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",isbn:"978-1-80356-357-2",printIsbn:"978-1-80356-356-5",pdfIsbn:"978-1-80356-358-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"3aba1eb3600a8c9ff880c628f70b3298",bookSignature:"Ph.D. Delfín Ortega-Sánchez",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11481.jpg",keywords:"Integrated Curriculum, Transdisciplinarity, Integrated Active Learning, Educational Programs, Contemporary Social Problems, Critical Thinking, Creative Thinking, Social Thinking, Agenda 2030, Sustainable Development Goals, Educational Paradigm, Social Reality",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 18th 2022",dateEndSecondStepPublish:"March 18th 2022",dateEndThirdStepPublish:"May 17th 2022",dateEndFourthStepPublish:"August 5th 2022",dateEndFifthStepPublish:"October 4th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Internationally recognized researcher in the field of historical and social science education. Author of more than 100 publications, awarded three Doctorate degrees and the National End of Degree Award, granted by the Ministry of Education to the best academic records of Bachelor's degrees in Spain. Dr. Ortega-Sánchez has been Vice-Rector for Social Responsibility, Culture, and Sports at the University of Burgos since 2021.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"302925",title:"Ph.D.",name:"Delfín",middleName:null,surname:"Ortega-Sánchez",slug:"delfin-ortega-sanchez",fullName:"Delfín Ortega-Sánchez",profilePictureURL:"https://mts.intechopen.com/storage/users/302925/images/system/302925.jpg",biography:"I hold a PhD in Didactics of Social Sciences from the Autonomous University of Barcelona, a PhD in Educational Sciences from the University of Burgos, and a PhD in History from the University of Extremadura. My research interests focus on the construction of identities in the History and Geography teaching, gender mainstreaming in initial education and training for teachers, the didactic treatment of relevant social problems and controversial issues in the teaching of the social and human sciences, and the application of educational technology in the specific field of social sciences. I am currently a Social Sciences teacher and researcher at University of Burgos (Spain).",institutionString:"University of Burgos",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Burgos",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429339",firstName:"Jelena",lastName:"Vrdoljak",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429339/images/20012_n.jpg",email:"jelena.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"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:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.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"}}]},chapter:{item:{type:"chapter",id:"52267",title:"Adhesive Materials for Biomedical Applications",doi:"10.5772/64958",slug:"adhesive-materials-for-biomedical-applications",body:'\nSutures, wires, and staples are routine ways for achieving closure of superficial or internal tissues, yet there are several limitations to these traditional closure methods. For instance, the application of sutures is time-consuming and requires the penetration of surrounding tissues, causing additional damage [1] and increasing potential for infection [2]. The suture points also cause high stress concentration [3], which can result in more pain for the patient. Gaps in the injury site left behind due to incomplete suturing can cause leakage, and depending on the type of fluid (bowel content, bile, or cerebral spinal fluid), serious clinical complications could result [4, 5]. Finally, there are surgical situations where sutures, staples, and wires are difficult, if not impossible, to implement, such as in minimally invasive laparoscopic surgery [2, 6], or when trauma results in large-scale incompressible hemorrhage [7].
\nOver the past few decades, a variety of new flexible polymers with bioadhesive properties have emerged, which offer alternatives to traditional closure methods. These polymers have the ability to fill irregularly shaped cavities or be spread over large areas of tissue to quickly form a seal that mitigates bleeding. Commonly, the monomer or macromer components are applied as liquids and solidify on the tissue via in situ polymerization or cross-linking reaction. Polymeric bioadhesives have been studied for approximating tissues in surface wounds (glues), controlling bleeding (hemostats), and closing of fluid or air leaks (sealants) [8]. This review will outline the main classes of bioadhesives that have been studied for these applications, both in the clinic and in scientific literature, including cyanoacrylates, proteins, hydrogels, polysaccharides, and nature-inspired synthetic polymers. An emphasis is placed on polymer chemistry, mechanisms of adhesion, and the advantages and disadvantages of each material class. Because it is impossible to compare quantitative data generated by various researchers in separate experiments [1], the descriptions will emphasize qualitative findings. The final component of this review focuses on emerging applications for bioadhesives in regenerative medicine and the unmet needs that still exist.
\nCyanoacrylate tissue adhesives are monomers that polymerize in the presence of aqueous milieu to create a solid layer that joins apposed wound edges [9]. The liquid monomers have a high reactivity; thus, polymerization happens in seconds without addition of a catalyst or elevated temperature [1]. When the monomers are applied on tissue, the liquid flows into the existing crevices, sealing by a mechanical interlock upon curing [1]. The NH3 groups in tissue also participate in the polymerization, contributing toward the strong bonding that cyanoacrylates form [10].
\nCyanoacrylates have been successfully applied in a clinical setting. Dermabond®, composed of. 2-octyl-cyanoacrylate (Figure 1A), was approved by the FDA in 1998 for the closure of topical skin incisions. The polymer degrades in 7–10 days [1]. Dermabond was compared to the use of metal clips in the closure of wounds from thyroidectomy in 70 patients [11]. In terms of quality of skin closure and cosmetic outcomes, both closure methods yielded similar results. However, according to patient input, postoperative management was easier in the Dermabond group. Poly(2-octyl-cyanoacrylate) has also been reported to have antimicrobial properties for 72 h after it is first applied. The cured material, applied on superficial wounds, was an effective barrier against infection when used with best approximation of wound lips after plastic surgery [12].
\nThe structures of the cyanoacrylate tissue adhesives (A) 2-octyl-cyanoacrylate and (B) N-butyl-2-cyanoacrylate.
Another clinical study was conducted on 35 patients with inguinal hernias that were repaired with a prosthesis fixed with n-hexyl-α-cyanoacrylate. Results were compared with fixation with sutures. The use of cyanoacrylate adhesive instead of sutures did not alter the relapse rate, but it did significantly reduce surgical time and postoperative pain with no complications [13]. N-hexyl-α-cyanoacrylate was also used successfully in a rat model of microvascular anastomosis. In the experimental technique being evaluated, the thermoreversible polymer Polaxomer® 407 was injected into both ends of severed blood vessel. The ends were then approximated, and the glue was applied circumferentially. The method was reported as easy to apply, faster than sutures, and produced a lower foreign body response [14]. Idle et al. [15] reported successful use of N-butyl-2-cyanoacrylate (Figure 1B) as a hemostatic agent to prevent hemorrhage after tooth extraction. At 2 months, the glue was completely resorbed and the tooth socket healed.
\nThere are some drawbacks to cyanoacrylate adhesives that limit the use to external, temporary applications. For instance, the mechanical properties of cyanoacrylate adhesives have been reported to be weaker than sutures [16]. In addition, the cured sealant is brittle, and thus, researchers have sought to modify the polymer structure to enhance flexibility. Poly(L-lactide-co-ε-caprolactone (PLCL) is a synthetic copolymer that was used as an additive in ethyl-2-cyanoacrylate (EC) and allyl-2-cyanoacrylate (AC) monomers. All formulations containing PLCL resisted breaking when subjected to 30 cycles of bending stress. In contrast, EC and AC broke after one and seven cycles, respectively [17].
\nThere are also concerns over potential cytotoxicity and inflammatory responses associated with the use of cyanoacrylate adhesives. Degradation of cyanoacrylates occurs via hydrolysis. The by-products, cyanoacetate and formaldehyde, can potentially cause toxicity [18–20]. The first cyanoacrylate adhesives applied for medical purposes were ethyl-2-cyanoacrylate (Figure 2A) and methyl-2-cyanoacrylate (Figure 2B). These short-chain monomers exhibited fast degradation upon polymerization, allowing for the accumulation of higher amounts of formaldehyde and/or cyanoacetate in the tissue. These monomers have been abandoned [1] and replaced with those with longer alkyl chains, like n-hexyl-α-cyanoacrylate, N-butyl-2-cyanoacrylate, and 2-octyl-cyanoacrylate, although concerns over the use of these formulations exist as well. The biocompatibility of Glubran 2®, an n-butyl cyanoacrylate-based adhesive, was evaluated. Extracts of cured glue were applied over a monolayer of L929 fibroblast cells. Severe cytotoxicity was observed with the undiluted extracts, which disappeared when the extracts were diluted 1:10 [21]. In a clinical report, a foreign body response was observed 3 weeks after using of Dermabond to seal a superficial wound on the wrist of a 39-year-old [22]. The authors recommend informing patients of the potential risk of an inflammatory response to cyanoacrylate glues.
\nThe structures of short-chain cyanoacrylate tissue adhesives, (A) ethyl-2-cyanoacrylate and (B) methyl-e-cyanoacrylate.
Recently, cyanoacrylates were used in the development of self-healing materials. Self-healing materials are those that are engineered to prevent failure through an autonomous repair mechanism. In the first reported use of cyanoacrylate in this area, the polymer was combined with acrylate bone cement, poly(methyl methacrylate) (PMMA) [23]. In this work, polyurethane shells were used to encapsulate 2-octyl cyanoacrylate monomers, which were embedded in the PMMA to form a composite upon cure. The 2-octyl cyanoacrylate was released from the polyurethane shells and polymerized upon contact with moisture. In doing so, it filled cracks and defects that formed inside the PMMA, reinforcing the matrix. Incorporation of the 2-octyl cyanoacrylate slowed down progressive crack propagation under loading compared with unreinforced PMMA cement. In subsequent work [24], it was shown that reinforced specimens were able to withstand twice as many repetitive loading cycles before failure compared with unreinforced specimens. Cyanoacrylate films with a broad range of nanostructured architectures were also created [25]. In order to achieve this, N-octyl-2-cyanocrylate was electrospun and an air pump was used to precisely direct the nanosized polymer fibers to a wound bed. The deposited fibers formed a flexible, high strength membrane that was used to effectively arrest bleeding in in vivo models of liver and lung resection.
\nGelatin is derived from the hydrolysis of collagen [6] and widely used in biomedical applications because of its biocompatibility and degradability [26]. Gelatin is capable of forming physically cross-linked hydrogels, but the mechanical strength is low and the hydrogels do not possess adhesive properties [27]. For this reason, gelatin-based tissue adhesives use chemical cross-linking and often also include additional polymer additives.
\n(A) The chemistry of cross-linking gelatin with formaldehyde and (B) the network that is formed by the reaction of resorcinol with formaldehyde.
The cross-linking of gelatin with glutaraldehyde via a Schiff’s base reaction.
