\r\n\tHomeostasis is brought about by a natural resistance to change when already in the optimal conditions, and equilibrium is maintained by many regulatory mechanisms. All homeostatic control mechanisms have at least three interdependent components for the variable to be regulated: a receptor, a control center, and an effector. The receptor is the sensing component that monitors and responds to changes in the environment, either external or internal. Receptors include thermoreceptors and mechanoreceptors. Control centers include the respiratory center and the renin-angiotensin system. An effector is a target acted on to bring about the change back to the normal state. At the cellular level, receptors include nuclear receptors that bring about changes in gene expression through up-regulation or down-regulation and act in negative feedback mechanisms. An example of this is in the control of bile acids in the liver.
\r\n\tSome centers, such as the renin-angiotensin system, control more than one variable. When the receptor senses a stimulus, it reacts by sending action potentials to a control center. The control center sets the maintenance range—the acceptable upper and lower limits—for the particular variable, such as temperature. The control center responds to the signal by determining an appropriate response and sending signals to an effector, which can be one or more muscles, an organ, or a gland. When the signal is received and acted on, negative feedback is provided to the receptor that stops the need for further signaling.
\r\n\tThe cannabinoid receptor type 1 (CB1), located at the presynaptic neuron, is a receptor that can stop stressful neurotransmitter release to the postsynaptic neuron; it is activated by endocannabinoids (ECs) such as anandamide (N-arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG) via a retrograde signaling process in which these compounds are synthesized by and released from postsynaptic neurons, and travel back to the presynaptic terminal to bind to the CB1 receptor for modulation of neurotransmitter release to obtain homeostasis.
\r\n\tThe polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) and are synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs) mediate significant effects in the fine-tuning adjustment of body homeostasis.
\r\n\t
\r\n\tThe aim of this book is to discuss further various aspects of homeostasis, information that we hope to be useful to scientists, clinicians, and the wider public alike.
Recent developments in nanoscience and nanotechnology were strongly supported by significant advances in nanofabrication. The growing demand for the fabrication of nanostructured materials has become increasingly important because of the ever-decreasing dimensions of various devices, including those used in electronics, optics, photonics, biology, electrochemistry, and electromechanics (Henzie et al., 2004; Fan et al., 2006). In particular, a societal revolution is expected with the miniaturization of mechanical, chemical or biological systems known as microlectromechanical systems (MEMS) (Lee et al. 2012), or micrototal analysis systems (µTAS) (Reyes et al. 2002, Dittrich et al. 2006, West et al. 2008).
Among all fabrication processes, photolithography has been strongly developed since few decades to fulfil to the needs of the microelectronics industry. Researches in this area were essentially motivated by finding ways to provide new solutions to pursue the trend towards a constant decrease of the size of the transistors as stated in the "Moore\'s law" (Moore, 1965). To reach these objectives, lithographic fabrication methods have been widely diversified leading to DUV lithography (Ridaoui et al., 2010), X-ray lithography (Im et al., 2009) and e-beam lithography (Gonsalves et al. 2009) to quote a few. Although some of these techniques exhibit resolution of less than 10 nm, these methods are inherently 2D. Unlike conventional microelectronics components, many MEMS or µTAS devices (motors, pumps, valves…) require 3D fabrication capability to insure the same function as the corresponding macroscopic device. Thus, lithographic fabrication of 3D microstructures has emerged and has been divided in two categories depending if they give access to restricted or arbitrary 3D pattern fabrication. On the first hand, specific structures as periodic patterns have been made using self-assembly (Shevchenko et al. 2002), layer-by-layer assembly (Kovacs et al. 1998), soft lithography (Quake et al. 2000), and holographic photopolymerization (Campbell et al. 2000). However by these techniques, no free-moving or complex microstructures have been achieved. On the other hand, arbitrary 3D patterns have been realized by using the so-called direct write technologies which gathers ink-based writing (Lewis et al. 2004), microstereolithography (Maruo et al. 2002) and two-photon stereolithography (TPS) (Kawata et al. 2001; Maruo et al. 1997). Though examples of submicrometer resolution have been demonstrated for ink-based writing (Lewis et al. 2004) and microstereolithography (Maruo et al. 2002), these techniques are mainly used for micro or macrofabrication.
In this context, two-photon stereolithography which is an advanced version of microstereolithography appears of high interest since it offers intrinsically sub-100 nm resolution. Additionally to its unique ability of writing arbitrary structures with sub-100 nm features without use of any mask, TPS is also an attractive fabrication process due to the versatility of materials used including polymers, biopolymers, ceramics, metals, and hybrid materials.
The aim of this chapter is to review some recent works about two-photon stereolithography and its applications. In the first part, a brief introduction to TPS and the fundamental concepts will allow illustrating its interest and its current development. The second part will be dedicated to the most relevant materials developed for TPS regarding to the applications targeted. Furthermore, some typical applications where 3 dimensionalities play a crucial role will be highlighted. Finally, the last part will describe the recent advances in TPS both from the writing speed and the resolution (Li et al. 2009) in order to compete with other nanofabrication techniques. As the result, the contribution of this chapter is to propose a comprehensive overview of fundamental issues in TPS as well as its current and future promising potential.
One of the first attempts to fabricate 3D structures arised from IBM in 1969 (Cerrina, 1997). By combining electrodeposition and X-ray lithography, high-aspect ratio metal structures were obtained. Further works on X-ray lithography gave rise to the well-known process LIGA in the early 1980s (Becker et al. 1984). Despite the maturity of the technique and demonstration of some 3D complex structures, their application has not been widespread due to the availability of synchrotron radiation sources and X-ray masks.
Historically speaking, TPS began with the 3D microfabrication process using photopolymers developed by Kodama in 1981 (Kodama, 1981). Further developments lead to the birth of stereolithography, then microstereolithography to achieve resolution down to 1 µm. Even if in some cases, submicrometer resolution has been demonstrated (Maruo et al. 2002), it is still challenging to obtain microstructures with nano or submicron features due to the layer-by-layer nature of this technique. To overcome this drawback, Wu et al. (Wu et al. 1992) proposed the two-photon lithography concept which is based on the nonlinear optical process of two photon absorption (TPA). This work was directly inspired of the first demonstration of localized excitation in two-photon fluorescence microscopy by Denk et al. two years before (Denk et al. 1990). However, the feasibility of TPS TPS is also called two-photon polymerization (TPP), multiphoton absorption polymerization (MAP), 3-dimensional Direct Laser Writing (3D DLW) or 3-dimensional lithography.
Contrary to conventional stereolithography techniques where polymerization is induced by absorption of a single photon, TPS is based on two photon absorption (TPA) process. TPA and more generally multiphoton absorption (MPA) process have been first predicted in 1931 by Marie Goeppert-Mayer (Goeppert-Mayer, 1931) and then verified experimentally thirty years later (Kaiser et al. 1961), thanks to the advent of laser. Finally, two-photon photopolymerization was experimentally reported for the first time in 1965 as the first example of multiphoton excitation-induced photochemical reactions (Pao et al. 1965). However, it’s only with the commercialization of tunable solide ultrashort pulse laser like Ti:Sapphire laser in the 1990s that application of TPA is widespread in various domains like biology imaging (two photon fluorescence microscopy) or microfabrication (TPS).
A. Mechanism of TPA when simultaneous excitation occurs. B and C. Illustration of two methods for increasing the probability that TPA occurs: density of photon is increased by B. spatial compression using objectives with high numerical aperture, C. temporal compression using ultrafast lasers.
Two different mechanisms have been described for TPA: the sequential excitation and the simultaneous two-photon excitation. In the frame of TPS, only the second one is involved (Figure 1A). In this case, a virtual intermediate state is created by interaction of the material with the first absorbed photon. In order to reach the first real excited state, a second photon has to be absorbed during the short lifetime (around 10-15 s) of this virtual state. To increase the probability of such a non-linear absorption process, high density of photons is requested. Consequently, in main applications (including TPS) where TPA is involved, objectives with high numerical aperture (NA) and ultra short pulse laser are employed for increasing spatial and temporal density of photons, respectively (Figure 1B and C). The main interest of TPA compared to single photon absorption is that excitation is localized within the focal volume of a laser beam. Consequently, it gives access to 3D microfabrication since the polymerization threshold is not reached out of the focal volume. Typically, volume less than 1 µm3 can be addressed. In parallel to the technical developments for TPA, molecular engineering has been strongly developed to design molecules or molecular architectures with large TPA cross section. An exhaustive review on this point can be found in reference (He et al. 2008) and few typical examples will be given in the next section.
The typical TPS setup is composed of three main parts: (i) the excitation source, (ii) the computer-aided design (CAD) system and (iii) the scan method. The excitation source with high intensity is important to favor TPA process. Even if Ti:Sapphire laser operating at 800 nm are often used, Baldeck and coworkers have demonstrated that TPS could be performed successfully by using a cheap Nd-YAG microlaser operating at 532 nm (Wang et al. 2002). The CAD system has to be chosen carefully since trajectories can influence the writing time and more important the mechanical resistance of the final structure. Finally, the scan method will have a crucial impact of the throughput of the writing process. The first possibility is to use Galvano mirrors for horizontal scanning coupled to piezoelectronic stage for vertical scanning which presents the advantage to scan with high speed. However, the total horizontal range accessible by this optical system is limited to few ten of micrometers due to spherical aberration when using objectives with high numerical aperture. The most popular solution consists to scan in x, y and z direction by using a piezoelectric stage. While the scan speed is low compared to previous option, few hundred of micrometer can be scanned.
Schematic typical experimental TPS set-up.
As depicted in Figure 2, a typical set-up is composed of a mode-locked Ti:Sapphire laser as excitation source which presents duration pulse of ten hundred of femtosecond at 800 nm, repetition rate around 80 MHz and average output power of 1-3 W. The intensity of the laser is controlled by an optical or mechanical shutter. Before the introduction of the beam into the microscope, it is expanded so as to overfill the back aperture of the objective. By tightly focusing the pulsed laser beam (ns to fs pulses) into a multi-photon absorbing material, it is possible to trigger a photoreaction (e.g. photopolymerization) inside a volume below the dimension of the voxel. Complex structures (such as in Figures 3, 4, 6 and 8) can then be generated by moving in the laser focus in the 3 dimensions inside the monomer substrate. Usually, samples are placed on a 3D piezoelectric stage, and then move above the fixed laser beam by CAD. Upon the irradiation, only areas exposed at the focal point are polymerized further than the polymerization threshold, leading to the desired structures after washing away the unsolidified photoresist. Finally, the back reflection is collected by an additional port and send to a CCD to monitor the fabrication in real time.
Basically, the formulation destined to TPS is composed of 2 main components: a photoinitiator system and a monomer. The two-photon photoinitiator is a species, or a combination of chemicals able to absorb efficiently two photons to generate excited states from which reactive species can be created. One of the most important parameter is the two-photon absorption cross section that directly characterizes the capacity of the photoinitiator to absorb two photons. The reactive species (radicals or ions) must be able to initiate polymerization of the monomers that constitute the building blocks of the final material. After initiation, propagation and termination reactions take place as observed in the sequences of classical polymerization scheme.
In principle, any one-photon photopolymerizable system can be adapted to TPS, provided that a suitable TPS photoinitiator can be added to the monomer system. Most of the published works deal with free radical photopolymers. The main reason is relative to a wider availability of free radical photoinitiators.
