\r\n\tCell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms inaction of certain genes, proteins, and pathways involved in cell survival or death after exposure to toxic agents. The methods used to determine viability are also common for the detection of cell proliferation. A cell viability assay is performed based on the ratio of live and dead cells. This assay is based on an analysis of cell viability in cell culture for evaluating in vitro drug effects in cell-mediated cytotoxicity assays for monitoring cell proliferation. Various methods are involved in performing a cell viability assay, including the dilution method, surface viable count, roll tube technique, nalidixic acid method, fluorogenic dye assay, and the Trypan Blue Cell Viability Assay. The cell viability assays can determine the effect of drug candidates on cells and be used to optimize the cell culture conditions. The parameters that define cell viability can be as diverse as the redox potential of the cell population, the integrity of cell membranes, or the activity of cellular enzymes.
\r\n\tCytotoxicity is the degree to which a substance can cause damage to a cell. Cytotoxicity assays measure the ability of cytotoxic compounds to cause cell damage or cell death. Cytotoxicity assays are widely used in fundamental research and drug discovery to screen libraries for toxic compounds. The cell cytotoxicity and proliferation assays are mainly used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. In a cell-based assay, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be classified in to different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) Raman micro-spectroscopy.
\r\n\tMedical devices have been widely used in various clinical disciplines and these devices have direct contact with the tissues and cells of the body, they should have good physical and chemical properties as well as good biocompatibility. Biocompatibility testing assesses the compatibility of medical devices with a biological system. It studies the interaction between the device and the various types of living tissues and cells exposed to the device when it comes into contact with patients.
\r\n\t
\r\n\tThe book will cover original studies, reviews, all aspects of Cell Viability and Cytotoxicity assays, methods, Biocompatibility of studies of biomedical devices, and related topics.
A key element in all lithography processes is resist material; unfortunately its inhomogeneity is the main source of most lithography problems. Resist inhomogeneity can be any kind of variation in its thickness, arrangement of its molecules, chemical composition, and concentration of materials in it. Homogeneity of the resist layer before exposure and also after development is required to achieve low product variation, high production yield, high resolution and small patterns. If the resist layer does not have enough homogeneity and so its thickness, chemical composition or the molecular structure changes on a wafer or from a wafer to another wafer; dimensions of the patterns will change from one device to the other. This change will cause increased variation of the product’s specifications. Dramatic variations may even mar some of the products and will reduce production yield. Resist inhomogeneity in relatively small dimensions increases the so called line edge roughness. This is generally defined as the root mean square of the line width variation along a patterned line. In the other words, if the resist properties randomly changing from place to place; dimensions of the final pattern will randomly change from place to place. For example, if one tries to pattern a line with a constant width, while the resist properties are changing in distances smaller than the length of the line, the line width will fluctuate along its length. If one tries to pattern a line thinner than these fluctuations; at some parts the width of the fabricated line will be zero. So, such a variation in the resist properties can limit both the ultimate patterning resolution and the smallest achievable pattern. Even if the resist inhomogeneity does not considerably alter the pattern geometry, it can cause variation in the etch resistance of the resist. Consequently, device dimensions and properties may vary randomly.
This chapter will cover different types of inhomogeneities in different resists and lithography processes, their origins, effects; and methods to increase the resist homogeneity. At first the basic issues in wafer level homogeneity in different step of lithography will be discussed; and effect of each lithography parameter in each step will be describe. Then, last section will focus on the most important problems in nano lithography. These problems include, resist’s molecular agglomeration and line edge roughness, which are the main limiting factors of nano lithography‘s ultimate resolution and yield. Latest developments in solving these problems and improving the resist homogeneity to nanometer scale will be described. Here by an industrial lithography process capable of making patterns smaller than 5nm will be described in detail. These are one of the smallest patterns ever made in an industrial lithography and an important key factor in successful fabrication of these patterns is making a homogeneous layer of resist.
First criteria for choosing an appropriate resist material is dictated by the exposure technology. Exposure technology determines the wavelength of the photon or electron beam the resist should be sensitive to. Resist’s tune to be negative or positive, is generally choosen to minimize the exposed area. The reason is, exposing a large area and keeping small dimentions unexposed, usually increases inhomogeneity and so called proximity effects. To trasfer the resist’s pattern to other layer(s) two different types of processes can be used, etching and lift-off. Etching transfers the resist’s pattern to the underlying layer; while lift-off transfers the negative of the resist’s pattern to the layers which are deposited after lithography on top of the resist. Thus, etching processes are transfering the positive of the resist’s image while lift-off processes are transfering its negative (reversed) image. So, choosing resist’s tune to be negative or positive, also depend on the pattern transfer process to be etching or lift-off. For instance, if it is desired to pattern a hole by electron beam lithography in a wide blank film of aluminum, and it is designed to transfer the pattern by reactive ion etching (RIE). Then, a positive tune resist is needed. Because, if a negative tune resist be used, it will be necessary to expose a very large area, and such an exposure will introduce proximity problems, will take a very long time and will increase the exposure noise. So, the edge roughness and other inhomogeneities and deformities will increase. On the other hand if the pattern will be transferred by lift-off, a negative tune resist should be used. If one needs to make a pillar, the choice of negative or positive tune resist will be the opposite.
Next constrain for choosing a resist is its underlying layer and/or layer that may be coated on top of it. Because some resists do not adhere to some materials at all, may degrade near them, or react with them. So, the resist should be compatible with the other materials and processes used in device fabrication. For example it is not possible to use PMMA resists on copper.
An other common constrain to choose a resist is its etch resistance. In the other words, the resist should be able to hold up during the etching process. Most of the resist materials are designed to hold up in a specific etching process and using them with other pattern transfer process will introduce process complications or loss of patterning quality. For instance, SU-8 resists pill off in KOH wet etching solutions and cannot be used to gether with KOH wet etching. PMMA resists cannot hold up in oxigen plasma. So, they cannot be used with reactive ion etching processes which are incorporating oxigen plasma.
With modern exposure tools and established resists, generally the contrast is not a major issue and desired contrast can be easily achieved by tuning the exposure dose and development parameters. Thus, after considering the mentioned constrains, usually there are plenty of different resists applicable to the process. In order to minimize the product variation, maximize the yield and improve the resolution, it is necessary to choose a resist which can give the highest homogeneity.
Most of the commercially available and widely used resists are composed of a photon or an electron sensitive polymer, a solvent and some additives. The ultimate homogeneity of a resist layer is dictated by the structure of the polymer material itself. In most of these resists the Steric compatibilities between the tactic sequences of the polymer molecules [19] and Van der Waals attractions [17] drives the smaller polymer molecules to diffuse and attach to the bigger molecules and make granules of about 20 nm big (figure 1).
Granular Structure of Resist. 200x200 nm atomic force microscope (AFM) scan of a resist’s surface is showing its granular structure resulted from agglomeration of polymer molecules. The resist is a commercial PMMA and coated on a silicon wafer in a standard process.
If the mentioned forces be enough strong, and the polymer chain be enough long and flexible; they can even make the polymer chain to collapse on itself. The diffusion rate of the developer is much faster between the granules and at their boundaries than inside the granules. In addition, these granules are much less soluble in the developer than the rest of the material. So, the resist material in the granules will not dissolve in the developer and these granules will be extracted and released one by one in to the developer.
Consequently, the size and solubility of these granules will limit the lithography resolution and line edge roughness (figure 2) [9, 19]. So, in order to increase the resist homogeneity, it is necessary to reduce the aggregation and formation of these granules; or choose a resist with less aggregation or smaller granules.
Effect of Resist’s Granular Structure in Development. a) Schematic representation of a resist layer with granular structure. b) During the development the granules are being extracted and a rough edge is left behind.
Generally, if the final resist layer will be much thicker than the length of the polymer chain; then, more rigid polymers with more 3-dimentional structures will result in less aggregation, e.g. if final resist layer be thicker than about 100 nm; surface roughness of hydrogen silsesquioxane (HSQ) or Calixarene be less than poly methyl methacrylate (PMMA), SAL ® (Shipley Inc.) or ZEP ® (Nippon Zeon Ltd.) [17]. In such conditions, smaller polymer molecules will results in smaller granules, e.g. Calixarene results in a smoother surface than HSQ if the resist thickness is more than about 100 nm. On the other hand, if the resist thickness is in the order of or less than the polymer length, more flexible and longer polymers will result in a more homogeneous surface, e.g. if the resist thickness be 20 nm, Novolac will result in a rougher surface than polyvinyl phenol [21].
Although, the existence of smaller polymer chains in a solution of longer polymers, prevents the resist layer from shrinking after removal of the solvent; they will increase the granule formation by diffusing into the bigger chains. So, the best polymer to make a very thin and homogeneous layer is a long and heavy polymer with a narrow molecular weight distribution and a one dimensional and flexible structure.
The other ingredient of a resist is its solvent which is a liquid that transfers the resist material to the substrate. This solvent should not degrade and should prevent the polymer molecules to reach each other and from particles. Because, if the resist molecules get very close to each other they will bind by the mentioned forces and make small particles or aggregations. To reduce the polymer aggregation, it is required to reduce the concentration of the polymer in the solvent. Hereby, the probability of two polymer molecules colliding to each other will reduce; but, to prevent partial coverage of the substrate by the resist layer and also to prevent the early aging of the resist and formation of particles, the polymer concentration should not reduce below a certain value. In addition, if a very low viscosity solvent be used and a thicker layer be required, it will be necessary to reduce the spin coating speed too much, which will increase the wafer level resist thickness variation.
To improve the surface coverage of the resist, other materials can be added to the resist solution to improve its adhesion to the surface. In some resists these are enhancing the sensitivity, dark erosion or contrast as well.
Potentilly the most homogeneous resists are self assembled surface mono layers (SAM) [12, 15, 18, 2]. These are a few nanometer long molecules that can bind to the substrate’s dangling bonds only at a specific site located at one end of the molecules (figure 3). In ideal case, interaction between the molecules themselves and the substrate, results in a perfect 2-dimentional lattice of an arranged mono layer on the substrate.
Unfortunately, SAMs are very sensitive to the material beneath them. So, not only they are very sensitive to surface contamination, but also, it is not possible to use them on different materials. In addition, they have a very limited etch resistance. Hydrogenated dangling bonds have also been used as an atomic monolayer resist [16]. Although they may have potential of providing atomic resolution lithography, they are even more severely suffer from the lack of etch resistance and high sensitivity to the surface. Monolayer resists are mostly in the research stage and yet they have not found vast industrial applicability.
Schematic representation of a self assembled surface mono layer (SAM) resist. In this case linear resist molecules have made an arranged coating on the wafer.