The earliest gelatin-based adhesive is composed of gelatin, resorcinol, and formaldehyde. Referred to as GRF glue, it forms a seal in situ because the formaldehyde cross-links with the gelatin (Figure 3A) and the resorcinol (Figure 3B) to form a network. The resorcinol is added to augment the mechanical properties of the adhesive [10]. The composition of GRF glue comprises 18% by weight of formaldehyde, despite the well-known concerns over its toxicity [1, 6]. Braunwald et al. [28] evaluated GRF glue in an in vivo canine model, noting that the degree of irritation caused by the formaldehyde depended on the vascularity of the tissue. Excess formaldehyde may be diluted and washed away in areas where there is high enough blood flow. However, due to concerns over the safety of GRF glue, the formulation was later revised to replace a portion of the formaldehyde in the adhesive with glutaraldehyde, which is less histotoxic [29, 30]. Glutaraldehyde forms a Schiff’s base with the free amines on gelatin, forming cross-links in the network just as formaldehyde does (Figure 4). This updated formulation was called gelatin-resorcinol-formaldehyde-glutaraldehyde (GRFG) glue. When applied in the liver of rats, no evidence of necrosis was found and it was shown to be an effective sealant and hemostat. Another group modified the GRFG formulation by adding 2.5% sodium carboxymethylcellulose (CMC). This created a “jelly” consistency for the glue, helping to prevent migration away from the target tissue site. The jelly was applied in humans to seal air leaks and found safe for shallow cuts in the lung [31]. Despite some successful outcomes, glutaraldehyde is technically classified as a toxic substance, so safety concerns prevent approval of GRF/GRFG glues by the FDA in the United States [32, 33].
\n\n\nResearchers have looked into alternative cross-linkers for gelatin that are potentially less toxic than glutaraldehyde and formaldehyde. Rapidly polymerized elastic gelatin networks were also produced via photochemical cross-linking in the presence of ruthenium II trisbipyridyl chloride [RuII(bpy)3]2+ catalyst and ammonium persulfate oxidant [34]. Visible light causes the photolysis of the [RuII(bpy)3]2+. The Ru(II) and sulfate radicals oxidize tyrosine residues, present on gelatin, allowing formation of an intermolecular dityrosine cross-link. When gelatin was modified with additional phenolic (tyrosine-like) residues, the sealant stiffness increased by a factor of five and swelling was restricted compared with gels made from unmodified gelatin due to the increased cross-linking density [35]. Blends of modified and unmodified gelatin can give tunable elasticity and elastic modulus [33]. The reagents were found to be non-toxic at the concentrations used to make the gels [35].
\nIn another study, cholesterol chloroformate was used to partially convert the amino groups on the gelatin to cholesterols. Cross-linking occurred by mixing a combination of cholesterol-modified gelatin with disuccinimidyl tartrate. Covalent bonding also occurred with collagen in the surrounding tissue extracellular matrix (ECM). Moreover, adhesion was enhanced due to the hydrophobic cholesterol groups, which promoted polymer chain penetration into the tissue and anchoring to cell membranes [36].
\nN-(3-dimethyl-aminopropyl)-N’-ethylcarbodiimide hydrochloride, a water-soluble carbodiimide (WSC), was shown to be an effective cross-linker of gelatin, but high concentrations (20 mg/mL) negatively impacted cell viability. The group was able to decrease EDC concentrations in the adhesive by functionalizing the gelatin with N-hydroxysuccinimide (NHS) groups [37]. N-hydroxysuccinimide (NHS) esters are known to react with primary or secondary amines (Figure 5). In this reported study, the addition of low concentrations of NHS (1 mg/mL) allowed the EDC concentrations to be decreased to 10 mg/mL without compromising adhesive strength and maintaining high cell viability (89–100%) [37].
\nReaction scheme for NHS ester conjugation to a primary amine.
Another approach involves the use of enzymatic cross-linking. The advantage of this route is that the gelation occurs under physiological conditions. Transglutaminase are ubiquitous in nature and catalyze the reaction between lysine and glutamine, resulting in cross-linking of proteins (Figure 6). Chen et al. [38] used this enzyme to introduce cross-links into gelatin under moist conditions. The adhesive did not cause cell death in rat retinal tissue when applied in vivo for 2 weeks. It is important to note that since the cross-linking reaction causes release of ammonia, local tissue damage or inflammation is possible.
\nThe cross-linking of gelatin via the enzyme transglutaminase [
Another type of protein-based adhesive is based on albumin and glutaraldehyde. Albumin is an abundant protein found in the blood of mammals. Glutaraldehyde cross-links albumin to itself and to the proteins in the surrounding tissue at the repair site via a Schiff’s base reaction. The albumin network forms a rigid, brittle solid [29]. Bioglue® is a bovine albumin-based glue available on the market that is approved for cardiac and vascular surgery [39]. Bioglue is less histotoxic than GRF glue and has superior bonding ability [40, 41]. Bioglue was successfully used to clinically treat bronchopleural fistula [42], partial renal nephrectomy [43], and vascular anastomoses [44]. Due to the presence of glutaraldehyde, there are still safety concerns with its application in certain areas of the body with high cellularity. For instance, adverse effects were reported on nerve function in a porcine model when the adhesive was applied directly onto the phrenic nerve [45].
\nDe Somer et al. [46] developed an autologous albumin glue to avoid the immune response associated with bovine components. Fresh human plasma was ultrafiltered to concentrate the plasma proteins, which were then combined with glutaraldehyde. The autologous glue exhibited higher compliance than rigid Bioglue, likely due to the presence of fibrinogen in the concentrated blood plasma. The disadvantage of this method is that it requires 60 min of preparation time once the plasma is obtained. As an alternative to cross-linking with glutaraldehyde, another group prepared a modified tartaric acid with two active NHS ester groups and combined it with human albumin [47]. Subcutaneous implantation in mice indicated the adhesive was safe, eliciting a mild inflammatory response, but the results were not compared side by side with an adhesive cross-linked with glutaraldehyde.
\nFibrin adhesives work by mimicking the biochemical reactions of the last stage of clotting [48, 49]. The resulting clot at the site of repair is a cross-linked network of proteins that also forms covalent linkages with the surrounding tissue, allowing adhesion to occur. Fibrin glues are applied as hemostats to stop bleeding, in addition to being used as sealants to achieve closure [6].
\nIn general, fibrin sealants are composed of three major protein building blocks: fibrinogen, thrombin, and factor XIII, which are derived from human or bovine plasma [1]. Upon mixing the constituents, the thrombin converts the fibrinogen to fibrin monomers. The fibrin monomers will self-assemble into a fibrin polymer, forming a network weakly held together by hydrogen bonds. At the same time, thrombin activates factor XIII, which catalyzes the formation of cross-links in the fibrin polymer and between the polymer and the surrounding tissue, providing a stable the clot [49–51]. The sealants also contain calcium ions, since they are required for the reactions in the clotting cascade [52]. Commercial fibrin sealants, available in the United States, have components derived from blood banks and include TISSEEL®, CrossealTM, Beriplast®, and Evicel® [53]. Because fibrin glue is one of the oldest developed adhesives, it has a long list of reported applications, such as the repair of nerves [54], gastrointestinal tracts [55], topical wounds [56], and ophthalmology [57].
\n(A) Rabbit liver lobes shown before injury, (B) after the resection injury, and (C) after FSF application [
The components are either lyophilized powders that require reconstitution prior to use, or liquid products that are stored frozen then thawed and mixed together in the surgical field [58]. The fibrinogen and thrombin components, supplied separately, can be applied successionally or simultaneously, with a dual-syringe or spray device. The material properties of the clot, and thus its clinical performance, will be determined by its elasticity, tensile strength, and adhesion strength (Kjaerd 2000). For this reason, several groups have studied the polymerization and cross-linking characteristics of fibrin sealants. It was reported that key factors to ensuring glue performance are adequate fibrinogen content, effective mixing of the components, and maintenance of factor XIII activity [59]. Sierra et al. [60] found that the tensile strength, modulus of elasticity, burst strength, and failure strength, all increased with fibrinogen concentration.
\nSpray application of fibrin adhesive may have advantages over simultaneous and sequential drip application because spray application results in the most homogenous clots [61] and allows for better control over severe bleeding over large areas, which can occur after trauma. A self-expanding fibrin sealant foam (FSF) was characterized [62]. For preparation, the sealant was placed in a pressure-resistant bottle with liquefied gas propellant, which converted the fibrin components to foam at atmospheric pressure. It was used to arrest bleeding in a rabbit liver resection (Figure 7).
\n\nAs another option, fibrin sealants have been made available as ready-to-use lyophilized powders that can be stored at room temperature. Fibrocaps (Raplixa; ProFibrix BV, Leiden, The Netherlands, a subsidiary of The Medicines Company) is dry powder thrombin and fibrinogen that can be applied straight to the wound site to form the clot [58]. For compressible injuries, lyophilized fibrinogen and thrombin have been combined with gauze (Larson 1995), as well as collagen sheets (Nistor 1997).
\n\n\nFibrin glues are well known for being completely non-toxic and biodegradable [1], yet there are some disadvantages that limit their applicability in advanced applications. First, degradation in vivo will occur within days, a time frame that could allow for rebleeding. Aprotinin is a molecule consisting of 58 amino acids that is added to commercial fibrin glues to slow down its cell-mediated degradation [63]. When simply codissolved in a fibrin gel, aprotinin can freely diffuse out due to its small size. To prolong degradation time further, aprotinin has been covalently conjugated to fibrinogen [64]. Varying the levels of conjugated aprotinin allowed for control of the degradation time.
\nA second drawback to fibrin sealants is that they are mostly derived from human donors, or from the blood of animals with compatible clotting systems, limiting their availability, making them expensive, and introducing the possibility of transmission of blood borne pathogens. One option that has been investigated is deriving the protein components from animals where the evolutionary distance from humans is large, thus allowing for minimized risk of disease transmission. Fibrin components have thus been derived from salmon [65, 66] and crotalus durissus terrificus snake venom [67]. Another option is to use completely autologous fibrin glue. The Vivostat® System is an automated device that allows for the production of 5 mL of fibrin sealant from 120 mL of the patient’s blood [68]. When Kjaergard et al. [69] compared its performance to commercially available Tissucol® and Beriplast®, autologous glue exhibited a higher elongation at break. However, the sealant takes about 30 min to prepare. Another report described a totally recombinant human sealant that exhibited comparable hemostatic efficacy to a commercial plasma-derived sealant in a porcine hepatic excision model [70].
\nA third important drawback to fibrin sealants is the poor adhesion properties, especially in wet environments, and low mechanical properties compared with most elastic tissues [2]. Researchers have been developing fibrin glues with alternative structures that lead to improved physical properties. A genipin cross-linked fibrin adhesive was described that was used to seal small defects in the annulus fibrosus of the intervertebral disc [71]. Genipin is a plant-based chemical cross-linker reactive with amines and reported to have low cytotoxicity [72]. Fibrin gels that were cross-linked with genipin were dimensionally stable over the 21-day in vitro study and exhibited higher shear stiffness than fibrin gels that were not cross-linked with genipin. In another study, elastic gels were produced via photochemical cross-linking of fibrinogen using [RuII(bpy)3]2+ and ammonium persulfate. Overall, fibrinogen gels cross-linked with this method are reported to have a higher tensile strength than Tisseel® [73].
