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",isbn:"978-1-80356-966-6",printIsbn:"978-1-80356-965-9",pdfIsbn:"978-1-80356-967-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"f86a9f720cc3ac0f1c385d0367ea89b9",bookSignature:"Dr. Fiaz Ahmad and Prof. Muhammad Sultan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11624.jpg",keywords:"Agricultural Waste, Reuse, Reduction, Soil Health, Recycling, Agriculture and Environment, Modelling and Simulation, Agro-Industrial Waste, Bioresource Processing, Processing and Management, Crop Residue, Forest Waste",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 8th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"22 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Fiaz Ahmad is a researcher in the field of Agricultural Engineering with fifteen years of field and academic experience, currently in charge of the Agricultural Machinery Design Laboratory at Bahauddin Zakariya University. He applied for two patents at the national level.",coeditorOneBiosketch:"A renowned researcher in the field of Agricultural Engineering with 14 years of academic experience at Bahauddin Zakariya University. Winner of various prestigious fellowships, awards, and research grants. Published 250+ articles along with several books and chapters. Guest editor of seven ISI-SCI journals for publishers like SAGE, MDPI, and Frontiers.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"338219",title:"Dr.",name:"Fiaz",middleName:null,surname:"Ahmad",slug:"fiaz-ahmad",fullName:"Fiaz Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/338219/images/system/338219.png",biography:"Dr. Fiaz Ahmad is an assistant professor and lecturer at the Department of Agricultural Engineering, Bahauddin Zakariya University, Multan, Pakistan. He obtained his Ph.D. in Agricultural Bioenvironmental and Energy Engineering from Nanjing Agriculture University, China, in 2015, and completed his postdoctorate in Agricultural Engineering from Jiangsu University, Zhenjiang, China, in 2020. He was awarded a fellowship from the Higher Education Commission of Pakistan for Ph.D. studies and from the Chinese Government for post-doctoral studies. He earned a BSc and MSc (Hons) in Agricultural Engineering from the University of Agriculture, Faisalabad, Pakistan, in 2004 and 2007, respectively. He is the author of more than fifty journal and conference articles. He has supervised six master’s students to date, and is currently supervising six master and two doctoral students. Dr. Ahmad has completed three research projects with his research interest focusing on the design of agricultural machinery, agricultural waste management, artificial intelligence (AI), and agricultural bioenvironment.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}}],coeditorOne:{id:"199381",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sultan",slug:"muhammad-sultan",fullName:"Muhammad Sultan",profilePictureURL:"https://mts.intechopen.com/storage/users/199381/images/system/199381.png",biography:"Muhammad Sultan is an Assistant Professor at the Department of Agricultural\r\nEngineering, Bahauddin Zakariya University, Multan (Pakistan). He completed his Ph.D.\r\nand Postdoc from Kyushu University (Japan) in the field of Energy & Environmental\r\nEngineering. He was an awardee of MEXT and JASSO fellowships (from the Japanese\r\nGovernment) during Ph.D. and Postdoc studies, respectively. He also did a Postdoc as\r\na Canadian Queen Elizabeth Advance Scholar at Simon Fraser University (Canada) in\r\nthe field of Mechatronic Systems Engineering. He worked for Kyushu University\r\nInternational Institute for Carbon-Neutral Energy Research (WPI-I2CNER) for two years.\r\nCurrently, he is working on 4 research projects funded by the Higher Education\r\nCommission (HEC) of Pakistan. He has completed six projects in past in the field of\r\nagricultural engineering. He has supervised 10+ M.Eng. and Ph.D. thesis and 10+\r\nstudents are currently working under his supervision. He has published 120+ journal\r\narticles, 100+ conference articles, 13 book chapters, and 6 books. He is serving as guest\r\neditor for the journals like Sustainability (MDPI), Agriculture (MDPI), Energies (MDPI),\r\nAdvances in Mechanical Engineering (SAGE), Frontiers in Mechanical Engineering, and\r\nEvergreen Journal of Kyushu University. His research is focused on developing energy-\r\nefficient temperature and humidity control systems for agricultural storage, greenhouse,\r\nlivestock, and poultry applications. His research keywords include desiccant air-\r\nconditioning, evaporative cooling, adsorption heat pump, Maisotsenko cycle (M-cycle),\r\nenergy recovery ventilators; adsorption desalination; wastewater treatment.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440212",firstName:"Elena",lastName:"Vracaric",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440212/images/20007_n.jpg",email:"elena@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6418",title:"Hyperspectral Imaging in Agriculture, Food and Environment",subtitle:null,isOpenForSubmission:!1,hash:"9005c36534a5dc065577a011aea13d4d",slug:"hyperspectral-imaging-in-agriculture-food-and-environment",bookSignature:"Alejandro Isabel Luna Maldonado, Humberto Rodríguez Fuentes and Juan Antonio Vidales Contreras",coverURL:"https://cdn.intechopen.com/books/images_new/6418.jpg",editedByType:"Edited by",editors:[{id:"105774",title:"Prof.",name:"Alejandro Isabel",surname:"Luna Maldonado",slug:"alejandro-isabel-luna-maldonado",fullName:"Alejandro Isabel Luna Maldonado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10359",title:"Landraces",subtitle:"Traditional Variety and Natural Breed",isOpenForSubmission:!1,hash:"0600836fb2c422f7b624363d1e854f68",slug:"landraces-traditional-variety-and-natural-breed",bookSignature:"Amr Elkelish",coverURL:"https://cdn.intechopen.com/books/images_new/10359.jpg",editedByType:"Edited by",editors:[{id:"231337",title:"Dr.",name:"Amr",surname:"Elkelish",slug:"amr-elkelish",fullName:"Amr Elkelish"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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Hidden behind the high-quality ride service provided by HSR is the tremendous effort and huge budget spent on the inspection and maintenance work, which is more challenging with increasing speed and capacity.
\nWith long-term numerous cycles of loading and unloading, both rail tracks and train wheels are suffering from vibrations and stresses caused by wheel/rail interactions, leading to fatigue, wear, plastic deformation, cracks and other deteriorations. The wheel/rail interactions are intense with average contact stresses over 1000 MPa under normal operating conditions, and this number can go much higher upon specific situations (wheel flange/rail edge contact while train turning, poor conforming wheel and rail profiles, etc.) [1]. Moreover, to author’s knowledge with recent research work on contact mechanics using NDT approaches, machine element contacts including wheel/rail contacts are essentially contacts between the asperities due to surface roughness of the contact bodies, and the asperity contacts indicate hyper-stress concentration beyond 4000 MPa at the contacting peaks [2]. Under such high stresses, components of the rail system are deteriorating rapidly in various forms and the deteriorated structures create a worse operating environment, adding the occurrences of failures. A typical failure is rolling contact fatigue (RCF) causing a series of subsequent rail defects (squats, transverse cracks, spalling and gauge corner cracks).
\nThe rail also takes up impact load from running trains intermittently due to wheel defects, rail irregularities or at certain areas rail turnouts, rail joints, etc. The intense vibrations caused by wheel/rail interactions and impacts are transmitted bidirectionally from the wheel/rail interface up to the coach and down to the rail slab simultaneously. In terms of HSR, to meet the high standard requirements of smooth operation under high speed, the components utilised are different from those in conventional rail lines. For example, the rail tracks are strengthened with high resistance to wear, and multi-layer concrete forms up the rail slab with CA mortar layer serving as the damping instead of traditional ballast. These measures add ride comfort in HSR operation, but make the system more ‘brittle’ with reduced capability in vibration absorption, hence add the risks of cracks in the rail system. A recent example is the giant crack (44 cm long) found in an operating Japan Shinkansen bullet train in December 2017, causing interruption of service and great social panic [3]. Similar cases can be highly possible on ballastless rail tracks leading to more catastrophic consequences, calling for more reliable and thorough inspection actions.
\nNDT techniques have long been used for inspection in rail system since the 1920s. With integrated ultrasonic probes or eddy current sensors, the NDT systems are able to check surface and internal defects along the rail in either contact or non-contact manner. The NDT inspection is conducted through manual inspection device or inspection vehicle. Conventional inspection vehicles are normally attached to a traction locomotive to carry out inspection. In the age of HSR, many countries have developed high-speed comprehensive inspection vehicles (CIVs) for the more complicated inspection tasks, such as the ‘East-i’ CIV in Japan, the ‘IRIS320’ CIV in France, and the ‘No. 0’ CIV in China, etc. Inspection content of the high-speed CIVs covers from geometry data of rail infrastructure to dynamic behaviours of trains. Despite of the wide range of data types, the NDT techniques require interruption of train service to conduct the inspection. To provide early alarming in prevention of further consequences in terms of accidents similar to the Japan Shinkansen case, continuous real-time information of in-service rail system is highly desired, which puts forward the introduction of online monitoring to this area. Since wheel/rail interaction is the core part of the rail system, this chapter mainly focuses on the inspection and monitoring methods of wheel and rail defects.
\nVarious types of wheel OOR/defects occur on HSR in-service, which influence operational safety and give rise to high maintenance cost. These defects take on many patterns, such as flats, eccentricities, polygons, corrugations on block-braked wheel treads, missing pieces of tread material owing contact to fatigue cracking and other random irregularities [1, 4]. Generally, they can be categorised into two major types: local defects and periodic OOR all around the wheel. The former can cause severe repeated wheel-rail impacts, while the latter leads to abnormal vibrations of vehicle-track system at certain frequencies [5].