The resist material should be stored in a clean low sodium glass, Teflon or HD-PE bottle. There should not be any plastic with a softener near the resist. The bottles can be cleaned in hot acetone and then in hot isopropyl alcohol (IPA) and should completely dry before putting the resist in it. After each refilling a waiting period of several hours is necessary to outgas air bubbles from the resist. The filled bottles should be stored in a dry and dark place, preferably inside the clean room. The storage temperature should be enough high to prevent particle formation and sedimentation, and enough low to prevent evaporation, degradation and decomposition of photo initiator. Usually the best storage temperature is between 5 °C to 10 °C.
Inappropriate storage or aging of the resist will result in formation of nitrogen bubbles, and particles and gradually conglomeration of them to bigger clusters. All of them will result in so called comet like inhomogeneity (figure 5.a). In an aged resist the photo initiator is lost. Therefore, development rate decreases and dark erosion increases. Aging also reduces the adhesion of the resist to the surface. This reduction will result in undesired undercuts, pill off of the resist during the development and will change the pattern dimensions. It is also recommended not to store partially used bottles for a long time. Because, the nitrogen can dissolve in the resist and the dissolved nitrogen can cause bubbles or popping during the baking or exposure. Frequent opening of the resist bottle will also result in evaporation of the solvent which will increase the resist viscosity and thickness.
Substrates should be cleaned before the resist coating. This cleaning decrease the surface roughness by removing particles and contamination; and also it will increase the resist homogeneity by removing contaminants and increasing the adhesion of the resist. Loss of adhesion may reduce the homogeneity by resulting in pill-off of the resist, or under cut in some parts. Contamination on the surface will result in pattern variations and homogeneity reduction as well.
In general the cleaning process will depend on the substrate’s material. In the case of silicon substrate, an appropriate cleaning process can contain the following steps: first, dipping in piranha (H2O2(25%) : H2SO4 (97%) 1:3 v:v) for more than 5min; hereby not only most of contaminants will dissolve in the solution, but also, SiO2 will grow in to the silicon. So, the Si/SiO2 interface will be kept clean. Second, dipping in diluted HF (1-5%) will remove the oxide with all the remained contaminants attached to it. Third, dipping in SC-1 (H2O2 (25%) : NH4OH (25%) : H2O 1:1:5 v:v:v) for about 10 min at 75 °C; forth, dipping in diluted HF again. Fifth, dipping in SC-2 (HCl (30%): H2O2 (25%) : H2O 1:1:6) for about 10 min at 80 °C; and finally, dipping in the diluted HF again and then blow drying with nitrogen. After this process the surface dangling bonds of the silicon should be hydrogenated (H-passivated), and consequently the resist will have a very good adhesion on it. If for any reason it does not be possible to completely remove the oxide from the surface, the surface will be hydrophilic to some degree. The resist will not have a good adhesion to a hydrophilic surface. In addition, a hydrophilic surface will easily absorb moisture. So, it is necessary to bake it for a few minutes at more than 120 °C (preferably in an oxygen free environment). This baking process will dehydrate the surface e.g. in the case of silicon it will remove the OH- groups from the silicon dangling bonds.
If for any reason it does not be possible to produce sufficient adhesion between the substrate and the resist material. It will be necessary to use an adhesion promoter. It is a material that coats the surface before resist coating. On one side it binds to the substrate and on the other side adheres to the resist layer which comes on top. For example, Hexamethyldisilazane (HMDS) binds to the SiO2 surface, and then releases its ammonia. So, a methyl group remains bound to the surface (figure 4). Many resists have a very good adhesion to this methyl group. Possibly the HMDS coating will be thicker than a monolayer. Such a HMDS layer can release considerable amount of ammonia during the baking process. The released ammonia diffuses in to the resist material and crosslinks the resist molecules. In this case the complete development of the resist will be impossible. So, considering the fact that we need just a monolayer of the HMDS, thinner HMDS coatings are better. It is also necessary to dehydrate the substrate before HMDS coating. Another common adhesion promoter is TI PRIME ® (Microchemical Inc.); it works like HMDS; but, it automatically makes a monolayer by baking at 120 °C. So, it does not have the complications of the HMDS.
Schematic representation of chemistry of HMDS adhesion promoter working on a silicon substrate. a) Dangling bonds of silicon atoms and native oxide are occcupied with OH groups, leaving a hydrophilic surface that cannot adhere to resists. b) HMDS molecules have left their NH group and bind to the silicon atoms on the surface, leaving a hydrophobic surface that strongly adheres to resists.
Some resists are available in rolled sheets of several centimeters by a few meters. These sheets can be laminated on the substrate. In the case of the liquid resists, it is possible to put a layer of the resist solution on the substrate by wetting a cylinder by the resist solution and rolling the cylinder on the substrate; but, the most widely used methods of resist coating are spaying the resist solution on the substrate; or dispensing it on the substrate; and then, rotating the substrate with high speed to obtain a very thin and homogeneous layer.
By rotating the wafer, the centrifugal force tries to spread the resist to the edges of wafer and eventually fling it off the edges of the wafer. On the other hand, the adhesion of the resist to the substrate and viscosity of the resist are trying to keep the resist on the substrate. At the same time, evaporation of the solvent gradually increases the resist viscosity and makes it impossible for the centrifugal force to move the resist material off the wafer. In ideal situation, the end result of these competing forces will be a homogeneous and thin layer of the resist material on the substrate.
Resist Inhomogeneities Caused by Spinning. a) A comet inhomogeneity in the resist which is caused by a particle in the resist. b) Inhomogeneities caused by insufficient amount of dispensed resist and too long acceleration time. The lower wafer accelerated in 30 s, the upper one in 20 s and the left one in 10 s.
The spin coating consists of the following stages [14]:
At first small puddle of the resist is dispensed on the wafer near its centre. The amount of the dispensed resist usually is a few milliliters or less. For bigger wafers and more viscose solutions, more resist should be dispensed; and for less viscose resists and smaller wafers, less resist is needed. In many cases it is beneficial to dispense the resist through a micrometer sized filter to filter out the particles and bubbles. It is necessary to dispense the resist from close proximity of the wafer and prevent dropping off the resist on the wafer. Otherwise air bubbles may generate and cause comet shape thickness variations (figure 5.a). These so called comets can also be generated by bubbles or particles in the resist or on the wafer. If the amount of the dispensed resist be too small, depending on the acceleration, some triangular shaped areas with no resist will appear near the edges (figure 5.b).
Wafer should be accelerated to the final rotation speed and this acceleration should be precisely tuned. When the wafer rotates with a constant speed with no accelleration, the centrifugal force moves the resist outward on a radial direction. So, if there be some topographical features perpendicular to this radial movement, it will not be covered homogeneously by the resist. By the angular acceleration, the resist will make a spiral path instead of a direct radial path. This spiral movement during accelleration can increase the homogeneity of the coating on the topographical features. If the acceleration be too low (long acceleration time), some triangular shaped area with no resist will appear near the edges (figure 5.b). When the rotation speed of the wafer becomes enough high, aggressive expulsion of the resist from the wafer edges can be observed (figur 6.a). Due to the acceleration and the speed difference between the upper and lower layers of the resist, spiral vortices may be briefly visible. It is very important not to stop the spinning at this time. Otherwise, large resist thickness variations will remain on the wafer. By continuation of spinning, eventually the resist will be thin enough that the viscous shear drag exactly balances the rotational acceleration.
In this stage, wafer rotates with a constant speed and the resist rotates with the same speed meanwhile the resist thickness gradually reduces. The resist thickness is almost uniform at this stage (figure 6.b), and gradual chang of interference colors of the whole surface of the resist due to reduction of its thickness is often visible. If a relatively thick resist layer is desired, it is possible to stop the spinning at this stage; but, in order to have high reproducibility and lower wafer to wafer thickness variation, usually the spinning is continued for a longer time. In addition, edge effects are more pronounced at this stage. Because, the fluid flows very gradually outward to edges, this flow is not enough strong to instantaneously make the resist to fly off the edges. Infact the resist is gathered on the edges and only when a significantly thick layer forms on the edges, small amounts of resist can fly off the wafer in small droplets or thin fibers. This thicker resist layer on the edges is called edge bead. The edge bead not only reduces the useful area of the wafer but may cause sticking to the mask. The edge beads are inversely proportional to the spinning speed.
Formation of Edge Bead during the Spinning. a) Schematic representation of the second stage of spin coating when resist explodes from the wafer edges. b) Schematic representation of the third stage of spin coating when resist flys off the wafer in very small amounts and edge bead forms.
By continuation of spinig flow of resist on the substrate reduces to zero. At this stage most of the thickness reduction is due to the solvent evaporation. This evaporation is enhanced by the flow of air due to the rotation. This stage happens at the relatively flat tail of the spin-curve (figure 7). The best time to stop the spinning is during this stage when the highest homogeneity and reproducibility is achievable. The overall spinning time required to get to this point depends on the resist viscosity and the spinning speed. For more viscose resists it takes more time to get to this point and the final resist layer will be thicker. By using higher spinning speeds, this time will reduce as well as the resist thickness.
If
Spin speed curves for 2 and 7% PMMA in chlorobenzene.
After spin coating of thick resist layers, it is usually beneficial to wait for few minutes. This waiting time allows the resist to relax on the surface. Thus, the edge bead and other thickness variations will reduce. Then the resist should be baked. The baking is a process in which the wafer is heated to 50 °C to 250 °C before exposure. This process is necessary to evaporate the solvent content and harden the reisit to prevent formation of nitrogen bubbles, sticking to the mask, improving the resist adhesion and minimizing the dark erosion. After spin coating the solvent content of the resist is usually about 20 to 40%. During the baking process this solvent content reduces by diffusion from depth to surface and evaporation of the solvent at the surface. So, the solvent content of the resist at the resist top surface is less than areas deep in the resist. By increasing the baking time the solvent content decreases (figure 8).
Solvent content of a PMMA based resist as function of time for two different resist thicknesses. Baking was done on a hot plate at 90 °C.
In order to have a more reproducible process, the baking time should be in the flat region of the figure 8. To have a homogeneous resist layer the solvent content of the resist should be less than a few percents. To increase the throughput it is desired to reduce the baking time by increasing the baking temperature; but, too high baking temperature may introduce cracks in thicker resists and eventually degrade the resist material. Too high temperature or too long soft bake will also decrease the development rate and contrast.
Baking can be done on hot plates or in itrogen oven (in a state of the art process that will be described in the last section a rapid thermal processing system should be used). Usually baking in nitrogen oven takes more time than hot plate, but, it can result in a better resist homogeneity. Regardless of equipment used for baking, temperature gradients on the wafer and in different parts of the equipment should be minimized.
