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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"197",leadTitle:null,fullTitle:"The Clinical Spectrum of Alzheimer's Disease -The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies",title:"The Clinical Spectrum of Alzheimer's Disease",subtitle:"The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies",reviewType:"peer-reviewed",abstract:"The Clinical Spectrum of Alzheimer's Disease: The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies is highly informative and current. 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She received her undergraduate degree from Cornell University, Ithaca, N.Y., M.D. from the Weill College of Medicine at Cornell University, and masters in public health (M.P.H.) from the Blumberg School of Public Health at Johns Hopkins University, Baltimore, MD. Dr. de la Monte completed her residency in Anatomical Pathology and fellowship in Pediatric Pathology at The Johns Hopkins Hospital, and a fellowship in Neuropathology at the Massachusetts General Hospital. She received postdoctoral research training at the Massachusetts General Hospital. Currently, Dr. de la Monte directs research on the role of insulin resistance as a mediator of neurodegeneration in relation to Alzheimer’s disease, alcoholism, obesity, diabetes, and development. 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\r\n\tThis book intends to present the latest information and modern management of bone-related tumours. Not only from Benign to malignant but also tumours conditions are covered in a detailed and succinct way. It will aim to cover an array of areas in particular tumour including pathology, pathogenesis, genetic basis, oncology modern methods of diagnosing, screening for tumours and aetiological causes, and advice on how to prevent and other early diagnosing strategies. The current concept of bone tumours and tumour management has changed rapidly over the past decades. Therefore, a fresh look at this topic is needed and is timely.
\r\n\r\n\tThe book will aim to include the latest information used in current practice and current research areas on which the future practice will be based on. Not only on modern investigation and diagnosing tools biopsy techniques and radiological imaging but also modern concepts for managing these tumours. The three main areas in managing involve radiotherapy chemotherapy and surgical oncology and the latest advances in these fields are intended to be discussed. This book will aim to benefit not only trainees of surgery, oncology medicine, orthopaedics but also medical students, general practitioners, and anybody interested in the field of bone tumour management.
",isbn:"978-1-80356-930-7",printIsbn:"978-1-80356-929-1",pdfIsbn:"978-1-80356-931-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"cf7dd688b160a1ba07e3179613684f16",bookSignature:"Dr. Hiran Wimal Amarasekera",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11651.jpg",keywords:"Osteosarcoma, Choindro - Sarcoma, Ewing's Sarcoma, Osteoma, Chondroma, Enchondromas, Bone Cysts, Myelo Proliferative Disease, Plasma Cells, Lymphomas, Soft Tissue Sarcomas, Bone",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 6th 2022",dateEndSecondStepPublish:"June 15th 2022",dateEndThirdStepPublish:"August 14th 2022",dateEndFourthStepPublish:"November 2nd 2022",dateEndFifthStepPublish:"January 1st 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Works as a clinician, orthopaedic surgeon, Researcher, academic teacher, examiner, and educator in the field of medicine and orthopaedics. Pioneering work on anatomy and blood supply to joints mainly hip joints and causative factors leading to avascular necrosis was done at the University of Warwick, and the University of California Los Angeles.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"67634",title:"Dr.",name:"Hiran",middleName:"Wimal",surname:"Amarasekera",slug:"hiran-amarasekera",fullName:"Hiran Amarasekera",profilePictureURL:"https://mts.intechopen.com/storage/users/67634/images/system/67634.png",biography:"Hiran Amarasekera is a Consultant Orthopaedic Surgeon Currently practicing in Sri Lanka. After obtaining the MBBS from Kasturba medical college, Manipal, Inda, he completed the MS in Surgical sciences from the University of Colombo. He obtained the fellowship of the Royal College of Surgeons of Edinburgh (FRCS Ed) and board certification in 2003. \n\nHis special interests are in the areas of young adult hip and knee problems, sports injuries, lower limb arthroplasty, and keyhole joint surgery, and revision arthroplasty. His present research is focused on non-surgical and minimally invasive alternative treatment for osteoarthritis. He worked and trained in many countries for over twenty including India, Sri Lanka, Australia, United States, and the UK.\n\nAs a keen researcher, he has completed an MPhil from the University of Warwick and completed a research fellowship at the University of California Los Angeles, (UCLA). \n\nPresently, he works as a medical educator, as an honorary senior lecturer at the University of Kelaniya and Kothalawela Defense University in Sri Lanka. He is an examiner of medical students both in Sri Lanka and the UK and a course provider for Trauma courses run by the college of surgeons and was elected a fellow of Sri Lanka College of surgeons in 2013.\n\nDr. Amarasekera is the editor of the Journal of Sri Lanka Orthopaedic association and council member. He is a reviewer for the Journal of Bone and Joint Surgery (Br) e and Bone and Joint Journal (BJJ) and a member of the editorial board of the Sri Lanka Journal of Surgery (SLJS). \n\nHe has over 50 international publications, presentations and several book chapters to his credit and has reviewed over 100 papers for journals of BJJ and SLJS.\n\nAfter joining IntechOpen in 2012 he authored three book chapters and edited several open access books with them.",institutionString:"University of Warwick Science Park",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Warwick Science Park",institutionURL:null,country:{name:"United Kingdom"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429341",firstName:"Paula",lastName:"Gavran",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"paula@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"9500",title:"Recent Advances in Bone Tumours and Osteoarthritis",subtitle:null,isOpenForSubmission:!1,hash:"ea4ec0d6ee01b88e264178886e3210ed",slug:"recent-advances-in-bone-tumours-and-osteoarthritis",bookSignature:"Hiran Amarasekera",coverURL:"https://cdn.intechopen.com/books/images_new/9500.jpg",editedByType:"Edited by",editors:[{id:"67634",title:"Dr.",name:"Hiran",surname:"Amarasekera",slug:"hiran-amarasekera",fullName:"Hiran Amarasekera"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6755",title:"Recent Advances in Arthroscopic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"5c122c5b88bdc03c130d34ad2ac2d722",slug:"recent-advances-in-arthroscopic-surgery",bookSignature:"Hiran Wimal Amarasekera",coverURL:"https://cdn.intechopen.com/books/images_new/6755.jpg",editedByType:"Edited by",editors:[{id:"67634",title:"Dr.",name:"Hiran",surname:"Amarasekera",slug:"hiran-amarasekera",fullName:"Hiran Amarasekera"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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These characteristics could be achieved by using chitosan to prepare carriers of drugs. It is almost the only cationic polysaccharide in nature with a great innate medical potential. Chitosan, a cationic polymer of natural origin, is a remarkable example of an excipient which currently has enormous potential for using in pharmaceutical dosage forms because of its properties as polyelectrolyte with reactive functional groups, gel-forming capability, high adsorption capacity, biodegradability and biocompatible and non-toxic to living tissues as well as having antibacterial, antifungal and antitumor activity. These functional properties provide suitability and extensive pharmaceutical applications such as for the preparation of drug delivery systems (drug conjugate, micro/nanoparticles, hydrogels, emulsions, biodegradable release system, etc.) and for regenerative medicine for many components such as proteins/peptides, growth factors, anti-inflammatory drugs, antibiotics intended to be administered in non parenteral routes (oral, topical, intranasal, vaginal, rectal and ocular). Interesting applications of chitosan has been receiving considerable attention since it has been developed systems more versatile by the incorporation of chitosan and other components in novel systems. They have provided a strategy for the functionalization by modulating physicochemical properties (hydrophilicity, surface charge, etc.) improving the encapsulation, stability, and protection of drugs. The recent development of nanotechnology and the various processes of funcionalization of chitosan have increased and improved its functionality as drug carrier.
This work reviews the drug carrier systems using chitosan to improve and increase the delivery of drugs for non parenteral routes. The most important properties of chitosan, the types of systems intended to be used for non parenteral routes, the strategies for the functionalization of chitosan systems by the incorporation of other components, advantages and limitations, and the relevance of pharmaceutical, pharmacological and toxicological experimental studies are reviewed in different drug carrier systems from chitosan.
Chitosan is an abundant polysaccharide, it has the peculiarity of being the unique cationic biopolymer of natural origin [1, 2]. It is obtained from the chitin, the most second abundant polysaccharide in the nature [3, 4]. The wide variety of natural sources of chitosan include: structural components of the cell walls of certain fungi, algae and bacteria species, and in the egg shells of nematodes. Nevertheless, the principal source is the shells of mollusks and the exoskeleton of the phylum
The chemical structure of chitosan is ideally formed only by 2-amino-2-deoxy-β-D-glucopyranose, the deacetylated form of D-glucosamine, and chitin is ideally formed only by 2-acetamido-2-deoxy-β-D-glucopyranose, which is the acetylated form of D-glucosamine. However, the real found structure of chitosan, as well as the one of chitin, is a copolymer of 2-amino-2-deoxy-β-D-glucopyranose and 2-acetamido-2-deoxy-β-D-glucopyranose, in which both the deacetylated and the acetylated forms of D-glucosamine are randomly distributed along the whole copolymer chain. This is the reason why chitosan comprises a wide group of fully and partially deacetylated chitins. The two kind of D-glucosamine residues are linked by β(1→4)-glycosidic bonds. It is accepted chitosan is composed predominantly of the deacetylated form of D-glucosamine [1, 2, 4, 6, 7, 11-13]. The Figure 1 represents the chemical structure of chitin and chitosan.
Commercial chitosans have a deacetylation degree of 85%, and its elemental composition is 44. 11 % of carbon, 7. 97 % of nitrogen, and 6. 84 % hydrogen [6]. When chitosan is obtained using an alkaline process, the degree of deacetylation can be controlled if the time, temperature and the concentration of alkali and chitin are also controlled. In addition to these processing factors, the degree of acetylation, the distribution of acetyl groups along the biopolymer chain, and the molecular size distribution of chitosans change depending of the source of chitosan. All these factors determine chitosan physicochemical and biological properties [13, 14].
Chitosan is distinguished by its solubility in dilute aqueous acid solutions derived from its polycationic character [9] and its insolubility in most solvents. In function of deacetylation degree, a chitosan polymer becomes soluble in dilute acidic medium; the minimum deacetylation level for solubilizing is 40-60%. The solubility of the polymer, the inter-chain interactions due to hydrogen bonds and the hydrophobic character of the acetyl group are affected by the distribution of N-acetyl groups along the biopolymer chain [13]. The solubility of chitosan is also affected by the formation of crystalline structures as a result of intra- and inter-macromolecular hydrogen bonds in the solid state; crystalline domains appear to be the main factor limiting for chitosan aqueous solubility [15]. Between acidic and neutral pH conditions, chitosan develops positive net charges because of its polycationic nature [9, 13]. Chitosan is positively charged due to primary amino groups, the magnitude of the charge density is dependent on the degree of deacetylation, pH, and ionic strength [9]. In weakly acidic aqueous solutions of inorganic acids (phosphoric and sulfuric acids) and organic acids (formic, acetic, tartaric, and citric acids), amino groups are partially protonated, while a total protonation is reached at pH 4. 0 [15]. Another chemical characteristic of chitosan is its metal binding capacity attributed to its chelating ability of the amine groups [5]. Table 1 shows some intrinsic (structural characteristics of chitosan) and extrinsic parameters that affect some functionality parameters [16-18].
Chemical structures of chitin and chitosan and their monomers: a) 2-acetamido-2-deoxy-β-D-glucopyranose or β-D-GlcNAc and b) 2-amino-2-deoxy-β-D-glucopyranose or β-D-GlcN.
Physical properties of chitosan depend of factors as the molecular weight distribution, the acetylation degree and the source of chitosan. In Table 2 are listed some physical properties of reported in scientific literature and commercial chitosans from different sources [19-22]. The solution conformation of chitosan can occur as rod-like, spherical or random coil conformations in function of the molecular weight distribution and degree of acetylation; the molecular mass affects the intrinsic viscosity and radius of gyration [23] while the degree of acetylation determines in turn the electric charge which is directly related to the solution conformation of chitosan [20]. When the charge on the chitosan chain increases, its conformation in solution expands and the viscosity increases substantially [24].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t•Molecular weight •Deacetylation degree •Presence of contraions •pH •Solvent | \n\t\t\t•Viscosity of the chitosan solutions is affected by the presence of the amino groups with a pKa value of 6. 3 (as a strong base its polielectrolyte nature affects the hydrodynamic ratio in solution) [16]. | \n\t\t
\n\t\t\t\t | \n\t\t\t•Molecular weight •Deacetylation degree •Chitosan concentration •Presence of contraions •pH •Temperature | \n\t\t\t•At pH above 7 and at low temperatures (≈25ºC) the hydrogels are greatly swollen [17]. •Hydrogels are more compact and irregular when the deacetylation degree (D.D.) of chitosan is increased [18]. | \n\t\t
\n\t\t\t\t | \n\t\t\t•Molecular weight •Deacetylation degree | \n\t\t\t•Lower molecular weights leads to a faster biodegradation rates than higher molecular weights. •Deacetylation degree is determinant, increasing the presence of charged moieties leads to faster degradation rates. | \n\t\t
\n\t\t\t\t | \n\t\t\t•Acid concentration •Ionic strength •Deacetylation degree | \n\t\t\t•Chitosan is soluble at a higher concentration of hydrogen ions (below at a pH of 6) [16]. | \n\t\t
Correlation of intrinsic properties and extrinsic factors that affect its functionality and structural conformation
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tWhite | \n\t\t\t\n\t\t\t | White | \n\t\t\tWhite to beige | \n\t\t
\n\t\t\t\t | \n\t\t\tPowder | \n\t\t\t\n\t\t\t | Powder | \n\t\t\tPowder/chips | \n\t\t
\n\t\t\t\t | \n\t\t\t0. 245 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t6. 96 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t83. 1 | \n\t\t\t89 | \n\t\t\t73 | \n\t\t\t>75 | \n\t\t
\n\t\t\t\t | \n\t\t\t347 mPa. s | \n\t\t\t540 ml/g [η] | \n\t\t\t563. 7 cP | \n\t\t\t\n\t\t |
\n\t\t\t\t | \n\t\t\t\n\t\t\t | 1. 72 | \n\t\t\t0. 23 (tapped) | \n\t\t\t0. 15-0. 3 | \n\t\t
\n\t\t\t\t | \n\t\t\t[19] | \n\t\t\t[15] | \n\t\t\t[21] | \n\t\t\t[22] | \n\t\t
Some physical properties of reported in scientific literature and commercial chitosans
Rheological properties of chitosan solutions are independent of the ionic strength and the pH, this behavior can be related to the fact that the ionic strength within certain range does not affect the conformation in solution [23, 25]. In organic acid solutions as acetic acid ones, the viscosity curves for chitosan solutions consist of two distinct viscosimetric behaviors, the first one is a Newtonian zero-shear viscosity region and second one is a shear rate dependent apparent viscosity region. An increase in chitosan concentration produces a pseudoplastic behavior, i. e., a higher shear rate dependence of viscosity [9] while at a lower concentration exhibits a shear thinning behavior [25]. The pseudoplastic behavior is explained because as the polymer concentration increased, the freedom of movement of the individual chains becomes more restricted due to the correspondingly increased number of entanglements between chitosan chains [9]. Table 3 shows viscosities of various chitosan samples [21, 26-29]. Because chitosan undergoes acid-catalyzed hydrolysis, chitosan presents an irreversible decrease in viscosity in dilute acid medium [28], the degree of hydrolysis depends on the molecular weight and degree of acetylation: the higher the values of both parameters, the quicker decrease in the viscosity and, consequently, in the viscosity-average molecular weight [29].
