Cartilage repair techniques
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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He is a member of the Royal College of Physicians and Surgeons of Glasgow, Association of Coloproctology, European Society of Coloproctology, British Medical Association, and British Hernia Society, and has been awarded the William Cullen Prize from the Royal College of Physicians of Edinburgh for his work on faecal incontinence.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"169437",title:"Associate Prof.",name:"John",middleName:null,surname:"Camilleri-Brennan",slug:"john-camilleri-brennan",fullName:"John Camilleri-Brennan",profilePictureURL:"https://mts.intechopen.com/storage/users/169437/images/system/169437.JPG",biography:"John Camilleri-Brennan MD (Melit), MD (Dundee), FRCSGlas, FRCSGenSurg, MFSTEd is a Consultant in General and Colorectal Surgery and colorectal clinical lead with NHS Forth Valley in Scotland, and honorary clinical associate professor with the University of Glasgow. He also holds the posts of Associate Director of Surgical Examinations with the Royal College of Physicians and Surgeons of Glasgow, and is also an elected Member of the Council of this College. A graduate of the University of Malta, he received his postgraduate surgical training primarily in Dundee and Aberdeen. A travelling fellowship by the Royal College of Physicians and Surgeons of Glasgow enabled him to pursue further studies in colorectal surgery at the University of Minnesota, USA. His research on rectal cancer led to a doctorate from the University of Dundee. He is the recipient of the William Cullen Prize from the Royal College of Physicians of Edinburgh for his work on faecal incontinence.",institutionString:"Forth Valley Royal Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Forth Valley Royal Hospital",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:"347259",firstName:"Karmen",lastName:"Daleta",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"karmen@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"7861",title:"Current Topics in Faecal Incontinence",subtitle:null,isOpenForSubmission:!1,hash:"972893234025c3c64bca793654086b70",slug:"current-topics-in-faecal-incontinence",bookSignature:"John Camilleri-Brennan",coverURL:"https://cdn.intechopen.com/books/images_new/7861.jpg",editedByType:"Edited by",editors:[{id:"169437",title:"Associate Prof.",name:"John",surname:"Camilleri-Brennan",slug:"john-camilleri-brennan",fullName:"John Camilleri-Brennan"}],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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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"44622",title:"Cartilage Tissue Engineering: The Role of Extracellular Matrix (ECM) and Novel Strategies",doi:"10.5772/55917",slug:"cartilage-tissue-engineering-the-role-of-extracellular-matrix-ecm-and-novel-strategies",body:'Articular cartilage is a hyaline cartilage that consists primarily of extracellular matrix with a sparse population of cells, lacking blood vessels, lymphatic vessels and nerves. The only cell type within cartilage is the chondrocyte and has a low level of metabolic activity with little or no cell division and is the responsible for maintaining in a low-turnover state the unique composition and organization of the matrix that was determined during embryonic and postnatal development. The biological and mechanical properties of articular cartilage depend on the interactions between the chondrocytes and the matrix that maintain the tissue. Chondrocytes form the macromolecular framework of the tissue matrix from three classes of molecules: collagens, proteoglycans, and non-collagenous proteins and maintain the extracellular matrix (ECM) by low-turnover replacement of certain matrix proteins [1, 2].
Aggrecan and type II collagen are the most abundant proteins found within the ECM in the articular cartilage and they are linked together by a number of collagen-binding proteins including cartilage oligomeric matrix protein (COMP), chondroadherin and other minor collagens on their surface. Aggrecan is a large aggregating proteoglycan which is in association with hyaluronan (HA) and link protein (LP). These aggregates are responsible for the turgid and they provide the osmotic properties to resist compressive loads and retain water. Also contain a variety of small leucine-rich repeat proteoglycans (SLRPs) as decorin, biglycan, fibromodulin and lumican where they help maintain the integrity of the tissue and modulate its metabolism [3, 4].
The chondrocyte is responsible for both the synthesis and the breakdown of the cartilaginous matrix but the mechanisms that control this balance are poorly understood [4]. The distribution of load across the joint is an important function of the articular cartilage for avoid excessive load affecting both cartilage and bone. It has been demonstrated that articular chondrocytes are able to respond to mechanical injury where biological stimuli such as cytokines and growth and differentiation factors contribute to structural changes in the surrounding cartilage matrix. It has been demonstrated that many non-mechanical and mechanical factors such as load clearly have a role in the initiation and propagation the processes of OA. The OA is the most common joint disease allowing dysfunction and pain. The OA is characterized by changes in chondrocyte metabolism that leads to elevated production of proteolytic enzymes, cartilage damage and loss of joint function. It have been described several mechanisms that can lead to OA, among of these mechanisms are mechanicals, bone changes and changes in the cartilage extracellular matrix [5, 6]
Aging, cartilage senescence and reactive oxygen species (ROS) are normal changes in the musculoskeletal system that contribute to the development of OA, but the mechanisms are poorly understood [5]. Inflammation is considered as a very early event in OA perhaps induced by joint trauma affecting chondrocytes in the cartilage and synovial cells (fibroblasts and macrophages) to produce cytokines as interleukin-1-beta (IL-1β) and tumoral necrosis factor-alpha (TNF-α), and other signaling molecules as proteoglycans to switch to or increase catabolic processes [6]. Obesity has been described as a risk factor for OA by increased mechanical load factors and degenerative knee pain. The mechanisms between obesity and OA are not completly understood but, it has been found the release of fat molecules that can affect the processes in the joint, including adipokines as visfatin and leptin, perhaps affecting the inflammatory response [7, 9]. Malalignment of the knee joint plays an important role in the development of early osteoarthritis changing the center of pressure of articular cartilage and subchondral bone. Varus or valgus malalignment of the lower extremity results in an abnormal load distribution across the medial and lateral tibiofemoral compartment and being increased in patients with knee osteoarthritis and is increased in patients with overweight. However, studies examining the relationship between malalignment and early knee osteoarthritis have produced conflicting results. The association between malalignment and OA changes is based on radiographic changes mainly and different multicenter OA studies [10-12]. Meniscus is an important tissue in the system of the knee. It is function is the load transmission and absortion shock. Complete or partial loss of meniscal tissue alters the biomechanical and biological of the knee joint modifying the pattern of load distribution and the instability of the knee. Meniscal narrowing, cartilage loss and chondral lesions increase the risk of secondary OA with cartilage degeneration. This secondary OA is associated to chondral damage, ligamentous instability, and malalignment with reduction in the shock absorption capacity of the knee [13-15]. Extrussion has been associated with articular changes according to their depth into partial-thickness and full-thickens defects. Partial-thickness lesions are considered less symptomatic with little evidence of progression on osteoarthritis. Full-thickness chondral and osteochondral lesions frequently cause symptoms, and they are considered to predispose to premature osteoarthritis [16]. Osteochondritis dissecans studies have demonstrated knee joint dysfunction and high prevalence of osteoarthritic change after fragment removal and all the studies take in account the limitation of a small defect size from 1.5 to 4.0 cm2 as well the zone and the location of the defect in the cartilage [17, 18]. The anterior cruciate ligament (ACL) is the knee ligament most common disrupted. ACL lesion frequently is associated to other ligamentous structures like, menisci, the articular cartilage or subchondral plate [19, 20].
Articular cartilage is composed of four distinct regions and they differ in their collagen fibril orientation: (a) the superficial or tangential zone (200 μm), (b) the middle or transitional zone, (c) the deep or radial zone and (d) the calcified cartilage zone. The superficial zone is composed of thin collagen fibrils in tangential array parallel to surface with a high concentration of decorin and lubricin and a low concentration of aggrecan. The middle zone is composed thicker collagen fibrils more random organized. The deep zone is composed the collagen bundles thickest and arranged in a radial fashion, orthogonal to the surface, and the calcified cartilage zone, located above subchondral bone and the tidemark that persists after growth plate closure and is composed of matrix vesicles, vascularization and innervation from the subchondral bone. The collagen type in the calcified zone surrounding the cells is type X as in the hypertrofic zone of the growth plate [21, 22], [23]. From the superficial to the deep zone, cell density progressively decreases. The chondrocytes in the superficial zone are small and flattened. The chondrocytes in the middle zone are rounded, and the deep zone chondrocytes are grouped in columns or clusters and they are larger and express markers of the hypertrophy as well. Differences in expression of zonal subpopulations may determine the zonal differences in matrix composition and in the mechanical environment [24, 25].
Chondrocytes live at low oxygen tension within the cartilage matrix, ranging from 10% at the surface to less than 1% in the deep zones.
It is no clear how chondrocytes maintain their ECM under normal conditions since they lack access to the vascular system but gene expression and protein synthesis may be activated by injury. The aging may affect the properties of normal cartilage by altering the content, composition and structural organization of collagen and proteoglycans. The normal function of the articular cartilage within the joint is to be elastic and have high tensile strength and these properties depend on the extracellular matrix [28]. The chondrocytes produce, in appropriate amounts, this ECM that consist of structural macromolecules of type II collagen fibers, proteoglycans, non-collagenous proteins and glycoproteins, organized into a highly ordered molecular framework. The collagen matrix gives cartilage its form and tensile strength. Proteoglycans and non-collagenous proteins bind to the collagenous network and help to stabilize the matrix framework and bind the chondrocytes to the macromolecules of the network. The matrix protects the cells from injury due to normal use of the joint, determines the types and concentrations of molecules that reach the cells and helps to maintain the chondrocyte phenotype [29, 30].
The ECM surrounding the chondrocytes has been divided into zones depending on their distance from the cell. The pericellular matrix is localized immediately around the cell, the territorial matrix is next to pericellular matrix and the most distance is the interterritorial matrix. Each matrix zone is characterized by different types of collagens as shown in figure 1.
The organization of normal articular cartilage. The organization of chondrocytes is divided in superficial, middle or transitional, deep or radial and calcified cartilage zones with a boundary or tidemark between the first three zones and the calcified zone. The extracellular matrix is divided depending the distance from the chondrocytes. The pericellular zone is the matrix surrounding immediately the chondrocytes. The territorial zone is the next to pericellular zone and the interterritorial zone is the most distant. Every zone has specific characteristics related with the shape of the chondrocyte as well the activity and the expression of different molecules by the cell.
The pericellular matrix is a region surrounding chondrocytes in the articular cartilage where diverse molecules as growth factors have interaction with the receptors expressed on the membrane cell of chondrocyte. This region is rich in proteoglycans as aggrecan, hyaluronan and decorin. Type II, VI and IX are collagen most concentrated in the pericellular network of thin fibrils as fibronectin. Type VI collagen forms part of the matrix immediately surrounding the chondrocytes and may help them to attach to the macromolecular framework of the matrix. This pericellular matrix enclosed cells has been termed chondron. The territorial zone contains type VI collagen microfibrils but little or no fibrillar collagen. The interterritorial cartilage matrix is composed of a collagen type II, type XI collagen and type IX collagen integrated in the fibril surface with the non-collagen domain, permitting association with other matrix components and retention of proteoglycans. These collagens give to the cartilage form, tensile stiffness and strength [31-33].
Cartilage contains a variety of proteoglycans that are essential for its normal function. These include aggrecan, decorin, biglycan, fibromodulin and lumican each proteoglycan has several functions determined. The proteoglycans are very important for protecting the collagen network. Other non-collagen molecules as the matrilins and cartilage oligomeric protein (COMP) are also present in the matrix. COMP acts as a catalyst in collagen fibrillogenesis, and interactions between type IX collagen and COMP or matrilin-3 are essential for proper formation and maintenance of the articular cartilage matrix. Perlecan enhances fibril formation, and collagen VI microfibrils connect to collagen II and aggrecan via complexes of matrilin-1 and biglycan or decorin [34].
Throughout life, the cartilage undergoes continual internal remodeling and the chondrocytes replace matrix macromolecules lost through degradation. Therefore normal matrix turnover depends on the ability of chondrocytes to detect alterations in the macromolecular composition and organization of the matrix, including the presence of degraded molecules, and to respond by synthesizing appropriate types and amounts of new molecules. In addition, the matrix acts as a signal transducer for the cells. Loading of the tissue due to use of the joint creates mechanical, electrical, and physicochemical signals that help to direct the synthetic and degradative activity of chondrocytes [22, 35].
Chondrocytes respond to the mechanical and biochemical changes in ECM through signaling events by various cell surface growth factor receptors and adhesion molecules. ECM proteins can determine the cell behavior, polarity, migration, differentiation, proliferation and survival by communicating with the intracellular cytoskeleton and transmission of growth factor signals. Integrins and proteoglycans are the major ECM adhesion receptors, which cooperate in signaling events, determining the signaling events, and thus the cell function [36].
Integrins are heterodimeric transmembrane receptors formed of eighteen α subunits and eight β subunits and they are non-covalently assembled into 24 combinations. The integrin dimers bind to different ECM molecules with overlapping binding affinities determining expression patterns and the downstream signaling events in the cell. Integrins respond specifically to the molecular composition and physical properties of the ECM and integrate both mechanical and chemical signals through direct association with the cytoskeleton. Integrins recognize and bind to the Arg-Gly-Asp (RGD) motif that they are attachment sites for integrin mediated cell adhesion. It has been demonstrated that high density of RGD motifs allows a precise spatial distribution pattern of integrins for specific cellular response among ligand molecules [36, 37].
Integrins can activate several signaling pathways independently and frequently they act synergistically with other growth factor receptors as insulin receptor, type 1 insulin-like growth factor receptor, VEGF receptor, TGF-b receptor, platelet-derived growth factor-b (PDGF-b) receptor and epidermal growth factor (EGF) receptor [37,38].