During the baking process, water content of the resist layer reduces. While a certain amount of water in the resist layer is necessary to have a reasonable development rate. Considering the fact that the water is absorbed from ambient on the surface, some time after baking is needed to let the water to penetrate deep in to the resist layer. So, if the exposure done immediately after the baking, development rate will be different in different depths in the resist. Such an inhomogeneity will change the pattern’s cross section profile (figure 9). The time needed to have a homogeneous rehydration, is varying between a few seconds to tens of minutes depending on the resist thickness and other parameters. If the humidity of the yellow room be less than 45% the resist will not be able to absorb enough water, and if the humidity of the room be more than 55% the resist adhesion will decrease by absorption of water on the substrates surface. The best condition for the yellow room is 22 °C and 45% ralative humidity.
Since most of the resist materials are sensitive to ultraviolet, UV free yellow light is used in areas of the clean room where lithography in done; so, lithography rooms are also called yellow rooms. Although the resist coated substrates can be stored for months in yellow room conditions without chemical degradation of resist material, any unnecessary elongation of the lithography process is not recomended and can reduce the homogeneity.
Effect of resist rehydration on the pattern cross section after development. a) Rehydration was complete. b) Rehydration was happened in the upper half of the resist layer. c) There was no rehydration.
In order to have a homogeneous pattern in ultraviolet (UV) lithography, the exposure dose variation should be less than 10% along the wafer. In addition, the exposure should be done on an anti vibration table. The wafer and the mask should be precisely aligned to the lenses or mirrors. The exposure tool and especially the mask should be clean and free of particles. If the chromium mask has defects in the form of small holes or cracks, using lower exposure dose will reduce their effect. In other words, although increasing the exposure dose increases the contrast, it can reduce the homogeneity. Reducing the gap between the mask and the wafer will enhance the resolution as well as the homogeneity. However, this reduction usually increases the probability of mask contamination and may damage it, and shortens mask’s longivity. Variation of the reflection coefficient of the substrate beneath the resist can also cause inhomogeneity in the UV exposure.
In the case of electron beam lithography it is recommended to put the samples at the centre of the sample stage directly under the column. Because, for exposing the areas away from the centre, the beam should bend more; and this bending increases the beam noise by coupling the electrical noise of the deflector; enlarges the spot size, and increases the effects of aberations. The electrical and acoustic noise should be minimized during the electron beam exposure. Turning off the lights of the lithography room, especially florescent lights during the exposure decrease the noise level. Any electrical inhomogeneity, edge or thick insulator layers on the substrate can introduce randomized beam fluctuation. This fluctuation is caused by charging, and inhomogeneous or fluctuating electrical fields near the wafer.
Frequent opening or exposure of the developer to air leads to carbon dioxide absorption by the developer and after exhaustion of its buffer; it will result in lower development rate. In addition, by using a developer for lot of wafers, concentration of the developed resist in it will increase. Consequently, the development time will increase too. As a rule of thumb, if the resist content of a developer reaches one tenth of a percent, the development rate will decrease about ten percent. Very low development rate usually is accompanied by reduction of contrast and increase of dark erosion. Consequently it will pronounce the effect of resist thickness variations and inhomogeneities. On the other hand, if the development time be too short; reproducibility and homogeneity will reduce. Because, it will be difficult to produce a repeatable and homogeneous flow of the developer on the substrate, in a very short time compared to the development time. Also strong developers tend to roughen the resist’s surface and decrease the resolution by making a thick gel like layer between the developer and the resist (these effects will be further discussed in the next section). Usually preferred development time is between 30 s to 3 min. Development time is a function of temperature, concentration and exposure dose. So, it is necessary to precisely control the temperature of the developer and keep it homogeneous by constant stirring. Development rate increases with the exposure dose to some point and then it remains constant (figure 10). Thus, to have a better repeatability and homogeneity, the exposure dose should be in the flat region of figure 10’s curve. Substrate compatibility of the developer should be considered too. For example alkaline developers attack aluminum and its alloys.
Some times after the development the wafers are baked again. This application of high temperature after development is called hard bake. Although hard baking can increases the stability of the resist layer and its adhesion to the substrate; but, it can also result in cracks, rounding of the edges, reflow of the resist and consequently reducing the resolution.
Development rate versus exposure dose for a UV resist (AZ 9260) that baked for 10 min at 100 °C.
As it mentioned earlier in this chapter, the most important problem that limits the ultimate resolution of industrial lithography can be granular structure of the resist material (figure 1). The formation mechanism of these granules is:
After spin coating and during backing process, bigger polymer molecules fold on themselves; due to the attraction between the monomers on the same chain. Hence, end-to-end distance of the polymer reduces to much shorter than its length. Moreover, solvent evaporation reduces the radius of gyration. During the solvent evaporation, the big polymer molecules immobilize sooner, while the smaller molecules are still highly mobile and because of the intermolecular attractions, these small molecules penetrate to the long molecules. This aggregation makes about 20 nm to 60 nm big granules.
Because the development is much faster at the granule boundaries, granules release one by one into the developer instead of dissolving (figure 2). This effect increases the RMS of surface roughness to more than 250 pm and the RMS of line edge roughness to more than 2 nm, and determines the smallest patternable structure. An approved method to reduce this problem is a very short time thermal processing, which does not give enough time to the short polymer molecules to penetrate into the longer molecules, while using higher temperature to evaporate all of the solvent in the limited time. A detailed study of using this method to obtain a very homogeneous layer of PMMA and making patterns smaller than 5 nm by electron beam lithography (EBL) follows.
As a typical substrate, p-type <100> silicon is used in this study. Usually it is needed to pattern a thin film on the substrate. This thin film may be a part of the final device or maybe used as a mask to make patterns in other layers. Here, a thin film of ruthenium is used on the substrate. Ruthenium has high ion milling etch rate, so, it does not need a thick layer of resist to hold up the etching process; ruthenium has high conductivity, so, the charging effect during the electron beam exposure will be minimum; it has small grain size, so, it can make a thin, continuous and smooth film which will not increase the resist inhomogeneity; ruthenium has compatibility with different surfaces [24], and the possibility to be used as a mask to etch other material beneath the ruthenium. In addition, ruthenium activates C–H and C–C bonds and benzene decompose on ruthenium at 87 °C, thus it helps the solvent to outgas during baking, while there is no dehydrogenations bellow 277 °C. Thus, it will not damage the PMMA in the backing process, while PMMA has good adhesion on it. To make the ruthenium layer; after RCA cleaning of the substrate, 10 nm ruthenium sputtered on the samples. In order to improve PMMA adhesion and uniformity, samples annealed at 400 °C. Hereby, the contact angle of PMMA solution on the substrate’s surface reduced to less than 5 °C.
Samples were coated with 2% 950K PMMA in chlorobenzene by spinning at 6000 rpm for 50 s with 1s acceleration and 10 s deceleration time. This long deceleration time increases the resist homogeneity. The best thermal processing for this process found to be: increasing the sample temperature from 21 to 250 °C in 1 s and keeping it in that temperature for about 15 s and cooling it down to 21 °C in 1 s (figure 11).
Effects of Different Baking Processes on Line Edge Roughness. a) RMS of surface roughness versus line edge roughness; obtained by baking the resist in different thermal processes. b) RMS of surface roughness versus baking time for different baking temperatures.
Highest resolutions and smallest patterns in industrial lithography have been achieved by using electron beam to pattern PMMA. By using PMMA as the electron beam resist; lines as thin as 5 nm [23, 3, 22] and 10 nm gaps [7, 13] have been reported. 5 nm pillars have been achieved by etching thicker pillars [5, 10]; but, without using the described method to solve the problem of resist aggregation, holes smaller than 10 nm had not achieved [8, 1, 6].
Unlike patterning lines, in patterning holes, there is a very confined space for developer to penetrate through the exposed area. In addition, there is a very small space for the dissolved resist to diffuse in to the bulk developer. So, to overcome this problem, and to overcome the intermolecular force between the unexposed walls and the exposed PMMA, ultrasonic agitation should be used.
AFM Investigation of Effect of baking process on Line Edge Roughness. a) Line edge of a PMMA that baked for 15 s at 250 °C. b) Line edge of a PMMA that baked for 3h at 165 °C. c) Line edge of a PMMA that baked for 10 s at 300 °C. d) Cross section profile of a, b and c; axes are scaled in nanometers. Lowest line edge roughness and highest contrast are obtained in sample a, while in sample c the resist is degraded.
Other problems in patterning small holes are the gel thickness at the interface between the exposed resist and the developer (related to the radius of gyration) and developer induced swelling. To overcome these problems a weak developer, and cold development, should be used. This process is successfully used to make sub 5 nm patterns. For making such a small pattern, the only available industrial lithography process is electron beam lithography (EBL). In this study, electron beam exposure performed by Vistec VB_6HR with 50 keV acceleration voltage and 150 pA current (by increasing the acceleration voltage and decreasing the current, spot size reduces). Optimized development condition is 7:3 v:v isopropyl alcohol (IPA) in water in ultrasonic bath at 12 °C. After the development, ion milling for about 65 s at 80 mA beam current with 375 V acceleration voltage used to transfer the PMMA pattern to the ruthenium layer beneath. Then, the resist residue striped by 1, 2-dichloroethane:acetone 1:1 v:v to completely remove the PMMA without affecting the underlying surface [11].
The almost linear relation between the surface roughness and line edge roughness (Figure 11.a) substantiates a common source for both of them and the mentioned theory of PMMA granules. In samples which have been baked at temperatures lower than 230 °C, surface roughness and line edge roughness are improving by increasing the baking time (Figure 11.b). This improvement is due to reduction of solvent content in the resist by evaporation. By baking in higher temperatures for a very short time, a significant improvement in surface roughness and line edge roughness appears. By baking at 250 °C for 15 s the lowest surface roughness and line edge roughness are obtained which are about 100 pm (figure 11.b) and 1 nm (figure 12.a), respectively. By reducing the baking time, PMMA molecules do not have enough time to diffuse and form the granules, while due to the high temperature all the solvent evaporates. By further increasing the baking temperature, resist thinning and line edge rounding increases considerably, which is an indication of losing the contrast and degradation of the resist material (figure 11.b).
If ultrasonic agitation do not be used for development, small holes will not completely develope, no matter for how long they were developed (a partially undeveloped hole could not result in a highly visible object in SEM image after ion milling). Doing the development in higher temperatures takes much shorter time but in higher or lower temperatures or stronger developers (such as methyl isobutyl ketone:IPA 3:1 v:v), contrast will be much lower and pattern edge roughness will be much higher that patterning small holes will not be possible. However, by using the mentioned optimized development process, holes smaller than 5 nm were obtained on the PMMA (figure 13).
