Phage procapsids and capsids.
\r\n\t
",isbn:"978-1-83768-248-5",printIsbn:"978-1-83768-247-8",pdfIsbn:"978-1-83768-249-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"8bc7ffd7544fff1901301c787e64fada",bookSignature:"Prof. Magdy Elnashar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11998.jpg",keywords:"Preparation, Characterisation, Applications, Immobilised Cells, Biomaterials, Biofibers, Resins, Polysaccharides, Biocomposites in Health Sciences, Biocomposites in the Chemical Industry, Nanobiocomposites, Nano-Composites",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 27th 2022",dateEndSecondStepPublish:"July 29th 2022",dateEndThirdStepPublish:"September 27th 2022",dateEndFourthStepPublish:"December 16th 2022",dateEndFifthStepPublish:"February 14th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"22 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Prof. Magdy Elnashar received his M.Sc. Degree in Chemistry from the Cairo University, Egypt, in 1998, and his Ph.D. Degree in Biochemistry from the University of Leeds (top 100 in the world). He was the head of the Group of Encapsulation and Nanobiotechnology at the Centre of Advanced Sciences in Egypt. Prof. Elnashar has 6 patents, and 11 Awards in teaching, research, and commercialization. His scientific interests include the production of nano to macro beads, biopolymers grafting, and immobilized enzyme",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"12075",title:"Prof.",name:"Magdy",middleName:null,surname:"Elnashar",slug:"magdy-elnashar",fullName:"Magdy Elnashar",profilePictureURL:"https://mts.intechopen.com/storage/users/12075/images/system/12075.jpg",biography:"Prof. Magdy Elnashar was born in Cairo, Egypt in 1972. He recevied his M.Sc. Degree in Chemistry from the Cairo University, Egypt, in 1998 and his Ph.D. Degree in Biochemistry from the University of Leeds, UK, in 2005. \nProf. Elnashar was awarded several prizes, among which the Prize of the National Research Center for promoting science in the field of Biotechnology in 2010 and the Prize of the President of the National Research Centre for the best applied article in 2009. His current position is the Head of Biopolymers & Nanobiotechnology Group at the Center of Excellence, National Research Center in Egypt. \nProf. Elnashar’s fields of interest are in the production of Nano to Macro Beads, Biopolymers Grafting, Immobilized Enzymes, Drug Delivery Systems, Nano Magnetic Particles, Diagnostic Kits (Immunology) and Water Purification.",institutionString:"Curtin University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Curtin University",institutionURL:null,country:{name:"Australia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"14",title:"Materials Science",slug:"materials-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466998",firstName:"Dragan",lastName:"Miljak",middleName:"Anton",title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/466998/images/21564_n.jpg",email:"dragan@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. A unique name with a unique work ethic right at your service."}},relatedBooks:[{type:"book",id:"6320",title:"Advances in Glass Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6d0a32a0cf9806bccd04101a8b6e1b95",slug:"advances-in-glass-science-and-technology",bookSignature:"Vincenzo M. 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Langer, Institute Professor at Massachusetts Institute of Technology, together with Joseph P. Vacanti, MD a pediatric and transplantation surgeon-scientist at Massachusetts General Hospital and Harvard Medical School [1]. They recognized that in all fields of reconstructive surgery less than 30% of patients needing an organ transplant were able to obtain one [2], and that an alternative approach of engineering viable tissues and organs using cell culture techniques was needed to address this limited supply [3]. As a result, “an interdisciplinary field of research that applies the principles of engineering and the life sciences towards the development of biological substitutes that restore, maintain or improve tissue function” has been created with the ultimate goal of repairing injured and diseased organs [1].
\nOriginally, the concept of tissue engineering required a triad of cells, scaffolds and signaling molecules. The cells, preferably derived autologously from the patient, can be stem cells, progenitor cells or mature cells. After expansion, they are seeded on a porous and resorbable scaffold and cultured in the presence of signaling molecules such as growth factors, specific metabolites, morphogens and adhesins [4]. Today, it is known that additional conditions are required so as to obtain the desired tissue. Depending on the type of tissue and the application, it may be necessary to add mechanical [5] and/or bioelectrical stimulation [6, 7], or increase the oxygen levels during cell culture in the bioreactor [8].
\nThe focus of this chapter is to describe the different types of scaffolds used for tissue engineering with a particular emphasis on fiber-based scaffolds that are mostly fabricated on textile processing equipment. The desirable properties of the various types of scaffolds will be enumerated and the specific advantages of using fiber-based structures will be explained.
\nFigure 1 represents the desired structural, mechanical and chemical properties that every tissue engineering scaffold should possess. The structure needs to have open pores that facilitate the passage of nutrients and waste products to and from the cells in the interior of the scaffold. The average pore size and pore size distribution are critical so as to ensure that cells, which may measure 10–50 μm in size, can infiltrate into the interior of the scaffold. This is particularly crucial for endothelial cells that are responsible for the formation of vasa vasorum and internal vascularization of the scaffold tissue.
\nRequired properties of tissue engineering scaffolds.
The surface properties of the scaffold should be suitable from both chemical and topographical points of view so as to enable cell attachment and proliferation. To this end surfaces are often coated or modified with extra cellular matrix proteins, such as collagen or fibronectin, to promote cellular interaction. It is assumed that all surfaces are biocompatible so as elicit cell interaction and avoid a cytotoxic response.
\nThe scaffold structures fabricated by a number of conventional methods, such as solvent casting, particulate leaching, gas foaming, phase separation and freeze drying are illustrated in Figure 2. The porous structures are inconsistent and there are limited processing options to alter the average pore size and the pore size distribution. Hence the mechanical performance in any direction is limited, especially for scaffolds that need to support mechanical loading during cell culture. In addition, a number of the polymer materials require the use of toxic organic solvents that increases the risk of cytotoxic effects during cell culture.
\nPorous structures of non-textile tissue engineered scaffolds.
As seen in Figure 3, there a number of textile technologies that can and have been used to fabricate tissue engineering scaffolds. They include weaving, weft knitting, warp knitting, braiding, nonwoven production and electrospinning. Each of these technologies is described in the following sections, which discuss both the concepts and principles as well as examples of their application.
\nPorous structures of fiber-based tissue engineered scaffolds.
Weaving is a conventional textile fabrication technology that is widely used in tissue engineering applications, because it enables a 3D scaffold to be fabricated that can imitate the mechanical and biological features of native human tissues. Woven structures are basically formed by interlacing two sets of yarns, namely, warp and weft yarns. With various interlacing and pattern designs, woven fabrics are categorized as plain, twill and satin weaves (Figure 4). Compared with knitted and braided structures, woven fabrics have better mechanical strength and structural stability [9]. The properties of woven fabrics, such as thickness, porosity and strength, can be easily adjusted and modified by woven design selection and the density of the warp and weft yarns [10].
\nWoven designs showing plain, twill and satin weaves [
A tendon is a crucial linkage between a muscle and bone, and it plays an important role in the movement of the joints, such as the rotator cuff tendon which allows shoulder movement. When a tendon ruptures or tears, it causes dysfunction of the joint. The complex multilayered avascular structure limits the rate and potential for healing [11, 12, 13]. Tissue engineered scaffolds not only need to have excellent mechanical properties such as high tensile stress and modulus, but also should have excellent biological properties to promote rapid host cell growth and tissue regeneration.
\nCommercial woven scaffolds, such as X-Repair (Synthasome, CA, USA) and Biofiber™ CM (Tornier, MN, USA) made from biodegradable polymers, are already used clinically for tendon repair. Derwin et al. reported using the woven poly-l-lactic acid (PLLA) X-Repair patch to provide bridging reinforcement for a shoulder tendon in a canine model. Post-operatively the augmented and repaired tendon was 23% significantly stronger, and after 12 weeks the patch reinforcement showed less tendon retraction and significantly greater stiffness (26%), and ultimate load (35%) compared to those animals that were repaired without a patch [14]. For the first time in 2014, Proctor successfully used the X-Repair woven patch with an arthroscopic approach to repair a series of patients who presented with a large-to-massive rotator cuff tear. He reported that the surgery provided substantial functional improvement for 83% of patients after 12 months and 78% of the patients after 42 months [15]. Ratcliffe et al. compared the mechanical properties of a number of commercially available synthetic and extracellular matrix (ECM) scaffolds, and found that only the X-Repair was able to provide a similar stress-strain curve to a human or canine infraspinatus rotator cuff tendon with a short toe region and high strength (Figure 5) [16].
\nStress–strain curves for the human and canine infraspinatus rotator cuff tendon, and for the products used in the repair of rotator cuff injuries [
More recently, a woven structure has been used together with non-woven layers to assemble a laminated multilayered scaffold (Figure 6A) to closely match the mechanical properties of a human rotator cuff tendon and provide nanofiber
Recent woven scaffold innovations for tendon repair applications. (A) Composite multilayer woven and electrospun scaffold [
Islam et al. manually wove plied and crosslinked electrochemically aligned collagen threads (ELACs) using pins into a scaffold for rotator cuff tendon repair (Figure 6B) [19]. The scaffold has approximately 60% of the functional strength of a comparable sized native rabbit infraspinatus tendon, a stiffness close to that of a native tendon and the ability to initiate tenogenic differentiation of human mesenchymal stem cells [20].