The heparan sulfate proteoglycans (HSPGs) contribute to the organization of the matrix by binding to the many core matrix molecules via HS chains as laminin, fibronectin and collagen. The chondroitin sulphate proteoglycans (CSPGs) as aggrecan, versican, brevican and the small, leucine-rich proteoglycans such as decorin and biglycan also bind to and regulate a number of growth factors, such as members of the TGF family. The hyaluronic acid is a glycosaminoglycan synthesized on the cell surface and is responsible for the gel-like consistency of cartilage by its hydroscopic properties [36, 39].
During normal or pathologic physiology of the cartilage, the ECM must be remodeling and degraded to allow the chondrocytes for processing and deposition of new matrix by specific proteases. There are two well-known families of proteases that are involved in the biology of the ECM, the matrix metalloproteinase (MMP) and the desintegrins and metalloproteinases with thrombospondin motif (ADAMTS) families. The MMP-13 is involved in the cleavage of fibromodulin and type IX collagen and is present and active in the pathological process of cartilage as OA and rheumatoid arthritis. The aggrecanases family’s ADAMTS-4 and ADAMTS-5 play an important role in cartilage damage during early OA which cleavage the glycosaminoglycans chains that are the key contributors to the maintenance of the charge density, the osmotic environment and water retain important characteristics of the mechanical properties of the cartilage [40, 41].
The extracellular matrix has structural and functional relevance, it’s a highly organized and assembled macromolecular structure, also provide cellular adhesion environments, activation and inactivation of growth factors and regulatory cytokines. The proteolytic processing of ECM components, results in the production of fragments with biological effects on migration, proliferation and cellular organization.
When any component of the ECM has a disorder, could generate chondrodysplasia, it means alterations in the development and growth of cartilage. Chondrodysplasias are caused by various mutations in genes involved in cartilage development and finally in the formation and growth of the long bones. These mutations also often alter the formation of other tissues.
Achondrogenesis type II, is a chondrodysplasia classified as collagenopathy type II. In this family are located several chondrodysplasia caused by mutations in the gene for collagen II, which is the most abundant protein in cartilage [42]. These dysplasias are, achondrogenesis type II, hypochondrogenesis, congenital espondiloepiphysial dysplasia and Kniest dysplasia, among others. Collagen II is a homotrimer (three identical chains encoded by the COL2A1 gene located on chromosome 12. This collagen is mainly found in the hyaline cartilage and vitreous humor, so its deficiency is associated with abnormalities of the spine, of the epiphysis and eye problems. Despite their differences these dysplasias share clinical and radiological manifestations, so the axial skeleton is affected more than the limbs, cleft palate, myopia and retinal degeneration [43].
Furthermore, other disorders of matrix components such as collagen IX and XI, which interact with the collagen II to form supramolecular structures, are closely related phenomena.
It is found that the Osteogenesis Imperfecta (OI) is caused by molecular defects of collagen type I[44] and metaphyseal chondrodysplasia Schmid type is caused by errors in collagen type X biosynthesis [45], the latter is characterized by alterations in vertebrae and in the metaphysis of long bones, also show reduction of the area of reserve cartilage in growth plate and in the articular cartilage, alters the contents of bone and there is an atypical distribution of the matrix components of the growth plate.
The cartilage oligomeric matrix protein (COMP) is a member trombospondins family, and its alteration causes pseudoachondroplasia, this disorder shows short limbs and lax ligaments [46], the growth plate is shorter and the area of hypertrophic cartilage is reduced.
Cartilage needs molecular signals for development and maintenance, such as growth factors, which in many cases are regulating the synthesis of the ECM, and may be found active or latent in the extracellular matrix. Bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-β), growth and differentiation factor 5 (GDF-5), are signals related to the development and growth of cartilage, alterations in these molecules cause some malformations, such as the brachypodism (short limbs) [47].
Cartilage matrix is rich in sulfated proteoglycans and the gene encoding for sulfate transporter called DTDST (Dystrophic Dysplasia Sulfate Transporter) in patients with dystrophic dysplasia was found mutations in this gene, and shown to be deficient cartilage sulfating [48].
Campomelic dysplasia is a rare disease associated with XY individuals who possess varying degrees of sex reversal. SOX-9 is a transcription factor structurally related to the gene SRY (sex-determining region Y) required for testicular development. However, SOX-9 also directly regulates the gene for type II collagen, the main molecule of the cartilage matrix and therefore of chondrocyte differentiation [49, 50, 51].
The inactivation of the gene coding for the mouse gelatinase B, defined the mechanism that controls the final step of the chondrocyte maturation [52]. Gelatinase B is an enzyme present in the extracellular matrix of cartilage and its activity is related to the control of apoptosis of hypertrophic chondrocytes and the vascular tissue. This study hypothesized the existence of chondroclast, these cells of myeloid origin express gelatinase-B and are located in the cartilage/bone region and resorb cartilage matrix.
Based on the above is to emphasize the importance of the extracellular matrix as a modulator of cellular differentiation of chondrocytes, the extracellular components correlate with the differentiation state. That is, collagen I is present at early stages of differentiation and maturation, in mesenchyme and perichondrium; collagen II is on mature cartilage and collagen X is exclusive of hypertrophic cartilage also collagen type I are expressed in terminal stages of chondrocytes [53].
The ECM not only serves as a binder that gives form to tissues in addition to their structural role has physiological functions. The chondrocytes are in the array a series of signals that allows them to gain some cell shape and organization of the cytoskeletal network. Cell morphology that can modulate many physiological functions such as proliferation, differentiation, cell death and gene expression. This transmembrane receptor-mediated would be able to receive the extracellular signal from the ECM and transduce the signal into the cell, triggering a response by the chondrocyte differentiation [54].
Integrins are transmembrane receptor consisting of one α subunit and a β, are only functional to form the α-β heterodimer on the cell membrane. β1 family of integrins are major receptors of ECM molecules and have the ability to allow cell adhesion and simultaneously issuing an intracellular signal to which the cell responds in different ways, as also interact with integrins the cytoskeleton and molecules involved in signal transduction.
It has been shown that integrins interaction with extracellular matrix molecules affects cytoskeleton organization, proliferation, differentiation and gene expression in fibroblasts and epithelial cells.
In addition we have studied the survival and differentiation of chondrocytes, including the deposit in the interstitial matrix of collagen type X could be mediated by integrins [55]. Inhibition of integrin b1 subunit with a neutralizing antibody blocks the deposition of collagen X in the interstitial matrix and growth of the breastbone is decreased. Moreover, the chondrocytes are significantly smaller, show a disorganization of the actin cytoskeleton and show increased apoptosis.
There is also evidence that blocking the β1 subunit of integrins in an in vitro model of differentiation of cartilage inhibits cartilage nodule formation and the synthesis of collagen type II [56].
However, the study of the role of these receptors in the process of chondrocyte differentiation is not yet well established, but it would be of significant importance in determining the relationship of the extracellular matrix to the chondrocyte.
Articular cartilage mineralization frequently accompanies and complicates osteoarthritis and aging. Several works has demonstrated that certain features of growth cartilage development are shared in degenerative cartilage. These include chondrocyte proliferation, hypertrophy, matrix mineralization and apoptosis. Development of growth plate is regulated by growth factors signaling and cellular interactions with the extracellular matrix (ECM). Parathyroid hormone related protein (PthrP) and Indian Hedgehog (Ihh) are central mediators of endochondral development; PthrP is abundant in synovial fluid of osteoarthritic patient but Ihh expression is diminish in OA cartilage, Fgf-18 is a regulator of chondrocyte proliferation and its intra-synovial application in OA rat results in cartilage generation. Also, Wnt signaling plays an important role in chondrocyte differentiation in growth plate, Wnt-5a promotes chondrocyte prehypertrophy and inhibits chondrocyte hypertrophy unlike Wnt-4 that induces chondrocyte hypertrophy and increases its expression in early stage of osteoarthritis. On the other hand, is pronounced imbalance of cartilage matrix turnover in osteoarthritic cartilage, and results in mayor deposition of collagen type I and X, reduced expression of collagen type II. Thus, the rate of chondrocyte hypertrophy is higher on growth plate and OA articular cartilage than healthy articular cartilage, it recap the signaling in cartilage growth plate. But, although articular and growth plate cartilages share several features, there are one important difference, the rate of cartilage hypertrophy. What is the signal that makes the difference? In the ECM we could find some elements to answer this question.
Traditionally it has been thought that osteoarthritis is a disease of wear or tears consequence of articular cartilage due to aging or following injury. The limited regenerative capacity of cartilage cannot reverse its destruction, it is sometimes triggered by an inflammatory response from the synovial, inflammation occurs when the condition is called osteoarthritis [57]. Until recent years genetic mutations were excluded as a risk factor or predisposition to osteoarthritis. The first genes identified to OA encode components of the extracellular matrix, such as Collagen
Although exists different types of cartilage, they are very similar but have different functions. Articular cartilage and cartilage growth plate are good examples. In general, the molecular mechanisms of chondrocyte differentiation in both cartilages are equivalent. However, for the function of synovial joints is essential that chondrocytes maintenance in prehypertrophic state differentiation, while the longitudinal growth of bone depends on the proliferation and differentiation of chondrocytes in the growth plate to the hypertrophy and bone formation [67, 68]. We can even talk about a model that relates the structure and function of cartilage based on histological and functional differences of both cartilages. Both in the cartilage growth plate and in articular cartilage chondrocytes can be found at various stages of differentiation, but the organization and activity of chondrocytes differ in each stage of both cartilage.
In the growth plate chondrocytes reserves represent an immature state and are organized in tiny rows of small round cells, embedded in an abundant extracellular matrix rich in collagen type II and aggrecan, proliferating chondrocytes are stacked as "coins" several rows forming compact occupying a large area of the growth plate, the first rows are more proliferation activity than the rows deep; prehypertrofic chondrocytes (mature) are larger cells that have exited the cell cycle and express Ihh, a key molecule in cartilage differentiation, these cells secrete and accumulate a large amount of carbohydrates and finally the hypertrophic chondrocytes are cells of highest volume and high alkaline phosphatase activity, the ECM is mainly composed of collagen type X and begins to calcify, some cells degenerate and die by apoptosis leaving the spaces occupied to consolidate osteoblasts and bone tissue. This process is known as endochondral ossification which regulates the growth of bone in terms of cartilage differentiation. It is noteworthy that an important signaling center in this process is the perichondrium, which are very small and flattened cells surrounding the cartilage and expressed PTHrP [69] and Fgf-18 [70], which respectively induce and inhibit the proliferation of chondrocytes, the receiver PPR and PTHrP [71] is expressed in the upper rows, whereas the Fgf-18 receptor and FGF-R3 is found in the deeper cell layers of proliferating chondrocytes. Patch is Ihh receptor and is expressed in the perichondrium, so that Ihh induces the expression of PTHrP and this in turn induces proliferation and expression of Ihh in the growth plate. This regulatory loop promotes the longitudinal growth of the mold of cartilage, but it is necessary that the mold is rigid. For this, the FGF18 inhibits the proliferation of cartilage to regulate expression of Ihh and this result in the differentiation of chondrocyte hypertrophy up. This signaling cascade also occurs during the formation of joint cartilage, where bone formation is more limited as in the secondary ossification centers.
Articular cartilage has apparently different stages of differentiation of chondrocytes, only that which corresponds to the resting chondrocytes have important differences in the composition of the ECM, as the presence of lubricin, the Collagen type IIa the aggrecan, CD44, ASC, [72, 73] these cells are most abundant in the articular cartilage cells for proliferation area are not organized in rows and have very low proliferation rate, making them more similar to the prehypertrophic cartilage, as the rate of is very slow maturation, hypertrophic chondrocytes make up a small area of just one or two cell lines the border between cartilage and bone, known as "water mark" (tide mark).
The joints that separate from each other skeletal elements serve as important signaling centers during skeletal development, and regulate the proliferation and maturation of chondrocytes. It is well known that chondrocyte maturation is crucial for endochondral ossification and to define the final size of each skeletal element. In the end, the processes of the formation of joints and cartilage differentiation of skeletal elements are strongly related. The limb skeletal elements are formed by endochondral ossification, the process begins with the aggregation of mesenchymal cells that form the pre-cartilaginous condensation, this condensation increases the proliferation of chondrocytes and forms a "bar" initial cartilage [74]. It has been proposed that the first step for the formation of the joint is that it inhibits differentiation of prehypertrofic chondrocytes in cells located in the region of the joint prospecting, outside the influence of signals that promote maturation of the cartilage, while neighboring cells continue their differentiation process to form bone hypertrophy and subsequently by endochondral ossification, so contributing to the formation of adjacent skeletal elements [75]. Cells suspected joint region form the interzone, characterized by a highly packed region of flattened cells, these cells produce other types of collagen and collagen type I and III, unlike chondrocytes that produce collagen type II. The interzone also expressed molecules such as Wnt-9a [76] and Bmp antagonists like noggin [77], which remain the property of these cells not chondrogenic. Some cell adhesion molecules such as integrin α5β1 also regulate the formation of joints by controlling the differentiation of chondrocytes [78], whereas other signaling molecules that are expressed in the interzone as Wnt-4, Fgf-18, Gdf (5, 6 and 7) and several members of the Bmp, promote growth and differentiation of adjacent cartilaginous elements [79]. It is likely that different cell types present in a mature synovial joint, including synovial cells, articular chondrocytes and permanent joint capsule cells originate in the interzone. Permanent articular chondrocytes originating from the interzone, are very similar to chondrocytes in the growth plate, and although both cell types are hyaline cartilage and functions have important differences. The most important difference is that articular chondrocytes decrease its maturation toward hypertrophy of chondrocytes unlike the growth plate which we observed a wide region of hypertrophic chondrocytes, as this process allows for the ossification and growth of long bones. Hypertrophic chondrocytes are the highest volume and produce a very specific extracellular matrix rich in collagen type X. The hypertrophy of chondrocytes is followed by apoptosis, the invasion of blood vessels, osteoclasts and other mesenchymal cells from the perichondrium and production of bone matrix. Therefore, the size and fine structure of the long bones depends on the coordinated regulation of proliferation, maturation and hypertrophy of chondrocytes in response to many extracellular signals. The protein Indian hedgehog (Ihh) and peptide related to Thyroid Hormone (PTHrP) play a critical role in these processes, Ihh is produced by prehypertrophic chondrocytes and induces the expression of PTHrP in the perichondrium which in turn regulates the rate of chondrocytes which exit the cell cycle and continue to hypertrophy [80]. Ihh also stimulates proliferation of chondrocytes and controls the differentiation of mesenchymal cells into osteoblasts in the collar bone. Thus, when the chondrocytes stop expressing Ihh activates the expression of Runx-2 and Runx-3 [81], some transcription factors required for hypertrophy of chondrocytes and differentiation of osteoblasts. On the contrary, in particular FGF-18 [82] expressed in the perichondrium and through its receptor Fgf-R3 expressed in cartilage prehypertrofic cartilage negatively regulates cell proliferation and promotes the hypertrophy of chondrocytes, the constitutive activation of FGFR3 results in dwarfism [83] and may inhibit the formation of joints, this confirms the idea that proliferating chondrocytes may have two possible destinations, become pre-articular chondrocytes or prehypertrophic chondrocytes.
