Application of ecological engineering approach for terrestrial and aquatic systems.
\r\n\tAccording to the protection and control strategies in recent years; Although WHO has reduced the rates somewhat with the application of mass medication in children in places where the prevalence of roundworm is over 20%, to control morbidity and eliminate STN as a public health problem, the mathematical applications have been to apply the treatments to adults as well.
\r\n\r\n\tIn this book, roundworms transmitted through soil or arthropods; Developments in epidemiology, life cycles, pathophysiology, clinical diagnosis, management, and public health control in the world will be reviewed with the contribution of studies on this subject from past to present. In addition, this book aims to highlight the connection between helminths and autoimmune and allergic diseases: the determination, treatment, and control strategies.
",isbn:"978-1-80356-714-3",printIsbn:"978-1-80356-713-6",pdfIsbn:"978-1-80356-715-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"5edc96349630be8bb4e67170be677d8c",bookSignature:"Dr. Nihal Dogan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11801.jpg",keywords:"Ascaris, Trichuris, Hookworms, Strongyloides, Wuchereria, Brugia, Onchocerca, Trichinella, Larval Infection, Visceral Larva Migrans, Cutaneous Larva Migrans, Ocular",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 23rd 2022",dateEndSecondStepPublish:"May 27th 2022",dateEndThirdStepPublish:"July 26th 2022",dateEndFourthStepPublish:"October 14th 2022",dateEndFifthStepPublish:"December 13th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A leading academic in parasitology at the Department of Microbiology at the Faculty of Medicine of Eskişehir Osmangazi University, expertise in hydatid cysts, toxoplasma, leishmania, parasitic diseases transmitted by water and intestinal parasites. She wrote numerous book chapters on infectious diseases, clinical parasitology, clinical microbiology, and medical microbiology laboratory applications and manuals.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"169552",title:"Dr.",name:"Nihal",middleName:null,surname:"Dogan",slug:"nihal-dogan",fullName:"Nihal Dogan",profilePictureURL:"https://mts.intechopen.com/storage/users/169552/images/system/169552.png",biography:"Prof. Dr Nihal Doğan is the leading academic in the Field of Parasitology at the Department of Microbiology at the Faculty of Medicine of Eskişehir Osmangazi University since 1993. She was granted a professorship in 2008 and has expertise in parasitology and epidemiology of parasitic diseases. She took part as an executive academic on 6 projects hydatid cysts, toxoplasma, leishmania, parasitic diseases transmitted by water and intestinal parasites. Her research is published in more than 40 national and international journals and she took part as a keynote speaker and as abstract and poster presenter in more than international and national congresses and conferences. She wrote numerous book chapters on infectious diseases, clinical parasitology, clinical microbiology and medical microbiology laboratory applications and manuals. \nShe concluded her Master and PhD Thesis at Eskişehir Anadolu University and Eskişehir Osmangazi University Medical Faculty and focused on the field of diagnosis and seroepidemiology of Toxoplasmosis. She visited the University of Virginia Department of Parasitology as a visiting researcher in 2003 for 3 months and worked on the diagnosis of Entamoeba histolytica and Universidad De Chile Faculty of Medicine as an observer researcher in 2016 for 1 month and worked on Trypanosomes.\nHer research interests include medical ethics, seroepidemiological survey; intestinal, blood, tissue and ocular parasites, vector-borne diseases, zoonotic parasites.",institutionString:"Eskisehir Osmangazi University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"13",title:"Immunology and Microbiology",slug:"immunology-and-microbiology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466998",firstName:"Dragan",lastName:"Miljak",middleName:"Anton",title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/466998/images/21564_n.jpg",email:"dragan@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and 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:"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:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3569",title:"Biodegradation",subtitle:"Life of Science",isOpenForSubmission:!1,hash:"bb737eb528a53e5106c7e218d5f12ec6",slug:"biodegradation-life-of-science",bookSignature:"Rolando Chamy and Francisca Rosenkranz",coverURL:"https://cdn.intechopen.com/books/images_new/3569.jpg",editedByType:"Edited by",editors:[{id:"165784",title:"Dr.",name:"Rolando",surname:"Chamy",slug:"rolando-chamy",fullName:"Rolando Chamy"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"80235",title:"Bioremediation of Hazardous Wastes",doi:"10.5772/intechopen.102458",slug:"bioremediation-of-hazardous-wastes",body:'The increase in human activities triggers environmental pollution through the generation and disposal of hazardous wastes in aquatic and terrestrial habitats [1]. Most of these pollutants include inorganic (heavy metals) and organic matter (polyaromatic hydrocarbons (PAH), petroleum hydrocarbons compounds (PHC)) which may cause negative effects on the ecosystem and possibly react with other abiotic factors that attribute to the effect on the structural arrangement of terrestrial and aquatic habitats [2].
In terms of the environment and ecology system, the proper and safe disposal of these hazardous wastes is a key priority for a sustainable ecosystem. This involves the use of various treatment procedures to clean up hazardous waste. For detoxifying heavy metals, radionuclide and organic polluted soils, physicochemical techniques such as filtration, precipitation, electrochemical treatment, soil washing and chelating, oxidation/reduction, ion exchange, reverse osmosis, and stabilization/solidification have been employed. These environmental clean-up procedures have various disadvantages, including inefficiency, the need for a large number of chemical reagents, energy, and high cost, as well as the formation of secondary by-products [3].
Bioremediation is a cost-effective and environmentally tolerable technology that employs a biological process to reduce environmental risks caused by toxic substances and other hazardous pollutants. To treat polluted multiphase systems and sustain the native ecosystem, a combination of bioremediation techniques will be effective. The fundamental premise of bioremediation is to reduce contaminant solubility by adjusting pH, modifying redox processes, and adsorbing toxic substances from polluted sites [3]. Environmental remediation always requires human assistance to achieve effective remediation of contaminants and restoration of ecological balance. However, remediation can be destructive to the ecosystem [4], if the application is not properly addressed to meet the eco-friendly standard required to combat the contemporary issues of pollution [4, 5]. Most small-scale applications of bioremediation approaches using bioremediation agents such as bacteria, fungi, plants, and organic materials have been successful with variation in results, although bioremediation on a large scale has not been widely validated [4]. This chapter aims to propose a cost-effective and eco-friendly bioremediation strategies that could reduce or remove contaminants from the environment and thus stabilizing the ecosystem from heavy metal pollution and oil spills.
There are a lot of different physical, chemical, and biological processes commonly termed bioattenuation, which make pollutants smaller in terms of their size and toxicity as well as how much of them there are. Some examples of these processes are sorption, volatilization, chemical or biological stabilization, and the transformation of contaminants. This entails removing pollutant concentrations from the surrounding through biological methods or perhaps incorporating (oxic and anoxic biodegradation, plant and animal sorption), physical occurrences (changes in weather conditions, dispersion, dilution, diffusion, volatilization, sorption/desorption), and chemical reactions (ion exchange, complexation, abiotic change) [6, 7, 8]. For instance, natural biodegradation and biotransformation are incorporated within the broader notion of common restriction [9, 10]. At the point when the site is contaminated with chemicals, the environment acts in 4 different approaches to facilitate remediation [11]:
Microbes or microorganisms living in soil and groundwater may consume just a small number of chemical or manmade chemicals available as dietary nutrients. When they have completely digested the chemical, they can convert it to water and non-toxic gases.
Chemical compounds can stick to or sorb to the soil, which prevents them from contaminating groundwater or escaping the location.
As contamination travels through soil and groundwater, it can blend in with clean water. This diminishes or weakens the contamination.
Certain chemicals, such as oil and solvents, can disappear, hence, they can transform from liquids to gases within the soil or groundwater. As a result, if these gases reach the earth surface via the air, they may be pulverized by sunlight.
Additionally, if natural attenuation is insufficiently rapid or complete, bioremediation will be accelerated or augmented via biostimulation, bioaugmentation, bioventing, or biopile [11, 12].