\nHuman bone has a complex hierarchical and lamella structure of mineralized collagen fibrils which makes it difficult to replicate the complex ECM structure for better cell growth and bone regeneration [21]. By adjusting the pore size and structure of the woven fabric a potential scaffold candidate can address the required mechanical and biological features of an ideal tissue engineering bone scaffold [22]. Recently, a three dimensional (3D) woven structure has shown potential for bone regeneration.
\nPolylactic acid (PLA) and silk fibroin were combined and electrospun into nanofibers and fabricated into a woven multilayer fabric with subsequent mineralization using simulated body fluid. This approach significantly improved the scaffold’s compression resistance and enhanced cell proliferation by promoting osteogenic differentiation of mesenchymal stem cells (MSC) [21]. This stem cell differentiation was also confirmed by Persson et al. who seeded cells onto a 2.4 mm thick 3D woven scaffold made from wet spun PLA and hydroxyapatite (HA) composite fibers (Figure 7) [23]. A 3D engineered woven poly(ϵ-caprolactone) (PCL) scaffold was created for the purpose of assisting deposition of cartilaginous and mineralized matrix from marrow-derived human bone for repairing chondral or osteochondral defects [24]. By using subchondral bone anchor in a porcine
(A) Schematic view of a 3D orthogonal woven scaffold, the PLA/HA 3D woven scaffold has five warp layers (x-direction) and six weft layers (y-direction), bound together by a warp set through-the-thickness (z-direction) and (B) cell mineralization (arrow) occurred on PLA/HA 3D woven scaffold after 35-days of culture in osteogenic induction medium [
With the problems of aortic valve insufficiency and stenosis, patients need heart valve replacement surgery to regulate blood flow between the left ventricle and the aorta [10]. The ideal scaffold should be able to simulate the native valve in terms of an active change of shape, size and stiffness of the cusp, annulus, sinus, and sinotubular junction during the cardiac cycle [28]. Textiles have been used to fabricate heart valves because of their unique structural and mechanical characteristics that enable the production of unique anisotropic properties [10].
\nWu et al. proposed a novel engineered valve design of combining a woven fabric with a hydrogel to mimic the heterogeneous and anisotropic features of native heart valves [29]. The scaffold was composed of a polyacrylonitrile (PAN) electrospun weft yarn and a multifilament PAN warp yarn with a methacrylated hyaluronic acid (Me-HA) or methacrylate gelatin (Me-Gel) layer for encapsulation of human aortic valve interstitial cells. The composite scaffold showed a similar initial toe, transient, and peak tangent regions in a stress-strain curve under load, similar to that of native aortic valve leaflets. High cell viability and layered cell penetration through the fibrous network were obtained after 14-days of
When patients suffer from atherosclerosis or an aneurysm, they may need an arterial prosthesis or stent-graft to replace or bypass the occluded or dilated vessel. Woven textiles have a long history of being used to fabricate arterial protheses with non-degradable synthetic polymer yarns, such as polyester, for long-term therapy of large caliber vessels. For tissue engineered vascular grafts, woven structures are less frequently used compared to other textile structures with more flexibility, such as electrospun non-woven webs and knitted structures [30, 31, 32, 33, 34]. However, weaving technology is capable of producing complex branched tubular structure for vascular application, such as seamless bifurcated or trifurcated endovascular prostheses [35].
\nYokota has proposed a small diameter vascular graft with inner diameter equal to 4 mm, fabricated by combining a collagen microsponge with a plain-woven tube made from sheath-core yarns, namely, polyglycolic acid (PGA) as the sheath and poly-l-lactic acid (PLLA) as the core (Figure 8A) [36].
\n(A) The small diameter vascular graft with plain weave fabricated from bicomponent yarn with PLLA core fibers and PGA sheath fibers [
After 12 months of implantation in a canine carotid animal model, the graft showed no evidence of thrombogenic activity or aneurysm formation. Instead there was evidence of excellent in situ tissue regeneration [36]. The same group then examined the reconstruction potential of the vessel wall by implanting a woven patch into the canine pulmonary artery (Figure 8B and C). Similarly, no aneurysm and thrombus formation were observed after 6 months but a monolayer of endothelial cells and layers of smooth muscle cells were presented [37]. The ability to promote
Weft knitting technology dates back to the sixteenth century when the Reverend William Lee in England invented a knitting frame to produce woolen hosiery. Weft knitted fabrics can include three main types of stitches: jersey, rib and interlock structures, which can be fabricated from a single yarn [39].
\nCompared with weaving and warp knitting, weft knitting has superior compliance and flexibility of design. When used with advanced biodegradable materials, such as poly-l-lactic acid (PLLA), polyglycolic acid (PGA) and polyurethanes (PU), their mechanical performance is predictable whether or not they serve as the reinforcing component of a tissue engineering scaffold [40, 41]. Structural instability and fabric permeability are the two main concerns relating to the performance of weft knitted fabrics. The use of advanced coatings and immersion techniques compensate for these limitations, and the combined scaffolds provide improvements in device function [42, 43]. To date, various implantable scaffolds have been fabricated as weft knitted structures, including a cardiac support device (CSD), aortic valves, vascular prostheses and nerve guides [42].
\nIn the event of a heart attack or myocardial infarction (MI), the muscle wall of the left ventricle will experience a remodeling process [44]. Today, the major challenge is how to provide the mechanical support for the left ventricle and deliver stem cells to the target area where the infarct occurred. For this application, the scaffold needs to be extensible and match the different compliances of the left ventricle in the radial and longitudinal directions [45].
\nUntil now, Boublick et al. developed a knitted cardiac patch that has been developed and assessed by
(A) Three courses of weft knitted loop structure and (B) SEM image of knitted heart patch. Scale bar: 500 μm [
Related to the heart patch concept, a biodegradable knitted heart cap has proven to have a beneficial effect when used in a canine heart failure model (Figure 10). After comparing the healing response of a biodegradable (PGA) heart cap with that of a non-degradable (PET) heart cap in a canine cardiac model, Kitahara et al. pointed out that the failure of the CorCap™ cardiac support device was that it was knitted from a non-degradable material, which was polyester (polyethylene terephthalate) (PET) yarns. The improved heart function of using biodegradable PGA in a canine model has supported this conclusion, which is consistent with the clinical data for the CorCap™ device [48, 49].
\nKnitted cardiac support devices. (A) Non-degradable PET knitted device (left) and a degradable PGA knitted device (right) and (B) The implanted device after implantation around the ventricles of the canine heart [
Surgical aortic valve replacement (AVR) is conducted on patients with aortic valve stenosis [50]. The expectancy of the replacement valve to continue to function is from 10 years to a lifetime, which requires the implanted valves to have excellent durability and biocompatibility. The most challenging aspect of the surgery is the risk of post-surgical paravalvular leak, increasing the risk of the heart failure and other severe complications [51, 52]. Lieshout et al. developed a knitted scaffold for the aortic valve from polycaprolactone yarn. The fabric was knitted into a rectangular patch with three leaflets (Figure 11).
\nThe appearance of a weft knitted heart valve. (A) External lateral view and (B) top view of heart valve after application of fibrin gel layers [
During valve opening and closing, the knitted leaflets performed well with complete coaptation and no collison with the aortic wall. In an
A vascular graft is a common and useful therapy to rebuild small diameter blood vessels and treat the symptoms of atherosclerotic vascular disease [55]. However, to date only yarns spun form permanent or non-degradable polymers have been used to fabricate commercial large caliber prostheses.
\nWith the objective of developing a resorbable small diameter vascular prosthesis, Xie et al. designed a weft knitted/electrospun PLA/PLCL tube with comparable compliance to a human saphenous vein [33]. Zhang et al. has also fabricated a small diameter vascular scaffold by weft knitting electrochemically aligned collagen (ELAC) yarns into a tubular structure on a circular weft knitting machine (Figure 12).
\nThe circular knitting machine for weft knitting tubular fabric.
The tube serves as the backbone of the scaffold and provides sufficient mechanical support and structural integrity. Also, by utilizing collagen as the material, the scaffold has demonstrated advanced endothelial cell adhesion [56, 57]. Although a common complaint of weft knitted structures has been their poor dimensional stability and their tendency to unravel from the unsecured end, these are surmountable issues that can be controlled by knitting a backloop binding-off structure or sewing a reinforcing edge seam along the cut edge.
\nA novel approach to fabricating a nerve guide is to combine weft knitting technology with freeze drying to form a high porosity scaffold. After being injured, the distal stump of the peripheral nerve is unable to repair the gap between neurons. So to bridge this gap, a nerve guide with good compliance can be used to evaluate the neural signals and promote axonal growth [58]. Wang et al. designed and fabricated a chitosan scaffold for nerve tissue engineering. The knitted chitosan tubular fabric was fitted onto a mandrel and immersed in a chitosan solution. Acupuncture needles were then inserted into the hollow chitosan tube to create inner pores for guiding neural growth and proliferation. Following the immersion process, the scaffolds were freeze dried to form interconnected micropores in both the outer wall and inner matrix. The knitted scaffold provided sufficient compressive resistance and recovery to serve as a nerve guide scaffold. A porous microstructure improved the axonal elongation and migration of the neural cells [59].