During the formation of the skeleton some chondrocytes are involved in the growth of long bones and ossification. At this early stage, the GDF-5 signaling is essential for the formation of joints and articular cartilage [84, 85], its expression is delimited in the interzone and begins just before forming the joints, on the other hand, the Bmp-7 is important for the chondrocyte maturation and bone formation and is expressed in the perichondrium of the skeletal elements in formation and growth [86], but not expressed in the perichondrium of the developing cartilage. Although the induction of the joint is initiated by the expression of Wnt-9a in the interzone and the interzone chondrocytes lose their phenotype [76], GDF-5 signaling is essential for the joint and articular cartilage formation. Ihh is another important molecule for skeletal development, Ihh inhibits Wnt-9a expression and is maintained in skeletal growth and endochondral ossification, as when it reaches a certain size decreases the expression of Ihh and thereby activates the expression of Wnt patway induces hypertrophy of chondrocytes and bone formation [87]. It is noteworthy that during the OA Wnt signaling is overactivated [65] and GDF-5 is down-regulated, which suggests a recapitulation of endochondral ossification during OA. Furthermore, when the receptor Bmp-RIA is inactivated in mouse generated phenotypes similar to human osteoarthritis and when activated the Wnt pathway by blocking antagonist Dkk [64], reverse the process of articular cartilage destruction and endochondral ossification, this suggests that these pathways permit the maintenance of adult articular cartilage.
Not only in the embryonic stages imbalance of proliferative signals and bring important consequences hypertrophy in articular cartilage, osteoarthritis is a striking example of this imbalance of signals. There are animal models that recapitulate this degenerative joint disease, as in the case of the mutant mice of Smad-3 [63], a molecule that transduces the TGF-β signal. Molecular analysis of these mice shows ectopic expression of type X collagen in the articular cartilage and increased hypertrophy of chondrocytes; this shows the TGF-β as an inhibitor of differentiation of articular chondrocytes. Similarly, the cancellation of Mig-6 in mice results in early degeneration of joints [66], as evidenced by degradation of articular cartilage, fibrous tissue formation and growth of osteophytes. It is well known that articular cartilage injuries may result in osteoarthritis, fibrous tissue formation is an immediate healing response to a traumatic injury, and the healing is often promoted by TGF-β, which in turn could induce osteophyte formation that recapitulates chondrogenesis and endochondral ossification in adult articular cartilage.
During development are constantly chondrocytes proliferation and differentiation, thus skeletal elements grow in length and ossify, as mentioned earlier, articular cartilage chondrocytes have a low rate of proliferation and differentiation, this makes them different and allows articular cartilage is kept almost throughout life. What keeps the ever-growing cartilage during development is the molecular signals that modulate the rate of growth and differentiation, these signals are regulated by the perichondrium. The perichondrium has progenitor cells that are very useful for cartilage repair, its similar to bone, the periosteum is important for bone repair, such as fractures. While the perichondrium is maintained until adult stages, the perichondrium is disappearing from the stage young individuals, which is why the low capacity of regeneration of cartilage [88].
The hyaline articular cartilage is a highly specialized tissue and its main function is to protect the bone from friction in the joints [89, 90], once articular cartilage is damaged their ability to self-repair and regeneration is limited as mentioned above. Cartilage injuries are mainly associated with anterior cruciate ligament, patellar dislocation, followed by a meniscectomy [91]. Osteochondral lesions of the knee are determined mainly by arthroscopic knee surgery [92, 93], which is seen mainly in traumatic injuries, together with abnormal stresses on the knee.
To determine the treatment for the repair and regeneration of articular cartilage injury, have developed different techniques, the techniques described are focused on the repair, reconstruction or regeneration of tissue. The repair methods (drilling or microfracture) support the formation of new tissue fibrocartilaginous [94, 95] while the reconstructive method seeks to fill the defect with allografts (OATS) combining with miniarthrotomy arthroscopy. And finally the regenerative methods that rely on bioengineering techniques to develop a hyaline cartilage tissue graft or autologous chondrocyte cell matrices (Table1).
\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
[96] | \n\t\t\tDrilling with lavage and debridement | \n\t\t\tRemoval of osteophytes and knee abrasion | \n\t\t\t\n\t\t |
[97] | \n\t\t\tPerform subchondral drilling of the lamina | \n\t\t\tTissue repair and pain relief | \n\t\t|
[98] | \n\t\t\tElimination of subchondral lamina | \n\t\t\tSignificant symptomatic improvementin 75% of patients | \n\t\t|
[99, 100] | \n\t\t\tMicrofracture | \n\t\t\tPerforation of the subchondral lamina by arthroscopy, it promotes the release of mesenchymal cells in the lesion, forming a plug of tissue | \n\t\t\tAvoids necrosis associated with the use of the drill and preserves the subchondral surface. The results observed in the medium term, mainly in young patients, about 20% of patients do not reach after five years. | \n\t\t
[101- 104] | \n\t\t\tChondrogenesis induced stimulation of bone marrow (AMIC) | \n\t\t\tFollowed by a micro abrasion bill and placing a collagen scaffold on the defect, inducing the formation of fibrocartilage by migrating mesenchymal cells and the expression of cytokines and tissue repair | \n\t\t\tStimulation of bone marrow has limited mechanical strength and may even degrade the cartilage is repaired with fibrous tissue or fibrocartilage so that there is tissue degeneration. \n\t\t\t | \n\t\t
[105- 107] | \n\t\t\tMosaicplastyandtransplantosteochondral allograft | \n\t\t\tIs based on obtaining osteochondral cylinder obtained from areas of low load from the distal femur, which are grafted into the defect | \n\t\t\tThe results are limited in large lesions due to donor site morbidity and healing of the seams in the recipient | \n\t\t
[108- 110] | \n\t\t\tAutologous chondrocyte implantation | \n\t\t\t1st Generation: In this technique, cartilage cells are injected under a cover of periosteum is sutured into the defect. 2nd. Generation: is replaced cover membrane or periosteum biomaterials, which can have different components | \n\t\t\tIt has been reported good results in most patients after 10-20 years after implantation. In the second generation transplants with areas of fibrocartilage, possibly because of low cell density and lack of proliferative capacity. This technique replaces healthy cartilage to regularize the defect. | \n\t\t
[111] | \n\t\t\tAutologous chondrocyte implantation induces extracellular matrix | \n\t\t\t3rd. Generation: In this technique, autologous chondrocytes cultured on a three-dimensional artificial scaffold | \n\t\t\tHas been used in the past two decades, with this type of membranes hypertrophy is reduced by 5%, after 3 to 6 months membrane is reabsorbed. | \n\t\t
Cartilage repair techniques
Each of these procedures is associated with improvement of these techniques with the use of biomaterials or with the use of growth factors. In the autologous chondrocyte implantation of the second generation is required arthrotomy so this technique becomes more complicated. In order to facilitate and improve the technique and quality of the tissue repair, has developed a method which has proved more effective and easy to implement in the knee joint [112, 113] develop and autologous chondrocyte implantation induced extracellular matrix of the third generation.
This technique is mainly based on the autologous cultured chondrocytes on a biocompatible three-dimensional scaffold which is subsequently implanted into the defect. As in the technique of autologous chondrocyte implantation of the second generation, it requires a prior arthroscopic surgery where a piece of cartilage obtained from a zone of no load of the knee joint (intercondylar notch or the lateral edge of the trochlea) after obtaining the sample fragment is processed to obtain chondrocytes in culture.
Cartilage fragments are disintegrated mechanically to obtain smallest fragment, is performed subsequent enzymatic digestion to release trapped chondrocytes in the matrix of collagen. Expansion of chondrocytes was performed in 8 weeks. Days before implantation chondrocytes are seeded on a scaffold or membrane [112] Rich in collagen, which is considered a three-dimensional extracellular biomaterial consists mainly of collagen I and III, the scaffold contains glycosaminoglycans, proteoglycans and glycoproteins [111, 114, 115] cells are capable of synthesizing a typical matrix of chondrocytes facilitating cell adhesion and influence the morphology, migration and differentiation of cells.
The main advantages of autologous chondrocyte transplantation induced extracellular matrix (third generation) is that no cell loss is not presented hypertrophic tissue growth, requiring only a second incision is a safe procedure for treatment of injuries symptomatic articular cartilage surgery facilitates reducing the operating time and the need for open surgery compared to traditional surgery for autologous chondrocyte implantation (second generation). While in the second generation technique leads to form hyaline cartilage on the surface showing fibrosis and proliferation of small blood vessels (reactive fibrosis), by the use of periosteum, so that in this case it is advisable the use of membrane collagen
In recent years they have sought new strategies for cartilage repair, with technological advances have currently been proposed the use of scaffolding or matrix on which cells can grow. Among the scaffolds used in the clinic (Table 2) are those that are based on collagen, hyaluronic acid and fibrin as these provide a substrate normally found in the structure of native articular cartilage. Collagen is a major extracellular matrix protein, exists to provide strength and stability to the connective tissues. At the clinic is used collagen I-III as scaffolds for growing chondrocytes in order to improve the structural and biological properties of the graft [116, 117] this is used as a sponge, foam, gel and membrane form, all these are subject to enzymatic degradation. Hyaluronic acid is another important component of articular cartilage matrix and is a glycosaminoglycan that is involved in homeostasis [118, 119] provides viscoelasticity to synovial fluid, is credited as a lubricant and shock absorbing properties, is essential for the correct structure of proteoglycans in articular cartilage. Between scaffolds containing hyaluronic acid is the Hylaff-11, which is an esterified derivative of hyaluronic acid and is used for growing chondrocytes in three dimensions, has been shown that when using this type of scaffold maintaining the chondrocyte phenotype, so that chondrocytes are capable of producing the proteins and molecules characteristic of a hyaline cartilage [120-122]. Fibrin is a protein involved in blood coagulation, is regarded as a biomaterial for cartilage repair, as can be found in gel form, having an adhesive function that is also biocompatible and biodegradable [123]. However in vivo studies in animals have shown to have low mechanical stability and can also trigger an immune response [124, 125], fibrin because this has only been used clinically to ensure healthy cartilage tissue-engineered the [126-128].
\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
[126, 129- 132] | \n\t\t\tCarticel | \n\t\t\tCollagen I-III | \n\t\t\t2nd and 3rd generation | \n\t\t\tThree-dimensional multi-layer keeps the chondral phenotype | \n\t\t
[113] | \n\t\t\tMatricel | \n\t\t\t2nd generation | \n\t\t||
[133, 134] | \n\t\t\tCaReS® | \n\t\t\tCollagen I hydrogel | \n\t\t\t2nd generation | \n\t\t\tIt presents a significant functional improvement as well as acting on the levels of pain. | \n\t\t
[135- 136] | \n\t\t\tHyalograft-C | \n\t\t\tHyaluronic acid | \n\t\t\t3rd generation | \n\t\t\tMaintaining the chondral phenotype, absence of inflammatory response, formation of hyaline cartilage | \n\t\t
[137] | \n\t\t\tHyalgan® | \n\t\t\t-------------- | \n\t\t\tIndicated for the treatment of osteoarthritis of the knee, improves mobility and reduces pain. | \n\t\t|
[113] | \n\t\t\tTisseel | \n\t\t\tFibrin | \n\t\t\t3rd generation | \n\t\t\tFibrin is an integral component of the extracellular matrix induced chondrocytes, so that the new cartilage is well integrated into the underlying subchondral bone. Moderate application of fibrin \n\t\t\t | \n\t\t
[138] | \n\t\t\tCartipatch | \n\t\t\tAlginate Hydrogel-agarose | \n\t\t\t-------- | \n\t\t\tHyaline cartilage was observed in eight of the 13 patients treated, clinical improvement at 2 years of treatment \n\t\t\t | \n\t\t
Biomaterials most used in the clinic, with different components for the repair of articular cartilage by autologous transplantation method of chondrocytes from second and third generation.
Based on the foregoing and which is being used in the clinic and according to results obtained in patients who have been treated with different biomaterials has been observed that although there is a suitable biomaterial that contributes to the production of extracellular matrix to provide the right conditions for chondrocyte cell differentiation. So it is necessary to propose new biomaterials that help produce extracellular matrix, capable of activating a cascade of signaling that can form a cartilage which has structural properties suitable for tissue repair, as well as having viscoelastic properties and to provide mechanical stability.
