scan modes are useful in understanding the total pool of masses present in the sample analyzed, product ion scan helps in obtaining structural information of a precursor ion. Precursor ion scan is suited to find structural homologs of a selected fragment ion. In multiple reaction monitoring mode (MRM), a selected parent ion (Q1 mass) is fragmented within the collision cell and selected fragment ion analyzed by the detector. Together this series of events forms a reaction where multiple ions are monitored, hence the term multiple reaction monitoring.
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3.3 Linear ion trap mass analyzer
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The quadrupole ion trap and the related quadrupole mass filter were invented by Paul and Steinwedel [47]. A quadrupole ion trap (QIT or 3D-IT) mass spectrometer operates with a three-dimensional quadrupole field. The QIT is formed by three electrodes: a ring electrode with a donut shape placed symmetrically between two end cap electrodes. QIT is a RF only quadrupole that acts a storage device and ions are focused to center of trap by collision with helium gas. Motion of ions in trap is regulated by axial and radial frequencies. The quadrupole ion trap can store only a limited number of ions before space charging occurs. To circumvent this effect, most instruments have an automatic gain control procedure (AGC). This procedure exactly determines the adequate fill time of the trap to maximize sensitivity and minimize resolution losses due to space charge. Ion motion can be modified either by exciting the radial or the axial frequencies by applying a small oscillating potential at the end cap electrodes during the RF ramp. Linear ion trap enables higher sensitivity than triple quadrupole mass spec analyzers in full scan mode, given the capability of ion accumulation before traveling to the detector (Figure 7).
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Figure 7.
Schematic diagram of linear ion trap mass analyzer.
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There are more than a few important features which impact the time necessary to attain a mass spectrum (duty cycle): (i) injection time (0.5–500.0 ms), (ii) scan speed (5000–20,000 m/z units/s), (iii) separation of the parent ion and fragmentation in tandem MS or MSn. Contrarily to the triple quadrupole, MS/MS is not performed in space but in time. Fragmentation happens with the assistance of helium as collision gas. Also, duty cycles for fragmentation (MS/MS) are much shorter in linear ion trap when compared to triple quadrupole mass analyzer. One major challenge in linear ion trap is to trap precursor ion and fragment in the same space. Often, due to this disadvantage, fragmentation spectra generated in linear ion trap differs from that of triple quadrupole CID. Also, number of MRM transitions that can be monitored in linear ion trap are quite less [4, 5, 6, 7, 8] when compared to QqQ mass analyzers (~100 MRM transitions can be monitored).
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Due to the high sensitivity in MSn mode, ion traps are particularly attractive for qualitative analysis in drug metabolism, metabolomics and proteomics studies. Similar sensitivities to QqQ mass analyzer can be achieved for quantitative analysis on linear ion trap, but at the price of precision and accuracy.
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While linear ion traps mainly function on radial ejection, next generation mass analyzers called quadrupole linear ion trap use axial ejection. This led to discovery of hybrid triple quadrupole mass analyzers, where Q3 performs the function of both quadrupole and linear ion trap [48, 49]. Unlike linear ion trap that fragments precursor in time, these hybrid analyzers perform fragmentation in space. The major advantage of this analyzer is that qualitative and quantitative analysis can be performed in the same LC–MS run.
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3.4 Time of flight mass analyzer
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Discovered in 1940’s, time of flight mass analyzers achieved popularity after 1990’s. Time of flight operates on principle of “time that ions need to cross in a field free tube of about 1 m length” [50, 51]. The motion of an ion is characterized by its kinetic energy Ec = 0.5 m x v2 (m = mass, v = speed). Therefore, the time ions fly through the tube is directly proportional to their m/z value. The velocity of the ions formed is generally low and they are accelerated by strong electric fields (2000–2030,000 V) in the direction of the detector. Low mass ions reach the detector more rapidly than high mass ions. Due to the short flight time (50–100 msec) and the good transmission, a spectrum can be generated within 100 ms over an almost unlimited mass range. Mass resolution of time of flight mass analyzer depends on the length of flight tube and reduced kinetic energy spread of the ions. Length of flight tube is directly proportional to mass resolution. Kinetic energy spread can be reduced by increasing time delay between ion formation and acceleration, also known as delayed pulse extraction. Also, positioning of electrostatic mirror in the drift region of ions increases the mass resolution (Figure 8).
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Figure 8.
Schematics representation of a quadrupole time of flight mass spectrometer.
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Briefly, the ions with high energy penetrate deeper into the ion mirror region than those with the same m/z at a lower energy. Because of the different trajectories, all ions of the same m/z reach the detector at the same time. With the reflectron the flight path is increased without changing the physical size of the instrument. Commercial TOF instruments are available to operate in either linear mode or reflectron mode. Even though ESI can be coupled with TOF, but the combination of MALDI and TOF is most popular as both operate on the principle of pulsed technique. Coupling of ESI with TOF needs orthogonal acceleration to drive continuous beam of ions [52].
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Time of flight instruments are designed to use for qualitative analysis with MALDI or atmospheric pressure ionization. MALDI hyphenated with time of flight analyzer enables the identification of large molecules such as proteins, peptides, lipids and polymers. MS/MS information can also be obtained by CID in drift tube with the assistance of nitrogen or argon as collision gas. However, as quadrupole technology is so successful for both qualitative and quantitative analysis, TOF analyzers are used as a hybrid platform with quadrupole analyzers. In these hybrid systems, TOF analyzer replaces Q3 of a triple quadrupole system. These hybrid systems are termed as QTOF mass spectrometers. QTOF systems offer high mass resolution (~40,000) and sensitivity. Accurate mass measurements are especially useful in metabolite identification studies and peptide analysis [53]. Various other hydrid TOF platforms have been reported including, linear ion trap, quadrupole ion trap and TOF-TOF mass spectrometers [54, 55, 56].
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3.5 Orbitrap mass analyzer
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Orbitrap mass analyzer operates on principle of Fourier transform, where orbital trapping of ions around an electrode system is achieved with the assistance of electrical field [57]. The orbitrap is formed by a central spindle-like electrode surrounded by an electrode with a barrel-like shape to create an electrostatic potential. The m/z is a reciprocal proportionate to the frequency of the ions oscillating along the z-axis. Detection is performed by measuring the current image of the axial motion of the ions around the inner electrode. The mass spectrum is obtained after Fourier transformation of the image current. The orbitrap provides a mass resolving power exceeding 100,000 and a mass accuracy ~3 ppm. To be operational as a mass spectrometer the orbitrap requires external ion accumulation, cooling and fragmentation (Figure 9).
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Figure 9.
Schematic representation of operation of orbitrap mass analyzer.
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The first commercial instrument to utilize this capability, LTQ Orbitrap Classic, was introduced by Thermo Fisher Scientific in 2005, which later underwent many innovations with the addition of a collision cell after the C-trap in LTQ Orbitrap XL, addition of electron transfer dissociation (ETD) capabilities, followed by MALDI source operating at reduced pressure with high-end LTQ Orbitrap XL MALDI instrument, and finally a stacked ring rf ion guide (so called S-lens) brought about 10-fold higher transfer efficiency in the MS/MS mode.
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Typically, the highest resolving powers available in TOF devices are several times lower than the resolution in Orbitrap, although recent multipass TOF devices are capable of ultrahigh resolution (R ≥ 100,000 at m/z 400) [58, 59]. While TOF accompanies similar resolution in both MS and MS/MS modes, orbitrap suffers from low resolution in MS/MS mode. Orbitrap technology will endure to progress towards increased resolving power, acquisition speed, sensitivity and mass accuracy. These developments will indisputably open the arena for new applications as the Orbitrap instruments are getting more prevalent and exploring into new areas of research.
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4. Applications in drug discovery
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4.1 ADME studies
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Drug discovery research was solely driven by chemists and pharmacologist in early 1990’s, when very little is known about drug absorption, distribution, metabolism and elimination (ADME). However, it did not take much time before researchers realized the importance of optimizing ADME properties of NCE’s for successfully driving drug discovery programs [60]. In this section, we highlighted importance of ADME in drug discovery and its relation to mass spectrometry.
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Drug metabolism also known as xenobiotic biotransformation is the process by which lipophilic compounds gets eliminated from the body after getting converted to hydrophilic species that are easily filtered through kidney. While metabolism is desired in few cases where metabolites are the active species producing efficacy, there are metabolites that are toxic in nature. In such cases, where toxic by-products are produced, metabolism is not desired. Metabolism as a discipline drawn its first attention after the publication of RT Williams on Detoxification mechanisms [61].
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Drug metabolism over the years with the aid of mass spectrometry technology has evolved in understanding the metabolic pathways of NCE’s and also to identify the metabolites (both desired and undesired) [62, 63, 64, 65]. Mass spectrometry was initially hyphenated with gas chromatography to understand the metabolic behavior of NCE’s. Gas chromatography worked well for analyzing volatile compounds and its metabolites, however it did not suit for nonvolatile and thermolabile compounds. With the advent of liquid chromatography that can handle and separate components without subjecting to evaporation, it became prevalent as an analytical tool for understanding drug metabolism in drug discovery and development [66, 67].
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As a part of understanding the metabolic properties, NCE’s will be initially screened for metabolic stability in across species (human/rat/dog/mouse/monkey) and in various matrices including microsomes/S9 fractions/cytosol/hepatocytes, plasma, tissue homogenates, and buffer. If metabolism is not desired then compounds will be screened for their stability in relevant matrices and compounds with moderate to high stability (defined by half-life and intrinsic clearance) are further optimized for additional ADME properties. Various Phase 1 metabolic reactions including oxidation, demethylation, hydroxylation and phase 2 metabolic reactions covering glucuronidation, sulfation, methylation, amino acids conjugation and glutathione conjugation can be quantitatively and qualitatively studied using LC–MS/MS. Additionally, for compounds that are unstable, understanding the soft spots responsible for instability helps medicinal chemists to make relevant structural modifications in order to stabilize the unstable compounds. Understanding the soft spots precisely, needs the assistance of high-resolution mass spectrometry instruments such as TOF and Orbitrap. With the accurate mass information obtained from these mass spec’s, identifying a metabolite structure will be spot on.