Warp knitted fabrics are formed by wales which are vertical columns of yarns looped in the warp or machine direction. Warp knitted fabrics gain popularity in many medical applications due to the superior structural stability, the avoidance of yarn raveling after cutting to size, and higher suture retention strength in comparison with weft knitted fabrics.
\nThe knitting productivity of warp knitted fabrics is usually much higher than for weft knitted fabrics. However, the yarn preparation for warp knitting is more challenging due to yarn beam preparation. There are fewer design pattern options for warp knitted fabrics than for weft knits because the warp knitted design is limited by the pattern drum on the machine, which is more difficult to create complex structures [61]. Two dimensional (2D) warp knitted fabrics have been widely adopted for biomedical applications due to their superior structural stability and durability. For example, most permanent hernia repair meshes are warp knitted so as to provide high tear resistance and bursting strength, reliable stabilization of the fascial tissue in the abdominal wall, no raveling when cut to size and limited contraction during healing [62]. Other permanent applications involve commercial arterial prostheses, aortic valve rings [53] and artificial skin [63].
\nOn the other hand, only a few resorbable warp knitted fabrics are being developed as tissue engineering scaffolds. Secant Medical LLC (Telford, PA, USA) is developing a warp knitted fabric using degradable yarns for a tissue engineering application [64]. In order for a tissue engineering scaffold to mimic the volume and complexity of natural tissue a 3D warp knitted structure is required, and for this application, a warp knitted spacer fabric is the preferred structure. Spacer fabrics are defined as a 3 layer sandwich structure with two outer layers of fabric, each knitted on its own row of needles, and a third inner spacer layer as shown in Figure 13A. In addition to having the advantages of a warp knitted fabric, such as high bursting strength, high elongation, high porosity and low Young’s modulus, the 3D spacer fabric is a one piece multi-layered structure with high volume to weight ratio, softness, breathability, moisture permeability, compression resistance and excellent recovery properties [65, 66].
\nProCAD warp knit simulation of a 3D warp knitted spacer fabric (A); a spacer fabric knitted with monofilament yarns (B) and multifilament yarn (C) in the middle spacer layer [
The spacer yarn that lies in the thickness direction provides the mechanical support and the high total porosity needed for a tissue engineering scaffold. The yarns ensure a high surface area for cell attachment and proliferation, and the porous structure is highly interconnected which allow fluids carrying nutrients and waste by-products to flow through the entire structure [67]. The technical face, back and spacer layers are all knitted independently. So distinct characteristics can be designed and incorporated into the same fabric by means of changing the yarns and the construction in each layer. The distance between the two needle beds, also known as the void volume or “total porosity”, can be altered by the knitting pattern in the spacer layer, which defines the macro level. At the same time, the size, twist and texture of the filament yarns, and their individual cross-sectional shape defines the micro level. The unique spacer layer determines the thickness of the scaffold, ranging from about 100 μm to several centimeters. Space fabrics are knitted from monofilament or multifilament yarns as shown in Figure 13B and C. A monofilament yarn consists of one thick filament per yarn so the yarn stiffness is higher and the fabric compression resistance is higher than a multifilament spacer fabric. Multi-filament yarns have several filaments per yarn, sometimes there can be hundreds of filaments. The higher the filament count, the finer each fiber. So multifilament spacer fabrics have extraordinary surface areas with high porosity [61].
\nWarp knitting is a promising technology to fabricate basic and complex scaffolds for tissue engineering applications. Warp knitted scaffolds have a high potential for commercial success because they can adapt to FDA-compliant materials without sacrificing their property requirements. The warp knitted fabric has great structural stability and suture retention performance, which is crucial in any clinical application. The unique type of 3D warp knitted spacer fabric, has proven to be biocompatible in lab trials with excellent cell attachment and tissue penetration into the 3D scaffold network. It is also an attractive candidate in complex tissue engineering applications such as at muscle-tendon junctions.
\nBraiding technology, developed in the 1800s [68], is the process of interlacing three or more yarns obliquely to form either tubular or flat fabrics. In order to braid a tube one needs to use an even number of yarns, half rotating clockwise, and the other half rotating counter-clockwise. If a flat braid is needed, then one needs to use an odd number of ends. By increasing the number of sets of yarns or the thickness of the yarns, one can obtain a thicker or wider product with superior mechanical performance [69]. These designs can be a hollow or solid construction with either a uniform or variable cross-sectional shape [69]. Braiding technology has traditionally been used to fabricate textile structures such as ropes, but it is gradually gaining attention in biomedical applications, such as sutures, stents and in tissue engineering (TE) scaffolds for the repair of connective tissues, nerve guides and vascular prostheses.
\nBraiding angle, the most important geometrical parameter of braided structures, is defined as the angle between the braided yarns and the longitudinal direction. Braiding angles can range from 0° to 90° while they are usually between 30° and 80°. In comparison with a woven structure, the yarns in a braid are able to rotate and slide at the crossing points when under an external force. This offers braided structures with superior flexibility [70].
\nTubular braids or ropes are mainly used in medical applications, which are manufactured with an even number of yarns arranged around a circle. The two common structures that have been developed are the diamond braided structure with each yarn crossing above and below the other yarns (1/1) and the regular braided structure with each yarn crossing over two of the other yarns (2/2) (Figure 14). In addition, other braided structures can be developed. For example, axial yarns can be introduced in the longitudinal direction to form a tri-axial braided structure [71].
\nThree types of braided structure.
The most widely used braiding machine for fabricating tubular braids has two sets of bobbins mounted on spindles moving along two tracks. One set of bobbins revolves in the clockwise direction and the other set revolves in the counter-clockwise direction, in order to form the braided pattern (Figure 15) [68, 72].
\nSchematic diagram of braiding machine.
Yarns wrapped on the bobbins are pulled continuously and interlaced with each other at the braiding point. The braided yarns are then wound up on a scroll or take-up package. By adjusting the ratio of the braiding velocity and the take-up velocity, different braiding angles can be obtained which significantly affect the performance of the braided product.
\nBraided scaffolds have frequently been used for tubular or rope-like tissue engineering scaffolds because of their precise and predictable porous structure and adjustable performance to mimic natural structures and properties [73, 74]. Extensive tissue ingrowth and mechanical characteristics that match natural tissues can be achieved with the appropriate selection of materials, braiding parameters and suitable pore size [75]. First, the mechanical and physical performance are considered as the most important criteria for designing a braided tissue engineering scaffold, followed by the question of biocompatibility.
\nFor rope-like braided scaffolds, the braiding angle is the key to affect their mechanical properties. The cover factor, combined with the braiding angle, needs to be measured in order to evaluate the physical properties of the tubular braided scaffold. The easiest way to measure braiding angle (\n
Diagram of braiding angle. D: outer diameter of braided scaffold; p: axial distance of braiding yarn in one spiral.
For tubular braided scaffolds, the cover factor is defined as the percentage of the mandrel’s surface covered by yarns and calculated with Eq. (1) [76]:
\nwhere
Radial compression, tensile and bending measurements are commonly used to evaluate the mechanical properties of braided scaffolds, especially tubular braided scaffolds.
\nAccording to ISO 25539-2012 [77], the radial force test with a radial compression machine and the crush resistance test with a parallel plate tester are highly recommended to evaluate the radial compressional properties of tubular braided scaffolds (Figure 17A and B) [78, 79]. A uniaxial tensile test (Figure 17C) [75, 80] and a three-point bending test (Figure 17D) [81] are measurements used to evaluate the tensile strength and bending stiffness of braided scaffolds, respectively.
\n(A) Radial compression machine; (B) parallel plate compression tester; (C) uniaxial tensile measurement; (D) diagram of three-point bending measurement.
For tissue engineering applications, braided scaffolds are required to have good cell adhesion and cell proliferation. At present, different biomaterials are used to fabricate various braided scaffolds for tissue engineering applications such as tendon/ligament reconstruction, cartilage, bone, vascular grafts and nerve regeneration.