\nAlthough natural materials such as fibrin have the advantages of biodegradability and biocompatibility, the various shortcomings in fibrin properties have led to the development of synthetic polymer networks [74]. Engineers have more control over mechanical and degradation properties than with natural materials because polymer structure can be tailored. In these sealants, hemostasis is achieved using reagents that cross-link the polymer network, while binding with tissue, to close the injured site. Poly(ethylene glycol) (PEG) is an FDA-approved material that has been extensively used as the main component in synthetic adhesives [32].
\nFocalSeal is formed from two different aqueous solutions of reactive macromers, (A) PLAm-PEGn-PLAm diacrylate and (B) PTMCm-PEGn-PTMCm diacrylate.
FocalSeal® was FDA-approved in 2000 for sealing air leaks after lung surgery. The sealant is provided to surgeons in two parts (primer and sealant). The primer is an aqueous solution of a triblock copolymer of poly(lactide) and polyethylene glycol (PLA-PEG-PLA) with acrylated end groups (Figure 8A). The sealant is an aqueous solution of poly(ethylene glycol)-co-trimethylene carbonate-co-lactide (PTMCm-PEGn-PTMCm) with acrylated end groups and a photoinitiator, eosin Y (Figure 8B). The primer and sealant solutions are combined immediately before application to the target area in the body. Upon exposure to light (450–550 nm), the macromers polymerize to form a cross-linked network due to the reaction between the acrylate groups [75]. The adhesion occurs due to mechanical interlocking, in other words, the liquid monomer solution infiltrates the pores and irregularities in the tissue surface, and, upon gel formation, adhesion occurs [32]. Over time, the lactide and trimethylene carbonate groups degrade by hydrolysis and the PEG chain are cleared by the kidneys. The sealant takes 3–4 weeks to resorb [1]. FocalSeal was evaluated as a dural substitute in a canine craniotomy model [75]. All treated sites remained free of leaks of cerebrospinal fluid (CSF) for the 56-day study. In a later clinical trial, 100% of the 46 patients receiving the dural sealant after cranial surgery remained free of CSF leaks [76]. FocalSeal was used with 100% success as a supplement to sutures or staples to repair air leaks after pulmonary resection in pigs [77]. It was also used successfully to repair retinal breaks [78].
\n\nA drawback to photopolymerization is that it may not be ideal for all parts of the body, as ultraviolet light cannot infiltrate tissue located greater than 5 mm of depth into the body [79]. Further, photoactivation makes application of the sealant difficult in the case of a hemorrhage [80]. There is a danger of releasing free radicals into the physiological environment [1]. Another disadvantage of FocalSeal specifically is that it can swell up to 300% of its original weight [81]. This could limit its application in areas of the body where there is potential for nerve compression [82].
\nThe reactive components of DuraSeal, (A) trilysine and (B) pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate.
DuraSeal® is a two-component system of trilysine (a tetramine cross-linker, Figure 9A), dissolved in a pH 10 borate buffer. The second is pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate (a 4-arm PEG encapped with N-hydoxysuccinimide (NHS) esters), dissolved in a sodium phosphate buffer (pH = 4) (Figure 9B) [1]. Upon mixing, the trilysine reacts with the NHS ester groups, generating the cross-linked hydrogel. In addition, upon contact with the amine groups in the extracellular matrix, the NHS-functionalized PEG chains will covalently bond with the surrounding tissue, providing adhesion combined with mechanical interlocking. Degradation takes place over 4–8 weeks [83]. One of the earliest reports of DuraSeal was in 2003 [84], when it was characterized to be an effective adjunct to sutures for dural closure in a canine model. A clinical trial with DuraSeal was reported in 2011 [85]. A total of 158 patients underwent spinal surgery requiring dural incision. 100% of the 102 patients that received DuraSeal combined with sutures had complete closure, compared with only 64% in the control group that received sutures alone.
\n\nThe combination of (A) a PEGylated lysine dendron and (B) PEG succinimidyl valerate results in the formation of a PEG-LysNH2 hydrogel, shown in (C) dyed with green food coloring [
After gelation, DuraSeal can swell up to 50% after application [1]. To minimize swelling, another formulation was developed, DuraSeal® Xact Adhesion Barrier and Sealant System (DSX). Compared with DuraSeal, it has an increased cross-link density by modification of the ratio of PEG to trilysine [1, 86]. Villa-Camacho et al. [87] reported a novel sealant that uses similar chemistry to DuraSeal. Here, a PEGylated lysine dendron in dissolved in buffer at pH 9 is combined with solubilized PEG succinimidyl valerate at pH 6.5 (Figure 10). The hydrogel forms spontaneously upon mixing. The ability of the adhesive to withstand pressures analogous to human arterial pressures was demonstrated ex vivo.
\n\nCoSealTM is a two-component tissue sealant. The first component 20% (w/v) buffer solution of a 4-arm PEG polymer of 10 kDa molecular weight end capped with thiol groups (pH 9.6) (Figure 11), and the second component is a 20% (w/v) buffer solution of pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate (pH 6.0) (Figure 9B). The components are reactive with each other and the proteins in the surrounding ECM [88], providing adhesion via chemical bonding and mechanical interlocking. The hydrogel degrades within several weeks due to hydrolysis. In one of the earliest studies with CoSeal, it lessened blood loss and time to hemostasis in bleeding rabbit arteries compared with using a tamponade [89]. CoSeal has been reported as cumbersome to use because it is supplied as a powder, which requires mixing back and forth 20 times to dissolve [90]. It has also been reported to swell to 400% of its original size [1, 90]. Likely related to the high swelling characteristics, the mechanical strength of CoSeal has been found to be weaker than DuraSeal and other commercially available protein-based and cyanoacrylate sealants [30].
\nStructure of thiol end capped 4-arm PEG used in CoSeal®.
The structure of aldehyde-terminated poly(ethylene glycol)-poly(D,L-lactide) (PEG-PLA) block copolymers prepared by Murakami et al. [
Another group of PEG adhesives uses Schiff’s base chemistry as the cross-linking reaction. For example, an 8-arm PEG molecule was functionalized with either aldehyde or amine groups. When combined in water, it spontaneously formed gels because of the reaction between the aldehyde and free amine groups [91]. Gels formed from PEG arms that were 10 kDa in size were stiffer than those formed from 20 kDa due to higher cross-link density. In vitro lap shear testing showed that the adhesive was stronger than fibrin glue (Tissucol). It swelled to about 200% of its original weight, which is less than CoSeal and FocalSeal. The results of a direct contact cell assay with L929 fibroblasts showed no cytotoxicity associated with the cured gels. Aldehyde-terminated poly(ethylene glycol)-poly(D,L-lactide) (PEG-PLA) micelles were also prepared (Figure 12) by dissolving the block copolymer in aqueous media. A hydrogel forms in ~2 s when a polyallylamine is added to the micelles. Adhesive strength of the network was found to be proportional with aldehyde concentration, with the strength of the high aldehyde content adhesives comparable to fibrin glue [80].
\n\nResearchers continue to innovate systems that allow them to achieve high adhesive strengths, ease of use, fast curing, biodegradability, and biocompatibility with alternate methods of cross-linking. Hu et al. [92] incorporated peptide substrates of transglutaminase into linear or branched polymers of PEG. The in situ formed gels exhibited adhesive strengths to porcine skin comparable to that of fibrin glue [92].
\nSystems have been developed that are combinations of synthetic and natural components. These have potential to exhibit improved biocompatibility compared to systems that are completely synthetic. For instance, cells do not adhere to PEG hydrogels. Hynes et al. [93] chose poly(L-lysine) (PLL) to be incorporated into PEG structure because the charged side chain promotes cell survival and adhesion. Macromers of PEG/PLL, shown in Figure 13, were formed hydrogels via photopolymerization and shown to support survival and differentiation of neural precursor cells. Another group [94] reported a gelation system consisting of the following components: calcium-loaded liposomes composed of 1,2-bis(pal-mitoyl)-sn-glycero-3-phosphocholine (DPPC), human recombinant factor XIII, thrombin, and 4-arm PEG, each arm terminating in a 20-mer sequence derived from fibrin. Heating the system to 37°C causes the liposome bilayer to melt, releasing the calcium and activating factor XIII, causing gelation to occur in 9 min.
\nThe molecular structure of PEG/PLL macromers for the formation of photopolymerized hydrogels developed by Hynes et al. [
Besides improving biocompatibility, researchers are working on developing stronger PEG adhesives. For example, by combining silk, which has a high mechanical strength, with PEG, a sealant was produced with fast curability, superior adhesion strength to CoSeal, and swelling ratios of only 60–70% due to the hydrophobicity of the silk [90].
\nIn situ forming tissue sealants have also been prepared from natural polysaccharides, which are composed of repeat units of naturally occurring sugars, making them inherently biodegradable non-immunogenic [1]. Like synthetic polymers, the chemical structure of polysaccharides can be modified to induce spontaneous or light-triggered gelation in situ and enhance adhesion strength with surrounding tissue.
\nPhotopolymerization of polysaccharides that are functionalized with acrylate or methacrylates along the backbone is one way to achieve in situ gel formation. In this case, the polysaccharide may be applied in liquid form, where it will penetrate the crevices in the tissue. Upon polymerization, reacted acrylates or methacrylates form covalent cross-links and the resulting gel seals the area [95]. An example is the methacrylation and photopolymerization of hyaluronic acid (HA), a linear polysaccharide consisting of alternating β-(1–4) linked 2-acetamine-2-deoxyglucose and β (1–3) linked d-glucuronic acid (Figure 14A). Methacrylate-functionalized hyaluronic acid (HA) (Figure 14B) was applied to corneal lacerations in rabbits to allow for network formation upon irradiation [96]. This produced a flexible clear patch that sealed 97% of the corneal lacerations and retained its shape and size for the duration of the 7-day study. The authors hypothesized that the high molecular weight, entangled 3D structure of the HA slowed down its enzymatic degradation in vivo.
\nChemical structure of (A) hyaluronic acid and (B) methacrylated hyaluronic acid.
As an alternative to photopolymerization, oxidation of polysaccharides to aldehyde groups using sodium periodate [97] is widely applied for forming polysaccharide networks. The aldehyde functionalities readily react amine-containing molecules via Schiff’s base reaction to internally cross-link a polysaccharide to itself and surrounding tissue ECM [7]. Sodium alginate (Figure 15) derived from brown algae, functionalized with both methacrylate and aldehyde groups, was investigated as a tissue sealant. Cross-linking of the methacrylate groups was achieved by visible light. Simultaneously, the aldehydes reacted with the amines in the surrounding ECM, allowing for covalent attachment to surrounding tissue. Gels that were methacrylated, but not oxidized, maintained mechanical integrity during burst pressure tests, but delaminated from the substrates easily. On the other hand, materials that received both methacrylate and aldehyde groups did not exhibit delamination before failure [98].
\nThe chemical structure of sodium alginate.
The chemical structure of dextran.