Additionally to the photoinitiator and monomers, other chemicals can be added in TPS systems like inhibitors (to control the polymerization threshold and thus spatial extend of polymerization - some examples will be given in the next section), and additives to bring specific properties (fluorophores, metal nanoparticles, quantum dots, etc...). The choice of the monomer is in relation with the final application whereas the choice of the photoinitiator integrates the irradiation wavelength and nature of the monomer.
structures realized by TPS with A. polyacrylate derivatives (λexc: 532 nm; average power : 20 µW; writing speed: 45 µm.s-1 ;
As illustrated in Figure 3, different examples of 3D structures have been realized with various materials. Interest of such structure will be discussed in each corresponding material sub-section. The next paragraphs are aimed at giving some examples of systems and associated applications.
Among different monomers available, acrylate monomers have been the most widely used for TPS. The reason for this success is a wide range of commercially available acrylate monomers with tailored properties: chain length, number of reactive function, viscosity, polarity to quote a few. Moreover, acrylate monomers exhibit a high reactivity and good mechanical properties that allow complex 3D structures being created.
In parallel, a wide choice of free-radical TPP photoinitiators has been developed. Highly efficient two-photon absorbing systems such as 4,4\'-dialkylamino trans-stilbene (Cumpston et al. 1999) and other bis-donor bis(styryl)benzene or bis(phenyl)polyene (Lu et al. 2004; Zhang et al. 2005; Rumi et al. 2000) were employed for two-photon initiated free radical polymerization. Other conjugated photoinitiators as fluorenes (Belfield et al. 2000; Martineau et al. 2002, Jin et al. 2008) and ketocoumarins (Li et al. 2007) derivatives also demonstrated remarkable TPS properties. Finally, another promissing strategy is the direct photogeneration of highly reactive radicals such as α-aminoalkyl ones.
In particular, Malval et al. demonstrated an elegant strategy to improve the efficiency of thioxanthone-based systems (Malval et al. 2011, Figure 3A). New hybrid anthracene-thioxanthone system assembled into a chevron-shaped molecular architecture was proposed. A strong increase in the two-photon absorption cross section by more than a factor of 30 as compared to thioxanthone was observed. As a consequence, anthracene-thioxanthone constitutes a suitable two-photon initiating chromophore with a much higher efficiency as thioxanthone used as reference. At λexc = 710 nm for instance, the two-photon polymerization threshold of anthracene-thioxanthone was shown to be five times lower with respect to that of thioxanthone.
Additional examples of polyacrylate structures realized by TPS can be found in figure 4 section 4.1.
Cationic photoinitiated polymerization of epoxides, vinyl ethers and methylenedioxolanes has received increasing attention, owing in large part to the oxygen insensitivity of the cationic process (Belfield et al. 1997a and 1997b). Moreover, cationic photoresist appears as an interesting choice from application point of view since UV negative tone photoresists have demonstrated their interest for microelectronics, optics, microfluidic or MEMS.
However, the difficulty to design efficient TPA photoacid generators has limited the development of TPA cationic photoresists. For this reasons, many efforts have been devoted to increase the sensitivity of such systems. First approach was based on sensitizers such as coumarin (Li et al. 2001), phenothiazine (Billone et al. 2009), or thioxanthone (Steidl et al. 2009) associated to a commercial PAG such as onium salts. Second approach relies on a molecular association of the acid generator functionality into the structure of the two-photon active chromophore. In the latest case, the reactivity of the PAG is no longer limited by diffusion and thus a significant improvement of the photopolymerization efficiency was demonstrated (Zhou et al. 2002; Yanez et al. 2009; Xia et al. 2012).
Among other application, the epoxy-based photoresists are extremely interesting when complex structures with high aspect ratio are needed. Indeed, thanks to their good mechanical properties, they have been successfully used for application in microfluidic (Maruo et al. 2006) or MEMS (Bückmann et al. 2012).
Despite their advantages, polymers have intrinsic limitations for some applications. For instance, their mechanical properties at high temperature or in contact with solvents degrade rapidly. They also present low refractive index that limits their use in optical applications. Their toxicity may prevent them from use in contact with living organisms. For these reasons, alternative strategies have been developed to combine the advantages of 3D structuration by TPA and functional materials.
The sol-gel route is interesting in the frame of micro-nano-fabrication since it allows the fabrication of inorganic or hybrid organic-inorganic materials at relatively low temperature. The first strategy followed for combining lithography and sol-gel materials consisted in developing hybrid precursors that can undergo both sol-gel hydrolysis-condensation reaction and photoinduced crosslinking (Blanc et al. 1999; Soppera et al. 2001). These materials, also called Ormorcer® or Ormorsil® have been adapted to TPA by use of suitable photoinitiators and interesting applications in the frame of optics (Ovsianikov et al. 2008) or biology (Klein et al. 2011, see Figure 3B, C) were demonstrated. These materials were mostly used in optics since the refractive index of the material can be tuned by adding metal alcoxides. However, in these hybrid materials, the proportion of organic moieties in the crosslinked material is still important, so many efforts have been dedicated to the formulation of fully inorganic materials (Passinger et al. 2007).
Another important class of inorganic materials is metals. Metals nanoparticles, nanostructures or thin layers are indeed very interesting for electrical connections in devices and also for their plasmonic properties. Recent works have been reported on the fabrication of 3D metallic structures by combining TPS and silver evaporation (Rill et al. 2008). However, by this process, full metal coverage is challenging and induces a supplementary step. Therefore, several groups have developed more direct strategies based only on TPS. For instance, Prasad et al. have fabricated submicrometric plasmonic structures which exhibit interesting conductive properties (Shukla et al. 2011). More recently, Spangenberg et al. also demonstrated that a silver complexe can be used as TPA photoinitiating system and as precursors for nanoparticles fabrications, leading in a single step to a polymer-metal nanoparticles nanocomposite (Spangenberg et al. 2012). Such routes open the doors towards microstructures with conductive properties or magnetic properties that can be useful for MEMS actuation.
One other very important and growing field of applications for TPA materials is relative to biological applications. TPA microstructuring has been extensively used the last years to propose micro and nanostructured surfaces with tailored chemical composition to be used as model substrates to investigate the development of biofilms. The unique advantage of TPS is to propose real 3D structures that mimic with more accuracy the local environment of cells or bacteria than planar surfaces. In this context, polymer matrixes have been widely used but also, sol-gel materials were proposed since they are biocompatbile materials that can be used as inert topological matrixes, as illustrated in Figure 3B and 3C (Klein et al. 2011). Additionally, biological materials like trypsin or collagen precursors were developed to propose a direct writing route for 3D biocompatible structures. Besides the interest of allowing a direct writing of complex structures, an advantage of TPA microfabrication is to be adapted for integration of microstructures in closed environment. For example, Iosin et al. demonstrated the possibility of integrating trypsin’s micropillars in a microfluidic system (Figure 3D). Trypsin is an enzyme used for catalyze the degradation of specific peptide. Interestingly, by following the variation of fluorescence intensity resulting from the peptide clivage, the authors have shown that trypsin structures kept its enzyme catalysis activity.
Although numerous materials have been designed to fulfill the requirements of various applications, there is still an important demand for optimizing current systems. Besides, with the emergence of STED–like lithography (for STimulated Emission Depletion, see next section), designs of new photosystems will be crucial for the development of such technique.
As shown through several examples, TPS is a powerful and attractive technique for present and futures applications. Due to the need of a well-controlled 3D nanofabrication technique, several commercial set-ups have emerged on the market since 5 years. However TPS suffers from two main drawbacks for a more largely widespread in other scientific area or in industries. The first roadblock concerns the low-throughput of the process. Indeed, TPS is based on a serial process (i.e. point-by-point writing) which is a serious problem when mass production is needed. Moreover, compared to low-throughput techniques like e-beam lithography, resolution achievable by TPS is still 1 or 2 order of magnitude lower.
In this section, we will discuss about different approaches to address these specific points and highlight some recent developments which answer mostly to these drawbacks and promise a brilliant future to TPS.
Because of the rapid improvement of TPS resolution in the past decade, a special attention has to be care on the way to define and measure it. In the most of works, “resolution” corresponds to the lateral and/or axial features size of single voxel or single line. Different methods such as ascending scan method (Sun et al. 2002) or suspending bridge method (DeVoe et al. 2003) have been proposed in order to improve the accuracy of the measurements. However, these two methods suffer from drawbacks which are the difficulty to avoid the truncation effect and the unknown influence of material’s shrinkage. Therefore, though less information is provided, most of the groups define resolution as the width of a single line on the surface.
Nevertheless, with the emergence of several STED-like lithographies, more precise definition of resolution has become necessary in order to compare their abilities. Although extension of the famous Abbe’s criterion introduced in conventional or two-photon absorption microscopy can be extended to TPS to describe the optical limitation of the lithography system, ultimate resolution for a given optical lithography system has to be determined by considering the role of the photopolymer. Indeed, in the frame of the writing of two close lines, due to consumption of photoinitiators and diffusion of various species (photoinitiator, scavengers), the writing process of the second line can be strongly affected. This effect is sometimes referred as the resin’s memory. Thus strong dependence with respect to the initial concentrations of photoinitiator as well as the viscosity of the matrix is expected. Up to date, no mathematical model includes all the parameters. Therefore, as suggested by Fischer et al. (Fischer et al. 2012), a better solution for determine both axial and lateral resolution would be the fabrication of a 3D periodic unit as a crystal photonic for a given photopolymerizable system. It has to be mentioned that typical ratio between axial over lateral resolution in TPS is ranging from 2 to 5 depending of optical conditions. In the next part, one has to keep in mind that the resolution or feature size is given for both an optical and chemical system.
Since the microbull with 120 nm features size realized by Kawata and coworkers (Kawata et al. 2001), various approaches have been attempted to improve the resolution of TPS (Figure 4).The first approach which is still used nowadays relies on the design of high-efficiency photoinitiators. By this method, linewidths of 80 nm have been measured (Xing et al. 2007). Another approach based on the use of a shorter wavelength has allowed writing of 3D structure with 60 nm feature size (Haske et al. 2007). Indeed, as dictated by the extended to TPS Abbe’s criterion, lateral resolution is proportional to the wavelength. However, the wavelength can not be reduced indefinitely since the material may absorb linearly at shorter wavelength and consequently lead to the lost of the intrinsic resolution of TPS. Finally, more recent and impressive feature size was obtained by an enhanced version of TPS inspired by STED microscopy (Li et al. 2009). The principle of this technique will be described in detail in the next section. With 800 nm excitation wavelength, voxel of 40 nm height have been achieved, that represents λ/20. This spectacular result has to be compared with the voxel of 600 nm height obtained by using conventional TPS where excitation wavelength is set at 800 nm which corresponds to λ/1.33. Even if no experimental evidence has been shown for lateral resolution by this technique, λ/20 is also clearly achievable. Further insight of this new technique is addressed in the next subsection.