This bioremediation approach invigorates the activity of native microbes by adjusting the environmental parameters or the introduction of nutrients [11, 13]. This is carried out with the incentive of natural or normally prevailing parasites or microbial communities [7, 11, 13]. Successive steps involve providing manures, development enhancements and minor elements. Also, by giving other natural prerequisites including pH, temperature and oxygen to enhance their digestion rate and degradation pathway [10, 12]. Similarly, the presence of pollutants even in small quantities can act as a stimulant by spinning for bioremediation proteins. Typically, this type of deterioration is followed by the provision of organic or inorganic nutrients and oxygen to promote the metabolism of native microbes for effective remediation [6]. These nutrients are the fundamental building blocks of life, enabling microorganisms to synthesize vital components such as enzymes, energy, and cell biomass required to degrade the toxin [6, 14]. However, nitrogen, phosphorous and carbon are significantly required to enhance metabolism.
This procedure entails sequentially adding contaminant-degrading microbes (inherent/non-native/genetically modified) to improve the biodegradative efficiency of the native microbial community in the polluted site [8, 11]. Thus, to rapidly grow the natural microbial population and accelerate breakdown at the pollutant’s location. Microorganisms that predominate in polluted sites on a global scale, may surely change significant amounts of harmful substances into non-poisonous structures. This process converts pollutants to by-products like carbon (IV) oxide and water, as well as metabolic intermediates that serve as critical nutrients for cell development [15, 16]. Microorganisms can also be isolated from the remediation environment, cultured autonomously, genetically engineered, and then reintroduced to the site [8, 11]. For persuade, all basic microbes are prevalent in locales where soil and groundwater are polluted with chlorinated ethenes, for example, tetrachloroethylene and trichloroethylene [7, 8, 11]. These are employed to facilitate the effective removal and conversion of these pollutants to non-poisonous ethylene and chloride by in situ microbes [10].
Additionally, genetically modified microbes have been shown to degrade a broad range of environmental contaminants effectively. Since the metabolic pathway can be altered to produce less puzzling and harmless end products [8, 17]. Genetically engineered microorganisms (GEM) have shown viability in bioremediation of soil, groundwater and activated sludge, proving effective degradation abilities of extensive integration of chemical and physical contaminations. GEMs have better enzyme abilities, which makes them better at breaking down a wide spectrum of aromatic hydrocarbons and making the soil more fertile [14, 18]. There are several types of hydrocarbon-degrading microorganisms that include the genera
It is the practice of venting oxygen through the soil to encourage the development of natural or injected microbes and fungus in the soil by supplying oxygen to the soil microbes, which has been termed as bioventing [8, 11, 14]. The use of low air flowrates to supply sufficient oxygen to sustain microbial movement has long been a typical practice in aerobic degradation of substances, and it has been for many years. For example, several scientists have demonstrated that bioremediation of oil-contaminated soil utilizing bioventing may be achieved with reasonable success [19]. Consequently, petroleum residuals and their by-products are biodegraded, and volatile organic compounds, when destroyed, release vapors that slowly permeate through the biologically dynamic soil environment.
Biopile, also known as biocells, bioheaps, biomounds and composts piles are employed to minimize the toxicity of total petroleum hydrocarbon constituents via microbial respiration. Biopiles are an ex-situ bioremediation technology that consists of piling polluted soil onto a compost pile (biopiles) or cells (biocells) or mounds (biomounds) or heaps (bioheap) and stimulating oxic metabolism in the soil via aeration or introduction of minerals or nutrients, bulking agents, and subsequently confining it in a treatment bed with polyethylene material to avoid evaporation, surface runoff, and volatile emissions. Biopiles treatments can transform pollutants into low-toxic by-products through biological processes by utilizing already existing microorganisms to breakdown fuels and oils into carbon dioxide and water.
The biopile technology is made up of commercial roll-off dumpsters or containers that have been turned into fully contained bioremediation units. The biopile units have an impermeable liner to decrease the possibility of leachate movement to the subsurface ecosystem. Excavated soils are combined with soil additives and placed on a treatment area with leachate collecting devices and some type of aeration to maximize and regulate the rate of biodegradation. Air is introduced to the biopile mechanism of piping and pumps, which either power air into the heap under a specific tension or draw air through the heap under a negative tension [8, 20]. Microbial movement, for instance, can boost the adsorption and degradability of petroleum pollutants during funneling and siphoning operations. Biopiles, such as biocells, bioheaps, biomounds, and compost, might alleviate public concern about excavated soil contaminated by vigorously remediable hydrocarbons [8, 13, 19].
Utilizing plants for bioremediation is highly dependent on their ability to break down certain pollutants [21, 22, 23, 24]. Phytoremediation is the process of utilizing plants to degrade, eliminate, or convert contaminants to less hazardous chemicals [25]. Even though plants have been used for soil purification for centuries, scientists have contributed to its advancement and expanded its scope of application throughout the years [7, 11, 13, 14, 17, 18]. This involves the removal of metals, pesticides, solvents, explosives, and raw petroleum, as well as a variety of other pollutants from soils, water (surface and subsurface), and vaporous contaminants [7, 11, 14]. When the plants have accumulated enough toxins, they are harvested and disposed of. Figure 1 shows a graphical presentation of different types of phytoremediation as each mechanism is explained as follows:
Phytostabilization: this entails using plants to minimize soil erosion, so immobilizing contaminants by limiting their movement and accessibility in the soil via the plant roots. Additionally, it prevents metals from moving to the soil or the surface of underground water.
Phytovolatilization: this involves the use of plants to minimize soil erosion, so immobilizing contaminants by limiting their movement and accessibility in the soil via the plant roots. Additionally, it prevents metals from moving to the soil or the surface of underground water.
Phytodegradation: this process includes the degradation or modification of pollutants in the plant tissue by enzymes.
Phytoextraction: this approach involved the extraction of contaminants from the soil and their accumulation in the shoots. Upon that, these plants’ leaves are gathered, burned for energy, and the metals retrieved from the ash are regenerated.
Phytofiltration or rhizofiltration use roots to accumulate and sequester contaminants from polluted water.
Phytostimulation or rhizodegradation: plant roots are employed to digest organic pollutants in the rhizosphere environment and through microbial activity.
Schematic presentation of phytoremediation process (adapted from [
This is when two or more bioremediation methods work together to remove contaminants from the environment. This kind of bioremediation technique can be effectively applied in a multi-contaminated environment. The combinative strategy most likely to be suitable and effective in boosting bioremediation of bauxite residue is a combination of bioaugmentation (incorporation of inocula) [8, 11] and biostimulation (introduction of nutrients to enhance the activity of microorganisms) of the indigenous community in bauxite residue [11, 13].
In this scenario, for instance, biostimulation using organic or inorganic compounds can be applied as the first or basic treatment while bioventing or bioaugmentation using engineered microbes can be applied subsequently as a secondary or tertiary treatment to facilitate the removal or degradation of recalcitrant compounds. Combinations of bioaugmentation and biostimulation have also proven effective, albeit they do not always show significant improvements over bioaugmentation alone. Given the nearly consistent advancement seen with bioaugmentation technology, it is anticipated that bioaugmentation will improve on the outcomes obtained so far with biostimulation for bauxite waste cleanup (provided an appropriate choice of the microbes and adequate trials are prioritized). Based on the simplicity of obtaining and introducing the inoculum, the most suited approach for future research and field trials is combinative bioremediation using biostimulation and bioaugmentation technology.
Several bioremediation mechanisms for reducing or oxidizing contaminants have been discovered over time, such as adsorption, physio-biochemical (biosorption and bioaccumulation) bioleaching, biotransformation, biomineralization, and molecular mechanisms [7, 11].