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Similarly, other in vitro parameters such as permeability, protein binding, solubility, lipophilicity, CYP inhibition and CYP induction also play a key role in drug disposition [15, 68, 69]. All of these assays have high sensitivity requirements and demand quantification of analytes within a few nanomolar range. For example, in case of permeability assessment, low permeable compounds such as atenolol permeate poorly from apical to basolateral side complicates the quantification of the apparent permeability values, if analyzed with low sensitive detectors. Likewise, fraction unbound values for highly protein compounds such as warfarin were such low that it demands highly sensitive detectors to accurately quantify such low levels. Needless to mention that all of the assays performed to optimize ADME properties of NCE’s require highly sensitive detection systems. Hence, with its superior detection sensitivity, mass spectrometer has become an indispensable tool to understand the in vitro ADME properties of NCE’s.
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As discussed in the previous sections, even though there exist many ionization techniques, atmospheric pressure ionization (API) was more successful in drug metabolism studies, given its rapid, specific and sensitive methodologies for the identification of drugs and its metabolites. Mass spectrometer instruments types used in ADME studies vary from those that provide nominal mass information and accurate mass information. Nominal mass instruments such as triple quadrupoles are useful for quantitative applications, whereas accurate mass instruments including QTOF and Orbitrap are used for both quantitative and qualitative applications.
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Of the atmospheric pressure ionization techniques available, ESI and APCI are the most commonly used. While APCI can accommodate high flow rates and produce high sensitivity, nevertheless analytes are subjected to higher temperatures in the evaporation process and hence as an ionization technique is not suitable for thermolabile (esp. glucuronides, N-oxides and sulfates) compounds. However, ESI is comparatively a soft ionization technique and could efficiently ionize these fragile compounds without degradation. As a whole, mass spectrometer exhibits both qualitative and quantitative applications in drug metabolism studies. However, in case of other ADME battery of assays as described above, mass spectrometer is used majorly for quantitative applications.
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4.2 Metabolite identification
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Metabolite identification (Met-ID) provides a variety of inputs in drug discovery and development which includes in vitro metabolite profiling in early stages of lead identification/optimization, followed by in vitro/in vivo correlation in late stage lead identification, characterization of putative metabolites, cross-species comparison to identify the right tox preclinical species, understanding drug–drug interactions, and identifying pharmacologically active or toxic metabolites and the mechanisms by which they are formed [70, 71].
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Met-ID is quite challenging when it comes to a) identification of vast number of diverse metabolites, b) metabolites that are of low abundance, and c) high throughput analytical requirements to screen majority of early leads in preclinical drug discovery [72]. Even though there exist various platforms such as triple quadrupole, linear ion trap, and Qtrap to quantitatively/qualitatively identify metabolites, they turned obsolete due to nominal mass information they generate and are no longer valuable [73].
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The term mass resolution is used to describe the mass resolving power according to the degree to which two analytes with close m/z values can be separated and identified. A practical and convenient way of evaluating the mass resolution of an instrument is the use of the full width at half maximum (FWHM) definition in which the m/z/Δm/z ratio is calculated, where m/z is the mass-to-charge value of an ion peak and Δm/z is the full width at half the maximal height of the peak. Nominal mass instruments generate resolution in low thousands (1000–4000), which cannot separate isobaric ions with similar nominal m/z value. However, high resolution mass spectrometers provide resolution in the range of higher thousands (10000–100,000), that successfully identify and separate isobaric ions (Figure 10).
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Figure 10.
Increased resolution separating two closely arranged analytes with similar nominal m/z values.
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For a given nominal mass, there exists many possible molecular structures for an assigned biotransformation pathway. Hence, for an accurate molecular structure the metabolite has to be scaled up in larger quantities and measured using NMR spectroscopy. However, scaling up metabolites to “mg” quantities need tremendous efforts, resources and is not an economical approach. Later, with the discovery of high-resolution mass spectrometers such as TOF and Orbitrap, that provides accurate mass to the fourth decimal, enabled accurate prediction of molecular structures of metabolites [74, 75, 76, 77, 78, 79].
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In principle, as long as data can be measured accurately, high-resolution data is sufficient to demonstrate the presence or absence of defined species. Apart from high resolution masses, modern mass spectrometers also generate data with higher accuracy. The term mass accuracy is used to define how close the mass measured by the mass spectrometer is to the theoretical exact mass of an ion. Mass accuracy is typically expressed as a relative mass error using the ratio of the difference between the experimental and theoretical m/z values over the theoretical m/z value of an ion.
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Metabolite identification studies are typically performed in full scan mode (or) data dependent scan mode. In full scan mode, accurate mass information of parent ions is studied to understand the biotransformation pathways. However, to propose soft spots for metabolites, data dependent scans consisting of combination of full scan and product ion scans are performed. Metabolites in general can be considered as off springs to the parent molecular ions that carry similar fragments as that of parent ion (or) neutral loss fragments. In case of similar fragments to that of parent ion, these fragments can be considered unmodified and are similar to that of parent. Whereas, if the fragment ions are accompanied by a mass change for a given biotransformation pathway, then metabolite soft spot can be proposed with precision to that fragment ion (for example, in case of hydroxylation, neutral loss fragment in metabolite carries an additional mass of 16 amu) [80]. Additionally, apart from fragmentation scans accompanied with full scan, few other specific dependent scans consisting of neutral loss scan, and precursor ion scans are used to study various biotransformation pathways including glucuronidation, glutathione conjugation, sulfation (for example, glucuronidation is accompanied by a specific neutral loss of 176 da and glutathione conjugation by a neutral loss of 129 da in positive mode) [81, 82]. These specific scan functions are helpful in eliminating the background noise and identify the metabolites that exist even at lower abundance.
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One major challenge in metabolite identification using LC–MS technology, is quantifying the relative abundance of metabolites. As mass spec quantitation is accompanied by many source/gas and compound dependent parameters that aid in the efficient ionization and detection, minor modifications in the metabolite structures alter the sensitivity by few orders of magnitude. Hence, quantitative results using mass spectrometer for the metabolites for which synthetic standards are not available, is not feasible. Additionally, it is difficult to synthesize each and every metabolite and determine their concentrations accurately. Alternatively, few researchers used LC-UV hyphenated with mass spectrometer to measure the relative abundance of metabolites. However, as majority of metabolites exist in low abundance, it becomes difficult to measure their relative abundance by UV spectroscopy. Also, UV is prone to differences in analytical sensitivities with minor modifications in structure. Hence, future mass spectrometers need to be designed to address these key concerns and facilitate evaluation of both quantitative and qualitative aspects of metabolites.
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4.3 Pharmacokinetic analysis
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Screening paradigm in drug discovery includes evaluation of compounds for their ADME properties by various in vitro assays. The datasets obtained from these assays help in rationalizing the synthetic chemistry efforts and make progress towards a pool of lead compounds that exhibit promising in vitro ADME properties. However, in vitro screening consists of unique assay platforms that can only answer a specific question of interest and can never cover all aspects of complex biological systems. Hence, it warrants the screening of selected lead compounds in preclinical species such as rats, mice, dog, pig and monkey, before progressing to clinic [83, 84]. Role of LC–MS/MS in performing bioanalysis of pharmacokinetic samples was well reported in the literature [85, 86, 87, 88].
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Design of pharmacokinetic studies varies from single route administration with few sampling points followed by multiple route administration with detailed time course evaluation. Samples of various natures ranging from blood, plasma, serum are collected to analyze the systemic concentration levels. Additionally, to understand the tissue distribution of compounds, various tissues including liver, intestine, brain, spinal cord, heart, lungs, kidneys, skin and adipose tissue are also analyzed. Initially, lead compounds are dosed intravenously to understand the disposition parameters such as volume of distribution, clearance, half-life and mean residence time. Compounds that possess decent pharmacokinetic parameters in intravenous route are further evaluated in alternate (enteral and parenteral) routes to assess bioavailability and exposure parameters (Cmax, Tmax, AUC0-last). To determine plasma concentrations as low as “ng” levels, sensitive analytical detectors are needed. HPLC-UV detector systems are proven robust for analyzing concentrations at higher “μg” level. However, as UV detection is not specific, it suffers from high background noise when biological samples are analyzed. High background noise in turn causes quantitation issues at the lower portion of calibration curve. On the other hand, LC–MS/MS detection system is considered to be highly specific and selective, as background noise can be eliminated by analyzing selected analytes of interest with desired m/z ratios. Also, mass spectrometric detection is considered highly sensitive than UV spectroscopic detection. Altogether, these advanced features, enabled LC–MS/MS to overcome the limitations of UV detection and is more frequently used in drug discovery and development for the bioanalysis of pharmacokinetic samples.
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Of the various mass spectrometers available in the market, triple quadrupole LC–MS/MS systems have demonstrated tremendous success when it comes to quantitative applications. Monitoring specific reaction transitions that consist of parent and fragment ion, with associated source/gas and compound dependent parameters makes the mass spectrometer highly specific, selective and sensitive. Pharmacokinetic study samples are in general monitored for plasma concentrations over the time profile and hence triple quadrupole systems have achieved greater success. However, exploratory studies performed to understand metabolic pattern and biotransformation mechanisms of NCE’s again need the assistance of linear ion traps and high-resolution mass spectrometer platforms (Orbitrap and TOF). As pharmacokinetic study samples are of biological origin and complex in nature, extracts obtained after sample preparation complicate the bioanalysis on LC–MS/MS. This phenomenon in broad terms is termed as Matrix effects. Causes of matrix effects and strategies to mitigate these effects are discussed in detail in the succeeding section.
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Typically, pharmacokinetic studies are performed by administering a single test item in preclinical species. However, screening of single test item is labor intensive, not economical and demand higher turn-around times to generate pharmacokinetic data. Hence, researchers have come up with an alternate strategy, where a pool of compounds are administered in single dose, a technique well-known as cassette dosing or N-in-one dosing. The foundation for designing cassette dosing strategy comes from the ability of LC–MS/MS to analyze multiple test items without any chromatographic separation [89, 90, 91, 92]. However, disadvantages with cassette dosing include altered pharmacokinetics due to drug–drug interaction potential, non-feasibility of pooling compounds with close molecular weights and compounds with differing physicochemical properties posing formulatability issues. Compounds with differing physicochemical properties comes with a challenge of formulating the selected pool of compounds in a single formulation vehicle. While issues with physicochemical properties and close molecular weights can be taken care of, drug–drug interaction appears to be of a major concern. One approach to minimize DDI’s is by administering the compounds at minimal doses, collectively not exceeding the dose of single test item administration [93]. Also, dosing volumes can be kept as low as possible. Additionally, along with pool of unknown compounds, a quality control compound with known pharmacokinetic parameters can be administered. Pharmacokinetic study results of unknown compounds can be considered acceptable, as long as quality control compounds fall within the set acceptance criteria. Compounds with less than 5 da difference in molecular weight are difficult to pool, when triple quadrupole systems are used for analyzing the pharmacokinetic samples. However, this challenge can be overcome by considering high resolution mass spectrometric analysis. Typical pharmacokinetic parameters studied from intravenous administration include half-life (t1/2), clearance (Cl), volume of distribution (Vz), mean residence time (MRT), area under the curve (AUC0-last; AUC0-inf), whereas parameters such as Cmax, Tmax and area under the curve are studies in other routes of administration. When compounds are dosed in multiple routes, along with intravenous route of administration, absolute bioavailability values are calculated.
