\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control. \r\n\t
",isbn:"978-1-80355-667-3",printIsbn:"978-1-80355-666-6",pdfIsbn:"978-1-80355-668-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"52f8a3a1486912beae40b34ac557fed3",bookSignature:"Ph.D. Yogendra Shah",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",keywords:"HIV, Dengue, Zika, West Nile Virus, Chikungunya, Rabies, SARS-CoV2, MERS-CoV, Hanta Virus, Influenza, Whole Genome Sequencing, DNA Sequencing",numberOfDownloads:107,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2021",dateEndSecondStepPublish:"November 1st 2021",dateEndThirdStepPublish:"December 31st 2021",dateEndFourthStepPublish:"March 21st 2022",dateEndFifthStepPublish:"May 20th 2022",remainingDaysToSecondStep:"7 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Shah obtained his Ph.D. degree in Veterinary Medicine from Hokkaido University, Japan. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah",profilePictureURL:"https://mts.intechopen.com/storage/users/278914/images/system/278914.jpg",biography:"Dr. Yogendra Shah is a consultant microbiologist/virologist, senior research microbiologist, and lecturer at Seti Provincial Hospital, COVID-19 PCR laboratory, National Zoonoses and Food Hygiene Research Center, and Kathmandu College of Science and Technology, Nepal. He obtained a Ph.D. in Veterinary Medicine (Bacteriology) from the Graduate School of Veterinary Medicine, Hokkaido University, Japan, in 2017. His research focuses on better understanding the molecular epidemiological features/transmission dynamics of infectious diseases and zoonotic infectious diseases in Nepal by employing molecular techniques like ELISA, polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and DNA sequencing. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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\n\t\t\t
1. Introduction
\n\t\t\t
Biomineralization is the process by which mineral crystals are deposited in an organized fashion in the matrix (either cellular or extracellular) of living organisms (Boskey, 1998). In simple terms, it can be described as the widespread and fascinating process by which living organisms produce minerals (Sigel et al., 2008; Stephen and Lowenstam, 1989). In this process, a living organism provides a chemical and physical environment that controls the nucleation and growth of a unique mineral phase. Often these materials exhibit hierarchical structural order, leading to superior physical properties not found in either their inorganic counterparts or in synthetic materials. The incorporation of inorganic compounds, such as salts, into biological structures often lends the structures hardness or rigidity. Almost 70 different mineral types are known to be formed by organisms from all the kingdoms. Examples include silicates in algae, carbonates in diatoms and invertebrates, and calcium phosphates and carbonates in vertebrates. These minerals adopt complex and genetically determined shapes, are often aligned to form arrays, and fulfill many different functions. These include the mechanical functions of exo- and endo-skeletons, temporary storage of minerals, stiffening of soft tissues, and much more. In vertebrates, especially mammals, bone and tooth are major biominerals.
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Bones are living, growing tissue. During our lifetime, bone is constantly being renewed; there is localized removal of old bone (resorption) and replacement with newly formed bone. This coupled process is called bone remodeling. Biomineralization of bone—essential for its hardness and strength—involves a well orchestrated process in which crystals of calcium phosphate are deposited on the matrix produced by bone-forming cells (Weiner et al., 1999). Because bone formation consists of components including cells, matrix, and inorganics, the process is investigated by different research fields including cellular and molecular biology, organic and inorganic chemistry, crystallography, and material science (Figure 1).
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Figure 1.
Components of bone biomineralization. Bone forming cells (osteoblasts) produce extracellular matrix on which minerals are deposited.
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Special attention has been paid to apatite materials because of their physicochemical properties, thermal stability, and biocompatibility that make them suitable for biomedical applications (Narasaraju et al., 1996). The usage of apatite-related biomaterials mainly focused on bone substitution or bone cements in the early years of study (Ono et al., 1990), however, the target has expanded to bone regeneration and drug delivery systems (Komleva et al., 2002). Therefore, material characteristics, including cellular and tissue compatibility, biodegradability, and drug loading capacity, should be improved. Moreover, it is desirable to create materials that can actively instruct cell fate in the area surrounding the material to enhance bone regeneration. To obtain such materials, research has focused on developing ideas based on biological mineralization systems. In this chapter, the latest research trends related to biomimetic apatite materials as well as biomimetic fabrication of apatite related biomaterials are introduced.