Environmental pollutants (both organic and inorganic) can be absorbed by microorganisms at specific sites in their cell structure that do not require the dissipation of energy. There are many various kinds of chemicals connected with bacterial cell walls, but their extracellular polymeric substances (EPS) are of particular importance since they have been shown to have significant effects on corrosive base characteristics and metal adsorption [10, 26]. Several studies on the metal binding behavior of EPS have revealed that it has a remarkable capacity to absorb complex metals by a variety of processes that combine ion exchange and micro-precipitation of metals [10, 13]. Bioremediation research and application are still limited in the present scenario due to a lack of understanding of the genetic traits and genome-level properties of the organisms used in metal adsorption, the metabolic route, and the kinetics of metal adsorption [7].
In microscopic organisms, inhibition is advanced through two mechanisms: detoxifying (changing the detrimental metal’s state and rendering it inaccessible) and dynamic efflux (siphoning poisonous heavy metals from cells) [7, 9]. In wastewater or soil, the fundamental redox (oxidation and reduction) reaction occurs between hazardous metals and microorganisms. Additionally, microbes oxidize heavy metals, causing them to lose electrons, which are recognized by active electron acceptors (nitrate, sulphate and ferric oxides) [26]. Additionally, the biosorption process, which consists of a biosorbent’s increased affinity for sorbate (metal ions), is repeated till a balance between the two components is established [18, 26]. For instance,
Bioaccumulation is a term referring to the combination of active and passive techniques of hazardous metal bioremediation. Additionally, bioremediation may entail aerobic or anaerobic microbial activity [10, 12, 13]. Aerobic degradation frequently involves the addition of oxygen atoms to the reactions via monooxygenases, dioxygenases, hydroxylases, oxidative dehalogenases, or chemically active oxygen molecules produced via catalysts including ligninases or peroxidases [10, 11, 12, 13]. Anaerobic contaminant corruptions comprise initial enactment reactions followed by oxidative degradation with the assistance of anaerobic electron acceptors. The act of Immobilization refers to the process of reducing the activation of significant metals in a polluted environment by modifying their physical or synthetic state [7, 12]. Microbes muster metals from polluted sites through leaching, filtering, chelation, methylation and redox transformation of harmful metals [12, 17]. Since significant metals cannot be entirely eliminated, the cycle modifies their oxidation state or organic complex to make them more soluble, less poisonous and precipitated [9, 14].
In bioleaching, naturally occurring microorganisms such as bacteria and fungi solubilize metal sulphides and oxides from ores and secondary wastes. Adsorption, ion exchange, membrane separation, and selective precipitation are some of the processes used to purify solubilized metals. It is a cost-effective and environmentally beneficial technique because it consumes less energy and produces no hazardous gases. It has been applied to leach metals from low-grade ores, and it now provides a substantial global business in the extraction of metals like copper, cobalt, gold, nickel, uranium, zinc, and other elements [27].
This is the procedure for altering the structure of a chemical substance to produce a molecule with higher polarity. Moreover, this metal-microbe interaction process converts hazardous metal and organic chemicals into a less poisonous form. This mechanism has emerged in microorganisms to assist them in adjusting to variations in their surroundings. Bacterial cells have a significant surface-volume ratio, a rapid pace of proliferation, a rapid rate of metabolic activities, and are easy to keep sterile [27]. As a result, they are perfect for biotransformation. Various methods, such as condensing and hydrolyses, forming new carbon bonds, isomerization, inserting functional groups, and oxidation, reduction, and methylation, can be used to attain this objective. Metals may be volatized, reducing their lethal nature, as a result of these interactions.
Biomineralization refers to the mechanisms by which microbes produce minerals, and it can lead to metal extraction from solution, which can be used for decontamination and biorecovery. Dead biota and related products may also serve as a model for mineral deposition, with physicochemical parameters determining whether the process is reversible or not. There are several prevalent microbe-precipitated biominerals with unique chemical features such as high metal sorption capacities and redox catalysis. However, some biominerals can be deposited at nanoscale dimensions, resulting in additional physical, chemical, and biological features that can be used in practical applications [28].
Different components of genetically altered bacteria, such as Deinococcus geothemalis, are active in the removal of heavy metals [9, 14, 18]. Hg2+ reduction has been recorded at high temperatures as a result of the expression of meroperon from
The promising bioremediation technique involves the application of bioturbators. Bioturbation is made up of a series of processes triggered by microbenthic fauna that influences sediment physicochemical characteristics and affects the microbial population which partake in the distribution of nutrients [29]. Bioturbation involves a series of activities such as the reworking of particles, bioirrigation, and other benthic biota related behaviors (i.e. nutrition mode and grazing by animals and organisms) that were responsible for transportation and distribution of porewater and particles along the water-sediments interface [30]. The distribution of dissolved contaminants can be a reworking of sediments by bioturbators through facilitating transportation and biomixing efficiency from overlying water and porewater to deep layers of the sediment [31, 32, 33].
The term “bioturbation” relates to the procedure of completely transforming dangerous hazardous substances into harmless or naturally occurring chemicals. Bioturbation can be done in situ (for example, in field conditions) or ex-situ (for instance, in a microcosm or under controlled conditions). Both scenarios entail the utilization of plants, parasites/fungi, and microorganisms as bioremediators for the biodegradation of toxic pollutants, even though individualized end product may be a different component [34, 35, 36]. Thus, complete breakdown of the contaminants by the bioremediators directly or indirectly may influence the residue structure [34, 37]. Figure 2 presents significant types of contaminant improvement approaches by bioturbators (benthic fauna) in the contaminated environment to facilitate residue treatment.
Schematic representation of bioturbators activities in sediments (i) biodiffusors, (ii) upward conveyors, (iii) downward conveyors, and (iv) regenerators.
Biodiffusors: this is performed through microorganisms’ activities, which often result in the biomixing of uniform and irregular sediments over short separations, resulting in particle interchangeability via molecular diffusion.
Upward conveyors: these are organisms that live vertically head-down in the sediments. They transfer particles from the residue’s deep horizons to its surface. Gravity then returns the particles to the base under the influence of feces pellet agglomeration at the sediment surface.
Downward conveyors: these are head-up feeders that actively pick and consume particles near the surface, as well as discharge in deeper residual layers.
Regenerators: these microorganisms dive into the leftovers and constantly maintain burrows, so transferring dirt from depth to the surface.
The role and effectiveness of bioturbators in bioremediation is dependent on several conditions, such as the chemical type and quantities of contaminants, the physicochemical properties of the environment, and their accessibility to microbes [38]. Bioturbators are responsible for vital changes in the biological and physicochemical aspects of soils and water [38, 39]. Additionally, aerobic bioturbation can increase benthic digestion and supplement components by stimulating oxygen-consuming bacterial networks that are concerned with pollutant mitigation [8, 11]. In other words, bioturbators are well-suited for a dual-purpose mechanism, namely the production of degradative enzymes for specific contaminants and resistance or protection from significant relative dangerous substances such as heavy metals [15, 38, 39]. Controlling and simplifying bioremediation procedures is a difficult process due to a large number of components including the presence of a microbial community with the ability to detoxify pollutants, the contaminants’ accessibility to the microbial community, and abiotic conditions (soil type, temperature, pH, oxygen or other electron acceptors, and substrates) [6, 16, 39].
Bioturbation influences the sediment-water interface’s biological, physical, and chemical properties which accounts for the high rate of mineralization of organic matter in the aquatic environment [40]. This operation changes the sediment column distribution of the contaminants [41]. Bioturbation and biotransport can affect the physicochemical characteristics of sediments and sediment pollutants [42, 43, 44]. Bioturbation controls the organic matter and nutrient digestion enhances pollutant mobility and transformation [45, 46, 47, 48]. The biosorption of organic contaminants into the organic matter during bioremediation reduces its bioavailability for plants (phytoremediation) or degrading organisms (bioaugmentation) [49]. Atrazine removal from sediments is promoted and positively influenced by the adjustment of organic matter and earthworm bioturbation activities, which increases contaminant bioavailability and atrazine sorption rate on their microsites [46, 50]. Previous studies reported positive contributions of earthworm bioturbation to organic pollutant transformation and biodegradation [51, 52] by modifying pore size and metabolism of degrading bacteria groups or accelerating mineralization in bioaugmented soils [50].