Due to its degradation in acidic media, chitosan dissolved quickly after swollen in gastric juice and could not achieve sustained release in the gastrointestinal tract [30]. In order to obtain chitosan derivatives with new functionality and to extend its uses in a greater number of pharmaceutical applications, chitosan has been subjected to various chemical modifications. The chitosan structure has been modified through trimethylation, N-succinylation, thiolation, azidation, sugar-modified chitosan, chitosan-dendrimer hybrids, cyclodextrin-linked chitosans, crown-ether-bound chitosan, chemical grafting of chitosan, enzymatic modification of chitosan. These reactions yield chitosan-based derivatives that retain the biodegradability and non-toxicity characteristic of chitosan [1].
Chitosan is able to form physical gels, these gels retain the main properties of this polysaccharide, in particular, biocompatibility. The process of gel formation depends on the initial concentration of the polymer and charge density, which is determined by the degree of deacetylation [31]. The degree of hydration of chitosan hydrogels are affected by the molecular weight of chitosan [32]. Chitosan hydrogels have been investigated as potential vehicles for targeted drug delivery [15] specially seems to be suitable for sustained-release drug [32, 33].
Polycationic character of chitosan opens the possibility for interactions with negatively charged molecules (anions and polyanions) [34] and allows the forming of polyanion-chitosan complexes with polyanions such as heparin, carboxymethylcellulose, carrageenan, alginate, Pluronic, dextran sulfate, and xanthan have been produced [35-51]. The complexes formed by chitosan with other polymers can be divided into hydrogen bonding complexes, polyelectrolytes complexes, coordination complexes and self-assembly complexes based on dominant intermolecular interactions [52]. Some chitosan-based non-stoichiometric polyelectrolyte complexes are soluble at physiological pH and ionic strength [53], because polyelectrolyte complexes are formed in aqueous solutions, it should be taken into account molecular information as the molecular weight of chitosan, its mass distribution, the degree of deacetylation, the location of free and acetylated amino groups in the polymer chain, chain length, and conformation of molecules in solution [34]. The synthesis mechanism of chitosan-polyanions complexes can be the result of changing the chemical structure of component polymers, such as molecular weight, flexibility, functional group structure, charge density, stereoregularity, and compatibility, as well as synthesis conditions: pH, ionic strength, concentration, mixing ratio, and temperature [30].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Oxidative fragmentation (1% NaNO2) of chitosan | \n\t\t\t91. 3 | \n\t\t\t659. 4 | \n\t\t\t1. 05 dL/g (intrinsic, in 0. 25 mM acetate buffer, 0. 05-0. 3 g/dl of chitosan, 25°C) | \n\t\t\t[26] | \n\t\t
Oxidative fragmentation (4% NaNO2) of chitosan | \n\t\t\t90. 19 | \n\t\t\t864. 2 | \n\t\t\t0. 21 dL/g (intrinsic, in 0. 25 mM acetate buffer, 0. 05-0. 3 g/dl of chitosan, 25°C) | \n\t\t\t[26] | \n\t\t
1% NaOH, 21 hr, 4% HCl, 2 hr | \n\t\t\t75. 9 | \n\t\t\tNot determined | \n\t\t\t830 cP (1% acetic acid, 1% chitosan) | \n\t\t\t[27] | \n\t\t
4% HCl, 2 hr, 1% NaOH, 21 hr | \n\t\t\t76. 3 | \n\t\t\tNot determined | \n\t\t\t2919 cP (1% acetic acid, 1% chitosan) | \n\t\t\t[27] | \n\t\t
Demineralization 1N HCl, 30 min, room temperature after decolorization 0. 315% NaOCl, 5min, room temperature | \n\t\t\t73 | \n\t\t\t10. 59 | \n\t\t\t563. 7cP(1% acetic acid, 1% chitosan, 25°C) | \n\t\t\t[21] | \n\t\t
Deproteinization 3. 5%NaOH, 2hr, 65°C after decolorization 0. 315% NaOCl, 5min, room temperature | \n\t\t\t70 | \n\t\t\t9. 63 | \n\t\t\t444. 9 cP1% (1% acetic acid, 1% chitosan, 25°C) | \n\t\t\t[21] | \n\t\t
Viscosity of chitosan related to deacetylation degree (D. D. ), molecular weight (M. W. ) of chitosans produced by different methods.
In addition to the electrical charge, dipole-dipole interactions, as well as hydrogen and hydrophobic bonds are determinant for the formation of complexes with polyanions [34]. As a matrix for releasing drugs, chitosan complexes must allow the controlled release either modulating tissue drug levels or spatially-placing (or temporarily-placing) a drug in some region of the body to maintain efficacy and stability of drugs within the matrix. For drug delivery systems for gastrointestinal, respiratory, ophthalmologic, cervical, and vaginal routes, the mucins are hydrophilic saline gels that are thickened by natural anionic glycoproteins. Here, a cationic polymer as chitosan is ideal [52].
Chitosan has excellent properties such as hydrophilicity, biocompatibility, biodegradability, antibacterial and adsorption applications, and a very low toxicity [54-57]. The biocompatibility of chitosan is generally regarded as the ability of the newly developed material to interact with living cells, tissues, or organs by not being toxic or injurious and not triggering immunological reactions or rejections while functioning appropriately in vitro and in vivo [57]. Accordingly the features mentioned above, besides the chitosan being used for drug delivery, is used in tissue engineering, gene delivery, nasal drug and vaccine delivery [58]. The formulation of chitosan with a drug may alter the pharmacokinetic and biodistribution profiles, and for pharmaceutical applications it is necessary to take in account the route of administration, its concentration, contact time and cell types that enter in contact with chitosan or chitosan complexes [58-63]. In Table 4 are listed some biological and toxicological properties of chitosan in several biological systems [64-75].
Due to its good biocompatibility and biodegradability properties, chitosan provides a useful excipient for mucoadhesive drug delivery systems in order to prolong the mucosal residence time. An inconvenient issue about chitosan, it is that glucosamine from shellfish may not be suitable for allergic people to shellfishes [10]. Although chitosan has not yet been related directly to cases of allergic reactions, some cosmetics or nutraceuticals products prepared with chitosan are related to skin irritation or even anaphylaxis [21, 76, 77]. It is possible that proteins from shellfish such as tropomyosin and arginine kinase remain as residues on the chitosan and chitin, being these substances responsible for such allergic reactions [78]. As a result of this review, no allergenic reactions produced to nasal membranes have been found reported. Arai et al. found that chitosan has an LD50 comparable to sucrose of >16 g/kg in oral administration to mice [79]. No oral toxicity was found in mice treated with 100 mg/kg chitosan nanoparticles (80 kDa, 80% DD) [80]. Exposure of rat nasal mucosa to chitosan solutions at 0. 5% (w/v) over 1 h caused no significant changes in mucosal cell morphology compared to control [81]. From most studies reported it appears that chitosan shows minimal toxic effects and this approves its adoption as a safe material in drug delivery. Others authors studied the safety of a chitosan bandage in shellfish allergic patients (shellfish allergy prevalence of 2. 8% in adults) showing that all subjects tolerated the bandage without reaction. Although larger cohort studies should be considered, the results from this study are encouraging and consistent with two previous studies demonstrating the safety of other chitin-derived products in patients allergic to shellfish [82].
\n\t\t\t | \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t||||
Antitumor activity against HepG2, A549, and PC3 model tumor cell | \n\t\t\t100 87. 5 | \n\t\t\tPentamers Octamers | \n\t\t\tIC50 < 50 μg·mL−1 \n\t\t\t | \n\t\t\t[64] | \n\t\t
Prevent leakage and bleeding from lung punctures | \n\t\t\t99 98 | \n\t\t\t230 kDa 300 kDa | \n\t\t\t2. 3% (w/v) 2. 3% (w/v) | \n\t\t\t[65] | \n\t\t
Reduction of 25-30% in plasmatic cholesterol in rats | \n\t\t\t\n\t\t\t | \n\t\t\t | 5% of the diet | \n\t\t\t[66] | \n\t\t
Decreasing of fat digestibility, mineral absorption and vitamin E level in rats fed with high-fat diets | \n\t\t\t90 | \n\t\t\tNot specified | \n\t\t\t50g/100g of solids | \n\t\t\t[67] | \n\t\t
Prevention the symptoms of isoprenaline-induced myocardial infarction in rats | \n\t\t\t85-87 | \n\t\t\t750kDa | \n\t\t\t2% of the diet for 60 days | \n\t\t\t[68] | \n\t\t
Reduction of body weight and plasma triacylglycerol concentration in mice | \n\t\t\tNot specified | \n\t\t\t46 kDa | \n\t\t\t300 mg/Kg daily administrated | \n\t\t\t[69] | \n\t\t
\n\t\t\t\t | \n\t\t||||
Against E. coli | \n\t\t\t20% 11% | \n\t\t\t55, 155 5, 300 | \n\t\t\t50-100 ppm 2500-10000 ppm | \n\t\t\t[70, 71] | \n\t\t
Against L. monocytogenes | \n\t\t\t10 (56 kDa) | \n\t\t\t5, 150 | \n\t\t\t1000 ppm | \n\t\t\t[72] | \n\t\t
Against S. typhimurium | \n\t\t\t15-25% (150 kDa) | \n\t\t\t5, 150 | \n\t\t\t1000 ppm | \n\t\t\t[72] | \n\t\t
Maximum inhibition of absorption of Streptococcus sobrinus by hydroxyapatite (anti-plaque activity) | \n\t\t\t50-60% | \n\t\t\t5-6 | \n\t\t\t250 ppm | \n\t\t\t[73] | \n\t\t
\n\t\t\t\t | \n\t\t||||
Aspartic acid salt of chitosan in B16F10 cells | \n\t\t\t78% | \n\t\t\t<50 | \n\t\t\t(IC50)2. 50 mg/mL | \n\t\t\t[74] | \n\t\t
Aspartic acid salt of chitosan in Caco-2 cells | \n\t\t\t87% | \n\t\t\t20, 45, 200, 460 | \n\t\t\t(IC50)670, 650, 720 mg/mL | \n\t\t\t[75] | \n\t\t
Some biological and toxicological properties of chitosan related to deacetylation degree (D. D. ), molecular weight (M. W. ) and its concentration in several biological systems.
An important aspect in the use of polymers as drug delivery systems is their metabolic fate in the body or biodegradation [54]. Degradation of chitosan by thermal, acidic, enzymatic, and irradiation process have been reported [28, 29, 60-63, 83- 85]. In general, both rate and extent of chitosan biodegradability in living organisms are dependent on the degree of deacetylation [54]. Enzymatic degradation of chitosan is sensitive to the supermolecular structure of the polymer [83], in human body lisozyme produces the hydrolysis of chitosan [86]. Aminosugars released as a result of its biodegradation can be used in the metabolic pathways of glycosaminoglycans and glycoproteins in the body [87, 88]. In the stomach, some chemical degradation is wide catalysed by gastric acid [54], but it is not hydrolyzed by human digestive enzymes [69], its lack of absorption in the human body provides chitosan a function as dietary fiber [56]. In the case of the systemic absorption of hydrophilic polymers such as chitosan, they should have a suitable Mw for renal clearance [54].
The administration of chitosan in humans has been extensively studied (Table 5) [89-94]. The chitosan exhibits a hypocholesterolemic effect, the administration of chitosan, regardless of their molecular weight, coupled with ascorbic acid, produce a decreased fat absorption. When chitosan enters in contact with gastric fluids, forms a gel that traps lipids preventing their absorption in the intestine. Sodium ascorbate enhances the gelling and flexibility of chitosan, increasing the amount of fat that is stuck [95]. By blocking the absorption of fat is inhibited the atherosclerotic plaque formation, reducing the risk of atherosclerosis in hypercholesterolemic persons [88], besides that no deterioration occurs in the intestinal mucosa causing anti-hypercholesterolemiants as cholestyramine [96].