Improving spatial resolution of two-photon microfabrication by different strategies during the past decade. a) the famous microbull exhibiting 120 nm features size due to intrinsic properties of TPS (λ = 780 nm, λ/6.5;
In the recent past, the diffraction resolution barrier of fluorescence light microscopy has been radically overcome by stimulated emission depletion (STED) microscopy. Since its theoretically (Hell et al. 1994) and experimentally (Klar et al. 1999) birth, STED delivers nowadays routinely images of biological samples with a resolution down to 10-20 nm. Due to its great achievements in life-science, STED and more globally super resolution microscopy have been recognized as the “method of the year” in 2008 in Nature Methods. Finally, world record lateral resolution down to 5.6 nm using visible light has been reported by Hell’s group (Rittweger et al. 2009). In STED, a first short laser pulse is used to bring fluorescent molecules in their excited state. In order to de-excite these chromophores through stimulated emission, a second laser pulse (usually at longer wavelength to avoid one photon absorption) has to occur after vibrational relaxation of the excited electronic state but before fluorescence occurs i.e. few ps to few ns later than the first laser pulse. The efficiency of the deactivation strongly depends on the intensity and the wavelength of the depletion pulse, as well as the time delay of depletion pulse versus the excitation pulse. The precise localization of fluorescence arises from the spatial phase shaping of the depletion beam. The latter causes de-excitation to occur everywhere except in a region at the center of the original focal volume. The idea to translate these groundbreaking concepts to optical lithography has been evoked in 2003 (Hell et al. 2003), but first demonstration applied to TPS has been published only 6 years later (Li et al. 2009). Nowadays, in the frame of STED-like optical lithography, 3 different depletion mechanisms have been reported in the literature. In all cases, two laser beams are used, one for excitation and a second one for deactivation as illustrated in Figure 5. Whereas the excitation beam allows the formation of species (i.e radicals) which initiate the polymerization, the phase shaped deactivation beam allow photophysically or photochemically inhibition of the reticulation around the central excited zone. Depending of the phase mask used, the voxel can be reduced along the axial direction (bottle-beam shape, see Figure 5B) or along the lateral direction (donut shape).
A. Schematic experimental set-up for STED-like optical lithographies. B. False-color, multiphoton-absorption–induced luminescence images of the cubes of the PSFs of the excitation beam, the phase shaped deactivation beam, and both beams together. Adapted from reference (
Among the three STED-like optical lithography methods, the so called two-color photoinitiation / inhibition lithography (2PII) is the only one based on a
The first attempt to translate the spectacular optical resolution from STED microscopy to lithography has to be attributed to Fourkas’s group (Li et al. 2009). Contrary to 2PII, deactivation is based on a
Thanks to the longer lifetime of the intermediate, a second configuration has been successfully used: depletion effect has been performed with continuous laser which cancel the need to control the delay between excitation (800 nm) and depletion (800 nm) beams. By using the later configuration and a bottle beam profile for the depletion beam, voxels of 40 nm height have been achieved. In the frame of this study, the depletion effect is so sensitive that the excitation beam can induce itself the deactivation. Interestingly, for a RAPID compatible photoinitiator, the linewidth increases at faster scan speed. In the opposite, in conventional photoinitiator, faster scan and consequently weaker exposure dose yields to decrease of the linewidth. This opposite effect for RAPID photoinitiator is explained by the depletion effect done by the excitation beam. Indeed, slow down the scan speed allow to excited photoinitiator to be deactivate. Smartly, the authors have taken benefit of this unexpected dependence towards scan speed to propose system insensitive to abrupt change of trajectory (Figure 6). In this case, photopolymerizable system combines both conventional and RAPID photoinitiators. Finally, according to conclusions of Wegener and coworkers (Fischer et al. 2012), because the depletion time-constant is between 15 and 350 ms in case of RAPID lithography, writing speed is comprised between 30 µm.s-1 to 150 µm.s-1. While this speed corresponds to typical speeds used in academic field, this slow speed might be an obstacle for its use in industry (see section 4.2).
A, B Large and close view of fabrication of sinusoidal structures with a conventional photoinitiator, respectively. C, D Large and close view of fabrication of sinusoidal structures with a RAPID photoinitiator, respectively. E, F Large and close view of fabrication of sinusoidal structures with a mixture of conventional and RAPID photoinitiators, respectively. Reproduced from reference (
For efficient STED, molecules have to present large oscillator strength between the ground state S0 and the first excited sate S1 to favor later depletion. Because of their use in fluorescence microscopy, such type of molecules has also to exhibit strong fluorescence quantum yield. But this relatively long lifetime excited state (usually few ns) allows the depletion to take place.
In contrary, common photoinitiator exhibit low oscillator strength and are designed to present efficient intersystem crossing (ISC) yielding to reactive species which can give rise to radical and further to polymerization. Moreover, excited state lifetime of photoinitiator is usually found to be around 100 ps which would result in the use of high power pulses shorter than 100 ps to induce depletion. Unfortunately, with this large pulse energy, depletion could be competed by multiphoton absorption leading to undesired polymerization. Compare to previous STED-like lithography technique, STED lithography requires the use of two distinct-wavelength short pulse lasers for both excitation and deactivation. In addition, pulse delay between the two beams has to be controlled carefully. While this configuration seems more constraining than 2PII and RAPID, higher scan speed (around 5 m.s-1) is expected (Fischer et al. 2012).
STED lithography experiment has been attempted with isopropylthioxantone (ITX) as a photoinitiator. But further experiments such as pump-probe experiment have shown that the STED mechanism was not the main depletion pathway (Wolf et al. 2011) as claimed in previous work (Fischer et al. 2010). Based on the pump-probe experiment in ethanol (Wolf et al. 2011), a better suitable candidate appears to be the dye (7-diethylamino-3-thenoylcoumarin) (DETC) since stimulated emission was clearly demonstrated.
However, because the S1 lifetime of a molecule usually depends on the solvent, a detailed and adapted pump probe study of DETC in the monomer has been realized (Fischer et al; 2012). While it has been shown that stimulated emission was not the only possible pathway, it was the first clear evidence of the possibility to perform true STED lithography. Fast and slow components of depletion were observed to exhibit opposite wavelength dependencies which indicate the existence of two distinct depletion mechanisms (Figure 7A). The fast component was ascribed to stimulated emission depletion, since its spectral dependence fits nicely the spectrum of the stimulated-emission (SE) cross-section. The slow component was not assigned in the frame of this study and further studies have to be accomplished to unravel this point. It has to be noted that at longer wavelength the relative strength of the fast component is weak regarding those of slow component.
Interestingly, STED lithography pump-probe experiment with the same photopolymerizable system, but with a depletion wavelength set at 642 nm has been performed by Harke and coworkers (Harke et al. 2012). In this experiment, pulse delay experiment has been realized, but no evidence of STED has been observed. Nevertheless, the unique component of depletion effect presents a timescale in the same range as typical triplet lifetime. The authors assume that the depleted excited state is not the singlet state S1 as in STED, but the triplet state T1. Besides, one possible and well-known pathway to deplete the triplet state proposed by the authors is the reverse intersystem crossing (ReISC).
Until now, only 3 pump-probe experiments have been performed by two distinct groups. Even if these studies lead to different observations and conclusions, it can certainly be explained by the use of different experimental conditions (depletion wavelength, pulse delay, excitation wavelength). Thus results illustrate the need to improve the knowledge in STED-like lithography process to define requirements list for efficient STED lithography photoinitiators.
A. Spectral sensitivity of the different processes for 10 mW depletion power. Due to pronounced single photon absorption, depletion is not possible in grey area. B. schematic illustration of the different pathway involved in the depletion of DETC. Reproduced from references (Fischer et al. 2012 and
The recent progresses of STED-like lithography have allowed new very promissing applications in photonics. 3D polarization-independent carpet cloak for visible light have been fabricated for the first time which demonstrate the unique ability of TPS as 3D fabrication method (Fischer et al. 2011). In this case, 3D photonic crystal exhibits distance between two lines of 375 nm and 175 nm in axial and lateral directions, respectively. This has to be compared with the 510 and 210 nm values found in the frame of conventional TPS for axial and lateral directions, respectively. Whereas noticeable improvement has been shown for axial resolution, the gain in lateral resolution is less remarkable. This is explained by the use of a bottleneck beam shaping for the depletion beam. While combination of bottleneck and donut phase masks could be used to shape the beam and so to improve simultaneously lateral and axial resolution, it may be interested for specific applications to use only bottleneck beam since it can induce a more spherical voxel (ratio of 2.1 in this example).
Owing to its current and unique fabrication ability and its potential ability regarding to high-throughput (5 m.s-1 scan have been predicted for pure STED lithography), an exponential increase of works on this becoming hot topic is expected in the near future.
To conclude about these STED-like section, it has to be mentioned that because of the relative novelty of STED-like optical lithographies (since 2009) and the fact that until now only 5 groups in the world have shown their skills to design such type of experiment, new insights are expected to appear rapidly in the near future. Interdisciplinary research has to be lead in order to propose a STED lithographic set-up with the dedicated optimized materials for few tens of nanometers in three dimensions. This will give birth of the first 3D arbitrary nanofabrication technique.
An alternative method to improve the resolution is to add a quencher in the photopolymerizable system. In presence of quencher, the photoinduced radical can be quenched which consequently prevents polymerization. By this way, it has been shown that the radical diffusion can be controlled resulting in the confinement of the polymerization region (Tanaka et al. 2005). However, in this reported work, the concentration of quenching molecules has to be much larger than those of radical produced in order to result in an effective deactivation. Therefore, Lu and coworkers designed a novel photoinitiator with a radical quenching moiety (Lu et al. 2011). In this case, an intramolecular radical deactivation can occur leading to a more efficiently control of radical diffusion than in the case of an intermolecular one. As a result, finer features can be formed. However, by these methods no sub-diffraction gaps between two lines have been demonstrated, and only small effects on the feature size have been observed. More recently, Sakellari and coworkers proposed another route to control the extent of the polymerization region (Sakellari et al. 2012). From their point of view, since a nondiffusing quencher results only in an increase of the polymerization threshold, they proposed to add a mobile quencher. Contrary to other works (Tanaka et al. 2005, Lu et al. 2011) where the quencher plays its inhibitor role by interacting with the photoinitiator or the generated radical, the quencher used in this work is an amine-based monomer. It interacts with other monomer or become part of the polymer backbone without compromising the mechanical stability of the structure. Last but not least, the amine functions allow a future metallization or further chemical functionalization. By this method, fabrication of woodpile structures with 400 nm intralayer period has been achieved for the first time with a
A. Microstructures realized by intramolecular quenching method. Scale bars are 5 µm. B. SEM images of photonic crystal fabricated by diffusion assisted high resolution TPS and diffraction pattern generated by the photonic device. Reproduced from references (λexc: 780 nm; average power : 7.70 mW; writing speed: 66 µm.s-1,
Recently, 40 nm feature size has been obtained by combining chemical and optical approaches (Emons et al. 2012). The measurement of feature size has been performed by suspending bridge method. From a chemical point of view, the authors have demonstrated that the addition of a crosslinker (pentacrylate derivative) allow a resolution enhancement of a factor 2 (150 nm feature size versus 82.5 nm with a 50 fs pulse laser). As expected, the addition of crosslinker should play a positive effect on the resolution since it allow to the suspended line to be maintained during the development step. In the other hand, an additional resolution enhancement has been achieved by using shorter laser pulse: the use of 8 fs instead of 50 fs allows improving feature size of the line from 150 nm to 90 nm for photoresin without cross linker.
In addition to the above optical and chemical tricks, further improvement of resolution can be achieved by other minor technical development like high hybrid optics diffractive (Burmeiter et al. 2012).
To conclude, recent technical developments of TPS open the doors to strong improvement of the resolution. Even if the diffraction limit has been beaten both in lateral and axial direction thanks to different methods such as the STED-like lithography or the diffusion-assisted high resolution TPS, effort research has to be focus on new photopolymerizable system to benefit completely of the intrinsic resolution achievable by the different techniques. For STED-like lithography, optimization of the photopolymerizable system should lead to feature size around 10 nm. Finally, when comparing the different technique, a particular attention has to be taken into account concerning the maximum scan speed for future use in industry. This will be the object of the next section.