\nThere are two major causes behind initiation and development of wheel tread local defects: thermal cracking and rolling contact fatigue (RCF) [6]. Several factors, such as speed, axle load, wheel-rail adhesion, wheel material and braking conditions, also have some effects on deterioration rates of wheel tread [7]. In HSR operation, wheel wear rate can increase quickly due to the high operation speed, high stiffness track, wide wheel-rail impact frequency, intense vibrations and high speed flow [5, 7, 8]. Wheel defects can cause abnormal vibrations and have the potential to impose damage to both track and vehicle components such as sleepers, rails, wheelsets and bearings, increase the likelihood of derailment and deteriorate operational safety and comfort owing to high vibration amplitudes [1, 9]. Previous research found that the load history of axle bearing and bogie frame may fluctuate due to the influence of wheel roughness and lead to fatigue cracks [10]. Wheel defects also result in an increase in the noise both inside and outside the train [11, 12] which can be annoying for both passengers on the train and residents along the rail line [5]. For high-speed trains, the high-magnitude impact loads generated by a defective wheel can excite various vibration modes for the wheelsets and thereby contribute to abnormal increases in the stress states of wheel axle under high-speed conditions [13].
\nThe studies of wheel polygonisation were stated some three decades ago when some of polygonal wheels were detected on high-speed trains (ICE, Germany). Wheel polygonisation with one, three and four harmonics around circumference has been found on disc-braked wheels in ICE, in which the third harmonic dominated for solid steel wheels, while the second harmonic was common for rubber sprung wheels [5]. The research on high-order polygonisation (15–25 orders) had not been carried out until recent years, when new problems and challenges in HSR operation were raised. For HSR, there is an increasing demand for relative studies on this problem because it is reported that high-order polygonisation with very small radial deviation (< 0.05 mm, or <20 dB re 1 μm) can cause abnormal vibration and even failures to the bogie components. The influences of polygonal wheels on track structure and vehicle components are studied by [13, 14]. It is revealed that: (1) the wheel-rail impact normal force increases with the deepening of the wheel polygonal wear; (2) the amplitude of the normal force fluctuation depends mainly on the wavelength and depth of the wheel polygonal wear on the wheel running surface; and (3) the stress load cycles induced by wheel polygonisation can considerably increase the propagations of the initial crack in the wheel axle.
\nAs per increasing of demand for HSR, rail defects have become a critical challenge in operation because an incident could cause more losses when trains run at higher speed. Many researchers have proposed classification methods for typical types of rail cracks derived from different propagation orientations of rail defects [15, 16]. The most common rail defects are caused by inappropriate manufacturing and inappropriate use of rails, and they mainly include transverse defects (TD), detail fractures (DF) and split heads. TD (Figure 1a) is one of the most critical type of cracks that appear in railheads propagating along lateral direction. DF (Figure 1b) has an origination point and grows radially from the origination point. These types of defects are caused by inappropriate use such as excessive stress concentrations. The vertical split heads (VSH) (Figure 2a), which usually originate from manufacturing anomalies, cause the second most train derailments (after TD).
\nTransverse defect and detail fracture [
Split head [
RCF has become a significant economic and safety challenge for HSR and metro lines. Fatigue fracture occurs as a result of a periodic loading applied to the materials which exceeds its fatigue limit. Normally, it will lie between 35 and 60% of the tensile strength of rail [17]. Once a fatigue crack has initiated, it will spawn with every period of loading. At the beginning, it is very gentle and then quicker until a critical size is achieved [18]. Typical RCF originating at rail surface includes head checks, surface gauge corner head checks and squats. The cracks generate as the rails experience huge impacts from the wheels [19, 20] and the fatigue damage results from the normal and shearing stresses of the wheel-rail interaction [21]. A micro-crack may induce surface spalling effect when it propagates from the railhead to inner parts of the rail. In addition, RCF can cause corrugation and bolt hole cracks on the rails, significantly influencing track structure. Generally, there are six classes of corrugation: short-pitch corrugation, light rail corrugation, corrugation on sleepers, contact fatigue corrugation, rutting and roaring rails and heavy haul corrugation [22].
\nThe most effective and common strategy to control the wheel defects is wheel re-profiling [5] which can eliminate local defects and polygonisation and reduce the resulting noise and vibration [4]. In modern HSR wheel maintenance, many modern depots are equipped with a wheel re-profiling facility known as a wheel lathe and the wheelsets are not necessary to be disassembled during re-profiling. However, the wheel re-profiling always follows a time or mileage-base schedule per earlier experience or supplier’s specification. Consequently, it can decrease the wheel diameter and thereby shorten the service lives of the healthy wheels which are scheduled to be re-profiled. Therefore, there is a large economic incentive for adopting condition-based maintenance (CBM) scheme based on advanced NDT and SHM techniques, to reduce maintenance costs of wheelsets and efficiently preventing the hazards imposed by wheel defects. There are two main types of CBM approaches: in-service (online) condition monitoring and in-depot (offline) inspection [23]. The former one provides real-time condition information for maintenance planning, while the latter approach, normally done at a fixed interval, can offer accurate measurement for condition assessment of vehicle components.
\nWheel tread roughness measurement (in-depot inspection) is a direct way of collecting wheel condition information for maintenance, monitoring profiles in conjunction with wear problems. With wheel roughness measurement data, the wheel re-profiling strategy can be optimised using data-driven wear model [24]. The NDT technologies employed by roughness measurement include linear variable differential transformer (LVDT), the mechanical displacement probe, the rotation sensor, electromagnetic acoustic transducer (EMAT) [25], laser-ultrasonics [26], laser-air hybrid ultrasonic technique (LAHUT) [27] and other novel NDT techniques [28, 29, 30]. Some even allow the trains run at a low speed during inspection [30]. However, for measurement methods using ultrasound pulse-echo technique, it is sometimes difficult to detect wheel flats because they usually have smooth edges that do not generate echoes [31]. There are now many commercial devices that allow the measurement to be done in depot with high efficiency, such as ØDS measurement instrument, Miniprof, MÜLLER-BBM, etc.
\nExisting online wheel condition monitoring systems mainly include trackside wheel impact load detector (WILD), force gauges installed on sleeper pads, distributed sensors based on Brillouin optical time domain analysis (BOTDA), accelerometer-based trackside detector, acoustic detectors, laser- and video camera-based detectors, etc.
\nBy deploying strain gauges and accelerometers on the rail, it is possible to measure wheel-rail contact force or rail acceleration response when a train passes over the instrumented rail section. These devices report impact as either a force at the wheel-rail contact interface or a relative measure of the defect [10]. The most common WILD is composed of a series of strain gauge load circuits mounted on the neutral axis of the rail between two adjacent fasteners in several consecutive sleeper bays to quantify the wheel-rail interaction force.
\nJohansson and Nielsen [1] made use of this set-up to build a detector on the rail web in nine consecutive sleeper bays. Nielsen and Oscarsson [32] used both rail web and rail foot strain gauges to measure the wheel impact load and rail bending moment. Stratman et al. [33] proposes new criteria for removal of wheels with high likelihood of failure, based on two real-time SHM trends that were developed using data collected from in-service trains. Filograno et al. [34] developed an FBG-based sensing system comprising FBG strain gauges mounted at both rail web and rail foot enables train identification, axle counting, speed and acceleration detection, wheel imperfections monitoring and dynamic load calculation. They have expanded the application of this system in the Madrid-Barcelona HSR line [34]. An FBG-based wheel imperfection detection system that can provide in-service measurement of wheel condition was developed by The Hong Kong Polytechnic. It offers a comprehensive health monitoring scheme for vehicle and track in the entire railway network of Hong Kong [35]. A monitoring system has been proposed with FBG sensors implemented on rail tracks to detect wheel local defects such as wheel flats and polygonisation [36]. The impacts of wheel/rail interactions caused by wheel local defects are reflected as subtle anomalies in response to signals collected by FBG sensors, and the deployed system is shown in Figure 3a. The detecting results match well with those from offline inspection (Figure 3b).
\nHigh-speed train wheel defect detection using online FBG-based system [
In addition to the strain gauge-based detector, there are other methods for online wheel load measurement to assess the condition of passing wheels, such as force gauges installed on sleeper pads, distributed sensors based on Brillouin optical time domain analysis (BOTDA), etc. Besides, there are also some commercial WILDs, such as WheelChex® system, GOTCHA system (optic fibre-based wheel-flat detection and axle load measurement system), and MULTIRAIL WheelScan.
\nAccelerometer-based systems can provide 100% coverage of the circumference of a wheel of any size in defect detection [10]. Skarlatos et al. [37] used two B&K accelerometers placed on the rail foot to pick up the rail vibration signals for diagnosis of wheel defects. Belotti et al. [38] used four consecutive accelerometers and an inductive axle-counter block which help to discriminate the response corresponding to each wheel. Seco et al. [39] proposed a trackside detector which has eight accelerometers installed on both bend zone and straight zone. However, the acceleration data are difficult to convert to wheel-rail impact load, which is widely used as wheel local defect indicator [5]. This is mainly because the measured acceleration signal could not directly refer to the excitation of each wheels, and sometimes an additional axle counter is needed [23]. Furthermore, their performance might be limited by their repeatability and by the analysis applied to the accelerations acquired.
\nThe commonly used noise detector is called trackside acoustic array detectors (TAADs), which make use of arrays of high-fidelity microphones to listen to the audible noises produced by the passing trains [40]. There are also some commercially available systems, such as trackside acoustic detection system (TADSTM) and the RailBAMTM [41, 42]. However, these systems are specialised in wheel bearing fault diagnosis rather than wheel tread defect detection. For the slight flat defect of high-speed train wheel (flat depth < 0.5 mm), this method may not be applicable because when the train runs at high speed (>200 km/h), the prediction accuracy can be limited [11].