Fat absorption depends on the degree of deacetylation and the viscosity of chitosan. The greater degree of deacetylation and a high viscosity of the chitosan cause a higher absorption of dietary fat [66]. Chitosan also reduces cholesterol, urea and creatinine, and increases of hemoglobin levels, which may be used as coadyuvate in the treatment of patients with kidney failure [89]. Chitosan can cause wound healing and fibrosis decreasing mortality genitourinary surgery, and produce a hemostatic effect, which is attributed to the interaction between the cell membrane of the erythrocytes and chitosan, being this interaction independent of the classical cascade of coagulation [97].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t45 mg/tablet per 12 weeks | \n\t\t\tReduction of urea, cholesterol, creatinine levels in serum. | \n\t\t\t[89] | \n\t\t
\n\t\t\t\t | \n\t\t\tFour tablets, 400 mg/tablet, per day with low calorie diet for 4 weeks | \n\t\t\tVariable adverse effects in 5% of treated subjects | \n\t\t\t[90] | \n\t\t
\n\t\t\t\t | \n\t\t\t0, 4. 5, 6. 75 g of chitosan per day for eight weeks, no dietary restrictions | \n\t\t\tNo effect on serum content of vitamins A, E, D, alpha carotene, beta carotene. Modest reduction in plasma cholesterol concentrations | \n\t\t\t[91] | \n\t\t
\n\t\t\t\t | \n\t\t\tLocal percutaneous Ho-166/chitosan complex injections | \n\t\t\tComplete tumor necrosis in 77. 5% of treated patients | \n\t\t\t[92] | \n\t\t
\n\t\t\t\t | \n\t\t\t5 g of chitosan | \n\t\t\tPrevention of blood pressure after a high in salt meal | \n\t\t\t[93] | \n\t\t
\n\t\t\t\t | \n\t\t\t1. 2 g of chitosan per day, no dietary restrictions | \n\t\t\tMild reduction in total and LDL cholesterol, few adverse effects observed | \n\t\t\t[94] | \n\t\t
Effects of chitosan and complexes containing chitosan administrated on humans with different health problems.
Biodegradation of chitosan and chitin implies the cleaving of the β(1→4)-glycosidic bond between the two kind of D-glucosamine residues that form its chemical structure. Biodegradation of chitosan has been assessed by enzymatic methods using enzymes from different sources. The lysozyme (EC 3. 2. 1. 17) is an enzyme which degrades chitosan and chitosan-conjugates by cleaving the β(1→4) bonds between N-acetyl-D-glucosamine residues; lysozyme also degrades β(1→4)-glycosidic bonds between the N-acetylmuramic acid and N-acetyl-D-glucosamine residues in peptidoglucan [98]. Lysozyme exists in various human body fluids and tissues with concentrations from 4 to 13 mg/L in serum and from 450 to 1230 mg/L in human tears [99]. The rate of biodegradation of chitosan by the lysozyme is affected by the degree of deacetylation; initial degradation rates increase with a decreasing degree of deacetylation.
Some chitosan derivatives exhibit a faster degradation rate than chitosan, for example with the increasing of the molar ratio of glycolic acid to chitosan of poly(glycolic acid) grafted chitosan the rate of degradation gradually increased [100].
Chitin polyphorms exhibit different rates of degradation. Lysozyme degrades β-chitin more readily than α-chitin due to the weak intermolecular forces of the latter. In β-chitin the degree of deacetylation is decisive for the degradation behavior of chitin [101].
Chitinases are enzymes present in fungi, insects, and bacteria, these enymes degrades chitin to olygosaccharides. In general, microbial endo-chitinases hydrolyze β(1→4)-glycosidic bonds randomly. Chitinases isolated from different organisms have widely different characteristics. In human the presence of chitinases is associated to allergic reactions. Human chitinases with enzymatic activity have been identified, but they have not been investigated with regards to the degradation of chitosan and/or its derivatives [52].
Biodistribution, in vivo and in vitro toxicity using various chitosans of different molecular weights and degrees of deacetylation and derivatives would provide data that could help correlate chitosan\'s structure and safety profile [48]. Some derivatives increase in toxicity and any residual reactants must be carefully removed [49]. In laboratory mice, the LD50 of chitosan is similar to that of salt or sugar (16 g/kg of body weight) [50].
A considerable amount of work has been published on chitosan and its potential use in drug delivery systems. In recent years considerable research has been focused on noninvasive routes, such as mucosal (oral, buccal, nasal, pulmonary and vaginal) and (trans)dermal. Chitosan has a cationic character because of its primary amino groups. These primary amino groups are responsible for properties such as controlled drug release, mucoadhesion, in situ gellation, transfection, permeation enhancement, and efflux pump inhibitory properties.
The mucoadhesive properties are also based on its cationic character. The mucus gel layer exhibits anionic substructures in the form of sialic acid and sulfonic acid substructures. Based on ionic interactions between the cationic primary amino groups of chitosan and these anionic substructures of the mucus, mucoadhesion can be achieved. In addition, hydrophobic interactions might contribute to its mucoadhesive properties. Moreover, several studies have shown the effects of chitosan systems for the drug delivery. The molecule has been widely used in a variety of pharmaceutical multipurpose excipients capable of increasing aqueous solubility and drug stability [102].
Owing to nasal obstacles such as low membrane permeability, a short local residence time, and high turnover rate of a secretion in nasal cavities, the bioavailability of nasally administered drugs is often comparatively poor [103]. In order to overcome those problems, chitosan particles or polyelectrolyte complexes have been studied for nasal delivery of therapeutic proteins [104-106]. It was found that insulin loaded chitosan nanoparticles enhance nasal drug absorption to a greater extent than relevant chitosan solutions.
Chitosan has been also used recently via intranasal in many studies particulary in vaccines as a potent mucosal adjuvant. In a study, the matrix protein 1, which is highly conserved in all influenza A strains, was purified and used for immunization (twice at an interval of 3 weeks) of BALB/c mice by intranasal drip using chitosan as adjuvant to test the efficacy as vaccine. The results showed that nasal administration of 100 μg of the matrix protein 1 in combination with chitosan could not only completely protect the mice effectively against the homologous virus (H9N2) but also protect 70% and 30% of the mice against the heterologous H1N1 and H5N1 viruses, respectively, indicating that the matrix protein 1 is a candidate antigen for a broad-spectrum influenza virus vaccine and the adjuvant chitosan significantly improved the efficacy of the vaccine. This vaccine could provide effective protection against unknown influenza virus infection in future [107].
Microparticles (with suitable range for vaccine delivery) and gels using chitosans with different molecular weight and solubility as adjuvant/delivery system for mucosal (nasal) immunization against bovine herpes virus 1(BHV-1) showed that when the virus was incorporated into microparticles, the particle size was increased (p < 0. 05). Narrower particle size distribution was obtained with water soluble chitosan compared to that of base chitosan particles at different molecular weights (p < 0. 05). This difference can be attributed to difference in solubility of chitosans [108]. Similar results were reported in other studies [109-112]. With blank microparticles prepared with base chitosan at different molecular weights, the surface appearance and morphology were observed to be similar (with a smooth surface and spheroids). When the particles were loaded with the antigen; the surface appearance of the microparticles was changed with the increasing molecular weight of chitosan (Figure 2). These results suggest that antigen is entrapped within the microparticles, as well as associated with the surface of the microparticles [108]. Similarly, increased particle size and surface roughness with antigen loading has been reported by other groups [113, 114]. These systems are promising adjuvant/delivery systems for non-invasive delivery of antigen tested as well as for other antigens.
Moreover, the nasal administration of vaccines can induce specific IgA antibody responses at distant mucosal sites, including the upper and lower airway mucosa and the small and large intestines, as well as the nasopharynx, salivary glands, genital tract, and tonsils, because of the dissemination of antigen-specific lymphocytes in the common mucosal immune system (immunocompetent cells in the body, such as M-cells, T-cell, B-cell, dendritic cells, and macrophages) [114-116].
Chitosan-based formulations have been used for the delivery of drugs to specific sites of the body such as oral cavity, stomach, small intestine and colon. The site-specific delivery of the drug to the oral cavity can be used to treat a number of diseases of the mouth, such as stomatitis, periodontal disease, fungal and viral infections, and oral cavity cancers, thereby avoiding the first pass metabolism effect. In this sense, some points should be considerate for buccal administration of drugs, such as maintain the device in its position for many hours against buccal motion and salivary flow, which could reduce the mucosal absorption. Consequently, the dosage form must have good adhesive properties and show an efficient control of drug delivery. Investigations have shown in several studies that drug release is influenced by swelling and erosion of the matrix, whereas matrix adhesiveness can be modulated using different mixtures of polymers, both adhesive and not. Here, investigations have reported that the chitosan has good mucoadhesiveness and a significant enhancing effect on the permeation of drugs across the buccal mucosa [117, 118]. The applications using chitosan include chlorhexidine loaded chitosan microparticles, which showed a determination effective of antibacterial activity of chitosan from thermosensitive hydrogel (with or without drugs) or as activator for the antibacterial process [119]. Chitosan microspheres based drug delivery is applicable for systemic as well as for local therapy. In case of oral drug delivery, the use of microspheres loaded with antibiotics would be beneficial for gastric diseases such as peptic ulcer [21],
With respect to the colon drug delivery, some microcrystalline cellulose core beads containing 5-aminosalicylic acid produced by extrusion-spheronization were coated with chitosan and Aquacoat® ECD mixtures. An adequated selection of the coating thickness and the chitosan level in the coat could minimize drug release in simulated intestinal fluid and provide zero order release. These products could also be used to achieve controlled release of drugs in the small intestine. Beads coated with chitosan/ Aquacoat® showed to be susceptible to the action of rat cecal and colonic enzymes and demonstrated their potential for colon specific drug delivery [120].
Various ophthalmic vehicles, such as inserts, ointment, suspensions, and aqueous gels, have been developed in order to lengthen the resident time of instilled dose and enhance the ophthalmic bioavailability. Chitosan based systems have the potential for improving the retention and biodistribution of drugs applied topically onto the eye. One of the pharmaceutical forms most investigated are the
SEM micrographs of blank (A) and BHV-1 loaded microparticles (B) prepared with water soluble chitosan; chitosan base-low molecular weight (50-1000 kDa): blank (C), BHV-1 loaded microparticles (D); chitosan base-medium molecular weight (300-2000 kDa): blank (E), BHV-1 loaded microparticles (F); chitosan base-high molecular weight (500-5000): blank (G), and BHV-1 loaded microparticles (H). This figure is reproduced with the permission [
Another interesting study reported chitosan microparticles to be administered via ophthalmic. The
Transdermal drug delivery systems can deliver drugs for systemic effects through skin at controlled rate (can be interrupted if it necessary), with the advantage of avoiding the first pass metabolism effect [130-134]. An example of this could be obtained with the lidocaine hydrochloride-loaded transdermal chitosan patches as a drug reservoir, which released the drug in a manner prolonged at 95% chitosan degree of deacetylation [135].
In a recent study, warfarin-β-cyclodextrin loaded chitosan nanoparticles for transdermal delivery were successfully prepared by ionic gelation method. Chitosan nanoparticles were found to be spherical, smooth and with narrow size distribution. They showed high drug entrapment efficiency and well accepted yield. The release profile from nanoparticles showed an initial burst effect followed by a slow and continuous release phase. The nanoparticle formulation enhanced the permeation of warfarin through excised rat skin in a constant and continuous profile. Therefore, it could be concluded that this formulation enhanced the controlled release and the permeation of warfarin, offering a promising system for the transdermal delivery [136].
In order to regenerate some loss or damaged tissue and organ,
Chitosan is a non-toxic, biocompatible and biodegradable polymer and has attracted considerable interest in a wide range of biomedical and pharmaceutical applications including drug delivery, cosmetics, and tissue engineering. The primary hydroxyl and amine groups located on the backbone of chitosan are responsible for the reactivity of the polymer and also act as sites for chemical modification. However, chitosan has certain limitations for use in controlled drug delivery and tissue engineering. These limitations can be overcome by chemical modification. In order to achieve high mucoadhesive properties, this polymer needs to exhibit also high cohesive properties as the adhesive bond otherwise fails within the mucoadhesive polymer rather than between the mucus gel layer and the polymer. In case of chitosans, however, these cohesive properties are also comparatively weak. Although they can be strongly improved by the formation of complexes with multivalent anionic drugs, multivalent anionic polymeric excipients, and multivalent inorganic anions, this strategy is only to a quite limited extent effective, as the cationic substructures of chitosan being responsible for mucoadhesion via ionic interactions with the mucus are in this way blocked. The combination of chitosan with other materials appears to be a common theme in various reports. Blending with other polymers is widely investigated. Blends with synthetic and natural polymers can imbibe the wide range of physicochemical properties and processing techniques of synthetic polymers as well as the biocompatibility and biological interactions of natural polymers.
A significantly improved oral bioavailability of buserelin was demonstrated with mucoadhesive polymers such as chitosan and carbomer to rats. This effect, however, could not be observed anymore when chitosan was combined with the polyanionic carbomer in the same formulation [141]. Trimethylation of the primary amino group of chitosan provides an even more cationic character of the polymer. When trimethylated chitosan is additionally PEGylated, its mucoadhesive properties are even up to 3. 4-fold improved [142]. Due to the immobilization of thiol groups on chitosan, its mucoadhesive properties can also be strongly improved, as the thiolated polymer is capable of forming disulfide bonds with mucus glycoproteins of the mucus gel layer, placing it among the most mucoadhesive polymers known so far [143]. In addition, as inter- and intrachain disulfide bonds are also formed within chitosan itself, thiolated chitosan exhibits substantially improved cohesive properties. Recently, the mucoadhesive properties of thiolated chitosans were even significantly further improved by the preactivation of thiol groups on chitosan via the formation of disulfide bonds with mercaptonicotinamide.
Chitosan, the second most abundant polysaccharide next to cellulose, has been adopted as having great potential application as a protein drug carrier for oral administration due to its outstanding properties of non-toxicity, biocompatibility, biodegradability and low cost [144, 145]. Oral administration of drugs represents the easiest and the most convenient route of drug delivery. Therefore, the enhancement of oral bioavailability of some drugs particularly those with poor aqueous solubility, is gaining increasing attention for successful development of oral treatment. Chitosan based hydrogel systems can be designed to deliver drugs locally to the stomach or the upper part of tract to improve bioavailability. It was tested by confocal laser scanning microscopy that amoxicillin loaded pH-sensitive hydrogels composed of chitosan and poly(g-glutamic acid) could be infiltrated in the cell–cell junctions and interact with
Another investigation reported that the oral bioavailability of acyclovir could be improved 3-fold and 4-fold due to the incorporation of this drug in chitosan and thiolated chitosan, respectively. Within this study, a prolonged residence time in particular of thiolated chitosan microparticles in duodenal and jejunum regions was observed. These data need to be confirmed in human volunteers. So far, an improved oral bioavailability of various model drugs could be shown in human volunteers for mucoadhesive formulations likely because of an intimate contact of the delivery system with the absorption membrane and a prolonged mucosal residence time of the delivery systems [148].