Patterned Holes in PMMA. a) High magnification SEM image of a small hole patterned on the PMMA layer. b) An array of the patterned hole with different diameters. Arrows are showing the small holes. The PMMA was spun at 6000 rpm on a 10 nm thick layer of ruthenium. Then, backed at 250 °C for 15 s, exposed by 50 keV electron beam, and developed in IPA:H2O 7:3 v:v at 12 °C.
By baking the samples at 250 °C for 15 s, the development time was more than 2 min, but for the samples baked in lower temperature for longer time, it is less than 1 min. The reason is, if the PMMA has granular structure, the development rate at the boundaries is much higher than in the granules. So, the granules release during the development. However, by using the fast baking process, resist is homogeneous. So, there is no granule boundary and it takes a longer time for the PMMA to gradually dissolve in the developer.
The resist thickness in this process is about 58 nm and before and after the development, there is no measurable change in the resist thickness. The resist can hold up for about 70 s in the mentioned ion milling process. So, it can be used as a mask for etching 20 nm of copper, 15 nm of aluminum, ruthenium, tantalum, or some other materials in ion milling. Hereby, open holes smaller than 5 nm obtained on the ruthenium without significant pattern enlargement during the etching process (figure 14). It worth to mention that the etch rate of the ruthenium layer in SF6/O2 plasma in typical reactive ion etching (RIE) processes is almost zero. Therefore, the ruthenium thin film can be used as a mask for RIE of silicon, silicon dioxide or nitride.
High magnification SEM image of a hole patterned in the ruthenium layer by transferring the PMMA pattern to it by ion milling.
Wafer level homogeneity of resist layer is crucial to minimizing product variation and it is also one of the most important factors in having a high production yield. This chapter provided the guidelines for increasing the wafer homogeneity. In order to precisely optimize the process parameters, it is necessary to perform a range of experiments in the framework of a design of experiment (DOE). The guidelines and trends provided here will be useful to find the optimum condition in a shorter time. These guidelines can also be used as a troubleshooting tool for solving common lithography problems. In the last section, nanometer scale inhomogeneity of the resist which is a consequence of polymer agglomerations, described. Overcoming the problem of these nanometer scale inhomogeneities is important in nanolithography, especially to improve the resolution and making small patterns. A state of the art process to solve this problem described in details. This process has resulted in some of the smallest patterns ever made in an industrial lithography. However, polymer resists have their own intrinsic homogeneity limitations. For atomic resolution lithography, further research in using surface monolayers or crystalline resists for making patterns; and application of atomic layer deposition instead of etching, will be valuable.
Hypopharyngeal carcinoma is relatively rare in all head and neck cancers (approximately 3–5%) [1, 2]. The overall worldwide age-standardized incidence rates occur at a rate of 0.8 per 100,000 (1.4 in men and 0.3 in women) in hypopharyngeal cancer [3]. Bangladesh had the highest incidence with 4.8 per 100,000 [4]. In the past four decades, the incidence of hypopharyngeal cancer has declined smoothly in America, in part due to decreasing intake of tobacco [5, 6, 7]. Overall, it is five times greater in males than in females [8] and mainly occurs in the aged 50 to 70 years [5, 9]. However, this tumor rarely occurs at young ages [10].
Epidemiologic studies showed a series of potential environmental risk factors for hypopharyngeal carcinoma development. Tobacco consumption (> 90% of patients) and alcohol abuse (> 70% of patients) are the two well-established risk factors for hypopharyngeal squamous cell carcinoma [11, 12, 13]. Heinz Maier et al. reported a time-response correlation between tobacco intake and hypopharyngeal cancer. Besides, the amount of alcohol consumption is also related to cancer development. Compared to non-smokers, it increased the risk by 9.5-fold (adjusted for alcohol consumption) for the long-term smoker (40–60 tobacco years). Also, alcohol drinkers increased the risk of this cancer that was up to 125.2-fold (adjusted for tobacco consumption) for alcoholics (> 100 g/day) [13]. Moreover, there is a synergistic carcinogenic effect between tobacco use and alcohol abuse [14]. Quitting smoking and refrain from drinking may reduce the risks of hypopharyngeal cancer.
Other risk factors, such as nutritional factors, diet, Plummer-Vinson syndrome, gastroesophageal reflux disease [15], and chronic infectious diseases have been reported to increase the risk of hypopharyngeal tumor. An inadequate caloric intake may lead to cancer cachexia, associated with a poor prognosis for hypopharyngeal carcinoma [16]. Plummer-Vinson syndrome is responsible for post-cricoid carcinoma, characterized by dysphagia and iron deficiency anemia [17, 18]. It has been reported that oncogenic viral infection has a close relationship with head and neck cancers. The human papillomavirus (HPV) is involved in the malignant transformation of oropharyngeal carcinoma [7]. Epstein–Barr virus (EBV) infection is relevant to nasopharyngeal carcinoma (NPC) tumorigenesis [19]. Nevertheless, HPV and EBV infection in hypopharyngeal cancer are rare [20, 21, 22]. To date, the possible role of HPV in tumorigenesis of hypopharyngeal cancer is still controversial, EBV as well [23, 24].
In hypopharyngeal cancer, most histological types are squamous cell carcinoma (SCC) (up to 95%). That is usually represented poorly differentiated [25]. Adenocarcinoma is less frequent than in hypopharyngeal malignancies, accounted for around 5%. Other rare malignant tumors: papillary (exophytic) squamous cell carcinoma, verrucous carcinoma, and lymphoepithelial-like carcinoma, have been reported. However, the non-epithelial neoplasms that may arise in the hypopharynx include mucosal malignant melanoma, synovial sarcoma, fibrosarcoma, and liposarcoma, are not included [26]. Both histologic confirmations and histopathologic grading of squamous carcinoma should be recorded in hypopharyngeal cancers.
There are three parts to the pharynx: nasopharynx, oropharynx, and hypopharynx. As part of the pharynx, the hypopharynx is located behind the entire length of the larynx. It extends from the plane of the epiglottis to the lower border of the cricoid cartilage. Moreover, the pharynx is further classified into three regions (Figure 1): (1) the piriform sinuses, (2) the posterior pharyngeal wall, and (3) the post-cricoid area.
Anatomical subsites of hypopharynx. (A) The pharynx includes three parts: The nasopharynx, oropharynx, and hypopharynx. (B) The hypopharynx is situated posterior to the larynx. It is further subdivided into the pyriform sinuses (left and right), posterior pharyngeal wall, and post-cricoid area.
The pyriform sinus, a bilateral area, is bounded by the aryepiglottic fold and laterally by the esophagus’s upper end. The posterior pharyngeal wall is bounded from the superior level of the epiglottis to the lower border of the cricoid cartilage and from the vertex of one pyriform sinus to the other. The post-cricoid region lies on the arytenoid cartilages’ level and connecting to the plane of the inferior border of the cricoid cartilage.
In general, hypopharyngeal cancer occurs most in the piriform sinuses in 60–85% of patients, followed by the posterior pharyngeal wall up to 10–20% and rarely in the post-cricoid area in 5–15% of patients (Figure 2) [9, 27]. Also, during these three hypopharyngeal subsites, the tumor of the pyriform sinus and the posterior pharyngeal wall is mainly in males, while post-cricoid carcinoma is more often occurs in females [5, 9].
Typical subtypes of hypopharyngeal carcinoma. (A, D) The pyriform sinus carcinoma (left) (red arrow) involving the left side of aryepiglottic fold in endoscopy (A) and (D) CT scan. (B, E) The posterior pharyngeal wall carcinoma (red arrow) in endoscopy (B) and (E) CT scan. (C, F) The hypopharyngeal carcinoma (red arrow) arising from the post-cricoid region in endoscopy (C) and (F) CT scan. (G) The patterns of hypopharyngeal carcinoma. (H) The percentages of hypopharyngeal carcinoma in three subtypes.
Early in hypopharyngeal cancer is not easy to be found due to the asymptomatic for an extended period. Something sticking or irritative sensation in the throat could be the early symptoms. If the tumor increases to a considerable size, sore throat, increasing dysphagia, and referred otalgia on swallowing may be present. Besides, progressive dysphagia frequently leads to significant weight loss.
A neck mass is now recognized as the typical clinical manifestation of hypopharyngeal carcinoma. There are a rich lymphatic network and vascular anatomy in the neck, allowing tumors to easily metastasize to the cervical nodal. Clinically, more than half of patients have enlarged cervical nodes at initial presentation because of the vibrant lymph nodes network in the pharynx [28]. The neck metastases rate is higher (> 75% of patients) in pyriform sinus cancers, as compared with the neck metastases rate in the posterior pharyngeal wall and post-cricoid cancers [29, 30]. Lymphatics from pyriform sinuses usually result in levels II-III and retropharyngeal node metastasis. And the posterior pharyngeal wall lymphatic metastasis area is more occurred to level II lymph node metastasis. In contrast, lymph node metastasis of the post-cricoid region prefers to levels IV-VI metastasis [31, 32, 33].
The larynx functions mainly in airway protection and respiration, which is in front of the hypopharynx. The hypopharynx configuration may allow tumor invasion or involvement of these adjacent organs, for instance, the larynx. When the throat symptoms appear, the tumor is considered significant in particular hoarseness, invading the larynx. Furthermore, some of the patients may present aggressive laryngeal invasion with life-threatening airway obstruction.
Patients with hypopharyngeal cancer have an exceptionally high risk of diagnosing a synchronous or metachronous second primary cancer, which may be associated with the prognosis’s deterioration [34]. One possible mechanism causing second primary cancer in hypopharyngeal cancer is the phenomenon of “field cancerization” [35]. Anatomically, the cervical esophagus is originated at the upper esophageal sphincter, contiguous with the post-cricoid region and behind the lower border of the cricoid cartilage. The aerodigestive tract mucosa, including hypopharynx and esophagus epithelium, is the squamous epithelium. During the carcinogenesis process, both hypopharynx epithelium and esophagus epithelium are exposed to similar environmental risk factors resulting in multiple cancers in the aerodigestive tract [35, 36, 37]. Tobacco use and alcohol abuse are considered as the significant risks contributing to field cancerization.
In head and neck cancers, the overall incidence of the synchronous second primary cancer was estimated to be 12% [38]. However, hypopharyngeal cancer has a high incidence of second primary cancer. The commonest sites in the second primary cancer [39] were the esophagus (27%) and lung (6.34%) [40, 41, 42]. Therefore, patients with hypopharyngeal carcinoma are suggested to undergo regular surveillance endoscopy (Figure 3) and chest CT scan to detect a second malignancy. Precancerous lesions or neoplasm are the targets of surveillance endoscopy. In case of suspected neoplasm, an endoscopic biopsy can be done to diagnose second primary esophageal cancer. The use of narrow-band imaging (NBI) shows high accuracy to screen early esophageal lesions, Lugol chromoendoscopy (LCE) endoscopy as well [43]. Most of the second primary cancer followed the hypopharyngeal cancer diagnosis within one year [34, 40].