Despite the possibilities to fabricate 3D objects with sub-100 nm features in a single step, TPS use is as far as we know limited to scientific community. Indeed, owing to the point-by-point writing process, TPS appears as an extremely slow technique for mass production in industry. Typical writing speed range in academic research goes from few µm.s-1 to few mm.s-1 which has to be compared with the few m.s-1 used in industry for different laser process (ablation, laser control, rapid prototyping by inspired-stereolithography methods,…). Until 2003, as for resolution, the research effort for increasing the throughput of TPS was mainly focused to the synthesis of high-efficiency photoinitiators. Nevertheless, in the past decade several research groups have proposed various strategies to break down this technological bolt.
As an attempt to solve this problem, Sun et al. demonstrated the impact of the laser beam trajectory over the manufacturing time by significantly increasing the fabrication efficiency of 90% when using CSM (contour scanning method, also called vector mode) mode rather than RSM (raster scanning method) mode. As shown in Figure 9, in the raster mode, all voxels which constitute the volume whose contains the microstructure are scanned. In case of CSM mode, only the voxels defining the surface of the microstructure are scanned. As a result, it took 3 hours or 13 minutes to manufacture the micro-bull using RSM and CSM mode respectively (Sun, 2003). Further information on the role played by trajectories can be found laser and photonics review (Park et al., 2009).
Two fabrication strategies based on scanning mode: a) Raster mode, b) Vector mode (or contour mode), c) and d) SEM images of a microbull structures using RSM and CSM respectively. Reproduced from reference
For applications where the objects have to be completely filled such as microlens, an additional UV exposure step is done. However cracks in the structure might occur to leading to a dramatic decrease of desired performance.
To address the low-throughput of the method, LaFratta et al. have proposed to use TPS in tandem with soft lithography technique known as microtransfer molding (Xia et al. 1998). By this way, high-fidelity molds of structures with extremely high aspect ratios and large overhangs have been realized (LaFratta et al. 2004, Figure 10). Besides, in the frame of this work, more than ten replicas have been made from a single master without any significant deterioration of the resulting structures. Even if this technique have been applied to more complex structures such as arches or coils (LaFratta et al. 2006), a range of geometries or objects such as closed traps or micropumps are still impossible or currently too challenging to replicate using microtransfer molding. Finally, from our knowledge, no improvement or additional example of this technique has been recently reported in the literature, underlying the difficulties to separate the molder to the master without damage. Recent advances in soft lithography might facilitate the delivering step.
a) and b) SEM images of master and replica array of towers respectively, c) and d) SEM images of master and replica of coil respectively. Scale bars are 10 µm. Reproduced from reference
Another solution for boosting fabrication speed while avoiding geometric limitations associated with molding is the use of multi-focal strategy. This technical innovation has been first demonstrated by Kawata and coworkers in 2005 (Kato, 2005). By combining TPS with a microlens array, more than one hundred identical and individual 3D objects have been written simultaneously resulting in a two-order increase in the fabrication yield compared to single-beam TPS (Figure 11). In 2006, Kawata et al. succeed to write in parallel more than 700 hundred identical structures (Formanek, 2006) illustrating the high potential for large scale production.
a) and b) examples of two- and three-dimensional fabrication by mean of microlens array.
Recently, Ritschdorff et al. proposed a more general approach of multi-focal TPS to allow parallel but independently writing of different objects (Ritschdorff et al. 2012). Indeed, until this work, advanced TPS based on multi-focal strategy was dedicated to the creation of identical replicas or to the fabrication of a single structure with many identical sub-units. In the frame of this recent work, a proof-of-concept has been illustrated with the construction of biocompatible networks by using two independent sub-beams. In order to control each beam separately, the main beam is directed through a dynamic mask (typically a spatial light modulator). To extend this appealing strategy to numerous parallel and independently sub-beam, high-power lasers are required. Additionally to the increase of the fabrication’s speed, this work opens the doors to numerous and more flexible applications. For example, one could imagine making unlimited modifications into microfluidic systems, but more interestingly, generation of pattern with different exposure time will result to display gradients in chemical functionality, mechanical functionality or porosity which play a key role in tissue engineering.
However the promising potential of multi-focal TPS for speed up fabrication is quite obvious, two points have to be taken in consideration to use it as a tool in laboratory or industries. The first point concerns the use of an expensive amplified femtosecond laser in order to provide enough energy after each lens or dynamic mask. In addition, the laser beam intensity distribution has also to be perfectly controlled to deliver the same amount of energy for each lens and to fabricate uniform structures. It has to be mentioned that though this point may be a brake for scientific community, this is clearly not the case for its use in industry. A more serious issue with parallel fabrication is the precise control of alignment of the hundred forming laser beams with respect to the plan of the substrate. A tilt of less than 1° of the substrate will result in the fabrication of inhomogeneous structures which is unacceptable from a metrology point of view in industries.
In the literature, usual process speeds of several 100 µm.s-1 are reported with sub-100 nm resolution. More rarely, mm.s-1 can be reached while keeping a submicrometric resolution. Until recently, the fastest demonstration of microstructures with micrometric resolution has been realized by Fourkas’s group by using a very sensitive photoinitiator (Kumi et al. 2010). In the frame of this work, speed of 1 cm.s-1 was reported.
Since march 2012, a 300-micrometer long model of a Formula 1 race car has been fabricated by TPS in only four minutes while keeping micrometric resolution. Thus spectacular result means that a process speed of 5 m.s-1 is involved, which is the same order of other laser process used in industry. A video of the construction can be found on the website of the Vienna University (Vienna, 2012). Unfortunately, certainly due to economic interests, little information can be freely accessed. According to their website, the increase in speed results from efforts from a chemical and mechanical point of view.
After the pioneers works on TPS (Maruo, 1997), the research efforts were mainly focused on the synthesis of high efficient photoinitiators and materials in order to respectively speed up the writing process and to improve the mechanical, optical or chemical properties of the resulting 3D objects. Thanks to both the versatility of photopolymerizable systems and to the possibility to incorporate additional materials into the structures, TPS has attracted considerable attention over the past decade leading to enough mature technology. Indeed, despite the novelty of TPS, this is now daily used for broad range of applications such as creation of 3D components for microfluidic systems, tissue scaffolding, optical components, and so on. Besides, only 10 years after the first instance of 3D microstructures created by TPS, several companies have developed commercial 3D microfabrication set-ups which have supported the widespread of the technique in various research fields.
Recently, the rapid technical development of TPS provided much better structural resolution and high-throughput. The combination of all these improvements in a single commercial set-up will certainly boost the use of TPS in industry. From resolution point of view, the Abbe diffraction limit in optical lithography has been overcome by using and/or adapting a concept called STED originally from optical microscopy. The latter is already commercialized since 2005 by several well-known optical microscopy companies and is well expanded in life sciences. Interestingly, even if both in optical microscopy and lithography the diffraction limit has been beaten thanks to the STED principle, record for lateral spatial resolution in optical lithography (175 nm) is still far away from thus in optical microscopy (5.6 nm). In order to obtain comparable resolution, further investigations are required to enhance the comprehension of the photophysical and photochemical mechanism underlying the STED lithography. In particularly, a better understanding will give a list of criteria for novel photoinitiators devoted to this promising technique.
Concerning the throughput of the technique, speed of 5 m.s-1 has been recently announced by an European consortium (march 2012). For comparison, this speed is quite close to those used in conventional process in microelectronics industry such as control or ablation process (10 to 50 m.s-1). Such promising advances should allow overcome limit for mass production and consequently should reinforce the highly potential of TPS for industry.
To conclude, this technology opens up new perspectives in a wide range of applications such as rapid prototyping of micro- and nanofluidics, small-scale production of microoptics components, or 3D frameworks for cell biology. Finally, owing to its currently fast expansion and to the versatile science involved in all the chain, TPS appears as a fantastic and so appealing field of research for the next decades.
Agence Nationale pour la Recherche (ANR - Projects 2-PAGmicrofab ANR-BLAN-0815-03, NANOQUENCHING and NIR-OPTICS), CNRS and Région Alsace are gratefully acknowledged for financial supports.
Graft-versus-host disease (GVHD) is a debilitating complication that can determine the prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) and subject 40–60% of HSCT recipients to a risk of death and disability [1]. GVHD is composed of acute GVHD (aGVHD) and chronic GVHD (cGVHD). For the classification of the 2 types of GVHD, the classifier should be clinical manifestations instead of time after HSCT [2]. However, in many cases, aGVHD appears within 100 days after HSCT and causes severe inflammation mostly in the skin, gastrointestinal tract, and liver [3]. cGVHD generally occurs systemically 6 months or later after HSCT, and its symptoms are similar to those of autoimmune diseases [4]. Complex interactions between donor and host immune cells are implicated in the pathogenesis of GVHD. It is thought that aGVHD is induced primarily by donor T cells’ cytotoxic responses against host tissues through recognition of host polymorphic histocompatibility antigens [5]. On the other hand, the mechanisms of cGVHD are more complicated and still poorly understood [6]. Although the use of corticosteroids alone or in combination with immunosuppressive agents is the recommended first-line strategy for the treatment of GVHD, its efficacy is not satisfactory [3, 7]. The prevalence of allogeneic HSCT for the treatment of hematologic diseases has increased the need for the development of efficacious second-line therapies which can mitigate symptoms of GVHD without compromising a graft-versus-leukemia effect, where donor T cells eliminate host leukemia cells. To date, various signaling pathways and pathogenic events in the context of GVHD have been intensively investigated. As a result, several FDA-approved drugs for GVHD have recently emerged. This chapter concisely summarises therapeutic targets and newly emerging drugs for the 2 forms of GVHD with the goal to facilitate the development of novel GVHD treatments for human use.
aGVHD can occur after the engraftment of donor-derived cells in the transplant recipient [8]. Symptoms of aGVHD can develop within weeks after the transplantation [9]. It has been believed that aGVHD can primarily affect the skin, gastrointestinal (GI) tract, and/or liver [10]. HSCT recipients can manifest rash, increased bilirubin, diarrhea, and vomiting [11]. Most recently, mounting evidence suggests that other organs such as the central nervous system, lungs, ovaries and testis, thymus, bone marrow, and kidney can be susceptible to aGVHD [12].
Clinical manifestations of cGVHD are different from those of acute GVHD. The onset of chronic GVHD can be divided into the following 3 cases: (1) occurring when aGVHD is present, (2) emerging after a period of resolution from aGVHD, and (3) developing de novo [13]. Immune dysregulation and absence of functional tolerance are characteristic of cGVHD, and symptoms of cGVHD are reminiscent of those of autoimmune disorders [13]. Clinical presentations of cGVHD can be as follows: (i) rash, raised or discolored areas, skin thickening or tightening, (ii) dry eye or vision changes, (iii) dry mouth, white patches inside the mouth, (iv) diarrhea and weight loss, (v) shortness of breath due to lung disorders and (vi) abnormal liver function [14]. It was challenging for clinicians to reach an agreement on the diagnosis, the timing of treatment, and how to grade cGVHD [15]. In order to overcome these difficulties, the National Institute of Health (NIH) consensus created diagnostic criteria for cGVHD in 2005 and revised the criteria in 2014 [16, 17]. The authors considered the severity of involvement of the skin, mouth, eyes, gastrointestinal tract, liver, lungs, joint fascia, and genital tract in order to define manifestations of cGVHD in its target organs and establish a scoring system.