Several systems have been proposed to encapsulate insulin to improve oral insulin bioavailability, including polymeric hydrogels polymeric solid nano-particles and liposome-based carriers [149-153]. However, limitations related to the enzymatic degradation in the gastrointestinal tract and the low permeability across the intestinal epithelium are common problems in those systems [154, 155].
Contrarily, it was reported that insulin analog can be successfully encapsulated in chitosan microspheres with a high loading content. The quaternized groups on N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) can protect the insulin analog from the cross-linking reaction and maintain its activity. The positive charged chitosan microspheres also showed improved bioadhesion to the intestinal tract due to a strong interaction with the mucus. Evaluation using an in vivo diabetic model showed an optimal reduction in blood glucose level and compelling therapeutic effects after treatment with insulin analog loaded chitosan microspheres, which further confirmed the feasibility of using quaternized chitosan microspheres as insulin carriers for oral administration [156].
In case of oral drug delivery, the use of microspheres loaded with antibiotics would be beneficial for several diseases [157]. A particular problem related to a low molecular weight compound like ampicillin is the high permeability of the chitosan microbead matrix material. In order to overcome these restrictions, chitosan gel beads and microspheres are generally crosslinked chemically using glutaraldehyde or ethylene glycol diglycidyl ether [157]. However, residual glutaraldehyde and ethylene glycol diglycidyl ether in the chitosan microspheres give rise to health concerns and can cause undesirable effects including irritation to mucosal membranes. To solve these disadvantages of chemical crosslinking, researchers have proposed to apply chitosan microspheres reacetylated with acetic anhydride. The re-acetylated chitosan microspheres were able to interact closely with the gastric mucosa and to exhibit sustained delivery of entrapped antibiotic [158].
The factors affecting drug encapsulation efficiency, particle size, surface charge, surface hydrophilicity, pharmacokinetics and biodistribution were studied in clozapine-loaded nanoparticles coated with chitosan, pluronic F-68, polyethylene glycol (PEG) 4000 and polysorbate 80. The results proved that although a similarity in surface hydrophilicity, chitosan-stealth nanoparticles showed different pharmacokinetic profile and biodistribution behavior compared to polysorbate-stealth nanoparticles [159]. A great improvement in surface hydrophilicity was brought by chitosan and polysorbate 80 coatings. However, the in vivo particle uptake by the reticuloendothelial system was less pronounced with positively charged chitosan-stealth nanoparticles than with polysorbate 80. In another study, the thermal amide conjugation of COO− group of EDTA with NH2 group of chitosan was employed to prepare microparticles, which showed higher amphotericin B loading capacity, enhancement in the in vitro dissolution performance 12-fold and a nanoemulsion was produced in the size range of 70–90 nm [160]. On the other hand, microparticles were prepared entrapping ovalbumin as a model antigen following oral vaccination. In another investigation, methylated N-(4-N, N-dimethylaminocinnamyl) chitosan was used to coat microparticles, which demonstrated a greater swelling, mucoadhesive properties and a more sustained release than uncoated microparticles. Thus, this formulation represent a useful carrier to improve the immunogenicity of oral vaccines [161].
Galactosylated trimethyl chitosan-cysteine nanoparticles were developed for oral delivery of a
The buccal route is an alternative choice to deliver drugs to the application site. In addition, this route shows high acceptance by patients. An ideal buccal delivery system should stay in the oral cavity for hours and release the drug in a controlled way. Mucoadhesive polymers prolong the residence time of the drug in the oral cavity [163]. Based on its mucoadhesive as well as absorption enhancement properties, chitosan is a promising polymer to be used for buccal delivery, such as chitosan mixed with sodium alginate, which was studied as a vehicle in buccal tablets; while chitosan glutamate, interacted with polycarbophil and other anionic polymers and was proposed for bilaminated films and bilayered tablets [164, 165].
Chitosan salts have different physical properties and can have different effects on mucosa permeability [166, 167]. A combination of chitosan and Pluronic F-127 was investigated in one study, showing that the drug release systems for via buccal was improved and demonstrating that independently of chitosan salt type (citrate, acetate and lactate), mucoadhesion was significantly favoured when the concentration of Pluronic F-127 in the matrix was about 30% (w/w). Chitosan lactate gave good sustained release, controlled swelling, and higher mucoadhesion when combined with Pluronic F-127 present in the matrix at the above concentration (Figure 3). These results indicate that such a matrix could find useful application in buccal drug delivery systems [168].
Pictures of swollen matrices, containing different chitosan salt type (1—chitosan acetate; 2—chitosan citrate; 3—chitosan lactate) and different amounts of P407 [A—at about 50% (w/w); B—at about 30% (w/w); C—at about 12% (w/w)]. The images were taken 4 h after starting the swelling study. This figure is reproduced with the permission [
Other modifications such as, trimethylated chitosans seem to be promising exipients for drug delivery systems intended for buccal mucosa applications to enhance the absorption of hydrophilic macromolecules [169]. In another study, the potential of thiolated chitosan for peptide delivery systems via the buccal mucosa was investigated in pigs [170]. The therapeutic peptide PACAP was applied to pigs, and its bioavailability was determined in order to facilitate the treatment of type 2 diabetes. Due to its strong permeation enhancing properties, tablets based on thiolated chitosan raised continuously the plasma level of this peptide drug, allowing for therapeutic range levels to be maintained over the whole period of application. Furthermore, buccal bilayered devices with a mixture of nifedipine and propranolol as well as chitosan displayed promising potential for use in controlled delivery in the oral cavity [171].
Chitosan (derivatives) can interact with mucus and epithelial cells and induced a redistribution of cytoskeletal F-actin and the tight junction protein ZO-1 resulting in opening of cellular tight junctions and increasing the paracellular permeability of the epithelium [172, 173]. Besides their charge, other structural elements of these polymers likely contribute to their penetration-enhancing activity, since cationic polysaccharides such as quaternized diethyl aminoethyl-dextran were ineffective as an enhancer.
Colon specific drug delivery systems are gaining importance for use in the treatment of chronic diseases, such as irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, and also for the systemic delivery of protein and peptide drugs. By making use of this colon-specific degradation, chitosan has been discovered as useful coating in order to guarantee a site specific delivery. Radiolabelled (99mTc) tablets coated with a combination of pectin/chitosan/hydroxypropyl methylcellulose (3 + 1 + 1), for instance, were administered orally to human volunteers [174]. Within this study, gamma scintigraphy was used to evaluate the gastrointestinal transit of these tablets, showing that they remain intact through the stomach and small intestine. In the colon, the bacteria degraded the coat, and thus, the tablets disintegrated. In another study, it was developed a sustained dosage form for alpha-lipoic acid making use of ionic interactions between this anionic drug and chitosan used as carrier matrix. Studies in human volunteers showed a release maximum once the formulation had reached the colon [175].
Chitosan hydrogel beads coated with enteric polymer Eudragit S 100 were also investigated to be targeted to the colon; they prevented premature drug release in simulated gastric fluid, but delivered in the colon, because chitosan was degraded by the bacterial enzymes. Prednisolone, 5-aminosalicyclic acid, metronidazole, 5-fluorouracil and indomethacin are being investigated in chitosan formulations for the same purposes [176].
Mixes are being used to obtain some characteristics on the formulations. Here, blended chitosan with gelatin was used to improve the biological activity since (i) gelatin contains Arg-Gly-Asp (RGD)-like sequence that promotes cell adhesion and migration, and (ii) forms a polyelectrolyte complex [177]. Addition of gelatin affected the stiffness of 2D and 3D scaffolds, facilitated the degradation rate and maintained the dimension in the presence of lysozyme. The effect of blending chitosan with poly(ε-caprolactone) (PCL) also improved mechanical properties as well as cellular support [178]. The γ-poly (glutamic acid), a hydrophilic and biodegradable polymer, was also used to modify chitosan matrices and the γ-poly (glutamic acid)/chitosan composite matrix was found to enhance hydrophilicity and serum proteins adsorption, and to increase the maximum strength through addition of γ-poly (glutamic acid) in tissue engineering applications [179]. The mechanical properties and biocompatibility also were improved with galactosylated chitosan-based scaffolds by combining them with alginate. The scaffolds exhibited the usual pore configurations, and the pore sizes were dependent on the freezing pre-treatments, the molecular weight of chitosan and amount of galactosylated chitosan [180, 181].
Powder formulations of protein-loaded chitosan nanoparticles suitable for pulmonary delivery have been prepared by spray drying [182-184]. Moreover, insulin-loaded nanoparticles chitosan have been reported obtaining a good loading capacity (65–80%) and were fully recovered from the powder formulations after contact with an aqueous medium, and showed a fast release of insulin. The biocompatibility and penetration-enhancing effects of their chitosan powder formulations were examined in vitro using A549 and Calu-3 cells as models for alveolar and respiratory epithelial cells, respectively [185]. The formulations exhibited a very low cytotoxicity in both cell lines, but no effects on opening of tight junctions of the cells were reported. Further, CLSM studies did not reveal internalization of nanoparticles which contrasts previously reported studies [183]. The authors speculated that the total amount of chitosan used in their study was lower than that used in other publications. Moreover, the chitosan salt (glutamate) probably did not lose its charge after dispersing the particles in buffer [183].
An inhalable chitosan-based powder formulation of salmon calcitonin-containing mannitol as a cryoprotecting agent using a spray drying process was prepared. The effect of chitosan on the physicochemical stability of the protein was examined with chromatographic and spectrometric techniques [186]. The dissolution rate of the protein decreased when it was formulated with chitosan, which might be due to an irreversible complex formation between the protein and chitosan during the drying process [183]. On the other hand, chitosan-coated PLGA nanoparticle suspensions improved the absorption of calcitonin after pulmonary administration aerosolized with a nebulizer. The elimination of the chitosan-coated nanoparticles from the lungs was retarded as compared to non-coated particles, most likely due to the mucoadhesive properties of chitosan. It was shown that after pulmonary administration of the chitosan-coated particles the pharmacological action of calcitonin was prolonged as compared to that of the protein loaded in the non-coated nanoparticles [187]. In another study, the potential of chitosan oligomers and polymers for pulmonary delivery of proteins was studied. The absorption of interferon-α in rats was improved after pulmonary administration of aqueous solutions of the oligomers and the interferon-α. Among various oligomers, glucoseamine hexamers at a concentration of 0. 5% (w/v) showed the highest efficacy. Chitosan polymers were less efficient than the studied oligomers in increasing the systemic level of the interferon-α, likely due to their lower solubility in lung fluids [188].
Interesting results were obtained with N-trimethyl chitosan powder formulations of insulin using a drying process for pulmonary delivery [189]. The particles had an average volume aerodynamic diameter of 4 μm suitable for peripherally pulmonary deposition. After one-year storage at 4 °C, the particle characteristics were maintained and the insulin structure was largely preserved [189]. Pulmonary administration of N-trimethyl chitosan–insulin microparticles significantly enhanced the systemic absorption of insulin, with a bioavailability of about 95% relative to subcutaneously administered insulin.
It has been studied the development of a novel nanocarrier consisting of Lipoid S100 and chitosan or glycol-chitosan for the systemic delivery of low molecular weight heparin upon pulmonary administration. These nanosystems, formed by ionic gelation technique, provided both sufficient entrapment efficiency and mucoadhesive properties. Aerosolization of these formulations indicated that heparin could be delivered to the lung. Overall, these nanocarriers might have a use potential for systemic delivery of low molecular weight heparin as compared to free drug with a therapeutic potencial effect for the treatment of pulmonary embolism and other thromboembolic disorders [190]. The potential to deliver ofloxacin directly to alveolar macrophages via the respiratory route was enhanced from loaded glutaraldehyde-crosslinked chitosan microspheres in comparison with the ofloxacin powder. It suggests that chitosan microspheres are efficient delivery system of ofloxacin to cure tuberculosis [191].
Chitosan-coated gold nanoparticles have been investigated for mucosal protein delivery [192]. Chitosan was used as a reducing agent in the synthesis of gold nanoparticles and also as a mucoadhesive and penetration enhancer. Insulin was efficiently adsorbed (∼50%) through electrostatic interaction onto the surface of the coated nanoparticles and they were colloidally stable for 6 months. Intranasal administration of these nanoparticles in diabetic rats showed an improved pharmacodynamic effect as evidenced by higher reduction in blood glucose levels as compared to insulin-loaded sodium borohydride gold nanoparticles [192].
In another study nanoparticles consisting of chitosan and negatively charged cyclodextrin sulfobutylether-β-CD or carboxymethyl-β-CD derivatives were prepared and characterized [104]. It was demonstrated that chitosan– sulfobutylether-β-CD–insulin nanoparticles induced lower TEER values of Calu-3 cells than chitosan–carboxymethyl-β-CD–insulin nanoparticles. However, both insulin-loaded nanoparticles showed similar effects on reduction of rats\' plasma glucose levels upon intranasal administrations. It should be noted that, the plasma insulin concentrations of the treated animals which may give better indications in absorption enhancement properties of the formulations, were not determined [104]. Chitosan has been investigated as auxiliary agent in nasal drug delivery systems [193] due to mucoadhesive properties improving significantly nasal uptake of isosorbide dinitrate due to the co-administration of chitosan in rats [194]. In the same study, they showed a minor cilio-inhibiting effect of the polymer. In addition, fentanyl nasal spray formulations with pectin, chitosan, and chitosan–poloxamer 188 were developed for clinical evaluation to provide rapid absorption and subsequently increased bioavailability. The study was conducted in 18 healthy adult volunteers and revealed significantly increased systemic exposure as well as reduced times to peak plasma values for all formulations compared with oral transmucosal fentanyl citrate lozenge [195].