Moreover, several studies showed that bioturbation alters the physicochemical characteristics of the water-sediment boundary which promotes the bioavailability of inorganic pollutants to degrading organisms. This is achieved through the modification of sediment particle sizes, pore spaces, moisture content, nutrient content, turbidity, and total organic carbon of the vadose water-sediment [41, 43, 53]. Also, the bioturbation of benthic invertebrates through the mixing of sediments in the underground zone enhanced the electron acceptors (oxygen, nitrate and sulphate) entrance into the vadose zone which triggers geochemical changes that influence metal behavior [54]. The presence of these electron acceptors in the unsaturated zone can activate the RedOx reaction to change the chelating of metals affinities between liquid and solid phases to enhance the quantitative distribution and bioavailability of metal in the sediment [55]. The changes created by the bioturbation-attributed redox potentials, pH, organic content, pore spaces can affect metal sorption capacity and improve metal conversion from one phase to another e.g. Cd, Zn [56, 57, 58].
The activities of bioturbators are affected by some factors which modulate the rate of bioturbation for effective remediation of polluted environments. These factors include the variation in salinity, temperature, density, sediment grain size pH, and concentration.
Variation in salinities in the aquatic environment can influence the metabolism of nutrient and metal releases [59, 60], whether naturally and/or through human-related activities. Remaili et al. [61] noted that hypersalinity has a negative effect on the larger bioturbators which affects the activities of benthic organisms. Gonzalez et al. [62] study found that the salinity levels and tolerance of various bioturbators are distinct. The findings however suggest that ammonia release in the aquatic environment is significantly modified due to the effect of modulating conditions and distinguished by a higher salinity than other nutrients such as phosphorus [62, 63].
Regional variability in temperature is also a crucial factor that regulates the impact of bioturbation in pollutant remediation. In microbial response, metabolism, and degradation of organic matter and metals, temperatures played a fair modulatory function [64]. In the presence of bioturbation activities, the rise in temperatures increases the production of ammonium from the sediment, possibly due to the high level of hydrogenase in microbial species and the increased aerobic conditions in the sediment [64, 65]. Gonzalez et al. [62] reported that an increase in temperature is indirectly proportional to the nutrient dispersion as high temperature decreases nutrient flux (phosphorus) in the sediment but extreme temperatures may be devastating to the microbes. However, an increase in temperature corresponds to the increased rate of metal resuspension and metal solubility as a result of higher bioturbation rates [66, 67].
The bioturbator density influences bioturbation, control bioturbation efficiency for contaminant remediation, which correlates with the increased aerobic microbial activity and emission of pollutants. The increased bioturbation density increased phosphorus release and induced aerobic microbial activity but did not increase the release of ammonia. Animal density is a highly imperative factor, as study reveals that higher densities contribute toward greater degradation and mineralization of organic matter but may also increase nutrients in the overlying water and can, depending on the ecosystem studied, have counterproductive effects on recovery [66]. In response to pollution, the population of certain benthic species such as polychaetes [68] may increase as several systems are deprived of the use of other larger bioturbators.
Another element that influences the high level of organic matter and metals accumulation and the structure and metabolism of microbial communities and their metabolism is the sediment grain size [69, 70]. A recent study also shows a positive association between ammonia, phosphorus release, and aerobic microbial activity for the sediment grain size as Martinez-Garcia et al. [70] noted that the grain size showed less effect at low organic enrichments, but instead, at higher enrichments, coarse sediments contain less organic matter and nutrients while metabolism rate is enhanced. The contaminant bioavailability assessment can be affected by the susceptibility, grain size and behavior of microbes used in bioassays or observed on the ground, and the interaction between various species and microbial populations in highly polluted sediments depauperated by larger invertebrates [1, 71].
The concentration of organic or inorganic contaminants is another factor that regulates the activities of the benthic organisms [72] which tend to either reduce or hinder the activities of the benthic organism at a high concentration, beyond the tolerable limit, which can result in the death of these organisms at extreme condition due to toxicity [5]. Benthic organisms have varying tolerance limits for sediment contaminations and tend to possess special features or activities (such as bioaccumulation or biosorption) to enable them to adapt and function effectively in high pollutant concentrations. For metal remediation, abiotic factor-like pH which works closely with concentration may be a crucial modulating variable that determines the impact of bioturbation in the marine environment which can alter metal speciation and reactivity [66].
Therefore, sediment properties like particle size and concentration as well as contaminant shape (sulphides or organic carbon) can affect the bioavailability of the contaminant. Also, in most environments, temperature and type of organism activity or population density can increase or decrease contaminant exposure or bioavailability for bioremediation [61, 73, 74, 75].
Notwithstanding the benefits (such as environmental friendliness, selectivity, adaptability, self-reproducibility, and the ability to recycle bioproducts) of the bioremediation technique, some setbacks have hindered the successful application of this technology. The delay of the operations and the complexity in managing the procedures are the two most significant disadvantages of this technique of treatment. Since the elimination of significant concentrations of heavy metals is a priority, and that the world has become more aware of the environmental concerns caused by other approaches, microbial procedures offer the most rational and long-term answer for treatment. As previously stated, while a variety of microbial contaminant bioremediation techniques to address contamination have been developed, their extensive use and application on a commercial scale are still restricted by some factors. A further point to mention is that the long-term viability of microbial decontamination is still a subject of significant importance, given the paucity of investigations into its long-term performance. Due to the extremely high accumulation of inorganic contaminants (heavy metals) in heavily inhabited places of the world, updating existing microbial bioremediation technologies to an industrial level by making the procedures quicker, more reusable, and easier to regulate will be a big issue in the future. Furthermore, another limitation of bioremediation is that not all substances are biodegradable while some hydrocarbon components are recalcitrant to microbial breakdown, which restricts the scope of the remediation technique. Even when a material is biodegradable, its downstream operation and breakdown can result in the production of harmful by-products in some situations.
The potential for microorganisms to remediate water and soil pollutants to increase treated water consumption and soil fertility for agricultural output is gaining attention [11, 38]. Recently, research has been conducted to enhance the application of altered organisms delineated specifically to boost their affectability toward hazardous metals [11, 16, 38]. An organism whose genetics have been transformed by the use of synthetic methods, which are driven by an artificial genetic exchange between bacteria, is referred to as a “genetically engineered microorganism [11, 18]. By developing GEM, genetic engineering has enhanced the application and disposal of hazardous wastes in laboratory settings. In addition, the following protocols must be considered during the GEM process: (a) alteration of enzyme selectivity and affinity, (b) pathway development and modulation, (c) bioprocess advancement, surveillance, and control, and (d) bioaffinity bioreporter sensor utilization for chemical detecting, toxicity reduction, and endpoint evaluation [13, 18].
As there are several possibilities for improving degradation performance through genetic engineering approaches, such as genetically controlling the rate kinetics of known metabolic pathways to increase degradation rate, or completely infusing bacterial strains with new metabolic pathways for the degradation of previously recalcitrant compounds [6, 8]. Despite important genes for microorganisms are carried on a single chromosome, defining the specific genes needed for the catabolism of some of these novel substrates may be carried on plasmids [18, 76, 77]. Plasmids were entangled in the catabolism process. As a result, GEM can be successfully used for biodegradation purposes, necessitating immediate research and large-scale deployment. Genetically engineer microbes offer the benefit of developing microbial strains which can tolerate unfriendly upsetting circumstances and can be utilized as a bioremediation tool under different and complicated natural conditions [18, 37, 76, 77]. Additionally, GEM has encouraged the development of “microbial biosensors” capable of precisely quantifying the degree of pollution in a contaminated site.