Dextran is another polysaccharide that has been extensively investigated as a sealant in various combinations with other polymers. Dextran is a microbial product consisting of about 95% α-1,6-linked d-glucopyranose and 5% α-(1,3) linkages (Figure 16). Araki et al. developed a new bioadhesive that forms from the reaction of dextran aldehyde and ε-poly(L-lysine). The components were applied in a pulmonary air leakage model in a canine model. The sealant had significantly higher burst pressure than fibrin glue and degraded more slowly [99]. Structure-property relationships in this adhesive were studied further [8]. It was found that as the degree of oxidation (DOO) of the dextran increased, gelation time decreased. Gelation times ranged between 3 s (40% oxidation) to 60 s (12% oxidation) [8]. Increased DOO of dextran was also associated with a slower degradation time [100].
\nIn another study, dextran aldehyde was cross-linked with either 8-arm star PEG amine or linear PEG diamine [101]. A higher stability cohesion was observed for gels made from the 8-arm star PEG because the larger number of available amines allowed for a higher degree of cross-linking. Another group, Bhatia et al. [102] studied adhesives based on dextran aldehyde and 8-arm PEG. They reported the system to cure in less than 1 min, adhere in a water environment, and degrade hydrolytically. The adhesive was utilized to seal a 5-mm corneal incision in eyes of New Zealand white rabbits [103]. They found that sealants produced from higher polymer contents led to better sealing and higher leak pressures. Degradation occurred within three days, appropriate time frame for corneal epithelial healing, and no cytotoxicity was observed from the cured adhesive. In a follow-up work, the degradation time was extended to 5 days by using an 8-arm PEG containing two primary amine groups at the end of each arm, instead of one [104].
\nChondroitin sulfate (CS), a constituent of cartilage and corneas, is comprised of alternating glucuronic acid and N-acetyl-galactosamine groups (Figure 17) [1]. CS was functionalized with succinimidyl succinate (CS-NHS) and combined with 6-armed polyethylene glycol (PEG) amine as a corneal sealant [105]. This adhesive was developed as an alternative to using CS aldehyde, hypothesizing that using a CS with an intact backbone helps to preserve its biological activity. Upon mixing, the materials gelled within 1–2 min and cured polymers exhibited no cytotoxicity in vitro with rabbit primary epithelial, stromal, and endothelial cells. No adverse effects were found with implantation into in vivo swine cornea.
\nThe chemical structure of chondroitin sulfate.
Adhesives made out of chitin derivatives have the potential to be valuable additions to the presently developed spectrum of polysaccharide-based sealants. Chitin is comprised of repeat units of 1,4 b-linked N-acetyl-D-glucosamine (Figure 18A). Chitosan is formed from partially deacetylated chitin [106] (Figure 18B). Since chitin is highly hydrophobic and completely insoluble in water, chitosan is more often used in biomedical applications. Chitosan has been shown to have a number of biological advantages, including being beneficial for wound healing [107, 108], inherent hemostatic ability [109], and antimicrobial activity [110, 111]. Chitosan has adhesive properties due to the positively charged amino groups, which interact with negative charges in mucus [112] and cell membranes [113]. However, one downside to chitosan is that it has limited solubility in water at neutral pH. Thus, researchers modify chitosan with side groups that enhance solubility in water at physiological conditions. For example, chitosan was modified with lactose groups to enhance water solubility [106] and cross-linked in situ with the addition of photoreactive azide groups. The resulting rubber-like adhesive was an effective sealant in rabbit arteries and lungs. In another study, a new adhesive was developed based on 2-hydroxy-3-methacryloyloxypropylated carboxymethyl chitin derivatives (HMA-CM-chitin) and embedded chitosan nanofibers. It was shown in vitro to have comparable strength to cyanoacrylate since the nanofibers provided gel network reinforcement [108].
\nThe structure of (A) chitin and (B) partially deacetylated chitin, also referred to as chitosan.
The most extensively investigated class nature-inspired materials uses mussel adhesive proteins (MAPs). Mussels can adhere strongly to underwater structures, even in environments with high mechanical stresses. Mussels attach to surfaces because they secrete a thread-like adhesive called byssus, which is composed of 25–30 different types of MAPs [114, 115]. An amino acid residue in these proteins, tyrosine, is posttranslationally modified to 3,4-dihydroxy-phenylalanine (DOPA) residues, which contains a catechol group (Figure 19). Catechols can hydrogen bond with other catechols [116], as well as amino, hydrogen and carboxyl resides [117]. Catechols can be oxidized by metal ions or enzymes to form quinones (Figure 19). Quinones form covalent bonds with amine or thiol groups [114, 116, 118, 119]. Finally, the catechol group complexes with multivalent ions, such as Fe3+ [120, 121] to form networks. Researchers have been developing materials that recapitulate these mechanisms in order to achieve strong bonding in wet environments.
\n\nExtracting MAPs from mussels or genetically engineering the proteins can result in low yields [122]. Thus, catechol pendant groups have been attached to the backbone of natural and synthetic polymers to yield biomimetic adhesives. Catechol auto-oxidizes at slightly alkaline pH >8, or in the presence of oxidizing reagents, such as periodates [123]. Researchers use these methods to produce quinones in situ, which leads to covalent bonding with tissue. In some of the early work with mussel-inspired synthetic polymers, linear and branched PEGs were functionalized with either 1,2, or 4 DOPA end groups [124]. Gels were formed with the use of three different oxidation reagents: sodium periodate, horseradish periodate, and mushroom tyrosinase. Rapid gelation occurred when 2 or more DOPA functionalities were present on the PEG molecule. However, PEG-based hydrogels can act brittle, fracturing at low elongation [125]. Improvements in the mechanical properties of PEG-catechol hydrogels were achieved by using block copolymers of PEG and poly(caprolactone) with DOPA groups. Because PCL is hydrophobic, it prevented swelling of the hydrogels, so they were not as fragile. Moreover, PCL made the gels less brittle, since it has a high fracture strain [126]. In another work, poly[(3,4-dihydroxystyrene)-co-styrene] copolymers (Figure 20) were prepared [119]. The adhesive characteristics in the presence of periodate on plastic and wood surfaces were investigated and there was found to be an optimal pendant catechol concentration along the polymer backbone. When the concentration of catechol was too low, there were insufficient cross-linking sites available at the surface. Too high a concentration would bias the system toward internal cross-linking, and surface attachment suffered.
\n\n(A) 3,4-Dihydroxy-phenylalanine (DOPA) residues, with the catechol group indicated by the dotted line and (B) quinone formed from the oxidation of the catechol group.
The chemical structure of poly[(3,4-dihydroxystyrene)-co-styrene] copolymers developed by Matos-Perez et al. [
Fe3+ serves as a rapid cross-linker for DOPA-containing polymers by forming complexes with the catechol groups.
Qualitative (A) and quantitative (B) recovery tests for hydrogels composed of polyallylamine in solutions of FeCl3. In the qualitative tests (A), a blob of hydrogel was fractured and the fragments healed upon contact with each other. This process was quantified with dynamic oscillatory rheology (B) by shearing a hydrogel at increasing strain at 1 s−1 from 0.01 until 200% strain. The recovery was recorded at 1% strain and 1 s−1 [
Oxidizing reagents like periodate are expected to exhibit toxicity in biological systems [118]. Interestingly, DOPA in its unoxidized state has bioadhesive properties [114]. For instance, functionalization of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) block copolymers with DOPA end groups was performed. Gelation of these polymers in situ occurred because of the temperature-induced phase transition of the block copolymer. The results showed significantly improved adhesion over PEO-PPO-PEO alone [118]. Ryu et al. functionalized PEO-PPO-PEO with terminal thiol groups [127] and blended it with catechol-functionalized chitosan. Again, immediate in situ gelation was achieved via the thermal transition of the PEO-PPO-PEO. Adhesive characteristics were imparted to the system via the catechol groups on the chitosan, which hydrogen bonded with other catechol groups on the chitosan, the thiols, and components in the tissues. A novel approach was used by Fan et al. [128]. The system they designed consisted of DOPA conjugated gelatin, a rapid cross-linker Fe3+, and genipin. While the dopamine moieties impart interfacial adhesion with surrounding tissue, the Fe3+ served as a rapid cross-linker by forming complexes with the catechol groups (Figure 21). Because these complexes are unstable due to their reversibility, genipin was included in the formulation. It gradually reacted with the amino groups on the gelatin over hours, providing stable network cohesion over time. Metal-DOPA bonds can reform after breaking, so separated pieces of hydrogel can remerge when placed in contact with one another [129]. Krogsgard et al. [120] took advantage of this property to create “self-healing” DOPA-functionalized gels composed of polyallylamine in solutions of FeCl3. Oscillatory rheology quantitatively shows the spontaneous reformation of separated hydrogel pieces (Figure 22).
\n\n\n(A) Scanning electron micrographs of polyimide hairs in a gecko-inspired adhesive. (B) Example of bunching pillars, which could reduce adhesive strength of the adhesive (scale bar 2 μm) [
Another type of nature-inspired sealant comes from geckos. Geckos have an amazing ability to climb walls because their feet are covered with millions of tiny hairs that provide significant adhesion. Only in the last twenty years or so has the mechanism responsible for this adhesion become understood. While any submicron object can stick to a surface, the strength of the adhesion depends on the shape and chemistry involved [130–133]. In the case of hydrophilic materials, capillary action with absorbed water plays a role [132, 133]. In certain sub-micron size ranges, van der Waals forces also promote adhesion to surfaces. The diameter of gecko hairs is such that both capillary action and van der Waals forces are maximized [131], so they can climb surfaces of varying hydrophilicity [134]. To create a gecko-inspired adhesive, one must manufacture a flat surface containing pillars that are sufficiently flexible so they can act in unison to adhere to a substrate (Figure 23A). The density of pillars must be maximized in order to generate sufficient adhesion force [134]. Bunching of the pillars (Figure 23B) is one mechanism that decreases adhesive strength [134].
\n\nGecko adhesion disappears when submerged in water [135, 136]. An interesting approach to overcoming this limitation and developing a wet/dry adhesive was taken by a group who combined gecko- and mussel-inspired materials into one device. They fabricated pillars from poly(dimethyl siloxane) (PDMS). Separately, they synthesized a mussel mimetic polymer, poly(dopamine-methacrylamide-co-methoxy-acrylate) and used it to coat the PDMS. The addition of the mussel mimetic material to the PDMS increased its wet adhesion by 15 times. However, adhesion was only studied on inorganic surfaces [137]. Mahdavi et al. [138] developed a wet/dry gecko-inspired adhesive and examined adhesion to organic substrates. A micropatterned biodegradable (polyglycerol sebacate acrylate) elastomer was used. It was coated with oxidized dextran to introduce a mechanism for covalent cross-linking with tissue. Simultaneously, the aldehydes reacted with the free hydroxyl groups on the glycerol subunit of the elastomer. Coating the pillars of elastomer with the dextran significantly increased the interfacial adhesion strength in vitro and in vivo.