Recently, formulations prepared with chitosan and Pluronic F-127 as nasal delivery vehicles of vaccines have been reported [116, 196, 197]. In a study, some mice Balb/c mice were intranasally immunized with the antigen tetanus toxoid in the presence of chitosan, Pluronic F-127/chitosan or lysophosphatidylcholine (LPC) showing that the antigen specific IgA response in the nasal and lung washes of these animals had a significant increase in anti- tetanus toxoid mucosal IgA response in the group of mice immunized and boosted intranasally with Pluronic F-127/chitosan, enhancing the systemic and mucosal immune responses compared with those in the control groups. Successful mucosal vaccination is therefore largely dependent on the development of effective mucosal adjuvants. As it is well known, the adaptive humoral immune defense at the mucosa is mediated by the antibodies IgA that in mucosal secretions binds to the microbes and toxins present in the lumen and neutralize them by blocking their entry into the host [198, 199]. This nasal vaccine could induce not only systemic IgG antibody responses but also mucosal IgA antibody responses, which results in two layers of immune defense against infectious diseases. So, this study showed that the system represents a novel nasal vaccine delivery system to enhance immune response [200]. Important effects in the nasal delivery of vaccines were found, when the
Another objective was obtained with leucine-enkephalin loaded N-trimethyl chitosan nanoparticles, which were evaluated as a brain delivery vehicle via nasal route and prepared by ionic gelation method. The permeability of Leucine-enkephalin released from nanoparticles was 35 fold improved from the nasal mucosa as compared to Leucine-enkephalin solution. Fluorescent microscopy studies of brain sections of mice showed higher accumulation of fluorescent marker NBD-F labelled Leucine-enkephalin, when administered nasally by N-trimethyl chitosan nanoparticles, while low brain uptake of marker solution was observed. It was conclude that N-trimethyl chitosan nanoparticles could generate a significant improvement of bioactive Leucine-enkephalin levels in the brain when is intranasally administered [203].
Chitosan is a suitable material for the design of ocular drug delivery systems due to its nontoxic character, permeation enhancing properties, and physicochemical characteristics. Chitosan-based formulations used for ophthalmic drug delivery are hydrogels [203], nanoparticles [127], and coated colloidal systems [204]. Chitosan as well as Pluronic F-127, has recently been proposed as a material with a good potential for ocular drug delivery, since their solutions were found to prolong the corneal residence time of antibiotic drugs and nanocapsules coated with chitosan were more efficient to enhance the intraocular penetration of some specific drugs [205]. Making use of their in situ gelling properties, the formulations can be applied and distributed on the ocular surface in almost liquid form thereafter transforming into the gel status [203]. A combination of polycaprolactone nanocapsules as ocular carriers with the advantages of the cationic mucoadhesive chitosan and poly-L-lysine as coating was performed. Even though poly-L-lysine and chitosan displayed a similar positive surface charge, only chitosan-coated nanocapsules enhanced the ocular penetration of indomethacin with respect to uncoated nanocapsules. The authors suggested that an undetermined property of chitosan was responsible for this enhanced uptake [204].
In other studies chitosan-alginato microspheres or beads were investigated for the encapsulation of several drugs, proteins, cells and oligonucleotides, with promising results [206-211]. The complex has biocompatible and biodegradable characteristics, and limits the release of encapsulated materials more effectively than either alginate or chitosan alone [212]. A further advantage of this delivery system is its non-toxicity permitting the repeated administration of therapeutic agents. In another study, chitosan-sodium alginate nanoparticles entrapping gatifloxacin (a broad-spectrum antibacterial agent used in the treatment of ocular infections) were successfully formulated. The results showed that the drug was released over a period of 24 hours in a sustained release manner, primarily by non-Fickian diffusion. This new formulation is a viable alternative to conventional eye drops by virtue of its ability to sustain the drug release, for its ease of administration because of reduced dosing frequency resulting in better patient compliance [213].
Some mixes of polymers using chitosan could be used to prepare thermosensitive hydrogels which were a good choice to reduce local irritation in the skin caused by conventional transdermal patches (40 % of application-site skin reaction) due to components of the patch (acrylic adhesive, polyester, polyurethane, and silicone). Therefore, these formulations can also provide advantages for particular applications as it is transformed from a liquid to a gel when administered topically [214]. Additionally, modifications in the delivery of drugs could be achieved, such as that obtained for a hydrogel patch composed of chitosan and starch developed for cosmetic applications, in which a rapid curcumin release rate was observed [215].
Amino acid grafted chitosans posses a great potential for application in these biomedical fields, whereby a combination of the properties of chitosan and those belonging to different amino acid moieties could produce materials with synergetic properties. Moreover, this conjugation can enhance some properties of chitosan, such as its antimicrobial activity, which are important in the area of tissue engineering such as wound healing [216]. Many tissue analogs including cartilage, bone, liver, and nerve have been prepared using this engineering technology. Systems of blood clots based in chitosan–glycerol phosphate disodium salt were purposed since bleeding has been identified as an initiating event in post-surgical repair and it was hypothesized that microfracture-based repair could be improved by stabilizing the clot formed in the lesion with chitosan that is thrombogenic and actively stimulates the wound-healing process [217]. These systems were applied as implants to marrow-stimulated chondral defects in rabbit cartilage repair models, where they induced greater fill of chondral defects with repair of tissue compared to marrow-stimulation alone [218]. In another investigation, a chitosan– hydroxyapatite multilayer nanocomposite with high strength and bending modulus rendering the material suitable was prepared for possible application as an internal fixation of long bone fractures [219]. A series of chitosan-tricalcium phosphate composite scaffolds were developed for the same purpose using freeze-drying process, which provided macroporous composite scaffolds with different pore structures. The biocompatibility, evaluated subcutaneously on rabbits indicated that these scaffolds can be utilized in non-loading bone regeneration [220]. The use of biomimetic hydroxyapatite/chitosan–gelatin network composites in the form of 3D-porous scaffolds improved adhesion, proliferation and expression of rat calvaria osteoblasts on these systems [221]. Recently, a scaffold with calcium phosphate cement and chitosan fibers with improved resistance to fatigue and fracture was used to harvest human umbilical cord mesenchymal stem cells without an invasive procedure that is commonly required when studying bone marrow mesenchymal stem cells. This system had flexural strength of 26 MPa, while calcium phosphate cement control was 10 MPa. In addition, an excellent and higher viability of human umbilical cord mesenchymal stem cells was obtained with scaffolds using chitosan fibers than those controls without fibers. Human umbilical cord mesenchymal stem cells had excellent proliferation (300 and 700 cells/mm2 on 1 and 4 day, respectively) and viability on the scaffolds [222]. A study showed that the chitosan surface modified with fructose (ligand of asialo-glycoprotein receptor in hepatocyte) on porous chitosan scaffolds induced the formation of cellular aggregates and enhanced liver specific metabolic activities and cell density to a satisfactory level [223, 224]. Chitosan microfibers were also developed and coated with collagen. Schwann and fibroblast cells were cultured on the chitosan microfibers to be adhered to the surface of the systems. After 72 h, the Schwann cells had proliferated linearly while the fibroblast cells covered the surface of the chitosan microfibers. The chitosan microfibers provide very good scaffolds for many tissue engineering applications with the advantages of ease of fabrication, simplicity and cost effectiveness [225].
One of the most important routes to drug delivery is the oral pathway. The uptake of chitosan into the bloodstream is generally not investigated in oral administration studies. Chitosan\'s systemic absorption and distribution from this route of delivery may be largely dependent on the Mw. It is very likely that oligomers could show some absorption whereas larger Mw chitosans are excreted without being absorbed. This effect was seen with FITC-labeled chitosans with 3. 8 kDa (88. 4% degree of deacetylation) chitosan having the greatest plasma concentration after oral administration vs 230 kDa (84. 9% degree of deacetylation) having almost no uptake. Increasing Mw was seen to decrease the plasma concentration in this, one of the only studies investigating plasma concentration after oral administration [226]. Trimethyl chitosan oligomers/DNA nanoparticles were taken up in the gastric and duodenal mucosa and to some extent in the jejunum mucosa, ileal mucosa and large intestinal mucosal cells as shown by green fluorescent protein (GFP) expression [227]. Chitosan polymers are not absorbed by the gastrointestinal way and are unlikely to show biodistribution. Chitosan oligosaccharides however may be absorbed to some extent.
Although native chitosan has not been investigated, the intracellular uptake and distribution of chitosan/DNA complexes have been studied in vitro [228–230]. Chitosan polyplex uptake at 37 °C was 3-fold higher than at 4 °C [228] but this could be due to increased interaction and not an ATP dependent endocytic mechanism. The authors suggested nuclear localization and they also stated little dissociation of the DNA from the chitosan. In a more comprehensive study, Leong et al. stained for lysosomes and found some co-localization with chitosan DNA nanoparticles. However, the majority of the polyplexes were found in the cytosol [229]. A complex of doxorubicin with chitosan has also been studied; complexes enter cells through an endocytic mechanism which was not further elucidated [231]. Hydrophobic (5-β-cholanic acid) modified glycol chitosan nanoparticles were internalized into HeLa cells through all the endocytic mechanisms studied: clathrin coated vesicles, caveolae and macropinocytosis. This study agrees with that of Leong, in that some particles were lysosomal but most were not [232]. Unfortunately, these studies all involve nanoparticle uptake of relatively large (>100 nm) nanoparticles or aggregates of complexes and not just labeled chitosan. Dodane and Vilivalem reported that chitosan has membrane perturbing properties that do not decrease cell viability [233]. It is likely that chitosan and chitosan nanoparticles enter the cell via cell membrane perturbation due to the cationic charge. It is important to understand chitosan\'s cell trafficking and investigate both endocytosis and exocytosis. Such study should shed some light on chitosan\'s biocompatibility.
It is important to mention that cellular uptake kinetics may be altered due to the charge interaction (e. g. in the case of DNA complexes). This balancing, or reduction, of the positive charges on the chitosan molecule has effects on its interaction with cells and the microenvironment, often leading to decreased uptake and a decrease in toxicity. In the case of a covalent drug conjugate, the polymer\'s physicochemical properties (hydrophilicity) and conformation are altered (i. e. micelle formation) with a consequent effect on distribution and cell uptake [52]. Similar results were found for poly(dl-lactic-co-glycolic acid) nanospheres surface modified by adsorption of chitosan for pulmonary administration, which were preferentially taken up by human lung adenocarcinoma cells (A549) in a temperature dependent manner [234]. Moreover, cellular uptake of these nanocarriers increased with decreasing diameter to the submicron level and the cellular uptake of nanospheres were promoted through electrostatic interactions between the surface due to chitosan adsorbed and the negatively charged cell membrane without showing cytotoxicity. Internalization of nanospheres (200-nm) by A549 cells appears to occur predominantly through adsorptive endocytosis initiated by nonspecific interactions between nanospheres and cell membranes, and is partially mediated by a clathrin-mediated process. Thus, chitosan is suitable as a material for surface modification of systems for intracellular targeting because it could increase the interaction between the cell membrane and the systems [234]. The effect on the charge of the systems was also reported for a large array of N-(2-hydroxypropyl)methacrylamide (HPMA) based copolymers, which were internalized into the prostate cancer cells through multiple endocytic pathways: positively charged copolymers robustly engaged clathrin-mediated endocytosis, macropinocytosis and dynamin-dependent endocytosis, while weakly negatively charged copolymers weakly employed these pathways; strongly negatively charged copolymers only mobilized macropinocytosis [235].
The hydrophobicity of the systems as drug delivery vehicles for therapeutic applications is another physicochemical property which has been investigated on the cellular uptake. Here, a hydrophobic glycol chitosan system (5β-cholanic-acid conjugated glycol chitosan) was reported to show several distinct uptake pathways involved in their internalization with a single degree of substitution [232]. Moreover, different degree of substitution (or hydrophobicity) could affect the endocytosis of hydrophobically-modified polymers. The cellular uptake of nanoparticles prepared by a hydrophobically-modified chitosan (N-palmitoyl chitosan), was significantly enhanced with increasing the degree of substitution. The internalization of these systems was clearly related with the lipid raft-mediated routes. With increasing the hydrophobicity on polymer, the caveolae-mediated endocytosis became more important. The internalized nanoparticles transiently associate with CAV1 at cell membranes and at a peripheral CAV1- positive structure coupled with caveosomes before trafficking to the endosomal pathway [236].
In addition, the cell entry and subsequent intracellular trafficking of drug carriers using chitosan or a combination with another polymer are strongly dependent on their physicochemical characteristics, such as charge and molecular weight. In addition, the route of administration determines the uptake, concentration, contact time and cell types affected [52].
Chitosan is one of the most promising polymers because of its nontoxic, polycationic, biocompatible, and biodegradable nature and particularly due to its mucoadhesive and permeation-enhancing properties [237-239]. Moreover, the strong mucoadhesive property of chitosan is most important for drug delivery through the mucosal routes. In addition, the interaction of the positively charged chitosan with the negatively charged mucin layer and the tight junctions facilitates the paracellular transport of hydrophilic macromolecules by opening the tight junctions of the mucosal barriers [111, 239-242]. Additionally, chitosan is cheap [243]. Practical use of chitosan has been widely investigated due to its ability to form hydrogels, to its biocompatibility in physiological environments (enzymes chitosanase and lysozyme degrade chitosan and form harmless products), enhancing it with deacetylation reactions. Moreover, its biocompatibility was demonstrated with viable cartilage producing any untoward effect [216].
One of many investigations using chitosan is as vaccines vehicles, which have showed better efficacy than the approved injectables (induce strong systemic immune responses and represent a pharmaceutical form painful). Diverse chitosan microspheres have been evaluated for controlled drug release and to enhance the protection and permeation of the antigens in the nasal mucosa, inducing antigen specific immune responses in both the nasal mucosa and the systemic compartment [114, 115, 196, 197]. Besides, the induction site of the antigen-specific mucosal immune responses were found contained in a broad range of mucosal surfaces (nasal and vaginal routes and the salivary gland).