The current advancement in omics technologies, including genomics, proteomics, transcriptomics, and metabolomics, play a critical role in finding characteristics that optimize remediation solutions [7, 11, 78]. Consequently, phytoremediation was developed, a process for eliminating toxins or their metabolites from plant tissues. This usually shortens the life of the plant and finally volatilizes the toxins into the atmosphere [78]. This disadvantage can be mitigated by managing plants’ metal resistance, accumulation, and breakdown capacity in the presence of various inorganic toxins. To improve metal decomposition in plants, bacterial genes responsible for metal reduction can be integrated into plant tissues. As a result, plant-based bioremediation for a variety of significant metal poisons is cutting-edge due to its eco-friendliness. They are more effective at reducing dangerous substances than Physicochemical approaches, which are less environmentally friendly and potentially detrimental to human health [7, 8].
Notwithstanding, microbial genes can bridle in the transgenic plant for decontamination and collection of inorganic pollutants [7, 11]. The metal-detoxifying chelators, for example, metallothioneins and phytochelatins can give resistance to the plant by upgrading take-up, transport and amassing of different heavy metals [14, 78]. Similarly, transgenic plants with bacterial reductase can augment the volatilization of Hg and Se while absorbing the arsenic in plant shoots [17, 78]. Also, high-biomass-producing plants including poplar, willow and Jatropha can be applied for both phytoremediation and energy generation [7, 14, 26, 78]. Nonetheless, metals can only be removed from soil or water, which is why consuming metal-contaminated plants is advantageous. Thus, metal-accumulating biomasses should be properly preserved or disposed of to avoid posing an environmental hazard [20, 78].
Bioremediation methods include the introduction of growth stimulators (electron acceptors/donors) or nutrients to the rhizosphere to promote microbial growth and bioremediation characteristics of microbes or genetically engineered plants [6, 26, 78]. Multiple small organisms were generated with heavy metals by drainage using synthesized catalysts such as chromate and uranyl reductase in a particular rhizosphere [19, 26, 78]. Although genomics has been studied and applied mostly in microbial genetics and agriculture, such as genetic crops, and now serve as a bioremediation instrument [26, 76]. The application of genomics to bioremediation enables the microorganism to be dissected based on biochemical constraints as well as sub-atomic levels associated with the component [26, 76, 77].
Bioturbation is a very prolific and appealing technology for remediation, cleaning, management, and recovery of environmental contamination caused by microbial activity [11]. Furthermore, phytoremediation is successful at removing both inorganic and organic pollutants from residues or soils [7, 11, 12]. Nonetheless, investigation of resourceful bioremediation approaches for damaged aquatic environments that are based on these two processes to improve wastewater and soil treatment is necessary [10, 17]. Nonetheless, investigation of resourceful bioremediation technologies based on these two processes is important to improve soil and wastewater treatment [11, 17]. In addition, phytoremediation has been generally illustrated as a bioremediation process for heavy metals, such as lead, cadmium, copper, arsenic removal from contaminated soil or water [76, 77]. In essence, aquatic bioturbation combined with phytoremediation is a more effective and alternative method of removing heavy metals by improving cadmium transfers from overlying water to sediment and then into the root system of plants [15, 38].
Additionally, studies have demonstrated that earthworm movement greatly boosted phytoavailability by increasing soil macroporosity and generating cast around plant roots (Figure 3), implying that the physical effect of the earthworm’s bioturbation is a viable mechanism [20, 26]. Interaction between plants and soil-dwelling microorganisms can also enhance phytoremediation known as rhizosphere bioremediation. The study by Leveque et al. [52] to investigate the contribution of earthworm (as bioremediator or bioturbation agent) to phytoremediation showed that earthworms significantly increased the phyto-availability of metal by generating soil macroporosity and developing cast near plant roots in which the main mechanism appears to be the physical impact of earthworm bioturbation. Moore et al. [21], demonstrated the contribution and the effect of bioturbators in the remediation of organic contaminants using the phytoremediation technique. In the study,
Proffered approach to illustrate metal phytoavailability in earthworms’ activities (adapted from [
The use of nanomaterials is extensively gaining attention for components remediation of heavy metals and recovery of valuable via nanotechnology [8, 34]. Conversely, nanobioremediation, which employs nanoparticles to stimulate microbial activity to clear hazardous chemicals from groundwater and soil [14, 17]. Not only can this nanotechnology greatly cut the cost of cleaning contaminated regions, but it also significantly shortens the procedure’s duration. Metal chelating polymers require damaging solvents for mixing and ultrafiltration for division, which can be avoided by inventing metal limiting substances that can be reclaimed by adjusting their pH, temperature, or form, among other parameters [13, 19, 20]. One of the materials is nanoscale modified biopolymers, produced by microorganisms’ intrinsic and protein structure, and whose size can be adjusted at the subatomic level [13]. For instance, polymers and magnetosomes are fabricated proteins for the remediation of infections,
The technique entails using ecological and environmental engineering expertise to create and monitor a sustainable ecosystem or biological system that benefits both humans and the environment. Table 1 and Figure 4 illustrate how to apply ecological engineering in a way that is more beneficial to humanity while maintaining the natural balance. Nevertheless, the majority of these technologies are typically designed with the following objectives in mind: (i) conservation, (ii) ecosystem restoration, (iii) expanding ecological systems to the quantity, quality, and maintainability of their production, and (iv) assembling new ecological systems that would provide routine types of assistance [16, 39, 76, 77, 80].
Ecological-engineering approaches | Terrestrial examples | Aquatic examples |
---|---|---|
Using ecosystems to solve a pollution problem | Phytoremediation | Wastewater wetland |
Imitating or copying ecosystems to reduce or solve a problem | Forest restoration | Replacement wetland |
Recovering an ecosystem after significant disturbance | Mine land restoration | Lake restoration |
Existing ecosystems are modified in an ecologically sound way | Selective timber harvest | Biomanipulation |
Using ecosystems for benefit without destroying the ecological balance | Sustainable agroecosystems | Multi-species aquaculture |
Application of ecological engineering approach for terrestrial and aquatic systems.
Graphical representation of ecological engineering application to balance the ecosystem.
Bioremediation is a cutting-edge and promising approach for treating contaminated soil and water. Microorganisms are also known to generate and use a variety of detoxification methods, including biosorption, bioaccumulation, biotransformation, and biomineralization for the remediation of the contaminated site during the bioremediation process. However, recent bioremediation research, such as bioturbation, which uses live organisms (macrofauna) directly or indirectly with the environment to eliminate toxins, is gaining momentum. The use of organisms to detoxify and recover polluted soil and water has emerged as the most robust, straightforward, and profitable technique. Microorganisms in water and soil have been studied and equipped to eliminate or detoxify harmful compounds discharged into the ecosystem due to anthropogenic processes such as mineral mining, oil and gas production, pesticides, pigments, plastic, organic solvents, fuel, and industrial operations. Nevertheless, a lack of data on microorganisms’ cell reactivity to minor components and heavy metal poisons precludes their successful implementation. As such, the application of molecular genetic technology will enhance the efficiency and address most of the challenges in the large scale application of bioremediation technology.