\nThere are various types of wheel roughness monitoring systems based on laser and video cameras. Some typical or well-known detectors include wheel profile detectors (WPDs), MBV-systems, wheel profile measurement system (WPMS) and those based on light illumination devices, light-sensing devices, charge-coupled device (CCD) camera, and laser displacement sensors (LDSs).
\nWPDs are based on a combination of lasers and video cameras to automatically measure the wheel profile while train is in motion [40]. These data acquired from WPDs include wheel profile and wear, wheel diameter, height and thickness of the flange, back-to-back distance and wheel inclination. A prototype of a condition monitoring system called MBV-systems is presented by Lagnebäck [43] for measuring the profile of the wheels with a laser and a camera. An automatic WPMS based on laser and high-speed camera was installed on an iron ore line in Sweden in 2011 and can measure the wheel profile for speeds up to 140 km/h [44]. This system, which is in a CBM manner, has been attracting more and more interest from maintenance engineers in the Swedish railway sector. Zhang et al. [45] presented an online non-contact method for measuring a wheelset’s geometric parameters based on the opto-electronic measuring technique. The system contains a charge-coupled device (CCD) camera with a selected optical lens and a frame grabber, which was used to capture the image of the light profile of the wheelset illuminated by a linear laser. Besides, there are some newly designed laser-based online detectors, which are immune to vibration and on-site noise, easy to calibrate, with high efficiency of data acquisition and with high accuracy of positioning [46, 47].
\nManual inspection method is still widely used in most routine track inspections until today since it can directly figure out rail defects. However, it needs experienced workers and involves significant human input and judgement [48]. Therefore, NDT&E techniques, which enable rail inspection in an automated manner, are in need. NDT techniques were advocated for rail inspection as early as the 1920s [49]. Ultrasonic testing (UT) emerged in the 1960s became dominant in rail inspection [10, 50]. With the development of UT, European countries and Japan have released a variety of forms of ultrasonic rail flaw detection equipment, such as portable types, hand-push types, road and rail dual-use vehicles and specialised rail-testing trains [28]. While being extensively utilised, both the magnetic induction testing and conventional UT methods are not suitable for all defect scenarios; for example, they offer poor sensitivity to defects located in the rail web and rail foot [51]. A wide variety of inspection techniques are under research and development with the target to enhance the detection capability.
\nTo enhance accuracy, speed and detection rate in rail defect detection, many research efforts have been made to improve the detection methods and develop advanced UT techniques. The novel techniques include laser ultrasonic testing (LUT), phased array ultrasonic testing (PAUT), electromagnetic acoustic testing or electromagnetic acoustic transducer (EMAT), guided wave testing (GWT) and acoustic emission testing (AET).
\nCompared with traditional piezoelectric UT, LUT has its own merits such as non-contact and no coupling agent. The laser device can be located relatively far away from the rail with optic-fibre used as transmission media. This enables the establishment of trackside monitoring system. Besides, with good interference immunisation, laser can be used in measurement in adverse environment or high temperature. Pulsating laser works on solid surface and produces longitudinal wave, lateral wave and surface wave simultaneously. As a result, it can be applied to detect not only surface defects but also internal defects. Yet certain problems exist in LUT, such as low efficiency of light-sound energy transformation, weak ultrasonic signal and high cost of detection equipment.
\nNielsen et al. [52] developed an automatic LUT-based system for rail inspection, named LURI, which was tested on a railroad line containing man-made structural defects. This system can detect defects on the running surface of the rail, as well as horizontal and vertical flaws in the railhead. Kenderian et al. [53] developed the first non-contact testing system based on laser-air hybrid ultrasonic technique for rail defect inspection. The system can detect VSH defects and thermal fatigue cracks with a success rate of nearly 100%, and rail web defects with a rate of approximately 90%. Lanza et al. [54] developed a laser/air-coupled rail defect detection system, which can accurately locate rail transverse cracks by using laser emission and ultrasonic wave for detection.
\nPAUT, developed from the research on phased array radar, can detect cracks in different directions, depth and locations conveniently. Utrata and Clark [55] present groundwork of PAUT methods, which provided useful information and evidences for the positioning of phased array (PA) probes in rail flaw detection. PAUT is now widely applied in rail defect detection, covering railhead, rail web, rail base and weld areas. Institutes that carry out research on PAUT for rail defect detection include: Transportation Technology Centre Inc. (TCCI), Lowa State University, University of Warwick, University of Birmingham in UK, TWI Company and Socomate in France, etc.
\nWooh and Wang [56] developed a hybrid array transducer which is an assembly of a linear phase and a static array and can accurately assess real defects in rail specimens. Speno International Company [57] developed an ultrasonic rail testing equipment based on multi-element phased array technology and the equipment was installed on a trial inspection car which can achieve a speed of 80 km/h and a sampling rate of 6 kHz when detecting rail defects. TTCI [58] developed an Omni-scan PAUT system which was applied in on-site detection of TDs. Field test of the system was conducted on the Facility for Accelerated Service Testing (FAST) of TTCI.
\nEMAT, as a kind of excitation and detection technique of propagating ultrasonic wave, can provide detection of defects located in subsurface area of railhead. Thus, a promising method appears to be electromagnetic-acoustic method which is realised by EMAT transducers. Both transverse and longitudinal cracks in railhead can be detected by using EMATs, as shown in Figure 4 [59]. University of Warwick and University of Birmingham [60] developed a railway surface-detect inspection technique based on EMAT equipped with two EMAT converters, one for emitting surface Rayleigh waves and the other for receiving surface propagating Rayleigh waves. It is found that this technique can improve the inspection rate of horizontal and vertical defects on the railheads, compared with piezoelectric transducers. University of Warwick [61] designed a lab-based laser-EMAT system to investigate the ultrasonic surface wave’s generation, propagation and interaction on the railhead with a Michelson interferometer measuring the out-of-plane displacement. The Rayleigh-like wave generated by EMAT can flood the whole curve makes it capable to detect the gauge corner cracking.
\nRail cracks detection using EMAT [
GWT techniques have been widely investigated over the past decades because of the potential for long-range interrogation and detecting vertical-transverse defects under shelling and weld defects [62, 63]. They are ideal in SHM applications that can benefit from built-in transduction, moderately large inspection ranges and high sensitivity to small flaws. In rail applications, since ultrasonic guided wave can propagate through the discontinuous defects on rail surface, the screening effect of lateral cracks distributed underneath produced by surface detachment can be minimised.
\nRose et al. [63] developed a GWT inspection system with non-contact air-coupled and EMATs to transmit and receive guided waves for the detection of transverse defects under shelling. Wilcox et al. [64] developed a GWT system with a dry-coupled piezoelectric transducer array to detect smooth transverse-vertical defects and alumino-thermic welds, but this system requires interruption of the operation of trains. Lanza et al. [54] developed a GWT system using a pulsed laser to generate ultrasonic guided waves and air-coupled transducers to sense the guided waves for the detection of vertical cracks hidden below horizontal cracks. Park et al. [65] proposed a built-in active sensing system consisting of two piezoelectric patches in conjunction with both impedance and guided wave propagation methods for rail defect detection. Marine Technology Association of South Africa and Council of Scientific and Industrial Research [66] jointly developed solar power GWT detection system (Figure 5). The coverage of the single system for rail defect detection is up to 2 km. Imperial College London and Guided Ultrasonics Ltd. cooperatively developed a G-shaped scanning ultrasonic rail track detection device, which can inspect vertically distributed defects and alumino-thermic weld joint [67], as shown in Figure 6. It can effectively inspect 18-mm-deep defects under rail crossing nose.
\nMonitoring system on freight line in South Africa [
G-type scan guided wave in inspection device in UK [
Different from common ultrasonic inspection, acoustic emission (AE) is instantaneous elastic waves by quick release of localised energy in solid materials under external applied loads. AE events can be captured by the piezoelectric sensors, generated elastic waves along all directions. Many sensors can be utilised to document arrival time of the signals and the variation of frequency during the crack initiation process. Hence, the nature of cracks can be determined. Through experimental study, AE has been proven a feasible solution in defecting rail detection, especially in rotating machinery [68]. A simplified analytical model, which separates defects caused by AE activities from background noise, was proposed by Thakkar et al. [48]. They also investigated the physical interaction between AE and axial load, speed, as well as traction through experiment. It is found that AE signal can be used for analysing the defects on the surface of the rail under normal operating speed.
\nThe application of AET on rail defect detection is rarely reported. Previous research [69] shows that the benefit of AET may be limited due to imperfection of materials, which can produce different nature of signal source. Besides, the installation of the sensor may also affect the AE signal generation. It may also be affected by wheel and track defect for any misalignment [48]. Another concern of AET is signal processing for those AE waves that have similar amplitude with that of background noise produced by the rolling wheel [18]. Advanced data learning and updating methods have been investigated dealing with great uncertainties arisen from the online monitoring data for more accurate and efficient damage diagnosis. AE method incorporating Bayesian framework is utilised in an online rail turnout crack monitoring system developed by CNERC-Rail [70]. The method is able to detect defects without training data of damaged rail structure and the monitoring systems have been implemented on Shanghai-Nanjing HSR lines, as shown in left panel of Figure 7. The rail turnout conditions are indicated in a probabilistic manner through a structure health index (SHI), as shown in right panel of Figure 7.
\n(Left) Online HSR turnout condition monitoring system; (right) defect diagnosis method with model updating approach [
Magnetic particle testing [71] can be used easily to detect the specimen surface defects. But, the result is very sensitive to the specimen surface condition. If the specimen surface is coated or wet, the reliability of the detect result will decrease a lot. Therefore, removing the coating materials and surface drying are necessary before testing.