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Current fast LC–MS/MS instruments enable analysis of mixture of analytes with minimal separation, shorter run times and also feasible for hyphenation with ultra-fast liquid chromatography systems. Additionally, latest LC–MS/MS systems are capable of analyzing thousands of samples every week due to higher loading capacity of samples in autosampler, shorter run times and introduction of 96/384 well plate formats.
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Test samples are analyzed against a calibration curve and a set of quality control samples. Calibration curve consists of 8–10 known standards and quality controls span the calibration curve at a minimum of 3 levels. Typical accuracy limits for qualifying the calibration and quality control samples is set as ±20%. Typical turnaround times for execution of pharmacokinetic studies right from dosing initiation to generation of pharmacokinetic parameters spans 1–2 weeks. Importance of high throughput bioanalysis and its role in drug discovery is discussed in detail in the section below.
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\n
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4.4 High throughput bioanalysis
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With the combinatorial chemistry efforts leading to synthesis of hundreds of compounds in early phases of drug discovery, there is a constant need for analytical platforms that can quickly churn out data and help in accelerating the discovery process. LC–MS/MS with proven track record as a reliable analytical platform had undergone evolutionary changes to support high throughput demands of drug discovery [60, 70, 87, 94, 95, 96]. These strategies include advancements in chromatographic columns, where lower dimensions and microbore HPLC columns cut short run time to one minute per sample. Quick sample run times help in analyzing higher number of samples with in the given stipulated time [97]. Faster gradient methods with LC pumps that can handle higher pressure also enable analysis with shorter run times [98]. With the invention of monolithic HPLC columns that can be operated at high flow rates in the order of 5–6 mL/min, analytical run times were significantly reduced [99, 100, 101]. One disadvantage of these columns is that the high flow rates translate in to higher usage of mobile phase, making it an expensive alternative.
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Another approach for increasing sample throughput is by the use of parallel HPLC columns, where the effluent from two HPLC systems could be combined and assayed by using the MRM/SRM capabilities of the MS/MS system [102, 103]. One more approach in enhancing the throughput is through staggered analysis approach. Here, multiple HPLC columns are used, but the injection time is staggered such that the “analytical window” can be selected sequentially in order to maximize the use of the MS/MS system and increase sample throughput [104].
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On the other hand, throughput can also be increased by pooling of samples, provided the sensitivity is not seriously compromised. When these samples are analyzed on triple quadrupole systems, care must be taken to have molecular weight differences by at least 5 da. Typically, 4–5 analytes can be pooled and analyzed. Only challenge with pooling/cassette strategy (even with high resolution mass spectrometers) is its non-suitability for isomeric compounds. With advancements in instrumentation technology, modern LC autosamplers are designed to accommodate higher sample load. There are autosamplers that can accommodate as high as twelve 96 well plates. Higher loading capacity of autosamplers enable unattended analysis of large number of samples (Figure 11).
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Figure 11.
Pictorial representation of LC–MS/MS system with higher loading capacity of autosampler.
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When it comes to sample preparation, robotic platforms can be used to screen larger pool of compounds across various in vitro assays. However, this strategy can also be used for processing of in vivo samples, provided if the sample cohort is higher. In general, automated robotic sample preparation platforms are quite often used for screening of compounds in in vitro assays. These robotic platforms help in decreasing the manpower involved and time taken for performing the assays. However, main disadvantage with robotic platforms is the need for preparation of larger volumes of reagents and the cost factor involved. Hence, it is not recommended to use these platforms unless there exists a larger library of compounds.
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\n
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4.5 Matrix effects
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With the sample nature being biological in origin, supernatants obtained after sample preparation consists of many endogenous components that compete with the analyte of interest and result in either suppression/enhancement of ionization. This process of alteration of the ionization of analytes is termed as matrix effects. The “matrix” refers to all components in the sample other than analyte(s) of interest. Matrix effects are defined as “interference from matrix components that are unrelated to the analyte” [105, 106]. The process of ion suppression/enhancement is in general referred as matrix effect and is main subject of various published reviews [107, 108, 109, 110, 111, 112].Matrix effects result in significant deviation in precision and accuracy of results which in turn debate the reliability of pharmacokinetic parameters of NCE’s generated. Matrix effect alters the sensitivity, reproducibility and challenges the reliability of analytical techniques. Although matrix effects occur as a result of various exogenous and endogenous components, one major area of concern is formulation excipients (an exogenous component) used in the preparation of formulations. Dosing vehicles are generally used at high concentrations to solubilize test articles of highly lipophilic nature [113, 114, 115]. This in turn can be instrumental in causing matrix effects, thereby questioning the reliability of preclinical PK parameters. This phenomenon has been reported by us in the past for various excipients such as PEG 400 [110, 116, 117], Cremophor EL [111, 118] and Solutol HS15 [112, 119].
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Several mechanisms have been proposed to explain matrix effects, but the exact process remains uncertain [120, 121]. Various mechanisms by which matrix components cause ion suppression are as follows:
Charge competition between analyte and matrix components [122, 123].
Change in droplet surface tension leading to formation of large droplets and insufficient desolvation [121, 124].
Preferential ion evaporation due to matrix components gathering at droplet surface.
Change in mass of analyte ion due to ion pairing and adduct formation
Co-precipitation with non-volatile matrix components [125].
Gas phase deprotonation.
\n
Reduction of matrix effects can be achieved through various strategies including decreasing the level of matrix components, improving chromatographic separation of interfering materials from the analyte, various sample preparation strategies, lower injection volumes, and even by simple dilution of samples to reduce the overall concentrations of both analyte and co-extracted materials [126, 127]. Switching ionization sources will also help in mitigating the matrix effects [112, 116, 118, 119]. Matrix effects occurring in the early time point samples can be monitored, using another aliquot of the early time point samples analyzed at a higher dilution [128].
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\n
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5. Conclusion
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Over the past few decades, technological advancements in mass spectrometer enabled it to surpass other detection platforms and evolve as an indispensable analytical tool to support the bioanalytical needs of drug discovery and development. Current generation mass spectrometers could efficiently handle both qualitative and quantitative aspects of bioanalysis. Additionally, the likelihood of hyphenation of mass spectrometers with ultrafast liquid chromatography systems, extended its applications to high throughput bioanalysis. Even though significant achievements were made in the past, instruments will continue to get more and more sensitive and become better acquiescent to automation.
\n
\n\n',keywords:"mass spectrometer, mass analyzers, ionization sources, DMPK, ADME, LC–MS/MS, matrix effects",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68389.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68389.xml",downloadPdfUrl:"/chapter/pdf-download/68389",previewPdfUrl:"/chapter/pdf-preview/68389",totalDownloads:946,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:1,totalAltmetricsMentions:1,impactScore:0,impactScorePercentile:33,impactScoreQuartile:2,hasAltmetrics:1,dateSubmitted:"August 28th 2018",dateReviewed:"July 3rd 2019",datePrePublished:"July 31st 2019",datePublished:"November 13th 2019",dateFinished:"July 31st 2019",readingETA:"0",abstract:"Mass spectrometry as an instrument is popular, given its sensitivity, selectivity, speed and robustness. In this chapter, we have briefly deliberated on various mass spec platforms, their hardware components and specific applications in preclinical drug discovery with a special emphasis on drug metabolism and pharmacokinetic assays. Basic principle of operation of mass spectrometer and various ionization techniques/mass analyzers was explicitly discussed. Compatibility of mass spectrometers with ultrafast LC and various throughput techniques, enabled evaluation of thousands of compounds with quick turnaround times. Faster generation of results corresponding to in vitro ADME and in vivo pharmacokinetic assays, aid medicinal chemists to refine their combinatorial synthetic chemistry efforts and expedite the lead optimization and identification phases of drug discovery. Mass spectrometer is a powerful tool for both qualitative and quantitative applications. While quantitative applications include measurement of absolute/relative concentrations, qualitative features assist in identification of molecular structures of metabolites and putative biotransformation pathways. Qualitative inputs are more precise and accurate, with the advent of high-resolution mass spectrometry technology. Although, mass spectrometry has many built-in advantages, it also suffers from matrix effects, as the samples analyzed are mostly of biological origin and are complex in nature. In this chapter, we have defined the nature of matrix effects and various approaches by which these matrix effects can be mitigated.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68389",risUrl:"/chapter/ris/68389",book:{id:"8380",slug:"mass-spectrometry-future-perceptions-and-applications"},signatures:"Vijayabhaskar Veeravalli, Lakshmi Mohan Vamsi Madgula and Pratima Srivastava",authors:[{id:"271928",title:"Dr.",name:"Vijayabhaskar",middleName:null,surname:"Veeravalli",fullName:"Vijayabhaskar Veeravalli",slug:"vijayabhaskar-veeravalli",email:"vveerav1@jhmi.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Atmospheric pressure ionization",level:"1"},{id:"sec_2_2",title:"2.1 Electrospray ionization (ESI)",level:"2"},{id:"sec_3_2",title:"2.2 Atmospheric pressure chemical ionization (APCI)",level:"2"},{id:"sec_4_2",title:"2.3 Atmospheric pressure photo ionization (APPI)",level:"2"},{id:"sec_5_2",title:"2.4 Matrix assisted laser desorption ionization (MALDI)",level:"2"},{id:"sec_7",title:"3. Mass analyzers",level:"1"},{id:"sec_7_2",title:"3.1 Quadrupole analyzer",level:"2"},{id:"sec_8_2",title:"3.2 Triple quadrupole mass analyzer",level:"2"},{id:"sec_9_2",title:"3.3 Linear ion trap mass analyzer",level:"2"},{id:"sec_10_2",title:"3.4 Time of flight mass analyzer",level:"2"},{id:"sec_11_2",title:"3.5 Orbitrap mass analyzer",level:"2"},{id:"sec_13",title:"4. Applications in drug discovery",level:"1"},{id:"sec_13_2",title:"4.1 ADME studies",level:"2"},{id:"sec_14_2",title:"4.2 Metabolite identification",level:"2"},{id:"sec_15_2",title:"4.3 Pharmacokinetic analysis",level:"2"},{id:"sec_16_2",title:"4.4 High throughput bioanalysis",level:"2"},{id:"sec_17_2",title:"4.5 Matrix effects",level:"2"},{id:"sec_19",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Thomson JJ. Rays of positive electricity and their application to chemical analyses. Proceedings of the Royal Society. 1913;89:1-20\n'},{id:"B2",body:'Gohlke RS. Time-of-flight mass spectrometry and gas–liquid partition chromatography. Analytical Chemistry. 1959;31:535-541\n'},{id:"B3",body:'Arpino P, Baldwin MA, McLafferty FW. Liquid chromatography–mass spectrometry. II. Continuous monitoring. Biomedical Mass Spectrometry. 1974;1:80-82\n'},{id:"B4",body:'Ito Y, Takeuchi T, Ishii D, Goto M. 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1. Introduction
The root canal configuration is complex and has many variations depending on the group of teeth. Understanding and mastering this internal anatomy is essential for the planning and executing endodontic therapies [1].