Several studies have been conducted on chemically modified chitosan systems through their concomitant use with adjuvants for a synergistic effect, and through the mannosylation of chitosan for target the receptor-mediated. The chemically modified chitosan systems combined with other adjuvants have showed to have an increased immunostimulatory in nasal vaccine delivery [114, 115]. Another advantage of chitosan formulations is its cationic property, which has been also exploited to deliver a tissue plasminogen activator to substrates of the fibrin network or insulin to mucosa surfaces [244, 245]. Nasal delivery of insulin from solutions and gels based of chitosan incremented greatly the permeability and transmucosal absorption, which could avoid the pain and inconvenience of injections of insulin in patients [246, 247). Moreover,
Systems based in chitosan can provide advantages by their mucoadhesive properties overcome to the conventional formulations such as those for via ophthalmic, that are eliminated from the precorneal area immediately upon instillation because of lacrimal secretion and nasolacrimal drainage, needing a frequent instillation of concentrated solutions to achieve the desired therapeutic effects [248, 249]. In order to lengthen the resident time of instilled dose and enhance the ophthalmic bioavailability various conventional and non conventional (colloidal drug delivery systems, such as liposomes, biodegradable nanoparticles and nanocapsules) ophthalmic vehicles based in chitosan have been developed, but their use is reduced due to some adverse effects such as blurred vision from ointment or low patient compliance from inserts [250]. In order to avoid the blurred vision, a combination of chitosan and Pluronic F-127 could be used for the preparation of in situ forming gels with improved mechanical and mucoadhesive characteristics for prolonged precorneal residence time in vivo [251].
Mucoadhesive properties are also important for the buccal administration, which involve the direct entry of the drug into the systemic circulation avoiding the first pass hepatic metabolism. This route is easily accessible for self medication where the drug can be easily administered or if necessary, removed from the site of application. In order to maintain the device in its position for many hours against buccal motion and salivary flow, which could reduce the mucosal absorption, the dosage form must have good adhesive properties and show an efficient control of drug delivery. These characteristics have been obtained with systems using chitosan alone, modified chitosan, chitosan mixed with other components such as, sodium alginate or using chitosan glutamate proposed for bilaminated films and bilayered tablets [117, 118, 164]. In adittion, chitosan has the potential to be a safe pharmaceutical excipient for non-parenteral drugs. Altohoug it was approved for dietary applications in Japan, Italy and Finland and it has been approved by the FDA for use in wound dressings, more studies must be performance to ensure its safety. In Table 6 summarizes mains advantages in applications of chitosan systems by use other components.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Chitosan and carmomer | \n\t\t\tImproved oral bioavailability of buserelin. | \n\t\t\t[141] | \n\t\t
Chitosan and PEGylated | \n\t\t\t3. 4-fold was improved its mucoadhesive properties of chitosan. | \n\t\t\t[142] | \n\t\t
Preactivation of thiol groups on chitosan via the formation of disulfide bonds with mercaptonicotinamide | \n\t\t\tMucoadhesive properties of thiolated chitosans were even significantly improved. | \n\t\t\t[143] | \n\t\t
Chitosan and poly(g-glutamic acid) and chitosan and polyacrylic acids | \n\t\t\tThis combination could be infiltrated in the cell–cell junctions and interact with | \n\t\t\t[252] | \n\t\t
Modified chitosan hydrogels loaded with metronidazole, tetracycline and theophylline | \n\t\t\tModified chitosan hydrogels loaded with metronidazole, tetracycline and theophylline could bypass the acidic environment of the stomach and release the loaded drug into the intestine | \n\t\t\t[252] | \n\t\t
Chitosan and thiolated chitosan | \n\t\t\tChitosan and thiolated chitosan are used to improve the oral bioavailability of acyclovir 3-fold and 4-fold. | \n\t\t\t[148] | \n\t\t
Chitosan with glutaraldehyde or ethylene glycol diglycidyl | \n\t\t\tChitosan with glutaraldehyde or ethylene glycol diglycidyl are used to load antibiotics. | \n\t\t\t[174] | \n\t\t
Chitosan microspheres reacetylated with acetic anhydride | \n\t\t\tThe re-acetylated chitosan microspheres were able to interact closely with the gastric mucosa and to exhibit sustained delivery of entrapped antibiotic | \n\t\t\t[175] | \n\t\t
Clozapine-loaded nanoparticles with chitosan and polysorbate 80 | \n\t\t\tA great improvement in surface hydrophilicity was brought by chitosan and polysorbate 80 coatings | \n\t\t\t[176] | \n\t\t
Pectin/chitosan/hydroxypropyl methylcellulose (3 : 1: 1) | \n\t\t\tThis formulation had reached the colon | \n\t\t\t[174] | \n\t\t
Chitosan and pluronic F-127 | \n\t\t\tDrug release systems for via buccal was improved and demonstrating that independently of chitosan salt type (citrate, acetate and lactate), mucoadhesion was significantly favoured when the concentration of Pluronic F-127 in the matrix was about 30% (w/w). | \n\t\t\t[175] | \n\t\t
Trimethylated chitosans | \n\t\t\tSandri et al. (2005) showed that trimethylated chitosans seem to be promising exipients for drug delivery systems intended for buccal mucosa applications to enhance the absorption of hydrophilic macromolecules. | \n\t\t\t[169] | \n\t\t
Chitosan hydrogel beads coated with enteric polymer Eudragit S 100 | \n\t\t\tChitosan hydrogel beads coated with enteric polymer Eudragit S 100 to be targeted to the colon, prevented premature drug release in simulated gastric fluid, but delivered in the colon, because chitosan was degraded by the bacterial enzymes. | \n\t\t\t[159] | \n\t\t
Chitosan with gelatin | \n\t\t\tHuang et al. (2005) blended chitosan with gelatin to improve the biological activity. | \n\t\t\t[177] | \n\t\t
Chitosan with poly(ε-caprolactone) | \n\t\t\tThese blending membranes improved mechanical properties as well as cellular support. | \n\t\t\t[178] | \n\t\t
The γ-poly (glutamic acid) (γ-PGA) a hydrophilic and biodegradable polymer | \n\t\t\tThis formulation was also used to modify chitosan matrices and the γ-PGA/chitosan composite matrix was found to enhance hydrophilicity and serum proteins adsorption, and to increase the maximum strength through addition of γ-PGA in tissue engineering applications. | \n\t\t\t[179] | \n\t\t
Chitosan and PLGA | \n\t\t\tYamamoto et al. showed that chitosan-coated PLGA nanoparticle suspensions improved the absorption of calcitonin after pulmonary administration. | \n\t\t\t[187] | \n\t\t
Chitosan-coated gold nanoparticles | \n\t\t\tChitosan-coated gold nanoparticles have been investigated for mucosal protein delivery. | \n\t\t\t[253] | \n\t\t
Chitosan nanoparticles with cyclosporine A | \n\t\t\tChitosan nanoparticles with incorporated cyclosporine A in improving the delivery of drugs to the ocular mucosa. | \n\t\t\t[127] | \n\t\t
Main advantages in applications of using of chitosan with different materials.
Several limitations of the systems using chitosan alone, modified chitosan, or chitosan mixed with other components could be mentioned. One of the most important is the general rapid clearance of the formulations in the mucosal surface owing to the mucociliary clearance and the presence of a variety of metabolic enzymes (cytochrome P-450 enzymes, conjugative Phase II enzymes, nonoxidative enzymes, and proteolytic enzymes that could reduce the absorption) of drugs administered via nasal using conventional chitosan formulations [254]. Nonetheless, these limitations are reduced when the drugs are entrapped in micro or nanoparticles using chitosan and other components.
Chitosan, has shown a hypoglycemic effect in streptozotocin (STZ)-induced diabetic animals [255- 257]. Other studies also found that low molecular weight chitosan (average MW about 2. 0 x 104 Da) as well as chitosan oligosaccharides can reduce plasma glucose level in diabetic animals [258, 259]. On the other hand, when chitosan is used as a coat in liposomes, it helps in delaying intestinal transit time so as to increase absorption of insulin. An increase in chitosan molecular weight caused increase in the hypoglycemic efficacy of chitosan-coated insulin liposomes. The hypoglycemic efficacy of the liposomes coated by chitosan 1000 kDa was markedly superior to that of the liposomes coated by other chitosans. Both increasing and decreasing chitosan concentration, the hypoglycemic efficacies of chitosan-coated insulin liposomes were decreased and the systems were not able to protect insulin from enzymatic digestion [260]. Thus, diabetic patients should be careful when administering chitosan if they not eating above.
Chitosan systems have limited applications in drug delivery and tissue engineering due to their hydrophilic nature and insolubility in certain physiological conditions (eg. blood-brain barrier), due to chitosan is soluble at pH values below 6. 5 [261]. Besides its mucoadhesive and controlled release properties chitosan is also able to increase the paracellular permeability due to the opening of tight junctions which has been shown for various routes of delivery such as for nasal or intestinal drug delivery. However, no effect on the paracellular permeability could be observed at pH 7. 4, which is the physiological pH of blood [262]. This indicates that chitosan solutions are not effective as permeation enhancer at neutral pH values, because of the missing solubility of chitosan at neutral and alkaline pH values. Chitosan in form of particles can overcome this problem, because particles need not to be dissolved.
It is important to mention that the modification of the polymer can change the properties of the systems. Chitosan can be readily modified by reactions at the amino and hydroxyl groups present in the molecule, but adequate optimizations of the formulations need to test, increasing costs, time, and toxicological studies. It is important to mention, that some derivatives increase in toxicity and any residual reactants must be carefully removed [51]. Additionaly, studies of
Potential applications of chitosan as weight supplement in the market as well as drug carrier in pharmaceutical formulations and as an important material able to prepare regenerative structures for bones and cartilages have been investigated. Thus, this work summarizes recent pharmaceutical developments using chitosan, modified chitosan or mixes with other components as drug carriers for the most non parenteral routes of administration including oral, topical, intranasal, and ocular, etc. Various therapeutic agents, such as anticancer, anti-inflammatory, antibiotics, antithrombotic, steroids, proteins, amino acids, antidiabetic and diuretics have been incorporated in chitosan-based systems as carriers to improve the dissolution rate of poorly soluble drugs and to achieve controlled release. Although, chitosan systems have limited applications in drug delivery and tissue engineering due to their hydrophilic nature and insolubility in certain physiological conditions (eg. blood-brain barrier) due to chitosan is soluble at pH values below 6. 5, chitosan particulate systems can be used as carriers for encapsulate drugs and to enhance their bioavailability and delivery. The primary amines of chitosan impart these valuable physicochemical properties including particular interactions with cells, proteins and living organisms. On the other hand, the safety of chitosan could also be achieved in shellfish allergic patients since it was shown that the subjects have tolerated the polymer without reaction demonstrating the safety of other chitin-derived products in patients allergic to shellfish. Since chitosan has the hydroxyl and amino functional groups, important results have been obtained by reacting chitosan with controlled amounts of multivalent anions (functional groups) to control hydrophobic, cationic and anionic properties enhancing the vectorization, the stability, and the mucoadhesively (to prolong the drug residence time) of the drug carrier systems. These properties of chitosan, especially their intrinsic antibacterial activity, their ability to bind anionic molecules such as growth factors, glucosamine glycans and DNA and their ability to be processed into a variety forms are also used to generate suitable structures for bone and cartilage regeneration. However, more studies to improve their mechanical properties are essential for this type of application. Although many successful systems of chitosan have been developed, more toxicity tests must be conducted in order to ensure their safety when it is incorporated in other systems.
The authors acknowledge a grant from UNAM (PAPIIT TA 200312 and PACIVE NCONS-17). The authors acknowledge the material provided with the Figures 2 and 3 in this work "Reprinted from European Journal of Pharmaceutical Sciences, 41(3-4), Günbeyaz, M., Faraji, A., Ozkul, A., Puralı, N., Senel, S., Chitosan based delivery systems for mucosal immunization against bovine herpesvirus 1 (BHV-1), Pages No 531–545., Copyright (2010)., and "Reprinted from Journal of Controlled Release, 102(1), Cafaggi, S. ; Leardi, R. ; Parodi, B. ; Caviglioli, G. ; Russo, E., Bignardi, G., Preparation and evaluation of a chitosan salt–poloxamer 407 based matrix for buccal drug delivery, Pages No 159–169., Copyright (2005)., with permission from Elsevier.
Peptic ulcers are not a modern disease. Ulcers have plagued mankind since the age of Hippocrates (born 460 BCE), who had been known to use honey and mastic oil for symptomatic relief. Record of surgery for a gastric ulcer was found written in stone in the temple of Aesculapius at Epidaurus as described by Goldstein in 1943: “A man with an ulcer in his stomach…Asklepios opened his stomach, cut out the ulcer, sewed him up again, and loosed his bonds. He went away whole, but the chamber was covered with his blood” [1], (Goldstein HI. Ulcer and cancer of the stomach in the middle ages. J Internal Coll Surgeons. 1943;
Exactly 100 years after Rydygier’s groundbreaking surgery, pathologist Dr. Robin Warren met Dr. Barry Marshall at the Royal Perth Hospital, Australia during internal medicine fellowship training. Sharing an interest in the physiology of gastritis, they spent 2 years studying the stomach and discovered the spiral bacteria
In the wake of Marshall and Warren’s achievement, new therapies evolved against peptic ulcer disease. Proposed treatments have been published since the 1990s and updated to reflect the advancements in diagnostics, resistance to antibiotics, and geographic prevalence patterns. General regimens include acid-reducing agents and various antimicrobials [1]. Medical therapy has proven to be largely successful in combating H. Pylori, with eradication rates of 70–95% across several trials [5, 6]. The patterns of peptic ulcer disease have therefore shifted from a once-common surgical problem to an entity treated effectively through oral medications.
Several studies have shown that hospitalizations for peptic ulcer disease have declined since the 1980s [7, 8, 9, 10]. However, despite improvement due much in part to the advancement of medical therapy, PUD persists in the population with a lifetime prevalence in of 5–10% and incidence of 0.1–0.3% yearly. Roughly 10–20% of these patients experience complications, including hemorrhage and less commonly, perforation [11]. The sequelae of PUD complications are often life-threatening and it is in these cases that surgical evaluation must be sought.
The current role for surgery in peptic ulcer disease is largely in the emergent setting, with bleeding, perforation, and obstruction as the major indications for intervention.
