Specifications of the developed test bed.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"3811",leadTitle:null,fullTitle:"Immune Response Activation",title:"Immune Response Activation",subtitle:null,reviewType:"peer-reviewed",abstract:"The book Immune Response Activation is aiming to analyse the multifaceted aspects of the immune response, treating a number of representative cases in which the immune response is, on one hand, activated against pathogens, and, on the other hand, involved in pathologic settings, leading to allograft rejection, allergy and autoimmunity. 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\r\n\r\n\tThis book intends to provide a comprehensive overview of the current state-of-the-art in engineered wood products and their uses for wood manufacturers, engineers, architects, builders, researchers, and students.
",isbn:"978-1-83962-772-9",printIsbn:"978-1-83962-771-2",pdfIsbn:"978-1-83962-790-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"421757c56a3735986055250821275a51",bookSignature:"Dr. Meng Gong",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10584.jpg",keywords:"Growth Features, Ultramicroscopic Features, Polymer-Treated Timber, Chemical-Treated Wood, Laminated Strand Lumber, Oriented Strand Lumber, Laminated Veneer Lumber, Parallel Strand Lumber, Ceiling Tiles, Floor Systems, MSR Lumber, I-Joists",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 27th 2021",dateEndSecondStepPublish:"February 24th 2021",dateEndThirdStepPublish:"April 25th 2021",dateEndFourthStepPublish:"July 14th 2021",dateEndFifthStepPublish:"September 12th 2021",remainingDaysToSecondStep:"11 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A leading researcher in wood technology and engineering, Director of the University of New Brunswick's Wood Science and Technology Centre (Canada), and holder of the New Brunswick Innovative Research Chair in advanced wood (Canada).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"274242",title:"Dr.",name:"Meng",middleName:null,surname:"Gong",slug:"meng-gong",fullName:"Meng Gong",profilePictureURL:"https://mts.intechopen.com/storage/users/274242/images/system/274242.jpg",biography:"Dr. Meng Gong is the leading researcher and director of the Wood Science and Technology Centre (WSTC), the University of New Brunswick (UNB), Canada. He received his Master’s degree in wood technology and Ph.D. in wood engineering from Nanjing Forestry University (China) and UNB, respectively. He worked, as a JSPS post-doctoral fellow, in the Wood Research Institute, Kyoto University (Japan). He has published more than 150 referred journal and conference papers on wood technology and engineering, numerous industry-oriented technical reports, and co-authored the book 'Fracture and Fatigue in Wood” published by John Wiley & Sons Ltd., and authored the book chapter 'Lumber-based Mass Timber Products in Construction' published by IntechOpen. Dr. Gong leads research on wood quality, wood modification and engineered wood products in the WSTC. He dedicates himself to R&D of modified wood and engineered wood products and their uses in construction. Dr. Gong is a voting member of the Canadian Commission on Construction Materials Evaluation, National Research Council, Canada, and a fellow of the International Academy of Wood Science.",institutionString:"University of New Brunswick",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of New Brunswick",institutionURL:null,country:{name:"Canada"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@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. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"51410",title:"Load Leveling Utilizing Electric Vehicles and their Used Batteries",doi:"10.5772/64432",slug:"load-leveling-utilizing-electric-vehicles-and-their-used-batteries",body:'\nThe massive dissemination of electric vehicles (EVs) is believed to be able to improve the total energy efficiency of the vehicles as well as reduce the emission of greenhouse gases and oil consumption [1]. In Japan, considering that the gasoline price, total annual driving distance, electricity price during night time, and fuel consumption of both gasoline-fueled vehicle and EV are 110 JPY l−1, 10,000 km, 12 JPY kWh−1, and 15 km l−1 and 6 km kWh−1, respectively, the total operational cost of EV may be less than 30% of gasoline-fueled vehicle. Furthermore, the acceleration in the development of EV also has been influenced strongly by some various factors including fluctuating oil and gas prices, successful advancements in battery technology, and broader supporting infrastructure [2, 3]. Unfortunately, there are still some challenging problems to expand in a broader scope of the community including high capital cost, long charging time, and relatively short travelable distance [4]. In addition, although the operational cost of EVs is cheaper than the conventional gasoline-fueled vehicles (internal combustion engine–based vehicles), the initial cost of EV is still higher due to high production cost.
\nTo further reduce the initial and operational costs of EV (increase its economic performance), innovative value-added utilization of EV is requested. Furthermore, massive deployment of EVs can disturb significantly the grid electricity, especially when individual charging of EVs in large capacity and number occurred. According to [5], in case that a half of vehicles in Kanto (Tokyo and its surroundings) area are transformed to EVs and half of them are demanding a quick charging simultaneously, about 7.31 GW of additional electricity supply is required. Recently, to give an answer to the above problems, the idea of vehicle-to-grid (V2G) has been proposed and investigated [6–8].
\nThe adoption of EVs to support the electricity of grid or any electricity-related system becomes possible because of controllable charging and discharging behaviors resulting in the possibility of scheduled and coordinated charging and discharging. Therefore, the parked and connected EVs can be assumed as a largely bundled battery which is able to consume (absorb) the electricity from the grid, store it, and release back to the grid. In addition, V2G can be achieved when minimally three fundamental preconditions are totally satisfied: (1) an electricity line connecting both EV and power grid, such as charging station, (2) a communication system transferring the information and control command between EV and grid operator, and (3) an accurate and trusted metering system facilitating fair service measurement [9]. Furthermore, in case that there is any demand for electricity, the grid operators and/or energy management system (EMS) are able to dispatch a control command instructing the connected EVs to discharge their stored electricity to the grid. On the other hand, they can instruct the connected EVs to absorb the electricity due to surplus of electricity or decrease of electricity demand. Therefore, the balance between supply and demand, as well as quality of grid electricity can be maintained.
\nV2G provides various possible ancillary services to the electricity grid or any electricity-related system such as load leveling and spinning reserve. In addition, the distributed EVs also can be assumed as a large-scale energy storage (battery) which is potential to be bundled and utilized to minimize the effect of fluctuating supply. As EVs are moving from and to different times and places, they also could be employed as an energy carrier transporting the electricity in different places and times due to some factors such as electricity price difference and emergency condition. From the economic analysis, the massive adoption of EVs to give ancillary service to the grid (V2G) is considered beneficial because the projected profit is still significantly higher than the initial cost of EVs, especially the battery including the consideration of battery wear and life cycle [4]. This feasibility study has been performed based on the actual data of EVs, especially the life cycle of battery.
\nUntil now, battery cost stands as the highest share in total EV production cost. In addition, as the number of produced EVs increases, the number and total capacity of the used batteries increase accordingly. According to [10], the EV batteries are generally replaced after their storage capacity drops to about 70–80% of its initial capacity. The decrease in battery capacity leads to shorter possible driving range. Therefore, although these used EV batteries are not appropriate anymore for EVs, they can be reutilized as a stationary energy storage (stationary battery). This kind of battery utilization is believed to be able to further improve the overall economic performance of EV as well as reduces their impacts to the environment because it can lengthen the battery end-of-life. The study on the utilization of EV batteries acting as stationary battery to take part in ancillary service to certain EMS or grid can be found in several literature [11, 12].
\nSeveral studies focusing on theoretical analyses of the application of both EVs and used EV batteries have been conducted well. However, those studies are generally lack of experimental investigation including demonstration tests and real application. This chapter deals mainly with the employment of EVs and used EV batteries in supporting the electricity in any typical small-scale EMS including both theoretical and experimental studies. In addition, the results from the demonstration test are also studied and analyzed.
\nCharging of EVs basically can be categorized into three different capacities: (a) slow charging with capacity lower than 4 kW, (b) fast charging with capacity of 10–20 kW, and (c) ultrafast charging with a maximum capacity of 50 kW or higher [13]. Ultrafast charging is conducted generally under high DC voltage and current. In Japan, this ultrafast charging follows the standard of CHAdeMO (the acronym of “charge de move”, equivalent to “move by charge”) which offers charging capacity of 10–50 kW. Until the end of 2015, there are about 6000 ultrafast chargers following CHAdeMO standard across Japan [14]. CHAdeMO chargers can facilitate bidirectional electricity flows resulting in possible charging and discharging of EVs. In addition, intelligent controlling system is also generally installed inside the charger, hence high level communication and control can be achieved.
\nThe management of energy, especially the electricity, is usually coordinated and controlled by certain independent operator. In North America, independent system operator (ISO) and regional transmission operator (RTO) act as the independent and neutral organizations that are responsible to coordinate, control, and monitor the electric transmission throughout the state or region [15]. In addition, ISO and independent transmission operator (ITO) were established in Europe which are quite similar with ISO/RTO in North America. The main differences between the US-type ISO/RTO and the EU-type ISO/ITO are the absence of profit motives, and participation and transparency of all the involved stakeholders [16]. ITO in Europe owns the assets and it belongs to certain stakeholders, but has a regulation to guarantee its independence. On the other hand, ISO is fully unbundled operator having no assets although still belongs to certain stakeholders.