\nTissue engineering is a fast-growing area of research that seeks to rebuild damaged tissues and organs. Current strategies involve seeding biomaterials, called scaffolds, with cells and/or biologically active molecules that allow or induce tissue regrowth in a three-dimensional structure [139]. Tissue engineering of certain areas in the body, particularly cartilage [122] and the intervertebral disc [140, 141], is not thought to be clinically feasible without a scaffold that can form an interface with surrounding tissue, eliminating the risk of dislocation and restoring mechanical functionality by adequately transmitting forces to and from the surrounding tissue [122, 140–142]. A scaffold could potentially be sutured in place, but ideally, it would integrate with surrounding tissues via a bioadhesive mechanism while supporting encapsulated cellular function.
\nFibrin was the first class of adhesives to be studied for tissue engineering because the gels are completely biocompatible, biodegradable, and capable of delivering growth factors [143, 144]. Additionally, fibrin has been shown to be permissible to in vitro mesenchymal stem cell differentiation toward a chondrogenic lineage [145]. Promising in vivo results with fibrin have been reported in adipose [146], bone [147, 148], cardiac [149], and neural tissue engineering [150]. Despite these positive results, there are significant limitations with using fibrin adhesives for some tissue engineering applications. Fibrin glues are unstable over time, thus making them non-ideal for the long repair processes [151]. The low mechanical properties make the glues inappropriate for load bearing applications [152, 153], like cartilage and the intervertebral disc. Fibrin gels also have a low cohesive strength with tissue [154, 155].
\nBesides fibrin glue, the efficacy of other bioadhesive polymers as in situ forming cell carriers for tissue engineering has not been extensively studied. Rather, the biocompatibility of cured adhesives with surrounding cells is typically investigated in the development of new glue formulations. The presence of reactive molecules, such as glutaraldehyde, aldehydes, NHS esters, or the presence of toxic monomers, as in cyanoacrylates, is likely to adversely affect encapsulated cells prior to gel network formation. Only a few groups have sought to investigate this. Adhesive hydrogels composed of gelatin, coupled to oxidized hyaluronic acid (DOO 40%), and cross-linked with adipic acid dihydrazide were characterized as cell carriers. The adipic acid dihydrazide (Figure 24) bridged hyaluronic acid-gelatin molecules via an imide bond. Intervertebral disc cells were encapsulated within the gels by suspension in the macromer solution prior to cross-linking. Two days after gel formation, viable cells were shown to be attached to the material [156]. Chondrocytes were shown to survive for 3 weeks after being encapsulated within chondroitin sulfate-NHS networks and combined with bone marrow and recombinant bone morphogenetic protein-2 [157]. These are promising preliminary results, but it is important to note that most current bioadhesive polymers have functional groups that are not only reactive with components of ECM, but cell membranes, as well. More in-depth studies are warranted, as experimental outcomes are likely to be impacted by cell type and density, material reactivity, concentration of reactive groups, and the presence of biomolecular signals such as growth factors.
\nChemical structure of adipic acid dihydrazide.
Wiltsey et al. [142] investigated the use of polysaccharides without reactive groups as bioadhesive tissue engineering scaffolds. Thermosensitive copolymers of poly(N-isopropylacrylamide) grafted with chondroitin sulfate (PNIPAAm-g-CS) containing mucoadhesive alginate microparticles as the adhesion mediators were developed. Below its lower critical solution temperature (LCST) around 30°C, PNIPAAm-g-CS forms a miscible solution with water. Above the LCST, the PNIPAAm becomes hydrophobic and an elastic hydrogel is formed without the use of monomers or cross-linkers [158]. Alginate microparticles and human embryonic kidney 293 cells were suspended in aqueous solutions of PNIPAAm-g-CS and encapsulated in the polymer network upon gelation at physiological temperature. Inclusion of the alginate microparticles significantly increased the tensile adhesive strength compared with PNIPAAm-g-CS alone and fibrin glue. Also, the formulation exhibited significantly less cytotoxicity than PNIPAAm-g-CS formulations containing CS-aldehyde as the adhesion mediator. The microparticle-hydrogel composites are now being investigated as scaffolds for intervertebral disc tissue engineering.
\nDue to differences in mechanical properties and cellularity in the various tissues of the body, it would be impractical to develop one sealant that can serve all applications [6]. However, there are some basic requirements that all sealants must have in order to meet present and future clinical needs:
\nEasy to apply and rapid solidification to conform to irregular shaped defects or tissue areas.
Able to provide sufficient mechanical support to the injured tissue as it heals.
Strong adhesion in order to maintain approximation of tissue pieces, prevent dislocation, and/or ensure adequate transmission of forces across tissue/implant interface.
Provoke a minimal degree of inflammation or toxicity from surrounding tissues with no risk of disease transmission.
Biodegradation within a time frame that corresponds to the gradual formation of new tissue.
Able to promote tissue growth and repair by acting as a suitable 3D culture system by promoting cell adhesion and extracellular matrix production.
Possible to produce in large scale quantities and cost effective.
Presently, no current bioadhesives have been shown to fulfill all these requirements. Unanswered questions still exist on the suitability of the current formulations for tissue engineering applications. As the field of biomedical sealants evolves to encompass new applications, researchers are working to develop new formulations with increasing biocompatibility, adhesive strength, flexibility and degradability. These advances promise to improve clinical outcomes by enhancing bleeding control and wound healing. In the long term, the use of bioadhesives in tissue regeneration research will become more prominent. New innovations will pave the way towards making orthopedic and musculoskeletal tissue engineering clinically successful in the future.
\nThe author is supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number 1R15 AR 063920–01. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. The author also gratefully acknowledges Tobi Schwartz-Cassell for editing and proofreading assistance.
\nFunctional foods are such types of foods that are highly nutritious and have a potential health benefits besides their basic nutritional values. Functional foods contain either supplements or other additional ingredients designed to improve the health of the general population. Foods are being examined and improved which may reduce chronic disease risk and optimize health. Japanese has first developed the concept of functional foods in 1980. At that time, their health care costs were escalating and the Ministry of Health and Welfare initiated to approve some foods which were documented with their health benefits and used for improving the health of the aging population [1].
Functional food components are bioactive compounds used in the manufacture of functional foods. They are potentially beneficial compounds found either naturally in foods or added to them as functional ingredients. The functional food components are carotenoids, isothiocyanates, dietary fiber, phenolic acids, fatty acids, plant stanols and sterols, flavonoids, polyols, soy protein, prebiotics and probiotics, phytoestrogens, vitamins, and minerals. Research-based evidence suggested that there is a relationship between functional food components, health, and well-being [2]. Therefore, functional food components can be used in the treatment and prevention of diseases, as they have health-promoting roles at various stages of disease control. Phytochemicals are plant-derived, non-nutritive, and biologically active functional food components that function in the body to prevent certain non-communicable diseases [3]. About 900 phytochemicals are found in foods and 120 g of foods or vegetables may have around 100 different types of phytochemicals [4]. The earlier concept was that functional food components occur mainly in plant foods, such as whole grain, fruits, and vegetables. However, functional food components are also found in animal products; these are milk, fermented milk products, and cold-water fish. These animal source food components are probiotics, prebiotics, symbiotic, conjugated linolenic acid, long-chain omega-3, -6, and -9 polyunsaturated fatty acids, etc.
Functional foods can be made by different approaches, such as (1) eliminating harmful components from the food (e.g. allergic protein), (2) increasing the concentration of a component in the food by fortification with micronutrients or any other ingredient, (3) eliminating excessive component mainly a macronutrient like fats and producing a beneficial component such as chicory inulin, (4) increasing stability or bioavailability of a component to produce a functional effect or to reduce the disease risk, and (5) adding a new component in the foods which has the beneficial effect, e.g. antioxidant.
In this chapter, functional food ingredients, including their sources and physiological functions, are discussed.
The carotenoids are the most widespread and important fat-soluble pigments in nature and they have varied health functions. Most carotenoids consumed foods are beta-carotene, alpha-carotene, gamma-carotene, lycopene, lutein, beta-cryptoxanthin, zeaxanthin, and astaxanthin.
Carotenoids are available in plants, fruits, flowers, algae, and photosynthetic bacteria. The other sources of carotenoids are non-photosynthetic bacteria, yeasts, and molds.
Carotenoids are used as antioxidants in dietary supplements. They are also used as colors in foods and beverages and as pigments in poultry and fish farm, and as food ingredients. Carotenoids have an important role in human health. The main dietary source of vitamin A is beta-carotene. Protective effects of carotenoids have been identified against serious disorders, such as cancer [5], heart disease [6], and degenerative eye disease [7]. The role of carotenoids as antioxidants and as regulators of the immune response system is also recognized.
Dietary fibers are the portion of plant-derived foods. They cannot be fully fragmented by human digestive enzymes. Fibers are non-starch polysaccharides, such as cellulose, hemicellulose, galactooligosaccharides, polyfructose, gums, mucilages, pectins, and lignin. These are soluble or insoluble fibers that pass through the stomach and small intestine undigested, but they are fermented by bacteria in the colon when they reach the large intestine.
Beans, whole grains, brown rice, popcorn, nuts, baked potato with skin, berries, bran cereal, oatmeal, and vegetables are the sources of dietary fibers.
Fibers are fermented and produced short-chain fatty acids in the colon that provide important health benefits. Some fibers are manufactured and added to food products to provide similar health benefits without adding calories called functional fibers. These are cellulose, polydextrose, maltodextrin, and inulin. There are several potential health benefits of the consumption of dietary and functional fibers. Fibers reduce the incidence of constipation [8], irritable bowel syndrome [9], lower cholesterol, and reduce the incidence of coronary and cardiovascular heart diseases [10], prevent obesity [11] and diabetes [12], avoid colon cancer [13], and increase survival in breast cancer [14]. However, there are some adverse effects of excessive intake of dietary fiber, such as intestinal obstruction (in susceptible individuals), dehydration (due to a fluid imbalance), increase in intestinal gas, resulting in distention and flatulence, and reduced absorption of vitamins, minerals, proteins, and calories from the gut [15].
Essential fatty acids (EFAs) cannot be synthesized by the human body but the body requires them for good health and therefore, they must be obtained through diet. Essential fatty acids are long-chain polyunsaturated fatty acids. They are called “good fats” and they increase the levels of high-density lipoprotein (HDL) and decrease the levels of low-density lipoprotein (LDL). Alpha linoleic acid and linolenic acid are the primary essential fatty acids in the human body.
Sources of essential fatty acids are mackerel, salmon, cod liver oil, herring, oysters, soybeans, sardines, flax seeds, anchovies, caviar, walnuts, chia seeds, and canola oils.