Corticosteroids are used with or without immunosuppressive drugs as the first-line therapy for aGVHD and cGVHD in clinical settings [3, 7, 18, 19]. However, approximately 50% of patients who receive steroid therapy will be resistant to it, although mechanisms of steroid resistance remain to be elucidated [3, 7, 18, 19]. In addition, corticosteroid therapies also cause various undesired effects such as diabetes, obesity, osteoporosis, hypertension, glaucoma, and liver damage [20]. Thus, medical settings are in need of effective treatments of steroid-refractory aGVHD and cGVHD [3, 7, 18, 19].
GVHD has a complex pathophysiology, which initially begins with damage to host tissues by chemotherapy and radiation therapy before allogeneic HSCT (Figure 1) [21]. Due to this, damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), and inflammatory cytokines are released [22]. These stimuli activate host dendritic cells (DCs), leading to the expression of major histocompatibility complex class I (MHC-I) and class II (MHC-II) on the host DCs [22]. The mature host DCs activate donor-derived T cells in the graft [22]. The activated donor T cells migrate to aGVHD-susceptible organs and promote the excessive production of pro-inflammatory cytokines such as interferon (IFN)-γ and interleukin (IL)-17 [23, 24]. It results in abnormal inflammation and tissue damage [23, 24]. While it is believed that donor-derived CD4+ and CD8+ T cells play a pivotal role in mediating aGVHD [25], several other types of immune cells are reportedly involved in the pathogenic process of aGVHD [26]. Neutrophils contribute to the development of intestinal aGVHD [27]. A previous report suggests that neutrophils in the ileum migrate to mesenteric lymph nodes, presenting antigens on their MHC-II and promoting T cell expansion [28]. Donor monocyte-derived macrophages with potent immunological functions are implicated in the pathophysiology of cutaneous aGVHD by secreting chemokines, stimulating T cells, and mediating direct cytotoxicity [29, 30]. In contrast, regulatory T cells (Tregs) are thought to serve a suppressive role in aGVHD without significantly reducing the graft-versus-leukemia (GVL) effect [31, 32]. Recent reports suggest that donor-derived natural killer (NK) cells can have an inhibitory effect in aGVHD by promoting the depletion of allo-reactive T cells while showing the GVL effect [33]. A recent study indicates that the occurrence and severity of aGVHD could be associated with the disordered reconstitution of CD56high NK cells [34].
The overview of aGVHD pathogenesis. The preconditioning regimen causes tissue damage. It generates DAMPs, PAMPs and proinflammatory cytokines such as TNFα, IL-1β and IL-6, which activates host APCs. The activated APCs present antigens to donor T cells, and the activated T cells infiltrate aGVHD target organs and produce an excessive amount of IFNγ and IL-17, leading to abnormal inflammation and tissue damage. This figure is created with BioRender.
While mechanisms of cGVHD are still incompletely understood, recent evidence suggests that there are several observations characteristic of cGVHD (Figure 2) [35]. The thymus is damaged due to the conditioning regimen and/or the prior occurrence of aGVHD, leading to impaired negative selection of alloreactive CD4+ T cells [36]. Alloreactive T cells are activated by antigen-presenting cells (APCs), resulting in their expansion and polarization toward type 1, type 2, and type 17 helper T (Th1, Th2, and Th17) cells [35]. These immune deviations lead to the production of proinflammatory and profibrotic inflammatory cytokines such as IFNγ, IL-6, IL-17, IL-4, and transforming growth factor β (TGFβ), which skew macrophages and fibroblasts towards proinflammatory and/or profibrotic phenotypes [35]. Consequently, inflammation and fibrosis are induced in cGVHD target organs [37]. The damaged thymic epithelial cells (required for the generation of Tregs as well as the negative selection) also cause a decrease in the number of Tregs [38]. Furthermore, the dysregulation of B cells causes autoreactive B cells to arise and produce autoreactive antibodies [39]. The emergence and activation of autoreactive B cells presumably stem from B cell exhaustion induced by aberrant levels of B cell-activating factor (BAFF) in the lymphoid microenvironment [40, 41].
Overview of cGVHD pathogenesis. The thymus is damaged due to the preconditioning regimen and/or aGVHD. Due to the damage, the negative selection of alloreactive T cell is impaired. Alloreactive T cells are polarised into Th1, Th2 or Th17 cells. Th1 cells produce IFNγ, which drives macrophages to an M1-like phenotype to promote inflammation. IL-4, IL-10 and TGFβ produced by Th2 cells facilitate macrophage differentiation into an M2-like phenotype. Activation and proliferation of tissue fibroblasts are induced by (i) TGFβ from Th2 cells, (ii) PDGFα and TGFβ from M2-like macrophages and (iii) IL-6 and IL-17 from Th17 cells, leading to collagen production and fibrosis. B cells are activated by IL-6 and IL-17 from Th17 cells, and the alloreactivity of B cells is presumably induced by an excessive amount of BAFF. As a result of the above events, systemic inflammation and fibrosis are induced, and autoimmune-like manifestations are observed. This figure is created with BioRender.
When the T cell receptor (TCR) interacts with an MHC-antigenic peptide complex, it induces molecular and cellular changes in T cells [42]. A wide range of signal transduction pathways in T cells is stimulated due to this interaction, leading to the activation of a variety of genes [43]. Effector enzymes such as kinases, phosphatases, and phospholipases are involved in the TCR signaling pathways, which are integrated by non-enzymatic adaptor proteins acting as a scaffold for interactions between proteins [42]. These intracellular signaling pathways can determine the features of immunity mediated by T cells [44].
The B cell receptor (BCR) complexes on inactivated B cells act as self-inhibiting oligomers [45]. The BCR signaling pathways are initiated, when BCR is bound to an antigen and induces actin-mediated nanoscale recombination of receptor clusters [46]. Due to this event, the BCR oligomers are opened and the ITAM domains are revealed, resulting in the transduction of intracellular signals which are crucial for B cell development, activation, proliferation, differentiation, and antibody production in health and disease [47].
In 2017, FDA approved ibrutinib, which targets B cells and T cells, for the treatment of cGVHD. Ibrutinib was the first FDA-approved drug for steroid-refractory cGVHD, and it was a significant milestone for GVHD research [48]. Ibrutinib is reported to modulate the functions of B cells and T cells by potently inhibiting Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) [49], which are involved in the B cell signaling and T cell signaling pathways, respectively. Treatment of cGVHD-affected recipients with ibrutinib resulted in decreased serum-autoantibodies and B-cell proliferation [50]. Data from the clinical trials show that symptoms of cGVHD improved in 67% of patients treated with ibrutinib [48].
The Purinergic signaling pathways play a crucial role in a range of physiological systems including the immune system. In the purinergic signaling pathways, extracellular purine nucleosides and nucleotides such as adenosine and adenosine triphosphate (ATP) are used as signaling molecules that mediate the communication between cells through the activation of purinergic receptors [51]. There are four types of P1 (adenosine) receptors (A1, A2A, A2B, and A3). P2 receptors are subdivided into P2X and P2Y [52]. P2X receptors have seven subtypes (P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7), and P2Y receptors have 8 subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) [52].
As demonstrated by several studies using mouse models of aGVHD, extracellular ATP is augmented in aGVHD-affected mice, and purinergic signaling is implicated in the pathogenic process of aGVHD (Figure 3) [53]. The conditioning regimens prior to allo-HSCT can induce tissue damage, leading to the release of DAMP molecules including ATP, which activates purinergic signaling [53]. The involvement of extracellular ATP is evidenced by the fact that the injection of the soluble ATP diphosphohydrolase (ATPDase) can reduce inflammation in aGVHD target organs and the serum level of IFNγ [53, 54].
Link between GVHD and the therapeutically targetable purinergic signaling pathways. In aGVHD, ATP is produced due to tissue damage. Host APCs and donor T cells can be activated by the P2X7 receptor, which results in the progression of aGVHD. The activation of donor Tregs can also be induced by the ATP-activated P2X7 receptor, which leads to the reduction of Treg survival and the progression of aGVHD. CD39 and CD73 on donor Tregs can degrade ATP to adenosine. Adenosine can activate the A2A receptor on donor T cells, which culminates in the decrease in the number of CD4+ and CD8+ T cells and the reduction of aGVHD. In cGVHD, ATP is also released because of tissue damage and may promote fibroblast-to-myofibroblast transition through the ATP-activated P2X7 receptor, leading to the augmented collagen production and the progression of tissue fibrosis. In contrast, the ATP-activated P2Y14 receiptor may prevent cellular senescence in macrophages and mitigate cGVHD. This figure is created with BioRender.
Evidence suggests that; (i) P2X7 is a crucial P2X receptor in the development of aGVHD after the release of extracellular ATP, (ii) the expression of the P2X7 receptor is elevated in PBMCs in aGVHD patients, (iii) the liver, spleen, skin, and thymus in aGVHD-affected mice show the increased expression of the P2X7 receptor, (iv) the ATP-induced the activation of the P2X7 receptor on host APCs can facilitate the stimulation, proliferation, and survival of donor T cells during aGVHD and (v) the P2X7 activation on host APCs may be associated with the expression of microRNA mir-155 [53, 55, 56, 57].
While the host P2X7 receptor is shown to play an integral role in the development of aGVHD, the donor P2X7 receptor is also a contributor to this disease. Evidence suggests that (i) the activation and proliferation of donor CD4+ T cells and (ii) the metabolic fitness of donor CD8+ T cells are also enhanced by the activated donor P2X7 receptor [58, 59]. In addition, the activation of P2X7 on donor Tregs can reduce their suppressive ability and stability of Tregs, promoting their conversion to Th17 cells [60].
Inhibition of the P2X7 receptor is reported to mitigate aGVHD in conventional and humanised mouse models of aGVHD. Treatment of allogeneic HSCT recipient mice with the P2X7 inhibitor pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) can increase the survival rate and the number of Tregs, and reduce the serum level of IFNγ and histological aGVHD [53, 54]. Administration of the P2X7 inhibitor brilliant blue G (BBG) to allogeneic HSCT recipient mice can also prevent weight loss and reduce inflammation in the liver and the production of inflammatory cytokines [56]. Furthermore, a crystal structure of the P2X7 receptor in complex with the inhibitor AZ10606120 has been reported (PDB: 5U1W) [61], and this structural information could be useful for the design and synthesis of novel P2X7 inhibitors which can be used in clinical settings.
The P2Y2 receptor is also reported to contribute to the pathogenesis of aGVHD [22, 57]. Evidence indicates that the number of cells expressing the P2Y2 receptor is increased in the intestinal tract in aGVHD-affected mice and that the increased P2Y2 expression enhances the severity of intestinal aGVHD [62]. Of note, knock-out allogeneic HSCT recipient mice of the P2Y2 receptor show an increased survival rate and decreased cytokine levels [62]. However, in the case where the P2Y2 receptor in donor cells is knocked out, no such improvement is observed [62]. In contrast, literature precedent suggests that the activation of the P2Y2 receptor can promote the migration of Tregs to sites of inflammation and thereby mitigate aGVHD [63]. Due to the dual functions of the P2Y2 receptor, targeting the P2Y2 receptor for the treatment has been challenging and there have been no reports about systemic injection of P2Y2 inhibitors/activators for the treatment of aGVHD [64].