\nEddy current testing is very simple and easy to detect surface and shallow internal cracks [28]. Eddy current sensors have been mounted on the bogie of track inspection cars and equipped in roller-guided trolleys for mobile inspection of rails [28]. They are able to detect surface and near-surface defects in the railhead but fail to locate internal defects.
\nThe alternating current field measurement (ACFM) technique is an electromagnetic inspection method that uses hand-held probes, and computerised control, data acquisition and computational models. ACFM is more efficient than conventional inspection methods due to a reduced need for surface preparation and an ability to work through surface coatings. ACFM also has an added benefit that it is not only capable of detecting flaws but can also detect size defects for length and depth [72]. In 2000, TSC with the support of Bombardier Transportation began the development of an advanced ACFM system for application in the rail industry. Following the experimental work on the train axles, it became evident that an ACFM system could be deployed to detect RCF cracking on rails. This led to the development of a pedestrian-operated ACFM walking stick [73]. The inspection of the railhead is carried out by sequentially scanning across the group of sensors enabling the uninterrupted inspection of the rail. The system can detect and size gauge corner cracks and head checks smaller than 2 mm in depth. However, the ACFM sensors cannot quantify squats accurately and are unable to detect short-wave corrugation and wheelburns.
\nIn recent years, optic fibre sensors have been advocated for application to rail infrastructure monitoring. The FBG sensors have merits of being immune to electromagnetic interference (EMI) and no power supply is needed on-site. A monitoring system based on the FBG technology has been developed and installed on an operating rail line in Hong Kong for real-time and continuous detection of rail strain and temperature, rail breaks, axle counting, wheel imperfection assessment and dynamic loading identification [35]. Wang et al. [74] proposed a rail performance monitoring and safety warning system and implemented this system on a rail line by deploying FBG sensors in the rail web and at the expansion joints between supporting concrete slabs. Yoon et al. [75] proposed a distributed fibre sensory system based on Brillouin scattering and a correlation domain analysis technique for longitudinal strain monitoring of rails. Ni et al. developed a deformation monitoring system for an in-service HSR tunnel using an FBG-based monitoring system [76]. An array of FBG bending gauges was deployed at the rail slab of a segment inside the tunnel. Upon occurrences of deformation, there would be relative rotation between two adjacent bending gauges. Phase shift of the FBG sensors caused by the relative rotations was recorded, and the deformation can then be derived, resulting in a profile of the deforming rail slab, and the deformation of the tunnel can be inferred.
\nFBG sensors for detecting acousto-ultrasonic signals have been studied since the mid-1990s [77]. The conventional interrogation technique for FBGs as sensing elements utilises their spectral encoding and decoding capabilities for the measurand; however, the spectral decoding capability cannot be used to detect high-frequency signals (e.g., acoustic and ultrasonic waves) due to the low wavelength scanning speed. Appropriate demodulation techniques capable of high-sensitivity detection of high-frequency waves are necessary to develop acousto-ultrasonic FBG sensors. There are two main approaches to detecting acoustic and ultrasonic waves with FBGs: the first one uses a narrowband light source to illuminate the FBGs and demodulate the power intensity variation when the waves impinge on the FBGs, while the second one uses a broadband light source and an optic filter. Minardo et al. [78] conducted a numerical investigation on the response of FBGs subjected to longitudinal ultrasonic waves. Ni et al. [79] have developed a hybrid monitoring system using FBG sensors to interrogate ultrasound signals emitted by PZT sensors (Figure 8). The hybrid system has been verified in lab and a test line in mainland China.
\nSchematic set-up of the FBG-PZT monitoring system [
With embedded hybrid monitoring systems of FBG and PZT sensors, the SHM techniques have shown their promising prospect in HSR, enabling real-time monitoring of structural conditions of in-service trains and rail infrastructure. To realise large-scale utilisation on numerous HSR lines worldwide, practical solutions ought to be achieved concerning both economic and efficient aspects, answering for the need of early warning and quick decision-making upon emergencies in high-speed operation and guiding the potential development direction of SHM applications on HSR in the coming decades.
\nWireless sensing network (WSN) provides a cost-effective approach eliminating wires and enabling remote sensing, which largely enhances the practical applicability of SHM [80, 81]. A wireless-based system was designed to monitor the performance of rail vehicles by Nejikovsky and Keller [82]. The communication in the WSN system can be made through satellite and Ethernet, while data are uploaded onto cloud for storage and transmission to control room far away from site; system data transmission plan can be found in the aforementioned railway tunnel deformation project [76]. Particularly, in terms of near-field communication, radio frequency identification (RFID) has been proposed as a competitive candidate [83], which provides a new thinking on emerging RFID modules in normal sensors. The passive RFID sensors embedded in the HSR structures need no wired power supply and can be activated by passing trains, sending structural condition information.
\nContinuous online monitoring of HSR over multiple HSR lines puts forward the difficulty in storage and analysis with massive data collected. The authors’ team has long been dedicated to damage diagnosis and prognosis of HSR based on monitoring data with updating and learning methods. Facing the data amount issue, compressive sensing, which is able to sample data at sub-Nyquist sampling rate while maintaining almost all the original information, is being actively investigated to streamline the axle box acceleration data from an operating high-speed train and has successfully verified the feasibility of sub-Nyquist data acquisition in HSR online monitoring [84, 85]. This is of great significance to wireless sensing and RFID where transmitted data amount is limited.
\nVarious sensing technologies have long been benefiting rail industries with systematic and reliable inspection and monitoring. In turn, the vigorous development of HSR has been pushing research in sensing technologies with flourishing state-of-the-art deliverables coming out. The HSR is expanding worldwide, satisfying people’s growing demands in travelling with ease and comfort, and bringing heavier inspection and maintenance tasks. In response to the expanding HSR network, conventional offline inspection will still be the primary approach taking up most of the work, and online SHM will be a powerful supporting tool playing a more important role and reflecting real-time states of the operation HSR systems. The use of sensors will be less solitary and separated but more in a combined manner containing multi-disciplinary subjects from mechanical engineering, civil engineering, electrical engineering to computer science, mathematics, etc. Moreover, the requirements to contemporary sensing go beyond fundamental functions of accuracy and reliability to flexibility, portability and environment-friendly. Taking advance of nature of railway, the SHM applications on HSR can do more than environment-friendly. The concept proposed by the authors, a high-speed train with embedded sensing systems can be treated as an integrated moving sensor, capable of gathering information not restricted to structural conditions, but air conditions inside and outside the car body concerning surrounding environment and people’s health. Having accomplished multiple SHM projects on HSR lines, we are initiating just calling a start, and in the near future, the encounter of sensing technologies and HSR will continuously foster reciprocal developments, paving a high-speed path to structural well-being, sustainable environment and social health.
\nThe authors appreciate the funding support by the Ministry of Science and Technology of China and the Innovation and Technology Commission of Hong Kong SAR Government to the Hong Kong Branch of Chinese National Rail Transit Electrification and Automation Engineering Technology Research Center (Grants Nos. 2018YFE0190100 and K-BBY1).
\nGlobal prevalence estimates suggest that approximately 196 million people lived with age-related macular degeneration (AMD) in 2020. Of these, 10.4 million people were living with moderate to severe vision impairment. In 2030, AMD is estimated to affect 243 million people due to aging [1]. The pathogenesis of AMD results from complex multifactorial interactions, including metabolic, genetic, and environmental [2]. AMD has been classified into two major subtypes: non-exudative or dry AMD and exudative or wet AMD. Although dry AMD represents 90% of patients, exudative AMD causes more severe loss of vision, being the target of most investigations [3]. These patients require very regular clinic visits, and the chronicity of anti-vascular endothelial growth factor (anti-VEGF) therapy can substantially impact the quality of life of the patient and the caregivers [4, 5]. This decrease can compromise anti-VEGF therapy compliance and explain the undertreatment of patients observed in real-world studies and the waiver of patients involved in clinical trials [6, 7]. New trials are focusing on improving the therapeutic options, particularly on the decrease of the associated burden. This chapter describes the current research on therapeutical approaches to treat the dry and exudative forms of AMD. Figure 1 summarizes the drugs and stages of development.
Summary of new drugs in the pipeline for the management of age-related macular degeneration (AMD).
The information was gathered from a medical literature review and ongoing clinical trials and their results in the area of AMD treatment using PubMed database (https://www.ncbi.nlm.nih.gov/pubmed). The words or medical head subjects used were: AMD and clinical trials. All relevant articles were imported into Zotero (Version 5.0, Center for History and New Media at Universidade George Mason, USA), and duplicate articles were deleted. We selected the promising therapies according to action mechanisms and excluded all therapies that had failed in clinical trials. Comments, editorials, and articles not written in English were not analyzed.
Although lampalizumab (anti-factor D Fab) and eculizumab (inhibitor of the activation of terminal complement) failed to slow geographic atrophy progression, the complement system has been implicated in the pathogenesis of geographic atrophy, and so, research on how to inhibit the complement system did not stop [8, 9].
Pegcetacoplan (APL-2; Apellis Pharmaceuticals, Waltham, Massachusetts, USA) is a synthetic molecule that selectively inhibits C3, effectively downregulating all three complement pathways. Phase 2 of the FILLY clinical trial compared patients receiving intravitreal injection (monthly and bi-monthly) with a control group. The results showed a 29% reduction in the rate of geographic atrophy and a better outcome in the monthly injection group. Moreover, it was observed that the risk of neovascular AMD was higher (18%) in the group subjected to monthly injections when comparing with the group subjected to bi-monthly injections (8%) and with the control group (1%) [10]. A phase 3 trial is currently in the recruitment phase (NCT03525600) [11].