In patients with perforated peptic ulcer disease with significant pneumoperitoneum, extraluminal contrast extravasation on diagnostic study, or signs of peritonitis, operative treatment is recommended [11]. It is further suggested that the operation is performed promptly (within 24 hours) to decrease morbidity and mortality [12, 13]. Endoscopy currently has no role in the treatment of acutely perforated peptic ulcers. The laparoscopic and open approaches have both been described in the management of perforated peptic ulcers. Selection of surgical approach is based at least partially on surgeon experience and available equipment. In unstable patients, open surgery is favored. Several studies have pointed to comparable outcomes between open and laparoscopic surgery including overall postoperative complication rate, mortality, and reoperation rate. Laparoscopic surgery may have advantages in reducing hospital stay, lowering rate of surgical site infection, and less postoperative pain when compared to open surgery [14, 15, 16]. Robotic-assisted laparoscopic surgery has not been widely used for perforated or bleeding peptic ulcers and is not currently recommended in an emergent setting.
Several factors will tailor the ultimate surgical intervention to be performed. These include ulcer location, ulcer size, history of prior surgeries, prior ulcer treatment and patient stability. With gastric ulcers, excision of the ulcer with reconstruction of the resultant defect is the operative goal. For gastric ulcers located in the greater curvature, antrum, or body of the stomach, a wedge excision of the ulcer usually can be performed easily with linear staplers. Wedge resection results in both closure of the perforation and obtaining a tissue sample for biopsy—a critical consideration give the reported 4–14% rate of malignancy in perforated gastric ulcers [17]. Ulcers along the lesser curvature present a challenge given the proximity to the GE junction and the left gastric arterial flow. In distal lesser curvature ulcer cases, a distal gastrectomy may be considered. The proximal ulcer close to the gastroesophageal junction may require a subtotal gastrectomy with a subsequent Roux-en-Y esophagogastrojejunostomy.
It is important to note that perforations of the pyloric channel and the duodenum are functionally grouped together. Treatment of a small perforated duodenal ulcers (<2 cm) classically involves pedicled omentum placed into the defect as a repair. Primary repair, with or without an omental patch has also been described. Historically, an omental patch has been advocated to buttress a primary repair; however, recent studies point to no meaningful difference in leakage rate or mortality with addition of this step [18]. The operative approach to larger duodenal ulcers requires thorough calculation and a large range of interventions are available based on each patient’s individual scenario. An omental patch repair in duodenal ulcer perforations that are greater than 2 cm in size have an increased rate of postoperative leaks (up to 12%) [17]. Partial gastrectomy with subsequent reconstruction via a gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II) may be performed to address the ulcer and restore gastrointestinal continuity. Additionally, the jejunum can be used in a pedicled graft or serosal patch approach. The involvement of the duodenum containing the ampulla of Vater is a particularly arduous challenge. When in doubt, the integrity of the ampulla should be investigated with intraoperative cholangiography. Damage-control procedures such as the Roux-en-Y duodenojejunostomy or pyloric exclusion may be warranted in patients with tenuous stability. The duodenostomy tube should be considered as last-resort procedure when the patient’s hemodynamic status on the operating table will not allow for a more complex operation. An emergent Whipple comes with a high rate of morbidity and mortality and should generally not be attempted.
The evolution of endoscopic skills and technology in the last several decades has brought this technique to the forefront of bleeding ulcers and often obviates the need for surgical intervention. Early endoscopy (within 24 hours) is first-line therapy with the employment of therapeutic endoscopic interventions as needed, along with the initiation of parenteral proton pump inhibitors [11]. Roughly 10–20% of patients will have recurrent bleeding despite endoscopic therapy, at which time repeat endoscopy should be considered [19]. Patients who remain hemodynamically stable thereafter without high-risk ulcer features may then be safely discharged with continued oral PPI management. Surgery becomes warranted in cases of bleeding peptic ulcers when endoscopy fails or when the patient is deemed high-risk of a rebleeding event. Large ulcers (>2 cm) and hypotension at rebleeding are reported independent factors of predicting failure in further endoscopic treatment. Other features reported to prompt surgical consultation for further management include pulsatile bleeding, visible blood vessels in posterior duodenal ulcers, and transfusion requirement greater than 6 units of blood in the first 24 hours [20].
The surgical procedures currently used in bleeding gastroduodenal ulcers are on a spectrum of minimal to definitive interventions. The principal objective in life-saving surgery is hemorrhage control, which may be achieved through simple intraluminal oversewing or ligature, plication, or excision of the ulcer and repair of the defect [20]. The initial procedure may also include control of the arteries of the stomach or duodenum through direct ligation.
The management of emergent PUD has largely left out procedures that were designed to address the underlying problem--a once common consideration in all patients with PUD up until the 20th century. Acid-reducing procedures historically included division of the vagus nerve at various points in order to decrease the acetylcholine-mediated secretion of acid from parietal cells [21].
The truncal vagotomy is the division of the anterior and posterior trunks of the vagus nerves roughly 4 cm proximal to the gastro-esophageal junction. Stimulation of parietal cells is interrupted through this procedure; however, the lack of sympathetic input to the stomach results in a lack of relaxation, thereby decreasing the propulsion of solids from the stomach into the small intestine. Therefore, a concomitant drainage procedure, consisting of a pyloroplasty or antral resection would be performed. A selective vagotomy is similar but involves division of the vagus nerves at the more distal anterior and posterior branches after the level of the celiac and hepatobiliary branching. The highly selective vagotomy (HSV) was tailored to avoid the need for a drainage procedure. The HSV involves division of the nerve fibers supplying the parietal cells of the fundus and body of stomach, sparing the “crows’s foot” fibers innervating the antrum and pylorus. Given the rise of medical management, the role of the vagotomy with or without drainage procedures in peptic ulcer disease is limited to very few cases [22].
The main indication for consideration of an acid-reducing procedure are patients whose disease is refractory to medical management or those who cannot reliably participate or tolerate proton-pump inhibitors. Specifically, it is cases of duodenal ulcers (Type II and III) in which a vagotomy may be considered--gastric ulcers (TYpe I, IV) are not related to acid hypersecretion and therefore resection alone is indicated. In emergent situations, including bleeding duodenal ulcers and perforated duodenal ulcers, the use of a vagotomy is debated and is often surgeon-dependent. In general, the presence of peritonitis, shock, abdominal abscess, delay in treatment over 24 hours, or severe concurrent medical illness are contraindications to lengthening the surgery by adding a vagotomy to the rest of the surgical management plan [22, 23].
In the era of rapidly advancing surgical instruments and techniques, innovations in peptic ulcer disease surgery are rising in efforts to improve patient outcomes. The robotic platform is emerging as a feasible alternative to surgical treatment in the elective settings for many diseases. There have a been case reports of gastric resections performed safely with the assistance of the surgical robot, and whether the robot has a wider role for peptic ulcer disease merits exploration [24, 25]. Most prior reports of robotic assisted laparoscopic surgery for the stomach are those done for malignancy.
The pedicled omental plug for a large duodenal ulcer is a described twist on the classic omental patch closure. In this procedure, a nasogastric tube is inserted through the oropharynx and down through the perforation. A tongue of omentum is then secured to the tube via sutures and withdrawn into the stomach, where it is sutured to the ulcer edges. This omental plug shows promise, as was associated with a lower recurrent leak and duodenal stenosis rate in a randomized trial comparison against the standard omental patch [26]. Falciform flaps may be a feasible option in patients who do not have a viable omentum [27].
With the introduction of SARS-CoV-2 to the world’s collective biome we have observed unprecedented patterns of illness, with both the aversion of presenting to an affected hospital and the virus itself affecting disease across multiple organ systems. We here present a look at the relationship, if any, between COVID-19 and peptic ulcer disease.
It is well-known that COVID-19 presents with respiratory symptoms; however, several other manifestations are being seen. In one study comprised of over 20,000 patients, up to 29% had enteric symptoms including abdominal pain, nausea, vomiting, and diarrhea [28]. The pathophysiology of gastrointestinal tract manifestations of COVID-19 is thought to stem from several biochemical mechanisms including infection of the GI tract/liver leading to cellular inflammation and damage, dysbiosis enhancing the inflammatory response and cytokine storm, and affliction of the neuroenteric system [29].
GI bleeding is a reported, though less common manifestation associated with COVID-19. A rather high prevalence of PUD complicated by bleeding was noticed in one cohort of patients with moderate-to-severe ARDs caused by COVID-19 [29]. In another study performed on COVID-positive hospitalized patients undergoing endoscopy (n = 106), one-fourth of the studied population had peptic ulcers while an additional 16% had erosive/ulcerative gastro-duodenopathy [30]. The mainstay of treatment in peptic ulcer disease is proton-pump inhibitors; however, at least one study has demonstrated that PPI treatment is associated with worse outcomes in those infected by SARS-CoV-2 and development of COVID-19 when compared to individuals who are not taking a PPI [28]. The mechanism responsible for this finding remains unclear.
Another factor to consider in patients afflicted with peptic ulcer disease is the pattern of behavior in seeking medical evaluation during a pandemic. As the admissions for COVID-19 related respiratory illnesses increased dramatically, several hospitals reported decreased admissions and emergency medicine visits for non-COVID related diseases [31, 32, 33]. Theories concerning this trends in admissions during the pandemic include failure to present to a hospital secondary to fear of contracting COVID-19, which may have made some cases of illness more profound up to the point of death in the community [33]. The first United States Coronavirus epicenter in New York performed a multicenter study looking specifically at emergent general surgery admissions. Comparison to prior years indicated that there was an overall decrease in admissions with an overall increase in mortality. Peptic ulcer disease was one of the seven diagnoses that was observed [34]. A delay of 12 hours was found in 10 cases of complicated peptic ulcer disease in one institution during a two-month period [35]. The question arises if the increase in mortality is at least in part attributable to delayed presentation.
The full clinical spectrum of COVID-19 has not yet fully been elucidated. There is surprisingly limited data on the relationship between COVID-19 and peptic ulcer disease. The pathogenesis of ulcers in the setting of SARS-CoV-2 affliction may be related to direct gastric epithelial damage, stress resulting from the acute disease, or active mucosal inflammation sustained by cytokine storming [36]. Development of treatment guidelines in COVID-19 positive patients who sustain gastrointestinal manifestations of disease warrants further investigation.
Peptic ulcer disease remains a healthcare issue across the world and requires an interdisciplinary approach. In linking H. Pylori and NSAID use to peptic ulcers, pioneering efforts in controlling PUD have largely been seen in the primary care setting. However, complications from PUD persist in the population, and surgical intervention will continue to play a role in the very worst of the disease burden. It is therefore the responsibility of the surgical community to advance care through innovation of technique to provide optimal outcomes. This is especially true in the era of a pandemic where healthcare dynamics are adversely affected.