The second primary cancer in hypopharyngeal cancer. (A, B) Hypopharyngeal cancer involving pyriform sinus (red arrow) by endoscopy and CT scan, respectively. (C, D) Second primary esophageal cancer of hypopharyngeal cancer, imaged with (C) white light endoscopy; (D) narrow-band imaging.
To assess the patient’s condition, a thorough history of presenting symptoms must be obtained. It also is crucial to document and quantification of tobacco or alcohol use history. And then, a complete head and neck examination should be performed. Neoplasm and its extent can often be seen on indirect or laryngoscopy tests. While the post-cricoid growths may difficult to diagnose on the laryngoscopy. The pooling of secretions in the pyriform sinus is indicated to cervical esophageal involvement. Both sides of the neck should be examined to evaluate cervical lymph nodes, and the level, number, size, and mobility of palpable lymph nodes should be carefully documented.
In early cases, endoscopy of the laryngopharynx is best performed in the patient under suspicion of malignancy. The panendoscopy can evaluate the entire scope of cancer and find a synchronous primary at any other site. A biopsy can be done under general anesthesia with endoscopes. It is essential for histological typing. Since lymphonodi cervical metastasis often occurs as the first symptom, a fine-needle aspiration (FNA) in the neck is recommended.
Nowadays, the application of imaging measurement offers an efficient approach for evaluating the tumor extent, lymph nodal staging, potential laryngeal impingement, and cartilage involvement. A CT enhanced scan of the laryngopharynx and neck is exceptionally worthy in evaluating laryngeal cartilage invasion. At the same time, MRI is better for the soft-tissue extension. They are complementary examinations of each other and reveal the tumor invasive range. Due to the distant metastasis (approximately 6% of patients) in hypopharyngeal cancer, a chest CT scan or PET/CT is also recommended [44].
The newly updated TNM classification system (8th edition), an anatomic-based classification, was published in 2017 by The American Joint Committee on Cancer (AJCC). This cancer stage classification aims to provide information for the clinical trial, cancer control activity, therapy selection, and outcome. Compared to the previous version, the new vision reflects a better understanding of cancer therapy and research design. Here we showed an overview of modifications in cancers of pharynx: (1) the revision of TNM classifications in nasopharyngeal cancer; (2) the division of pharyngeal malignancies into HPV-related (p16+) oropharyngeal cancer, oropharynx (p16-) and hypopharynx cancer, and nasopharyngeal cancer; (3) the extranodal extension (ENE) is formulated into the N category for non-viral related head and neck cancer for the first time [45]. Besides, the TNM staging of hypopharyngeal cancer is delineated inFigures 4 and 5.
TNM classification of hypopharyngeal cancer. The TNM staging system is the common language for classifying the extent of spread of cancer. Here we reveal the newest edition in hypopharyngeal carcinoma.
Prognostic stage of hypopharyngeal cancer.
Generally, the cancer of hypopharynx has an abysmal prognosis in all head and neck cancers. Numerous patients (75–80%) are advanced-stage ones (stage III/IV) when initially diagnosed [46, 47]. About 60–75% of patients with cervical lymph node metastasis (N1–3) were detected [46, 47].
A population-based study reported that the five-year overall survival (OS) rate increased from 37.5% (1973–1989) to 41.3% (1990–2003) [9]. Also, Henry T. Hoffman, etc., showed the five-year disease-specific survival segregated into clinical stages increased: 63.1% (stage I), 67.6% (stage II), 41.8% (stage III), and 22% (stage IV), respectively [48]. Although the treatments have improved, the tumor recurrence within one year and half of first recurrences with distance metastases [1]. Unfortunately, about 50% of the untreated cancer patients surviving within four months after the initial diagnosis, and less than 20% of patients surviving more than one year [49, 50].
Different treatment strategies, surgery, and nonoperative treatment were adopted according to the scope of the tumor. However, the existing literature has limitations due to the shortage of multicenter large sample randomized controlled tests. In the setting of unbalanced development in economic, academic, and medical conditions in different regions, remain in the effect of treatment, it is difficult to unify the mode of diagnosis and treatment, and the differences are present in curative effects. The general principle is to improve the postoperative life quality for patients on the premise of ensuring that the tumor is removed completely. Treatment selection requires optimizing swallowing and speaking functions to prevent a long-term aspiration and tracheostomy/G- tube dependence and acquire a balance between disease cure and anatomical preservation of tissue [19, 51].
In addition to taking effective measures to accurately determine the scope and clinical stage of the tumor, multidisciplinary treatment (MDT) should also run through the whole process of tumor diagnosis, treatment, and rehabilitation to gain optimal rehabilitation effect.
Refinement in technology has improved radiation oncology across the past 20 years. The newer “more precise” techniques, such as intensity-modulated radiotherapy, compared with standard therapy, ameliorate locoregional control of hypopharyngeal carcinoma [52, 53, 54]. These techniques extend the concentration of dose to the primary tumor and concomitantly lower collateral injuries to normal tissues [53]. The results of the retrospective analysis showed the similarity between the long-term survival prognosis of primary radiotherapy and laryngectomy [55, 56, 57]. However, prospective evidence is limited for the similarity between locoregional control and survival rates [46, 58, 59]. Postradiation local control rate was achieved in 68–90% of patients with T1 tumors and approximately 75% cases in T2 lesions [58, 60, 61, 62]. The goal of radiation with concurrent chemotherapy is to acquire speaking and swallowing functional of invaded area and laryngeal preservation rates for five years above 70% [52, 63, 64]. Radical radiation-related injuries to the neck tissues need to be taken seriously, including substantial acute and late toxicity (Figure 6). Although a majority of acute toxicities are temporary (such as radiation-related dermatitis usually alleviated within 6–12 weeks of treatment), permanent xerostomia at least partly is present invariably. Post-radiotherapy complications such as aspiration and chronic dysphagia may also occur in some cases, depending on the permanent feeding tube. The incidence is growing associated with intensive protocols (e.g., concurrent chemoradiotherapy). Therefore, effective quality assurance mechanisms and appropriate expertise are needed to be established to limit treatment-related toxicity and optimize results.
Radiotherapy toxicity of neck.
The skin injury often occurs during radiotherapy, including red swollen of skin, painful blisters, and pigmentation.
Open surgery is also an available approach for early-stage lesions compared with radiotherapy [65]. The posterior pharynx tumors can be excised through the transhyoid approach [66, 67]. Meanwhile, reservation of the internal branch of the superior laryngeal nerve is necessary. The transhyoid approach is critical for the disease that cannot be exposed transorally, especially in advanced tumors [51]. The more noticeable problem is that the postoperative T1T2 diseases with high-risk factors (e.g., positive margins, positive lymph nodes, extracapsular tumor extension) and locally advanced tumors should perform radiotherapy [68].
For T1/T2 tumor, minimally invasive surgery with reducing morbidity has become a surgical option for patients. In addition to open surgery, a variety of transoral surgical techniques/instrumentation, such as laser, plasma, oral robot surgery, and so on, setting primary tumor resection as a rising feasible option, with preserving laryngeal function [69, 70]. Transoral surgery (TORS/TLM) are considered as promising alternatives with better functional consequence compared with open surgery. It presents fewer complications than open surgery with nasogastric tube dependence down from 31–3% within 1 year [71]. Supporters of surgery pose that the transoral method rise the laryngeal conservation rate by over 70% through lots of single-institution series [72, 73].
Over the past few decades, with growing prevalence in a transoral path for getting into the upper aerodigestive tract, especially transoral laser surgery (TOLS), which initially was used for cancer of the larynx, gradually spread to the hypopharyngeal tumor [72, 73, 74, 75, 76]. Local control and cancer-free survival rates via radiotherapy and open surgery inT1/T2 diseases have been achieved through transoral routes, especially in early-stage lesions [72, 77, 78, 79, 80]. The procedural complications of TOLS include fistula, granulation tissue formation, and fatal bleeding. [77, 78, 79, 80]. But, in other TOLS series reported, 83% of patients were received adjuvant treatment (radiotherapy or concurrent chemoradiotherapy) after TOLS according to pathologic outcomes [77, 78, 79, 80]. In T3, T4 cases, because of the limitation of detailed data about the use of TOLS for these lesions, the potential effects (if any) of TOLS remains poorly explained [78, 79]. Transoral robotic surgery has been considered a valid treatment for early hypopharyngeal carcinoma [81, 82, 83]. Meanwhile, it is also regarded as more appropriate for early cases without adjuvant treatment [81].
The complete resection of the tumor should be taken as the premise, with the corresponding bilateral neck dissection, combining with intraoperative frozen section examination to achieve radical procedures. If the postoperative pathological or histological examination indicates high-risk factors, postoperative adjuvant radiotherapy is required.
For the need of larynx-preservation, non-surgical treatments are considered as valid notions involved when appropriate [84]. At present, the non-operative treatment of larynx reservation is mainly combined with radiotherapy and chemotherapy (such as simultaneous radiotherapy and chemotherapy, induction chemotherapy sequential radiotherapy). Targeted therapy and immunotherapy are still being explored. The advanced patients involved postoperative adjuvant radiotherapy acquired improvement of local control, cancer-free survival rate, and overall survival [60, 85, 86, 87, 88].
For stage IV malignancy, chemotherapy (induction therapy or concomitant therapy) heightens therapeutic efficacy, which is better in locoregional control and survival rates than radiation alone and combination therapies (surgery + radiation [84, 89, 90, 91, 92]. A randomized trial including 202 cases indicated that chemotherapy group (induction chemotherapy +radiotherapy) achieve almost same disease survival as immediate surgery, with13.1% (the chemotherapy group) versus 13.8% (the surgery group) in a 10-year overall survival rate and with 8.5% versus 10.8% in10-year progression-free survival rates [93]. For optimizing chemotherapeutic effectiveness, organ-preservation strategies have to be abandoned in some advanced diseases in order to optimize chemotherapeutic effectiveness [94]. Pretreatment organ dysfunction, e.g., status vocal cord fixation and tracheostomy dependence, are related to posttreatment poor functional outcomes [95].
When considering organ-preservation strategy, the therapeutics must be implemented not only for saving of the anatomical units but also the return of upper aerodigestive function [96, 97, 98]. Meanwhile, the advanced patients with extensive invasion of surrounding tissue and serious decline of pharynx and larynx function present low pathologic complete response by non-operative treatment. The opinions of various disciplines should be integrated into decision-making. The American Society of Clinical Oncology (ASCO) guidelines recommend total laryngectomy for T3/T4patients with heavy tumor load and poor laryngeal function before induction chemotherapy [99].