Avacincaptad pegol (Zimura; Iveric Bio, New York, New York, USA) is a C5 inhibitor. Phase 2/3 GATHER1 clinical trial showed a significant reduction of geographic atrophy growth over 12 months, probably due to C3 activity preservation. A second confirmatory trial (GATHER2) is underway [12].
Retinal neuroprotection strategies have been studied for dry AMD, including apoptosis and necrosis prevention, and oxidative injury reduction [13].
Elamipretide (Stealth Biotherapeutics) is a mitochondria-targeted drug thought to reduce mitochondrial dysfunction. Phase 1 of the ReCLAIM clinical trial showed that elamipretide was safe, well-tolerated and that this drug may improve vision in patients with intermediate AMD, manifested as high-risk drusen [14]. Phase 2 ReCLAIM-2 clinical trial is underway [15].
Brimonidine tartrate (Allergan) is best known in glaucoma as the intraocular pressure (IOP) lowering agent. Phase 2A of the BEACON clinical trial assessed the intravitreally delivery of brimonidine through a delayed delivery system. Results showed a lower rate of geographic atrophy progression, although not statistically significant [16]. Phase 2B of the BEACON clinical trial demonstrated a reduction in geographic atrophy progression using higher doses of brimonidine [17]. Phase 3 of IMAGINE and ENVISION clinical trials are being designed [16].
One of the earliest changes in the retina that precede AMD symptoms is the formation of toxic vitamin A dimers.
ALK-001 (Alkeus Pharmaceuticals) is a chemically modified form of vitamin A that replaces the vitamin A in the body to prevent toxic vitamin A dimers. Studies demonstrated functional preservation of visual function in animal models [18]. Phase 3 of the SAGA clinical trial will measure the extent to which treatment with the oral capsule of ALK-001 slows geographic atrophy progression [19].
Cell therapy is an alternative strategy when the naturally existing cells are already too damaged to be preserved using neuroprotective agents. Human pluripotent stem cells (hPSCs) comprise human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs). There are two subtypes of cell-based treatments: stem cell therapies that involve delivering new retinal pigment epithelial (RPE) cells to the subretinal space, and non-stem cell therapies based on cell implantation, which generates protective factors [20].
MA09-hRPE (Astellas Pharma) is hESC-derived Retinal Pigment Epithelium (hESC-RPE). The phases 1/2 clinical trial results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine [21, 22, 23].
CPCB-RPE1 (The California Project to Cure Blindness-Retinal Pigment Epithelium1) is a polarized monolayer of hESC-RPE ultrathin, synthetic parylene substrate designed to mimic Bruch’s membrane. This therapy involves a subretinal implant. It was demonstrated the feasibility and safety of CPCB-RPE1 subretinal implantation in a comparable animal model [24]. Phase 1/2A of the clinical trial suggests that CPCB-RPE1 may improve visual function [25, 26].
Inflammation has been implicated in AMD pathogenesis and progression, even though it is no classical inflammatory disease like uveitis [27].
Doxycycline (Oracea; Galderma Laboratories, Fort Worth, Texas, USA) is an antibiotic that belongs to the tetracycline class of antibiotics and plays a role in immunomodulation, cell proliferation, angiogenesis, and the regulation of inflammation. Phase 3 of the TOGA clinical trial includes patients with geographic atrophy randomized in groups treated with Oracea® or placebo. The results are pending [28].
FHTR2163 (Genentech/Roche) is a new antibody delivered by intravitreal injection that inhibits the HTRA1 gene associated with geographic atrophy. Phase 2 of the GALLEGO clinical trial will evaluate the safety, tolerability, and efficacy of intravitreal injections of RG6147, administered every four or every eight weeks for a total of approximately 76 weeks, in participants with geographic atrophy secondary to AMD (when compared with the sham control) [29].
Potentially more durable anti-VEGF agents may reduce the burden of intravitreal injections, help stabilize the disease and improve compliance with treatment.
Brolucizumab (Beovu; Novartis, Basel, Switzerland) is the most recent intravitreal anti-VEGF agent to receive FDA approval. It is a humanized single-chain antibody fragment with a molecular weight of 26 kDa. Phase 3 of the HAWK and HARRIER clinical trials showed that brolucizumab was non-inferior to aflibercept regarding visual function as at week 48, more than 50% of the eyes treated with 6 mg of brolucizumab were maintained on q12w dosing intervals. Moreover, anatomic outcomes favored brolucizumab over aflibercept, and the overall safety results were similar between the two drugs [30].
Abicipar pegol (Allergan) is a novel class of molecules referred to as designed ankyrin repeat proteins (DARPin) that bind VEGF-A. DARPin is smaller and has a high affinity to VEGF, leading to greater stability and a longer-acting effect. The results of phase 3 of the SEQUOIA and CEDAR clinical trials showed that the eight and 12-week abicipar regimens were non-inferior to the ranibizumab’s monthly regimen, but patients had a much higher risk of developing intraocular inflammation (15% and 15.4% vs. 0%) [31, 32, 33]. The company modified the manufacturing process after finding impurities in the formulation, and subsequently, the MAPLE study showed a decrease in the incidence of intraocular inflammation to 8.9% [34]. A license for abicipar pegol was already submitted to the
Conbercept (Chengdu Kanghong Biotech Co., Ltd.) is an antibody that targets VEGF-A, VEGFB, VEGF-C, and placental growth factors. It was approved to treat exudative AMD in China in 2013. Phase 2 of the AURORA and phase 3 of the PHOENIX clinical trials showed the safety and efficacy of conbercept with three initial monthly treatments followed by quarterly treatments compared with the sham group [35, 36]. Phase 3 of the PANDA-1 and PANDA-2 global clinical trials compare maintenance doses of conbercept every 8 or 12 weeks with doses of aflibercept every eight weeks; results are expected in 2022 [37, 38].
OPT-302 (Opthea Limited) is a soluble form of the human VEGF receptor-3 (VEGFR-3), expressed as an Fc-fusion protein molecule design to inhibit VEGF-C and VEGF-D. Results from phases 1 and 2 of the ShORe and COAST clinical trials showed that this molecule was safer and had better visual outcomes than ranibizumab alone [39, 40]. Phase 3 of the ShORe and COAST clinical trials will be double-masked and sham-controlled. Treatment-naïve patients will be enrolled to assess the efficacy and safety of 2.0 mg OPT-302 combined with anti-VEGF-A therapy by comparison with anti-VEGF-A monotherapy (standard of care). Opthea expects to initiate patient recruitment in the first half of 2021 [41].
Faricimab (Roche, Genentech) is a novel bispecific antibody that targets both angiopoietin-2 (Ang-2) and VEGF-A. Phase 2 of the STAIRWAY clinical trial suggests that faricimab can be an effective maintenance therapy for exudative AMD with a dosing interval of 16 weeks [42, 43]. Phase 3 of the TANAYA and LUCERNE clinical trials will compare faricimab given every 16 weeks with aflibercept given every eight weeks [44, 45]. FDA requests for faricimab are expected to occur in 2021 for diabetic macular edema and in 2022 for exudative AMD.
KSI-301 (Kodiak Sciences) is a novel intravitreal, anti-VEGF antibody biopolymer conjugate designed to block all VEGF-A isoforms. Phase 1 of the DAZZLE clinical trial showed excellent safety, strong efficacy, and considerable durability in most patients for three or more months [46]. Phase 2 of the DAZZLE clinical trial is a prospective, randomized controlled clinical trial designed to evaluate the safety and efficacy of KSI-301 [47].
ONS-5010 (Outlook Therapeutics, Inc) is an ophthalmic formulation of bevacizumab. Phase 3 clinical trials compare monthly doses of ONS-5010 with a ranibizumab regimen of 3 monthly doses followed by quarterly doses [48]. FDA approval is expected in 2021 or 2022, and 12 years of exclusivity, protecting against bevacizumab biosimilars, are expected.
FYB201 (Formycon and Bioeq), SB11 (Samsung Bioepis), and Xlucane (Xbrane Biopharma) are biosimilars for ranibizumab under development that are expected to reach the market in less than one year when the patent for ranibizumab expires [49, 50, 51].
Aflibercept biosimilars are in phase 3 of clinical trials and are expected to reach the market between two and three years when the patent for aflibercept expires.
Although regorafenib, pazopanib, and LHA510 failed, other therapies showed promising results [52, 53, 54]. These formulations have the great advantage of being less invasive, but they can decrease the possibility of monitoring treatment compliance, as it happens with glaucoma patients medicated with lowering ocular hypertension drops.
PAN-90806 (PanOptica) is a topical formulation of a small molecule, a tyrosine kinase inhibitor (TKI), to treat wet AMD. In phase 1/2 of a dose-ranging clinical trial, more than half of patients receiving PAN-90806 once a day for 12 weeks completed the study without needing anti-VEGF rescue therapy. Fourteen of the 51 patients in the study, 88% experienced clinical improvement of their condition or their disease’s stability [55].
Squalamine lactate (Genaera Corporation) is an amino sterol derived from the dogfish shark’s cartilage that blocks VEGF, PDGF basic fibroblast growth binding calmodulin and its chaperones. A phase 2 clinical trial showed improved vision when squalamine lactate was used in combination with anti-VEGF treatments [56, 57].
The extended-release options may also reduce the burden of intravitreal injections.
The port delivery system (PDS; Hoffmann-La Roche) is a permanent, refillable implant, which is surgically placed at the pars plana through an incision in the sclera. PDS continuously releases concentrated ranibizumab by passive diffusion into the vitreous cavity.