\nIn Japan, community energy management system (CEMS) has been proposed and demonstrated. The main purpose of CEMS is realizing a resilient and smart community, especially related to efficiency in energy utilization and minimization of CO2 emission. The concept of CEMS comes from the demand to optimize the energy services, maximize the potential economy, and minimize the environmental impacts. CEMS coordinates and monitors all the energy supply and demand throughout the community, hence improving the comfort, security, and safety of the whole community members. In CEMS, the streams of energy and information are flowing simultaneously covering supply, demand, storage, and distribution. As a system, CEMS must be robust and secured because it deals with individual information and its authentication.
\nBasic concept of CEMS.
Figure 1 shows the basic concept of CEMS. CEMS has an important role of monitoring and controlling all the energy involved in the community. It becomes the core of efficient, secured, and optimized energy utilization throughout the community. CEMS is able to communicate with other entities inside and outside its authority. Inside the community, CEMS communicates intensively with its lower EMSs such as home energy management system (HEMS), building energy management system (BEMS), and factory energy management system (FEMS). In addition, it also may communicate directly with EVs distributed in the community which are not controlled under certain EMS. CEMS is also able to communicate with other CEMS, large-scale energy providers (utilities), transmission operators, and energy storage operators.
\nInside the community, CEMS initially forecasts both energy supply, especially generable renewable energy (RE) and demand. This forecast is usually performed based on historical (for several years before) and meteorological data. Furthermore, it calculates the most optimized energy balance in terms of quality, security, and economic cost. In case the energy balance between the supply and demand cannot be self-achieved inside the community due to lack of power generation capacity, high and fluctuating demand, and emergency condition, CEMS communicates with other CEMS, utilities, and energy storage providers to deliver or increase their power to the community. On the other hand, in case there is surplus electricity inside the community (due to high supply and/or low demand), CEMS can offer to other CEMS or utilities to buy this surplus electricity.
\nCEMS is also performing a demand side management (DSM). DSM includes efficient energy usage and demand response (DR) in demand side, instead of adding larger generation capacity at the supply side. DSM can be considered as a dispatchable resource, in which the consumer lower voluntarily their demand, therefore the grid quality can be maintained without any additional power supply.
\nEVs can be applied to support the grid electricity, mainly providing energy storage and ancillary services, due to the above-mentioned characteristics. As energy storage, EVs can be charged when the electricity price is relatively low because of surplus electricity in supply side, including RE and excess power, and lower demand (such as during night time). Furthermore, the ancillary services which can be performed by EVs to support the grid electricity mainly cover frequency regulation (up and down regulations), electricity storage, and spinning (synchronous) reserve. Compared to other energy storages or generators, EVs have a very advantageous characteristic which is its ability to charge and discharge instantaneously their electricity once they received the command from the operator or EMS. The above-mentioned ancillary services are required to preserve the balance between supply and demand of electricity, therefore the electricity can be appropriately reliable.
\nTo participate in the ancillary services, the EV owners are requested to have any service contract with the operator or EMS. Possible utilization contract schemes of EVs to support the grid electricity or any electricity-related system are shown in Figure 2. In general, the participation of EVs in the electricity market could be conducted through two types of participation contracts, they are direct and aggregator-based contracts. To facilitate a communication between EVs and operators, a real time data collection is conducted by vehicle information system (VIS) in a certain time interval from EVs covering battery state of charge (SOC), position (GPS data), and predicted arrival time. VIS might be owned and managed directly by EMS, aggregator or it is independent as service operator which provides EV information services to EMS and aggregator.
\nPossible contract schemes of EV in EMS: (a) direct contract and (b) aggregator-based contract.
In a direct contract, the EV owners have the service contract directly with the energy service providers (EMS). In this contract scheme, both the electricity and information are transferred privately and directly between EVs and energy service provider. Therefore, this type of contract is considered applicable for a relatively small-scale EMS, including BEMS and FEMS, and in where EVs are parked and connected to the chargers for relatively long time, for example during working hours. The main advantage of this type of contract scheme is the ability to optimize the profit for the involving entities (EV owners and EMS). Furthermore, controls for both charging and discharging are more simple and faster as EVs are directly and fully under control of EMS. The report in this chapter describes mainly on this type of contract scheme.
\nOn the contrary, in an aggregator-based contract scheme, EV owners have service contracts with the aggregators which are providing and managing electricity services. Therefore, there is no direct contract between EV owners and EMS or other electricity-related entities. The information including EV position (GPS), battery condition (SOC), and estimated arrival time is basically coordinated by aggregator via VIS. Based on these data, the aggregator calculates the available number of EVs as well as the total capacity of the battery which is potential for power services. Furthermore, the aggregator can offer and negotiate for electricity services with other electricity-related entities including aggregators, EMS, and/or electricity utilities. It is assumed that this kind of contract scheme is suitable to be adopted for comparatively large-scale EMS or electricity utilities. The participating EVs are not only located in certain single place, but they might be distributed in different places as long as both electricity connection and communication are available and possible to perform ancillary services. The electricity absorbed from and discharged to the grid can be transferred through power wheeling service utilizing the available distribution and transmission lines. Aggregator acts as service operator, hence they offer some possible ancillary services to the EV owners. On the contrary, the EV owners have the right to select the offered ancillary service programs and receive the service fee from the aggregator.
\nLoad leveling has a strong correlation with the management of both electricity demand and supply. The main objective is to lower the total grid load (electricity purchased from grid) during peak-load hours and avoid the electricity usage higher than the contracted power capacity by shifting the load from peak to off-peak-load hours. In this study, load leveling is conducted by employing both peak-shift and peak-cut. The former is defined as dislocating the electricity load during peak-load time to off-peak-load time. It can be performed by utilizing the stationary battery or other power storage devices which can absorb and store the electricity during off-peak-load time and discharge it during peak-load time. The latter is described as the effort to reduce the electricity which is purchased from the grid. In real practice, this can be conducted by generating its own energy supply especially during peak-load hours, such as RE, or by purchasing the electricity from other entities including the connected EVs. In the case that additional power supply is purchased from EVs, EVs are considered as energy storage and carrier which are storing and transporting the electricity from and to different times and places. Therefore, the economic performance of EVs can be improved by participating in this kind of ancillary services.
\nAlmost all of EVs adopt lithium-ion batteries to store the electricity with consideration of high-energy density, high stability, long lifetime, and relatively lower environmental impact. Charging and discharging behaviors of EVs are influenced by some factors including SOC and temperature [13]. Temperature influences some interface properties of the batteries including viscosity, density, dielectric strength, and ion diffusion capability [17]. Lower temperature results in poor charging and discharging performances because of lower performances of those properties as well as electrolyte limitation [18]. In addition, as temperature decreases, the transfer resistance increases [19].
\nRelationship among charging rate, battery SOC, and charging time during EV charging in different seasons: (a) winter and (b) summer.
Aziz et al. [13] have performed an experimental study confirming the effect of battery SOC and temperature to the charging behavior of EVs in both summer and winter using DC ultrafast charger (maximum charging rate of 50 kW). Figure 3 shows their experimental results, i.e., the relationship among the charging rate, battery SOC, and charging time. Generally, charging rate is influenced strongly by the SOC of battery. EVs with lower battery SOC can absorb higher electricity and their charging rate decreases gradually as their battery SOC increases. In addition, charging in relatively higher temperature (summer) results in higher charging rate, therefore shorter charging time can be achieved. Lithium-ion batteries are generally charged employing a constant current (CC)-constant voltage (CV) method. Charging under higher temperature leads to higher charging current, therefore shorter charging time can be realized.
\n\n\nThe conceptual diagram of integration of EVs and used EV batteries in supporting the electricity in a small-scale EMS is presented in Figure 4. To take part in the ancillary services coordinated by EMS, there must be an initial contract between the EV owners EMS, either direct contract or aggregator-based contract through third entity such as an aggregator. Because of the mobility characteristic of EVs, their charging and discharging behaviors can be fully controlled by EMS in case EVs are connected to the designated charging stations. In addition, the used EV batteries are employed as stationary storage which are always connected to and managed completely by EMS. These used EV batteries are utilized mainly for peak-shift. Therefore, they are charged when the electricity price is low, such as during night time, and discharged during peak-load time or when the electricity price is relatively high, such as noon time. Hence, the amount of electricity which is purchased from the grid during peak-load time can be reduced, resulting in total low electricity cost.
\nConceptual diagram of integration of EVs and their used batteries to small-scale EMS.