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\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
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\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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in Chile has been practiced since the 1920s; however, it was not until the 1990s that aquaculture became an important sector here. 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Díaz, Susana Muñoz and Carlos Riquelme",authors:[{id:"208847",title:"Dr.",name:"Ivonne",middleName:null,surname:"Lozano",slug:"ivonne-lozano",fullName:"Ivonne Lozano"},{id:"208895",title:"Dr.",name:"Nelson F.",middleName:null,surname:"Díaz",slug:"nelson-f.-diaz",fullName:"Nelson F. Díaz"},{id:"208897",title:"Dr.",name:"Carlos",middleName:null,surname:"Riquelme",slug:"carlos-riquelme",fullName:"Carlos Riquelme"},{id:"208898",title:"MSc.",name:"Susana",middleName:null,surname:"Muñoz",slug:"susana-munoz",fullName:"Susana Muñoz"}]}],mostDownloadedChaptersLast30Days:[{id:"56612",title:"Reproduction in Goats",slug:"reproduction-in-goats",totalDownloads:2917,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Reproductive activity of the goat begins when the females reach puberty, which happens at 5 months of age. The ovarian or estrous cycle is the period between two consecutive estrus. It is also the time that lasts the development of the follicle in the ovary, until rupture occurs and ovulation takes place, which coincides with the appearance of estrus. This chapter will describe the physiological and endocrinological bases of estrus in the goat. Likewise, factors affecting the presence of estrus and ovulation will be described. At another point, synchronization of estrus and ovulation, factors affecting the presence of estrus and external symptoms of estrus, will be described. To achieve synchronization of estrus or induction of ovulation within or outside the breeding season, it may be necessary to manage light hours, male effect, and/or use of hormones. The importance of artificial insemination is described, as well as the current situation of this technique worldwide. Currently, the techniques of artificial insemination in goats have been limited worldwide, due to the lack of resources of producers and trained technicians. The techniques of artificial insemination with estrous synchronization programs and ovulation with current research results will be described.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"Fernando Sánchez Dávila, Alejandro Sergio del Bosque González\nand Hugo Bernal Barragán",authors:[{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila"},{id:"206127",title:"Dr.",name:"Alejandro Sergio",middleName:null,surname:"Del Bosque-Gonzalez",slug:"alejandro-sergio-del-bosque-gonzalez",fullName:"Alejandro Sergio Del Bosque-Gonzalez"},{id:"206128",title:"Dr.",name:"Hugo",middleName:null,surname:"Bernal-Barragán",slug:"hugo-bernal-barragan",fullName:"Hugo Bernal-Barragán"}]},{id:"58095",title:"The Innovative Techniques in Animal Husbandry",slug:"the-innovative-techniques-in-animal-husbandry",totalDownloads:3811,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"Technology is developing rapidly. In this development, the transfer of computer systems and software to the application has made an important contribution. Technologic instruments made farmers can work more comfortable and increased animal production efficiency and profitability. Therefore, technologic developments are the main research area for animal productivity and sustainability. Many technologic equipment and tools made animal husbandry easier and comfortable. Especially management decisions and applications are effected highly ratio with this rapid development. In animal husbandry management decisions that need to be done daily are configured according to the correctness of the decisions to be made. At this point, smart systems give many opportunities to farmers. Milking, feeding, environmental control, reproductive performance constitute everyday jobs most affected by correct management decisions. Human errors in this works and decisions made big effect on last product quality and profitability are not able to be risked. This chapter deal with valuable information on the latest challenges and key innovations affecting the animal husbandry. Also, innovative approaches and applications for animal husbandry are tried to be summarized with detail latest research results.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Serap Göncü and Cahit Güngör",authors:[{id:"215579",title:"Prof.",name:"Serap",middleName:null,surname:"Goncu",slug:"serap-goncu",fullName:"Serap Goncu"},{id:"218971",title:"Dr.",name:"Cahit",middleName:null,surname:"Güngör",slug:"cahit-gungor",fullName:"Cahit Güngör"}]},{id:"58486",title:"Quality of Chicken Meat",slug:"quality-of-chicken-meat",totalDownloads:3344,totalCrossrefCites:19,totalDimensionsCites:28,abstract:"Chicken meat is considered as an easily available source of high-quality protein and other nutrients that are necessary for proper body functioning. In order to meet the consumers’ growing demands for high-quality protein, the poultry industry focused on selection of fast-growing broilers, which reach a body mass of about 2.5 kg within 6-week-intensive fattening. Relatively low sales prices of chicken meat, in comparison to other types of meat, speak in favor of the increased chicken meat consumption. In addition, chicken meat is known by its nutritional quality, as it contains significant amount of high-quality and easily digestible protein and a low portion of saturated fat. Therefore, chicken meat is recommended for consumption by all age groups. The technological parameters of chicken meat quality are related to various factors (keeping conditions, feeding treatment, feed composition, transport, stress before slaughter, etc.). Composition of chicken meat can be influenced through modification of chicken feed composition (addition of different types of oils, vitamins, microelements and amino acids), to produce meat enriched with functional ingredients (n-3 PUFA, carnosine, selenium and vitamin E). By this way, chicken meat becomes a foodstuff with added value, which, in addition to high-quality nutritional composition, also contains ingredients that are beneficial to human health.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Gordana Kralik, Zlata Kralik, Manuela Grčević and Danica Hanžek",authors:[{id:"207236",title:"Dr.",name:"Gordana",middleName:null,surname:"Kralik",slug:"gordana-kralik",fullName:"Gordana Kralik"},{id:"227281",title:"Prof.",name:"Zlata",middleName:null,surname:"Kralik",slug:"zlata-kralik",fullName:"Zlata Kralik"},{id:"227283",title:"Dr.",name:"Manuela",middleName:null,surname:"Grčević",slug:"manuela-grcevic",fullName:"Manuela Grčević"},{id:"227284",title:"BSc.",name:"Danica",middleName:null,surname:"Hanžek",slug:"danica-hanzek",fullName:"Danica Hanžek"}]},{id:"56453",title:"Goat System Productions: Advantages and Disadvantages to the Animal, Environment and Farmer",slug:"goat-system-productions-advantages-and-disadvantages-to-the-animal-environment-and-farmer",totalDownloads:4368,totalCrossrefCites:5,totalDimensionsCites:20,abstract:"Goats have always been considered very useful animals. Goats success is related to its excellent adaptability to the difficult mountain conditions, extreme weather and low value feed acceptance, versatile habits and high production considering their size. These are some reasons because goats are among the first animals to be domesticated. In terms of evolution, goats could be separated by their dispersion area in three large groups: the European, the Asian, and the African. Global goat populations, mainly in Africa and in Asia, have increased for centuries but very strongly in the past decades, well above the world population growth. They are also used for forest grazing, an integrated and alternative production system, very useful to control weed growth reducing fire risk. Despite some exceptions, no large‐scale effort to professionalize this industry has been made so far. There are consumers for goat dairy products and there is enough global production, but misses a professional network between both. Regarding goat meat, the world leadership also stays in Africa and Asia, namely in China, and there is a new phenomenon, the spreading of goat meat tradition through Europe due to migrants from Africa and other places with strong goat meat consumption.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"António Monteiro, José Manuel Costa and Maria João Lima",authors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"},{id:"203680",title:"Prof.",name:"Maria João",middleName:null,surname:"Lima",slug:"maria-joao-lima",fullName:"Maria João Lima"},{id:"203683",title:"MSc.",name:"José Manuel",middleName:null,surname:"Costa",slug:"jose-manuel-costa",fullName:"José Manuel Costa"}]},{id:"70760",title:"Induction and Synchronization of Estrus",slug:"induction-and-synchronization-of-estrus",totalDownloads:1745,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Estrus cycle is a rhythmic change that occur in the reproductive system of females starting from one estrus phase to another. The normal duration of estrus cycle is 21 days in cow, sow, and mare, 17 days in ewe, and 20 days in doe. The species which exhibit a single estrus cycle are known as monstrous and species which come into estrus twice or more are termed polyestrous animals. Among them some species have estrus cycles in a particular season and defined as seasonal polyestrous. It includes goats, sheep, and horses. On the other hand, cattle undergo estrus throughout the year. The estrus inducers can grossly be divided into two parts, that is, non-hormonal and hormonal. Non-hormonal treatments include plant-derived heat inducers, mineral supplementation, uterine and ovarian massage, and use of Lugol’s iodine. The hormones that are used in estrus induction are estrogen, progesterone, GnRH, prostaglandin, insulin, and anti-prolactin-based treatment. Synchronization can shorten the breeding period to less than 5 days, instead of females being bred over a 21-day period, depending on the treatment regimen. The combination of GnRH with the prostaglandin F2α (PGF2α)- and progesterone-based synchronization program has shown a novel direction in the estrus synchronization of cattle with the follicular development manipulation.",book:{id:"8545",slug:"animal-reproduction-in-veterinary-medicine",title:"Animal Reproduction in Veterinary Medicine",fullTitle:"Animal Reproduction in Veterinary Medicine"},signatures:"Prasanna Pal and Mohammad Rayees Dar",authors:[{id:"299126",title:"Dr.",name:"Mohammad Rayees",middleName:null,surname:"Dar",slug:"mohammad-rayees-dar",fullName:"Mohammad Rayees Dar"},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal"}]}],onlineFirstChaptersFilter:{topicId:"25",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82991",title:"Diseases of the Canine Prostate Gland",slug:"diseases-of-the-canine-prostate-gland",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.105835",abstract:"In dogs, the most frequent diseases of the prostate gland are benign prostate gland hyperplasia (BPH), acute and chronic prostatitis, squamous metaplasia, and prostate tumors. New diagnostic tools comprise diagnostic markers in the blood and urine, as well as advanced imaging methods. The therapy can be initialized with the 5α-reductase-inhibitor finasteride or an anti-androgenic compound, and prolonged with a long-acting gonadotropin-releasing-hormone (GnRH)-agonist such as deslorelin. In case of prostatitis, effective antibiotics must be applied for weeks. Antibiotics must be able to penetrate into the prostate tissue; fluoroquinolones, clindamycin, and erythromycin are good choices and are in addition effective against mycoplasms. The chronical prostatitis cannot be differentiated from a neoplasia by sonography; a biopsy, histological, and bacteriological examination are required. Tumors of the prostate gland are seldom and mostly occur in castrated but in intact dogs. For the final diagnosis, a biopsy must be taken. Partial and total resection of the prostate gland by use of laser technique is possible but coincedes with many side effects and the prognosis is still futile. Immunotherapy combined with NSAIDs, targeted noninvasive thermotherapy, BRAF gene inhibitors, or prostate artery chemoembolization are promising methods.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Sabine Schäfer-Somi"},{id:"82956",title:"Potential Substitutes of Antibiotics for Swine and Poultry Production",slug:"potential-substitutes-of-antibiotics-for-swine-and-poultry-production",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.106081",abstract:"Early of the last century, it was detected that antibiotics added to the animal feeds at low doses and for a long time can improve technical performances such as average daily gain and gain-to-feed ratio. Since then, the antibiotics have been used worldwide as feed additives for many decades. At the end of the twentieth century, the consequences of the uses of antibiotics in animal feeds as growth promoters were informed. Since then, many research studies have been done to find other solutions to replace partly or fully to antibiotic as growth promoters (AGPs). Many achievements in finding alternatives to AGPs in which probiotics and direct-fed microorganism, prebiotics, organic acids and their salts, feed enzymes, bacteriophages, herbs, spices, and other plant extractives (phytogenics), mineral and essential oils are included.",book:{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg"},signatures:"Ho Trung Thong, Le Nu Anh Thu and Ho Viet Duc"},{id:"82905",title:"A Review of Application Strategies and Efficacy of Probiotics in Pet Food",slug:"a-review-of-application-strategies-and-efficacy-of-probiotics-in-pet-food",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.105829",abstract:"In companion animal nutrition, probiotics (direct-fed microbials) are marketed as functional ingredients that add value to pet foods due to the impact they have on gastrointestinal and immune health of dogs and cats. The nature of the beneficial effect each probiotic strain exerts depends on its metabolic properties and perhaps most importantly, the arrival of a sufficient number of viable cells to the large bowel of the host. Pet food manufacturing processes are designed to improve food safety and prolong shelf-life, which is counterproductive to the survival of direct-fed microbials. Therefore, a prerequisite for the effective formulation of pet foods with probiotics is an understanding of the conditions each beneficial bacterial strain needs to survive. The aims of this chapter are: (1) To summarize the inherent characteristics of probiotic strains used in commercial pet foods, and (2) To review recently published literature on the applications of probiotics to pet foods and their associated challenges to viability.",book:{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg"},signatures:"Heather Acuff and Charles G. Aldrich"},{id:"82773",title:"Canine Transmissible Venereal Tumor: An Infectious Neoplasia in Dogs",slug:"canine-transmissible-venereal-tumor-an-infectious-neoplasia-in-dogs",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.106150",abstract:"Canine transmissible venereal tumor is the oldest cancer in dogs and is transplanted via viable cancer cells. This cancer has a specific host, easy transmission, noticeable gross lesions, a predictable growth pattern, an immunologic relative host response, unique molecular characteristics, and is responsive to chemotherapeutic treatment. These points make researchers and practitioners interested in this cancer. Genital cases are noticeable and therefore easier to diagnose and treat than extragenital cases. By contrasting the anatomical features of the two types of cases, we highlight the uniqueness of canine transmissible venereal tumors and discuss the diagnosis, treatment, and prevention of this ancient cancer.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Chanokchon Setthawongsin, Somporn Techangamsuwan and Anudep Rungsipipat"},{id:"82797",title:"Anatomical Guide to the Paranasal Sinuses of Domestic Animals",slug:"anatomical-guide-to-the-paranasal-sinuses-of-domestic-animals",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106157",abstract:"Paranasal sinuses are paired cavities within the skull, which develop by evagination into the spongy bone between the external and internal plates of the cranial and facial bones. Thus, each sinus is lined by respiratory epithelium and has direct or indirect communication to the nasal cavity. The purpose of this chapter is to present an anatomical reference guide of the paranasal sinuses in domestic animals, including large and small ruminants (cattle, buffalo, sheep, and goats), camels, canines (dog) and equines (horse and donkey), appropriate for use by anatomists, radiologists, clinicians, and veterinary students. Topographic descriptions and the relationships between the various air cavities and paranasal sinuses have been visualized using computed tomography and cadaver sections images. The anatomical features (including head bones, muscles, and soft tissues) have been compared using both dissected heads and skulls and computed tomography images. This chapter will therefore be useful as a normal reference guide for clinical applications.",book:{id:"10665",title:"Updates on Veterinary Anatomy and Physiology",coverURL:"https://cdn.intechopen.com/books/images_new/10665.jpg"},signatures:"Mohamed A.M. Alsafy, Samir A.A. El-Gendy and Catrin Sian Rutland"},{id:"81844",title:"Typical Changes in Carbon and Nitrogen Stable Isotope Ratios and Mercury Concentration during the Lactation of Marine Mammals",slug:"typical-changes-in-carbon-and-nitrogen-stable-isotope-ratios-and-mercury-concentration-during-the-la",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.103067",abstract:"The increase and decrease in the δ15N values of offspring owing to the suckling of δ15N-enriched milk (nursing) and the feeding shift from milk to solid food (weaning), respectively, are thought to be common traits observed in mammals. However, there are a few studies on lactation in marine mammals, especially large whales, because samples of calf, lactating mother, and milk are difficult to obtain. In this chapter, we review the studies on reproduction of marine mammals using δ13C and δ15N values analyzed in several tissues and describe the typical changes reported to date in those values and Hg concentrations in offspring and milk during lactation. Next, we present data on ontogenetic changes in δ15N and δ13C profiles and Hg concentration, especially focusing on the lactation period, in muscle samples of hunted bowhead whale, and stranded common minke whale (mysticetes), Dall’s porpoise (odontocete), and the harbor seal (phocid). Finally, we compare the δ15N and δ13C values in muscle samples of calves from common mink whale, Dall’s porpoise, and killer whale and suggest that these values could be excellent proxies for maternal forging habits and trophic levels.",book:{id:"11335",title:"Marine Mammals",coverURL:"https://cdn.intechopen.com/books/images_new/11335.jpg"},signatures:"Tetsuya Endo and Mari Kobayashi"}],onlineFirstChaptersTotal:25},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. By addressing hot topics in veterinary sciences, we aim to gather authoritative texts within each issue of this series, providing in-depth overviews and analysis for graduates, academics, and practitioners and foreseeing a deeper understanding of the subject. Forthcoming texts, written and edited by experienced researchers from both industry and academia, will also discuss scientific challenges faced today in Veterinary Medicine and Science. In brief, we hope that books in this series will provide accessible references for those interested or working in this field and encourage learning in a range of different topics.",coverUrl:"https://cdn.intechopen.com/series/covers/13.jpg",latestPublicationDate:"August 7th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"19",title:"Animal Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/19.jpg",isOpenForSubmission:!0,annualVolume:11415,editor:{id:"259298",title:"Dr.",name:"Edward",middleName:null,surname:"Narayan",slug:"edward-narayan",fullName:"Edward Narayan",profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",biography:"Dr. Edward Narayan graduated with Ph.D. degree in Biology from the University of the South Pacific and pioneered non-invasive reproductive and stress endocrinology tools for amphibians - the novel development and validation of non-invasive enzyme immunoassays for the evaluation of reproductive hormonal cycle and stress hormone responses to environmental stressors. \nDr. Narayan leads the Stress Lab (Comparative Physiology and Endocrinology) at the University of Queensland. A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},{id:"20",title:"Animal Nutrition",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",isOpenForSubmission:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. 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He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. Gonzalez-Sanchez",slug:"juan-a.-gonzalez-sanchez",fullName:"Juan A. Gonzalez-Sanchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico System",country:{name:"United States of America"}}},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}}]}},subseries:{item:{id:"7",type:"subseries",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11403,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. 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