While ATP is released in damaged tissues in allogeneic HSCT recipients and promotes inflammation, it is also degraded to adenosine by CD39 and CD73 [53]. In particular, a murine study indicates that CD39 and CD73 are highly expressed on CD150high Tregs [65]. As shown by a study using a mouse model of aGVHD, inhibition of CD39 and CD73 with adenosine 5′-(α,β-methylene)diphosphate (APCP) leads to the increase in the number of splenic CD4+ and CD8+ T cells, the serum levels of IFNγ and IL-6, and the mortality rate [66]. These data suggest that CD39 and CD73 play an alleviatory role in aGVHD. Evidence demonstrates that the production of adenosine by CD39 and CD73 results in the activation of the adenosine A2A receptor [66, 67, 68]. The activated A2A receptor can induce the expansion of donor Tregs and thereby mitigate aGVHD-induced inflammation [66, 67, 68]. The blockade of A2A with the antagonist SCH58261 exacerbates aGVHD by elevating the levels of TNFα, IFNγ, and IL-6 and the number of CD4+ and CD8+ T cells in sera [66]. In agreement with this report, the A2A agonist ATL-146e reduced weight loss and mortality in aGVHD-affected mice by (i) increasing serum IL-10 and reducing serum IFN-γ and IL-6, (ii) precluding the activation of splenic CD4+ and CD8+ T cells, and the infiltration of T cells into GVHD target organs [67]. Other A2A agonists, ATL-370 and ATL-1223, are reported to exert similar therapeutic effects on aGVHD [68]. Moreover, a crystal structure of the A2A receptor in complex with the activator ZM241385 has been reported (PDB: 5WF5) [69], and this structural information could facilitate the creation of novel A2A activators which can enter the clinic.
Although there are few to no reports about a link between purinergic signaling and cGVHD pathogenesis, activation of the P2X7 receptor is reported to promote fibroblast-to-myofibroblast transformation and contribute to the development of fibrosis [70]. The activation of the P2X7 receptor enhances Ca2+ influx and skews fibroblasts towards a fibrogenic phenotype, leading to augmented collagen production [70]. Considering fibrosis is a significant hallmark of cGVHD, the investigation into a correlation between purinergic signaling and fibroblast activity in cGVHD could open up a new window for the elucidation of mechanisms of cGVHD and the development of novel drugs for cGVHD (Figure 3). Furthermore, stress-induced cellular senescence in immune cells is reported to play a detrimental role in the pathogenesis of ocular cGVHD [71, 72], and a murine study indicates that the P2Y14 receptor modulates stress-induced cellular senescence in hematopoietic stem/progenitor cells [73]. Given these findings, the P2Y14 receptor may be a regulator of stress-induced cellular senescence in cGVHD, and development of agonists of the P2Y14 receptor could benefit cGVHD patients.
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are regarded as a central communication junction for the immune system [74]. In the JAK/STAT signaling pathways, the cytoplasmatic kinase JAKs interact with the transcription factor STATs, and more than 50 cytokines and growth factors are involved in the JAK/STAT signaling pathways [75]. Mammals have 4 JAKs (JAK1, JAK2, JAK3, JAK4) and 7 STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) [76], and the dysregulated JAK/STAT signaling pathways contribute to a variety of human diseases, which makes this signaling a promising drug target [77].
In the early phase of aGVHD, tissue damage due to the preconditioning regimen and the disease results in the release of DAMPs, leading to the increased expression of MHC on APCs at the infusion of donor cells [78]. Donor T cells are activated via direct or indirect allorecognition, and the activated donor T cells produce IFNγ to initiate the JAK/STAT signaling pathways through IFNγ receptors [78]. The resultant increase in the expression of the chemokine receptor CXCR3 on T cells enhances their migration to aGVHD target organs, which promotes tissue damage [79].
While clinical manifestations of cGVHD are different from those of aGVHD, they have similarities in some aspects of the pathogenic processes [80]. The JAK/STAT signaling pathways in the context of cGVHD have been intensively investigated [81]. Tregs play a crucial role in the reduction of cGVHD, and JAK1/JAK2 signaling pathways are thought to negatively regulate the development and proliferation of Tregs, as indicated by the fact that JAK2 inhibition can promote Treg proliferation [82, 83]. Tissue fibrosis is highly problematic in cGVHD, and M2-like macrophages producing TGF-β are presumably a key player [84]. IL-10 skews macrophages towards an M2-like phenotype through the IL-10 receptor-JAK1/STAT3 pathway [85]. Given these reports, it would be intriguing to investigate an association between macrophages and the JAK/STAT signaling pathways in the development of cGVHD-induced fibrosis.
Many researchers have focused on the development of inhibitors targeting JAK/STAT signaling pathways for the treatment of aGVHD and cGVHD [81]. As demonstrated by several preclinical data, inhibition of the JAK/STAT pathways can mitigate GVHD without affecting the GVL effect [81] Most recently, the JAK1/JAK2 inhibitor ruxolitinib has been approved by FDA for aGVHD and cGVHD. In 2019, FDA approved ruxolitinib to treat steroid-refractory aGVHD patients 12 years or older [86]. The clinical trials show that the day-28 overall response rate (ORR) was 100% for Grade 2 aGVHD, 40.7% for Grade 3 aGVHD, and 44.4% for Grade 4 aGVHD [86]. In 2021, FDA approval was also granted to ruxolitinib for the therapy of steroid-resistant cGVHD patients 12 years or older [87]. The clinical trial data demonstrate that the ORR was 70%, and the median durations of response, which were calculated from first response to progression, death, or new systemic therapies for cGVHD, were 4.2 months [87]. A crystal structure of JAK2 in complex with ruxolitinib is provided in the PDB database (PDB: 6VGL) [88], and this structural information could be useful for the design of more potent and selective JAK1/JAK2 inhibitors. Another promising JAK1 inhibitor is itacitinib [89]. Data from a phase 1 clinical trial of itacitinib shows that 70.6% of steroid-refractory cGVHD patients were treated in a satisfactory manner [90]. Furthermore, two clinical trials of itacitinib for cGVHD have recently commenced (ClinicalTrials.gov identifier: NCT04200365, NCT03584516). It is of great medical significance that novel drugs targeting the JAK/STAT signaling will continue to be developed for the treatment of aGVHD and cGVHD.
The transcription factor nuclear factor kappa B (NF-κB) controls the expression of various genes important for the induction of inflammatory responses in innate and adaptive immune cells [91]. NF-κB is a family of heterodimers or homodimers generated from different combinations of the following 5 proteins: p65/RelA, RelB, c-Rel, p105/p50 (NF-κB1), and p100/p52 (NF-κB2) [92]. Among them, the p50/p65 complex is thought to be the most abundant form of NF-κB dimer [93]. When NF-κB is inactive, it is retained in the cytoplasm by the IκB family of inhibitors [94, 95]. In response to a wide range of stimuli such as the proinflammatory cytokines IL-1 and TNF-α, IκB kinase (IKK) is activated to phosphorylate the 2 serine residues of IκBα [96]. The phosphorylation causes the 26S proteasome to induce the ubiquitination and degradation of IKβ. Subsequently, NF-κB is translocated into the nucleus and triggers gene transcription, leading to the production of proteins necessary for immune responses [97]. Thus, NF-κB is regarded as a therapeutic target for the treatment of various inflammatory diseases.
The NF-κB signaling pathways have captured increasing attention from GVHD researchers. It has been reported that the activation of RelB in APCs contributes to the expansion of donor Th1 cells and subsequent alloreactivity, which leads to the development of aGVHD [98]. The NF-kB signaling pathways can be survival and proliferation signals and contribute to B-cell alloantibody deposition and germinal center formation, which play a critical role in the pathogenic process of cGVHD [99, 100].
Bortezomib is an FDA-approved drug for the treatment of multiple myeloma and is known to be an indirect inhibitor of NF-κB [101]. A murine study suggests that aGVHD can be prevented by treatment with bortezomib early after allogeneic HSCT [102, 103]. Bortezomib is undergoing clinical trials for aGVHD (BMT CTN 1203), and the phase1/2 study shows that bortezomib can be used in combination with tacrolimus and methotrexate in a tolerable immunosuppressive regimen after allogeneic HSCT [104]. Bortezomib can also be effective for the treatment of cGVHD. NF-κB inhibition with Bortezomib is suggested to cause apoptosis of germinal center B cells during reconstitution, leading to the decrease in donor-derived B cell numbers and BAFF expression [103]. With these promising data, clinical trials of bortezomib for the treatment of steroid-refractory cGVHD are in progress (NCT01158105). At present, there are no NF-κB inhibitors approved by FDA for aGVHD or cGVHD. Generally, direct inhibitors are superior to indirect ones in terms of selectivity. Thus, novel direct NF-κB inhibitors with high selectivity are greatly anticipated for the treatment of GVHD.
The Hedgehog signaling pathways are involved in the regulation of cell proliferation, survival, and differentiation [105], and its aberrant activation contributes to detrimental events such as the self-renewal and metastasis of cancer stem cells [106]. In the absence of Hedgehog ligand (Hh), the activation of Smoothened (SMO) is inhibited by Patched (PTCH) [107]. Subsequently, the activity of glioma-associated oncogene homolog (Gli) is suppressed by a protein complex mainly composed of a suppressor of fused (SUFU), which phosphorylates Gli and prevents it from entering the nucleus. In the presence of Hh, the binding of Hh to PTCH precludes the SMO inhibition mediated by PTCH [107]. Activated SMO prevents phosphorylation of Gli mediated by the SUFU complex, leading to the migration of Gli to the nucleus and the induction of downstream target gene expression [107].
Fibrosis is a highly problematic feature of cGVHD, and a profibrotic activity of Hedgehog signaling in patients and mouse models of cGVHD has been reported [108]. Overexpression of Hh, which is an inducer of the Hedgehog signaling pathways, is observed in human and murine sclerodermatous cGVHD [108]. The downstream processes of the Hedgehog signaling pathway cause overexpression of Gli-1 and Gli-2, particularly in fibroblasts [109]. The abnormal expression of Gli-1 and Gli-2 may result in the overproduction of collagen and the resultant pathologic fibrosis in cGVHD target organs [109]. Furthermore, the Hedgehog signaling is suggested to contribute to the increase of profibrotic M2-like macrophages in the cGVHD-affected skin [109].
There are several inhibitors of the Hedgehog pathways. Among others, sonidegib, vismodegib, and glasdegib are SMO inhibitors approved by FDA for the treatment of basal cell carcinoma [110]. These 3 SMO inhibitors are currently undergoing clinical trials for cGVHD therapy (NCT02086513, NCT02337517, NCT04111497). According to a report of the Phase-1 trial of sonidegib, where 17 steroid-refractory cGVHD patients participated, protein expression of hedgehog signaling pathway molecules was decreased by treatment with sonidegib as judged by immunohistochemical evaluation of the skin [111]. With respect to the creation of novel SMO inhibitors for the treatment of GVHD, Lacroix et al. found a potential SMO inhibitor by performing structure-based virtual screening of 3.2 million available, lead-like molecules against Smoothened and subsequent biological validations of the top-ranked compounds [112]. This information could benefit the design and synthesis of more potent and selective inhibitors of SMO.