EMS is basically controlling all the electricity flows including demand and supply sides. Some types of small-scale EMSs include BEMS, FEMS, and HEMS. A direct contract scheme is adopted in this case. EMS requests the required information from different sources covering its own demand (load), weather information from meteorological agency, EV information from VIS, electricity condition in the community from CEMS, and grid electricity condition from utility. Regarding the weather information, EMS generally has a service contract with certain meteorological agency providing the weather forecast in a certain interval of time in a day. Based on the received weather forecast, EMS will estimate its own load, including base load and fluctuating load. The former is generally defined as the minimum load which is required to run the system for sequential 24 hours. Therefore, this kind of load is usually constant along the day and insignificantly effected by the weather or human behavior. On the contrary, the latter is determined as the load which is influenced strongly by the surrounding weather and human behavior. The fluctuating load includes air conditioning, heating, and lighting. Moreover, the possibly generated electricity from RE, such as wind and solar, is also predicted by EMS utilizing the weather information received from meteorological agency.
\n\nFigure 5 represents the average total load of the office building, especially in Japan, in four different seasons. The highest total building load takes place in summer, and is followed by one in winter, due to air conditioning demand. In addition, building loads in both spring and autumn are almost similar, which are lower than one in winter. Furthermore, daily peak-loads occur twice in a day (weekday), i.e., before noon and afternoon peak-loads. This is because of the immediate drop of load following the lunch break for about 1 hour. The afternoon peak-load mostly takes place in a longer duration, which is about 3 hours, and is higher than the before noon peak-load. Moreover, the highest value of peak-load during summer takes place during afternoon time (13:00–16:00) due to cooling demand. On the contrary, this highest value of peak-load moves to evening time (16:00–17:00) during other three seasons (autumn, winter, and spring) due to heating demand.
\nAverage electricity loads for office building in different seasons.
EMS also receives the EV information from VIS including their position (GPS data), battery SOC, and predicted arrival time. In addition, VIS monitors and collects the information from its EV members wirelessly. It might be an independent service operator and a part of EMS or aggregator. It is responsible to communicate with each EV and provide the collected data to the EMS or aggregator in which VIS has a contract with. In addition, these data are used for coordinating both charging and discharging of EVs, maintaining the balance of electricity and avoiding any peak-load in EMS. Furthermore, VIS is also able to provide additional services to the EV drivers/owners concerning the available ancillary service programs which are being offered by EMS or aggregator. Hence, the EV owners can select according to their interests or conditions. Furthermore, EMS can request the electricity utilities to provide the information including the electricity condition and price in advance (such as one day ahead). This information is important to plan and optimize the electricity supply as well as calculate the amount of electricity which should be purchased from utilities. In addition, EMS also calculates the charging and discharging behaviors of both EVs and used EV batteries which are available according to the information provided by VIS.
\n\nFigure 6 shows the assumed one day specific curve of EV battery SOC during a weekday. EVs are departed in the morning and they reach the destination (office building) at around 9 am. In this study, EVs are used for peak-cut during the afternoon peak-load due to higher peak-load and limited number of EVs in a demonstration test. EV discharging is stopped in case that the peak-cut (load leveling) finishes or the SOC of EV batteries drops to minimum SOC (SOCmin). SOCmin might be determined by the EV drivers/owners, EMS, or aggregator. In addition, EVs leave the office building at around 6 pm with minimum battery condition (SOCmin). On the other hand, in case that the total building load is relatively low (such as in the morning, lunch break, and night) EVs might be charged to enhance their discharging capacity or extending their traveling.
\nTypical SOC state of EVs in weekdays (commuting).
\nFigure 7 presents the basic concept of load leveling which is developed for a small-scale EMS employing EVs, used EV batteries and RE generators including photovoltaic (PV) and wind. Four main continuous steps are proposed: (1) forecasting of the possibly generated RE and building load, (2) load leveling calculation including peak-shift and peak-cut, (3) value recalculation and correction, and (4) charging and discharging controls of both EVs and used EV batteries. The first step, load and RE forecasting, is basically conducted by EMS for 24 hours ahead. Furthermore, because the electricity amount in Japan is measured for a duration of 30 min, the electricity amounts (kWh) in this study are also measured and calculated as the total summation for a duration of 30 min.
\nDeveloped load leveling concept utilizing EVs and their used batteries.
To forecast both load and possibly generated RE, EMS initially sends a request to meteorological agency to deliver the local weather forecast information. This weather information is very crucial for calculating the electricity which can be potentially generated by RE, such as PV and wind. Because the amount of RE generation is significantly smaller than the total load, in this study, this generated electricity from RE is used directly for peak-cut, hence it will be delivered directly and consumed entirely without being stored in the battery. Moreover, the weather information is also used to forecast the fluctuating load of the office building, especially to calculate the demand of air conditioning (cooling and heating) and lighting. The outputs from this first step include the predicted power generation from RE and daily load curves of the next day (defined as day starting from 00:00 to 24:00).
\nAs the building load and possibly generated electricity from RE have been predicted, EMS will calculate the achievable load leveling (peak-cut) for the next day. In order to realize it, EMS sends a request to VIS to calculate and send the information related to the available EVs, including their battery SOCs, which will potentially participate for the load leveling program. This information is required to estimate the total available electricity which can be supplied by the EVs for load leveling.
\nIn order to perform the given request by EMS, VIS initially collects the traveling schedule from the EV drivers (planned departure time and predicted arrival time). Next, EMS forwards this information, as well as calculates the total availability of EVs and their batteries, together with basic information including EV’s ID. This registration of traveling schedule is conducted up to 24 hours before the planned departure. Finally, using the data from the first and second steps, EMS is able to estimate the peak-cut threshold which can be applied for the next day.
\nIn this study, a peak-cut threshold is determined as the maximum electricity which is purchased from the electricity grid. To calculate this peak-cut threshold, some important factors need to be considered including price of electricity at the corresponding time, contracted power capacity, possibly generated electricity from RE, available electricity supply from other sources with low price, and potential energy storage.
\nIn case that the electricity which is consumed by the office building rises resulting in the condition that the purchased electricity from the grid increases and reaches nearly the calculated peak-cut threshold, EMS immediately sends the control command to both connected EVs and used EV batteries to release their electricity supporting EMS to cover the demand. Therefore, the electricity purchased from the grid can be kept to be the same to or lower than the calculated peak-cut threshold. As a result, a higher price of electricity during peak-load time or penalty due to higher capacity than the contracted one can be avoided.
\nWhen EVs are not connected to the designated charging stations, such as in motion or being parked in other places, the information of EVs is sent wirelessly to VIS in an interval of several seconds to minutes (adding and renewing the information). Thereafter, VIS transmits the updated data to EMS. EMS will recalculate the potential availability of electricity from EVs. Moreover, EMS also recalculates the building load based on the present real load of building and real weather which is measured using thermometer and hygrometer. Next, EMS renews its energy management plan, especially the calculated peak-cut threshold.
\nFurthermore, when EVs arrive at the office building and are plugged to the designated charging stations, EV start to communicate directly with EMS and bypassing VIS through the charging lines. EMS will read the information from EVs and update the previous data received from VIS, especially the battery SOC. As EVs are connected directly to EMS via charging station, EVs are completely under EMS management. Therefore, their charging and discharging behaviors are controlled completely by EMS. After receiving the updated data from EVs, EMS recalculates the peak-cut threshold accurately. As the electricity demand reaches the updated peak-cut threshold, EMS sends the control command to EVs and used EV batteries to discharge their electricity. After finishing the load leveling, EMS can manage the charging for EVs, hence another peak-load due to uncoordinated EV charging can be avoided.
\n\nFigure 8 shows the schematic diagram of the demonstration test bed developed in this study. Solid and dotted lines represent the electricity and information flows, respectively. In addition, Figure 9 shows the pictures of the developed test bed. This demonstration test bed was constructed in the factory area of Mitsubishi Motors Corporation which is located in Okazaki, Aichi prefecture, Japan. Due to limited number of EVs and used EV batteries in this study, this test bed is connected to the electricity of the main office building (office building is considered as BEMS), and not to the whole electricity of the factory. PV panels having total maximum capacity of 20 kW is installed at the rooftop of the test bed as RE generator. In addition, five Mitsubishi EVs, i-Miev G, are participating in this demonstration test. The drivers are the employees who are working in the factory and EVs are used for commuting purpose. Therefore, EVs are basically available during working hours, especially during the day. They are parked and plugged to charging stations installed in the test bed. Furthermore, five used EV batteries are also employed as stationary battery. These used EV batteries are basically detached from the same type of EVs after about one year usage.
\nSchematic diagram of the developed test bed.
Overview of the developed system involving PV, EVs, and used EV batteries.