\nBarber et al. [82] and Rothrauff et al. [83] reported that they had braided nanofibrous scaffolds (BNFSs) for tissue engineering tendons and ligaments. Several bundles of electrospun nanofibers were braided into rope-like scaffolds. Human mesenchymal stem cells (hMSCs) showed good adhesion and orientation after seeding and culturing on the BNFSs, and were also reported to promote hMSCs proliferation and key pluripotency gene expression. Cooper et al. [84] and Freeman et al. [85] developed braided scaffolds made with synthetic poly(l-lactic acid) for anterior cruciate ligament repair. The scaffolds mimicked the morphology and mechanical properties of the native ligament tissue and when tested in rabbits showed excellent healing and regeneration. In another study, Fang et al. developed a braided scaffold using antheraea pernyi silk fibroin for tissue engineering a tendon [86]. The scaffold was investigated
Sun et al. fabricated a gene-modified scaffold by lyophilizing the CHS mixture with braided silk cables for fibrocartilage application [87]. The scaffold, seeded with mesenchymal stem cells (MSCs), showed vigorous cell proliferation and differentiation to reconstruct the cartilage. Fujihara et al. successfully developed a braided carbon/PEEK composite to be used as a bone plate [88]. The bending properties of the braided composite were comparable with natural bone. In another study, Evans et al. developed a tubular braid to improve the efficiency of bone fracture treatment [89]. It was shown that changing the braid angle and the thickness of the tubular cast produced a stiffness similar to that of native bone. Ichihara et al. braided PLLA and PGA yarns coated with collagen to form a novel nerve guide tube for nerve regeneration [90]. The animal experiment showed fast recovery and good regeneration by using the scaffold, which suggested the potential for nerve gap repair. Zhang et al. designed a tri-layer graft from electrospun silk fibroin (SF) and poly(l-lactide-co-ε-caprolactone) (PLCL) and braided layers of silk yarns, to mimic the tri-layer structure of the intima, media, and adventitia of native blood vessels [91]. It was demonstrated that the braided outer layer significantly improved the mechanical properties of the construct. Besides good mechanical properties, and biocompatibility the prototype sample also exhibited appropriate anticoagulation properties as a result of the heparin coating.
\nNonwoven textiles can be distinguished from traditional textiles based on the fact that nonwoven textiles are manufactured directly from staple fibers or filaments and do not involve the intermediate yarn manufacturing process [92].
\nVarious definitions of nonwoven textiles are used by various nonwoven organizations. One of the most widely used definition is the one defined by the Association of Nonwoven Fabrics Industry (INDA), which is “A sheet, web, or batt of natural and/or man-made fibers or filaments, excluding paper, that have not been converted into yarns, and that are bonded to each other by any of several means” [93].
\nThus, nonwoven textiles essentially are characterized by those fabrics which are converted directly from fibers. As opposed to conventional textile manufacturing of woven or knitted fabrics, nonwoven manufacturing processes are characterized by cost effective and high productivity due to elimination of the yarn manufacturing step. The ability to process a wide range of raw materials from staple fibers to continuous polymer filaments adds to a versatility in the range of products that can be obtained from nonwoven textile processing [94].
\nNonwoven fabric manufacturing consists of three main steps: (1) selection of raw material fiber or polymer, (2) web formation, and (3) web consolidation and finishing [95]. Selection of the raw material or type of fiber is generally based on the requirement of specific properties for the end use application. Raw material for nonwoven fabrics includes staple fibers or polymers, binders for thermal or chemical web consolidation and finishing agents such as softeners, flame retardants, antimicrobials [95]. On the basis of web formation, nonwovens can be classified into two main categories, web formation from staple fiber and web formation from polymers. Staple-fiber-based web formation is further divided into two categories: dry laid webs and wet laid webs.
\nDry laid web formation includes opening and mixing of staple fibers and the formation of a thin layer of web of randomly laid or oriented individual fibers by air laying or a conventional carding machine. The single layered web is then laid into its final web structure by going through cross lapping or parallel laying to get a stable structural integrity. The orientation of fibers in the machine or cross direction can be engineered through these processes, depending upon the properties required in the final product [95]. Wet laid web formation includes initial mixing of the staple fibers in chemicals and water and then deposition of the mixture into a thin layer of web consisting of randomly laid fibers. The advantage of wet laid web formation is that fibers with very short staple length can be easily converted into a web [95]. Polymer based web formation is further divided into spunbonded and melt blown web formation. Both the processes include melting of the polymer into a dope which is then spun into fine filaments or microfibers and directly collected on a collection plate in the form of a web which can then be further processed for producing a hybrid nonwoven structure or can be finished into a final product [95]. Variables such as fiber type, fiber processing, type of web formation, web weight, uniformity and the presence of binder can impact the characteristics and properties of the final fabric [94].
\nWeb consolidation or web bonding processes are classified into three main types, which are mechanical, chemical and thermal bonding. Different types of web consolidation processes impart specific properties to the nonwoven fabric. Mechanical web bonding consists of two types: needle punching and hydroentangling. In both the processes a randomly laid or carded web goes through penetration with either barbed needles or high-speed water jets resulting in interlocking and bonding of the web in the form of a fabric with strength and stability. The properties of the scaffold such as thickness, total porosity, air permeability can be engineered by various machine variables such as the intensity and depth of penetration of the needles, the number of entanglements per specific surface area [94]. In chemical bonding, the adhesion of fibers in the web is achieved with the help of binders such as polyvinyl acid derived resins. The characteristics and amount of binder used determines the properties of the nonwoven fabric (Figure 18).
\nSchematic diagram of nonwoven web formation using a carded drylaid web and bonding with liquid chemical binder impregnation and drying.
For example, increasing the amount of binder results in increased strength and stiffness, but reduced softness and flexibility. Chemical bonding can be achieved by various methods such as saturation, foam, spray, and print bonding [94]. Thermal bonding involves binding the web using thermoplastic binders, such as fibers or powders. Thermal bonding techniques include hot calendering, air thermal bonding, ultrasonic, and radiant heat bonding. In thermal bonding, various surface characteristics can be introduced using calender bonding of different profiles including area bonding, point bonding, embossing and grid bonding [94].
\nFinishing of nonwovens includes various mechanical and chemical finishes such as calendering, heat setting, shearing, singeing, and applying antimicrobial and antistatic agents. The chemical finishes can be applied through processes such as padding, coating, laminating and newer finishing techniques such as plasma and microencapsulation [94].
\nNonwoven fabrics are characterized by properties such as high surface area and high porosity, which encourages researchers to study various types of nonwoven fabrics for applications in tissue engineering. Though currently there is no commercial product available, various studies have been conducted on nonwoven fabrics as tissue engineering scaffolds for
Electrospinning is one of the most popular techniques for fabricating tissue engineering scaffolds. Its widespread use is accredited to its ease of manipulation, cheap and accessible equipment needs, and its versatility. The technique can be applied to various materials, ranging from synthetic polymers such as PLA [103], PGA [104], PCL [105, 106], PU [107, 108], and their copolymers [109], to natural polymers such as collagen [110, 111], elastin [112], gelatin [113] and chitosan [114]. Electrospun scaffolds have been applied in various tissue engineering applications, such as skin [115], bone [107, 116], cartilage [113, 117], tendon [118, 119], ligament [118], nerve [105, 120], blood vessel [121], cardiac tissue [122], and aortic valve [108].
\nTypical experimental electrospinning setup.
Electrospinning is a fiber-forming method by injecting a conductive polymer solution or melt through a high-voltage field, and the fiber is stretched by the attenuating electrical force and collected on a grounded collector (Figure 19). It has a unique advantage in fabricating micro and nano-fibers that mimic the structure of the extra cellular matrix (ECM), such as the basement membrane of blood vessels. Hackett et al. [105], Zhang et al. [91] and our studies [57] have all demonstrated that an electrospun layer attached to the luminal surface of a vascular scaffold is able to reduce the pore size and facilitate endothelial cell proliferation. The nano-fiber web provides an ideal scaffold surface for endothelial cells that require a flat surface with nano-sized pores to form a monolayer on the vascular intima.
\nAnother advantage of electrospinning is that it is able to adapt to a wide range of materials. In order to fabricate a scaffold that mimicks the native ECM both structurally and biochemically, one can apply natural polymers such as collagen, elastin, and cellular components to the scaffold’s surface. Collagen, as the predominant protein in native ECM, has been reported by many researchers to be an attractive scaffold coating that leads to advanced cell adhesion, proliferation, and migration [123, 124]. Furthermore, the addition of cellular components to the electrospinning solution has also been described. Venugopal et al. [125] reported preparing an electrospun scaffold from a blend of gelatin and phytochemical components, such as hexadecanoic acid (HDA), octadecanoic acid (ODA) and N,N-diisopropyl(2,2,3,3,3-pentafluoropropyl)amine (DPA), which is able to promote primary human meniscus cells and human MG63 osteoblast-like cells to attach and proliferate for bone and cartilage tissue regeneration.
\nOn the other hand, its micro- or nanoscale structure turns out to be its limitation in fabricating a 3-dimentional scaffold. The small pore size prevents cell infiltration through its thickness, and so it does not regenerate bulk tissue with any thickness [108]. In addition, its mechanical weakness limits its translational ability. Thus, a composite scaffold by combining electrospinning with other textile technologies is an attractive strategy to take advantage of the different properties of different textile structures, and in this way promote the development of the novel and advanced tissue engineering scaffolds.
\nThis chapter has demonstrated the use of a number of textile fiber-based technologies that can be used to prepare resorbable scaffolds for a wide variety of tissue engineering applications. Each textile fabrication technique has its particular advantages in being able to control its physical dimensions (e.g. average pore size and pore size distribution), its surface topography and its mechanical properties, whether they be related to supporting tensile, compression, bending and shear forces, within a precise and predictable range.