Essential fatty acids help in the absorption of important nutrients and expelling of harmful waste products that support the reproductive, cardiovascular, nervous systems, and immune. They are also important for proper growth, neural development, and maturation of sensory systems in children. Other important roles of EFAs are to increase the production of prostaglandins that regulate body functions, such as blood pressure, heart rate, blood clotting, conception, and fertility. EFAs also play an important role in immune function by regulating inflammation and encouraging the body to fight infection [16]. Essential fatty acids are beneficial for those suffering from rheumatoid arthritis [17] and reduce tenderness in joints, swelling, and diminish morning stiffness. It has also been observed that EFAs are important elements for asthma [18], depression [19], bipolar disorder schizophrenia [20], hypertension [21], heart diseases [22], burns [23], photodermatitis, acne or psoriasis [24], cholesterol [25], obesity [26], insulin sensitivity [27], osteoporosis [28], attention deficit disorder or attention deficit hyperactivity disorder [29], age-related macular degeneration [30], dry-eye conditions, such as Sjögren’s syndrome [31]. Consumption of sufficient amounts of foods rich in omega-3 fatty acids reduces the risk of colorectal [32], breast cancer [33], and prostate cancer [34].
Isothiocyanates are compounds produced by hydrolysis of glucosinolates that are precursors of cruciferous vegetables. Some isothiocyanates are volatile and evaporated below the boiling point. Isothiocyanates hydrolyze at higher cooking temperatures and their bioavailability is affected by microwaving at high power [35].
Good sources of isothiocyanates are cruciferous vegetables, such as broccoli, brussels sprouts, watercress, Japanese radish, cabbage, cauliflower, and kale.
Several studies revealed that isothiocyanates and their metabolites decrease the risk of developing different types of cancer, such as stomach, breast, liver, esophagus, lung, small intestine, and colon [36, 37]. Isothiocyanates effect
Flavonoids are pigments synthesized by plants and there are many different subclasses, each comprising many different compounds, such as isoflavones (biochanin A, daidzin, daidzein, formononetin, glycitein, genistein); flavononols (astilbin, genistin, taxifolin, engeletin); anthocyanidins (cyanidin, malvidin, delphinidin, apigenin, peonidin, pelargonidin, petunidin); chalcones (okanin, butein); flavonols (isorhamnetin, quercetin, kaempferol, myricetin); flavanols (positive-catechin, negative-epicatechin, positive-gallocatechin, negative-epigallocatechin, negative-epicatechin gallate); flavones (apigenin, luteolin, chrysin, rutin); flavanones (eriodictyol, isosakuranetin, hesperidin, naringin, naringenin, taxifolin) [41].
Sources of flavonoids are fresh capers, elderberry juice, dried parsley, sorrel, red onions, rocket lettuce, fresh cranberries, goji berries, cooked asparagus, blackcurrants, dried oregano, grapefruit, lemons, orange juice, limes, oranges, grapefruit juice, artichokes, green tea, black tea, dried cocoa, dark chocolate, blackberries, cooked broad beans, pecan nuts, red table wine, apples, peaches, dried parsley, aronia, green pepper, bilberries, chickpeas, black currants, American bilberries, red cabbage, red currants, raspberries, and strawberries.
There are several health benefits of flavonoids, including antiallergic, antioxidant activities, antiviral [42], antitoxic, antifungal [43], antibacterial [44] and anti-inflammatory [45]. Recent researches identified the many defensive roles of flavonoids, these are eye diseases [46], heart diseases [47], hemorrhoids [48], diabetes [49], neurodegenerative diseases, such as Alzheimer’s or Parkinson’s [50], gout [51] and periodontal disease [52]. Flavonoids are also used for the prevention and treatment of different types of cancer, such as prostate [53], ovarian [54], pancreatic, colon, breast [55], leukemia, lung [56], esophageal [57], hepatocellular carcinoma [58], and renal cell carcinoma [59].
Phenolic acids contain a phenolic ring and a carboxyl functional group. Some examples of phenolic acids are protocatechuic acid, vanillic acid, p-hydroxybenzoic acid, ferulic acid, caffeic acid, p-coumaric acid, sinapinic acid, and syringic acid. Phenolic acids are absorbed through the walls of the intestine and serve beneficial roles, such as antioxidants and protect cellular damage by free-radical oxidation reactions.
Sources of phenolic acids are cereals, oilseeds, legumes, vegetables, fruits, beverages, and herbs. Besides these sources, they are also found in all food groups.
Phenolic acids have several health benefits, such as intake of phenolic acids decrease the risk of cardiovascular diseases, certain cancers, type II diabetes, and neurodegenerative disorders [60, 61, 62], through multiple putative mechanisms of actions, including antioxidation, glucoregulation, anti-inflammation, antiproliferation, and microbial modulation. Russo et al. [63] found a negative relationship between dietary intake phenolic acids (e.g. ferulic acid and caffeic acid) and prostate cancer and they showed that both phenolic acids are associated with reduced prostate cancer. Also, immunoregulation diseases, asthma, and allergic reactions are protected by caffeic acid which is phenolic acid. Caffeic acid has a positive role against colon cancer [64] and it has inhibitor properties of HIV-1 that act as a potential antiviral therapy [65]. It is also found that a higher intake of phenolic acids is significant lower mean systolic and diastolic blood pressure compared to a lower intake of phenolic acids [66].
Plant stanols and sterols are a group of substances made in the plant. The most important and ample of plant sterol is sitosterol. However, campesterol and stigmasterol are also significant quantitative of sterol. They reduce the absorption of cholesterol in the intestine and help to lower low-density lipoprotein (LDL) cholesterol levels in the blood without affecting high-density lipoprotein (HLD) cholesterol levels.
Sterols and stanols are found in the highest amount in foods, such as fruits, vegetables, seeds, nuts, legumes, cereals, and vegetable oils.
Plant sterols work as an anti-inflammatory, antioxidant [67], and antiatherosclerosis. Phytosterols have antifungal activity and protect against ulcers [68]. The intake of plant sterols can prevent different types of cancer, such as the esophagus, prostate [69], lung [70], breast [71], ovary [72], stomach, and endometrial [73]. LDL-cholesterol is a risk factor for cardiovascular diseases. Plant sterols or stanols prevent absorption of LDL cholesterol from the gut, as a result, serum levels of LDL are lower, and assumed that lowering LDL-cholesterol is expected to lower cardiovascular diseases.
Polyol is an organic compound and low-calorie carbohydrate-based sweetener. It is a hydrogenated version of carbohydrates. Its taste and texture are like sugar with half the calories. Polyols are used as sugar-free and low-calorie ingredients in many foods. There are various types of polyols, such as erythritol, isomalt, polyglucitol, lactitol, polyglycitol, mannitol, sorbitol, maltitol, and xylitol.
Polyols are found in some fruits, vegetables, and mushrooms.
Polyols are used in different industries for making foods, such as ice cream, chewing gums, frozen desserts, candies, and baked goods [74]. They are also used for frostings, canned fruits, beverages, yogurt, and tabletop sweeteners. Polyols have some important health benefits and they maintain good oral health [75]. They are also used for weight control and reduction of dietary glycemic load [74]. Polyols may play an important role in the maintenance of human digestive health as these are low digestible carbohydrates [76]. Sometimes overconsumption of polyol-containing foods may have laxative effects [74].
Soy protein is extracted from soybean and hence, it is a complete plant-based protein and it contains adequate amounts of all the essential amino acids. Health benefits of soy protein depend on consumption per day. Per person need to consume 25 g of soy protein or more every day to get results.
Whole soybeans are the source of soy protein and dietary fiber. Some selected soy food products are soya sauce (2 g protein of 18 g soy sauce), cooked and fermented soy (5 g protein of 28 g cooked and fermented soy), soybean curd (6 g protein of 84 g soybean curd), and soy veggie burger (11 g protein of 70 g soy veggie burger).
Soy protein has many potential health benefits. Beneficial effects of soy protein products on women are improvement of diet and cardiovascular status, prevention of certain types of cancer, health improvement following menopause, and obesity prevention [77]. Xiao et al. [78] have shown some chemopreventive activity of soy protein. The potential role of consumption of soy protein is reducing body weight and fat mass which reduces plasma cholesterol and triglycerides [79]. Soy protein may reduce the risk of cardiovascular disease, stroke, and coronary heath disease.
Phytoestrogens (PEs) are the compounds found in plans and they are not generated within the endocrine system in the human body and are consumed by eating phytoestrogenic plants. They have roles in the metabolism of proteins, carbohydrates, fats, and minerals in the human body and they act as estrogen hormone in the reproductive cycle in women [80]. There are three types of phytoestrogens, such as lignans (enterolactone or enterodiol), coumestans (coumestrol), and isoflavones (genistein, daidzein, glycitein).
The greater sources of phytoestrogens are soybeans, soy beverages, tofu, tempeh, linseed (flax), wheat, berries, sesame seeds, oats, barley, lentils, dried beans, rice, alfalfa, mung beans, apples, wheat germ, carrots, rice bran, and soy-linseed bread.
There are several health benefits of phytoestrogens. They affect the cardiovascular system [80] and skeleton and reduce the incidence of osteoporosis [81] and menopausal symptoms [82]. Phytoestrogens have cell proliferation inhibiting factors that prevent cancer. They have positive effect on prostate cancer [83], breast cancer [84], thyroid cancer [85], colorectal cancer [86], skin cancer [87] and endometrial cancer [88]. Soy foods containing PEs improve control of blood glucose and insulin levels [89]. There are antibacterial and fungistatic activities in some phytoestrogens which play an antiviral role [90].
There are two types of bacteria in our body, such as good bacteria and bad bacteria. Probiotics are living bacteria that provide health benefits by improvement of the balance of the intestinal microflora [91] when ingested in an adequate amount. Some yeasts also work as probiotics. There are so many types of probiotics, but
Some best probiotic foods are yogurt, traditional buttermilk, pickles, kombucha, kimchi, sauerkraut, cheese, and kefir.
Probiotic is used for the treatment of diarrhea [92],
Prebiotics are non-digestible fibers present in plants and help healthy bacteria to grow in the gut and make the human digestive system work better. Most of the prebiotics are oligosaccharides that stimulate selectively the growth of
Main sources of prebiotics are fruits, vegetables, and whole grains, such as apples, artichokes, asparagus, bananas, barley, berries, chicory, cocoa, dandelion greens, flaxseed, garlic, green vegetables, leeks, konjac root, legumes, oats, tomatoes, onions, soybeans, wheat, and yacon root. Also, some foods are fortified with prebiotics, for example, baby formula, bread, cereal, cookies, and yogurt.
Prebiotics work as anticarcinogenic, antimicrobial, and antiosteoporotic activities. Prebiotics are also used for the treatment of constipation, hepatic encephalopathy, and inflammatory bowel disease. There is a beneficial role of prebiotics in diabetes mellitus. Prebiotics also have an important role in improving mineral absorption and balance and enhancing the colonic absorption of some minerals. Prebiotics also ferment foods faster in the intestine and prevent constipation. Prebiotics reduce sepsis and mortality in premature and low-birth-weight infants [104].
Synbiotics are the combined products of both probiotics and prebiotics. The advantage of the combination of beneficial bacteria is the encouragement of beneficial bacterial growth. Synbiotics are produced by combinations of
As symbiotics are the combined products of prebiotics and probiotics, so the sources of symbiotics are the same as probiotics and prebiotics. However, this combination is produced commercially.