In order to explore root canal anatomy for better understanding, several benchmarks were chosen in combination with appropriate information from the literature, encompassing: general description of teeth, overall length and root’s length, chronology of root formation [2, 3, 4, 5, 6, 7, 8], the degree of canals curvature [9, 10, 11], the number of roots [12], root’s curvature and fusion [13], number and configuration of canals [12], diameter of the canal at 1, 2, and 5 mm from the apex [1, 14], apical foramen position, accessory canals, and lateral and apical ramifications [12].
The divergence of results reported in several studies may be due to the type of the study (clinical/laboratory study); however, different methods have been used in these studies.
Studies done in the laboratory to describe the internal anatomy include various types of methods:
Decalcification with injection of India’s ink [12, 15, 16]
Injection of sodium fluorescein and microscopy [17]
In vitro radio-opaque gel infusion and radiography [18]
In vitro endodontic with radiography and instruments [19] or only with instruments [20]
Clinical evaluation during endodontic treatment using enlargement or operating microscope [30]
In vivo treatment of the root canal and radiography [31]
2. The method of internal anatomy analysis
2.1 Conventional radiography
The retro-alveolar image shows the totality of each X-rayed tooth up to the apex, and provides information on canal anatomy as well as on the integrity of the periodontium [32].
Some studies combined the radiographic technique and radio-opaque sodium iothalamate gel infused in the root canal system [18]. In another use of radiography, Kulild and Peters [19] assessed the internal anatomy of 83 maxillary molars by taking radiography of instruments into the canals (Figure 1(a)).
Figure 1.
Methods of study of internal anatomy. (a) Conventional radiography with instruments showing a maxillary first molar with five roots [33]. (b) Cross section, from a CBCT imaging, representing the second mesiobuccal canal of a maxillary first molar [26]. (c) The 3D root canal system of each maxillary first molar was reconstructed with Micro-CT and mathematical modeling [10]. (d) Diaphanization technique showing the complexity of the internal morphology of a maxillary molar [15].
In a retrospective study of 520 completed endodontic treatments of maxillary second molar, radiographs reviewed were useful to detect the anatomical root and canal variations [31].
Unfortunately, the maxillary molar area is often a difficult area to obtain a good radiographic quality because of the superimposition of the maxillary process of the zygomatic bone [34].
2.2 Cone beam computed tomography (CBCT)
Several studies compared the use of cone beam computed tomography (CBCT) imaging to study root and canal anatomy with some laboratory methods such as histological sectioning and clearing technique and, more recently with the gold standard nondestructive high-resolution micro-computed tomography (Micro-CT) [26].
In order to identify the root canal system, CBCT was used next to charged coupled device (CCD) and photostimulable phosphor (PSP) [22]. For CCD and PSP, the endodontist evaluators correctly identified the number of root canal systems 78 and 80% of the time, respectively, when compared with CBCT 100%.
Numerous in vivo studies used CBCT to highlight the second mesiobuccal canal, with prevalence of 42.63 [21] and 70.5% [25] for the first maxillary molar, and between 34.32 [21] and 41.6% [25] for the second maxillary molar (Figure 1(b)).
2.3 Micro-computed tomography (Micro-CT)
X-ray micro-computed tomography has also been denominated as micro-computed tomography, microcomputer tomography, high-resolution X-ray tomography, X-ray microtomography, Micro-CT, and similar terminologies. Nowadays, despite the impossibility of employing micro-CT for in vivo human imaging, it has been considered the most important and accurate research tool for the study of fine details of root canal anatomy [26].
In Markvart et al.’s [28] article, he investigated the Micro-CT and segmentation precision of the surface models of molars for the detection of small volumes, such as the reduced pulp cavity, formation of mineral deposits, detection of narrow root canals, and to improve the clinical and morphological understanding of the number of root canals and their configuration. Other study was done by Peters et al. [29] on 12 maxillary molars; Micro-CT was used to detailing root canal geometry.
Bjørndal et al. [35] correlated the shape of the root canals to the corresponding root surface of five maxillary molars. While in 2006, Lee et al. [10] measured the three-dimensional (3D) canal curvature in maxillary first molars using Micro-CT and mathematical modeling (Figure 1(c)).
2.4 Diaphanization
Diaphanization is a histological term that refers to the whole body, organ, or structure transparency [15].
Dental diaphanization has been frequently used to observe several anatomical features of the root canal system, including the presence and the type of root canal, number of roots, fusion, lateral canals, transverse anastomoses, position of apical foramen, and apical deltas [12], additional canals such as MB2 in mesiobuccal roots of maxillary molars [16] (Figure 1(d)).
To prove the effectiveness of diaphanization technique in the identification of root canal morphology, many authors compared between diaphanization and other techniques. Baratto Filho et al. [36] showed that the incidence of 4 roots in 140 maxillary first molars was high in vivo assessment (67.14%).
3. Permanent maxillary first molar
3.1 The anatomical particularities of the maxillary first molar
3.1.1 General
The maxillary first molars are the first permanent molars to erupt and sometimes referred to as 6-year molar; they erupt distal to the deciduous dentition and they are considered succedaneous, as they do not replace any deciduous teeth; they contact the maxillary second premolar on the mesial and the maxillary second molar on the distal, the maxillary first molars occlude with the mandibular first and second molars; and they are considered the cornerstones in the development of occlusion because of their eruption pattern and location in the arch [37].
Average dimensions (mm) of the maxillary first molar [37].
3.1.3.1 Crown dimensions
The mesiodistal crown dimension is greater than the cervico-occlusal crown dimension [2, 5, 6]; the average difference is as great as 3.3 mm and as small as 2.5 mm [2, 5] (Figure 2(a)).
Figure 2.
The crown dimensions (reprinted from 3D tooth atlas version 9) [37]. (a) Crown buccal dimension, (b) crown mesial dimension, and (c) crown occlusal dimension.
The buccolingual crown dimension is greater than the cervico-occlusal crown dimension [2, 5, 6], the average difference is as great as 4.1 mm and as small as 3 mm [6] (Figure 2(b)).
The buccolingual crown dimension is greater than the mesiodistal dimension [2, 5, 6]. Diamond [6] indicates that the two dimensions are the same. The inequity of the two measurements appears slight from an occlusal view [2] (Figure 2(c)).
3.1.3.2 Roots dimensions
The three roots are nearly the same length (within 1.5 mm), but the palatal root is the largest [3]: the mesiobuccal root is slightly longer than the distobuccal root [3]; the two buccal roots are approximately the same length [2]; and the distobuccal root is the shortest root [3] (Figure 3(a)).
Figure 3.
Roots dimensions (reprinted from 3D tooth atlas version 9) [37]. (a) Root length and (b) mesial root dimension.
The buccolingual dimension of the mesiobuccal root at its base equals two-third of the buccolingual dimension of the root trunk [3] (Figure 3(b)).
3.2 External root canal anatomy of maxillary first molars
3.2.1 Number of roots
The maxillary first molar root anatomy is predominantly a three-rooted form, as shown in these anatomic studies [12, 13, 18] of this tooth (Figure 4(a)).
Figure 4.
Variation of root number in maxillary first molar. (a) Buccal view of maxillary right first molar (reprinted from 3D tooth atlas version 9) [37]. (b) First maxillary molar with single root [38]. (c) Fusion of mesiobuccal and distobuccal roots [38]. (d) Maxillary right molar with bifurcated with double palatal root [39].
The single root or conical form of root anatomy in the first maxillary molar is very rarely reported [12, 13] (Figure 4b).
The two-rooted form is rarely reported, and may be due to fusion of the distobuccal root to palatal root (5%) [13], fusion of the mesiobuccal root and the palatal root (0%) [13], or fusion of the distobuccal root to the mesiobuccal root (6%) [12] (Figure 4(c)).
Over 95% of maxillary first molars had three roots and 3.8% had two roots in four studies that included 416 teeth, according to a literature review [40].
The four-rooted anatomy in its various forms is also very rare in the maxillary first molar and is more likely to occur in the second or third maxillary molars (Figure 4(d)).
Review data from two studies that included 2480 teeth show that the maxillary first molars had an incidence of C-shaped canals of 0.12% indicating that this type of anomaly is a rare occurrence in the maxillary first molar [40].
3.2.2 Shape of roots
3.2.2.1 Buccal aspect
The roots are described as all being roughly ovoid in cross-sectional form at the mid-root area [4] (Figure 5(a)).
Figure 5.
Buccal aspect of maxillary first molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Cross-sectional root form and (b) buccal bifurcation.
The buccal furcation is often near the junction of the cervical and middle thirds of the root [3]; the buccal bifurcation is located about 4 mm apical to the cervical line [2] (Figure 5(b)).