Surgery remains the preferred treatment for advanced-stage hypopharyngeal cancers [100]. Kinds of surgical manners are achieved in locally advanced cancers. Considering the possibility of aspiration after laryngeal preservation surgery, assessment of preoperative lung function is necessary. The cut margins (inferior or esophageal margin) must be extended carefully for safe boundaries. [25, 101, 102]. We should pay more attention to the extent of surgical margins, especially the inferior margin of the tumor (nearly to the esophageal part). Wide margins surgically are often considering in the skip disease and submucosal positive pathology. But researches have shown that patients did not benefit from extended edges (3–5 cm) compared with traditional (1–1.5 cm) incisal edges [103].
Partial pharyngectomy integrated with a partial laryngectomy, e.g.: vertical hemilaryngectomy, supraglottic laryngectomy, or supracricoid laryngectomy etc. is utilized in a series of hypopharyngeal cancers for hypopharyngeal cancers with small to medium lesions [104, 105, 106, 107]. Laccourreye et share their extensive experience with the methods described above in their researches, including 135 cases with pyriform fossa lesions [104, 105]. The patients were executed supracricoid hemilaryngopharyngectomy combined with postoperative induction chemotherapy (IC) (96%). Five-year actuarial survival rates were assessed at 46.7%, with tracheostomy tubes removed in all patients (average = 9 days), and a 91.9% recovering oral intake (gastrostomy-free) at one year [105]. The conservation of competing cricoarytenoid units is important to achieve good functional outcomes. The unit comprises a single arytenoid, cricoid cartilage, ipsilateral recurrent/superior laryngeal nerves, and ipsilateral intrinsic laryngeal muscles. At least a single company should be reserved to obtain suitable swallowing function and upper respiratory function [108].
Due to roughly 10% of lesions invade the thyroid parenchyma directly, the cases with macroscopic cancer extension outside the larynx should be performed thyroid lobectomy or total thyroidectomy. In salvage treatments, considering thyroid vessel damages in response to radiation, preoperative hypothyroidism screening (routine pre- and post-operative thyroid hormone screening) is often necessary [109, 110]. In a prospective study including 137 laryngeal/hypopharyngeal patients, the incidence of hypothyroidism after treatment for laryngeal or hypopharyngeal tumors is 47.7%, especially after combination treatment [110]. Hypoparathyroidism is an important consideration in treatment, so the reservation or reimplantation of parathyroid glands must be noted during cricopharyngeal resection and/or paratracheal + mediastinal lymph node dissection [103].
Laryngopharyngeal defect reconstruction is also an important approach for the surgeon to optimize surgery. The reconstruction presents a certain advantage in reducing the incidence of postoperative complications such as pharyngeal fistula, fatal bleeding, or infection. Meanwhile, it shows satisfactory outcomes in rehabilitating functions of speaking, swallowing, and breathing. The methods include local issue, regional flap or more vascularized free tissue transfer (Figure 7). Regional flaps contain the submental island flap, the supraclavicular island flap, the deltopectoral flap, the pectoralis, myocutaneous flap or latissimus dorsi myocutaneous flaps. Vascularized free tissue transfer methods include radial forearm free flap, anterolateral thigh free flap. In partial pharyngectomy with a partial laryngectomy, the small defects are repaired by local closure, and the larger defects (> 3 cm in size), regional flaps, and free tissue transfer are recommended. For partial pharyngeal defects with a total laryngectomy, despite other options, such as primary closure, primary closure with bolster flap, and regional tissue transfer, free tissue transfer has become one of the most utilized reconstructive selections. The major advantages of free tissue transfer are donor-site tissue, healthy tissue to repair circumferential defects. It is reconstructed in a tubular shape to provide a good swallowing tract and low incidence by avoiding entrance to other body cavities for total laryngopharyngectomy defects is usually rebuilt by the approaches such as enteric flap transposition, gastric pull-up, colonic Interposition, or jejunal free flap.
Surgical reconstruction of hypopharyngeal cancer involving the larynx and esophageal. (A) The tubular gastric reconstruction was applied to repair the esophagus by video-assisted thoracoscopic surgery (VATS). (B, C) Inset of the gastric tube into the operative cavity of total laryngopharyngectomy.
Almost all patients with hypopharyngeal carcinoma have a high incidence of lymph node metastasis in the neck [30, 111]. Pyriform fossa cancer has the highest cervical metastasis rate (> 75%), while the lymph node metastasis rate of the posterior pharyngeal wall and posterior ring carcinoma is currently between 30% and 60% [29, 30, 111, 112]. For clinically negative (cN0) neck, the high-risk lymph node group must be included in the scope of dissection. Bilateral neck dissection should be considered with the tumor across the midline and tumors located in the posterior pharyngeal wall, medial Pyriform wall, or posterior annular region [96, 111]. In the cN0 cases, most of the lymph nodes with positive pathological examination were located in levels II and III of the lateral neck [46, 111, 113, 114]. Thus levels II to IV should be taken into consideration for elective neck dissection in the CN+ patients, despite the low incidence of metastases at levels I and V, the cutting of levels I through V is incorporated into an overall neck dissection for reducing relapses in a node. The internal jugular vein (IJV), sternocleidomastoid muscle, and accessory nerve are recommended to be preserved and attacked directly by cancer.
Paratracheal (level VI) and retropharyngeal nodes must be brought to attention because of The risk of tumor invasion [46, 115]. Paratracheal positive nodes (level VI) are frequently involved by tumors located in the pyriform apex or post-cricoid area [111, 116, 117, 118, 119]. A series of reports by Chung et al. poses a 27.9% occult metastasis rate in IV nodes with a much worse prognosis (26% vs. 55% 5-year disease-specific survival) [119]. So paratracheal node dissection should be strongly involved in this crowd both for the thoroughness of removing all tumor and strict disease staging. The retropharyngeal nodal disease is common in lateral pyriform and posterior pharyngeal, existing in 40% of advanced patients [120]. Retropharyngeal nodes should be taken into adjuvant radiotherapy in the setting of unremovable surgically. In advanced stages, these positive nodes clinically/radiographically may be an indication for non-surgical treatment [120].
Due to most tumors relapse within two years after initiate treatment, rigorous surveillance should be followed three months after treatment until two years and every six months for 3–5 years to screen early local recurrence and second primary tumors [121, 122, 123]. A favorable scanning should involve a combination of history, physical, endoscope, images (CT, MRI, PET/CT), and biopsy [124]. For suspicion cases, repeated biopsies are necessary for positive results. PET/CT has been demonstrated to be more accurate than CT/MRI for screening false-positive results [125, 126]. Surgery is considered an optimal option for recurrent cases (especially small recurrent). For unresectable recurrence or metastatic, re-irradiation or re-irradiation+chemo is one selection with improving median survival. Meanwhile, related toxicities cannot be ignored, with complications range from 9 to 32% in adjuvant chemotherapy cases [127, 128]. Therefore, the multidisciplinary team must seek a balance between the serious toxic reactions and the rescue therapy while paying attention to the progress of the disease in the long term.
There are not many options available for recurrent and metastasis, so it is urgent to develop new targeted agents in this population. The innovative drugs may be proved as another promising avenue for recurrence and metastasis. A variety of molecular targeting drugs are developed in the exploratory stage. These drugs have anti-cancer affection on aberrantly expressed intracellular proteins. In recent years, immunotherapy has been proved to ameliorate overall survival over standard, single-agent therapy for platinum-refractory cases [129, 130]. Anti-programmed cell death 1 (PD-1) therapies were assessed as a treatment for platinum-refractory recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Meanwhile, a small number of patients with the PD-1 approach acquire lower toxic effects than traditional therapies. Immunotherapy brings hope to this subtype of treat-limited patients [130, 131].
The primary type of hypopharyngeal cancer is squamous cell carcinoma, with a poor prognosis. Approximately up to a third of patients are diagnosed with second primary esophageal cancer. The infrequent incidence of hypopharyngeal cancer limits the extensive clinical trial application. Early-stage disease achieved successful tumor management after treatment (radiation alone or surgery resection). However, despite the improvements of therapy, measures alone may not be sufficient to preserve the laryngeal function in advanced-stage ones. Formulating an accurate and useful treatment plan depends on a comprehensive assessment of the patient’s general condition and tumor staging before treatment. To explore a functional tumor remission and improve survival outcomes, researchers are seeking a balance between swallowing-voice rehabilitation and organ preservation. Also, the treatment requires cooperation involved specialized expertise and a multi-disciplinary team to benefit patients. Future directions will focus on refining surgery to afford functional organ preservation and radiotherapy techniques. Furthermore, it is important to regard to influence patient outcomes; there also needs to be more emphasis on non-surgery therapy’s toxicity.
This work was supported by grants from the Youth Program of Guangxi Natural Science Foundation of China (2018GXNSFBA281158) and High-level Talent Introduction Plan of the First Affiliated Hospital of Guangxi Medical University (the fifth level).