Components | \nProperties | \nValue | \n
---|---|---|
PV panels | \nType | \nMonocrystalline | \n
Capacity | \n20 kW | \n|
Direction, angle | \nSouth, 30° | \n|
PCS capacity | \nAC 200 V, 100 A | \n|
EVs | \nType | \ni-Miev G | \n
Number | \n5 | \n|
Battery capacity | \n16 kWh | \n|
Charging capacity | \nDC 370 V, 15 A | \n|
PCS capacity | \nAC 200 V, 15 A | \n|
Used EV batteries | \nOriginal EV | \ni-Miev G | \n
Number | \n5 | \n|
Condition | \n1-year usage | \n|
Battery capacity | \n16 kWh | \n|
Charging capacity | \nDC 370 V, 15 A | \n|
\n | PCS capacity | \nAC 200 V, 15 A | \n
Specifications of the developed test bed.
EMS is controlling the balance of both demand and supply of the main office building and test bed. EMS also forecasts and measures the demand of the office building. In addition, VIS is also developed as an independent system which communicates with EVs and transmits the received information to EMS. Table 1 shows the detailed specifications of the developed demonstration test bed.
\nThe drivers submit their daily traveling plans to VIS up to one day before the scheduled departure. To facilitate this, a web-based system has been developed facilitating the drivers to input and check their traveling plan from any computers or mobile devices. If EVs are not connected to the designated charging stations of EMS, such as in motion, EVs send their data to VIS in an interval of 10 s wirelessly. In addition, VIS transmitted the received data from EVs to EMS simultaneously. EMS receives EV data from VIS and weather information from meteorological agency. Although the weather information is received basically one day before, meteorological agency will update these data automatically once there is any renewal or correction in the weather information.
\n\nUsed EV batteries are utilized for peak-shift. Charging of used EV batteries is practically performed from midnight to morning (00:00–06:00). Threshold for charging and discharging of both EVs and used EV batteries is set to SOC 90% and SOC 40%, accordingly. In addition, load leveling is designed to be conducted during afternoon peak-load time starting from 12:00 until 18:00 (6 hours duration) because the total amount of potentially available electricity from EVs and used EV batteries is limited and very small compared to the total load of the office building. In addition, to diminish the effect of ambient temperature on charging and discharging behaviors of used EV batteries, the storage room of used EV batteries is controlled to have a temperature of 25 °C throughout the year at.
\nThe load of office building is estimated as the sum of the base load and fluctuating load, especially the air conditioning demand. The air conditioning demand is calculated using historical data for several previous years and forecasted ambient temperature received from meteorological agency. The demand of office building in certain typical time, Lt, can be simply approximated as follows:
\nwhere LBS, f, TOA, TST, and Δτ are the base load for 30 min interval (kWh) of the office building, functional relationship, outside ambient temperature (°C), room temperature inside the office building (°C), and time shift (h), respectively.
\nThe available electricity from EVs, PEV, which are in motion and not plugged in to the charging poles can be estimated as the correlation of SOC and the remaining distance (both are received from VIS), and can be represented as follows:
\nwhere SOCEV,t, CEV, dt, ηEV, and SOCmin are SOC of each EV (%), EV battery capacity (kWh), remaining travel distance to the designated charging station (km), power consumption of EV (kWh km−1), and minimum SOC threshold for discharging (%), respectively.
\nTo calculate the peak-cut threshold, a day load duration curve is initially created using the historical data of the averaged office building load for the same month in the last year. A peak-cut threshold, Pthr, can be approximated using Equation (3). Figure 10 shows the illustration of a day load duration curve.
\nwhere Pbat, n, and m are available power from used EV battery (kWh), number of load higher than peak-cut threshold, and number of EVs and used EV batteries, respectively.
\nIn general, a load duration curve lines up all the loads in a descending order. Therefore, in this demonstration test, a day load duration curve is created by sorting all 30 min duration of office building loads from the largest to the smallest loads. Therefore, the plotted area represents the total electricity consumed by the office building for a day (starting from 00:00 to 24:00). Furthermore, the generated electricity from PV panels is directly delivered to the building without being managed by EMS to be stored in the battery. In addition, the total electricity which can be obtained from connected EVs, used EV batteries, and PV panels is plotted on the top of a day load duration curve for the corresponding day while its bottom is kept to be straight at the same value of load. Therefore, the created straight line is a peak-cut threshold which is used in load leveling.
\nTypical load duration curve and the calculated peak-cut threshold.
A result of load leveling demonstration test of one representative weekday is shown in Figure 11. It consists of the total grid load (net electricity purchased from the grid), building load (the total load consumed by the office building), electricity generated by PV panels, and total charging and discharging from and to EVs and used EV batteries. Charging and discharging of EV and used EV batteries are represented as dotted blocks in positive and negative sides, respectively. The total grid load during after-noon peak-load time (load leveling test from 13:00 to 16:00) is significantly lower than the building load. This is because of the power generated by PV panels and peak-cut threshold which order the EVs and used EV batteries to discharge their electricity.
\nCharging and discharging of EVs and used EV batteries in negative sides mainly occur due to charging of used EV batteries during the night time and EVs charging during morning time (before the peak-load time) and during lunch break time. As used EV batteries are charged during night time, the grid load during this time is higher than the building load. EVs generally arrive at the office building at around 08:00 and they are connected to the designated charging stations of EMS. From this moment, charging and discharging behaviors are fully controlled by EMS. Because the building load is still lower than the calculated peak-cut threshold, EVs charging can be conducted until the building load reaches nearly the peak-cut threshold to increase the discharging capacity of the EVs during peak-cut. Moreover, additional charging starts again during noon break (12:00–13:00) because the building load drops drastically creating any marginal grid load.
\nResults of load leveling test during weekdays.
From Figure 10, the peak-load occurs twice, i.e., before noon and afternoon, respectively. However, before noon peak-load is lower than the one in afternoon time. The generated electricity by PV is always consumed directly without being charged, hence peak-cut for the before-noon peak-load is conducted only by PV. In addition, the afternoon peak-load starts usually from 13:00 after the end of lunch break time. During this time, the building increases significantly and when it reaches approximately the calculated peak-cut threshold, EMS sends immediately the control command to EVs and used EV batteries to discharge their electricity according to the required amount for load leveling. Hence, the purchased grid load can be kept to lower than the contracted power capacity.
\nHowever, due to the limitation of available number of EVs and used EV batteries, load leveling only can be performed in a relatively short duration of time. It is estimated that as the number of EVs and used EV batteries taking part in this ancillary service program increases, more significant effect of load leveling can be achieved. In addition, a longer duration of load leveling and lower value of peak-cut threshold can be obtained accordingly.
\n\nFigure 12 shows the total amount of load leveling in a day by each PV panels, EVs, and used EV battery for 8 months of duration of demonstration test. Furthermore, Figure 13 shows the averaged total load leveling by each PV panels, EVs, and used EV battery in different months. The used EV batteries have the largest and most stable load leveling share compared to EVs and PV. On the other hand, the generated electricity from PV is quite fluctuating because it is influenced strongly by the weather condition, especially solar intensity. Furthermore, the share of EVs in load leveling is also strongly influenced by their main usage as vehicle because it will affect significantly their SOC (available electricity for load leveling).
\nThe amount of load leveling in a day by each component (PV, EVs, and used EV batteries).
Averaged total load leveling by each component (PV, EVs, and used EV batteries).
The uncertainties are brought mainly by three factors: EVs, PV, and building load. These factors result in divergence between the predicted and real values. In this demonstration test, because the capacity of office building load is significantly larger than the total electricity which can be provided by PV panels, EVs, and used EV batteries, it is assumed that the strongest factor influencing this uncertainty is the building load, especially demands for air conditioning. Moreover, PV also gives an additional influence to this uncertainty due to its fluctuation.
\nAs the results of conducted demonstration test, the predicted grid load showed a relatively high similarity with the real grid load. However, the difference between the predicted building load and its real load is relatively large due to the above-mentioned uncertainties.
\nThe divergences in office building load and generated electricity from PV panels can be lowered by controlling the charging and discharging amounts from both EVs and used EV batteries. In addition, in this demonstration test, the uncertainty related to EV availability and its capacity do not show any significant impact. It is because the drivers of EVs are basically the employees who are working in the office building and almost the commuting routes are constant every day. It is considered that although there is an uncertainty on EVs’ availability and their capacity, the divergence between the predicted and real grid loads could be reduced as long as the capacity of the used EV batteries which are owned by EMS are able to cover those fluctuating factors.
\nThere are some important findings and suggestions which can be derived from the above theoretical study and demonstration test which are related to the employment of EVs and their used batteries to support the electricity in a small-scale EMS.
To calculate an optimum peak-cut threshold, an accurate forecast of both demand and supply is required. The demand forecast is influenced strongly by two main factors (especially the fluctuating load): weather condition and human behavior inside the building. To achieve more accurate weather forecast, timely update of weather information from meteorological agency and utilization of historical meteorological data are considered very important. In addition, regarding the forecasting of the human behavior, a construction of database and knowledge of specific behavior patterns of the office building is demanded. In case that the measurement of behavior patterns is relatively difficult to be performed, the method of guiding the behavior of the residence by establishing some regulations or policies might be taken.