\nFew experimental prototype tissue engineering structures have been accepted clinically, and fewer still have been approved by the US regulatory agency for commercial production, distribution and use. Additional work is needed in order to understand the complex biomaterial-cell-tissue interactions that occur at the scaffold interface. It is hoped that by describing in this chapter the success of using fiber-based scaffolds that more efforts and collaborations among interdisciplinary research teams will be able to overcome these challenges.
\nNone of the authors of this chapter have a ‘conflict of interest’ to declare.
All living systems have many diseases that are often caused by small organisms such as bacteria or infectious particles consisting of proteins, nucleic acids and sometimes lipids. These particles are called viruses, use the resources of living cells for their own propagation and can be transmitted from one organism to another. Each type of particle infects its own host cells, and they can survive outside living organisms in very harsh conditions. some of them continue to replicate with cells despite the host’s defence mechanisms and remain dormant (latent) in their host cell, e.g. herpesviruses which reactivate at a later date to produce further attacks of the disease if the host’s defence system weakens [1].
\nBacteriophages (or phages) are viruses that infect and use bacterial resources for their own reproduction. They are characterised by a high specificity to bacteria at infection and are very common in all environments. Their number is directly related to the number of bacteria present. It is estimated that there are more than 1030 tailed phages in the biosphere [2]. Phages are common in soil and readily isolated from faeces and sewage, as well as being very abundant in freshwater and oceans with an estimate of more than 10 million virus-like particles in 1 mL of seawater [3, 4].
\nWhy study the structure-function relationship of phages? Currently, there are substantial problems with diseases caused by bacteria, especially in hospitals. Many pathogenic bacteria exist such as
A powerful method to circumvent this resistance is the use of phages in the treatment of bacterial infections [9]. Most current studies of phage therapy have focussed on acute infections in animals [10]. In order to regulate the mechanisms of phage infection, we need to know not only the phage structure but also the phage-cell surface interaction mechanism and the process of switching the cell replication machinery for phage propagation. One important factor that has to be considered is how phages are reproduced. Phages have two ways of propagation: lytic and lysogenic [11]. In the first case, phages cause the compete lysis of a cell, where it breaks open and subsequently dies after phage replication. In the second type of replication, a phage integrates its genome into the host bacterium’s genome or forms a circular replicon in the bacterial cytoplasm. The bacterium then continues to live and reproduce normally, but the phage genome is transmitted to progeny cells at each subsequent cell division. Changes in cell conditions such as radiation or certain chemicals can release the phage genome, causing proliferation of new phages via the lytic cycle. Therefore, for medical treatments we need to use only lytic phages, so they will exist in an organism, while the pathogenic bacteria are around but only infect those bacteria that have the appropriate receptors in the outer membrane. This is an important factor that can be used to affect specific bacteria without harming those ones that are essential for the health of humans and animals [10]. In this review we will focus on tailed phages as they are abundant and well studied and could be beneficial to medicine [12]. We will describe the general organisation and structural features of their components revealed by current structural methods.
\nVirus classification is based on characteristics such as morphology, type of nucleic acid, replication mode, host organism and type of disease. The International Committee on Taxonomy of Viruses (ICTV) has produced an ordered system for classifying viruses (https://talk.ictvonline.org/taxonomy/). Phages are found in a variety of morphologies: filamentous phages, phages with a lipid-containing envelope and phages with lipids in the particle shell (Figure 1A). They have a genome, either DNA or RNA, which can be single or double stranded, and contain information on the proteins that constitute the particles, additional proteins that are responsible for switching cell molecular metabolism in favour of viruses and, therefore, the information on the self-assembly process. The genome can be one or multipartite and is located inside the phage capsid. Nearly 5500 bacterial viruses have been characterised by electron microscopy (EM) [15]. The shape of viruses is closely related to their genome, and a large genome indicates a large capsid and therefore a more complex organisation. The most studied group of phages is the tailed phages (order
(A) Representation of prokaryote bacteriophage morphotypes [
The first ideas on how viruses infect cells were based on results obtained by microbiology and bacteriology during the last century. Understanding the function of viruses and how this can be regulated and modified requires knowledge of their structural organisation. However, investigation of structure-function relationships needs a combination of different techniques. Microbiology has identified viruses as infectious agents, while bacteriology and light microscopy enabled us to identify specificity between viruses and host cell interactions and to recognise a level of survival of bacteria in the presence of different phages. In order to understand interactions at the molecular level, one needs to know the structural features of the viruses and their components at an atomic level. Different structural techniques are often utilised for smaller components, and the results fitted into larger EM structures.
\nX-ray crystallography was the first method used to study proteins at the atomic level, which is essential to reveal protein-ligand interactions that can boost or suppress protein activity. It is based on the principles of beam scattering within a crystal. By using specific software packages, a 3D electron density map of the protein that forms the crystal can be calculated [16]. However, to produce protein crystals, we need solutions of a protein at high concentration. The proteins have to be stable, and often mutations are made to remove their flexible parts, but this may produce different conformations to those that are required for their natural activity.
\nX-ray analysis is an efficient tool for analysis of protein complexes from a few kDa to hundreds of kDa in size. In order to study the structure of a large protein or a complex of several proteins, the process of crystallisation becomes a more challenging step. The development of cryoprotection in X-ray crystallography, where the crystals are flash frozen, has improved the quality of the data and often resulted in higher resolution. Nowadays, many structures of large protein complexes (up to 2–3 MDa) have been determined by X-ray analysis, but these projects have required decades to obtain high-quality crystals [17].
\nViruses are much bigger particles and often have flexible components. The large size of the complexes results in significantly bigger unit cells, which results in technical challenges in obtaining fine structural details. Viruses with a rigid icosahedral lattice of the capsid have been studied successfully by X-ray crystallography at near-atomic resolution. The first viral structure was that of the
Nuclear magnetic resonance (NMR) is an important technique that resolves structures of small proteins that are not suitable for crystallisation due to their flexibility. This method is based on exploiting the electrical charges and spins of the nuclei in a molecule. If an external magnetic field is applied, energy is transferred to the nuclei changing their state from the level of base energy to a higher energy. This energy is emitted when the spin returns back to its base level at a frequency corresponding to radio frequencies1. The signal that matches this transfer is measured and processed in order to yield a NMR spectrum [17, 20]. This technique is typically used for proteins of less than 200 amino acids and an upper weight limit of about 50 kDa, so it is unsuitable for the structural determination of complete viruses. However, it can be used to analyse flexibility of bigger complexes [21]. The NMR structures can be docked into low-resolution cryo-EM structures.
\nLight microscopy has been used for several centuries to study objects that are hardly visible to the naked eye. In conventional microscopy, resolution is mostly restricted according to the theoretical context of the Rayleigh criterion [22]. This limit is defined by the diffraction properties of light in lenses and has restricted our view to objects bigger than 250 nm. New developments in technology and advances in optical quality, electronics and software have delivered new options and extended the field of applications for electron microscopes allowing visualisation of single molecules. Electron microscopes use a beam of electrons (wavelength of less than 0.1 nm) instead of visible light
At the very beginning of EM evolvement, a method called negative staining was used for visualisation of biological complexes. In this case a drop of biocomplex solution is placed on a support grid and embedded in a heavy atom salt, usually uranyl acetate [24]. Since the specific density of the negative stain is much higher than the density of the biological molecules in the microscope, we can see the cast of the molecule merged into the surrounding stain. Where the stain did not penetrate into the molecule, one can see light spots in the image as the stain has blocked electrons. Sample preparation is fast and produces very high contrast. However, this technique does not allow fine details to be seen, and the particle becomes distorted due to the drying procedure required. The stain has a relatively large grain (up to 1.5 nm) that obscures details of the molecules under study.
\nNearly four decades ago, a cryo-technique for sample preparation was introduced that allows biocomplexes to be kept at nearly native conditions. A thin layer of sample on a grid is flash frozen at liquid nitrogen temperatures, thus trapping molecules in a native, hydrated state within a thin layer of amorphous ice [25]. This technique is used to study the structural organisation of biocomplexes by cryo-electron microscopy (cryo-EM) or electron tomography (cryo-ET). Until two decades ago, all data in EM was collected on films that had to be developed and digitised, which was time-consuming. The advent of charge-coupled devices (CCDs) allowed direct digital acquisition of images and the collection of large numbers of particles giving rise to structures of higher resolution. Later, direct electron detectors were introduced into EM and are now used in all high-end electron microscopes [26]. Together with new approaches in microtechnology and the automation of data collection, the results from image analysis have improved tremendously. Cryo-EM is now approaching the near-atomic resolution that had only been achieved by X-ray crystallography. New maps obtained by cryo-EM provide information on the main polypeptide chains and often reveal the positions of side chains. The current highest resolution of structures currently deposited in the EMDB is 1.5 Å [27], with many others at a resolution between 3.5 and 4 Å. At this resolution atomic models can be built and refined using the crystallographic methods.