Many advances in the field of cartilage tissue engineering have been closely connected to the improved performance of biomaterials. Successful cartilage tissue engineering relies on four specific criteria: (1) cells, (2) signaling molecules, (3) biomaterials, and the (4) mechanical environment. Furthermore, they should be biocompatible, non-toxic, bioresorbable and highly permeable to facilitate mass transport [139].
The use of scaffolds to support replication of chondrocytes for production of cartilage in vitro has been the most common approach for tissue engineering of cartilage, however, despite the apparent simplicity of cartilage, to our knowledge, tissue engineered cartilage has not been successfully reached so far [140-142].
In theory, a scaffold for tissue engineering should have a three dimensional porous structure forming an interconnected porous network. These structures should be made of biocompatible and biodegradable materials capable to provide mechanical strength, support cells ingrowth, promote cells adhesion, uniform cell spreading, and conserve phenotypes and functional characteristics of transplanted cells [143,144]. Unfortunately, this list of requirements looks too long and hard to accomplish. Probably this is one of the main reasons of why the advances in cartilage engineering have been too slow. But also we should rethink these concepts in order to find shorter and easier pathways to find more efficient and effective tissue engineering methods.
The vast majority of scaffolds used in tissue engineering are solid sponge-like porous structures that are seeded with cells in a culture media. Analyzing this approach from the basic principles for the design of biomaterials, the biomimetism, easily we can find out that this process lacks of this basic concept. In natural tissues, cells grow in a physiological environment which is more like a gel medium than a porous scaffold, they do not form tissues by populating porous structures, but they do it by creating their own ECM starting from a gel-like environment. Following this line, many researchers are proposing the encapsulation of cells in hydrogels instead of using porous scaffolds, looking to improve the biomimetic environment for cells [145,146,147,148].
Besides biomimetism, sponge-like scaffolds provides only a two dimensional surface for cell attachment, although their structure is 3D, cells attach to the walls of the scafflod, thus changing completely the way they are integrated into natural tissues. On the other hand hydrogels are capable to provide a real 3D environment when cells are seeded (encapsulated) into them [149].
Hydrogels are water-swollen, cross-linked polymeric structures [150] that possess unique mechanical and chemical properties that make them very attractive for a variety of biomedical applications; actually there are no other materials capable to display characteristics too close to natural tissues such as Hydrogels. Therefore hydrogels have been considered as a key material in the development of new biomaterials for tissue engineering and artificial organs fabrication.
Their particular properties come from their structure, composed of swollen randomly crosslinked networks of rod-like polymer chains with water filling the interstitial spaces.[151] Water commonly comprises more than 80% of the total volume. The physical properties of hydrogels are determined by the polymer composition and concentration, the cross-linking density between polymer chains [152], polymerization conditions [153], the addition of hydrophobic monomers which may create regions of more dense coiled or entangled chains, the introduction of composite materials such as rubber or glass, the use of cross-linking agents such as glutaraldehyde, and the use of freeze-thawing procedures to induce partial crystallinity [154].
Hydrogels can be classified by the type of crosslinking: covalently or ionic cross-linked, physical gels, or entangled networks [155]. The two first are the most common gels. Physical gels are formed by non-covalent interactions, such as hydrogen bonding, and hydrophobic interactions [156]. Covalently or ionic cross linked gels are considerably more stable than physical gels and once they are formed they may not be re-melted again.
Hydrogels can be obtained from natural or synthetic polymers. Natural hydrogels come from proteins and polypeptides (commonly collagen and gelatin), polysaccharides (i.e. alginate, agarose, hyaluronic acid, fibrin, chitin and chitosan). On the other hand, synthetic polymers come from man-made materials such as polyester (i.e. poly L-lactic and polyglycolic acid, poly ε-caprolactone, polypropylene fumarate), polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyurethane, polydiol citrates, polyhydroxyethyl methacrylate, and many others polymers [157].
Although hydrogel scaffolding technologies plays a crucial role in cartilage tissue engineering, several studies has been shown low success cartilage tissue repair. They are unable to generate cartilaginous tissues with similar properties to native cartilage [141-142].
There are a number of reasons for scaffolds failure, we summarized some of them:
The scaffold architecture should be designed to mimic the depth-dependent heterogeneity of articular cartilage structure or to generate multiphasic scaffolds to promote the simultaneous growth of bone and cartilage with a stable interface for engineering osteochondral tissue.
However, manufacturing scaffolds technologies are limited and no optimum architectures have been produce yet.
The study of biological cartilage development is still growing.
Not enough knowledge about:
the role of chondrocyte ECM and their implications during chondrogenesis.
the role of adhesion molecules and signaling pathways during chondrogenesis.
Culture chondrocytes
Dynamic cartilage ECM and their Nanomechanical properties.
Chemical variables in cell-scaffolds interactions, among others.
However towards designing biomimetic native environments cartilage is still a challenge due articular cartilage is intricately organized and heterogeneous tissue. This tissue reveals a highly defined structural organization that can be subdivided into two domains, the cartilage zones and the organization of the extracellular matrix. In that sense the ECM of articular cartilage is a unique environment with complex heterogeneity and spatial conformation very difficult to mimic. One of the most notable variations in this tissue is the spatial organization of collagen network and cells arrangement. [141]. Moreover cartilage presents different morphology, gene expression, matrix spatial array between cultured populations isolated from distinct cartilage zones [142]. However, intensive researches have been focus on the development of an ideal scaffold material with versatile properties that actively contribute to cartilage repair [158]. In that regard, there have been several attempts trying to recreate the different zones in cartilage by different hydrogel fabrication technologies, giving as a result tridimensional homogeneous structures with little resemblance to the native organization in cartilage, so it is necessary to material scientists thinking in others design hydrogel-scaffolding strategies trying to biomimetic hierarchical structures capable to deliver bioactive molecules such as growth factors with an ideal mechanical response and mediated by adhesive molecules in order to have an integration tissue [159].
Currently strategies in the design of biomimetic cartilage hydrogels are governed by the use of collagen Type I and derived from porcine small intestine submucosa implants. Although the chondrocytes typically lose their phenotype, the gene expression patterns changed when they are removed from their native environment, so give them a proper environment is necessary to keep its phenotype of chondrocytes in different populations to recreate the zonal organization [160]. In addition, biological trials
According with reference [163] concentrations of 12-25 million cells/cm2 are needed to increase the matrix production and mechanical properties of human adult chondrocytes under static conditions. Nevertheless, material researches are focus on fabrication of three-dimensional artificial arrays in form of hydrogels using macromolecules present in the cartilage inter-territorial matrix and trying to mimic the distinct cartilage zonal [160]; however, no substantial data of the formation of cartilage are reported.
Others approaches in cartilage tissue engineering are the use of hydrogel culture employed mesenchymal stem cells (MSCs) and the use of bioreactors in order to provide the necessary biochemical and biomechanical stimulations to enhance chondrogenesis [164,165]. Due to the many mentioned limitations related to chondrocyte sources, there is much effort to explore better alternative cell sources. Desirable characteristics for such sources include accessibility, availability, and chondrogenic capacity. Consequently, stem cells such as adult mesenchymal stem cells (MSCs) have emerged as promising cell sources for articular cartilage tissue engineering. Chondrogenic potentials of MSCs from different tissues have also been investigated and compared. Specifically, MSCs from bone marrow are the most popular considering they are easily harvested (via the iliac crest) and have good chondrogenic potential. Many in vitro and in vivo studies have revealed promising results of marrowderived MSCs combined with various biomaterials or growth factors for repairing cartilage defects [164,166]. Recently, Johnson et al. describe the discovery and characterization of kartogenin, a small molecule that induced stem cells to take on the characteristics of chondrocytes and improves joint function and promotes the regeneration of cartilage in vivo in two rodent models of chronic and acute joint [166].
Mechanical stresses are an important factor of chondrocyte function as they stimulate them to increase the synthesis of ECM components. In cartilage culturing processes the main types of mechanical forces currently being investigated are hydrostatic pressure, direct compression, shear environments [167, 168].
Finally, to better recapitulate the ECM environment for cartilage tissue engineering, researchers have to introduce several biological signals, including chondroitin sulfate (CS), hyaluronic acid (HA), and collagen type I and II, into tissue-engineered scaffolds to encourage tissue specificity [169]. CS, hyaluronic acid, and collagen type II have been shown to promote or enhance chondrogenesis of mesenchymal stem cells (MSCs) in hydrogel-based culture systems. In addition to the physical cues of native matrix, cells are exposed to an array of biological cues throughout the ECM that direct cellular behavior.
Cells are constantly interacting with the surrounding ECM, which gives rise to a dynamic transfer of information between the extracellular and intracellular space. In addition, biological trials
Tissue engineering should be the best way to achieve successful cartilage regeneration by combining novel biologically inspired scaffolds approaches, nanotechnology, cell sources such as stem cells, chondrogenic factors, and physical stimuli [165].
Herpesviridae is a large family of double-stranded DNA viruses, which is included in the recently classified order Herpesvirales. This family can be further classified into three distinct subfamilies:
The
Subfamily | \nGenus | \nSpecies | \nDisease | \n
---|---|---|---|
\n | \n\n | \n\n (Herpes simplex virus 1) \n (Herpes simplex virus 2) | \nAcute Herpetic gingivostomatitis, Keratitis, Conjunctivitis, Encephalitis, Dermal whitlow, Herpes labialis Herpes genitalis | \n
\n | \n\n ( | \nChickenpox/ shingles | \n|
\n | \n\n | \n\n (Human cytomegalovirus) | \nCongenital abnormalities | \n
\n | \n\n (Human herpesvirus 7) | \nFebrile illnesses | \n|
\n (Human herpesvirus 6A, 6B) | \nInfant rash Exanthem subitum | \n||
\n | \n\n | \n\n (Epstein–Barr Virus) | \nInfectious mononucleosis (Glandular fever), Burkitt’s lymphoma, Hodgkin’s lymphoma, Nasopharyngeal carcinoma, Oral hairy leukoplakia | \n
\n | \n\n (Kaposi’s sarcoma-associated virus or Human herpesvirus 8) | \nKaposi’s sarcoma | \n
Taxonomy of Human Herpesviruses [2].
EBV is ubiquitous virus, with a seroprevalence of more than 90% of the adult population worldwide. It was first identified in 1964 by Anthony Epstein’s group in a cell line from a Burkitt’s lymphoma biopsy [4, 5]. The EBV has also been identified as a B lymphotropic oncogenic virus owing to its capacity to convert resting B lymphocytes in vitro, inducing continuous dissemination of infected B cells and producing lymphoblastic cell lines (LCLs) [6]. This discovery was central to the identification of EBV as the first nominee human tumor virus. Subsequently, EBV was correlated with a variety of clinical malignancies, including Hodgkin’s Lymphoma (HL), post-transplant lymphoproliferative disease (PTLD) and X-linked lymphoproliferative disease (XLPD). The potential to invade other cell types other than B lymphocyte, such as T, natural killer (NK) and epithelial cells, has led to the association of EBV with other malignancies: peripheral T cell, nasal T or NK cell lymphomas, gastric and nasopharyngeal carcinomas (NPC) [3, 7]. However, infection with EBV induces contagious mononucleosis during or after adolescence [8]. Even though EBV exhibits a strong growth transforming capacity, that asymptomatically infects up to 95% of the human population, whereas it is perfectly immune-controlled [3].
\nThe virus is 122–180 nm in diameter. Epstein–Barr virion contains a linear, double-stranded DNA genome wrapped on an icosahedral capsid, approximately (100–110) nm in diameter, containing 162 capsomeres with a pore running down the long axis. The protein tegument with viral and cellular proteins including actin, tubulin, and cofilin separates the nucleocapsid from the lipid envelope that coats the virus and contains numerous viral glycoproteins (GP) spikes such as gp350/220, gp42, GH, GB and gp150 on the outer surface. These glycoproteins play an important role in cell tropism and recognition of receptors [8, 9] as shown in the Figure 1.
\nThe structure of EBV viral particle.
The double-stranded DNA (172Kb) linear genome encodes more than 100 proteins as well as non-coding functional RNAs (EBER RNAs, BART miRNAs, and BHRF1 miRNAs). There are some similar tandem terminal repeats (TR) of 0.5 kb at each terminal of the genome [10] and other internal direct repeats of 3 kb (IR) including the latency promoter (Wp) and the special short unique sequence domains (US)and UL (long). The US and UL sequences comprise nearly all of the genome encoding capacity [11] as shown in Figure 2. The EBV genome is classified as C genome, which is linear in a virus particle, but distributed as an episome in the nucleus of infected cells; circulating occurs by terminal repeat units (TRs) following B cell infection with EBV [11]. The first cloned and sequenced EBV strain was typing 1 EBV: B95.8, this strain was obtained from an infectious mononucleosis patient’s. Sequencing was based on previously generated EcoRI and BamHI restriction fragments (Figure 3). B95.8 strain is commonly used in labs around the world; however, a 13.6 kb portion of its genome is incomplete. Subsequently, the missing fragment was sequenced from the Raji strain and a revised EBV consensus genome was released several years later [12].
\nLinear Organization of the EBV genome.
Circular Organization of the EBV genome.
Two major types of EBV, type 1 and 2, have been described in humans based on major variations in EBNA-2 gene sequence [11]. Type 1 is dominant throughout most of the world, but the two types are equally prevalent in Africa. The EBNA-2 is the most variable locus in the EBV genome which is characterized by 70% identity at the level of nucleotide sequence whereas only 56% similarity at the amino acid level between these two types (3). In addition, the variation between type 1 and type 2 is also linked to the sequence variation in the viral latent genes EBNA-3A, EBNA-3B, EBNA-3C and EBNA-LP [13].
\nThe initial attachment of EBV is mainly regulated by the association between its envelope protein (gp350/220) and the cellular complement component receptor 2 (CR2/CD21) protein located on the B cell surface. This association activates Cluster of differentiation (CD21) receptor aggregation in the plasma membrane and also a tyrosine kinase signal transduction through CD19 that contributes to Nuclear factor-kappa B (NF- kB) activation and cell cycle entry [14].