Objective and accurate metering system to measure the amount of charged and discharged electricity to and from EVs is crucially demanded to enhance the trust and transparency. It can be performed by independent third party which is trusted by both EV owners and EMS/aggregator, especially in an aggregator-based contract scheme. The measurement can also include the participating duration, including stand-by time.
The increase in EVs number taking part in this ancillary service results in larger available capacity for load leveling (peak-cut). Unfortunately, this phenomenon is also potential to cause higher risk of larger fluctuation in case that EMS cannot forecast accurately the number of EVs. Installation of larger amount of stationary battery (used EV batteries) is considered potential to buffer and absorb this fluctuation through charging and discharging controls.
If some EVs which are participating in the ancillary service stop suddenly their service and demand an emergence charging due to some factors, such as traveling distance which will be traveled, EMS also must be able to coordinate this kind of sudden charging demand for EVs. The uncoordinated charging can result in creation of a new peak-load.
Compared to peak-load during summer, peak-load during winter is generally lower. However, peak-load during winter occurs mainly during evening time, around 17:00. This is because the heating demand inside the office building increases following the decrease in ambient temperature. It is important to note that the basic working hour also ends in this time, therefore there is any possibility that some EVs are demanding an additional charging before leaving the office. As a result, a new peak-load can occur during this time if the demand for EV charging is high. EMS must be able to also predict this kind of emergency and uncoordinated charging, hence a new peak-load can be prevented.
Additional number of EVs and total capacity of used EV batteries will be required when the amount of electricity generated by REs, including PV and wind, increase due to larger amount of fluctuating electricity in the supply side.
This chapter discussed the enhanced utilization of EVs and their used batteries to participate in ancillary service to support the electricity, especially in a small-scale EMS. In addition, experimental study based on the real data collected from the demonstration test bed has also been described. The study showed that it is feasible to utilize EVs and used EV batteries in supporting small-scale EMS. Furthermore, load leveling which determines initially the peak-cut threshold and, then controls both charging and discharging behaviors of EVs and used EV batteries based on peak-cut threshold is considered as a valid technique. As a result, the purchased electricity from the grid can be kept to be lower than the contracted power capacity.
\nAccurate forecast of both load and supply is considered as one of the important issues in this utilization, in addition to the availability forecast of EVs and their batteries. The supply includes the condition of electricity market, possible generated power by REs, and available electricity which can be supplied by EVs. Furthermore, highly accurate load forecast, especially the fluctuating load including human behavior and air conditioning, is also very essential to achieve an optimum target condition as it has been estimated by EMS.
\nSpinal cord injury (SCI) can be defined as damage to the spinal cord (SC). It causes anatomical and physiological changes that result in permanent or temporary alterations in its function [1]. The injury causes ionic deregulation, edema, ischemia, bleeding, free radicals production, and a generalized inflammatory response that will cause partial or total loss of sensitive and motor function below the site of injury [2, 3].
\nIn the United States, there are around 17,500 new cases of SCI per year, with an approximate prevalence of 280,000 people [4]. SCI is found most frequently in men (79.8%) than women (20.2%) and the age distribution reflects a bimodal performance with a peak between 15 and 29 years of age and another one on ages above 50 years [4, 5, 6]. Traffic accidents are the main cause of traumatic SCI (38%), and they are most prevalent in young people. The low impact accidents like falls are the second cause of SCI (31%), and they are more common among people older than 60 years old [5]. In Mexico, the estimated annual incidence of SCI is about 18.1 per million inhabitants. Statistically, the number of people involved rises each year [7].
\nThe Spinal Cord Injury could be divided by its etiology in traumatic and nontraumatic. The traumatic type is caused by physical damage (traffic accident, sportive, and fall), whereas nontraumatic is occasioned by an illness/sickness, such as tumors, infections or degenerative diseases which directly affect the SC [8]. In addition, SCI can be divided into primary and secondary injury [1, 9].
\nPrimary injury is caused at the moment of physical damage and leads to irreversible affection on gray matter during the first hour post-lesion. There are three main mechanisms of injury: contusion, when there is not a visible alteration in its morphology, producing a necrotic region at the injury area; laceration or transection, when there is an extreme trauma or penetration, affecting SC conduction of nervous impulses depending on whether the tissue is partial or totally transected; compression from vertebral fractures leading ischemic damage in the area where blood flow was disrupted [10, 11].
\nAfter injury, superficial blood vessels undergo to vasospasm which provokes damage in the microvasculature of gray matter [12]. Reduction in the perfusion has two important implications: hypoxia and ischemia; which may involve to neurogenic shock characterized by arterial hypotension, bradycardia, arrhythmia, and intraparenchymal hemorrhage that causes neuronal death by necrosis. Afterwards, primary injury provokes the rupture of blood brain barrier and a cascade of destructive secondary phenomena leading to a further damage in SC and neurological dysfunction [1, 13]. Therefore, the primary lesion results in the development of a succession of cellular and molecular changes that alter gene expression patterns, which are processes that are already part of the secondary injury [11, 12]. During the acute phase, injury to the blood vessels and severe hemorrhages cause massive influx of inflammatory cells, cytokines, and vasoactive peptides. This phase is almost characterized by ionic deregulation that leads to edema, thus interrupting the conduction of nerve impulses. Following, subacute phase involves a sequence of events like ischemia, vasospasm, thrombosis, inflammatory response, free radicals (FR) production, lipid peroxidation (LPO), and activation of autoimmune responses causing apoptosis. The huge inflammatory responses after the acute and subacute phase, together with the disruption of the blood-brain barrier (BBB), contribute to the progressively swelling of the SC. This generalized edema may increase the mechanical pressure of the SC, aggravating the injury [1, 11, 14].
\nTo counteract all these acute effects after SCI, neuroprotective strategies have been investigated to rapidly intervene decreasing the neuronal death occurring after damage mechanisms. Many pharmacological and nonpharmacological therapies have been developed, and others are still under investigation, this in order to improve the quality of life of patients.
\nAs we review previously, SCI leads to motor and sensory dysfunction, first with the primary mechanical injury and then with the complex cascade of secondary damaging events [15]. For several years, basic science, preclinical, and clinical studies are focused in overcoming elements involved in accurate recovery from SCI [1]. An ideal neuroprotective therapy must reduce neurological symptoms including degenerative changes; starting from there, we can discriminate between potential clinical therapies, which could have a better effect [16]. While these therapies are being searched, there are many preclinical and clinical investigations exploring pharmacological and nonpharmacological treatments.
\nThis range of therapeutic approaches includes: ionic channel blockers, inhibitors of NMDA and AMPA-kainate receptors, inhibitors of FR and LPO, anti-apoptotic drugs, calpain inhibitors, immunosuppressive or immunomodulatory drugs, immunophilin ligands, immunomodulatory peptides, hypoglycemic agents, and gonadal hormones.
\nTetrodotoxin (TTX) is a low-molecular-weight guanidine neurotoxin that acts as a specific blocker of voltage-gated sodium (NaV) channel [17]. TTX has neuroprotective properties by blocking NaV channels, preventing neuronal death by diminishing depolarization, cellular Na+/Ca+2 exchange, and neuronal glutamate release [18].
\nThe beneficial effects of TTX in preclinical studies include a reduction of white matter loss after SCI [17, 18, 19], promoting a motor function restoration. The effect of TTX is time-dependent [20]. The administration of TTX 15 minutes after a SCI helps to restore the function of hindlimbs [21]. Despite these promissory effects, there are some limitations for the use of TTX in patients, one of them is its toxicity. This may appear as a consequence of its systemic distribution and it can involve the blocking of diaphragmatic nerves ending in respiratory tract paralysis [17]. Even with previous findings, current studies are needed to improve its use in SCI.
\nRiluzole is a benzothiazole anticonvulsant drug with neuroprotective effects in the SCI [22]. One of the mechanisms by which riluzole operates is the inhibition in the presynaptic terminals of glutamate, and this helps to limit the glutamate-induced toxicity [23]. In addition, riluzole blocks the NaV-gated channels, avoiding swelling and neuronal acidosis. Riluzole blocks the entry of H+ to the neurons through the Na+/H+ exchanger; this prevents the Ca+2 from inducing the release of glutamate and excitotoxicity [22]. Investigations have shown that the interruption of events associated with glutamate release on the presynaptic space by reducing Ca+2 influxes provokes a glutamate-mediated LPO reduction [23, 24]. Administration of riluzole within 12 hours of SCI was well tolerated and suggests that it may have a beneficial effect on motor outcome [25].