Evidence suggested that symbiotics can reduce sepsis, lower respiratory tract infection, and mortality among low-birth-weight infants [105].
Vitamins are organic molecules and essential for the proper functioning of the human body. Vitamins are required in small amounts obtained from a correct diet. There are two types of vitamins such as fat-soluble vitamins and water-soluble vitamins. Fat-soluble vitamins are A, D, E, and K and they can be stored in the body. On the other hand, water-soluble vitamins are C and B-complex, such as vitamins B6, B12, niacin (B3), riboflavin (B2), biotin (B7), thiamine (B1), pantothenic acid (B5), and folic acid (B9). They cannot be stored in the body because the excess ingested is eliminated through human fluids, such as urine and transpiration, and hence necessary to ingest a daily amount of these vitamins [106].
There are different forms of vitamin A, such as retinol, retinal, retinoic acid, and all known as retinoids.
The best sources of vitamin A are beef liver, cod liver oil, spinach, sweet potato, carrots, broccoli, black-eyed peas, mango, sweet red pepper, cantaloupe, dried apricots, pumpkin pie, tomato juice, and herring.
Vitamin A plays an important role in many processes in the body, including immune function, reproduction, healthy vision, proper functioning of the heart, kidneys, lungs, and other organs, skink health and growth development. Vitamin A also helps to prevent lung and breast cancer [107]. Vitamin A can be used for the treatment of leukemia [108], skin disorders, and retinitis pigmentosa [109].
Vitamin B-complex is a product that is composed of B vitamins, such as thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), vitamins B6, biotin (B7), folic acid (B9), and B12.
Adequate amount of vitamins B sources are milk, cheese, eggs, liver and kidney, meat (chicken and red meat), fish (tuna, mackerel, and salmon), shellfish (oysters and clams), and dark green vegetables (spinach and kale).
Vitamin B-complex has several health benefits:
Thiamin/thiamine (B1) is used for the treatment of Alzheimer’s disease [110], congestive heart failure [111], and cancer [112].
Riboflavin (vitamin B2) is used to prevent cataracts [113] and migraine headaches [114].
Niacin (B3) is used to prevent insulin-dependent diabetes mellitus [115]. It has a significant role to treat high cholesterol and cardiovascular disease [116].
Pantothenic acid (B5) can help in wound healing [117] and play an important role to maintain cholesterol levels [118].
Vitamin B6 has a vital role to prevent cardiovascular disease [119], kidney stones, and immune and cognitive functions [120]. It is also used for the treatment of premenstrual syndrome [121]. Vitamin B6 can protect from side effects of oral contraceptives, nausea, and vomiting in pregnancy [122] and reduce depression.
Biotin (B7) is used for the treatment of diabetes [123] and in the prevention of some birth defects [124]. It plays a vital role in the treatment of cholesterol [125], brittle fingernails [126], seborrheic dermatitis [127], and hair loss.
Folic acid (B9) is used to prevent some pregnancy complications, such as fetal neural tube defects [128]. It may be used to prevent certain heart defects and limb malformations [129] and birth defects [130]. Folic acid is used to prevent colorectal and breast cancer [131], heart diseases [132], Alzheimer’s disease, and cognitive impairment [133].
Vitamin B12 plays an important role in the prevention of neural tube defects, cancer [134], cardiovascular disease [135], depression, Alzheimer’s disease, and dementia [136].
Vitamin C (ascorbic acid) is a very effective nutrient and the main sources of vitamin C are citrus fruit (oranges and orange juice), strawberries, peppers, broccoli, blackcurrants, brussels sprouts, and potatoes. It plays an important role against immune system deficiencies, cardiovascular disease [137], prenatal health problems, eye disease, and skin wrinkling. Vitamin C works as an antioxidant and can prevent scurvy, lead toxicity, and cancer [138].
Vitamin D is a combination of calciferol (
Vitamin E has several forms and the human body can use only alpha-tocopherol form. Good sources of vitamin E are plant-based oil (e.g. sunflower, soya, corn, and olive oil), nuts, seeds, fruits, and vegetables. The potential health benefits are moisturizing skin, wound healing, preventing cancer [139], reducing skin itching and eczema, psoriasis, preventing and minimizing the appearance of scars, uses for treatment of wrinkles, preventing sunburn, promoting nail health and enhance immune response [140]. Vitamin E is also used for the treatment of diabetes and dementia [141].
Vitamin K is a group of compounds and of them, the main are vitamin K1 and vitamin K2. The main sources of vitamin K1 are leafy greens vegetables and other vegetables (brussels sprouts, broccoli, cauliflower, and cabbage). However, sources of vitamin K2 are meats, fish, liver, cheeses, and eggs. Vitamin K plays an important role to prevent osteoporosis [142], vascular calcification [143], and cardiovascular disease. Besides these, it has other health benefit roles, such as bone health, cognitive health, and heart health.
Minerals are inorganic elements present in the soil and water and are important for the body to stay healthy. According to the human body demands, dietary minerals are two types, such as macro-minerals those are required in large amounts (e.g. calcium, phosphorus, magnesium, sodium, potassium, and sulfur), and micro- or trace-minerals those are required very small amounts (e.g. chromium, copper, cobalt, iron, fluorine, manganese, iodine, molybdenum, zinc, and selenium) [144].
Calcium is a nutrient that all living organisms need and it is the most common mineral in the human body.
The main sources of calcium are milk, cheese, yogurt and other dairy products, green leafy vegetables (curly kale and okra), soya drinks with added calcium, and bread made with fortified flowers.
Magnesium is one of the most important macro-nutrients for the human body.
Main sources of magnesium are avocados, legumes, nuts, seeds, tofu, whole grains, some fatty fish, dark chocolate, bananas, and leafy greens.
Magnesium plays an important role in bone health and cardiovascular health, prevents diabetes and migraine headaches [147], premenstrual syndrome, and anxiety.
Potassium is an important and necessary nutrient for the human body.
Potassium-rich foods are bananas, oranges, cantaloupe, honeydew, apricots, grapefruit, dried fruits, such as prunes, raisins and dates, cooked spinach and broccoli, potatoes, sweet potatoes, mushrooms, peas, cucumbers, and seafood. Milk, meat, yogurt, and nuts are also good sources of potassium.
An adequate amount of potassium intake may prevent high blood pressure [148] that may reduce cardiovascular disease and stroke [149]. People who eat potassium-containing fruits and vegetables may have higher bone mineral density and it also helps to preserve muscle mass. High potassium may help kidneys’ ability to reabsorb calcium and reduce kidney stones [150].
Chromium is an essential trace element that the human body needs in very small quantities to properly maintain some health functions.
The good sources of chromium are grape juice, whole wheat flour, brewer’s yeast, orange juice, beef, tomato juice, apples, and green beans.
Some important health benefits of chromium are it may be helpful for type II diabetic patients. It can decrease glucose levels and improve insulin sensitivity. Chromium supplements can be used to build muscle or trigger weight loss. Some side effects including watery stool, vertigo, headaches, and hives are reported for taking chromium supplements.
Copper is required in small quantities but it is an essential nutrient for the body.
Main sources of copper are organ meats (liver and kidneys), oysters, spirulina, shiitake mushrooms, nuts and seeds, lobster, dark leafy greens, whole grains, dried fruits (prunes, cocoa, and black pepper), and dark chocolate.
Copper helps to produce red blood cells, regulates heart rate and blood pressure, the absorption of iron, prevents inflammation of the prostate, in development and maintenance of bone, brain, and heart, and activates the immune system [151].
Iodine is an essential trace element and is required for the human body.
The important sources of iodine are fish (cod and tuna), shrimp, and other seafood. Dairy products (milk, yogurt, and cheese), eggs, prunes, lima beans, and iodized salt.
Iodine is essential for the synthesis of thyroid hormone that is required for metabolism. The deficiency of thyroid hormone is called hypothyroidism can lead to issues with fatigue, joint pain, and fertility problems. Iodine plays an important role in proper bone and brain development.
Iron deficiency is associated with several health impairments.
Good sources of iron are organ meats, red meat, turkey, shellfish, white beans, pumpkin seeds, quinoa, nuts, dark chocolate, dried fruits, soybean flour, lentils, tofu, sardines, spinach, broccoli, cooked oysters, and fortified breakfast cereals.
Iron is helpful for the treatment of anemia; it may reduce fatigue and improves muscle endurance. It has an important role in strengthening the immunity system. Iron improves cognitive function [152] and reduces bruising.
Selenium is an important macromineral and essential for the human body. Selenium deficiency is common in a certain part of the world as it can be affected by pH.
The sources of selenium are Brazil nuts, fish, ham, enriched foods, pork, beef, turkey, chicken, cottage cheese, eggs, brown rice, sunflower seeds, baked beans, mushrooms, oatmeal, spinach, milk and yogurt, lentils, cashews, and bananas.
Selenium has several health benefits, such as acts as a powerful antioxidant, may reduce the risk of certain cancers-lung [153], prostate [154], liver, colon [155], esophageal, and gastric [156]. It may protect against heart disease and prevents mental decline. Selenium is important for maintaining thyroid health, helping to boost the immune system, and reducing asthma symptoms.
Zinc is a vital and second-most-abundant and essential mineral for the human body.
The best sources of zinc are meat, shellfish, legumes, hemp seeds, nuts, dairy, eggs, whole grains, some vegetables, and dark chocolate.
Zinc is important for various functions in the body, such as helps to increase the immune system, uses in treating diarrhea, wound healing, works as an antioxidant and reduces chronic diseases, prevents age-related macular degeneration [157], improves sexual health, prevents osteoporosis, reduces neurological symptoms, protects from the common cold, boosts cognitive function, and increase learning and memory.
Functional food components are important compounds available in a variety of fruits, vegetables, and some animal products. They are also manufactured commercially. They have several health benefits for the human body. Many functional food components are antioxidants rich and help to neutralize free radicals, prevent cell damage, and reduce non-communicable diseases, such as cancer, diabetes, heart diseases and maintain health properly. To optimize health benefits and bioavailability of functional food components in the human body are critical factors. To maintain the levels required in the human body need an adequate amount of these components. Recent information in this regard is not sufficient. Therefore, need to provide more information to consumers to guide them effectively so that they can choose diets that contain adequate levels of health-promoting functional food components.
The author declares that there is no conflict of interest.
None.