3.2.2.2 Mesial aspect
The mesial bifurcation is located closer to the cervical line than the buccal bifurcation [2]. There is a smooth concavity extending occlusally and lingually from the furcation almost to the cervical line [2] (Figure 6(a)).
Figure 6.
Mesial aspect of maxillary first molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Mesial furcation, (b) lingual outline form, and (c) palatal root form.
The lingual root is the largest; it diverges boldly to the lingual [7], and it is bent like a banana [2, 3]. Figure 6(b,c).
3.2.2.3 Distal aspect
The distal bifurcation is located 5 mm or more apical to the cervical line, thereby being the most apically located furcation [2] (Figure 7(a)).
Figure 7.
Distal aspect of maxillary first molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Distal bifurcation and (b) distobuccal root.
The buccal surface of the distobuccal root is not located as far buccally as the mesiobuccal root; the distal surface on the distobuccal root has no longitudinal depressions [3].
The distobuccal root is the smallest, shortest, and weakest root and it is a little larger buccolingually than the mesiodistally [4] (Figure 7(b)).
3.2.2.4 Lingual aspect
The lingual root of the maxillary first molar has an average length of 13–13.7 mm, depending on the authors [2, 3] (Figure 8(a)). It is the third longest root in the maxilla after the canine and the second premolar [3].
Figure 8.
Palatal aspect of maxillary first molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Palatal root length and (b) buccal roots visibility.
The lingual root is the longest, largest, and strongest of the three first molar roots [4].
The lingual root is conical and has a bluntly rounded apex [2]. The buccal roots are visible from a lingual view due to their wide mesiodistal spread [3] (Figure 8(b)).
3.3 Internal root canal anatomy of maxillary first molars
3.3.1 Pulp chamber and canal entries
3.3.1.1 Morphology of pulp chamber
The bulk of the pulp chamber is contained within the root trunk, with only the pulp horns extending more coronally. Similar to the outer tooth contour, the pulp chamber is broader buccolingually than mesiodistally. The pulp chamber might undergo calcific metamorphosis, which will reduce its volume considerably [37].
A total of 134 maxillary first molars were studied by Acosta Vigouroux and Trugeda Bosaans [20]; the floor of the pulp chamber was found exactly in the center of the tooth; the most frequent shapes corresponded to trapezoids, rectangles, and inverted trapezoids [20] (Figure 9).
Figure 9.
The morphology of pulp chamber. (a/b) trapezoid form of the pulp chamber (reprinted from 3D tooth atlas version 9) [37]. (c) pulp chamber shape of maxillary first molar with three canals [41].
The transverse cross-sectional shape of the pulp chamber was trapezoidal in 94 teeth (81.0%); triangular-shaped pulp chambers were found in 13 teeth (11.2%). The shape of the pulp chamber was elliptical in 9 teeth (7.8%) as claimed by Thomas et al. [18].
3.3.1.2 Description and location of canal entries
As stated in Acosta Vigouroux and Trugeda Bosaans’ study [20], the largest funnel-shaped entry was that of the lingual canal, which was circular in 45.70% of the cases, and elliptical in 54.30%. The opening to the distobuccal canal was elliptical with a larger buccolingual diameter in 95% of the cases and circular in 5%, the mesiobuccal canal opens at a narrow groove leaning slightly toward the distal aspect and noticeably toward the lingual, which has its origin in the mesiobuccal angle of the floor of the pulp chamber [20].
The average horizontal distance between the MB1 and the MB2 is 1.21 ± 0.5 mm according to Spagnuolo et al. [27], and 1.55 ± 0.56 mm according to Peeters et al. [42] (Figure 10).
Figure 10.
The two locations of the second mesiobuccal (MB-2) canal orifices in a maxillary first molar : (a) first location, (b) second location [41].
Spagnuolo et al. [27] also depict a vertical distance between MB1 and MB2 of 1.68 ± 0.83 mm.
The access cavity has a rhomboid shape, due to the presence of four canals with the corners corresponding to the four orifices, as described in “Cohen’s Pathways of the Pulp” [41]; the access cavity should not extend into the mesial marginal ridge. From the distal side, the preparation can invade the mesial portion of the oblique ridge; the buccal wall should be parallel to a line connecting the mesiobuccal and distobuccal orifices (Figure 11).
Figure 11.
The shape of the access cavity of maxillary first molars from different views [41]. (a) Buccal view, (b) occlusal view, and (c) mesial view.
In a recent study done by Rover et al. [43] on 30 maxillary first molars, they assess the influence of contracted endodontic cavities (CECs) on root canal detection. The traditional endodontic cavities (TECs) were used as a reference for comparison. The results show that it was possible to locate more root canals in the TEC group in stages 1 and 2 than the CEC group.
3.3.2 Morphology of the canals
3.3.2.1 Mesiobuccal canal
According to a book chapter “Ingle’s Endodontics” [39], a meta-analysis has done by Cleghorn and Goodacre contained the most data of the mesiobuccal canal morphology, a total of 8515 teeth from 37 studies (Figure 12(a)).
Figure 12.
Three-dimensional configuration of internal anatomy of maxillary first molar. (a) Mesiobuccal canal (reprinted from 3D tooth atlas version 9) [37]. (b) Micro-CT data showing the detailed anatomy of root canal system [29].
The incidence of two canals in the mesiobuccal root was 57.1%, and of one canal was 42.9% in a weighted average of all reported studies. The incidence of two canals in the mesiobuccal root was higher in laboratory studies (61.1%) compared to clinical studies (54.7%).
The mesiobuccal canal has a similar volume (2.76 mm3), and considerably larger surface area (up to 24 square mm2) compared to the distobuccal one; canal lengths are similar and can reach up to 24 mm [29] (Figure 12(b)).
On 100 maxillary first molar studied by Karaman et al. [11]; the degree of primary curvature in type II, MB (25.63 ± 7.43°) and ML (34.74 ± 8.99°), and in type III, MB (27.33 ± 9.70°) and (ML 36.98 ± 9.41°) in clinical view was not significantly different.
As Vertucci claimed that the median canal diameter at 1, 2, and 5 mm from the apex for MB1 was 0.19, 0.37, 0.46 mm, respectively, buccally and lingually, and 0.13, 0.27, 0.32 mm mesially and distally; for MB2, the median canal diameter was: 0.19, 0.31, 0.38 mm, respectively, buccally and lingually, 0.16, 0.16, 0.16 mm mesially and distally [1].
3.3.2.2 Distobuccal canal
According to “Ingle’s Endodontics” meta-analysis [39]: 15 studies consisting of 2606 teeth, results show that the distobuccal root had only one canal in 98.3% of teeth studied, two canals were found in 1.7% (Figure 13).
Figure 13.
Distobuccal canal system of maxillary first molar (reprinted from 3D tooth atlas version 9) [37].
It is the smallest of the canals present in terms of volume, length, and surface area with around 2.25 mm3, 24 mm, and 18.75 mm2, respectively [29].
The distobuccal canal has a clear curvature of 0.29 ± 0.13 mm−1. However, it is generally less curve that the mesiobuccal root canals [29].
The median canal diameter at 1, 2, and 5 mm from the apex for the distobuccal canal was: 0.22, 0.33, and 0.49 mm, respectively, buccally and lingually, and 0.17, 0.25, 0.31 mm mesially and distally [1].
3.3.2.3 Palatal canal
In a literature review [40] already mentioned included 14 in vivo and in vitro studies based on 2576 maxillary first molars; 99.0% and 98.8% of the palatal roots contained one canal and a single foramen respectively, while the remaining of 1.0% contained 2 canals (Figure 14).
Figure 14.
Palatal canal system of maxillary first molar (reprinted from 3D tooth atlas version 9) [37].
Clinical cases reporting the existence of two canals within a palatal root are not uncommon [44], or two distinct palatal roots [45].
The palatal canal is the largest of the root canals present in maxillary molars, with regards to both length and volume; canal length may be up to 25 mm or more, the volume varies 6.96 ± 1.81 mm3, and area up to 30.43 mm2 [29].
The median canal diameter at 1, 2, and 5 mm from the apex for the palatal canal was: 0.29, 0.40, and 0.55 mm, respectively, buccally and lingually, and 0.33, 0.40, 0.74 mm mesially and distally [1].
The palatal canal is unique, wide, and rectilinear except for a slight curvature in order of 0.23–0.12 mm−1 [29].
The apical foramen is in the center of the apex in 18.0% of cases, and lateral in 82.0% of cases on the palatal root of the first maxillary molar [1].
4. Permanent maxillary second molar
4.1 The anatomical particularities of the maxillary second molar
4.1.1 General
The maxillary second molars are the seventh teeth from the midline, because they erupt at about age 12, they are occasionally referred to as 12-year molars [37].
They contact the maxillary first molar on the mesial and the maxillary third molar on the distal, and they occlude with the mandibular second and third molar [37].
Average dimensions (mm) of the maxillary second molar [37].
4.1.3.1 Crown dimensions
The mesiodistal crown dimension is greater than the occlusocervical crown dimension [2, 3]. The average difference is as great as 2.2 mm [3] (Figure 15(a)).
Figure 15.
The crown dimensions (reprinted from 3D tooth atlas version 9) [37]. (a) Crown buccal dimension, (b) crown mesial dimension, (c) crown occlusal dimension, and (d) occlusocervical crown dimension.
The buccolingual crown dimension is greater than the occlusocervical crown dimension [2, 3]. The average difference is as great as 4.3 mm [7] (Figure 15(b)).
The buccolingual crown is greater than the mesiodistal crown dimension [2, 3]. The average distance is as great as 2.3 mm [7] and as small as 1 mm [6] (Figure 15(c)).
The distal half of the crown has a smaller occlusocervical dimension than the mesial half [3] (Figure 15(d)).
4.1.3.2 Root’s dimensions
The buccal roots are about the same length [2], and the palatal root is the longest root [2, 3] (Figure 16(a)).
Figure 16.
Roots dimensions (reprinted from 3D tooth atlas version 9) [37]. (a) Root length, (b) mesial root dimension, and (c) distobuccal root dimension.
The mesiobuccal root is wider buccolingually than the distobuccal root [3] (Figure 16(b)).
The distobuccal root is shorter and exhibits less buccolingual dimension than the mesiobuccal root [3] (Figure 16(c)).