\nIn cryo-ET the samples are also flash frozen, but data is collected by tilting the grid with the sample between −60 and 60° around the horizontal axis (perpendicular to the optical axis of the microscope) with an increment typically of 2°. The 2D images taken at each angle are combined to calculate a 3D map of the object. The limitation in the range of the tilt results in a cone of missing data [28]. The resolution in structures obtained by cryo-ET is lower than that in single-particle analysis. However, this approach allows visualisation of important organelles within cells. If there are multiple small structures such as ribosomes or viruses, then each structure can be extracted and averaged. This is called subtomogram averaging and will give higher-resolution structures [29].
\nPhages may have different shapes and sizes (Figure 1A). The most studied group is that of tailed phages with a dsDNA genome, and it also represents the largest group (Figure 1B). The tailed phages have three major components: a capsid where the genome is packed, a tail that serves as a pipe during infection to secure transfer of genome into host cell and a special adhesive system (adsorption apparatus) at the very end of the tail that will recognise the host cell and penetrate its wall. Cell resources are used for the phage reproduction.
\nThe functional phage is a result of a multistep process that starts with all the necessary proteins produced by the host cell after infection: capsid, portal, tail, scaffolding, terminase, etc. (Figure 2). The capsids of the dsDNA phages often have fivefold or icosahedral symmetries [30], which are broken at one of the fivefold axes by the head-to-tail interface (HTI). The main component of the HTI is a dodecameric portal protein (PP) within the capsid. The PP represents the DNA-packaging motor, which is the crucial part of these nano-machines. The HTI also includes oligomeric rings of head completion proteins that play dual roles: (1) making an additional interface to molecules of ATP which provide energy for DNA packaging and (2) then connecting the portal protein and the tail. Some HTIs also serve as valves that close the exit channel preventing leakage of genome from the capsid but opening as soon as the phage is attached to the host cell. However, symmetries other than dodecameric have been found for nearly all PPs in vitro if the PPs are assembled under naive conditions, without any other phage protein components [31, 32, 33, 34, 35]. Typically, the main phage proteins have conservative folds despite low sequence similarity, although they may have different additional domains [36, 37].
\nSelf-assembly pathway of phages. Multiple copies of the capsid/scaffold complex bind the portal protein to form the procapsid; then, the scaffold proteins are ejected, and DNA is packaged into the procapsid, which expands to the size of the mature capsid. The head completion proteins (the stopper and the adaptor) are bound to the portal complex preventing DNA leakage. Next, decoration proteins bind to the capsid, and the tail, assembled separately or after DNA packaging, is attached; thus, the final infectious phage is produced. The preassembled tail attaches in
The phage tail is the structural component of the phage that is essential during infection. Its adsorption apparatus located on the distal end of the tail recognises a receptor, or the envelope chemistry, of the host cell and ensures genome delivery to the cell cytoplasm. In
The capsid of a phage has a precursor formation, named the procapsid, during the assembly process (Figure 2). Scaffolding proteins (SPs) drive the assembly process by chaperoning major capsid protein (MCP) subunits to build an icosahedral procapsid that is later filled with dsDNA. The SPs are bound to the portal complex during formation of a procapsid with scaffolding inside. The sequence of conformational changes from a procapsid to the phage capsid where genome has been packed is named as the maturation process and goes through a series of intermediates [19, 38, 39, 40]. Some phages like HK97 and T5 do not have a separate SP; instead, the capsid protein is fused with a scaffolding domain at the N-terminus. As soon as the procapsid is assembled, the scaffolding domain is cleaved off and then like the separate SP will be removed from the capsid to make room for the genome [38, 39]. Structures of procapsids and mature virions have been determined for a number of phages (Table 1). The spherical capsid shell expands during maturation and becomes thinner due to alterations in the inter- and intra-subunit contacts.
\nPhage | \nType of phage | \nCapsid protein | \nNo. of residues | \nM. Mass (kDa) | \nResolution (Å) | \nStructure analysis | \n
---|---|---|---|---|---|---|
HK97 | \ngp5 | \n385 282 (AC) | \n42 | \n3.44 (C) 12 (PC) | \nX-ray [42] EM [51] | \n|
Т5 | \npb8 | \n458 299 (AC) | \n51 | \n9 (C) | \nEM [52] | \n|
λ | \ngpE | \n341 | \n38 | \n6.8 (C),13.3 (PC) | \nEM [47] | \n|
SPP1 | \ngp13 | \n324 | \n35 | \n8.8 (C) | \nEM [53] | \n|
TP901-1 | \nORF36 | \n272 | \n29 | \n15 | \nEM [54] | \n|
TW1 | \ngp57* | \n352 | \n39 | \n7 | \nEM [55] | \n|
φ29 | \ngp8 | \n448 | \n50 | \n8 | \nEM [56] | \n|
T7 | \ngp10 | \n345 | \n37 | \n4.6 (PC) 3.6 (C) | \nEM [57] | \n|
P22 | \ngp5 | \n430 | \n47 | \n3.8 (PC) 4.0 (C) 3.3 (C) | \nEM [58, 59, 60] | \n|
ε15 | \ngp7 | \n335 | \n37 | \n4.5 | \nEM [50] | \n|
T4 | \ngp24 gp24* gp23 gp23* | \n427 417 (AC) 521 456 (AC) | \n47 44 56 49 | \n2.9 (monomer) 3.3 (EM) | \nX-ray [61] EM [62] | \n|
HSV-1 | \nVP5 | \n1374 | \n149 | \n4.2 (C) | \nEM [63] | \n
Phage procapsids and capsids.
AC—after cleavage; C—capsid; PC—procapsid
Most tailed phages have capsids of an icosahedral shape formed by multiple copies of one or more proteins. Icosahedral capsids are characterised by 12× fivefold, 20× threefold and 30× twofold axes, which give rise to 60 copies of the major independent parts [41]. A triangulation number (T number) describes the number of copies of the same protein within the independent part of the icosahedral lattice. The overall number of proteins in the virus corresponds to the T number multiplied by 60; for example, a T = 3 virus has 180 subunits [41]. Oligomers of the proteins that are located on the fivefold axes are referred to as pentons, while those complexes that are located on the faces of the icosahedron and form oligomers from six subunits are named as hexons.
\nStructural organisation of the major capsid proteins. (A) Siphophage HK97 (1OHG). The catalytic residues are shown in brown and circled. (B) Podophage ε15 (3 J40). (C) Podophage P22 (5UU5). (D) MyophageT4 gp23* (5VF3). The N-arm is dark blue, the P-domain is red, the A-domain is light blue and the E-loop is yellow. Extra inserted domains seen in P22 and T4 are magenta. The yellow linker in T4 is topologically equivalent to the E-loop seen in the other phages.
Crystal structures were obtained for the Hoc protein from the T4-like phage RB49 with the capsid-binding C-terminal domain 4 missing [71] and Soc protein from the T4-like phage RB49 [72]. The Soc molecules, which are required for capsid stability, interact with three gp23* subunits [62] although not all binding sites were fully occupied possibly due to differences in the gp23* I-domain linkers. The immunogenic outer capsid Hoc protein was found in two different sites within the asymmetric unit: at the centre of the hexon near the icosahedral threefold axis and in the hexon close to the fivefold axis [62]. The density of Hoc near the threefold axis was less interpretable than that near the fivefold axis.
\nIn phages and herpesviruses, one of the fivefold vertices of the capsid is replaced by a
All currently known PPs are homo-dodecamers when extracted from the viral capsids, as that symmetry is imposed during self-assembly in vivo. However, naive assemblies in vitro of the PP complexes have some variations in their rotational symmetry with 13-mers being observed for SPP1, T7 and HK97 [31, 33, 74]. HSV has been shown to have 11-fold, 12-fold, 13-fold and sometimes even 14-fold symmetry [34]. While monomers of the different PPs vary in size, all of them share a common fold—shown by EM and X-ray structures that were obtained for the φ29, SPP1 and P22 portals [75, 76, 77, 78] and by cryo-EM for T7 and T4 (Table 2) [69, 79]. All known PP monomers are characterised by four domains: clip, stem, wing and crown (Figure 4) [77]. The clip domain is exposed to the capsid exterior and involved in binding to the terminase for DNA packaging [75, 80, 81] and later to a head completion protein during the HTI assembly [82]. The first high-resolution structure of a phage PP was obtained for the φ29 phage (Figure 4A, [75]). The clip domain is linked to the wing region through a stem that comprises typically two α-helices and the outer loops (Figure 4B,C). X-ray structures of PP from φ29 and SPP1 phages revealed major helical components that form the central channel through which DNA enters and exits the capsid. The structures of other PPs obtained later have confirmed that this is a conserved element characteristic for all known PPs. The wing domain radiates outwards from the central axis and has an α-helix, which is the longest one and serves as a spine of the wing. It has an α/β sub-fold at its periphery [77]. The crown domain consists of α-helices and is relatively small in SPP1 and surprisingly long (213 aa) in phage P22 (Figure 4B,D, Table 2).