\nThe attachment of the second viral glycoprotein gp42 to the human leukocyte antigen class II receptor (HLA class II) activates the viral envelope fusion with the membrane of the cell and the viral entrance in a cycle that relies on the glycoprotein complex GH/GL and also on GB [16]. The GH/GL complex is supposed to serve as a receptor that activates GB-mediated fusion after gp42 binding to HLA Class II molecules. Thereafter, virion nucleocapsids are released into the cytoplasm and transported to nuclear pores on microtubules [13]. As a result, the viral linear genome is transferred to the nucleus of B lymphocyte and the viral genome is then retained in the nucleus as a covalently locked extrachromosomal episome [15].
\nFor epithelial cells, as there are no CD21 or HLA class II molecules on their surface, the entrance of EBV does not involve gp350/220 and gp42. Viral BMRF2 protein can mediates interaction with cellular β1 integrins [14]. The fusion of viral envelope is activated by the attachment of the viral gH/gL complex to 5–007vβ6/8 integrins, which is confirmed by the effectiveness of infection in virions missing gp350/220 glycoproteins. The EBV virion expresses three- gH / gL/ gp42 and two- gH/gL glycoprotein complexes that grant the capacity to invade either B cells or epithelial cells [13].
\nThe virus is endocytosed into a low pH vesicle where fusion occurs after the interplay of EBV glycoprotein gp350 and receptor type 2 (CR2). Glycoprotein gp42 is bound directly to GH and transforms dimeric GHGL in a trimeric gHgLgp42, modifying the conformation of gp42 to cause its attachment to the human leukocyte antigen (HLA) class II molecule. It will allow the central fusion machine to support effective B cell infection. Besides, GH can bind cellular components [16].
\nThe epithelial cells do not constitutively express HLA class II, which makes gp42 useless in the process of fusion. The interaction of dimeric GHGL complexes with integrins, however, replaces the cell fusion caused by the interaction between gp42 and HLA class II. The use of dimeric GHGL complexes to cause epithelial cell fusion and gHgLgp42 trimeric complexes to contribute to B cell fusion was expected that the virus would trigger B cells and epithelial cells to alter the viral tropism: The gp42 spike in epithelial viral particles makes it 100 times more infectious than the virus produced from B-cells. The opposite is not so dramatic: the B-virus is five times more contagious for the epithelial cell than the epithelial virus [17]. After binding to the primary B cell, most virions do not internalize with the epithelial cell and the infection can be significantly increased by co-culturing with EBV negative B cells. Such virions stay on the surface of the cell B and can then be passed via the formation of the intracellular synapse to CR2-negative epithelial cells. This transfer technique involves the interaction between gp350-CR2 and GH and GB viral glycoproteins. This mechanism has been suggested to allow EBV to enter both lymphoid and epithelial cells simultaneously [18].
\nThe lytic infection is characterized by the active release of new contagious virus particles, either infecting new human hosts or infecting other naive B cells in the same host. The lytic cycle is divided into three stages: Immediate-early (IE), Early (E), and Late (L). The expression of immediate early BZLF1 and BRLF1 genes included in the activation of the lytic process is activated by signal transduction by the B cell receptor (BCR) [16]. The BZLF1 is a viral transactivator protein responsible for activating the production of lytic genes and the repression of latent genes, resulting in cells’ death and the release of contagious virons. The signal transduction of BCR initiates BRLF1 development and also improves its production allowing the transition from latency to lytic cycle [14]. The BZLF1 protein is a bZIP-specific transcription factor close to c-FOS and C/EBP. The BZFL1 and BRLF1 motivate functions of early genes, such as viral DNA polymerase (BALF5) and thymidine kinase, to initialize viral DNA replication from the lytic origin of replication (OriLyt) in tandem with other direct and early gene products [13]. Late lytic genes encode viral structural proteins, including tegument proteins, glycoproteins, and BcLF1 main capsid proteins. Newly synthesized viral DNAs are packed into nucleocapsids in the nucleus of the cell, which moves across the nuclear membrane to the cytoplasm, creating vesicles carrying virons with an envelope. The vesicles fuse with the plasma cell membrane and the virus particles exocytose [19].
\nHerpesviruses are distinguished by their ability to establish and sustain a latent infection in their hosts. Latent EBV expresses its genes in one of three latency systems: Latency I, II, or III variations in either of these systems assist in the development of a distinct series of viral RNAs and proteins [20] Table 2 and Figure 4. This chronic infection is characterized by inhibition of viral replication and viral dormancy, and immune evasion in the host. The EBV determines latency in the B cell pool which is the long-term reservoir for the virus in vivo. Naive B cells infected with EBV in the Waldeyer ring proliferate as activated B bursts, which are close to antigen-activated B lymphocytes in terms of the structure and morphology of their cell surface [21].
\nEBV latent protein | \nFunction related to B-cell lymphomagenesis | \n
---|---|
EBNA1 | \nRegulation of viral DNA replication and transcription of many viral and cellular genes; It facilitates p53 disintegration and thus promotes tumorigenesis | \n
EBNA2 | \nOne of the main viral transcription factors; In combination with EBNALP, EBNA2 regulates the transcription of many of viral and cellular genes; Fundamental for B cell transformation | \n
EBNALP | \nEBNA2-mediated transcription activator, both for viral and cellular genes; Bypassing the innate immune response of cells; Fundamental for B cell transformation | \n
EBNA3A | \nTogether with EBNA3C, it suppresses the genetic transcription of BIM, p14, p15, p16 and p18 through epigenetic regulation; Prevents differentiation of B cells into plasma; Essential for B cell transformation | \n
EBAN3B | \nVirus-encoded tumor suppressor protein | \n
EBNA3C | \nTogether with EBNA3A, it suppresses the genetic transcription of BIM, p14, p15, p16 and p18 through epigenetic regulation; Assists G1-S and G2-M transformations of the cell cycle; Ubiquitin-proteasome pathway; Supresses p53-, E3F1- and Bim-mediated apoptosis; Activates autophagy necessary for B cell transformation | \n
LMP1 | \nFunctionally mimics CD40 signaling pathway; one of the major transcriptional regulators; Mainly activates NF-kB, JAK/STAT, ERK MAPK, IRF and Wn’t signaling pathways; Induces BCL-2 and a20 expression to prevent apoptosis; Essential for B cell transformation | \n
LMP2A | \nFunctionally mimics BCR signaling pathway; prevents apoptosis; EBV latency regulation | \n
LMP2B | \nRegulates LMP2A functions | \n
EBERs | \nMost of the non-coding viral RNA is found in all forms of latency programs; Affects the innate immune response and gene expression; Inhibits apoptosis dependent on activated dsRNA dependent protein kinase (PKR) | \n
miRNAs | \nTranscribed from BART and BHRF1 loci; maintains latently infected B cells through blocking cellular apoptosis | \n
Model for the establishment of EBV persistent latent infection.
Opposite to the lytic infection, replication of the viral genome in latent infection occurs through host DNA polymerase and from a separate source, Orig of replication. During latent infection, the viral genome is present as a closed circular, extrachromosomal plasmid or episome. The viral DNA is wrapped with host histone molecules and replicates steadily once throughout the cell cycle together with the host genome [22], this enabled EBV infected B blasts during proliferation to express all latent EBV genes which are known as latency III or growth-program that play important role in cell activation and proliferation.
\nThis is achieved by the expression of two viral latent membrane proteins (LMPs), LMP-1, and LMP-2A, which constitute a functional homolog of the CD40 receptor in B lymphocytes and often mimic the constitutively active BCR, respectively [23]. B cell migrates to nearby primary follicles to form germ centers and the viral transcription system switches to latency II or a default system to enable the B cells to differentiate into memory B cells, Latency II is characterized by the expression of LMPs and EBNA-1 protein.. In the absence of antigen-mediated signals, LMPs are necessary to provide cell survival signals needed to prevent apoptosis of latently infected B cells [23].
\nEpstein Barr-virus nuclear antigen-1(EBNA-1) protein is important for EBV DNA replication and for preservation of viral genome in the cells [20]. The memory B cells lately infected reach peripheral circulation and represent viral persistence reservoir; [24]. Such latently infected memory B cells with EBV are distinguished by a silence of the expression of viral protein in a program called latency 0 or latency-program which is intended to permit immune evasion and therefore lifelong persistence on the host. The expression EBNA-1 is enabled and allows the division of the viral genome in the cells carrying the virus. This is known as the transcription program Latency I or EBNA-1 only program [23]. From peripheral circulation, latently infected memory B cells migrate into oropharynx and tonsils and then differentiate into plasma antibody-producing cells. Reactivation of the virus is triggered and infectious viruses are created as they bear the virus. Therefore, these viral particles will infect additional hosts with new naive B cells [24].
\nThe oral route is the primary route of the EBV transmission commonly through bodily fluids, especially saliva [25]. However, it has been reported that EBV infection can also be transmitted after the transfusion of a large volume of fresh blood [26]. Although EBV has been detected in cervical secretions of 8% -28%, of women, it is still controversy on whether EBV is transmitted through sexual contact [27]. Possible spread via organ transplantation can occur which is of particular concern in association with subsequent infection by EBV [22]. Transmission by milk is also a possible route, but is a non-significant mode of EBV transmission [28].
\nEpstein–Barr virus types occur worldwide, but they differ in their geographic distribution. For instance, Type 1 is prevalent in population from Europe, America, China, and South Asia, while Type 2 is less prevalent in these populations and is more observed in African and Papua New Guinean populations. Over 90–100% of adults have been infected with EBV, and the infection is most commonly affecting those patients aged 2 to 4 years and those aged 15 years. Epstein–Barr virus causes approximately 90% of the cases of infectious mononucleosis, which is commonly seen in both the community and the hospital setting. Among infants and young children who are primarily infected with EBV, in Africa, and where Burkitt lymphoma is common, 50% of them are infected with this virus before their 1 year of age. About 70% of cases of PTLD are associated with Epstein–Barr virus (EBV), especially in cases that occur early after transplantation [29]. Recent studies from Kenya reported a striking overlap between increased incidence of malaria transmission and Burkitt lymphoma [30]. Furthermore, various studies have demonstrated the presence of 8: 14 translocation in both the endemic African Burkitt lymphoma and in the non-endemic tumor type (Europe, America, and Japan).
\nThe EBV is associated with many malignant diseases such as lymphomas, carcinomas, and also more benign such as infectious mononucleosis, chronic active infection. The EBV has also been suggested as a trigger/cofactor for some autoimmune diseases. Overall, 1–1.5% of the cancer burden worldwide is estimated to be attributable to EBV [2].
\nThe primary EBV infections of infants and children are often asymptomatic or have nonspecific symptoms, but infections of adolescents and adults frequently result in infectious mononucleosis (IM). Around 80% of infected adults mostly experience symptoms, including sore throat, cervical lymphadenopathy, weakness, upper respiratory infection, headache, reduced appetite, fever, and myalgia (muscle aches). It is characterized by a large number of lymphocytes, mainly CD8 + T-cells, which, as opposed to healthy individuals, can reach five to ten times more numbers in the blood. The causes of this expansion of T-cells in IM are not clear, but factors such as failure of natural immune control by natural killer (NK) cell, memory CD8+ T cells of memory of EBV or genetic background have been suggested [31].
\nThe severity of symptoms in primary EBV infection is associated with age and immune system of the patients. The complications of the disease include splenomegaly, and/or chronic hepatitis, pneumonia and lymphadenitis. Less common are complications, such as hemolytic/aplastic anemia, myocarditis, Guillain–Barré syndrome, encephalitis, and meningitis [32].
\nChronic active EBV infection is a rare disorder characterized by the presence of severe illness of more than six months’ duration, high virus-specific antibody titers and organ disease with the demonstration of EBV antigens or EBV DNA in tissue [32].
\nThe reactivation of latent EBV infection has been shown to occur following impairment of the cellular immune response which is important in the long-term control of persistent EBV infection. Chronic uncontrolled EBV reactivation may result in the development of carcinoma. The followings are diseases and cancers associated with EBV infection [3, 33, 34, 35, 36]:
X-linked Lymphoproliferative Syndrome-XLP (Duncan’s disease). It is an inherited disease of males, characterized by an uncontrolled increase in the number of cytotoxic T and NK lymphocytes where their activity is directed against normal cells of various organs. Subsequent studies showed that the disease has a variety of phenotypes after primary EBV infection, such as fatal infectious mononucleosis, hypogammaglobulinemia, and malignant lymphoma.
Post-transplant Lymphoproliferative Disorders (PTLD). They are a heterogeneous group of diseases characterized by uncontrolled proliferation of B cells (90%), T cells (9%), and NK cells (0.5%). 90% of PTLD lymphomas are EBV positive and they are typically limited to the lymph nodes. PTDL often occurs as a complication of both solid organ transplant (SOT) and hematologic stem cell transplant (HSCT) patients.
Leukoplakia Hairy Mouth. It is a benign, mild proliferative change in epithelial cells of the tongue and the nasopharynx. It is caused by EBV and occur usually in persons who are immunocompromised, most frequently seen in those infected with HIV.
Burkitt’s Lymphoma (BL). It is a rapidly growing malignant tumor composed of large D-type lymphoblasts and mainly affects facial bones, mandibles, and jaws. EBV-associated BL has an incidence of 5–10/100 000 children and accounts for up to 74% of childhood malignancies in the African equatorial belt.
Hodgkin’s Lymphoma (HL). It is a proliferative disease of the lymphatic system with a peak incidence in those between 20–30 years and after 50 years of their age, the risk of developing HL is four times higher in those infected with EBV as compared to the general population.