While elucidation of mechanisms of cGVHD is still elusive, chronic inflammation is characteristic of cGVHD [113]. Senescent macrophages contribute to ocular cGVHD in mice, and gray eyebrows, skin wrinkles and conjunctival cancer are observed in human cGVHD [71, 114]. These findings suggest that ageing in donor- and recipient-derived cells is induced in cGVHD [71]. Evidence suggests that chronic inflammation and age-related diseases are associated with the elevation of endoplasmic reticulum (ER) stress [115, 116]. Mukai et al found that ER stress was increased in organs affected by cGVHD in mice [117]. Treatment of cGVHD-affected mice with the known ER stress reducer 4-phenylburyric acid (PBA) resulted in mitigation of systemic inflammation and fibrosis induced by cGVHD [117]. Of note, PBA is approved by FDA for the treatment of urea cycle disorders, and its safety was proven [118]. Investigation at the cellular level indicates that ER stress contributes to fibrosis as well as inflammation induced by cGVHD. Elevated ER stress caused (i) the dysregulation of lacrimal-gland-derived fibroblasts and (ii) abnormal production of MCP-1/CCL2, IL-6, and connective tissue growth factor (CTGF) [117]. Suppression of ER stress with PBA reduced their abnormal production of the inflammatory and fibrotic molecules [117]. In addition, ER stress induced by cGVHD skewed splenic macrophages towards an M2-like phenotype, and treatment of them with PBA promoted their differentiation into an M1-like phenotype [117]. Several reports also indicate that the augmentation of M2-like macrophages is implicated in the progression of cGVHD [84, 119, 120]. M2-like macrophages are thought to contribute to the pathogenesis of fibrosis-associated diseases [121], and it seems to be the case with cGVHD. As these analyses were performed in a bulk population, further investigation will be needed. Macrophages and fibroblasts are known to be heterogeneous populations [122, 123, 124, 125]. In particular, mounting evidence suggests that macrophage heterogeneity is multidimensional and more complex than M1/M2 classification [126]. Hence, single-cell analyses could greatly facilitate the understanding of a correlation between ER stress and macrophages/fibroblasts in the development of cGVHD and make ER stress a more compelling therapeutic target for cGVHD therapy.
While aGVHD and cGVHD show different clinical manifestations, one of their common features is abnormal immune cell infiltration, which results in organ damage and severe inflammation and fibrosis. Mukai et al devised a novel therapeutic strategy for both types of GVHD by targeting vascular adhesion protein-1 (VAP-1) [127], which is known to be overexpressed in inflamed organs [128]. VAP-1 is an endothelial surface glycoprotein assisting leucocyte migration from the bloodstream to tissues and possesses the following 2 functional domains: a distal adhesion domain and a catalytic amine oxidase domain [129]. For infiltration into tissues, the amino group in leukocytes undergoes a nucleophilic attack on the carbonyl group in VAP-1 [129]. The subsequent catalytic conversion of the primary amine to the corresponding aldehyde allows immune cells to squeeze into tissues through blood vessels [129, 130]. Pursuant to their study with the use of a mouse model where aGVHD shifts to cGVHD [127], (i) the protein expression of VAP-1 is increased in organs with GVHD, where the number of inflammatory cells is accordingly augmented, (ii) blockade of VAP-1 with a novel inhibitor reduced the number of tissue-infiltrating leukocytes and thereby mitigated GVHD manifestations such as inflammation and fibrosis and (iii) the VAP-1 inhibition caused few to no severe adverse effects. Collectively, inhibition of VAP-1 could be an effective all-in-one approach for the treatment of aGVHD and cGVHD.
The Notch signaling pathways are cell-to-cell communication induced by interactions between Notch receptors (NOTCH1, NOTCH2, NOTCH3, and NOTCH4) and NOTCH ligands (Jagged1 (JAG1), JAG2, Delta-like 1 (DLL1), DLL3 and DLL4) [131]. Due to these intercellular interactions, the NOTCH receptor is proteolytically activated by an ADAM family metalloprotease and subsequently by the γ-secretase complex [132]. The sequential cleavages lead to the release of the intracellular NOTCH domain (NICD), which is a transcriptionally active fragment [133]. NICD migrates to the nucleus and binds to the DNA binding CSL/RBP-Jk factor, forming a transcriptional activation complex with a mastermind-like (MAML) family coactivator [133]. This final complex triggers the transcription of target genes which are important for biological processes such as proliferation, differentiation, and survival [134].
A correlation between the Notch signaling pathways and alloimmune responses has gained interest from GVHD researchers. Studies using animal models of aGVHD suggest that; (i) the Notch signaling promotes activation, differentiation, and alloreactivity of T cells [135] and (ii) dendritic cells with high DLL4 expression show an increase in the production of IFN-γ and IL-17 [136]. The Notch signaling is also implicated in the pathogenic process of cGVHD. A murine study shows that NOTCH1 and NOTCH2 as well as DLL1 and DLL4 serve significant functions in regulating proinflammatory cytokine production by T cells [137]. Investigation using
GVHD treatments by targeting the Notch signaling pathway have been reported. A series of experiments using a mouse model of aGVHD reveals; (i) inhibitors of γ-secretase block proteolytic activation of all the NOTCH receptors, but has severe toxicity in the gut epithelium, (ii) NOTCH1 inhibition using an antibody mitigates GVHD but causes serious toxicity and (iii) treatment with a combination of anti-DLL1 and anti-DLL4 reduces aGVHD without debilitating adverse effects while maintaining a GVL effect of donor T cells [139]. An anti-DLL1 antibody is also effective for the treatment of murine cGVHD in combination with an anti-DLL4 antibody [137]. Treatment with all-trans-retinoic acid (ATRA) prevents NOTCH2-induced BCR hyperresponsiveness, which plays a detrimental role in cGVHD pathogenesis [137]. It appears that NOTCH2 and DLL1/4 are promising drug targets for the treatment of the 2 types of GVHD. Therefore, it is highly anticipated that novel, selective inhibitors of NOTCH2 and DLL1/4 will be developed for use in human GVHD.
Rho-associated coiled-coil-containing protein kinases (ROCKs) are serine-threonine-specific protein kinases, and mammals have ROCK1 and ROCK2 [140]. ROCKs are downstream effector proteins of GTPase Rho, and abnormal activation of the Rho/ROCK pathways contributes to the development of various diseases [140]. In particular, ROCK2 is known to regulate (i) the balance of Th17 cells and Tregs and (ii) profibrotic pathways [141]. ROCK2 activation increases Th17 cell-specific transcription factors by promoting STAT3 phosphorylation [142]. In addition, when ROCK2 is activated by profibrotic mediators such as tumor growth factor-β (TGF-β), it causes myocardin-related transcription factors to activate profibrotic genes in fibroblasts [143, 144]. This profibrotic gene activation induces fibroblast-to-myofibroblast differentiation and the resultant increase in collagen production [143, 144].
A study using a cGVHD mouse model shows that treatment with belumosudil, which is a selective ROCK2 inhibitor, can substantially reduce cGVHD-induced fibrosis in the lung [145]. In 2021, belumosudil was approved by FDA for the treatment of cGVHD, and the clinical trial data show that the overall response rate was 75% (6% complete response and 69% partial response) [146].
ROCK1 is also thought to be involved in the development of fibrosis, and pan-ROCK inhibitors targeting ROCK1/2 are thereby expected to show better treatment outcomes for cGVHD [147]. Several pan-ROCK inhibitors have been granted approval for human use [148, 149, 150, 151] In particular, netarsudil has been approved by FDA for the treatment of glaucoma [151]. However, due to a lack of overall kinome selectivity of the reported dual ROCK1/2 inhibitors, there is still scope for improvement in pan-ROCK inhibitors [152]. Hu et al. has recently reported the synthesis and
While recent decades have seen significant technological and medical advances, aGVHD and cGVHD are still a major hurdle to successful allogeneic HSCT in clinical settings. Systemic corticosteroid therapy, with or without immunosuppressive agents, is the first-line treatment for GVHD, although it can cause severe adverse effects and approximately 50% of GVHD patients develop steroid-resistant GVHD. Thus, sophisticated treatments of steroid-refractory aGVHD and cGVHD are highly anticipated by medical settings. A great deal of effort has been invested in the elucidation of mechanisms of GVHD and development of safe and efficacious drugs for GVHD. Recently, several drugs have been approved by FDA for the treatment of steroid-refractory aGVHD and cGVHD. Despite this progress, there is still a need to create novel drugs with better efficacy for GVHD therapy. This chapter focused on druggable targets for the treatment of GVHD with an aim to stimulate various GVHD researchers (from medicinal chemists to biologists) to create novel drugs which can enter the clinic. While several signaling pathways have been intensively studied in the context of GVHD, there are underexplored signaling pathways. In particular, the purinergic signaling pathway is one of the understudied signaling pathways in GVHD. The P2X7, A2A, and P2Y14 receptors seem to be compelling drug targets for the treatment of GVHD, and clinical settings could benefit from safe and efficacious (i) inhibitors of the P2X7 receptor and (ii) activators of the A2A and/or P2Y14 receptors. However, the development of new drugs is a costly and time-consuming process. To overcome this setback, the use of AL/ML has captured great interest from many researchers and has been expected to substantially reduce the cost and time of drug development. A combination of AL/ML and molecular design could greatly facilitate the development of novel, effective, safe, and affordable drugs for the treatment of GVHD.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'At IntechOpen, the majority of OAPFs are paid by an Author’s institution or funding agency - Institutions (73%) vs. Authors (23%).
\n\nThe first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
\n\nHowever, as Open Access becomes a more commonly used publishing option for the dissemination of scientific and scholarly content, in addition to institutions, there are a growing number of funders who allow the use of grants for covering OA publication costs, or have established separate funds for the same purpose.
\n\nPlease consult our Open Access Funding page to explore some of these funding opportunities and learn more about how you could finance your IntechOpen publication. Keep in mind that this list is not definitive, and while we are constantly updating and informing our Authors of new funding opportunities, we recommend that you always check with your institution first.
\n\nFor Authors who are unable to obtain funding from their institution or research funding bodies and still need help in covering publication costs, IntechOpen offers the possibility of applying for a Waiver.
\n\nOur mission is to support Authors in publishing their research and making an impact within the scientific community. Currently, 14% of Authors receive full waivers and 6% receive partial waivers.