For the innovative treatment of cancer, it is necessary to boost target-based cancer therapy, ensuring that it could differentiate between normal and cancer cells while targeting cells [1]. Targeted cancer therapies are far better than the conventional method [2]. Therefore, targeted cancer therapy enjoys lesser unwanted side effects and an excellent molecular mechanism, which promotes minimum toxicity caused by chemotherapeutic drugs [3]. The rapid clearance from the body can be seen when the drug was administered in a higher tolerable dose, which ultimately leads to higher toxicity [4]. During targeted therapy, the drug could be modified to target biological transduction pathways and cellular factors. It also targets angiogenesis and apoptosis inducing molecules [5]. In recent years, several studies have been designed to investigate the effects of nanosized medicines inoperative targeting and diagnosis of cancer cells. Nanoparticles can possibly entrench drugs, theranostic agents, and genes [6]. It was also observed from the various research findings that, nanoparticular approach while drug targeting improves drug tolerability and bioavailability [7]. In formulation drug delivery, anchoring, fabricating, protection of payload from getting degradation by enzymes are possible [8]. The anchored nanoparticles can able to deliver a higher dose into tumor cells while bypassing the normal cells. The modified scaffold integration of nanoparticles facilitates biodistribution of specific drug delivery, which conjugates with ligands and eventually binds with tumor biomarkers [9]. Paul Ehrlich recently suggested a magic bullet, where two different targetings are possible with consistent therapeutic action [10]. In recent research articles and patents, it was often observed that many pharmaceutical carriers such as liposomes, micelles, polymeric nanoparticles designed from natural or synthetic sources were used to target chemotherapeutic medicaments in different cancer cells [11]. Many nanoparticles have passed phase II of the clinical trials stage. This suggests that effective active and passive targeting is possible, due to which greater specificity while selecting cancer target is achieved [12]. Nowadays, conjugation of antibodies, peptides, small chemical entities are versatile in delivering anticancer agents in the form of nanoparticle composite [13]. However, tumor targeting is not an easy job! Scientists are targeting tumors in three different mechanisms; (a) Where nanoparticles were pre-exposed with leaky vasculature of tumor cells and encountered with the reticuloendothelial system (RES) or enhanced permeability and retention (EPR) effects [14]. However, (b) active targeting is more advantageous, as inactive targeting, uncontrolled cell proliferative targeting of tumors, and pH and temperature-dependent targeting is possible. In physical targeting (c) pathological conditions such as pH and temperature play a key role. Nevertheless, targeting the tumor side also depends on the size of the nanoparticles. The nanoparticles, which are less than 7 nm, come under hydrodynamic diameters, easily passing through renal excretion [15]. The nanoparticles that are larger than 100 nm are eventually cleared from the circulation by the phagocytic system [16]. The nanoparticles’ surface charge also plays a pivotal role, as the particles’ cationic charge helps to facilitate internalization [17]. Sometimes surface addition of poly (sarcosine) and poly (ethylene glycol) [18] enhances the circulating half-life of the particles, on the other hand, preventing nanoparticles from getting engulfed by the reticuloendothelial system; by which accumulation of a certain amount of nanoparticles on the outer surface of the cancerous tissue is possible. To make nanoparticles more advanced, hooking ligands onto the nanoparticles’ body facilitates internalization into cancer cells.
To target cancerous cells, it is essential to target molecular aberrations. Effective nanoparticular therapy for cancer targeting relies on the ability to targets such genetic alterations to provide significant clinical benefits [19]. Nowadays, scientists are more focused on targeting p53, ALK PIK3CA, KRAS, G-NAQ, MET, BRAF, EGFR, CKIT genes, and certain pathways, i.e., PI3K/Akt/mTOR, etc. [20].
Ligands are a prerequisite for cancer. Recently, immunotoxin has obtained clinical approval from USFDA, and more than 100 ligand-targeted therapies are under clinical trials [21]. Newly developed phase-display techniques allow selective targeting with higher affinity. The bispecific antibodies and fusion proteins have been used for therapeutic purposes. Mostly the nanoreservior systems viz., niosomes, and polymeric nanoparticles are most suitable for ligand-based targeting [22]. However, pharmacokinetic behaviors and bio-distribution understanding of the molecules are still unknown. The principles of Ligands for cancer targeting can also be applied to the targeted delivery of gene medicines such as antisense oligonucleotides [23].
Most of the nanoparticles as specially lipid-based formulations and polymeric nanoparticles are emerging as the best carrier system to deliver the molecule in cancerous tissues [24]. Monoclonal antibodies and peptides are possibly the best carriers. The surface-bound ligands specifically bind to the target cells. The various techniques viz., covalent and non-covalent techniques help in effective active targeting of cancer cells (Figure 1).
Due to the active targeting, the nanoparticles are getting accumulated in the tumor site. Compered to non-targeted nanoparticles, actively targeted nanoparticles reach the tumor site with higher efficiency and through the endocytosis process, the nanocomposite triggers cancer cells death.
Receptor based targeting is being focused on ensuring the accurate delivery of carriers to their desired location [25]. It allows targeting not only to a localized tumor but also to traveling cancerous cells. This ensures precise delivery. Due to the excessive expression of receptors, targeting becomes easy. Ligands carry out the functionality through active targeting [26].
Receptor based targeting is being focused on ensuring the accurate delivery of carriers to their desired location [25]. It allows targeting not only to a localized tumor but also to traveling cancerous cells. This ensures precise delivery. Due to the excessive expression of receptors, targeting becomes easy. Ligands carry out the functionalization through active targeting (this has to be deleted) [27].
EGFR is a glycoprotein spanning across cell membranes. It is a target for Epidermal Growth Factor [28]. It initiates a signaling pathway leading to cell proliferation and mitosis. This is overexpressed in breast, colon, head and neck, ovarian tumors, and renal and glioma. The binding of antibodies against this receptor reduces cell proliferation. Many researchers prepared drug-loaded vesicles to target EFGR, which increased the drug’s efficacy more than 10-fold [29]. Recently, cancer varieties like colorectal, lung, head, and neck carcinoma showed resistance to EGFR targeting due to mutations in the gene causing inhibition of activation and hence signaling.
As interleukin receptors are majorly expressed, they are essential as a target for delivery. Among many varieties, types-3, 4, 6, 11, 13 & 16 were investigated as a target. The complex of ligand and receptor is taken inside the cell and hence helps cell growth and proliferation. But an overexpression may cause resistance to apoptosis and malignant growth (Table 1).
Interleukin type | Overexpressed in |
---|---|
IL-6 | Ovarian cancer |
IL-4 | Glioblastoma, ovarian cancer, lung cancer, breast cancer |
IL-3 | Chronic Myelogenous leukemia, acute myeloid leukemia blast |
IL-13 | Head and neck cancer |
Type of interleukin.
Various researchers used many ways to target IL receptors and obtained positive results such as reduced proliferation, enhanced uptake of carriers, decreased tumor volume, as well as accumulation and entry into the tumor as well as increased survival. This is not a full-proof strategy as blocking signaling of one type may be compensated with another type. And if the interleukins are blocked, it hinders the functioning of the immune system.
Folate receptor is a glycoprotein present on the external cell surface. It is rich in cystine content. It has three subtypes- α, β and γ [30]. It is responsible for the entry of folic acid into cell, which is important for nucleic acid synthesis. The α subtype is overexpressed in breast, lung, colon cancer, and mesothelioma [31]. According to studies from many researchers, positive results such as a reduced tumor volume, nuclear delivery of therapeutic moieties, increased survival of cells, upregulation of cell death were observed. As folate receptors are present in the body on abundant sites, the selectivity may not always be achieved. Also, there are no animal models for therapeutic advantages or toxicity profiling.
Integrins are proteins that bind to the extracellular matrix and promote cell binding to tissues. Due to this action, this receptor is essential in the progression and metastasis of tumors. ‘RGD motif’ is a polypeptide chain important for binding and has been majorly exploited as a drug target [32]. Targeting the RGD motif has advantages such as improved survival, reduced tumor mass, and tumor growth inhibition. A major drawback of integrin targeting is diseases such as progressing lymphadenopathy [33].
CD receptors initiate tumor development and can self-renew, overexpression of ABC, dormant. These features give tumor characteristics such as resistance, recurrence, and metastasis. Blocking these receptors prevents metastasis. CD subtypes 14, 22, 36, 44, 133 have been explored as drug targets for delivery. Targeting CD-44 receptors on cells allowed delivery into even the resistant tumors and showed enhanced cytotoxicity [34].
These are nuclear receptors binding to the hormone estrogen. Estradiol acts as a transcription factor and controls cell growth. Estrogen helps in the development of sexual and reproductive functions, initiation and forming of lungs, mammary glands, and prostate gland. These receptors are excessively expressed in the majority of types of breast cancers, making it an ideal target. Initially, hormone analogs were used as ligands to target, but the binding strength was not optimal due to the modified structure of hormones. Also, another drawback was excessive RES uptake of such liposomes, which was overcome by formulating stealth liposomes. These formulations showed reduced tumor volume [35].