Nasopharyngeal Carcinomas (NPC). It is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess which can extend to the base of the skull, palate, nasal cavity, or oropharynx [37]. Most NPC is associated with EBV infection, mainly in middle-aged patients and is more common in men than women [38, 39]. The International Agency for Research on Cancer (IARC) classified the EBV virus into the first group of carcinogens due to this association [40].
Sinonasal Carcinoma.
About 90% of head and neck cancers are squamous cell carcinoma (SCC), they originate from the mucosal lining that, causes tumor development in the nasal cavity and mouth, nasopharynx, larynx, esophagus and paranasal sinuses [41]. The International Agency for Research on Cancer (IARC) estimated that 16% of total new cancers, as well as 20% of deaths caused by cancers worldwide, were due to infections with EBV [3, 7]. Sinonasal carcinoma is a rare tumor comprised of about 1% of all cancers and 3% of all head and neck cancers [41, 42].
\nEBV has variously been linked with a number of autoimmune diseases including multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS) and rheumatoid arthritis (RA). The EBV links with these diseases include raised titers of EBV antibodies, decreased T cell response to EBV and elevated EBV viral load. It has been suggested that EBV triggers the activation state of the immune system by inducing the development of pro-inflammatory mediators, which may play a role in autoimmune pathogenesis [43].
\nOncogenesis is a cytological, genetic, and cellular transformation process that results in malignant tumors. Discovery of viral oncogenes and the discovery that they are derived from cellular genes called protooncogenes led to the understanding that c-onc genes have roles in different tumor types. The activation of viral oncogenes requires genetic changes in cellular protooncogenesby 3 genetic mechanisms: (a) Mutation (b) Gene amplification (c) Chromosome rearrangements. These mechanisms result in either an increase in protooncogene expression or a change in protooncogene structure [44]. The EBV-mediated B-cell change is associated with a global improvement in viral and cellular expression of genes. The biologic characteristics of the virus were instantly fascinating, as it was shown that cell lines could be determined from samples of Burkitt’s lymphoma (BL) and could propagate a virus that could strike primary B cells with EBV and turn them into immortalized cell lines [45]. This study of molecular phenotype led to the discovery of viral proteins that are necessary for latent infection and needed for cell transformation [46]. The mechanisms of EBV oncogenesis include:
\nEBV encoding oncogenes induce the changes in the host cellular signaling pathways that control proliferation, differentiation, cell death, genomic integrity, and recognition by the immune system.
\nLMP1, LMP2A, and LMP2B, latent membrane proteins are generated of the common viral locus with converging and interfering primary transcripts [47]. The LMP1 is one of the main EBV-encoded oncoproteins and it is a constitutively active mimic of cellular CD40 receptor. It is critically important for the EBV-induced B-cell transformation via the activation of NF-κB, c-Jun N-terminal kinase (JNK), and p38 cascades [48]. LMP1 also regulates cellular apoptosis by triggering the NF-κB pathway by increasing the antiapoptotic expression of Bcl2 via IRAK1 and TRAF6 whereIRAK1 is necessary for both p38 and p65/RelA phosphorylation [47]. Also, LMP1-stimulated proapoptotic polycomb complex protein (Bmi-1) is further been recruiting by EBNA3C for the transcriptional funnel of other genes. LMP2A acts as a functional homolog of the B-cell receptor (BCR) and thus promotes the survival of B-cells. Likewise, it is essential for the growth transformation of germinal center-derived B-cells which are BCR negative [48]. LMP2B negatively regulates LMP2A functions and transition from latent to lytic activation by depleting LMP2A-mediated BCR cross-linking and restoring Ca2+ mobilization [49].
\nEBNA1 is important for the DNA replication and maintenance of the viral latent genome. It binds to the viral episomal replication origin (OriP) and simultaneously to the host cell hromosomes that enable viral genome duplication during each cell cycle [50]. Through promotor selection, combined with comprehensive epigenetic control, EBNA1 can organize the shift between different latency programs, and EBNA1 can produce transcripts for different cells and help improve the control of telomeres on cell chromosomes [51]. The p53 and Mdm2 affected by the EBNA1 binding with ubiquitin-specified protease 7 (USP7), contributes to antiapoptotic activity control, likely by promoting survivin expression levels [52, 53].
\nEBNA2 and EBNALPare the first latent genes expressed following B-cell infection. EBNA2 is the main viral transcription factor responsible for activation of the expression of the entire repertoire of latent transcripts along with several host genes, utilizing cell transcription factors, RBP-J and EBF1 [50]. At the same time, EBNALP supports transcriptional regulation by EBNA2 via blocking off the activity of NCoR and RBP-J [51]. The EBNA2 contributes most strongly to the proliferation of B-cells through the activation of about 300 cell genes, such as the transcription of MYC and RUNX3 [51].
\nEBNA3 protein family consisting of EBNA3A, -3B, and -3C are transcription factors that precisely regulate host gene transcription and the proliferation of B-cells, particularly in the immunosuppression environment. Also, EBNA3B knockout virus-induced tumors demonstrated a lack of T-cell infiltrate and related CXCL10 chemokine activation [53]. In comparison, EBNA3A and EBNA3C cooperate as predominant viral oncoproteins by controlling the transcription of the cellular gene. This phenomenon is also true for EBNA3A [54].
\nThe EBNA3A and EBNA3C have been demonstrated to react with a long list of cellular proteins and transcription factors involved in the regulation of multiple cell signaling pathways [55]. Interactive partners for EBNA3C involve transcription factors, chromatin modulators (both histone deacetylase and histone acetylase enzymes), cell-cycle proteins including G1-S and G2-M transitions, metastases suppressors, post-translational modifiers, E3-ubiquitin ligase, ubiquitin-specific proteases, unfolded protein response (UPR) regulators, cell tumor suppressors, and oncoproteins [56]. The EBNA3C has been shown to form a complex with Chk2 and thus manipulates the G2/M step of the cell cycle [54]. Overall, the B-cell transformation and B-cell lymphoma are directly affected by the EBNA3 protectors by targeting main cell signaling cascades including cell cycle, apoptosis, and autophagy [56].
\nNoncoding viral transcripts.
A variety of noncoding RNAs (ncRNAs) in EBV infected B cells can be expressed, known as the EBV-encoded non-polyadenylated RNAs (EBER1 and EBER2) and numerous miRNAs [57]. Such ncRNAs are not necessary for the transformation of B-cells, but they are associated with immune evasion, and demonstrated in various forms of latency systems. In addition, EBER in situ hybridization is the most reliable and sensitive method to detect EBV infection in tissues of various EBV-related malignancies. EBER expression promotes the growth of B cells by blocking of PKR phosphorylation and inhibition of translational initiation factor eIF-2a and alpha-interferon (IFN-α)-induced apoptosis [56]. EBER can interact with ribosomal protein L22 that regulates protein translation, gene expression and PKR dependent apoptosis [58]. The EBER2 directly recruits PAX5 for the control of LMP2A expression, which has been verified by the usage of the EBER2 mutant virus with lower LMP2A expression [58]. EBV encodes more than 40 mature miRNAs, which are encoded at 2 different loci in the EBV genome: BHRF1 locus (BHRF1 miRNAs) and BART locus (BART miRNAs). The expression of various EBV miRNA is different among different cells. Viral miRNAs can either target other EBV transcripts or transcripts of host cells. BHRF1 miRNAs exhibit expression that is restricted to latency 3 whereas the BART miRNAs are expressed in all latency types. The expression of BHRF1 miRNAs in infected B lymphocytes, target multiple tumor suppressor proteins such as PTEN and P27KIP1 for the B-cell transformation. Viral miRNAs also inhibit the expression of several tumor suppressor genes, including DICE1, PUMA, PTEN and BCL2L11 to promote the survival of an epithelial cell [59].
\n\nTable 2 and Figure 5 explain the key latent transcription mechanisms of EBV.
\nSpecial features of EBV latent transcripts during B-cell transformation associated in the development of B-cell lymphoma.
Multiple genes have been reported to suppress antigen presentation. EBNA1 contains a Gly/Ala repeat sequence, through which proteasomal degradation and antigen presentation of the protein is impaired, while BNLF2A targets the transporter associated with antigen processing and blocks antigen presentation. BGLF5 represses HLA class I synthesis, whereas BILF1 downregulates cell surface expression of the molecule. It is highly likely that at least LMP1 and LMP2A, the viral functional mimic of CD40 and BCR, have tactfully evolved to modify those processes in the germinal center, and thus, these EBV gene products can deregulate the immune system for survival [60]. See section 1.1.8.
\nVirally-induced epigenetic alterations of the host genome are evident in EBV-associated cancers, which are the result of genetic mutations, changes involving DNA methylation and chromatin structure that in turn alter the expression of growth promoting or suppressing genes. Enhanced Ig-Myc translocation has been demonstrated in Burkitt lymphoma [31, 32] and silencing of tumor suppressor genes (e.g. p16INK4A) in many EBV-positive cancers. Several reports have demonstrated that the predisposition of individual HLA allele significantly affects the morbidity of EBV-positive proliferative disorders, particularly in NPC and Hodgkin lymphoma [34, 35, 36, 37, 38, 39]. LMP1 seems to induce genetic/epigenetic alterations by DNA hypermethylation and chromatin modifications [49].
\nIn response to primary EBV infection, both innate and adaptive antiviral responses have been activated. Despite the very effective immune response, the virus is not cleared.. A lifelong, latent infection is established within the memory B-cell and EBV genomes are propagated during the division of the transformed, latently infected B cells. During this period, broad range of EBV early gene products interfere with immune response which helps the virus to persist and to reactivate [60].
\nVarious pattern recognition receptors (PRRs) including cell surfaces and endosomal Toll- receptors (TLRs) and cytoplasmic DNA and RNA sensors are capable of detecting EBV particles. The EBV is identified by Toll-like receptors (TLRs) on the cell surface and in endosomes [61]. Virus-derived or virus-induced components can be detected by RNA and DNA sensors as well as by inflammasomes within the cytosol. TLRs, RNA and DNA sensors trigger a cascade of intracellular signaling events that enable the activation of the interferon regulatory factors (IRFs) and NF-κB. As a result, activated gene transcriptions induce the production of cytokines and type I interferon (IFN I). Different levels of these PRR signals are attacked by latent and/or lytic EBV proteins or EBV miRNA as recently seen [62, 63].
\nEBV can inhibit the synthesis of cellular proteins in infected cells through global mRNA destabilization. This mechanism is via the EBV DNase (alkaline exonuclease) BGLF5 regulated by the supplementary BGLF 5 RNase feature, which is expressed during the active period of infection and uses the same catalytic position as DNase action, but the substrate-bindings site is only partly shared by DNA and RNA substrates [62].
\nA significant number of lytic EBV proteins interact with host IRFs, which are the transcription factors that stimulate the synthesis of type IFN. The immediate-early EBV transactivator BZLF1, BRLF1 and tegument protein LF2 interact with IRF7 andIRF3, and inhibit its transcriptional activity on IFNα4 and IFNβ promoters resulting in the suppression of antiviral state induction. In addition, EBV protein kinase BGLF4 phosphorylates and inhibits IRF3 transcriptional activity, thus decreasing IFNβ expression [64].
\nThe EBV infection is linked to the decreased NF-κB--dependent gene expression. The expression of viral BZLF1 and cellular NF-κB is reciprocally inhibited. The higher levels of the NF-κB in the absence of BZLF1 instigate EBV latency, while increased expression of the BZLF1 after the induction of the lytic cycle overwhelms the minimal amount of the NF-κB [65].
\nSeveral EBV gene products have an impact on the function of effector molecules of innate immunity. The host cytokine colony-stimulating factor 1 (CSF-1) activates the differentiation of the macrophage, and the secretion of the IFN-α, EBV encodes the soluble form of the CSF-1 receptor BARF1, which neutralizes the effects of the host CSF, leading to the reduction of the IFN-secretion of EBV infected mononuclear cells. EBV BZLF1 counteracts intrinsic effector molecules in a variety of ways [62]. First, BZLF1 decreases TNF5–007 and IFNΔ receptors to minimize cellular susceptibility to these cytokines; second, BZLF1 induces SOCS3-signaling cytokine suppressor, which inhibits JAK/STAT signaling and thus promotes IFN-responsiveness Type I state; Third, BZLF1 triggers TGFβ immunosuppressive cytokine expression and disrupts the development of Promyelocytic leukemia bodies (PML-bodies) that may have antiviral activity [66].
\nThe EBV compromises the activation of both CD8 + and CD4 + T cells by interfering in different stages of HLA Class I and Class II antigen presentation pathways, especially during the productive phase of infection [67].
\nThe EBV encodes at least three proteins that independently interfere with antigen presentation through deregulation of the surface expression of HLA I in many ways to prevent EBV-specific (memory) T cell recognition [68]. BGLF5 induces degradation of HLA I-encoding mRNA and reduces the presence of peptide at the cell surface which inhibits T-cell recognition. Ut has been suggested that BNLF2adeplete peptides from the ER (HLA I loading compartment) and inhibits the importation of peptides by the antigen- transporter (TAP). BILF1, encoding a constitutively active G protein-coupled receptors (GPCR) which reduce the transportation of HLA I from the trans-Golgi network. In addition, cell surface turnover is increased and subsequently i degradation by lysosomal proteases. These proteins are expressed during the replicative process of EBV and function in tandem with the prevention of CD8 + T cells being recognized [67].