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Thin films are considered as backbone for advanced applications in the various fields such as optical devices, environmental applications, telecommunications devices, energy storage devices, and so on . The crucial issue for all applications of thin films depends on their morphology and the stability. The morphology of the thin films strongly hinges on deposition techniques. Thin films can be deposited by the physical and chemical routes. In this chapter, we discuss some advance techniques and principles of thin-film depositions. The vacuum thermal evaporation technique, electron beam evaporation, pulsed-layer deposition, direct current/radio frequency magnetron sputtering, and chemical route deposition systems will be discussed in detail.",book:{id:"5541",slug:"modern-technologies-for-creating-the-thin-film-systems-and-coatings",title:"Modern Technologies for Creating the Thin-film Systems and Coatings",fullTitle:"Modern Technologies for Creating the Thin-film Systems and Coatings"},signatures:"Asim Jilani, Mohamed Shaaban Abdel-wahab and Ahmed Hosny\nHammad",authors:[{id:"192377",title:"Dr.",name:"Asim",middleName:null,surname:"Jilani",slug:"asim-jilani",fullName:"Asim Jilani"},{id:"192972",title:"Dr.",name:"M.Sh",middleName:null,surname:"Abdel-Wahab",slug:"m.sh-abdel-wahab",fullName:"M.Sh Abdel-Wahab"},{id:"192973",title:"Dr.",name:"Ahmed",middleName:"H",surname:"Hammad",slug:"ahmed-hammad",fullName:"Ahmed Hammad"}]},{id:"17722",doi:"10.5772/23174",title:"Study of SiO2/Si Interface by Surface Techniques",slug:"study-of-sio2-si-interface-by-surface-techniques",totalDownloads:14141,totalCrossrefCites:13,totalDimensionsCites:35,abstract:null,book:{id:"332",slug:"crystalline-silicon-properties-and-uses",title:"Crystalline Silicon",fullTitle:"Crystalline Silicon - Properties and Uses"},signatures:"Rodica Ghita, Constantin Logofatu, Catalin-Constantin Negrila, Florica Ungureanu, Costel Cotirlan, Adrian-Stefan Manea, Mihail-Florin Lazarescu and Corneliu Ghica",authors:[{id:"50919",title:"Dr.",name:"Rodica V.",middleName:null,surname:"Ghita",slug:"rodica-v.-ghita",fullName:"Rodica V. 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The principles underlying RF‐magnetron sputtering used to prepare calcium phosphate‐based, mainly hydroxyapatite coatings, are discussed in this chapter. The fundamental characteristic of the RF‐magnetron sputtering is an energy input into the growing film. In order to tailor the film properties, one has to adjust the energy input into the substrate depending on the desired film properties. The effect of different deposition control parameters, such as deposition time, substrate temperature, and substrate biasing on the hydroxyapatite (HA) film properties is discussed.",book:{id:"5541",slug:"modern-technologies-for-creating-the-thin-film-systems-and-coatings",title:"Modern Technologies for Creating the Thin-film Systems and Coatings",fullTitle:"Modern Technologies for Creating the Thin-film Systems and Coatings"},signatures:"Roman Surmenev, Alina Vladescu, Maria Surmeneva, Anna Ivanova,\nMariana Braic, Irina Grubova and Cosmin Mihai Cotrut",authors:[{id:"193921",title:"Dr.",name:"Alina",middleName:null,surname:"Vladescu",slug:"alina-vladescu",fullName:"Alina Vladescu"},{id:"193922",title:"Prof.",name:"Roman",middleName:null,surname:"Surmenev",slug:"roman-surmenev",fullName:"Roman Surmenev"},{id:"193923",title:"Dr.",name:"Maria",middleName:null,surname:"Surmeneva",slug:"maria-surmeneva",fullName:"Maria Surmeneva"},{id:"193948",title:"Dr.",name:"Mariana",middleName:null,surname:"Braic",slug:"mariana-braic",fullName:"Mariana Braic"},{id:"194047",title:"Ms.",name:"Anna",middleName:null,surname:"Ivanova",slug:"anna-ivanova",fullName:"Anna Ivanova"},{id:"194048",title:"BSc.",name:"Irina",middleName:null,surname:"Grubova",slug:"irina-grubova",fullName:"Irina Grubova"},{id:"196398",title:"Prof.",name:"Cosmin Mihai",middleName:null,surname:"Cotrut",slug:"cosmin-mihai-cotrut",fullName:"Cosmin Mihai Cotrut"}]},{id:"21157",doi:"10.5772/24330",title:"Compilation on Synthesis, Characterization and Properties of Silicon and Boron Carbonitride Films",slug:"compilation-on-synthesis-characterization-and-properties-of-silicon-and-boron-carbonitride-films",totalDownloads:5194,totalCrossrefCites:6,totalDimensionsCites:19,abstract:null,book:{id:"326",slug:"silicon-carbide-materials-processing-and-applications-in-electronic-devices",title:"Silicon Carbide",fullTitle:"Silicon Carbide - Materials, Processing and Applications in Electronic Devices"},signatures:"P. Hoffmann, N. Fainer, M. Kosinova, O. Baake and W. Ensinger",authors:[{id:"56722",title:"Dr.",name:"Peter",middleName:null,surname:"Hoffmann",slug:"peter-hoffmann",fullName:"Peter Hoffmann"},{id:"56726",title:"Dr.",name:"Marina",middleName:null,surname:"Kosinova",slug:"marina-kosinova",fullName:"Marina Kosinova"},{id:"56727",title:"Prof.",name:"Wolfgang",middleName:null,surname:"Ensinger",slug:"wolfgang-ensinger",fullName:"Wolfgang Ensinger"}]}],mostDownloadedChaptersLast30Days:[{id:"52684",title:"Advance Deposition Techniques for Thin Film and Coating",slug:"advance-deposition-techniques-for-thin-film-and-coating",totalDownloads:7639,totalCrossrefCites:32,totalDimensionsCites:59,abstract:"Thin films have a great impact on the modern era of technology. Thin films are considered as backbone for advanced applications in the various fields such as optical devices, environmental applications, telecommunications devices, energy storage devices, and so on . The crucial issue for all applications of thin films depends on their morphology and the stability. The morphology of the thin films strongly hinges on deposition techniques. Thin films can be deposited by the physical and chemical routes. In this chapter, we discuss some advance techniques and principles of thin-film depositions. The vacuum thermal evaporation technique, electron beam evaporation, pulsed-layer deposition, direct current/radio frequency magnetron sputtering, and chemical route deposition systems will be discussed in detail.",book:{id:"5541",slug:"modern-technologies-for-creating-the-thin-film-systems-and-coatings",title:"Modern Technologies for Creating the Thin-film Systems and Coatings",fullTitle:"Modern Technologies for Creating the Thin-film Systems and Coatings"},signatures:"Asim Jilani, Mohamed Shaaban Abdel-wahab and Ahmed Hosny\nHammad",authors:[{id:"192377",title:"Dr.",name:"Asim",middleName:null,surname:"Jilani",slug:"asim-jilani",fullName:"Asim Jilani"},{id:"192972",title:"Dr.",name:"M.Sh",middleName:null,surname:"Abdel-Wahab",slug:"m.sh-abdel-wahab",fullName:"M.Sh Abdel-Wahab"},{id:"192973",title:"Dr.",name:"Ahmed",middleName:"H",surname:"Hammad",slug:"ahmed-hammad",fullName:"Ahmed Hammad"}]},{id:"68467",title:"Semiconductor Nanocomposites for Visible Light Photocatalysis of Water Pollutants",slug:"semiconductor-nanocomposites-for-visible-light-photocatalysis-of-water-pollutants",totalDownloads:1803,totalCrossrefCites:7,totalDimensionsCites:11,abstract:"Semiconductor photocatalysis gained reputation in the early 1970s when Fujishima and Honda revealed the potential of TiO2 to split water in to hydrogen and oxygen in a photoelectrochemical cell. Their work provided the base for the development of semiconductor photocatalysis for the environmental remediation and energy applications. Photoactivity of some semiconductors was found to be low due to larger band gap energy and higher electron-hole pair recombination rate. To avoid these problems, the development of visible light responsive photocatalytic materials by different approaches, such as metal and/or non-metal doping, co-doping, coupling of semiconductors, composites and heterojunctions materials synthesis has been widely investigated and explored in systematic manner. This chapter emphasizes on the different type of tailored photocatalyst materials having the enhanced visible light absorption properties, lower band gap energy and recombination rate of electron-hole pairs and production of reactive radical species. Visible light active semiconductors for the environmental remediation purposes, particularly for water treatment and disinfection are also discussed in detail. Studies on the photocatalytic degradation of emerging organic compounds like cyanotoxins, VOCs, phenols, pharmaceuticals, etc., by employing variety of modified semiconductors, are summarized, and a mechanistic aspects of the photocatalysis has been discussed.",book:{id:"7671",slug:"concepts-of-semiconductor-photocatalysis",title:"Concepts of Semiconductor Photocatalysis",fullTitle:"Concepts of Semiconductor Photocatalysis"},signatures:"Fatima Imtiaz, Jamshaid Rashid and Ming Xu",authors:[{id:"292882",title:"Dr.",name:"Jamshaid",middleName:null,surname:"Rashid",slug:"jamshaid-rashid",fullName:"Jamshaid Rashid"},{id:"302498",title:"Ms.",name:"Fatima",middleName:null,surname:"Imtiaz",slug:"fatima-imtiaz",fullName:"Fatima Imtiaz"},{id:"308434",title:"Prof.",name:"Ming",middleName:null,surname:"Xu",slug:"ming-xu",fullName:"Ming Xu"}]},{id:"17728",title:"Defect Related Luminescence in Silicon Dioxide Network: A Review",slug:"defect-related-luminescence-in-silicon-dioxide-network-a-review",totalDownloads:9472,totalCrossrefCites:46,totalDimensionsCites:98,abstract:null,book:{id:"332",slug:"crystalline-silicon-properties-and-uses",title:"Crystalline Silicon",fullTitle:"Crystalline Silicon - Properties and Uses"},signatures:"Roushdey Salh",authors:[{id:"48391",title:"Dr.",name:"Roushdey",middleName:null,surname:"Salh",slug:"roushdey-salh",fullName:"Roushdey Salh"}]},{id:"58469",title:"The Electrochemical Performance of Deposited Manganese Oxide-Based Film as Electrode Material for Electrochemical Capacitor Application",slug:"the-electrochemical-performance-of-deposited-manganese-oxide-based-film-as-electrode-material-for-el",totalDownloads:1736,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"The transition metal oxide has been recognized as one of the promising electrode materials for electrochemical capacitor application. Due to the participation of charge transfer reactions, the capacitance offered by transition metal oxide can be higher compared to double layer capacitance. The investigation on hydrous ruthenium oxide has revealed the surface redox reactions that contributed to the wide potential window shown on cyclic voltammetry curve. Although the performance of ruthenium oxide is impressive, its toxicity has limited itself from commercial application. Manganese oxide is a pseudocapacitive material behaves similar to ruthenium oxide. It consists of various oxidation states which allow the occurrence of redox reactions. It is also environmental friendly, low cost, and natural abundant. The charge storage of manganese oxide film takes into account of the redox reactions between Mn3+ and Mn4+ and can be accounted to two mechanisms. The first one involves the intercalation/deintercalation of electrolyte ions and/or protons upon reduction/oxidation processes. The second contributor for the charge storage is due to the surface adsorption of electrolyte ions on the electrode surface.",book:{id:"6083",slug:"semiconductors-growth-and-characterization",title:"Semiconductors",fullTitle:"Semiconductors - Growth and Characterization"},signatures:"Chan Pei Yi and Siti Rohana Majid",authors:[{id:"197956",title:"Associate Prof.",name:"S.R.",middleName:null,surname:"Majid",slug:"s.r.-majid",fullName:"S.R. Majid"},{id:"216449",title:"Ms.",name:"Pei Yi",middleName:null,surname:"Chan",slug:"pei-yi-chan",fullName:"Pei Yi Chan"}]},{id:"60792",title:"TCAD Device Modelling and Simulation of Wide Bandgap Power Semiconductors",slug:"tcad-device-modelling-and-simulation-of-wide-bandgap-power-semiconductors",totalDownloads:2113,totalCrossrefCites:15,totalDimensionsCites:15,abstract:"Technology computer-aided Design (TCAD) is essential for devices technology development, including wide bandgap power semiconductors. However, most TCAD tools were originally developed for silicon and their performance and accuracy for wide bandgap semiconductors is contentious. This chapter will deal with TCAD device modelling of wide bandgap power semiconductors. In particular, modelling and simulating 3C- and 4H-Silicon Carbide (SiC), Gallium Nitride (GaN) and Diamond devices are examined. The challenges associated with modelling the material and device physics are analyzed in detail. It also includes convergence issues and accuracy of predicted performance. 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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:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"June 11th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,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. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. 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Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. 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(Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null}]},{type:"book",id:"7656",title:"Fuzzy Logic",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7656.jpg",slug:"fuzzy-logic",publishedDate:"February 5th 2020",editedByType:"Edited by",bookSignature:"Constantin Volosencu",hash:"54f092d4ffe0abf5e4172a80025019bc",volumeInSeries:3,fullTitle:"Fuzzy Logic",editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",institutionURL:null,country:{name:"Romania"}}}]},{type:"book",id:"9963",title:"Advances and Applications in Deep Learning",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9963.jpg",slug:"advances-and-applications-in-deep-learning",publishedDate:"December 9th 2020",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"0d51ba46f22e55cb89140f60d86a071e",volumeInSeries:4,fullTitle:"Advances and Applications in Deep Learning",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. 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