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2. Basics of biominralization of bones
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To obtain biomimetic apatite materials or to develop biomimetic methods of fabricating them, it is crucial to understand the natural biomineralization process of bones. The biomineralization process of bone can be simply divided into three parts at the microscopic level as follows, though the process differs depending on the ossification manner (e.g. osteochondral, intramembranous), stage (e.g. development, fracture healing), region, or age.
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1) Osteogenic differentiation of mesenchymal stem cells (MSCs).
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2) Organization of matrix proteins secreted from osteoblasts.
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3) Nucleation and crystal growth of apatite minerals on matrix.
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2.1. Osteogenic differentiation of mesenchymal stem cells (MSCs):
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As a result of the capacity for self-renewal and differentiation, bone marrow derived stromal cells were first considered as stem cells and named mesenchymal stem cells (MSCs). However, in the bone marrow, stromal cells are a rare and heterogeneous population of cells that contain a mixture of progenitors at different stages of commitment to the mesodermal lineage and only a very small number of multipotential self-renewing stem cells (Caplan, 1991). It is now accepted that most bone marrow derived progenitor stromal cells can be considered, after in vitro proliferation, to be MSCs (Horwitz et al., 2005). Consequently, MSCs are typically defined as adherent, fibroblastoid-like cells that differentiate to osteoblasts, adipocytes, and chondrocytes in vitro. Despite their functional heterogeneity, in vitro MSCs are defined as nonhematopoietic cells (CD45-, CD14-, CD34-) but express other molecules, the combination of which is largely used for their description: CD73+, CD44+, CD105+, CD90+ and CD146+.
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Key factors
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In vivo and in vitro effects
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TGFbeta
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Can induce osteoblast differentiation at the early stage of immature cells but can also inhibit osteogenesis in committed cells.
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BMP2
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Osteochondrogenic factor; might initiate bone formation and bone healing and can induce expression of other BMPs
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BMP4
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Osteochondrogenic factor in vivo and in vitro
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BMP7
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Osteogenic factor in vivo and in vitro ; active on more mature osteoblasts
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Noggin
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Suppresses osteoblastic differentiation
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FGFb
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Mutations induce chondrodysplasia and craniosynostosis; can stimulate Sox9; might be a negative regulator of postnatal bone growth and remodeling
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IGF-I, II
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Stimulates growth plate formation, endochondrate ossification and bone formation by osteoblasts
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VEGF
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Most potent angiogenic and vasculogenic factor; crucial at the onset of bone formation
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PlGF
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Induces proliferation and osteogenic differentiation of MSCs; crucial for vascularization
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Wnts
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Depending on Wnt type, crucial for osteoprogenitor proliferation; can also inhibit final osteoblast maturation
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Ihh
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Pivotal role for growth plate and endochondral formation; can inhibit osteoblast differentiation; might induce PTHrP expression
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PTHrP
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Pivotal role for growth plate and endochondral formation; can induce or inhibit osteogenesis
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OPG
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Strongly inhibits bone resorption and has a pivotal role in bone Remodeling.
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RANKL
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Strongly stimulates bone resorption and has a pivotal role in bone remodeling
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MAPKs
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Crucial for regulation of intracellular signaling induced by osteogenic factors (still controversial)
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Runx2
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Master regulator of early osteogenesis; runx2_/_ mice died, with no bone formation
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\n\t\t\t\t\t\t\t
Osterix
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Master regulator of late osteogenesis, inhibiting chondrogenesis
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\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Dlx5
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Induces osteoblast maturation but inhibits osteocyte formation
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Msx2
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Induces proliferation of immature cells; responses depend on Dlx5 quantity
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NF-kB
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Inhibits the differentiation of MSCs and committed osteoblastic cells
As shown in Table 1 a range of cytokines modulate osteoblast differentiation, including bone matrix-derived transforming growth factor beta (TGF-), bone morphogenetic protein2 (BMP-2), BMP-4, and BMP-7, and their inhibitors noggin, chordin, gremlin, etc. Transcription factors that regulate the osteoblast include a range of homeodomain proteins: the activator protein (AP) family members Jun, Fos, and Fra, Smads, CCAAT/enhancer binding protein (C/EBP) and C/EBPδ, lymphoid-enhancing factor (a Wnt effector), activating transcription factor 4, Runt-related transcription factor 2 (Runx2), and osterix, the last 3 of which are considered master genes for osteoblast differentiation. Runx2 is critical for osteoblast differentiation and two homeobox protein Dlx5 and Msx2 regulate Runx2 activity via a protein-protein binding interactions (Shirakabe et al., 2001). Thus, owing to the specific signal activation including transcriptional dynamics, MSCs differentiate into osteoblasts (Figure 2).