The authors declare no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nYuekun Lai
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nPrevious years (alphabetically by surname)
\\n\\nAbdul Latif Ahmad 2016-18
\\n\\nKhalil Amine 2017, 2018
\\n\\nEwan Birney 2015-18
\\n\\nFrede Blaabjerg 2015-18
\\n\\nGang Chen 2016-18
\\n\\nJunhong Chen 2017, 2018
\\n\\nZhigang Chen 2016, 2018
\\n\\nMyung-Haing Cho 2016, 2018
\\n\\nMark Connors 2015-18
\\n\\nCyrus Cooper 2017, 2018
\\n\\nLiming Dai 2015-18
\\n\\nWeihua Deng 2017, 2018
\\n\\nVincenzo Fogliano 2017, 2018
\\n\\nRon de Graaf 2014-18
\\n\\nHarald Haas 2017, 2018
\\n\\nFrancisco Herrera 2017, 2018
\\n\\nJaakko Kangasjärvi 2015-18
\\n\\nHamid Reza Karimi 2016-18
\\n\\nJunji Kido 2014-18
\\n\\nJose Luiszamorano 2015-18
\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
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\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nYuekun Lai
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPrevious years (alphabetically by surname)
\n\nAbdul Latif Ahmad 2016-18
\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
\n\nGang Chen 2016-18
\n\nJunhong Chen 2017, 2018
\n\nZhigang Chen 2016, 2018
\n\nMyung-Haing Cho 2016, 2018
\n\nMark Connors 2015-18
\n\nCyrus Cooper 2017, 2018
\n\nLiming Dai 2015-18
\n\nWeihua Deng 2017, 2018
\n\nVincenzo Fogliano 2017, 2018
\n\nRon de Graaf 2014-18
\n\nHarald Haas 2017, 2018
\n\nFrancisco Herrera 2017, 2018
\n\nJaakko Kangasjärvi 2015-18
\n\nHamid Reza Karimi 2016-18
\n\nJunji Kido 2014-18
\n\nJose Luiszamorano 2015-18
\n\nYiqi Luo 2016-18
\n\nJoachim Maier 2014-18
\n\nAndrea Natale 2017, 2018
\n\nAlberto Mantovani 2014-18
\n\nMarjan Mernik 2017, 2018
\n\nSandra Orchard 2014, 2016-18
\n\nMohamed Oukka 2016-18
\n\nBiswajeet Pradhan 2016-18
\n\nDirk Raes 2017, 2018
\n\nUlrike Ravens-Sieberer 2016-18
\n\nYexiang Tong 2017, 2018
\n\nJim Van Os 2015-18
\n\nLong Wang 2017, 2018
\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
\n\nQi Xie 2016-18
\n\nXin-She Yang 2017, 2018
\n\nYulong Yin 2015, 2017, 2018
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Mahruf C. Shohel",coverURL:"https://cdn.intechopen.com/books/images_new/9974.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1062",title:"Psychopathology",slug:"psychopathology",parent:{id:"187",title:"Mental and Behavioural Disorders and Diseases of the Nervous System",slug:"mental-and-behavioural-disorders-and-diseases-of-the-nervous-system"},numberOfBooks:3,numberOfSeries:0,numberOfAuthorsAndEditors:101,numberOfWosCitations:14,numberOfCrossrefCitations:45,numberOfDimensionsCitations:76,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"1062",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"9530",title:"Anxiety Disorders",subtitle:"The New Achievements",isOpenForSubmission:!1,hash:"702af230f376b968ca17900a9007cab9",slug:"anxiety-disorders-the-new-achievements",bookSignature:"Vladimir V. Kalinin, Cicek Hocaoglu and Shafizan Mohamed",coverURL:"https://cdn.intechopen.com/books/images_new/9530.jpg",editedByType:"Edited by",editors:[{id:"31572",title:null,name:"Vladimir V.",middleName:null,surname:"Kalinin",slug:"vladimir-v.-kalinin",fullName:"Vladimir V. Kalinin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5272",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",subtitle:"from Theory to Practice",isOpenForSubmission:!1,hash:"385590e5c6f7983254a16476bbf06e7e",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",bookSignature:"Ghassan El-Baalbaki and Christophe Fortin",coverURL:"https://cdn.intechopen.com/books/images_new/5272.jpg",editedByType:"Edited by",editors:[{id:"157412",title:"Prof.",name:"Ghassan",middleName:null,surname:"El-Baalbaki",slug:"ghassan-el-baalbaki",fullName:"Ghassan El-Baalbaki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2997",title:"Psychiatric Disorders",subtitle:"New Frontiers in Affective Disorders",isOpenForSubmission:!1,hash:"330720e27a7629cb94bf484ef1e83db9",slug:"psychiatric-disorders-new-frontiers-in-affective-disorders",bookSignature:"Dieter Schoepf",coverURL:"https://cdn.intechopen.com/books/images_new/2997.jpg",editedByType:"Edited by",editors:[{id:"65393",title:"Dr.",name:"Dieter",middleName:null,surname:"Schoepf",slug:"dieter-schoepf",fullName:"Dieter Schoepf"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:3,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"51986",doi:"10.5772/64476",title:"Childhood Interpersonal Trauma and its Repercussions in Adulthood: An Analysis of Psychological and Interpersonal Sequelae",slug:"childhood-interpersonal-trauma-and-its-repercussions-in-adulthood-an-analysis-of-psychological-and-i",totalDownloads:3973,totalCrossrefCites:11,totalDimensionsCites:17,abstract:"Despite decades of prevention campaigns and research, childhood interpersonal trauma (i.e., psychological, physical and sexual abuse, psychological and physical neglect, witnessing interparental violence) remains an endemic problem with longstanding and deleterious negative effects on adult psycho-relational functioning. This chapter aims to present a comprehensive literature review of the repercussions associated with exposure to childhood interpersonal trauma. First, the nature and various forms of childhood interpersonal trauma are described. Subsequently, a review of the studies documenting disruptions in psychological and interpersonal functioning and the mechanisms explaining the development of each of these repercussions is unraveled. These repercussions include posttraumatic stress disorder, anxiety disorders, depression, personality disorders, affect dysregulation, substance use disorders, eating disorders, suicidal behaviors, alterations in attention and consciousness, disruptions in attributions, attachment, sexuality and violence in intimate relationships. Finally, suggestions for future research and intervention guidelines with childhood interpersonal trauma survivors are discussed.",book:{id:"5272",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",fullTitle:"A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice"},signatures:"Caroline Dugal, Noémie Bigras, Natacha Godbout and Claude\nBélanger",authors:[{id:"57536",title:"Prof.",name:"Claude",middleName:null,surname:"Belanger",slug:"claude-belanger",fullName:"Claude Belanger"},{id:"185951",title:"Ms.",name:"Caroline",middleName:null,surname:"Dugal",slug:"caroline-dugal",fullName:"Caroline Dugal"},{id:"185952",title:"Prof.",name:"Natacha",middleName:null,surname:"Godbout",slug:"natacha-godbout",fullName:"Natacha Godbout"},{id:"185953",title:"Ms.",name:"Noémie",middleName:null,surname:"Bigras",slug:"noemie-bigras",fullName:"Noémie Bigras"}]},{id:"51580",doi:"10.5772/64290",title:"“Growing from an Invisible Wound” A Humanistic-Existential Approach to PTSD",slug:"-growing-from-an-invisible-wound-a-humanistic-existential-approach-to-ptsd",totalDownloads:2866,totalCrossrefCites:7,totalDimensionsCites:9,abstract:"From a humanistic and existential perspective, posttraumatic stress disorder (PTSD) can be understood as a normal response to a threatening existential event. The humanistic-existential approach to understanding and treating PTSD also places particular emphasis on the meaning of the traumatic experience and on the awareness of the existential part of the self. Such an understanding conveys to a different approach to trauma assessment and potential for healing in the clinical encounter. In this chapter, we wish to provide a humanistic-existential understanding of trauma. To do so, we review the key humanistic-existential concepts for trauma conceptualization, assessment, and intervention. Afterwards, we present two different short case studies to illustrate and understand the humanistic-existential psychotherapeutic process and its diversity. In conclusion, we discuss the contribution and limits of a humanistic-existential approach to trauma conceptualization, assessment, and healing.",book:{id:"5272",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",fullTitle:"A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice"},signatures:"Mélanie Vachon, Prudence C. Bessette and Christine Goyette",authors:[{id:"184884",title:"Dr.",name:"Melanie",middleName:null,surname:"Vachon",slug:"melanie-vachon",fullName:"Melanie Vachon"},{id:"188110",title:"Dr.",name:"Prudence C.",middleName:null,surname:"Bessette",slug:"prudence-c.-bessette",fullName:"Prudence C. Bessette"},{id:"188111",title:"BSc.",name:"Christine",middleName:null,surname:"Goyette",slug:"christine-goyette",fullName:"Christine Goyette"}]},{id:"51883",doi:"10.5772/64842",title:"Countertransference in Trauma Clinic: A Transitional Breach in the Therapists’ Identity",slug:"countertransference-in-trauma-clinic-a-transitional-breach-in-the-therapists-identity",totalDownloads:1707,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"In line with the theoretical elaboration of countertransference in the trauma clinic, this article addresses the therapist’s relationship to the strangeness of the trauma, as well as his/her interaction with the cultural difference of the other, who is in this case, the traumatized patient. Thirty-one therapists were interviewed about their subjective experiences, using the methodology of interpretative phenomenological analysis. This article shows interesting subtleties in countertransference reactions to trauma narratives and sheds light on processes indicative of trauma transmission. Therapists interviewed could express experiencing moments of strangeness and inner disquiet; resonance in the defense mechanisms deployed by therapists and by patients at certain moments of the therapy; resorting to disregarding cultural interpretations/generalizations to make sense of an utterly painful situation and put a protective distance with the patients’ culture of origin.",book:{id:"5272",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",fullTitle:"A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice"},signatures:"Mayssa’ El Husseini, Sara Skandrani, Layla Tarazi Sahab, Elizabetta\nDozio and Marie Rose Moro",authors:[{id:"184097",title:"Dr.",name:"Layla",middleName:"Tarazi",surname:"Sahab",slug:"layla-sahab",fullName:"Layla Sahab"},{id:"184098",title:"Dr.",name:"Mayssa’",middleName:null,surname:"El Husseini",slug:"mayssa'-el-husseini",fullName:"Mayssa’ El Husseini"}]},{id:"51478",doi:"10.5772/64224",title:"The Impact of Cognitive-Behavioral Therapies for Nightmares and Prazosin on the Reduction of Post-Traumatic Nightmares, Sleep, and PTSD Symptoms: A Systematic Review and Meta- Analysis of Randomized and Non‐Randomized Studies",slug:"the-impact-of-cognitive-behavioral-therapies-for-nightmares-and-prazosin-on-the-reduction-of-post-tr",totalDownloads:1882,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Post-traumatic nightmares (PTNMs) can be treatment resistant to conventional treatments for post-traumatic stress disorder (PTSD). New cognitive and behavioral treatments (CBTs) for nightmares (NM) and pharmacological treatments, such as Prazosin, have been developed to directly reduce PTNMs. Objectives: The first objective was to evaluate the impact of CBTs for NM and Prazosin on the reduction of PTNMs in an adult population. A second aim was to explore the impact of these treatments in general PTSD symptoms and sleep. Method: A systematic search of English and French clinical studies on any CBTs and Prazosin treatments for PTNMs published from 1980 to 2012 was conducted in PsycINFO, MedLine, PILOTS,and ProQuest Dissertations and Theses. Results: The final sample was composed of 26 studies. The combined effect size (ES) for Prazosin was g = 1.30, 95% CI [0.61, 2.00], and for CBTs, it was g = 0.55, 95% CI [0.38, 0.72]. Conclusions: Prazosin had a large impact on PTNM reduction, while CBTs had a moderate impact. Specific NM treatments (Prazosin or CBTs) contribute to PTNM reduction and reduce PTSD and sleep symptoms. These findings are significant to the literature on PTSD and future studies should consider them. Several