4.2 External root canal anatomy of maxillary second molars
4.2.1 Number of roots
As stated in “Ingle’s Endodontics” [39], a majority of maxillary second molars in three anatomical studies were found to be three-rooted 88.6% (n = 1272); this result is lower than that found in the maxillary first molar, while the incidence of root fusion was 25.8% (n = 1960) as claimed in seven studies (Figure 17), and C-shaped canals with (4.9%) when compared to the maxillary first molar.
Figure 17.
Buccal view of maxillary right second molar with three roots (reprinted from 3D tooth atlas version 9) [37].
Other studies show different numbers. Indeed, the periodontologists Ross and Evanchik [46] observed 657 maxillary molars in 170 patients in their dental offices and concluded that the root fusion in the maxillary second molars percentage is up to 52.9% (n = 157) versus 47.1% (n = 140) without root fusion.
4.2.2 Shape of roots
4.2.2.1 Buccal aspect
The buccal roots are nearly parallel [2, 3]. The roots are relatively straight, and the second molar roots are relatively close together [3] (Figure 18(a)).
Figure 18.
Buccal aspect of maxillary second molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Root form/proximity, (b) root curvature, and (c) root trunk.
The roots have a distal inclination [2, 3] (Figure 18(b)). The root trunk is relatively long [3] (Figure 18(c)).
4.2.2.2 Mesial aspect
The lingual root is relatively straight [3] (Figure 19(a)).
Figure 19.
Mesial aspect of maxillary second molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Lingual root form and (b) mesiobuccal root surface form.
The mesiobuccal root has a similar morphology of the maxillary first molar, but the furrow that runs through its mesial face is less marked, or nonexistent [8] (Figure 19(b)).
4.2.2.3 Distal aspect
The lingual root apex is frequently aligned with the distolingual cusp tip [2] (Figure 20(a)).
Figure 20.
Distal aspect of maxillary second molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Lingual root apex location and (b) distobuccal root surface/form.
The distobuccal root of the second maxillary molar differs morphologically. The background the mesiobuccal root on a distal view is visible [8] (Figure 20(b)).
4.2.2.4 Lingual aspect
The lingual root is not curved when seen from the lingual view, but it does taper apically to a blunt or rounded apex. The buccal roots are spread out far enough that they are usually visible behind the lingual root from this view (Figure 21(a)).
Figure 21.
Palatal aspect of maxillary second molar roots (reprinted from 3D tooth atlas version 9) [37]. (a) Buccal roots visibility and (b) lingual root curvature.
The apex of the lingual root is in line with the distolingual cusp tip instead of the lingual groove, as was found on the first molar [2].
The palatal root curves distally [5] (Figure 21(b)).
4.3 Internal root canal anatomy of maxillary second molars
4.3.1 Pulp chamber and canal entries
4.3.1.1 Morphology of pulp chamber
The general outline of the pulp chamber in second maxillary molars resembles first molars; four pulp horns of various sizes are present corresponding to the arrangement of the cusps [37].
The floor of the pulp chamber is markedly convex, which gives the canal orifices a slight funnel shape [41].
In Karaman et al.’s [11] research, among 100 maxillary second molars, the shape of the pulp chamber can be trapezoidal about 74% (n = 74), triangular about 21% (n = 21), or elliptical about 5% (n = 5) (Figure 22).
Figure 22.
Photograph of three second maxillary molars with pulp chambers [11]: trapezoidal (a), triangular (b), and elliptical (c).
When four canals are present, the access cavity preparation of the maxillary second molar has a rhomboid shape, if only three canals are present, the access cavity is a rounded triangle, the mesial marginal ridge need not be invaded with the base to the buccal; if only two canals are present, the access outline form is oval and widest in the buccolingual dimension [41] (Figure 23).
Figure 23.
The shape of the access cavity of maxillary second molars from different views [41]: (a) buccal view, (b) occlusal view, and (c) mesial view.
4.3.1.2 Description and location of canal entries
The canals’ orifices in the maxillary second molars are closer mesially to each other than they are in maxillary first molar [41].
The three main orifices (MB, DB, and P) usually form a flat triangle and sometimes almost a straight line [41] (Figure 24).
Figure 24.
Canal entries [41]. (a) Three canal orifices in a maxillary second molar. (b) Two canal orifices in a maxillary second molar.
The mesiobuccal canal orifice is located more to the buccal and mesial than in the first molar; the distobuccal orifice approaches the midpoint between mesiobuccal and palatal orifices; and the palatal orifice usually is located at the most palatal aspect of the root [41].
The distance between orifices in pulp chamber floor was claimed as: 3.09 ± 0.22 mm in type II (n = 20), and 3.89 ± 0.23 mm in type III (n = 8) according to Karaman et al. [11].
4.3.2 Morphology of the canals
4.3.2.1 Mesiobuccal canal
As mentioned in the fifth chapter of “Cohen’s Pathways of the Pulp” [41]. Seventeen anatomical studies found a wide range of canal incidence in the mesiobuccal root; we calculated the average of one canal’s incidence, the results were 69.3%, of two canals was 29%, while the incidence of three and four canals was, respectively, 2.6 and 1% in two studies (Figure 25).
Figure 25.
Mesiobuccal canal system of maxillary second molar (reprinted from 3D tooth atlas version 9) [37].
There was a single apical foramen found in the mesiobuccal root over 68% in 1352 maxillary second molars studied [39].
The mean degrees of primary canal curvature that obtained for type II and type III configurations in maxillary second molar in clinical view were, respectively, (26.13 ± 9.18°) and (18.97 ± 4.71°) [11].
4.3.2.2 Distobuccal canal
These canals can be quite small and smaller at the mid-root and exit the pulp in a relatively straight line, occasionally there may be acute apical curves in mesial as well as distal directions [37] (Figure 26).
Figure 26.
Distobuccal canal system of maxillary second molar (reprinted from 3D tooth atlas version 9) [37].
The distobuccal roots exhibited a single canal over 99% of the time in 10 reported anatomical studies, according to Cleghorn and Goodacre [39].
Otherwise stated in a book chapter: “Tooth Morphology, Isolation, and Access” [41] reporting seven anatomical studies, one single canal was found in the rate of 100%.
4.3.2.3 Palatal canal
In maxillary second molars, palatal canals are mostly straight with an apical curve to the buccal, apical to this marker is a deposition of secondary dentin along the palatal surface of the palatal canal [37] (Figure 27).
Figure 27.
Palatal canal system of maxillary second molar (reprinted from 3D tooth atlas version 9) [37].
The internal canal morphology of the palatal root of the maxillary second molar was assessed in seven studies, showing the incidence of one canal over 99% [41]. While one study found that two palatal roots and two palatal canals occur in 1.47% of these teeth [31].
Neelakantan et al. [23] used CBCT to analyze 191 extracted maxillary second molars from an Indian population; the incidence of a single canal in a palatal root was 87.8%, and the presence of two or more canals was approximately 5.3%.
5. Conclusion
The roots’ variation and the canal system’s morphology knowledge constitute for each tooth a daily mission to the dental surgeon, in order to minimize the potential risks that lead to a failure of the therapy, especially in the endodontic.
An accurate diagnosis and a successful therapy could be resulted by highlighting the entire roots and canals network of molars in particular.
The preoperative radiography is the first complementary test to the diagnosis; although the results of the retro-alveolar radiography in ortho-centered incidence are important, they are not as significant as those of the meso-centric in terms of their impact, which appeared to display three roots of maxillary molars distinctly.
The cone beam computed tomography technology offers a high accuracy, when the data collected by the clinic and conventional radiography are not sufficiently contributory to the diagnosis. Unfortunately, the micro-computed tomography is not applicable in vivo human imaging; however, it forms a detailed means to evaluate the root canal anatomy quantitatively and qualitatively.
Respecting the maxillary molars’ axis, the endodontic access cavity in a trapezoidal shape allows: a direct access, and a possible discovery of an additional canal. This incidence appears to be increasing with the use of the surgical operating microscope during the access opening procedure, while a lower magnification of Galilean loupes are limited.
Furthermore, the canal entries could be located by using micro-openers, ultrasound inserts, round burs, or fine taper files. The use of dyes, with or without trans-illumination, could also be useful.
The working length must ideally be determined through an apex locator, and validated by retro-alveolar radiography. Cleaning and shaping with the k-files remains a prerequisite for Ni-Ti instrumentation.
The techniques that are used to fill a canal network of maxillary molars act according to the principle of vertical warm compaction or thermo-mechanical condensation with Gutta condenser.