\nPhage | \nPP | \nNo. of residues | \nM. Mass (kDa) | \nResolution (Å) | \nStructure analysis | \n
---|---|---|---|---|---|
HK97 | \ngp3 | \n424 | \n47 | \n\n | none | \n
T5 | \npb7 | \n403 | \n45 | \n\n | none | \n
λ | \ngpB | \n533 | \n59 | \n\n | none | \n
SPP1 | \ngp6 | \n503 | \n57 | \n3.4 (X-ray), ~7 (EM) | \nX-ray [77], EM [82] | \n
TP901-1 | \nORF32 | \n452 | \n52 | \n20 | \nEM [54] | \n
TW1 | \ngp24 | \n459 | \n51 | \n21 | \nEM [55] | \n
φ29 | \ngp10 | \n309 | \n36 | \n2.1 | \nX-ray [76] | \n
T7 | \ngp8 | \n536 | \n59 | \n8, 12 | \nEM [87] | \n
P22 | \ngp1 | \n725 | \n83 | \n10.5 (EM) 3.25 (X-ray) | \nEM [88] X-ray [78] | \n
ε15 | \ngp4 | \n556 | \n61 | \n20 | \nEM [89] | \n
T4 | \ngp20 | \n524 | \n61 | \n3.6 | \nEM [69] | \n
HSV-1 | \npUL6 | \n676 | \n74.2 | \n8 | \nEM [90] | \n
Phage portal proteins.
Structures of portal proteins. One chain of the PP is highlighted in red. (A) gp10 of φ29 (1FOU). (B) gp6 of SPP1 (2JES). (C) A gp6 SPP1 monomer with the crown, stem, wing and clip domains indicated. (D) gp1 of P22 (3LJ5). (E) gp8 of T7 (3J4A). (F) gp24 of T4 (3JA7).
Structures of the HTI. (A) The cryo-EM map of the SPP1 HTI coloured according to protein with the gp6 PP (blue), adaptor gp15 (brown) and stopper (purple) (EMD-1021 [
The tail organisation in phages depends on their type:
Phage | \nTail proteins | \nNo. of residues | \nM. Mass kDa | \nResolution (Å) | \nStructure analysis | \n
---|---|---|---|---|---|
HK97 | \nputative tail-component IPR010064, gp10 | \nnot defined | \nnot known | \nn/a | \nNone | \n
Т5 | \npb6 | \n464 | \n50 | \n2.2 6 | \nX-ray [97] EM [97] | \n
λ | \ngpV (TP) gpH (TMP) gpU (terminator) | \n246 853 131 | \n26 92 15 | \nn/a 2.7 | \nNMR [98, 102] X-ray [103] | \n
SPP1 | \ngp17 (TP) gp17* (TP) gp18 (TMP) | \n134 264 1032 | \n15 28 111 | \nn/a 14 | \nNMR (gp17) [104] EM [85] | \n
TW1 | \ngp12 (TP) gp14 (TMP) | \nNF 675 | \n18 72 | \n23 | \nEM [55] | \n
φ29 | \ngp9 (knob) gp12 (tailspike) | \n599 854 | \n68 92 | \n2.04 1.8–2.05 7.8 | \nX-ray [105, 106] EM [56] | \n
T7 | \ngp11 (TP) gp12 (TP) gp17 (fibres) | \n196 794 553 | \n22 89 62 | \n12.0 2.0 (X-ray) | \nEM (gp11,12,17) [87] X-ray (gp17) [107] | \n
P22 | \ngp10 (hub) gp9 (tailspike) | \n472 667 | \n52 72 | \n9.4 2.0 | \nEM, tomography [88, 91], X-ray [108, 109] | \n
ε15 | \ngp20 (tailspike) | \n1070 | \n116 | \n20n/r | \nEM [89, 110] | \n
T4 | \ngp19 (TP) gp15 (terminator) | \n163 272 | \n18 32 | \n4.11 3.4 15.0 3.2 | \nEM [111, 112] X-ray [113] | \n
HSV | \ndoes not have the tail | \nn/a | \nn/a | \nn/a | \nn/a | \n
Phage tail structures.
Bacteriophage tails. (A) The crystal structure of a monomer of T5 pb6 (5NGJ). The extra immunoglobulin domain is coloured yellow. (B) A slice of the combined EM map of T5 (EMD-3692) showing the fold symmetry of the tail. (C) The crystal structure of the N-terminal domain of the P22 TP gpV (2K4Q). (D) Cryo-EM map of SPP1 tails (gp17.1). (E) Cryo-EM map of SPP1 tails (gp17.1*). The protrusions are the size of an immunoglobulin domain. (F) The T4 cryo-EM map (EMD-8767) with fitted coordinates (5W5F). Alternate subunits in the central ring are coloured red and blue. The red circle in B and rectangles in D, E and F indicate the inner tail tube, γ—rotation between adjacent tail rings.
Most
Adsorption apparatus. (A) The EM map (EMD-5051) of P22 coloured according to the constituent proteins. The PP (gp1), the gp4 12-mer, the gp10 6-mer, the gp9 tailspikes and the gp26 cell-puncturing needle are in purple, green, red, blue and brown, respectively. (B) The crystal structures for the N-terminal head-binding domain (1LKT) and the C-terminal receptor-binding domain (1TYU) of P22 gp9 docked into the cryo-EM density (EMDB-5051). (C) The receptor-binding carboxy-terminal domain of T5 tail fibre pb1 (5AQ5). The five different domain regions are labelled. The N- and C-termini are indicated. (D) The EM map (EMD- 8868) of the TW1 tail showing the TP gp12 (in blue), gp15 (in green), gp16, gp18, gp27 (together in light brown) and the gp19 tailspikes (in purple). (E) The φ29 tailspike protein gp12 (3SUC). The four domains D1*, D2, D3 and D4 are labelled. (F) The crystal structure (1 K28) of the cell-puncturing device of T4 (gp27 ± gp5* ± gp5C)3. Each monomer within in the gp5 trimer is coloured in blue, green and orange, and each one in gp27 is coloured in magenta, red and cyan.
The structure of the T4 baseplate was assembled in vitro from gp10, gp7, gp8, gp6 and gp53, and the crystal structure was determined (4.2 Å) [141]. This indicated interesting differences compared to the structures when they are separately crystallised. However, about two-thirds of the structure was missing, but a cryo-EM structure of the same construct (3.8 Å) provided the positions of these missing parts [142]. The structures of T4 baseplate in its pre- and post-host attachment states were determined at 4.11 and 6.77 Å, respectively, by cryo-EM [111]. By combining high-resolution structures of the individual baseplate proteins, the authors were able to build a pseudo-atomic model for the baseplate proteins. The crystal structure at 2.9 Å of the gp5–gp27 cell-puncturing device was fitted into the EM structure (Figure 7F) [143]. Positions of gp27, gp5C (the C-terminal β-helix domain of gp5) and gp5* (the N-terminal OB-fold domain and the lysozyme middle domain) were identified. A monomeric protein gp5.4 caps the tip of the gp5 β-helix to sharpen the central spike [144]. During infection this spike punctures the cell membrane, and the lysozyme domain of gp5 digests the peptidoglycan in the
Structural studies of the currently known tailed phages have shown a common organisation, which implies that they have a single ancestor and diversity has arisen through evolution [37]. All phages have a similar pathway of self-assembly: a procapsid formed with the help of a SP (or sometimes a scaffolding domain); conformational changes induced by release of the SP create a space for the DNA, and assisted by DNA terminases, the genome is packaged into the procapsid. This step is typically named as the maturation of the capsid. The tail is then attached or assembled on the capsid to form the infectious virion. The MCPs are characterised by the HK97 capsid protein fold. However, phages have a very low sequence similarity, which leads to differences in how the capsid stability is arranged to withstand the high inner pressure of the genome. In some phages like HK97 and SPP1, the interactions between capsid proteins are strong and hold the capsid intact. In many phages the process of capsid maturation is linked to attachment of additional proteins that are named as auxiliary or decoration proteins. They are often essential to enhance the capsid stability. The HK97 capsid is held together by chain mail covalent links between the MCPs; in SPP1 and T5, the decoration proteins enhance stability of the capsid, but in λ, T4 and ε15 phages, these proteins are essential for keeping DNA inside the capsid [19, 52, 53].
\nThe HTIs play an important role in all tailed phages as they provide a channel for DNA to enter and exit the capsid and at the same time provide a covalent connection to either the preassembled tails or tails assembled on the capsid. They all contain a dodecameric PP positioned within the capsid at one of the fivefold vertices and that acts as a gatekeeper holding the DNA within the capsid even in very harsh environments. Like the capsid proteins, the PPs have a common fold with the conserved elements being involved in interactions with DNA [145]. They have mostly α-helical domains in their central part and β-layers in the wing domains that interact with the capsid to fix the PP position. Head completion proteins below the PP also have similar folds to each other.