\nNimodipine is a dihydropyridinic Ca+2 channel antagonist that boosts the brain’s blood flow, without compromising metabolism [26, 27]. It reduces malondialdehyde (MDA) levels, ED-1 markers for activated macrophages and myeloperoxidase (MPo). Studies have shown that nimodipine helps reducing FR, oxidative damage, resulting in the reduction of the damaged area and the infiltration of the inflammatory cells to the region, allowing SCI restoration [26]. Furthermore, the effect of inhibiting Ca+2 flux by nimodipine reduces apoptosis and tissue damage after SCI, increasing cell viability [27].
\nMemantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, which through the inhibition of hypoxic or ischemic damage/necrosis helps to prevent the secondary damage in SCI [28, 29]. The use of an NMDA antagonist limits neuronal glutamate exposure caused by excitatory amino acid neurotransmitters [29]. The use of memantine with anti-apoptotic agents like Q-VD-OPh boosts the neuroprotective effect through the reduction in apoptosis and necrosis mechanisms. Moreover, it provides better clinical and histological outcomes by limiting neuronal necrosis [28, 29].
\nGacyclidine is a noncompetitive NMDA antagonist that is able to reduce the extension of ischemic lesions in SCI. It has been proven that gacyclidine is efficient in enhancing the functional and histological condition of the injury, but their neuroprotective effects are time and dose-dependent [30, 31].
\nNBQX is an AMPA/kainate antagonist that during acute SCI improves mitochondrial function and diminishes reactive oxygen species (ROS) formation as well as LPO production [32, 33]. The treatment with NBQX reduces white matter loss following SCI. Further studies are needed to know more about its efficacious effects in acute SCI.
\nOmega-3 polyunsaturated fatty acids (ω-3 PUFAs) are structural compounds of the phospholipid membrane. They produce beneficial effects in neurodegenerative diseases by its anti-inflammatory, antioxidant, and membrane stabilizing properties [34]. ω-3 PUFAs, particularly docosahexaenoic acid (DHA), exert profound anti-inflammatory effects on the central nervous system (CNS), confer significant protection to the white matter, and help to increase neurite growth and synapse formation. DHA acts on cyclooxygenases (COX), cytosolic phospholipase A2 (cPLA2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [35, 36]. Deficiencies of lipids affect neural responses in CNS injuries, and this must predispose nerve cells to dysfunction [37]. According to previous findings, there are some investigations (Table 1) that have previously shown the effects of PUFAs in preclinical models.
\nTreatment outcome | \nRef. | \n
---|---|
α-linolenic acid (ALA) and DHA reduce lesion size and increase motor recovery and neuronal survival. | \n[34] | \n
DHA reduces microglia activation in both ventral and dorsal horns and increases motor recovery, promoting beneficial functional effect in SCI. | \n[38] | \n
ALA, combined with DHA, protects against neuronal necrosis and apoptosis. | \n[39] | \n
DHA induces a reduction in neutrophil number in SC epicenter. The administration confers histological protection and improves motor recovery. | \n[40] | \n
Prophylactic therapy with ω-3 has shown a reduction in cellular vulnerability. Supporting functional recovery, there is also an increase in levels of protein kinase B/Akt and CREB. | \n[37, 41] | \n
DHA plus rehabilitation enhance a functional, anatomical, and synaptic plasticity in cervical SCI. | \n[42] | \n
Polyunsaturated fatty acids in spinal cord injury.
Glutathione (GSH) is a tripeptide compound constituted by glutamine, glycine, and cysteine. The reduced form of GSH is glutathione-monoethyl-ester (GSHE), which is an endogenous, rechargeable antioxidant. Besides its anti-oxidant functions, GSHE plays a role in regulation of apoptosis, and it is important for cellular defense against ROS [43, 44]. Some studies have reported that GSHE diminishes SC LPO after SCI, while also acting as a vasodilator under conditions of oxidative stress [44, 45]. In addition, GSHE plays an anti-excitotoxic role by inhibiting the binding ligands to ionotropic glutamate receptors under redox modulation, which have been involved in excitotoxicity after SCI. As a consequence of the reduction of GSH after an injury, there is neuronal loss in the SC, probably due to oxidative stress and mitochondrial dysfunction. Combined therapy of GSHE with A91 resulted in a better motor recovery and axonal sparing associated with a higher axonal myelination [46]. The use of GSHE could be an interesting alternative for SCI therapy; however, it should be strongly evaluated before its use in clinical trials.
\nCaspase inhibitor Z-DEVD-fmk is a selective caspase-3 inhibitor that also has anti-inflammatory properties. Anti-apoptosis compounds are used to block apoptotic cell death but also to inhibit cytokine production. Treatment of SCI with z-DEVD reduces secondary tissue damage, ischemic injury, preserves motor function, and provides neuroprotection via the inhibition of cell death in all of cell types in the SC [47, 48]. Low doses of z-DEVD-fmk combined with basic fibroblast growth factor (bFGF) reduce neurological deficit in ischemia, therefore providing neuroprotection [49].
\nCaspase inhibitor z-LEHD-fmk acts as a selective caspase-9 inhibitor with anti-apoptotic properties. This drug helps decreasing levels of apoptosis biochemical markers, reducing lesion size and remaining active during treatment to maintain its therapeutic effect. Treatment with z-LEHD-fmk helps to prevent apoptosis in a variety of cell types like neurons, astrocytes, oligodendrocytes, and microglia populations [50]. Further studies are needed to understand more about its effects and benefits in acute SCI.
\nCalpains belong to the family of calcium-dependent nonlysosomal cysteine proteases, which can be found expressed through the CNS. They are involved in neurodegeneration, degradation of cytoskeleton, and apoptosis via caspase-3 due to its proteolytic activities, in SCI. The influx of Ca+2 stimulates Ca+2-dependent enzymes, within them are calpains, which seem to play a role in proteolysis by contributing to apoptosis in CNS cells. The cell death decreases mRNA expression and transcription of myelin basic protein (MBP) and proteolipid protein (PLP), which are axonal neurofilament proteins [49, 51, 52]. The administration of a calpain inhibitor such as E-64-d (1 mg/kg) to injured rats blocks apoptosis and helps to re-establish MBP and PLP genes [51]. The administration of other calpain inhibitors such as SJA 6017 and calpeptin has demonstrated their ability to induce neuroprotection after SCI [53, 54]. Despite the study efforts and the promising therapeutic effects for functional neuroprotection, there are no clinical trials testing these drugs, so further studies are needed for the use of calpain inhibitors in patients.
\nIndomethacin, a nonsteroidal anti-inflammatory (NSAID) drug, acts as a nonselective cyclooxygenase inhibitor. It has shown that it inhibits the synthesis of prostaglandins and ameliorates the effects of secondary injuries like tissue necrosis in SCI [55, 56, 57]. RhoA is a convergent intracellular pathway that limits axonal growth; its inhibition with indomethacin prevents oligodendrocyte loss and induces myelination across damaged white matter [58]. Nevertheless, the administration of nonselective cyclooxygenase inhibitors is a controversial issue since these compounds could inhibit platelet aggregation and may produce gastrointestinal ulceration [55]. Moreover, there is evidence that a single injection of indomethacin in SCI had a minimal effect on functional recovery and anatomical repair [57].
\nMeloxicam is a drug derived from enolic acid, which inhibits prostaglandin biosynthesis under inflammatory conditions via the inhibition of COX-2. It has minimal gastric toxicity. Meloxicam has shown to reduce SCI-induced oxidative stress and exert neuroprotection by inhibiting LPO, GSH depletion, and DNA fragmentation [59, 60]. Despite these interesting results, meloxicam has not been further studied. Therefore, more studies are needed to know about its clinical management in SCI.
\nCyclosporine A (CsA) is an immunosuppressant agent compound formed by 11 amino cyclic peptides, and it is obtained from Tolypocladium inflatum. CsA inhibits T-helper lymphocytes, cytotoxic and inflammatory responses in macrophages, inducible nitric oxide synthase (iNOs) expression avoiding the formation of nitric oxide (NO)-derived cytotoxic species, Cox-2 mRNA accumulation, tumor necrosis factor (TNFα) production and reduces cytokines and interleukins production (IL-1, IL-2, and IL-6). Also, CsA reduced the apoptosis of SC cells and increased the protein expression levels of cyclophilin-D (Cyp-D) and apoptosis-inducing factor (AIF) [61, 62]. This compound is capable of inducing motor recovery after SCI [63].
\nTacrolimus or FK506 is an immunosuppressant macrolide drug, isolated from Streptomyces tsukubaensis, and it is approved by The Food and Drug Administration (FDA) [64, 65]. An indirect neuroprotective effect results from its immunosuppressant action on T-cells that infiltrate SCI, and this action modulates inflammation. On the other hand, FK506 inhibits caspase-3 and NF-kB, improving functional recovery with the increase of rostral axonal sparing and oligodendroglial survival [66, 67]. Additionally, this compound is capable of reducing FR and thereby LPO. These neuroprotective effects improve if the administration of FK506 is during the first 30 min after injury [65]. The studies suggest that FK506 might be a good drug for treating SCI in humans.