Abbreviation
CBCT
cone beam computed tomography
Micro-CT
micro-computed tomography
CCD
charged coupled device
PSP
photostimulable phosphor
\n',keywords:"permanent maxillary first molars, permanent maxillary second molars, root canal complex, internal morphology, anatomic variation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67177.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67177.xml",downloadPdfUrl:"/chapter/pdf-download/67177",previewPdfUrl:"/chapter/pdf-preview/67177",totalDownloads:1240,totalViews:0,totalCrossrefCites:1,dateSubmitted:"December 16th 2018",dateReviewed:"March 8th 2019",datePrePublished:"July 10th 2019",datePublished:"January 22nd 2020",dateFinished:"May 16th 2019",readingETA:"0",abstract:"A successful endodontic treatment depends on a comprehensive knowledge of the morphology of canal and its variations, an appropriate access cavity, cleaning and shaping, and adequate root canal filling. Lack of knowledge in this regard and missing a root canal are among the most common causes of failure of root canal treatments. Most previous studies on maxillary molars have reported that they usually have three roots and four canals since an extra canal is often found in the mesiobuccal root. Other anatomical variations, such as an extra C-shaped canal, have also been reported in distobuccal and palatal roots. Thus, because of having a more complex anatomy compared to other teeth, maxillary molars have the highest rate of endodontic failure. Several studies have assessed the morphology of root canal anatomy in different populations using different techniques such as sectioning, root canal clearing, association of a dental operating microscope and ultrasonic tips, periapical radiography, and computed tomography scanning. Recently, CBCT was suggested to three-dimensionally explore the root canal details before an endodontic treatment. The purpose of this chapter was to highlight the importance of having a thorough knowledge about the root canal morphology of the permanent first and second maxillary molar.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67177",risUrl:"/chapter/ris/67177",signatures:"Said Dhaimy, Lamyae Bedida, Hafsa El Merini and Imane Benkiran",book:{id:"8837",type:"book",title:"Human Teeth",subtitle:"Key Skills and Clinical Illustrations",fullTitle:"Human Teeth - Key Skills and Clinical Illustrations",slug:"human-teeth-key-skills-and-clinical-illustrations",publishedDate:"January 22nd 2020",bookSignature:"Zühre Akarslan and Farid Bourzgui",coverURL:"https://cdn.intechopen.com/books/images_new/8837.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78923-840-2",printIsbn:"978-1-78923-839-6",pdfIsbn:"978-1-78984-522-8",isAvailableForWebshopOrdering:!0,editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"289623",title:"Prof.",name:"Said",middleName:null,surname:"Dhaimy",fullName:"Said Dhaimy",slug:"said-dhaimy",email:"saiddhaimy@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"297310",title:"Dr.",name:"Lamyae",middleName:null,surname:"Bedida",fullName:"Lamyae Bedida",slug:"lamyae-bedida",email:"lamyaebedida@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"297367",title:"Dr.",name:"Imane",middleName:null,surname:"Benkiran",fullName:"Imane Benkiran",slug:"imane-benkiran",email:"imanebenkiran@yahoo.fr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"298239",title:"Dr.",name:"Hafsa",middleName:null,surname:"El Merini",fullName:"Hafsa El Merini",slug:"hafsa-el-merini",email:"hafsaelmerini@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The method of internal anatomy analysis",level:"1"},{id:"sec_2_2",title:"2.1 Conventional radiography",level:"2"},{id:"sec_3_2",title:"2.2 Cone beam computed tomography (CBCT)",level:"2"},{id:"sec_4_2",title:"2.3 Micro-computed tomography (Micro-CT)",level:"2"},{id:"sec_5_2",title:"2.4 Diaphanization",level:"2"},{id:"sec_7",title:"3. Permanent maxillary first molar",level:"1"},{id:"sec_7_2",title:"3.1 The anatomical particularities of the maxillary first molar",level:"2"},{id:"sec_7_3",title:"3.1.1 General",level:"3"},{id:"sec_8_3",title:"3.1.2 Development",level:"3"},{id:"sec_9_3",title:"Table 1.",level:"3"},{id:"sec_9_4",title:"3.1.3.1 Crown dimensions",level:"4"},{id:"sec_10_4",title:"3.1.3.2 Roots dimensions",level:"4"},{id:"sec_13_2",title:"3.2 External root canal anatomy of maxillary first molars",level:"2"},{id:"sec_13_3",title:"3.2.1 Number of roots",level:"3"},{id:"sec_14_3",title:"3.2.2 Shape of roots",level:"3"},{id:"sec_14_4",title:"3.2.2.1 Buccal aspect",level:"4"},{id:"sec_15_4",title:"3.2.2.2 Mesial aspect",level:"4"},{id:"sec_16_4",title:"3.2.2.3 Distal aspect",level:"4"},{id:"sec_17_4",title:"3.2.2.4 Lingual aspect",level:"4"},{id:"sec_20_2",title:"3.3 Internal root canal anatomy of maxillary first molars",level:"2"},{id:"sec_20_3",title:"3.3.1 Pulp chamber and canal entries",level:"3"},{id:"sec_20_4",title:"3.3.1.1 Morphology of pulp chamber",level:"4"},{id:"sec_21_4",title:"3.3.1.2 Description and location of canal entries",level:"4"},{id:"sec_23_3",title:"3.3.2 Morphology of the canals",level:"3"},{id:"sec_23_4",title:"3.3.2.1 Mesiobuccal canal",level:"4"},{id:"sec_24_4",title:"3.3.2.2 Distobuccal canal",level:"4"},{id:"sec_25_4",title:"3.3.2.3 Palatal canal",level:"4"},{id:"sec_29",title:"4. Permanent maxillary second molar",level:"1"},{id:"sec_29_2",title:"4.1 The anatomical particularities of the maxillary second molar",level:"2"},{id:"sec_29_3",title:"4.1.1 General",level:"3"},{id:"sec_30_3",title:"4.1.2 Development",level:"3"},{id:"sec_31_3",title:"Table 2.",level:"3"},{id:"sec_31_4",title:"4.1.3.1 Crown dimensions",level:"4"},{id:"sec_32_4",title:"4.1.3.2 Root’s dimensions",level:"4"},{id:"sec_35_2",title:"4.2 External root canal anatomy of maxillary second molars",level:"2"},{id:"sec_35_3",title:"4.2.1 Number of roots",level:"3"},{id:"sec_36_3",title:"4.2.2 Shape of roots",level:"3"},{id:"sec_36_4",title:"4.2.2.1 Buccal aspect",level:"4"},{id:"sec_37_4",title:"4.2.2.2 Mesial aspect",level:"4"},{id:"sec_38_4",title:"4.2.2.3 Distal aspect",level:"4"},{id:"sec_39_4",title:"4.2.2.4 Lingual aspect",level:"4"},{id:"sec_42_2",title:"4.3 Internal root canal anatomy of maxillary second molars",level:"2"},{id:"sec_42_3",title:"4.3.1 Pulp chamber and canal entries",level:"3"},{id:"sec_42_4",title:"4.3.1.1 Morphology of pulp chamber",level:"4"},{id:"sec_43_4",title:"4.3.1.2 Description and location of canal entries",level:"4"},{id:"sec_45_3",title:"4.3.2 Morphology of the canals",level:"3"},{id:"sec_45_4",title:"4.3.2.1 Mesiobuccal canal",level:"4"},{id:"sec_46_4",title:"4.3.2.2 Distobuccal canal",level:"4"},{id:"sec_47_4",title:"4.3.2.3 Palatal canal",level:"4"},{id:"sec_51",title:"5. 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Department of Restorative Dentistry and Endodontics, Faculty of Dental Medicine, University Hassan II, Casablanca, Morocco
Department of Restorative Dentistry and Endodontics, Faculty of Dental Medicine, University Hassan II, Casablanca, Morocco
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The most commonly used parametric curves are, Bézier, B-splines, (NURBSs), and rational Bézier. Each and every one of them has special features, being the main difference between them the complexity of their mathematical definition. While Bézier curves are the simplest ones, B-splines or NURBSs are more complex. In mobile robotics, two main problems have been addressed with parametric curves. The first one is the definition of an initial trajectory for a mobile robot from a start location to a goal. The path has to be a continuous curve, smooth and easy to manipulate, and the properties of the parametric curves meet these requirements. The second one is the modification of the initial trajectory in real time attending to the dynamic properties of the environment. Parametric curves are capable of enhancing the trajectories produced by path planning algorithms adapting them to the kinematic properties of the robot. In order to avoid obstacles, the shape modification of parametric curves is required. In this chapter, an algorithm is proposed for computing an initial Bézier trajectory of a mobile robot and subsequently modifies it in real time in order to avoid obstacles in a dynamic environment.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Lucía Hilario Pérez, Marta Covadonga Mora Aguilar, Nicolás Montés\nSánchez and Antonio Falcó Montesinos",authors:[{id:"213131",title:"Dr.",name:"Lucía",middleName:null,surname:"Hilario Pérez",slug:"lucia-hilario-perez",fullName:"Lucía Hilario Pérez"},{id:"213132",title:"Dr.",name:"Marta Covadonga",middleName:null,surname:"Mora",slug:"marta-covadonga-mora",fullName:"Marta Covadonga Mora"},{id:"213144",title:"Dr.",name:"Nicolás",middleName:null,surname:"Montés Sánchez",slug:"nicolas-montes-sanchez",fullName:"Nicolás Montés Sánchez"},{id:"221922",title:"Dr.",name:"Antonio",middleName:null,surname:"Falcó Montesinos",slug:"antonio-falco-montesinos",fullName:"Antonio Falcó Montesinos"}]},{id:"58561",doi:"10.5772/intechopen.71663",title:"Search-Based Planning and Replanning in Robotics and Autonomous Systems",slug:"search-based-planning-and-replanning-in-robotics-and-autonomous-systems",totalDownloads:1144,totalCrossrefCites:3,totalDimensionsCites:2,abstract:"In this chapter, we present one of the most crucial branches in motion planning: search-based planning and replanning algorithms. This research branch involves two key points: first, representing traverse environment information as discrete graph form, in particular, occupancy grid cost map at arbitrary resolution, and, second, path planning algorithms calculate paths on these graphs from start to goal by propagating cost associated with each vertex in graph. The chapter will guide researcher through the foundation of motion planning concept, the history of search-based path planning and then focus on the evolution of state-of-the-art incremental, heuristic, anytime algorithm families that are currently applied on practical robot rover. The comparison experiment between algorithm families is demonstrated in terms of performance and optimality. The future of search-based path planning and motion planning in general is also discussed.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"An T. Le and Than D. Le",authors:[{id:"211542",title:"Mr.",name:"Than",middleName:null,surname:"Le",slug:"than-le",fullName:"Than Le"},{id:"211558",title:"Mr.",name:"An",middleName:"T.",surname:"Le",slug:"an-le",fullName:"An Le"}]},{id:"57484",doi:"10.5772/intechopen.71486",title:"Path Planning in Rough Terrain Using Neural Network Memory",slug:"path-planning-in-rough-terrain-using-neural-network-memory",totalDownloads:845,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Learning navigation policies in an unstructured terrain is a complex task. The Learning to Search (LEARCH) algorithm constructs cost functions that map environmental features to a certain cost for traversing a patch of terrain. These features are abstractions of the environment, in which trees, vegetation, slopes, water and rocks can be found, and the traversal costs are scalar values that represent the difficulty for a robot to cross given the patches of terrain. However, LEARCH tends to forget knowledge after new policies are learned. The study demonstrates that reinforcement learning and long-short-term memory (LSTM) neural networks can be used to provide a memory for LEARCH. Further, they allow the navigation agent to recognize hidden states of the state space it navigates. This new approach allows the knowledge learned in the previous training to be used to navigate new environments and, also, for retraining. Herein, navigation episodes are designed to confirm the memory, learning policy and hidden-state recognition capabilities, acquired by the navigation agent through the use of LSTM.