Phase 2 of the LADDER clinical trial showed similar functional and anatomical outcomes after nine months of treatment with ranibizumab delivered through PDS or monthly intravitreal injections of ranibizumab [58, 59]. The mean time for the first PDS refill was 15 months, with 80% of patients not requiring a PDS refill for six or more months. Phase 3 of the ARCHWAY clinical trial is ongoing [60].
GB-102 (Graybug Vision) is a depot formulation of sunitinib malate that might need only 2 or 3 treatments per year [61]. Phase 2 of the ALTISSIMO clinical trial evaluated the safety and effect duration of GB-102 intravitreal injections administered every six months compared to aflibercept intravitreal injections administered every two months [62]. The results are currently pending.
NT-503 (Neurotech Pharmaceuticals) is a biological sustained drug delivery device that can provide anti-VEGF therapy’s continuous delivery. Preliminary studies show that the device can be implanted safely in humans [63]. The results of phases 1 and 2 of clinical trials are pending [64].
Aflibercept Hydrogel Depot (Regeneron Pharmaceuticals and Ocular Therapeutix™) is a delivery system based on a PolyActive hydrogel copolymer’s microparticles. In studies with animals intravitreally injected with aflibercept hydrogel depot a, sustained and controlled release of aflibercept was achieved. No adverse effects in the eyes of healthy rhesus macaques were observed for up to 6 months [65].
pSivida Durasert Technology (EyePoint Pharmaceuticals, Inc.) can be used to deliver different drugs for extended periods (months or even years) with a single application. Delivery of a tyrosine kinase inhibitor in animals provided promising results [66].
Gene therapy is based on the insertion of an anti-VEGF coding sequence into retinal cells’ DNA through a viral vector.
ADVM-022 (Adverum) produces an anti-VEGF-A fusion protein delivered through intravitreal injection via the AAV.7 m8 viral vector. Phase 1 of the OPTIC clinical trial showed that treatment with a single injection prevented additional anti-VEGF treatment over six months [67, 68].
RGX-314 (RegenexBio) (Rockville, MA, USA) produces an anti-VEGF A fab delivered through a subretinal treatment via an AAV8 viral vector. Phases 1/2a of the AAVIATE clinical trial showed a decrease in injection burden without significant inflammation or adverse effects [69]. Phase 2b of the AAVIATE clinical trial will explore a suprachoroidal injection [70].
Retinostat (Oxford BioMedica) is a lentiviral vector expressing endostatin and angiostatin to inhibit angiogenesis potentially. Phase 1 clinical trial showed that the LentiVector® gene therapy platform safely and efficiently delivered genes to the retina resulting in stable, long-term expression [71].
AAV2-sFLT01 (Genzyme, a Sanofi Company) is a vector that expresses a modified soluble Flt1 receptor designed to neutralize the proangiogenic activities of VEGF via an intravitreal injection. Phase 1 clinical trial showed that AAV2-sFLT01 was safe and that there was good tolerance to this vector [72]. After three years of follow-up, AAV2-sFLT01 appears to be generally safe, well-tolerated and does not appear to raise any new safety concerns [73].
AAVCAGsCD59 (Hemera Biosciences) is a molecule that targets the terminal step of complement activation that leads to the formation of the membrane attack complex. Two-phase 1 clinical trials for both exudative and dry AMD showed that subretinal injection of AAV-CD59 attenuated the formation of laser-induced choroidal neovascularization by around 60% in mice, even when the site of delivery was distal to the laser-induced choroidal neovascularization site [74].
An alternative for genetic interference is small interfering RNA (siRNA) that inhibits the protein-coding genes and prevent protein synthesis. Delivery can be by the topical installation or intravitreal injection. Bevasiranib (Opko) was the first siRNA used, but it did not show efficacy in phase 3 of the COBALT clinical trial [75]. AGN211745 (Alergan) was designed to reduce pathologic angiogenesis mediated by both VEGF
PF-655 (Pfizer) is a siRNA that inhibits expression of the hypoxia-inducible gene RTP801, which inhibits the mammalian target of the rapamycin (mTOR) signaling pathway and reduces VEGF-A production. Results from phase 2 of the MONET clinical trial showed that the combination of PF-655 with ranibizumab led to an average gain in visual acuity superior to the one observed for patients under ranibizumab monotherapy [77].
There are many potential therapeutic options for AMD. New treatment options for dry AMD that slow disease progression or re-establish retinal cells are becoming a reality. For wet AMD, new drugs that could lead to a longer half-life in the vitreous, lower costs, and more potent anti-angiogenesis activity, should be approved soon. With the increase of population longevity, AMD incidence and prevalence will most probably increase, and these therapies may reduce both the societal and individual treatment burden. Although they are in the earlier clinical trial phases, the authors consider that the cell-based therapies for dry AMD and gene therapy for wet AMD are the more promising therapies for the future because they tend to correct the source’s problem. The new COVID vaccines also represent a significant step in this area, and these novel technologies may be future treatments for many other diseases.
The authors declare no conflict of interest.
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\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
\\n\\n\\n\\n
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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Anthocyanins are responsible for the color of red grapes and wines, hydroxycinnamic and hydroxybenzoic acids act as copigments, stilbenes as antioxidants and the flavan-3-ols are mainly responsible for the astringency, bitterness and structure of wines, being involved also in the color stabilization during aging. This chapter will focus on the chemical structures of the main polyphenols, their identification and quantification in grapes and wines by advanced analytical techniques, highlighting also the maceration and aging impact on the polyphenols evolution. The factors influencing the phenolic accumulation in grapes are also reviewed, emphasizing as well the relationship between phenolic content in grapes versus wine. Polyphenolic changes during the wine making process are highlighted along with the main polyphenol extraction methods and analysis techniques. This research will contribute to the improvement in the knowledge of polyphenols: their presence in grapes, the relationship with wine quality and the influence of the external factors on their evolution.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Violeta-Carolina Niculescu, Nadia Paun and Roxana-Elena Ionete",authors:[{id:"187102",title:"Dr.",name:"Roxana",middleName:null,surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"206056",title:"Dr.",name:"Violeta",middleName:"Carolina",surname:"Niculescu",slug:"violeta-niculescu",fullName:"Violeta Niculescu"},{id:"207020",title:"Mrs.",name:"Nadia",middleName:null,surname:"Paun",slug:"nadia-paun",fullName:"Nadia Paun"}]},{id:"58638",doi:"10.5772/intechopen.72823",title:"Occurrence and Analysis of Sulfur Compounds in Wine",slug:"occurrence-and-analysis-of-sulfur-compounds-in-wine",totalDownloads:1957,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Sulfur compounds play an important role in the sensory characteristics of wine. These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"66619",doi:"10.5772/intechopen.85692",title:"Contribution of the Microbiome as a Tool for Estimating Wine’s Fermentation Output and Authentication",slug:"contribution-of-the-microbiome-as-a-tool-for-estimating-wine-s-fermentation-output-and-authenticatio",totalDownloads:1095,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"Wine is the alcoholic beverage which is the product of alcoholic fermentation, usually, of fresh grape must. Grape microbiome is the source of a vastly diverse pool of filamentous fungi, yeast, and bacteria, the combination of which plays a crucial role for the quality of the final product of any grape must fermentation. In recent times, the significance of this pool of microorganisms has been acknowledged by several studies analyzing the microbial ecology of grape berries of different geographical origins, cultural practices, grape varieties, and climatic conditions. Furthermore, the microbial evolution of must during fermentation process has been overstudied. The combination of the microbial evolution along with metabolic and sensorial characterizations of the produced wines could lead to the suggestion of the microbial terroir. These aspects are today leading to open a new horizon for products such as wines, especially in the case of PDO-PGI products. The aims of this review is to describe (a) how the microbiome communities are dynamically differentiated during the process of fermentation from grape to ready-to-drink wine, in order to finalize each wine’s unique sensorial characteristics, and (b) whether the microbiome could be used as a fingerprinting tool for geographical indication, based on high-throughput sequencing (HTS) technologies. Nowadays, it has been strongly indicated that microbiome analysis of grapes and fermenting musts using next-generation sequencing (NGS) could open a new horizon for wine, in the case of protected designation of origin (PDO) and protected geographical indication (PGI) determination.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Dimitrios A. Anagnostopoulos, Eleni Kamilari and Dimitrios Tsaltas",authors:[{id:"180885",title:"Associate Prof.",name:"Dimitris",middleName:null,surname:"Tsaltas",slug:"dimitris-tsaltas",fullName:"Dimitris Tsaltas"},{id:"203761",title:"MSc.",name:"Dimitris",middleName:null,surname:"Anagnostopoulos",slug:"dimitris-anagnostopoulos",fullName:"Dimitris Anagnostopoulos"},{id:"271801",title:"Ms.",name:"Elena",middleName:null,surname:"Kamilari",slug:"elena-kamilari",fullName:"Elena Kamilari"}]},{id:"67444",doi:"10.5772/intechopen.86443",title:"Somatic Variation and Cultivar Innovation in Grapevine",slug:"somatic-variation-and-cultivar-innovation-in-grapevine",totalDownloads:1036,totalCrossrefCites:4,totalDimensionsCites:9,abstract:"Paradoxically, continuous vegetative multiplication of traditional grapevine cultivars aimed to maintain cultivar attributes in this highly heterozygous species ends in the accumulation of considerable somatic variation. This variation has long contributed to cultivar adaptation and evolution under changing environmental and cultivation conditions and has also been a source of novel traits. Understanding how this somatic variation originates provides tools for genetics-assisted tracking of selected variants and breeding. Potentially, the identification of the mutations causing the observed phenotypic variation can now help to direct genome editing approaches to improve the genotype of elite traditional cultivars. Molecular characterization of somatic variants can also generate basic information helping to understand gene biological function. In this chapter, we review the state of the art on somatic variation in grapevine at phenotypic and genome sequence levels, present possible strategies for the study of this variation, and describe a few examples in which the genetic and molecular basis or very relevant grapevine traits were successfully identified.