Authors are listed below with their open access chapters linked via author name:
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\\n\\nLiming Dai 2015-18
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\\n\\nVincenzo Fogliano 2017, 2018
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\\n\\nHarald Haas 2017, 2018
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\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
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\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
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\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
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\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
\n\nGang Chen 2016-18
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\n\nZhigang Chen 2016, 2018
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\n\nCyrus Cooper 2017, 2018
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\n\nWeihua Deng 2017, 2018
\n\nVincenzo Fogliano 2017, 2018
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\n\nBiswajeet Pradhan 2016-18
\n\nDirk Raes 2017, 2018
\n\nUlrike Ravens-Sieberer 2016-18
\n\nYexiang Tong 2017, 2018
\n\nJim Van Os 2015-18
\n\nLong Wang 2017, 2018
\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
\n\nQi Xie 2016-18
\n\nXin-She Yang 2017, 2018
\n\nYulong Yin 2015, 2017, 2018
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Therefore, rural people should make some strategy for the implementation of agroforestry model with suitable combination of trees and field crops, and this combination does not only generate income for the upliftment of socioeconomic value but also concerns the ecological and environmental stability on the sustained basis, i.e. emphasis should be more on scientific management of these models.",book:{id:"4757",slug:"precious-forests-precious-earth",title:"Precious Forests",fullTitle:"Precious Forests - Precious Earth"},signatures:"M.K. Jhariya, S.S. Bargali and Abhishek Raj",authors:[{id:"175133",title:"Dr.",name:"S. S.",middleName:null,surname:"Bargali",slug:"s.-s.-bargali",fullName:"S. S. 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However, persistent land use, monoculture, and intensified production processes have led to soil diseases. This, along with abiotic stress, and mainly salinity of soil and waters, water stress, and suboptimal temperatures, can lead to physiological disorders emerging in peppers, e.g., cracking and Blossom end rot, which induce plant senescence, and lower not only in yields, but also in product quality. Salinity and water shortage are the two main environmental problems that crops face in the Mediterranean Region. One way of overcoming stresses from an ecological or integrated crop management viewpoint is to use grafted plants as an adaptation strategy. Initially, grafting technology has expanded in Solanaceae and Cucurbitacea species to overcome biotic stress. Nowadays, grafts are being used as several approaches to cushion the impact of climate change on agricultural systems. Furthermore, grafts allow desirable varieties by organoleptic or productivity traits, but they are sensitive to abiotic stress and can be grown under abiotic stress. As far as we know, very few studies on grafted pepper plants under abiotic stress are available.",book:{id:"6171",slug:"climate-resilient-agriculture-strategies-and-perspectives",title:"Climate Resilient Agriculture",fullTitle:"Climate Resilient Agriculture - Strategies and Perspectives"},signatures:"Consuelo Penella and Angeles Calatayud",authors:[{id:"213492",title:"Dr.",name:"Angeles",middleName:null,surname:"Calatayud",slug:"angeles-calatayud",fullName:"Angeles Calatayud"},{id:"213498",title:"Dr.",name:"Consuelo",middleName:null,surname:"Penella",slug:"consuelo-penella",fullName:"Consuelo Penella"}]},{id:"65961",title:"The Disturbed Habitat and Its Effects on the Animal Population",slug:"the-disturbed-habitat-and-its-effects-on-the-animal-population",totalDownloads:1527,totalCrossrefCites:1,totalDimensionsCites:7,abstract:"Changes in the “habitat” may interfere with the normal functioning of all biological systems. The existence of relationships between environmental changes and health in humans and animal species is well known and it has become generally accepted that poor health affects the animal’s natural behaviors and animal welfare and, consequently, food safety and animal production quality. Microclimate alterations, husbandry-management conditions, quality of human-animal interactions, feeding systems, and rearing environment represent the main factors that could negatively affect animal welfare and may produce behavioral, biochemical, endocrine, and pathological modifications in domestic and wild animals. Particularly, high stress levels can reduce the immune system response and promote infectious diseases. Adverse socio-environmental factors can represent a major stimulus to the development of different pathologies. This chapter will discuss the main pathological modifications described in domestic and wild animals due to “disturbed habitat” paying more attention to critical points detected in standard breeding systems.",book:{id:"8833",slug:"habitats-of-the-world-biodiversity-and-threats",title:"Habitats of the World",fullTitle:"Habitats of the World - Biodiversity and Threats"},signatures:"Maria Teresa Capucchio, Elena Colombino, Martina Tarantola, Davide Biagini, Loris Giovanni Alborali, Antonio Marco Maisano, Federico Scali, Federica Raspa, Emanuela Valle, Ilaria Biasato, Achille Schiavone, Cristian Salogni, Valentina Bar, Claudia Gili and Franco Guarda",authors:[{id:"57235",title:"Dr.",name:"Maria Teresa",middleName:null,surname:"Capucchio",slug:"maria-teresa-capucchio",fullName:"Maria Teresa Capucchio"},{id:"291161",title:"Dr.",name:"Elena",middleName:null,surname:"Colombino",slug:"elena-colombino",fullName:"Elena Colombino"},{id:"291162",title:"Dr.",name:"Martina",middleName:null,surname:"Tarantola",slug:"martina-tarantola",fullName:"Martina Tarantola"},{id:"291163",title:"Dr.",name:"Davide",middleName:null,surname:"Biagini",slug:"davide-biagini",fullName:"Davide Biagini"},{id:"291164",title:"Dr.",name:"Loris Giovanni",middleName:null,surname:"Alborali",slug:"loris-giovanni-alborali",fullName:"Loris Giovanni Alborali"},{id:"291165",title:"Dr.",name:"Antonio Marco",middleName:null,surname:"Maisano",slug:"antonio-marco-maisano",fullName:"Antonio Marco Maisano"},{id:"291166",title:"Dr.",name:"Federico",middleName:null,surname:"Scali",slug:"federico-scali",fullName:"Federico Scali"},{id:"291167",title:"Dr.",name:"Federica",middleName:null,surname:"Raspa",slug:"federica-raspa",fullName:"Federica Raspa"},{id:"291168",title:"Dr.",name:"Emanuela",middleName:null,surname:"Valle",slug:"emanuela-valle",fullName:"Emanuela Valle"},{id:"291169",title:"Dr.",name:"Ilaria",middleName:null,surname:"Biasato",slug:"ilaria-biasato",fullName:"Ilaria Biasato"},{id:"291170",title:"Prof.",name:"Achille",middleName:null,surname:"Schiavone",slug:"achille-schiavone",fullName:"Achille Schiavone"},{id:"291171",title:"Dr.",name:"Cristian",middleName:null,surname:"Salogni",slug:"cristian-salogni",fullName:"Cristian Salogni"},{id:"291172",title:"Dr.",name:"Valentina",middleName:null,surname:"Bar",slug:"valentina-bar",fullName:"Valentina Bar"},{id:"291173",title:"Dr.",name:"Claudia",middleName:null,surname:"Gili",slug:"claudia-gili",fullName:"Claudia Gili"},{id:"291174",title:"Prof.",name:"Franco",middleName:null,surname:"Guarda",slug:"franco-guarda",fullName:"Franco Guarda"}]},{id:"36125",title:"Deforestation: Causes, Effects and Control Strategies",slug:"deforestation-causes-effects-and-control-strategies",totalDownloads:158126,totalCrossrefCites:31,totalDimensionsCites:96,abstract:null,book:{id:"2246",slug:"global-perspectives-on-sustainable-forest-management",title:"Global Perspectives on Sustainable Forest Management",fullTitle:"Global Perspectives on Sustainable Forest Management"},signatures:"Sumit Chakravarty, S. K. Ghosh, C. P. Suresh, A. N. Dey and Gopal Shukla",authors:[{id:"94999",title:"Dr.",name:"Sumit",middleName:null,surname:"Chakravarty",slug:"sumit-chakravarty",fullName:"Sumit Chakravarty"},{id:"101102",title:"Prof.",name:"Swapan Kr.",middleName:null,surname:"Ghosh",slug:"swapan-kr.-ghosh",fullName:"Swapan Kr. Ghosh"},{id:"101103",title:"Dr.",name:"C. P.",middleName:null,surname:"Suresh",slug:"c.-p.-suresh",fullName:"C. P. Suresh"},{id:"101104",title:"Dr.",name:"A N",middleName:null,surname:"Dey",slug:"a-n-dey",fullName:"A N Dey"},{id:"101105",title:"Dr.",name:"Gopal",middleName:null,surname:"Shukla",slug:"gopal-shukla",fullName:"Gopal Shukla"}]},{id:"55309",title:"Plant-Microbe Ecology: Interactions of Plants and Symbiotic Microbial Communities",slug:"plant-microbe-ecology-interactions-of-plants-and-symbiotic-microbial-communities",totalDownloads:4604,totalCrossrefCites:11,totalDimensionsCites:27,abstract:"Plant community dynamics are driven by the microbial mediation of soil resource partitioning and sharing by the inhibition of other host symbionts or sharing the broadly specific symbiotic fungi. The plant phenotype and ecology can be affected by the impact of the symbiotic microbes on the environment and competition for soil resources.",book:{id:"5877",slug:"plant-ecology-traditional-approaches-to-recent-trends",title:"Plant Ecology",fullTitle:"Plant Ecology - Traditional Approaches to Recent Trends"},signatures:"Ying-Ning Ho, Dony Chacko Mathew and Chieh-Chen Huang",authors:[{id:"198872",title:"Dr.",name:"Ying-Ning",middleName:null,surname:"Ho",slug:"ying-ning-ho",fullName:"Ying-Ning Ho"},{id:"199676",title:"Prof.",name:"Chieh-Chen",middleName:null,surname:"Huang",slug:"chieh-chen-huang",fullName:"Chieh-Chen Huang"},{id:"201133",title:"Dr.",name:"Dony",middleName:"Chacko",surname:"Mathew",slug:"dony-mathew",fullName:"Dony Mathew"}]},{id:"57881",title:"Forest Fire Monitoring",slug:"forest-fire-monitoring",totalDownloads:1685,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Thousands of hectares around the globe destroyed by forest fires every year causing tragic loss of houses, properties, lives, fauna and flora. Forest fires are a great menace to ecologically healthy grown forests and protection of the environment. This problem has been the research interest for years, and there are a number of solutions available to resolve this problem. In this chapter, a summary is given for all the technologies that have been used for forest fire detection with explanation of what parameters these systems looking for to understand the fire behaviour.",book:{id:"6304",slug:"forest-fire",title:"Forest Fire",fullTitle:"Forest Fire"},signatures:"Ahmad AA Alkhatib",authors:[{id:"215875",title:"Dr.",name:"Ahmad",middleName:null,surname:"Alkhatib",slug:"ahmad-alkhatib",fullName:"Ahmad Alkhatib"}]}],onlineFirstChaptersFilter:{topicId:"34",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:99,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:288,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. 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Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"13633",title:"Prof.",name:"Abdelhamid",middleName:null,surname:"Mellouk",slug:"abdelhamid-mellouk",fullName:"Abdelhamid Mellouk",profilePictureURL:"https://mts.intechopen.com/storage/users/13633/images/1567_n.jpg",institutionString:null,institution:{name:"Paris 12 Val de Marne 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learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö 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Isler",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",institutionURL:null,country:{name:"Turkey"}}}]},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"1177",title:"Prof.",name:"Antonio",middleName:"J. 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Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. 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Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"9",type:"subseries",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. 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