\nThe EBV has adopted several strategies for immune evasion that interfere with CD4 + T-cell immunity. The EBV receptor Gp42 can bind to the B-cell HLA class II molecules. The HLA Class II/peptide complex relationship blocks T-cell receptor (TCR)—class II interactions and prevents CD4 + T cell activation. Besides, protein GP42/gH/gLdecreases the HLA II cell surface expression by the HLA II mRNA degradation. Inhibiting the activities of CIITA promoters and, as a result, lowering the HLA II surface levels, EBV also encodes a viral IL-10 homolog (BCRF1) that has been identified as impairing the IFNβ signal. The IL-10 is an anti-inflammatory cytokine that can inhibit CD4 + priming and effector functions and modulates them; BCRF1 was suggested to inhibit CD4 + T-cell antiviral response similar to IL-10 [69].
\nThe EBV severely restricts latent infection viral protein expression to prevent host immune recognition. Different latency forms represent different stages from primary B cell infection to the transformation of the growth. Thus, in latency III cells, EBNA1inhibits its translation and proteasomal degradation. This strategy ensures adequate levels of EBNA1 to preserve the viral genome while decreasing the turnover of proteins to minimize the appearance of viral antigens to CD8 + T cells. LMP1 and 2 mediate NF-κB activation and decrease the TLR9 surface expression and accelerate the turnover of IFN receptors, resulting in a decrease in the incidence of IFN receptors. During latency II, the expression is limited to EBNA1 and LMP1, and 2. Latency I only contains an expression of EBNA1, and latency 0 occurs without any expression of EBV protein [70]. The EBV encodes different types of non-coding RNAs, including two EBV-encoded small RNAs (EBERs) that inhibit PKR activity and miRNAs that de-regulate T-cell attracting CXCL-11 chemokines and de-regulates T-bet and IFNΔ transcriptional regulator [71].
\nIn the vast majority of individuals, EBV is a harmless passenger, controlled easily by immune defenses, but in some individuals, EBV drives a broad range of diseases that can cause significant morbidity and mortality.
\nA vaccine is currently unavailable. A prophylactic vaccine which prevents acute disease, the most beneficial using the humoral immune approach, vaccines expressing the major viral envelop protein, gp350 have been developed. Most recently live recombinant vaccinia vaccine expressing gp350 protected two- thirds of the vaccinated infants [20]. as Also, therapeutic vaccines are investigated. These vaccines are based on direct peptide immunization approaches. The use of immunodominant HLA Class I and II epitopes of LMP1, LMP2, and EBNA1 may induce a strong and sustained T-cell response, which was demonstrated with some success primarily in reactivating CD4+ and CD8+ cell in vitro [72, 73].
\nThe use of antiviral therapy in EBV infection is limited. Antiviral therapy can be used as preemptive therapy of PTLD in EBV- organ transplant recipients. These agents can block EBV replication in donor B-cells and infection of recipient B-cells. Prophylactic intravenous ganciclovir after liver transplantation lead to decreasing of PTLD incidence, which may be due to a reduction in the number of latently-infected B-lymphocytes [29].
\nHuman Cytomegalovirus (HCMV) or human herpesvirus 5 (HHV-5) [74], is ubiquitous in human populations and was first isolated and cultivated in 1956 [56]. The HCMV derives its name from the Greek cyto-, “cell”, and -megalo-, “large”, because of the enlargement of virus infected cells, (cytomegaly), [75]. Human cytomegalovirus is a leading - cause of congenital viral infections with numerous consequences such as birth defects including intrauterine growth restriction, stillbirth, low birth weight, preterm birth, microcephaly, neurodevelopmental delay, cerebral palsy, hematological disorders, pneumonitis, blindness, and sensorineural hearing loss [76]. HCMV infection is typically clinically silent in immunocompetent hosts, with few mild symptoms like fever, myalgia andcervical lymphadenopathy. Individuals with weakened immunity – neonates, diagnosed with HIV/AIDS, and those on long-term immunosuppressive treatments, such as transplant recipients – HCMV infection often results in clinically severe diseases. The worst outcomes, including mortality and long-term morbidity, are with congenital infection [56].
\nA complete virus particle consists of a DNA core with a protein coat and external envelopes representing the extracellular infective form of a virus called virion [77]. The average size of viral particle varies between 200–300 nanometers and has linear double-stranded (235-kb) DNA genome which is enclosed by an icosahedral capsid. The capsid’s diameter is (110–130 nm) and made of 162 capsomeres (12 pentons and 150 hexons).. HCMV has three kinds of capsids: A capsid (only capsid shell), B capsid (capsid shell and assembled proteins), and C capsid (a mature capsid containing the viral genome). These three capsids represented in three various stages of capsid maturation that takes place in the nucleus of infected cells capsid is composed of at least 5 proteins, i- Major Capsid Protein (UL86), ii- Minor Capsid Protein (UL85), iii- Smallest Capsid Protein (SCP, UL48–49), iv- Assembly protein (Fragments of UL80) and v- Minor Capsid Binding Protein (MCP, UL46) [78].
\nThe widest layer inside the virion structure is the tegument layer that closely surrounds the capsid; anchoring the envelope to the tégumented capsid is believed to be essential. The layer of tegument is composed of several proteins like pp65/ppUL83, pp71/ppUL82, pp150/pUL32, and pp28/pUL99 which play main roles during the entry of virus (un-coating), intracellular capsid transportation and assembly [79]. The tegument is covered by a lipid bilayer called the envelope that keeps the entire virion intact. It interacts with the host cell membrane in target cells and thus plays a significant role in the attachment and entry of viruses. Lipid bilayer envelope is derived from cellular ER or endosomal membranes and associated with 23 viral glycoproteins. The viral glycoproteins gpUL55 (gB), gpUL73 (gN), gpUL74 (gO), gpUL75 (gH), UL100 (gM), gpUL115 (gL) and the pentameric complex consist of gL, gH and UL128–131, are known to play crucial roles in viral entry, cell-to-cell spread and virion maturation [80] (Figure 6).
\nStructure of an HCMV Virion.
Among herpesviruses, HCMV has the largest genome consisting of a linear dsDNA ranging from 220 to 240 kbp and comprising up to 250 opening reading frames (ORFs) [81]. The herpesvirus genomes are categorized into A-F sections depending on the organization of the genome segments (Figure 7). The genome of HCMV is classified as an E genome. The sequencing analysis of the HCMV genome has shown that it has a very complex structure. Generally, the genome is organized into two parts: The single long regions (UL) and unique small regions (US) flanked by terminal repeats (TR) and internal repeats (IR), UL-area ORFs and US-region ORFs are classified according to their location [82] (Figure 8). More than 70 viral proteins have been identified from the purified virions [83]. Only 50 proteins are important for viral replication, while the vast majority of HCMV proteins are involved in host immunomodulation via their interference with cellular signals [84]. HCMV encodes for at least 4 long polyad-encoded RNAs and 26 microRNAs which have major functions during host-virus and virus replication interactions [85].
\nThe six classes of herpesvirus genomes.
Illustration of the CMV life cycle from viral entry to egress of new infectious virions.
Cytomegalovirus virus (CMV) enters host cells through membrane fusion as shown in Figure 9. The viral entry involves the binding of viral glycoproteins on the surface of the viral lipid envelope and the specific receptors on the external membrane of the host cell [86]. This initial interaction makes the cell susceptible to further interactions that fuse the membranes and eventually disassemble and release the viral genomic DNA into the host cell. Many tegument proteins are thought to mediate the delivery of the DNA-containing nucleocapsid to the nuclear pore complex and the release of the viral DNA into the nucleus [87].
\nOverview of the human cytomegalovirus life cycle.
HCMV-gB mediates attachment to cells via binding to cellular receptors that include heparan sulfate proteoglycan, integrins, and epidermal growth factor receptor (EGFR) to promote the entrance process [9]. The heparan sulfate proteoglycan molecule permits the HCMV particle to attach closer to the cell membrane where viral glycoproteins bind to more specific receptors. This is mediated by gB and gH or their complexes, and many other viral protein complexes may also mediate the process of entry; a homodimer of gB known as gC-I, and a heterodimer composed of gM and gN which form gC-II and a heterotrimer of gH, gL and gO which form the gC-III complex. HCMV has two different routes of entry in different cell types [88]. Virus entry in fibroblasts is mediated by viral envelope glycoprotein complexes gH/gL-gB and gH/gL/gO via direct fusion at the plasma membrane. Aminopeptidase N (CD13) and Annexin-II may also serve as receptors to promote entry at the plasma membrane. The entry of CMV into other relevant cell types, such as endothelial cells, follows an endocytic route, clathrin is the major constituent of coated vesicles and plays an important role in the endocytic entry of viruses [89]. HCMV has a wide cell tropism and can infect different cell types [31], such as neuronal cells in the brain and retina [90], fibroblasts, epithelial and endothelial cells (EC) in lung and gastrointestinal tract [91], hepatocytes in the liver [90] and peripheral blood mononuclear lymphocytes (PBML) [92]. Infected monocytes can release infectious viruses into target organs through tissue-macrophage differentiation [93]. Efficient infection of EC of blood vessel may lead to separation of these cells and hematogenic dissemination may, therefore, be initiated [94]. Fibroblasts, on the other hand, are likely to contribute to the efficient development of HCMV and will help the establishment of the primary infection. HCMV can also infect various kinds of cells in vitro. However, the replication of viruses varies between different cell types. In fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, HCMV inducesproductive infection, while in poorly differentiated cells, such as myeloid-linear progenitor cells, viral replication is limited [91]. Fibroblasts are the most commonly used cells for HCMV cultivation in the laboratory because HCMV binds to fibroblasts with the efficiency of 2500–3000 particles per cell [94].
\nHCMV strains show broad variations in the relative pentamer and trimer rates of viral glycoproteins incorporated into virions, which correspond to the cell tropism differences between strains [93]. Many HCMV genes are capable of influencing viral cell tropism at the entry stage and most likely function by composite effects of gH/gL complexes.
\nHCMV infection of the cell leads to an active replication with the production of new viral particles that are released by exocytosis of the infected cells, known as the lytic phase [95]. The replication of viral DNA is dependent on the expression of certain viral proteins [96]. Gene expression of viral DNA takes place in three stages: immediate early genes (IE) expression, followed by early genes (E) and late genes (L) expressions [95]. The IE gene products act as transcription factors as well as trans-activators to regulate expression of the E and L genes. Two predominant nuclear phosphoproteins, IE1-p72 (Immediate Early 1 – Protein 72KD) and IE2-p86 (Immediate Early 2- Protein 86KD) have the key roles., IE1-p72 is expressed from the UL123 ORF during the IE phase of replication cycle. IE1-p72 transactivates the promoters of numerous HCMV early genes including gene products that facilitate the replication process. It also interacts with the p107 protein through a domain at the N-terminus of IE1-p72 and increase the p107- mediated repression of E2F promoters leading to the inhibition of p107- mediated growth suppression [97]. Therefore, it appears that IE1-p72 can induce E2F activity. The expression of IE1-p72 can promote S phase entry only in cells lacking p53 or p21 [96]. Controversial to that, IE1- p72 expression causes wild-type cells to arrest, most likely in G1 due to increased levels of p53 protein, which results in a p53-dependent induction of p21 expression and subsequent growth arrest [96, 97]. IE2-p86 is expressed from the UL122 ORF during the IE phase of the replication cycle and is essential for HCMV replication [98]. The protein IE2-p86 specifically interacts with pRb through more than one domain and induce pRb mediated repression of E2F promoters. The IE2-p86 disruption of pRb-E2F complexes enable E2Fs transactivation of its target genes [99]. However, IE2-p86 induces cells to enter S phase, an effect that could be attributed in part to IE2-p86 transactivation of the cyclin E promoter and induction of E2F activity [100].
\nPhosphoprotein 65 (pp65) is a tegument phosphoprotein that exhibits kinase activity. This protein may affect the activity of a specific subset of cytotoxic T –Lymphocytes (CTLs) by modification of IE1- p72, possibly through its phosphorylation and may interfere with its processing and/or degradation [82].
\nFollowing peak expression of IE regulatory proteins, early genes (E genes) become transcriptionally active (Figure 9). These proteins regulate replication process of HCMV DNA, such as a DNA-polymerase (UL54) and DNA primase (UL70) which sustain an efficient production of new viral progeny [89]. The L proteins, which are mainly structural components, are essential for virion assembly and egress. HCMV genome contains a cis-acting lytic origin of DNA replication (OriLyt) element to initiate bidirectional DNA replication (theta form of replication), followed by a rolling circle mode of replicationof viral DNA molecules and their incorporation into new virus particles [80]. The entire replication cycle for HCMV takes approximately 72 h and the mature new virions infect the new cells either by their release from the infected cells or by the spread via cell-to-cell mechanisms [80]. During latency, only selected IE gene transcription and translation of viral proteins occur and when conditions are favorable, the virus may be reactivated into lytic replication and new viral progeny occurs [101].
\nThe newly synthetized DNA is inserted into an immature B capsid after the pre-capsid assembly stage and becomes a fully mature C capsid. This DNA packed capsid, egresses through the nuclear membrane from the nucleus, through an envelope and de-envelopment cycle [102]. The mechanism of assembly of tegument proteins is still unclear. It has been suggested that tegument proteins are added to nucleocapsids sequentially starting in the nucleus and continuing in the cytoplasm, which provide stability during nucleocapsid translocation from the nucleus to the cytoplasm.. The final envelopment of tegumented particle occurs at ER/endosomal membranes. By transporting Rab3 secretory vesicles, mature particles are released by fusion of the vacuole with the plasma membrane and shed out by exocytosis [103] (Figure 9).
\nThe establishment of latency is one of the major biological characteristics of herpesviruses. Primary HCMV infection is often asymptomatic in a healthy person (immune-competent host) and leads to latent and recurrent infection [104].
\nThe MIE gene acts as a transactivator for transcribing the majority of encoded HCMV genes and is necessary for the virus replication and the lytic process of infection. During latency, cellular factors transcripts control the MIE promoter. These factors also suppress the chromatin around the MIE gene, which prevents the lytic cycle stage and is a part of preserving the latent stage of the infection [105].