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Pablo Carbonell-Bejerano, Carolina Royo, Nuria Mauri, Javier Ibáñez and José Miguel Martínez Zapater",authors:[{id:"287215",title:"Prof.",name:"Jose Miguel",middleName:null,surname:"Martinez Zapater",slug:"jose-miguel-martinez-zapater",fullName:"Jose Miguel Martinez Zapater"},{id:"287226",title:"Dr.",name:"Javier",middleName:null,surname:"Ibáñez",slug:"javier-ibanez",fullName:"Javier Ibáñez"},{id:"300441",title:"Dr.",name:"Pablo",middleName:null,surname:"Carbonell-Bejerano",slug:"pablo-carbonell-bejerano",fullName:"Pablo Carbonell-Bejerano"},{id:"300442",title:"Dr.",name:"Carolina",middleName:null,surname:"Royo",slug:"carolina-royo",fullName:"Carolina Royo"},{id:"300444",title:"Dr.",name:"Nuria",middleName:null,surname:"Mauri",slug:"nuria-mauri",fullName:"Nuria Mauri"}]},{id:"67833",doi:"10.5772/intechopen.87042",title:"Effects of Vine Water Status on Yield Components, Vegetative Response and Must and Wine Composition",slug:"effects-of-vine-water-status-on-yield-components-vegetative-response-and-must-and-wine-composition",totalDownloads:1125,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Despite Vitis vinifera L. is a drought-tolerant species—rainfed traditionally grown in a very diversity of climates—irrigation has more and more become a usual practice aimed to obtain regular yields along seasons and to control must composition. Results on vineyard irrigation are dependent on the timing, length and intensity of the water deficit. From budbreak to flowering, shoot growth is very sensitive to water stress, while reproductive growth is almost unaffected. Severe water deficit during fruit set can reduce yield by affecting ovary cell multiplication and expansion. During maturation water stress induces yield reduction by limiting berry growth; along this phase must composition is also affected. There is a positive, linear relationship between must sugar content and available water; however, no relationship has been found to either total acidity or pH. Biosynthesis of anthocyanins and fruity aromas is enhanced by water deficit. Usually, wines from moderate irrigation treatments scored the highest. There is a general agreement that severe, long water deficits diminish must quality, leaf area, fertility and yield, and it has a negative carryover effect on the next seasons by limiting wood reserves to be used the following seasons.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Pilar Baeza, Pedro Junquera, Emilio Peiro, José Ramón Lissarrague, David Uriarte and Mar Vilanova",authors:[{id:"222515",title:"Dr.",name:"David",middleName:null,surname:"Uriarte",slug:"david-uriarte",fullName:"David Uriarte"},{id:"285912",title:"Dr.Ing.",name:"Pilar",middleName:null,surname:"Baeza",slug:"pilar-baeza",fullName:"Pilar Baeza"},{id:"285917",title:"Dr.",name:"Mar",middleName:null,surname:"Vilanova",slug:"mar-vilanova",fullName:"Mar Vilanova"},{id:"285919",title:"Dr.",name:"Pedro",middleName:null,surname:"Junquera",slug:"pedro-junquera",fullName:"Pedro Junquera"},{id:"285922",title:"Dr.",name:"Jose Ramón",middleName:null,surname:"Lissarrague",slug:"jose-ramon-lissarrague",fullName:"Jose Ramón Lissarrague"}]}],mostDownloadedChaptersLast30Days:[{id:"58638",title:"Occurrence and Analysis of Sulfur Compounds in Wine",slug:"occurrence-and-analysis-of-sulfur-compounds-in-wine",totalDownloads:1957,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Sulfur compounds play an important role in the sensory characteristics of wine. These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"57497",title:"Recovering Ancient Grapevine Varieties: From Genetic Variability to In Vitro Conservation, A Case Study",slug:"recovering-ancient-grapevine-varieties-from-genetic-variability-to-in-vitro-conservation-a-case-stud",totalDownloads:1776,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"A great number of varieties have been described in grapevine; however, few of them are currently in use. The increasing concern on varietal diversity loss has encouraged actions for recovering and preserving grapevine germplasm, which represents valuable resources for breeding as well as for diversification in grapevine-derived products. On the other hand, it is expected that this important crop, which is distributed in warm areas worldwide, will suffer the climate changes. Therefore, it is also convenient the identification of intravarietal variability and the recovery of accessions well adapted to particular environments. In this chapter, we will contribute to highlight the importance of recovering ancient materials, the usefulness of SSR markers to determine their molecular profile, the importance to analyze their virus status, and the possibilities that offer biotechnological tools for virus sanitation and in vitro storage as a complement of field preservation. In this context, we have evaluated different grapevine accessions and developed in vitro culture protocols for micropropagation, sanitation, and storage grapevine cultivars. In this work, we report the results obtained for the historic variety “Valencí Blanc” (or “Beba”) and the historic and endangered variety “Esclafagerres” (“Esclafacherres” or “Esclafacherris”).",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Carmina Gisbert, Rosa Peiró, Tania San Pedro, Antonio Olmos,\nCarles Jiménez and Julio García",authors:[{id:"207745",title:"Dr.",name:"Carmina",middleName:null,surname:"Gisbert",slug:"carmina-gisbert",fullName:"Carmina Gisbert"},{id:"207748",title:"Dr.",name:"Rosa María",middleName:null,surname:"Peiró",slug:"rosa-maria-peiro",fullName:"Rosa María Peiró"},{id:"207749",title:"Ms.",name:"Tania",middleName:null,surname:"San Pedro Galán",slug:"tania-san-pedro-galan",fullName:"Tania San Pedro Galán"},{id:"207750",title:"Dr.",name:"Antonio",middleName:null,surname:"Olmos",slug:"antonio-olmos",fullName:"Antonio Olmos"}]},{id:"58633",title:"The Evolution of Polyphenols from Grapes to Wines",slug:"the-evolution-of-polyphenols-from-grapes-to-wines",totalDownloads:2029,totalCrossrefCites:5,totalDimensionsCites:13,abstract:"Polyphenols play an important role in the quality of wines, due to their contribution to the wine sensory properties: color, astringency and bitterness. They act as antioxidants, having positive role in human health. They can be divided into non-flavonoid (hydroxybenzoic and hydroxycinnamic acids and stilbenes) and flavonoid compounds (anthocyanins, flavan-3-ols and flavonols). Anthocyanins are responsible for the color of red grapes and wines, hydroxycinnamic and hydroxybenzoic acids act as copigments, stilbenes as antioxidants and the flavan-3-ols are mainly responsible for the astringency, bitterness and structure of wines, being involved also in the color stabilization during aging. This chapter will focus on the chemical structures of the main polyphenols, their identification and quantification in grapes and wines by advanced analytical techniques, highlighting also the maceration and aging impact on the polyphenols evolution. The factors influencing the phenolic accumulation in grapes are also reviewed, emphasizing as well the relationship between phenolic content in grapes versus wine. Polyphenolic changes during the wine making process are highlighted along with the main polyphenol extraction methods and analysis techniques. This research will contribute to the improvement in the knowledge of polyphenols: their presence in grapes, the relationship with wine quality and the influence of the external factors on their evolution.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Violeta-Carolina Niculescu, Nadia Paun and Roxana-Elena Ionete",authors:[{id:"187102",title:"Dr.",name:"Roxana",middleName:null,surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"206056",title:"Dr.",name:"Violeta",middleName:"Carolina",surname:"Niculescu",slug:"violeta-niculescu",fullName:"Violeta Niculescu"},{id:"207020",title:"Mrs.",name:"Nadia",middleName:null,surname:"Paun",slug:"nadia-paun",fullName:"Nadia Paun"}]},{id:"67760",title:"Production and Marketing of Low-Alcohol Wine",slug:"production-and-marketing-of-low-alcohol-wine",totalDownloads:1302,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Moderate wine consumption may be associated with specific health benefits and a healthy lifestyle. However, increased amounts of ethanol are cytotoxic and associated with adverse health outcomes. Alcohol reduction in wine might be an avenue to reduce alcohol related harm without forcing consumers to compromise on lifestyle and benefit from positive aspects of moderate consumption. The aim of this review is to give an overview of viticultural and pre and post fermentation methods to produce low-alcohol wine, and to summarize the current evidence on the consumer acceptance and behaviour related to low-alcohol wine. Strategies for the labelling and marketing of wines with reduced alcohol content are discussed.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Tamara Bucher, Kristine Deroover and Creina Stockley",authors:[{id:"289140",title:"Dr.",name:"Creina",middleName:null,surname:"Stockley",slug:"creina-stockley",fullName:"Creina Stockley"},{id:"289141",title:"Dr.",name:"Tamara",middleName:null,surname:"Bucher",slug:"tamara-bucher",fullName:"Tamara Bucher"},{id:"289142",title:"Ms.",name:"Kristine",middleName:null,surname:"Deroover",slug:"kristine-deroover",fullName:"Kristine Deroover"}]},{id:"57946",title:"Microbiological, Physical, and Chemical Procedures to Elaborate High-Quality SO2-Free Wines",slug:"microbiological-physical-and-chemical-procedures-to-elaborate-high-quality-so2-free-wines",totalDownloads:1617,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Sulfur dioxide (SO2) is the most preservative used in the wine industry and has been widely applied, as antioxidant and antibacterial agent. However, the use of sulfur dioxide implicates a range of adverse clinical effects. Therefore, the replacement of the SO2 content in wines is one of the most important challenges for scientist and winemakers. This book chapter gives an overview regarding different microbiological, physical, and chemical alternatives to elaborate high-quality SO2-free wines. In the present chapter, original research articles as well as review articles and results obtained by the research group of the Wine Technology Center (VITEC) are shown. This study provides useful information related to this novel and healthy type of wines, highlighting the development of winemaking strategies and procedures.