It is a receptor present on the cell membrane which is responsible for obtaining iron inside the cell. Iron binds to transferrin, and this complex binds to the receptor, which is then internalized [36]. Iron is necessary for many functions, such as DNA synthesis. This receptor can be targeted even if the tumor is Multi-drug resistant. Targeting this receptor has shown excellent results in resistant tumors such as increased formulation internalization, reduced drug required, higher cell death, and enhanced cytotoxicity [37]. This receptor’s drawback is its presence at non-malignant sites such as endocrine glands may cause a loss in efficacy.
Human epidermal growth factor receptor-2 (HER-2) is a receptor spanning across the cell membrane with having a protein kinase internal subunit [38]. It is excessively expressed in gastric, lung, breast, and ovarian cancers. Overexpression of this receptor makes it challenging to forecast carcinoma. But, commercial products such as Herceptin have shown a promise targeting this receptor [39]. Targeting the HER-2 may help in cases of tumors showing resistance. This type of targeting has also demonstrated reduced cancer cell viability, enhanced cytotoxicity in resistant tumors, and increased uptake in the studies. A significant drawback is the absence of any natural ligand for the HER-2 receptor, which makes targeting difficult [39].
Cancer cells are derived from normal body cells; hence they have a similar receptor constitution on the cell surface. Due to this lack of specialized markers, chemotherapeutic agents cannot differentiate between normal and cancer cells. Hence, they show toxicity. Keeping a low dose may result in resistance [40]. Therefore to achieve a specific targeting, antibodies specific for antigens presented by cancer cells can be targeted.
IgG is the majorly used antibody for targeting cancer [41]. Antibodies have ‘Y’ shaped structures where two arms have the sites for antigen binding. Monoclonal antibodies which are derived from a single clone of cells themselves or only the targeting fragments, can be used for cancer therapy. These agents bind the antigen and cause cell death by antibody-dependent toxicity, complement activation, or blocking signal transduction inside the cell. The antibody has a high affinity for its specific antigen and has excellent binding strength due to the presence of two binding sites. Entire antibodies may cause activation of the immune system inside the body. And due to their long half-lives, detection also becomes an issue. Using antibodies from species other than humans may cause severe allergic reactions. Hence to combat this situation, researchers have developed various molecules based on antibodies. Antibodies have been developed where binding sites from mouse have been attached to human antibody (chimeric antibody), humanized or human antibodies have also been developed. Researchers have separated the Fc fragments responsible for binding and have used them for targeting.
Antibodies usually target antigens that are unique to cancer cells or which are excessively expressed on the cell surface. The majority of antibodies induce cancer cell death by binding to their target receptor, either blocking the receptor or changing the receptor’s activation requirements [42]. They disturb signaling pathways responsible for cell growth and survival; hence, they end up killing the cells [43]. For example, Cetuximab is an antibody directed against EGFR. Epidermal growth factor upon binding to EFGR causes tumor growth, proliferation, and migration. EFGR is seen in many cancers. Cetuximab binds to EGFR and blocks the receptor hence preventing ligand binding and subsequent receptor dimerization. This process leads to apoptosis. Human epidermal growth factor receptor 2 is a member of the tyrosine kinase family. It is overexpressed in breast and ovarian cancers. The unique feature of this receptor is the absence of any known natural ligand. Instead, it forms dimers with other growth factor receptors and exerts its effects. Hence antibodies that are made to target this receptor prevent its dimerization with any other receptor and prevent survival.
Indirect action of antibodies involves host immune system participation and causes cytotoxicity by activation of complement system, antibody-dependent phagocytosis, and antibody-dependent cytotoxicity. Most antibodies are able to activate the complement system, which targets and destroys the cancer cell. Ofatumumab, an anti-CD20 antibody, intensifies the process of cytotoxicity through complement activation. Antibody-dependent phagocytosis occurs after a cancer cell opsonized by mAb attaches to a macrophage FcyRI glycoprotein. Then macrophage consumes such a marked cell [44].
Even if mAb therapy is successful, many patients show resistance to it. The resistance may be innate or acquired after exposure to antibodies. Natural resistance is already present in mutations in cancer cells prior to the therapy, and acquired resistance is received after the exposure to therapy [45]. Another limitation is the dependency of the therapy on the overexpression of receptors. Mutations of receptors and the components in the signaling pathway may decrease the efficacy of antibody-targeted therapy. If cells express a variant of the receptor, therapy’s potency may still decrease even if the binding site does not change [46].
Advancement in protein sciences has enabled scientists to produce antibody fragments with a smaller size but the same efficacy. The ideal characteristics of an antibody fragment are discussed in Figure 2.
Different characteristics of antibody fragments.
In the beginning, proteolysis was the method of choice to produce smaller antibody fragments [47]. These fragments had a molecular weight of around 54 kDa–100 kDa (Fab, Fab2). In the later stages, recombinant DNA technology was used to prepare univalent and bivalent fragments which had heavy and light chains of a variable section of antibody [48]. Such a structure was the smallest targeting unit to be generated. The two chains were joined with a flexible polypeptide linkage giving a ‘single chain variable fragment’ (scFv). It was convenient to use because of its small size and easy production.
In the 1980s, researchers isolated and screened a heavy chain of the murine antibody for its binding to lysosomes [49]. It was called a single domain antibody’ (dAb) as it contained only a heavy or light chain and had a meager molecular weight (15 kDa). However, it had drawbacks like poor solubility and aggregation, and a major issue was that the fragments did not retain the original’s binding efficacy [49]. Components from animals such as camels, llamas, and fish such as sharks were used as more soluble, but they suffered from immunogenicity issues. Efforts like immunization and bioengineering to reduce agglomeration were carried out for effective use in therapy [50].
Later the above types were converted from univalent to multivalent through protein engineering, which was then used to target multiple entities at once [51]. These multivalent fragments show slower dissociation from the receptor and high functionality. One great example of multivalent fragments is a ‘diabody’ formed by linking light and heavy chain by a single chain variable fragment to be self-assembled into a dimer [52]. Diabodies have an advantage such as moderate molecular weight, multivalency which give them characteristics like improved penetration in tissue, rapid clearance. These diabodies bind to tumor antigen as well as to CD3 cells to kill tumors through T-cell mediated toxicity. The mini body is another type of synthesized antibody fragment, which is a pair of single chains of variable fragments interconnected by-CH3 bonds, and a variable region specific for any antigen is attached to this pair. Minibodies are more suitable for targeted radiotherapy because they show better uptake and are cleared faster as compared to other types of fragments and are cleared rapidly. In the structure of the Mini body, the single variable region can be replaced by a cytotoxic agent, radioisotope, for its delivery.
Nanobody is the shortest antibody fragment. It is isolated from camelid heavy chains of variable antibody region. It is produced by making phage viral coat cover the desired fragment. As these antibodies do not have light chains, they are structurally different than normal antibodies. They have a concave antigen-binding region larger than other antibodies. Hydrophilic structures replace the usual hydrophobic amino acid residue. Such adjustments allow antigen-binding property even in the absence of light region. Another specific property is its ability to cross blood–brain barrier.
Antibodies that bind to the target can be coupled with a radionuclide, fluorescent molecules to obtain images of cancer. Antibodies that have longer half-life need more time for imaging and may blur the image. These fragments have a short half-life and higher permeability, which allow easy detection. Techniques such as Positron emission tomography (PET), Computed tomography (CT), Single-photon emission computed tomography (SPECT) are now being performed where the antibody fragments are employed [53].
Nuclear imaging is essential for the detection of cancer. Using fragments reduces nuclear exposure to radiation. The bifunctional connector connects antibody fragment and radionuclide, and such complexity easily accumulates at the tumor and gives clear visualization [54]. This method can be used to measure the absorption of drugs and the expression of receptors. One issue with the complex is increased radiation in the kidney due to complex breakdown and retention of radionuclide in the kidney [37].