\nImmunization with neural derived peptides (INDP) such as A91, a peptide derived from the 87–99 immunogenic sequence of myelin basic protein has shown to induce neuroprotection and motor recovery after SCI [68]. Its mechanism of action is related to the activation of T-lymphocytes inducing an anti-inflammatory Th2 response that allows microglia to differentiate into a M2 phenotype. Th2 response is capable of producing brain-derived neurotrophic factor (BDNF), a molecule strongly related to tissue protection [69]. INDP has shown that anti-A91 T-lymphocytes promote tissue protection by inhibiting the expression of iNOS, reducing ON production [68] and decrease LPO after SCI [70]. On the other hand, it has been shown that all these beneficial effects contribute to the preservation of neural tissue by preventing apoptosis [71], the survival of neurons in rubrospinal tract [72] and promoting a better neurological recovery in models of SCI [46]. Studies suggest that A91 might be an immune modulating treatment for SCI.
\nMetformin is a hypoglycemic agent used for therapy of type 2 diabetes mellitus; it is an AMP-activated protein kinase (AMPK) agonist. Metformin also acts through signaling pathway of mTOR and p70S6K causing an inhibition of apoptosis and inflammation. This drug is also capable of stimulating autophagy and reducing expression of NF-kB-mediated inflammation [73, 74]. Studies indicate that long-term use of metformin has been proved effective as a pharmacological treatment for some CNS disorders like Parkinson’s disease, Huntington’s disease, and ischemic brain injury. Using a rat model of traumatic SCI, the administration of metformin helps restoring the dysfunctional autophagy-lysosome pathways providing neuroprotection, decreasing neuronal death and mitigating apoptosis [75, 76]. The immediate administration of metformin after the injury showed diminishing complications, reflecting a decrease on histopathological signs of neuroinflammation, including TNFα and IL-1β inflammatory cytokines in the SC [73]. Although these outcomes are promising, subsequent studies are required to determine the risk ad optimal doses for the use of metformin on clinical studies.
\nAndrogens and estrogens are multi-active steroidal hormones that have neuroprotective effects in neural injuries; both testosterone and estradiol improve safeguard against apoptosis and promote motor and sensitive recovery. Also, reduce inflammation and FR generation and have been involved in regulating the expression of cytoskeletal proteins, promoting them as an increasing in neurite outgrowth [77, 78]. Studies in rats treated with estradiol have shown a reduction in the lesion size, an increase in white matter sparing, and an improving in motor function [77, 79, 80]. On the other hand, testosterone has shown to exert similar but not identical effects; it is neuroprotective against apoptosis in oxidative stress [77, 78]. A study with young adult female rats implanted with testosterone-filled silastic capsules reported regressive changes in motoneuron and muscle morphology after a SCI providing the possibility of improving motor function [81]. A study with administration of progesterone in rats improves neurological deficits and reduces inflammatory response. Prevents degeneration of motor neurons and reestablishes proliferation and differentiation of oligodendrocytes [82]. At the moment, investigations on the field conclude that gonadal hormones could be an effective alternative after SCI.
\nMethylprednisolone, minocycline, GM-1-ganglioside, and glyburide are some of the most investigated pharmacological therapies in clinical settings.
\nMethylprednisolone (MP) is a synthetic glucocorticoid, with anti-inflammatory and anti-oxidant effects [83, 84]. MP blocks the inflammatory cascade and disrupts neuron regeneration by inhibiting immunological cells [85, 86]. The potential neuroprotective effects of MP have been reported especially in the acute phase of SCI. According to some investigations, MP is capable of reducing FR production, Ca+2 influx, excitotoxicity, and immune-mediated phagocytosis over the course of hypoperfusion of SCI [87]. In addition, MP appears to have effect in apoptosis and autophagy regulation; however, the mechanisms are not clear [84]. While it remains the only option for acute SCI treatment in clinical settings, a debate regarding optimal dose, time of administration, efficacy, and adverse effects has dominated the field for years. There are three National Acute SCI Studies (NASCIS) and other clinical or biomedical investigations, in which the safety and efficacy of MP were assessed (Table 2) [88]. Despite the intense investigation, currently there is an important controversy regarding the real utility of this drug.
\nTreatment outcome | \nRef. | \n
---|---|
NASCIS I: Treatment with a dose 1.0 g daily promotes neurological recovery. The morbidity and mortality is increased. | \n[89] | \n
NASCIS II: Administration of (30 mg/kg intravenous bolus plus 23 hour infusion of 5.4 mg/kg) during the first 8 hours after injury causes neurological recovery seen from 6 weeks after the SCI. | \n[86] | \n
NASCIS III: Administration within 8 hours from the SCI, should maintain the administration for 48 hours to improve neurological function. | \n[90] | \n
Combination of riluzole and MP improves functional recovery and tissue sparing. In addition, beneficial effects on oxidative stress were observed. | \n[91] | \n
MP may cause acute corticosteroid myopathy, at doses recommended by the NASCIS. | \n[92] | \n
High-dose MP inhibits glucocorticoid receptors as well as having effects in LPO; however, their beneficial effects are independent of LPO inhibition. | \n[55] | \n
Administration of MP for treatment of SCI is not recommended. There is evidence that high-dose steroids are associated with harmful side effects including death. | \n[93] | \n
A comparative study of MP vs. A91-immunization showed that A91-immunization has a better efficiency promoting motor recovery. Combining MP with A91-immunization allowed to observe that MP has a transient immunosuppressive effect that eliminated the beneficial actions of A91-immunization. | \n[94] | \n
Effects of methylprednisolone in spinal cord injury.
Minocycline is a second generation tetracycline, a semi-synthetic antibiotic able to cross blood brain barrier, and it can be used to treat rheumatoid arthritis [95, 96]. Minocycline has neuroprotective effects when administered during the acute neural trauma. Current data suggest that minocycline has anti-inflammatory, immunomodulatory, and neuroprotective effects. These beneficial actions are achieved as a result of the inhibition of iNOS matrix metalloproteinases (MMPs), PLA2, TNF-α, caspase-1, and caspase-3. Moreover, minocycline enhances Bcl-2 and thus, reduces apoptosis, also, it decreases p38 mitogen-activated protein kinase (MAPK) phosphorylation and inhibits PARP-1 [97, 98, 99, 100]. Other studies report that minocycline can bind to Ca+2 and Mg+, reduces reactive astrocytes to increase oligodendrocyte viability in white matter, and inhibits the activation of microglial cells [101, 102]. A multi-center phase II trial was performed to explore the neuroprotective effect of minocycline; however, the results of the study did not establish a real improvement in SCI. Authors suggest further investigations in a multi-center phase III trial [103].
\nGangliosides (GM-1) are sialic acid-containing glycosphingolipids, present in cell membranes of CNS cells, specifically in the external leaflet of plasma membranes. They participate in the repair and maintenance of CNS [104, 105]. A randomized placebo-controlled (Phase II) trial with administration of GM-1 within 24 hours after injury was realized in 37 patients with SCI. The results of this study showed that GM-1 enhances the recovery of neurologic function after 1 year [104]. Further studies should be designed in order to provide more evidence about the efficacy of GM-1.
\nGlyburide (glibenclamide) is a FDA approved sulfonylurea drug widely used to treat type 2 diabetes; it has the ability to target receptor (SUR1) regulated Ca+2 activated [ATP] cation (NCCa-ATP) channels [96, 106]. After SCI, there are small hemorrhagic lesions at the epicenter of gray matter. Glyburide diminishes the progressive hemorrhage necrosis by jamming the interaction between SUR-1 and preforming subunits of NCCa-ATP channels located in endothelial cells. In addition, improves neurological function [107]. Actually, a phase I/II clinical trial is currently under way to test the safety and neuroprotective effectiveness of glyburide in patients with SCI [88].
\nThe most common preclinical nonpharmacological therapies in the acute phase of SCI are antioxidants, growth factors, and transplant of cultured cells like neural stem cells (NSCs), bone marrow stem cells (BMSCs), olfactory ensheathing cells (OECs), and Schwann cells (SCs).
\nFirst damage in the acute phase of injury is generated in membranes, membranes which are susceptible to the attack of ROS and reactive nitrogen species (RNS). ROS are produced in metabolic and physiological processes of cells; however, they are overproduced by inflammatory response. ROS and RNS induce LPO, which leads to demyelinating processes. Among the nonpharmacological therapies to prevent damage from FR are nonenzymatic antioxidants like vitamins.
\nVitamins are one of the main natural antioxidants. Table 3 shows some vitamins and their neuroprotective effect after SCI.