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Raúl Ferrer-Gallego, Miquel Puxeu, Laura Martín, Enric Nart, Claudio\nHidalgo and Imma Andorrà",authors:[{id:"207221",title:"Dr.",name:"Raúl",middleName:null,surname:"Ferrer-Gallego",slug:"raul-ferrer-gallego",fullName:"Raúl Ferrer-Gallego"},{id:"208597",title:"Dr.",name:"Miquel",middleName:null,surname:"Puxeu",slug:"miquel-puxeu",fullName:"Miquel Puxeu"},{id:"208598",title:"Dr.",name:"Laura",middleName:null,surname:"Martín",slug:"laura-martin",fullName:"Laura Martín"},{id:"208599",title:"Mr.",name:"Enric",middleName:null,surname:"Nart",slug:"enric-nart",fullName:"Enric Nart"},{id:"208600",title:"Dr.",name:"Claudio",middleName:null,surname:"Hidalgo",slug:"claudio-hidalgo",fullName:"Claudio Hidalgo"},{id:"208601",title:"Dr.",name:"Imma",middleName:null,surname:"Andorrà",slug:"imma-andorra",fullName:"Imma Andorrà"}]}],onlineFirstChaptersFilter:{topicId:"1411",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81659",title:"State-of-the-Art Knowledge about 2,4,6-Trichloroanisole (TCA) and Strategies to Avoid Cork Taint in Wine",slug:"state-of-the-art-knowledge-about-2-4-6-trichloroanisole-tca-and-strategies-to-avoid-cork-taint-in-wi",totalDownloads:28,totalDimensionsCites:0,doi:"10.5772/intechopen.103709",abstract:"Cork stoppers have been used for many centuries to seal wine in various vessels. Therefore, corks have become a traditional part of wine packaging in many countries and still play an important role for the entire wine industry. Nowadays, there is a wide option of bottle cork stoppers on the market, such as natural corks, agglomerated and technical stoppers (1 + 1), etc. These cork closures have a number of advantages, including positive sustainable and ecological aspects. Natural cork material can also be responsible for cork taint, which imparts musty/moldy or wet cardboard off-odors to the wine. However, corks are not the only source of cork taint in wine, as will be shown in the present chapter. Over the past decades, a number of compounds have been detected that can contribute to the cork taint. Among them, haloanisoles play a major role, in particular 2,4,6-trichloroanisole (TCA), which has been shown to be responsible for 50–80% or more of musty defect cases in wine. Currently, the cork and wine industries have developed a number of tools and technologies to effectively prevent cork tait in wine or to remove it if the wine is already contaminated. These practical as well as analytical questions about the TCA defects are the subject of the actual chapter.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Andrii Tarasov, Miguel Cabral, Christophe Loisel, Paulo Lopes, Christoph Schuessler and Rainer Jung"},{id:"78620",title:"Table Grapes: There Is More to Vitiviniculture than Wine…",slug:"table-grapes-there-is-more-to-vitiviniculture-than-wine",totalDownloads:142,totalDimensionsCites:0,doi:"10.5772/intechopen.99986",abstract:"Table grapes are fruits intended for fresh human consumption due to their sensory attributes and nutritional value. The objective of this chapter is to review the existing knowledge about table grapes, including a description of different varieties, with particular emphasis on the new highly appreciated seedless varieties. Following an introductory note on the world distribution and production of table grapes, also considering the impact of climate change, selected varieties of table grapes will be characterized in terms of their physiology, postharvest features, and consumer preferences. A morphological description of each variety, with emphasis on grape skin, grape rachis and grape cluster will be included. A final note on the drying of table grapes into raisins, and the most appropriate varieties for drying, will be given. The major changes occurring throughout the growth, development, and ripening phases of table grapes production will be discussed, regarding both physical (skin color and skin and pulp texture) and chemical (phenolic compounds, sugar content and acidity) parameters, as well as growth regulators.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Ana Cristina Agulheiro-Santos, Marta Laranjo and Sara Ricardo-Rodrigues"},{id:"79500",title:"New Insights about the Influence of Yeasts Autolysis on Sparkling Wines Composition and Quality",slug:"new-insights-about-the-influence-of-yeasts-autolysis-on-sparkling-wines-composition-and-quality",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101314",abstract:"Sparkling wines elaborated using the traditional method undergo a second fermentation in the bottle. This process involves an aging time in contact with the lees, which enriches the wine in various substances, especially proteins, mannoproteins and polysaccharides, thanks to the autolysis of the yeasts. As a result of this yeast autolysis, sparkling wines benefit from better integration of carbon dioxide and a clear sensory improvement, especially in the case of long aging. This chapter synthetizes the main results that our research group has obtained about the influence of yeasts autolysis on sparkling wines composition and quality during last years, making special emphasis on the capacity of the lees to release proteins and polysaccharides as well as on their capacity to consume oxygen and thus protect the sparkling wines from oxidation.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Pere Pons-Mercadé, Pol Giménez, Glòria Vilomara, Marta Conde, Antoni Cantos, Nicolas Rozès, Sergi Ferrer, Joan Miquel Canals and Fernando Zamora"},{id:"79110",title:"Microbial Decontamination by Pulsed Electric Fields (PEF) in Winemaking",slug:"microbial-decontamination-by-pulsed-electric-fields-pef-in-winemaking",totalDownloads:83,totalDimensionsCites:0,doi:"10.5772/intechopen.101112",abstract:"Pulsed Electric Fields (PEF) is a non-thermal technique that causes electroporation of cell membranes by applying very short pulses (μs) of a high-intensity electric field (kV/cm). Irreversible electroporation leads to the formation of permanent conductive channels in the cytoplasmic membrane of cells, resulting in the loss of cell viability. This effect is achieved with low energy requirements and minimal deterioration of quality. This chapter reviews the studies hitherto conducted to evaluate the potential of PEF as a technology for microbial decontamination in the winemaking process for reducing or replacing the use of SO2, for guaranteeing reproducible fermentations or for wine stabilization.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Carlota Delso, Alejandro Berzosa, Jorge Sanz, Ignacio Álvarez and Javier Raso"},{id:"78993",title:"pH Control and Aroma Improvement Using the Non-Saccharomyces Lachancea thermotolerans and Hanseniaspora spp. Yeasts to Improve Wine Freshness in Warm Areas",slug:"ph-control-and-aroma-improvement-using-the-non-saccharomyces-lachancea-thermotolerans-and-hanseniasp",totalDownloads:90,totalDimensionsCites:0,doi:"10.5772/intechopen.100538",abstract:"Lachancea thermotolerans is a yeast species that works as a powerful bio tool capable of metabolizing grape sugars into lactic acid via lactate dehydrogenase enzymes. The enological impact is an increase in total acidity and a decrease in pH levels (sometimes >0.5 pH units) with a concomitant slight reduction in alcohol (0.2–0.4% vol.), which helps balance freshness in wines from warm areas. In addition, higher levels of molecular SO2 are favored, which helps to decrease SO2 total content and achieve better antioxidant and antimicrobial performance. The simultaneous use with some apiculate yeast species of the genus Hanseniaspora helps to improve the aromatic profile through the production of acetyl esters and, in some cases, terpenes, which makes the wine aroma more complex, enhancing floral and fruity scents and making more complex and fresh wines. Furthermore, many species of Hanseniaspora increase the structure of wines, thus improving their body and palatability. Ternary fermentations with Lachancea thermotolerans and Hanseniaspora spp. sequentially followed by Saccharomyces cerevisiae are a useful bio tool for producing fresher wines from neutral varieties in warm areas.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Antonio Morata, Carlos Escott, Iris Loira, Juan Manuel Del Fresno, Cristian Vaquero, María Antonia Bañuelos, Felipe Palomero, Carmen López and Carmen González"},{id:"78970",title:"Alternatives to CU Applications in Viticulture. How R&D Projects Can Provide Applied Solutions, Helping to Establish Legislation Limits",slug:"alternatives-to-cu-applications-in-viticulture-how-r-d-projects-can-provide-applied-solutions-helpin",totalDownloads:182,totalDimensionsCites:2,doi:"10.5772/intechopen.100500",abstract:"Copper (Cu) and its based preparations have been used for over 200 years to control fungi and bacterial diseases in cultivated plants. Downy mildew caused by the obligate biotrophic oomycete Plasmopara viticola is one of the most relevant and recurrent diseases of grapevines. Recently, the use of Cu is being limited by some regulations because of its high impact at different levels (health and environmental problems). Due to its accumulation in soil, this metal causes a little controversy with the principles of sustainable production. Therefore, international legislation and initiatives have recently been arisen to start limiting its use, with the main goal to replace it. In this framework, some alternatives have been tested and others are recently being developed to replace, at least partially, the use of Cu in viticulture. Many of them, are being developed and tested under the scope of research and development EU funded projects. To not compromise sustainability targets in viticulture, results from these R&D projects need to be considered to assess the present risks of using Cu in viticulture and to better support establishing limits for its applications, considering soils vulnerability, while no sustainable alternatives are available in the market.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Mario De La Fuente, David Fernández-Calviño, Bartosz Tylkowski, Josep M. 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