\nPeople who have had an organ or bone marrow transplant and those with AIDS can develop serious illness caused by CMV. Typically, latent virus from a previous infection (the primary CMV infection may have occurred many years earlier) becomes active again because the person’s immune system is compromised [106].
\nTo establish viral latency and maintenance, the latency- gene product UL138 is required. HCMV-LUNA and UL138 are generated during HCMV latency and lytic infection and activate CD4 + T cells, resulting in the development of IL-10 and IFN-π; one with immunosuppressive effects and one with immune-activating effects that facilitate the replication and reactivation of latent HCMV. The produced IFN-β can promote macrophage differentiation, which can lead to reactivation and enhanced HCMV replication. UL138 also downgrades protein-1, MRP, which can lead to lower exports of C4 cell leukotriene, preventing DCs from entering lymph nodes and impairing an HCMV-specific immune response [105].
\nThe expression of the UL 111a gene, which encodes a functional IL-10 homolog with strong immunosuppressive effects, also offers HCMV strategy in viral latency to suppress the immune system. Through the latent infection process, UL111a undergoes alternative splicing, which results in the expression of a latency related transcript cmvIL-10, and the production of a protein that mimics the function of human immunosuppressive cytokine IL-10. This favors the infected cells not to be recognized by the immune system and to avoid clearance. Also, US28 and UL144 are expressed during latency redirect the immune response or block the immune recognition [107].
\nLatent HCMV infection also modulate the cell expression of MHC molecules class I in order to evade the immune response. At least four proteins encoded by (US) region of HCMV genome involved in inhibition of MHC class I expression, either by directly acting on MHC class I moleculeor acting on MHC class I-associated proteins, such as TAP (transporter associated with antigen processing) and tapas in [101]. These loci of HCMV DNA encodes several distinct IE proteins, pUL36, pUL37, and pUL37_1, which appear to stop engagement of the apoptotic signals associated with the tumor necrosis factor (TNF) family of receptors including Fas. As a result, the activation of Fas-associated death domain (FADD) is inhibited, which prevents activation of procaspase-8 FLICE (FADD-like interleukin-1 beta-converting enzyme) and ultimately prevent the active caspase-8 to cause the subsequent activation of downstream effector caspases and prevent apoptosis of the cells [107, 108].
\nThe spreading of HCMV from one person to another primarily occurs through infected bodily secretions such as saliva, blood, tears, milk, and urine [109]. Close or intimate person to person contact usually is necessary for viral transmission. Accordingly, sexual transmission has been implicated in the spread of CMV. Seropositivity is higher among persons with multiple sexual partners and histories of sexually transmitted diseases [110].
\nCytomegalovirus (CMV) may be transmited from mother to infant before, during or after birth. During pregnancy, vertical CMV transmission occurs via either passage of virions from maternal blood to the fetus and subsequent infection of the placenta or via the entry of infected maternal leukocytes, endometrial, or cervical cells into the fetal circulation. The infection ascending from the genital tract may also be possible. During birth, the infection of neonate occurs via the contact with infected maternal genital secretions. After birth, breastfeeding is the most frequent route of CMV transmission to the neonate [111]. Cytomegalovirus transmission also occurs naturally after receipt of an organ containing latent virus where these transplant recipients (who are undergoing immunosuppressive treatment) are at risk of contracting the disease [112].
\nCytomegalovirus (CMV) infection is common among patients of all age groups, but it has traditionally been considered as a problem in neonatal and immunosupressed patients. Cytomegalovirus infection in immunocompetent patients is usually asymptomatic or subclinical. Symptomatic disease usually results in mononucleosis-like syndrome. The symptoms are similar to classic mononucleosis, caused by the Epstein–Barr Virus. However, the mononucleosis syndrome associated with CMV typically lacks signs of enlarged cervical lymph nodes and splenomegaly [113]. Rarely, CMV infection in immunocompetent persons is associated with severe diseases such as enteritis, thrombotic disease, hemolytic anemia, thrombocytopenia, encephalitis, Guillain–Barré syndrome and myocarditis. Guillain–Barré syndrome is immune-mediated peripheral neuropathy characterized by neuromuscular paralysis. The first case of Guillain-Barré Syndrome associated with cytomegalovirus (CMV) infection was reported in a renal transplant recipient in 1970 [114].
\nCMV infection is one of the most important infectious complications of solid-organ transplantation and is responsible for serious, life-threatening diseases in patients infected with human immunodeficiency virus (HIV) and other immunodeficiencies [115]. CMV disease manifests in the vast majority of transplant recipients as a viral syndrome that includes fever, malaise, myalgia, or headache (sometimes called
Congenital infection refers to a condition where cytomegalovirus is transmitted in the prenatal period. Worldwide, approximately 1 in 100 to 500 babies are born with congenital CMV. Approximately 1 in 3000 will show symptoms and 1 in 7000 will die [117]. Congenital HCMV infection occurs after primary infection (or reactivation) during pregnancy. Congenital infections are less common in poorer communities with high seropositivity of, women in childbearing age.. In industrialized countries, up to 8% of HCMV seronegative mothers acquire primary HCMV infection during pregnancy, of which roughly 50% will transmit CMV to the fetus [118]. Between 10–15% of infected fetuses are born with the symptoms of congenital CMV disease, [119] which may include pneumonia, gastrointestinal, retinal, and neurological diseases [120].
\nHuman CMV is an ancient virus that is ubiquitous in human populations, reaching a prevalence of 100% in Africa and Asia, and approximately 80% in Europe and the USA, depending on socioeconomic status [121]. Seroprevalence rates of HCMV vary depending on age (higher rates are observed among older persons), geography (higher rates in developing countries), and socioeconomic status (higher rates in economically depressed regions) Figure 10 [122].
\nGlobally, rates of CMV seroprevalence in women of reproductive age and the incidence of congenital CMV infection. Studies have been performed in Australia, Belgium, Brazil, Canada, Chile, England, Finland, France, Germany, Ghana, India, Israel, Italy, Japan, South Africa, Spain, Sweden, Taiwan, Turkey, and the USA.
A comparison of literature estimates shows that congenital CMV-related disabilities are as common among newborns and children as other better known diseases such as Down syndrome, fetal alcohol syndrome, or spina bifida [123]. Of the approximately 30,000 United States babies born with an infection with CMV every year almost 20 percent are born with or experience permanent sequelae such as hearing loss, eyesight loss, brain damage or cognitive impairment.
\nThe contribution of congenital CMV infection to childhood hearing loss is of particular importance, with approximately 20% of moderate to profound bilateral sensorineural hearing impairment occurring due to congenital CMV infection [124]. Approximately 90% of newborns with congenital infection have no symptoms at birth; If symptoms are present, they are often nonspecific [125]. When disabilities such as hearing loss appear, often months or years later, it is usually too late to make a retrospective diagnosis that identifies congenital CMV infection as the cause. For an individual woman, the greatest risk of having a baby with congenital infection comes from the mother’s primary infection during pregnancy [126]. Consequently, babies of women who are CMV negative prior to pregnancy are particularly vulnerable to poor outcomes if the mother becomes infected during pregnancy. [127].
\nIn a nationally representative survey it has been stated that between 30% and 50% of United States women under 45 years of age are seronegative for CMV and that as many as a half a million US women of childbearing age experience primary CMV infections every year [128].
\nHCMV persistence is correlated with the interaction between the immune response of the host and the virus evasion mechanisms, where HCMV interferes with both adaptive immune responses and immune effectors. A variety of evasion strategies have been developed by HCMV to prevent selected dendritic cell functions. The differentiation of CMV infected monocyte into macrophages and CD1 a-positive Dendritic cells (DCs) is inhibited, which does not require viral replication [129].
\nThe innate immune system is essential in driving an efficacious acquired immune response. This includes the induction of type I interferons, activation of professional antigen presenting cells, and recruitment and activation of NK cells which themselves promote more efficient activation of antigen presenting cells and T cells. The binding and entry of HCMV into the cell initiates several pathways leading to the upregulation of NFkB and interferon regulatory factor 3 (IRF3) which can ultimately lead to the production of type I interferons and certain inflammatory cytokines. This innate cellular response to the initial stages of infection is mediated by Toll like receptor 2 (TLR2) signaling, which has been shown to recognize the viral surface glycoproteins gB and gH [130].
\nThe importance of NK in the innate immune response to HCMV is suggested by the extensive studies of mechanism of HCMV prevention of the activation of NK cells. NK cells are inhibited by signals sent via inhibitory receptors that interact with class I MHC molecules on the surface of target cell. Low surface levels of Class I MHC on HCMV-infected cells may also reduce the inhibitory signaling of NK. This could make the infected cells susceptible to NK cell cytotoxicity [131]. Two mechanisms describing HCMV-mediated inhibitory receptor signaling have been reported. Firstly, HCMV uses the host HLA-E pathway to inhibit NK cells via the CD94/NKG2 heterodimeric inhibitory receptor by promoting cell surface HLA-E expression. Viral UL40 protein contains a nonomeric peptide which binds HLA-E promoting its cell surface expression. Secondly, HCMV expresses a viral homologue of cellular MHC Class I, UL18. UL18 is trafficked to the cell surface where it binds to the inhibitory NK cell receptor, LILRB1 (LIR-1) with higher affinity than MHC Class I inhibiting LILRB1+ NK cell activation. HCMV encodes five genes controlling NK cell activation and cytotoxicity by the provision of inhibitory signals and suppression of activating signals. The pp65 tegument protein (UL83) dissociates CD3_ signaling from NKp30, whilst intracellular retention of CD155 and CD112 by UL141 prevents activation of NK cells via receptors CD226 and CD96, the remaining viral proteins interfere with a major receptor on all human NK cells (NKG2D) that mediated NK cell activation [132].
\nPrimary infection of HCMV provokes the production of antibodies specific for many HCMV proteins including structural tegument proteins such as (pp65 and pp150), envelope glycoproteins predominantly (gB and gH) as well as non-structural proteins such as the Immediate Early 1 protein (IE1, UL123).
\nIn human bone marrow transplantation studies where HCMV infection can cause significant morbidity, it was evident that there was a strong correlation between recovery of the CD8+ T cell population and protection from CMV disease. HCMV employs several mechanisms to interfere with the normal cellular MHC Class I processing and presentation pathways to prevent CD8+ T cell recognition. HCMV encodes at least four related glycoproteins, each with a unique mechanism to prevent antigen presentation. HCMV viral genes US2 and US11 degrade newly synthesized MHC class I heavy chains, US3 retains MHC-I in the endoplasmic reticulum by interfering with chaperone-controlled peptide loading and US6 inhibits the translocation of viral and host peptides across the endoplasmic reticulum membrane by the dedicated peptide transporter TAP (transporter associated with antigen processing) [133]. The action of these genes may not completely protect cells from CD8+ T cell recognition dependent on the T cell-antigen specificity. Whereas HCMV-infected cells expressing US2–11 prevent any presentation of IE antigen to human T cells, pp65 peptides were still presented. CMV-specific T cells are also marked by the lack of expression of the costimulatory receptors CD27 and CD28, which are otherwise commonly expressed on naïve T cells [134].
\nDuring primary infection, HCMV specific CD4+ T cells can be detected 7 days after the detection of HCMV DNA in peripheral blood in response to same ORFs asCD8 + T cells and pp65 and IE genes gB and gH. These cells produce T helper type 1 (Th1) cytokines IFNγand TNF. A large number of HCMV- encoded gene products target the MHC class I antigen presentation pathway in an effort to avoid recognition by CD8+ T cell [134].
\nHuman cytomegalovirus also avoids the CD4+ T cell response by several ways. Disrupting IFN- induced, upregulation of MHC class II molecules to the cell surfaces by preventing the expression of Janus kinase 1 and suppression of Class II transactivator mRNA. The virally-encoded gene product of US2 also suppress MHC class II presentation to CD4+ T cells by redirecting the HLA-DR-and HLA-DM- chains to the cytosol where they are degraded. HCMV re-programs human hematopoietic progenitor cells (HPCs) into immune-suppressive monocytes that express IL-10 in a process requiring US28. Recently a truncated transcript to UL111A, a viral homolog of the immunomodulatory cytokine IL-10, which is expressed during latency (cmvLA IL-10) has been shown to downregulate expression of MHC class I and class II molecules, inhibit both proliferation of mononuclear cells and the production of inflammatory cytokines [135].
\nThe lack of specific and effective treatments for HCMV infection has highlighted the need to understand HCMV host-cell interactions, including viral entry and host immune responses against this virus [136]. The HCMV vaccine is designed to be used to prevent infection or to prevent its re-activation in those infected already [137]. To eliminate and eradicate congenital HCMV infection, vaccination would be a priority. Several researchers have attempted to develop vaccines against HCMV, such as live attenuated vaccines, recombinant chimeric vaccines, and subunit vaccines such as glycoprotein B and tegument protein pp65 vaccines [138]. However, none of these vaccines exhibited effective protection, as well as, and to this day, no licensed HCMV vaccine is available.
\nStrategies to reduce Congenital CMV disease burden may be implemented at different stages, and include prevention of maternal infection, prevention of mother-to-child transmission, early detection and intervention by neonatal screening, and neonatal antiviral therapy. The principal sources of exposure for women of childbearing age are sexual contacts and children secreting the virus [136]. Pregnant women also should be advised to avoid close contact with individuals likely to shed CMV such as adults with symptoms consistent with mononucleosis and toddlers attending group day care. Preemptive therapy is an approach in which patients are monitored for early replication (ie, viremia by polymerase chain reaction [PCR]), and the antiviral drug is administered only when CMV replication is detected to prevent its progression to higher-grade viremia and CMV disease. Small, noncomparative studies have shown lower rates of CMV disease (especially delayed-onset disease) with preemptive compared with the use of antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors [139].
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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