\nTreatment | \nNeuroprotection mechanism | \nRef. | \n
---|---|---|
Vitamin E | \nIncreases functional recovery. Reduces cavitation and decreases FR, LPO, and glutathione peroxidase and improves functional recovery. | \n[108, 109, 110, 111, 112] | \n
Vitamin C | \nStops lipid hydroperoxyides formation and decreases membrane damage. Reduces necrotic tissues and improves functional recovery in rats. Inhibits ROS generation and LPO. Decreases levels of proteins like NF-kB, iNOS, and COX-2. Down-regulates the levels of TNFα and IL-1β. Modulates antioxidant status and MPO activity | \n[113, 114] | \n
Vitamin C + fluoxetine | \nCo-treatment with vitamin C + fluoxetine inhibits the blood-SC barrier disruption after SCI. Inhibits capillary fragmentation by reducing mRNA levels of MMP-9. Prevents degradation of tight-junction proteins, inhibits infiltration of neutrophils and macrophages. Inhibits apoptotic cell death and improves functional recovery. | \n[115] | \n
Vitamin A | \nIncreases the expression of IL-1β, IL-6, and TNFα after SCI. Systemic administration reduces early transcript levels of IL-1β, IL-6, and TNFα. Reduces blood-SC-barrier permeability and improves functional recovery | \n[116] | \n
Decreases levels of β-catenin, P120 catenin, occluding, and claudin5. Inhibits endocytoplasmic reticulum stress and caspase-12 expression. | \n[117] | \n
Vitamins in spinal cord injury.
Resveratrol is a natural polyphenolic compound that has exhibited beneficial health properties as well as antioxidant, anti-inflammatory, and antitumor effects. Resveratrol exerts a neuroprotective effect by regulating apoptosis [118]. Studies have shown that the anti-inflammatory effects of resveratrol are mediated mainly by sirtuin (SIRT) 1 [119, 120]. Resveratrol enhances locomotor recovery [121, 122, 123]. Furthermore, resveratrol increases nuclear factor erythroid 2-related factor (Nrf-2) activation, providing antioxidant effects [121]. Further investigation is needed in order to provide more evidence about the efficacy of this treatment.
\nThe use of growth factors like BDNF, transforming growth factor-β (TGF-β), and insulin-like growth factor-1 (IGF-1) as a therapy to improve morphological and behavioral outcomes after SCI has been topic of study of many investigations.
\nBDNF exerts a relevant function in the repair of neural tissue and plasticity in CNS [124, 125]. Nevertheless, recent studies have also shown that BDNF is capable of exerting neuroprotective effects. In acute phases of injury, several reports indicate that both, BDNF alone [126, 127] or in any combination [128, 129] has improved functional recovery, neuronal survival, and tissue preservation. Moreover, BDNF has potent antioxidant effects and may be involved in regulation of immune responses after an SCI [130]. BDNF after SCI requires careful selection to consider the location, mode, and time of application after an injury.
\nTGF-β is a pleiotropic molecule with specific key functions in cell differentiation, proliferation, migration, immunosuppression, and extracellular matrix metabolism [131]. TGF-β could also be contributing to neuroprotective mechanisms after SCI since it participates in the regulation of neuronal survival and orchestrates repairing processes in the CNS [132]. It has been previously observed that TGF-β administration reduces microglial activation and increases neuronal survival [133]. The early induction of TGF-β after SCI modulates the acute immune response, the formation of glial scar and improves functional recovery [134].
\nIGF-1 belongs to the family of insulin-related peptides, and it is the mediator of the anabolic and mitogenic activity of the growth hormone [135]. Aside from this, IGF-1 acts as a strong antioxidant [136] and pro-survival [137] factor in the CNS since it diminishes caspase-9 and elevates Bcl2 [138]. Experimental studies have shown that IGF-1 reduces edema and the upregulation of iNOS after SCI [139]. In the same way, it has been suggested that IGF-1 and erythropoietin protect against ischemic SCI in rabbits [140]. Therefore, the beneficial properties of IGF-1 make this molecule an interesting neuroprotective strategy in the acute phase of SCI.
\nStem cells have also been the focus of several investigations. Table 4 summarizes some of the neuroprotective effects exerted by stem cells like NSCs, BMSCs, OECs, and SCs.
\nTherapy | \nNeuroprotective effects | \nRef. | \n
---|---|---|
NSCs | \nIncrease functional recovery. Reduction in neutrophils and M1 macrophages. Downregulation of TNFα, IL-1 β, IL-6, and IL-12. Improve functional recovery and reduce neuronal apoptosis, microglia activation, reduce pro-inflammatory cytokines like TNFα, IL-1β, and IL-6. Improve locomotor and sensory function and increase mRNA expression of BDNF. | \n[141, 142, 143, 144] | \n
BMSCs | \nImprove locomotor function and tissue protection. Increase the neurotrophic growth factor. Stimulate M2 macrophage activation. Reduce cystic cavities size and suppress glial scar formation. | \n[145, 146, 147, 148] | \n
BMSCs + SCs | \nReduce the formation of the glial scar, remyelinate the injured axons, and promote functional recovery | \n[149] | \n
BMSCs + IGF-1 | \nInduce modulation of inflammatory cytokines and oxidative stress. Increase functional recovery and reduce activation of glial fibrillary acidic protein and increase myelination 4 weeks following SCI. | \n[150] | \n
BMSCs + OECs | \nReduce apoptosis and increase locomotor recovery. | \n[151] | \n
OECs | \nReduce cavity size, increase the neurofilaments sprouting and serotonin axons, and improve functionality. | \n[152] | \n
OECs + SCs | \nDiminish astrocyte number, microglia/macrophage infiltration and expression of CCL2 and CCL3. | \n[153] | \n
SCs | \nUpregulate the expression of NOS, activate the NO-dependent cyclic-GMP pathway, which enhances neuronal survival. Stimulate the expression of neural growth factor and BDNF. Reduce inflammatory cytokines and ROS. | \n[154, 155] | \n
SCs + NSCs | \nPromote neuronal differentiation, increase axonal regeneration/myelination, reduce neuronal loss, and improve functional recovery. | \n[156] | \n
Stem cell therapy in spinal cord injury.
Nonpharmacological therapies with clinical studies are hence limited in acute phases of the injury.
\nPilot studies cover the acute phase of SCI.
\nTransplants with human NSCs in phase I/IIa assessed the safety and neurological effects after SCI. Of 19 treated subjects, 17 were sensorimotor complete and two were motor complete and sensory incomplete. They demonstrated that 1 year after cell transplantation, there was no evidence of SC damage, syrinx or tumor formation, neurological deterioration, and exacerbating neuropathic pain or spasticity [157]. Additional studies should be designed in order to afford more evidence about the efficacy of NSCs.
\nRegarding bone marrow stem cells (BMSC), an interesting study reported data from 20 patients with complete SCI who received transplants of BMSC. They showed improvement in motor and sensory functions [158]. In addition, a study with autologous BMSCs in three patients in the sub-acute phase of injury (<6 months of disease) demonstrated that, these cells could be safely administered through intrathecal injection in SCI patients [159]. Other study showed that 45.5% of transplanted patients presented improved neurological function. They showed some degree of improvement in sensitivity and motor function as well as in sexual function. In two patients, neuropathic pain disappeared and bladder and bowel control increased [160]. Nevertheless, more investigation through clinical trials is required with a larger population of patients before further conclusions can be drawn.
\nTransplants with autologous OECs in three patients indicated that there were no adverse effects 1 year after transplantation. The neurosurgical process did not lead to any negative sequelae either during the operation or postoperatively. Additionally, they demonstrated the possibility of taking a nasal biopsy and reliably generating enough cells for transplantation within 4 weeks [161]. These observations suggest that autologous transplantation is safe but further researches are needed.
\nA Phase I clinical trial with autologous human SCs was conducted to evaluate the safety of transplantation into the injury of six subjects with subacute SCI. There was no evidence of additional SC damage, mass lesion or syrinx formation. They conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5–30 days of injury, and perform intra-spinal transplantation of highly purified autologous SCs within 4–7 weeks of injury [162]. Studies in acute phases using SCs are very few: therefore, more studies are needed in this area.
\nTiming as a specific prognostic factor in rehabilitation results and confirms that early specific rehabilitation treatment is associated with greater improvement. Several studies investigate the early rehabilitation as a therapeutic strategy to improve locomotor function, some of them have even shown physical functional independence [163, 164, 165]. Other studies indicated that in acute SCI physical therapy of body weight support on a treadmill and defined overground mobility therapy did not produce different results [166]. Further studies are required to afford conclusive results.
\nIn conclusion, there are several pharmacological and nonpharmacological treatments that have been tested in preclinical and clinical phases. However, so far have not yielded fully satisfactory results; even using combined therapies. Further studies are needed in order to identify novel therapeutic targets and strategies that provide a better medical care avoiding complications.
\nWe gratefully acknowledge to Universidad Anáhuac México Norte for the support to this chapter.
\nThe authors declare no conflict of interest.
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