It involves non-invasive assessment of disease and fluorescence imaging of tumors during surgery. This technique shows accurate and reliable results [55]. Heterodimeric antibodies are used to target two issues at once and have a stronger affinity than homodimer.
Antibody fragments can be coupled with microbubbles, and it enhances the targeting efficiency [56]. Photoacoustic imaging also can be performed with antibody fragments to give high-resolution images. The laser causes expansion of tissues, and it produces sound waves, which later can be converted to images by the ultrasonic transducer.
The selection of antigen is most important for targeting. The target antigen is highly expressed in cancer cells but not on a normal cell. Single, as well as multiple targeting, can be achieved through the use of an engineered antibody. Multivalent antibodies not only block signaling but also overcome resistance through multiple targets [57].
The delivery of anti-tumor drugs using antibody fragments is a common practice of targeting medicine to the tumor [58]. Such systems ensure accurate delivery and improve the pharmacokinetics of agents. Effector molecules such as siRNA cannot target and have very low uptake. Coupling them with antibodies shows enhanced tumor uptake and reduced side effects [59]. An example is CXC chemokine receptor siRNA delivered by coupling with anti-HER2 peptide fusion protein e23sFv-9R is used to target breast cancer cells, having an excess of HER-2 receptors, which promotes apoptosis. Immunotoxins also can be targeted for effective therapy. Immunotoxins from plants and animals may show a rapid immunogenicity and have toxic side effects that may be harmful to humans. For example, an immunotoxin was synthesized by a combination of
Tumor cells have barriers to protect them from the body’s immune system, such as an impenetrable stroma and immunosuppressive cells in the tumor environment [60]. Tumor cells block antigen overexpression and increase regulatory-T cells and hence escape the immune system of the body. Immunotherapy overturns this mechanism and brings about the death of cancer cells. Bispecific antibodies can target two antigens at once, including an antigen on the cancer cell and a receptor on the cell of the immune system. Then the proteins in cell death signaling are activated by phosphorylation, which then initiates apoptosis. Bispecific antibodies link two cells hence bypassing innate as well as acquired resistance.
Chimeric antigen receptor on T cells (CAR-T) is being focused on as a target of antibodies as it helps in specific recognition of cancer cells [61]. Upon activation, it shows a high amount of cytokine release, which then kills cancer cells. This also can help to circumvent tumor resistance for killer T-cells.
For immunotherapy, a specific target is required for the immune system to attack or else; there can be severe side effects related to immunity. Also, the extent of immune response should also be considered for the efficacy of the treatment. An immune response, which is too low may not be able to kill the malignant cells, and a very strong immune response may cause cytokine storms and harm the healthy cells instead.
IgG is the most explored antibody of choice for cancer targeting. Antigen binding if is the desired mechanism; only antigen-binding fragment can be separated and used. In such cases, the binding affinity and crystallization properties remain the same with smaller size and hybridization, which give enhanced tumor penetration. Also, modifications can be made to increase the specificity and valency of antibodies.
Involves changes in the structure of IgG to alter its natural properties to obtain desired attributes. The most common structural change includes changes in antibody binding region, e.g., ranibizumab. Right now, there are many fragment-based therapeutics in preclinical and clinical trials. The most advanced is otlertuzumab for treating chronic lymphocytic leukemia. Fragment-based derivatives are not able to activate the immune system without a crystallization region [62]. But they show advantages like enhanced penetration, longer circulation and increased diffusion in the tumor. Hybrids can also be made with Fc from IgG and scFv from a targeting antibody. They do not penetrate in the tumor but instead retain activities of Fc such as immunization.
IgG can only bind a single type of antigen. Hence it is bivalent but not bispecific. Hence, to increase the specificity, the valency of antibodies is being enhanced. Many different regions from different sources are connected together to form molecules that are multivalent and can bind to more than one type of molecules.
This is the most used type from multispecific modified IgG. These can bind to two different antigens at once. For e.g., blinatumomab is used for some types of acute lymphocytic leukemia. It binds to CD19 protein on the cancer cell and CD3 protein on T-cell. It causes the release of cytotoxic chemicals that kill the cancer cell. Dual affinity targeting agents are made from two separate light and heavy regions linked by disulfide bonds after translation.it can be stored for a long time and should be stable for a long time [63].
A combination makes multivalent antibodies of three or more antibody domains joined sequentially or in a row. These are proteins specific for two antigens containing two pairs of light and heavy variable regions connected in a single chain forming a polypeptide. By virtue of their multivalency, tandem Abs not only target tumors but also cause infiltration and destruction of tumors by killer T-cells. These have longer storage life, better pharmacokinetics, are highly potent [64].
Antibodies can be linked with other molecules such as proteins and peptides to form hybrids. Such combinations give altered biodistribution by targeting a different receptor, extend the half-life of formulation, or impart a new mechanism of action [65].
These hybrid molecules contain antibodies linked to a therapeutic agent. They combine the selective nature of antibodies with cytotoxicity of active agents [66]. It can reduce side effects to a minimum and shows maximum therapeutic success. Conjugates such as Mylotarg have been approved by the FDA. This has caused the emergence of many compounds that differ just by changing the method and site of conjugation. The drugs or linkers are attached to free lysine or cysteine, which gives different products based on the location of conjugation. The most recent trend involves forming a homogenous product by conjugation at particular sites only. It can be done by altering the structure of antibodies to incorporate non-natural amino acids, which act as a handle for attachment. Available tags have been discovered, such as sortase A tag, which attaches the drug to antibody at the glutamic acid site and attaches to therapeutic moiety through a polyglycine tag.
These are molecules synthesized using recombinant DNA technology. They combine targeting efficiency of IgG and various protein domains. This fusion affects selectivity and PK parameters extensively. Toxic proteins can be used to form immunotoxic compounds such as diphtheria toxin attached to antibodies. Dose-limiting toxicity and immunogenicity are the main challenges in the formation of such complexes. The most successful examples of protein fusion complex are bioactive proteins attached to the crystallization region of IgG. Amevive and zaltrap are two such complexes approved by USFDA for release in the market. This combination shows an excellent immune response against the tumor [67].
Types of antibody fragments.
There is no single magic remedy that acts against all of the diseases. Antibodies are ingenious proteins targeted toward specific foreign molecules inside the body. Their therapeutic use involves their ability to disrupt signal transduction, block receptor, which further affects cell growth and cell death. They also can be used to stimulate the immune system so as to destroy any foreign or ingenious harmful materials. IgG’s natural structure can be modified to remove problematic residues and add newly modified proteins for the purpose of targeting and immunostimulating. These attachments come with issues like immunogenicity, acquired resistance. But more research in field of antibody engineering is required to address this issue.
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',metaTitle:"Publication Agreement - Monograph",metaDescription:"IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.",metaKeywords:null,canonicalURL:"/page/publication-agreement-monograph",contentRaw:'[{"type":"htmlEditorComponent","content":"When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
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\\n\\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
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\\n\\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
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\\n\\nNothing 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.
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\\n\\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\\n\\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors 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 Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
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\\n\\nThird 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\\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces 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 (known as the "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 any fraudulent pre-contract misrepresentation or concealment.
\\n\\nWaiver: 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\\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\\n\\nSeverance: 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. Any 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\\nNo 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 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\\nGoverning 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\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\n\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work 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 Work 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 Author, and any Co-Author, confirms that they 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 Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\n\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe 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 Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\n\nThe Author shall respect confidentiality 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 Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication 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.
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\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work 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) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors 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 Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The 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 Co-Author.
\n\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing 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\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) 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.
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\n\nIntechOpen’s DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\n\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors 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 Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall 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\nThird 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\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces 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 (known as the "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 any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: 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\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\n\nSeverance: 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. Any 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\nNo 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 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\nGoverning 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\nPolicy last updated: 2018-09-11
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