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Nancy Arana-Daniel, Roberto Valencia-Murillo, Alma Y. 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Compared to the other O(nlog n) time near-shortest path approach (Kanai and Suzuki, KS’s algorithm), the path length of the Delaunay triangulation method is 0.28% longer than the KS’s algorithm with three Steiner points, but the computation is about 31.71 times faster. This, however, has only a few path length differences, which promises a good result, but the best computing time. Notably, these methods based on Delaunay triangulation concept are ideal for being extended to solve the path-planning problem on the Quadric surface or even the cruise missile mission planning and Mars rover.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Chi-Chia Sun, Gene Eu Jan, Chaomin Lu and Kai-Chieh Yang",authors:[{id:"36311",title:"Dr.",name:"Chaomin",middleName:null,surname:"Luo",slug:"chaomin-luo",fullName:"Chaomin Luo"},{id:"220894",title:"Prof.",name:"Gene Eu (Ching Yuh)",middleName:"Eu",surname:"Jan",slug:"gene-eu-(ching-yuh)-jan",fullName:"Gene Eu (Ching Yuh) Jan"},{id:"221450",title:"Dr.",name:"Chi-Chia",middleName:null,surname:"Sun",slug:"chi-chia-sun",fullName:"Chi-Chia Sun"},{id:"221451",title:"MSc.",name:"Kai-Chieh",middleName:null,surname:"Yang",slug:"kai-chieh-yang",fullName:"Kai-Chieh Yang"}]},{id:"63374",doi:"10.5772/intechopen.76895",title:"Motion Planning for Mobile Robots",slug:"motion-planning-for-mobile-robots",totalDownloads:1179,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter introduces two kinds of motion path planning algorithms for mobile robots or unmanned ground vehicles (UGV). First, we present an approach of trajectory planning for UGV or mobile robot under the existence of moving obstacles by using improved artificial potential field method. Then, we propose an I-RRT* algorithm for motion planning, which combines the environment with obstacle constraints, vehicle constraints, and kinematic constraints. All the simulation results and the experiments show that two kinds of algorithm are effective for practical use.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Xiangrong Xu, Yang Yang and Siyu Pan",authors:[{id:"217380",title:"Prof.",name:"Xiangrong",middleName:null,surname:"Xu",slug:"xiangrong-xu",fullName:"Xiangrong Xu"}]}],mostDownloadedChaptersLast30Days:[{id:"58561",title:"Search-Based Planning and Replanning in Robotics and Autonomous Systems",slug:"search-based-planning-and-replanning-in-robotics-and-autonomous-systems",totalDownloads:1137,totalCrossrefCites:3,totalDimensionsCites:2,abstract:"In this chapter, we present one of the most crucial branches in motion planning: search-based planning and replanning algorithms. This research branch involves two key points: first, representing traverse environment information as discrete graph form, in particular, occupancy grid cost map at arbitrary resolution, and, second, path planning algorithms calculate paths on these graphs from start to goal by propagating cost associated with each vertex in graph. The chapter will guide researcher through the foundation of motion planning concept, the history of search-based path planning and then focus on the evolution of state-of-the-art incremental, heuristic, anytime algorithm families that are currently applied on practical robot rover. The comparison experiment between algorithm families is demonstrated in terms of performance and optimality. The future of search-based path planning and motion planning in general is also discussed.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"An T. Le and Than D. Le",authors:[{id:"211542",title:"Mr.",name:"Than",middleName:null,surname:"Le",slug:"than-le",fullName:"Than Le"},{id:"211558",title:"Mr.",name:"An",middleName:"T.",surname:"Le",slug:"an-le",fullName:"An Le"}]},{id:"58361",title:"Path Planning on Quadric Surfaces and Its Application",slug:"path-planning-on-quadric-surfaces-and-its-application",totalDownloads:865,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In this chapter, recent near-shortest path-planning algorithms with O(nlog n) in the quadric plane based on the Delaunay triangulation, Ahuja-Dijkstra algorithm, and ridge points are reviewed. The shortest path planning in the general three-dimensional situation is an NP-hard problem. The optimal solution can be approached under the assumption that the number of Steiner points is infinite. The state-the-art method has at most 2.81% difference on the shortest path length, but the computation time is 4216 times faster. Compared to the other O(nlog n) time near-shortest path approach (Kanai and Suzuki, KS’s algorithm), the path length of the Delaunay triangulation method is 0.28% longer than the KS’s algorithm with three Steiner points, but the computation is about 31.71 times faster. This, however, has only a few path length differences, which promises a good result, but the best computing time. Notably, these methods based on Delaunay triangulation concept are ideal for being extended to solve the path-planning problem on the Quadric surface or even the cruise missile mission planning and Mars rover.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Chi-Chia Sun, Gene Eu Jan, Chaomin Lu and Kai-Chieh Yang",authors:[{id:"36311",title:"Dr.",name:"Chaomin",middleName:null,surname:"Luo",slug:"chaomin-luo",fullName:"Chaomin Luo"},{id:"220894",title:"Prof.",name:"Gene Eu (Ching Yuh)",middleName:"Eu",surname:"Jan",slug:"gene-eu-(ching-yuh)-jan",fullName:"Gene Eu (Ching Yuh) Jan"},{id:"221450",title:"Dr.",name:"Chi-Chia",middleName:null,surname:"Sun",slug:"chi-chia-sun",fullName:"Chi-Chia Sun"},{id:"221451",title:"MSc.",name:"Kai-Chieh",middleName:null,surname:"Yang",slug:"kai-chieh-yang",fullName:"Kai-Chieh Yang"}]},{id:"58388",title:"Path Planning Based on Parametric Curves",slug:"path-planning-based-on-parametric-curves",totalDownloads:1208,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Parametric curves are extensively used in engineering. The most commonly used parametric curves are, Bézier, B-splines, (NURBSs), and rational Bézier. Each and every one of them has special features, being the main difference between them the complexity of their mathematical definition. While Bézier curves are the simplest ones, B-splines or NURBSs are more complex. In mobile robotics, two main problems have been addressed with parametric curves. The first one is the definition of an initial trajectory for a mobile robot from a start location to a goal. The path has to be a continuous curve, smooth and easy to manipulate, and the properties of the parametric curves meet these requirements. The second one is the modification of the initial trajectory in real time attending to the dynamic properties of the environment. Parametric curves are capable of enhancing the trajectories produced by path planning algorithms adapting them to the kinematic properties of the robot. In order to avoid obstacles, the shape modification of parametric curves is required. In this chapter, an algorithm is proposed for computing an initial Bézier trajectory of a mobile robot and subsequently modifies it in real time in order to avoid obstacles in a dynamic environment.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Lucía Hilario Pérez, Marta Covadonga Mora Aguilar, Nicolás Montés\nSánchez and Antonio Falcó Montesinos",authors:[{id:"213131",title:"Dr.",name:"Lucía",middleName:null,surname:"Hilario Pérez",slug:"lucia-hilario-perez",fullName:"Lucía Hilario Pérez"},{id:"213132",title:"Dr.",name:"Marta Covadonga",middleName:null,surname:"Mora",slug:"marta-covadonga-mora",fullName:"Marta Covadonga Mora"},{id:"213144",title:"Dr.",name:"Nicolás",middleName:null,surname:"Montés Sánchez",slug:"nicolas-montes-sanchez",fullName:"Nicolás Montés Sánchez"},{id:"221922",title:"Dr.",name:"Antonio",middleName:null,surname:"Falcó Montesinos",slug:"antonio-falco-montesinos",fullName:"Antonio Falcó Montesinos"}]},{id:"63374",title:"Motion Planning for Mobile Robots",slug:"motion-planning-for-mobile-robots",totalDownloads:1177,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter introduces two kinds of motion path planning algorithms for mobile robots or unmanned ground vehicles (UGV). First, we present an approach of trajectory planning for UGV or mobile robot under the existence of moving obstacles by using improved artificial potential field method. Then, we propose an I-RRT* algorithm for motion planning, which combines the environment with obstacle constraints, vehicle constraints, and kinematic constraints. All the simulation results and the experiments show that two kinds of algorithm are effective for practical use.",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Xiangrong Xu, Yang Yang and Siyu Pan",authors:[{id:"217380",title:"Prof.",name:"Xiangrong",middleName:null,surname:"Xu",slug:"xiangrong-xu",fullName:"Xiangrong Xu"}]},{id:"58572",title:"Design and Implementation of a Demonstrative Palletizer Robot with Navigation for Educational Purposes",slug:"design-and-implementation-of-a-demonstrative-palletizer-robot-with-navigation-for-educational-purpos",totalDownloads:1194,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Nowadays, many kinds of robots are used in industries to help in manufacturing or placing objects. However, teaching young people and children about robot design and work can be difficult, turning this into a complicated area for them. This chapter provides a detailed description of the design and implementation of a robotic arm mounted on a mobile robot using the LEGO Mindstorms NXT kit® and the starter kit DaNI 2.0, designed by National Instruments®. The mobile palletizer robot takes a box from place A and navigates in the indoor environment until it reaches a predefined place B. The characterization of the robotic arm is based on a parallel structure considering that the end-effector has only two points to hold the object; the gripper is also built using LEGO®. The robot performs the path computed using an A-star algorithm; moreover, actions like moving up and down, opening and closing the gripper and picking up the box and putting it down are executed by the robotic arm using the central unit of the NXT kit. Each stage of the robot design and implementation is explained in detail using diagrams and 3D graphical views with the aim of illustrating the implementation step by step for educational purposes (mainly for young people or children).",book:{id:"6322",slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Dora-Luz Almanza-Ojeda, Perla-Lizeth Garza-Barron, Carlos Rubin\nMontoro-Sanjose and Mario-Alberto Ibarra-Manzano",authors:[{id:"182765",title:"Dr.",name:"Dora Luz",middleName:null,surname:"Almanza Ojeda",slug:"dora-luz-almanza-ojeda",fullName:"Dora Luz Almanza Ojeda"},{id:"191783",title:"Dr.",name:"Mario-Alberto",middleName:null,surname:"Ibarra-Manzano",slug:"mario-alberto-ibarra-manzano",fullName:"Mario-Alberto Ibarra-Manzano"},{id:"213261",title:"BSc.",name:"Perla Lizeth",middleName:null,surname:"Garza-Barrón",slug:"perla-lizeth-garza-barron",fullName:"Perla Lizeth Garza-Barrón"},{id:"223872",title:"Dr.",name:"Carlos Rubin",middleName:null,surname:"Montoro-Sanjose",slug:"carlos-rubin-montoro-sanjose",fullName:"Carlos Rubin Montoro-Sanjose"}]}],onlineFirstChaptersFilter:{topicId:"1303",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"25",type:"subseries",title:"Evolutionary Computation",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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