recommendations are proposed.",book:{id:"5272",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",fullTitle:"A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice"},signatures:"Katia Levrier, Carolyn Leathead, Delphine-Émilie Bourdon, Sophie\nLacerte, André Marchand and Geneviève Belleville",authors:[{id:"175626",title:"Prof.",name:"André",middleName:null,surname:"Marchand",slug:"andre-marchand",fullName:"André Marchand"},{id:"184054",title:"Dr.",name:"Katia",middleName:null,surname:"Levrier",slug:"katia-levrier",fullName:"Katia Levrier"},{id:"184055",title:"Dr.",name:"Carolyn",middleName:null,surname:"Leathead",slug:"carolyn-leathead",fullName:"Carolyn Leathead"},{id:"184056",title:"BSc.",name:"Sophie",middleName:null,surname:"Lacerte",slug:"sophie-lacerte",fullName:"Sophie Lacerte"},{id:"184057",title:"Dr.",name:"Geneviève",middleName:null,surname:"Belleville",slug:"genevieve-belleville",fullName:"Geneviève Belleville"},{id:"184058",title:"BSc.",name:"Delphine-Emilie",middleName:null,surname:"Bourdon",slug:"delphine-emilie-bourdon",fullName:"Delphine-Emilie Bourdon"}]},{id:"51992",doi:"10.5772/64900",title:"Acute Stress Disorder Diagnosis, Clusters, and Symptoms as Predictors of Posttraumatic Stress Disorder, and Gender Differences in Victims of Violent Crimes",slug:"acute-stress-disorder-diagnosis-clusters-and-symptoms-as-predictors-of-posttraumatic-stress-disorder",totalDownloads:1526,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Violent crimes represent a societal problem, and victims, namely women, often develop posttraumatic stress disorder (PTSD). Previous studies have identified acute stress disorder (ASD) as a predictor of PTSD, as well as dissociation. However, there are some inconsistencies regarding which cluster or symptom has better predictive power, and the impact of gender is still unknown in victims of violent crimes. The aim of this study was to determine the predictive power of full and partial ASD diagnosis, clusters, and symptoms according to gender. To do so, 39 women and 36 men were evaluated using validated semi-structured clinical interviews within 30 days post crime for ASD and 2 months later for PTSD. Results showed that 52% of individuals had full ASD and 20% has partial ASD, 40% had full PTSD and 17% had partial PTSD. Both full and partial ASD diagnoses, as well as all clusters, and most symptoms, were good predictors of PTSD. No gender differences were observed concerning the predictive power of ASD clusters and symptoms. The decreased emphasis on dissociative reactions in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) to establish an ASD diagnosis appears relevant to better identify women and men at risk of PTSD after a violent crime, and to deliver appropriate early preventive interventions.",book:{id:"5272",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",fullTitle:"A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice"},signatures:"Stéphane Guay, Myra Gravel-Crevier, Richard Boyer and André\nMarchand",authors:[{id:"194415",title:"Dr.",name:"Stephane",middleName:null,surname:"Guay",slug:"stephane-guay",fullName:"Stephane Guay"}]}],mostDownloadedChaptersLast30Days:[{id:"51986",title:"Childhood Interpersonal Trauma and its Repercussions in Adulthood: An Analysis of Psychological and Interpersonal Sequelae",slug:"childhood-interpersonal-trauma-and-its-repercussions-in-adulthood-an-analysis-of-psychological-and-i",totalDownloads:3967,totalCrossrefCites:11,totalDimensionsCites:17,abstract:"Despite decades of prevention campaigns and research, childhood interpersonal trauma (i.e., psychological, physical and sexual abuse, psychological and physical neglect, witnessing interparental violence) remains an endemic problem with longstanding and deleterious negative effects on adult psycho-relational functioning. This chapter aims to present a comprehensive literature review of the repercussions associated with exposure to childhood interpersonal trauma. First, the nature and various forms of childhood interpersonal trauma are described. Subsequently, a review of the studies documenting disruptions in psychological and interpersonal functioning and the mechanisms explaining the development of each of these repercussions is unraveled. These repercussions include posttraumatic stress disorder, anxiety disorders, depression, personality disorders, affect dysregulation, substance use disorders, eating disorders, suicidal behaviors, alterations in attention and consciousness, disruptions in attributions, attachment, sexuality and violence in intimate relationships. Finally, suggestions for future research and intervention guidelines with childhood interpersonal trauma survivors are discussed.",book:{id:"5272",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",fullTitle:"A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice"},signatures:"Caroline Dugal, Noémie Bigras, Natacha Godbout and Claude\nBélanger",authors:[{id:"57536",title:"Prof.",name:"Claude",middleName:null,surname:"Belanger",slug:"claude-belanger",fullName:"Claude Belanger"},{id:"185951",title:"Ms.",name:"Caroline",middleName:null,surname:"Dugal",slug:"caroline-dugal",fullName:"Caroline Dugal"},{id:"185952",title:"Prof.",name:"Natacha",middleName:null,surname:"Godbout",slug:"natacha-godbout",fullName:"Natacha Godbout"},{id:"185953",title:"Ms.",name:"Noémie",middleName:null,surname:"Bigras",slug:"noemie-bigras",fullName:"Noémie Bigras"}]},{id:"51580",title:"“Growing from an Invisible Wound” A Humanistic-Existential Approach to PTSD",slug:"-growing-from-an-invisible-wound-a-humanistic-existential-approach-to-ptsd",totalDownloads:2858,totalCrossrefCites:7,totalDimensionsCites:8,abstract:"From a humanistic and existential perspective, posttraumatic stress disorder (PTSD) can be understood as a normal response to a threatening existential event. The humanistic-existential approach to understanding and treating PTSD also places particular emphasis on the meaning of the traumatic experience and on the awareness of the existential part of the self. Such an understanding conveys to a different approach to trauma assessment and potential for healing in the clinical encounter. In this chapter, we wish to provide a humanistic-existential understanding of trauma. To do so, we review the key humanistic-existential concepts for trauma conceptualization, assessment, and intervention. Afterwards, we present two different short case studies to illustrate and understand the humanistic-existential psychotherapeutic process and its diversity. In conclusion, we discuss the contribution and limits of a humanistic-existential approach to trauma conceptualization, assessment, and healing.",book:{id:"5272",slug:"a-multidimensional-approach-to-post-traumatic-stress-disorder-from-theory-to-practice",title:"A Multidimensional Approach to Post-Traumatic Stress Disorder",fullTitle:"A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice"},signatures:"Mélanie Vachon, Prudence C. Bessette and Christine Goyette",authors:[{id:"184884",title:"Dr.",name:"Melanie",middleName:null,surname:"Vachon",slug:"melanie-vachon",fullName:"Melanie Vachon"},{id:"188110",title:"Dr.",name:"Prudence C.",middleName:null,surname:"Bessette",slug:"prudence-c.-bessette",fullName:"Prudence C. Bessette"},{id:"188111",title:"BSc.",name:"Christine",middleName:null,surname:"Goyette",slug:"christine-goyette",fullName:"Christine Goyette"}]},{id:"71699",title:"Students Anxiety Experiences in Higher Education Institutions",slug:"students-anxiety-experiences-in-higher-education-institutions",totalDownloads:1025,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Students studying at higher education institutions face many challenges. Students who attempt to overcome these challenges may alter their behaviors. This may negatively affect their psychological state and cause them to feel anxiety. Anxiety is most prominent among college students. Many students face anxiety when they think they cannot achieve their academic or non-academic purposes; however, sometimes anxiety can encourage students to think more critically about how to achieve their goals. Students cope with anxiety in different ways, but some may struggle. This probably causes many symptoms that affect their mental health. Therefore, they should alleviate the anxiety to keep their mental health and persist in the institution.",book:{id:"9530",slug:"anxiety-disorders-the-new-achievements",title:"Anxiety Disorders",fullTitle:"Anxiety Disorders - The New Achievements"},signatures:"Nabila Y. AlKandari",authors:[{id:"316508",title:"Prof.",name:"Nabila Y.",middleName:null,surname:"AlKandari",slug:"nabila-y.-alkandari",fullName:"Nabila Y. AlKandari"}]},{id:"71930",title:"Technologically Processed Highly Diluted Antibodies to S100 Protein in the Treatment of Neurotic Disorders: The Review",slug:"technologically-processed-highly-diluted-antibodies-to-s100-protein-in-the-treatment-of-neurotic-dis",totalDownloads:553,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Neurotic disorders (NDs) are among the most common mental diseases leading to a decrease in the quality of life, lack of socialization, and increased mortality. The diagnosis and treatment of all types of NDs are challenging. In the light of the ongoing search for an effective and safe therapeutic strategy influencing certain aspects of ND pathogenesis, technologically processed highly diluted antibodies to S100 protein (TP Abs to S100) seem to be a promising treatment option for patients with NDs. TP Abs to S100 possess stress-protective, anxiolytic, antidepressant, antiamnestic, and neuroprotective activities. In the current review, we describe the mechanisms of action and pharmacological effects of TP Abs to S100 demonstrated in nonclinical (preclinical) and clinical studies. Based on the data, we tried to evaluate the future prospects of the TP Abs to S100 as the drug of choice for ND treatment.",book:{id:"9530",slug:"anxiety-disorders-the-new-achievements",title:"Anxiety Disorders",fullTitle:"Anxiety Disorders - The New Achievements"},signatures:"Kristina Konstantinovna Khacheva, Gulnara Rinatovna Khakimova, Alexey Borisovich Glazunov and Victoria Vyacheslavovna Fateeva",authors:[{id:"298539",title:"Dr.",name:"Victoria",middleName:null,surname:"Fateeva",slug:"victoria-fateeva",fullName:"Victoria Fateeva"},{id:"301989",title:"Dr.",name:"Kristina",middleName:"Konstantinovna",surname:"Khacheva",slug:"kristina-khacheva",fullName:"Kristina Khacheva"},{id:"301990",title:"Dr.",name:"Khakimova Gulnara",middleName:null,surname:"Rinatovna",slug:"khakimova-gulnara-rinatovna",fullName:"Khakimova Gulnara Rinatovna"},{id:"319685",title:"Prof.",name:"Alexey",middleName:null,surname:"Glazunov",slug:"alexey-glazunov",fullName:"Alexey Glazunov"}]},{id:"71645",title:"Mental Distress among Medical Students",slug:"mental-distress-among-medical-students",totalDownloads:467,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Depression, anxiety, and stress affect the mental health of an individual. Previous studies have shown high rates of depression, anxiety, and stress among medical students throughout the world. Medical students are future doctors, but mental distress among them has negative effects on their output, which ultimately affects patient care and quality of life. This chapter will discuss various reasons of mental distress among medical students and proposed solutions for the well-being of medical undergraduates like providing proper student support service and more opportunities for extracurricular activities.",book:{id:"9530",slug:"anxiety-disorders-the-new-achievements",title:"Anxiety Disorders",fullTitle:"Anxiety Disorders - The New Achievements"},signatures:"Syeda Rubaba Azim",authors:[{id:"316533",title:"Dr.",name:"Rubaba",middleName:null,surname:"Azim",slug:"rubaba-azim",fullName:"Rubaba Azim"}]}],onlineFirstChaptersFilter:{topicId:"1062",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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