\nA much higher level of divergence is reflected in phage tail structures. The most common feature in all long-tailed phages is a central tube with a large number (30–40) of three- or sixfold circular rings of the major TPs. There is structural similarity between these major TPs: they have a similar fold of a β-sandwich flanked by alpha-helices and loops that provide links between adjacent rings. The helical tails have a typical rise of about 40 Å and rotation of around 20° between adjacent rings. Some tails also have appendages, which appear to have an immunoglobulin-like fold. Very little is known about the organisation of tail sheaths that have some similarities with type VI secretion systems, but sometimes they have extra appendages like immunoglobulin domains to help phages recognise their host cells. There is also some structural similarity of the TP with the tail terminator proteins and proteins in the T4 sheath.
\nEven higher diversity is found in the adsorption apparatus which are responsible for the recognition of the host cells and signalling the opening of the gate for the genome release. The tip of phage SPP1 recognises its receptor; induces the tail to be attached to the outer membrane of the host cell after disconnection of the tip. At the same time this interaction generates a signal that open the PP gate keeper. The T4 phage has a significantly more complex system of a baseplate which undergoes several steps of complex conformational changes.
\nInterestingly, the receptor-binding proteins also a have similar organisation: they are all trimers, usually intertwined with β-helical regions, and use their N-terminal domain to bind to the phage. Spikes and fibres are also found in many phages. However, the number of spikes or fibres varies significantly between phages. Podophages have trimeric tailspikes to recognise the specific host cell for infection. Like other phage components, they vary from six fibres in phage T7 to 12 in phage φ29, but they all have a β-helical fold. The fibres can have different roles within a phage, for instance, T4 has six long fibres that serve as host recognition and six short fibres which then extend and bind to the cell.
\nAntibiotics (especially of the broad-spectrum type) are very effective at killing infectious bacteria; however, they kill typically multiple bacterial species indiscriminately, thus destroying beneficial bacteria of the host microbiome as well. Since phages are specific to one species of bacteria, they are unlikely to perturb microbiome bacterial species. Current problems with antibiotic resistance require new approaches, and here phages can be used [12]. For medicinal purposes it is necessary to design a phage that will recognise the specific bacteria we want to eliminate [146]. Phages can be modified for high specificity in the recognition of pathogens. The high level of phage specificity is based on recognition of receptor characteristic for a given type of bacteria which is where the differences in the adsorption systems of different phages play a crucial role. The important task in studying phages is to find those that are able to kill only antibiotic-resistant bacteria. Here, the lytic phages are of most interest, since rather than stopping bacteria from producing a certain type of protein that will slow down the bacterium proliferation, like in the case of antibiotics, these phages destroy the bacteria’s cell wall and cell membrane completely. In addition, many bacteria develop biofilm—a thick layer of viscous materials that protect them from antibiotics. Some phages are equipped with tools that can digest this biofilm [147]. There are some problems with phages, since they are easy to use for topical applications, but often specific medications have to be administered internally. For phages to be used for delivery of drugs, they need to be more precise in their action. Consequently, we need to modify them so that the infectivity will be efficient by replacing the genome with DNA encoding specific enzymes and the adsorption apparatus made more effective. To develop these medical approaches, we need to know the phage organisation and the interactions between protein components at the atomic level. To achieve this hybrid, methods should be used including structural biology, biochemistry and microbiology [21].
\nThe authors are grateful to Dr. D. Houldershaw and Mr. Y. Goudetsidis for their computer support. The authors apologise for the incomplete coverage of known phage structures and have drawn on a limited subset, owing to space constraints.
\nThe authors declare no conflict of interest.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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One distinguished feature of the open source software (OSS) development model is the cooperation and collaboration among the members, which will cause various social networks to emerge. 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This chapter provides theoretical and practical view on different aspects: technical evolution of ICT tools, development and fostering of communication flow, personal aspects of IT communication, with important emphasis on building of trust within virtual teams. The reader can extract from this chapter guidelines for work in collaborative virtual environment, to run effectively either small projects, meetings and lectures or even more complex projects, distributed among several dislocated teams. The chronological overview of the continuous virtual communication in the last 15 years gives also fair suggestions about future evolution for the next decade.",book:{id:"8850",slug:"harnessing-knowledge-innovation-and-competence-in-engineering-of-mission-critical-systems",title:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems",fullTitle:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems"},signatures:"Nikola Vukašinović, Janez Benedičič and Roman Žavbi",authors:[{id:"294317",title:"Dr.",name:"Nikola",middleName:null,surname:"Vukašinović",slug:"nikola-vukasinovic",fullName:"Nikola Vukašinović"},{id:"294322",title:"Prof.",name:"Roman",middleName:null,surname:"Žavbi",slug:"roman-zavbi",fullName:"Roman Žavbi"},{id:"308791",title:"Dr.",name:"Janez",middleName:null,surname:"Benedičič",slug:"janez-benedicic",fullName:"Janez Benedičič"}]},{id:"70099",title:"Knowledge Redundancy Cycles in Complex Mission-Critical Systems",slug:"knowledge-redundancy-cycles-in-complex-mission-critical-systems",totalDownloads:714,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Based on a 20-year, 10-million case study programme of research, 98% of all innovation attempts end in failure. The main aim of the research has been to decode the underpinning, first-principle-driven ‘DNA’ of the 2% of successful attempts. Sitting right at the centre of this DNA is a triad of fundamentals: the need to embrace the dynamics of complex adaptive systems, the need to actively seek out and eliminate compromises and contradictions, and the need for industry domains to periodically unlearn knowledge that has become redundant. The chapter discusses all three of these pillars. Particular attention is paid to the knowledge redundancy topic, where the fact that the life-cycle of knowledge follows distinct, repeating patterns of evolution at meta, macro and micro- hierarchical levels is demonstrated. The research further demonstrates how organizations can use these patterns to objectively identify redundancy ‘pulse-rates’ and thus objectively manage both the acquisition of required new knowledge and the disposal of knowledge that is no longer fit for purpose. The research shows too that a key aspect of this ‘unlearning’ activity demands that organizational leaders acknowledge and accommodate the very human emotions that accompany change initiatives where the things that define a person’s competence become a hazard to the future success of the enterprise.",book:{id:"8850",slug:"harnessing-knowledge-innovation-and-competence-in-engineering-of-mission-critical-systems",title:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems",fullTitle:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems"},signatures:"Darrell Mann",authors:[{id:"297423",title:"Prof.",name:"Darrell",middleName:null,surname:"Mann",slug:"darrell-mann",fullName:"Darrell Mann"}]},{id:"69932",title:"Simplexity: A Hybrid Framework for Managing System Complexity",slug:"simplexity-a-hybrid-framework-for-managing-system-complexity",totalDownloads:726,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Knowledge management, management of mission critical systems, and complexity management rely on a triangular support connection. Knowledge management provides ways of creating, corroborating, collecting, combining, storing, transferring, and sharing the know-why and know-how for reactively and proactively handling the challenges of mission critical systems. Complexity management, operating on “complexity” as an umbrella term for size, mass, diversity, ambiguity, fuzziness, randomness, risk, change, chaos, instability, and disruption, delivers support to both knowledge and systems management: on the one hand, support for dealing with the complexity of managing knowledge, i.e., furnishing criteria for a common and operationalized terminology, for dealing with mediating and moderating concepts, paradoxes, and controversial validity, and, on the other hand, support for systems managers coping with risks, lack of transparence, ambiguity, fuzziness, pooled and reciprocal interdependencies (e.g., for attaining interoperability), instability (e.g., downtime, oscillations, disruption), and even disasters and catastrophes. This support results from the evident intersection of complexity management and systems management, e.g., in the shape of complex adaptive systems, deploying slack, establishing security standards, and utilizing hybrid concepts (e.g., hybrid clouds, hybrid procedures for project management). The complexity-focused manager of mission critical systems should deploy an ambidextrous strategy of both reducing complexity, e.g., in terms of avoiding risks, and of establishing a potential to handle complexity, i.e., investing in high availability, business continuity, slack, optimal coupling, characteristics of high reliability organizations, and agile systems. This complexity-focused hybrid approach is labeled “simplexity.” It constitutes a blend of complexity reduction and complexity augmentation, relying on the generic logic of hybrids: the strengths of complexity reduction are capable of compensating the weaknesses of complexity augmentation and vice versa. The deficiencies of prevalent simplexity models signal that this blended approach requires a sophisticated architecture. In order to provide a sound base for coping with the meta-complexity of both complexity and its management, this architecture comprises interconnected components, domains, and dimensions as building blocks of simplexity as well as paradigms, patterns, and parameters for managing simplexity. The need for a balanced paradigm for complexity management, capable of overcoming not only the prevalent bias of complexity reduction but also weaknesses of prevalent concepts of simplexity, serves as the starting point of the argumentation in this chapter. To provide a practical guideline to meet this demand, an innovative model of simplexity is conceived. This model creates awareness for differentiating components, dimensions, and domains of complexity management as well as for various species of interconnectedness, such as the aligned upsizing and downsizing of capacities, the relevance of diversity management (e.g., in terms of deviations and errors), and the scope of risk management instruments. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. 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Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. 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Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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