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2.2. Secretion of matrix proteins by osteoblasts
\n\t\t\t\t
Recruited and differentiated osteoblasts play a key role in biomineralization by secreting matrix proteins including collagen and non-collagenous proteins (NCP). Most tissues have been shown to contain a mixture of different collagen types. Bone, however, appears to contain almost exclusively type I collagen, with some type V (Broek et al., 1985). Type I collagen is the most common of the collagens in vertebrates. It comprises up to 90% of the skeletons of mammals and is also widespread all over the body, giving various tissues their mechanical strength and providing the major biomechanical scaffold for cell attachment and anchorage of macromolecules. Though type I collagen has multisectorial tasks, in bones type I collagen is mineralized with apatite crystals and gives mechanical strength and bone flexibility, and, moreover, it facilitates bone mineralization (Mirja et al., 2001).
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Other important matrix proteins secreted by osteoblasts are NCP, including osteopontin (OP), bone sialoprotein (BSP), osteonectin (ON), and osteocalcin (OC). OP has important roles in immune functions, acts as an important anti-apoptotic factor in many circumstances (Denhardt et al., 2001), and also functions as an adhesion protein involved in cell attachment and wound healing (Wang et al., 2008). It plays a pivotal role in anchoring osteoclasts or hematopoietic stem cells to the mineral matrix of bones and thereby regulates their fate (Nilsson et al., 2005). OP contains a string of polyaspartic acid residues as well as an RGDS sequence near the middle of the primary sequence, where it has higher affinity with hydroxyapatite (HAp). BSP is a phosphoprotein that contains large stretches of polyglutamic acids as well as the RGD integrin-binding sequence at its carboxy terminus (Ganss et al., 1999). Its expression is generally limited to the later stages of osteoblast differentiation and early stages of mineralization. BSP also has a high affinity for calcium ions. ON is an acidic, secreted extracellular matrix glycoprotein. ON binds strongly to HAp (Romberg et al., 1985) even in the presence of 4M guanidinium hydrochloride. Alkaline phosphatase (ALP) secreted by osteoblasts is responsible for increasing local inorganic phosphate concentration during apatite formation (Hoffmann et al., 2008). Notably, these NCP can adhere to collagen fibers via strong physical adsorption or covalent bindings. Therefore, NCP coupling with type I collagen is considered to be an important template for mineralization. Indeed, numerous studies indicate that HAp orientation correlates with collagen orientation (Iijima et al., 1997b). OC is abundant in the synthesized osteogenic matrix, binds to phospholipid vesicles in the presence of Ca2+, and also binds HAp. It has been stipulated that OC may function as a negative regulator of bone formation, although its exact role is unknown.
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Figure 2.
Schematic illustration of differentiation of mesenchymal stem cells.
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2.3. Nucleation and crystal growth of apatite minerals on matrix
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It now appears clear that type I collagen alone is biologically insufficient to induce mineralization. It is thought that in bone, an interaction between anionic proteins and type I collagen fibrils may provide a stereochemical orientation of negatively charged groups that acts as a HAp nucleator. In vitro studies of organic matrix on biological crystal formation have proved a powerful complement to ultrastructural approaches in the ongoing attempt to determine the mechanism of calcification in bone and epiphyseal cartilage. However, much confusion has been generated by the fact that anionic matrix molecules often act as calcification inhibitors in these systems by complexing calcium ions and, in some cases, inhibiting crystal growth by adsorption onto specific crystal faces. For example, an aspartate-rich protein adsorbs to specific faces of growing apatite crystal, inhibiting the development of these faces and hence altering the crystal morphology (Addadi and Weiner, 1985). An important conceptual breakthrough has been the realization that macromolecules with a high density of negatively charged groups may act as crystal nucleators if immobilized onto solid-phase surfaces (Linde et al., 1989).
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Similarly, amphipathic lipid monolayers or bilayers may promote calcification in an adjacent solution phase. Matrix vesicles secreted from osteoblasts are also considered to be a major site of biomineral nucleation (Figure 3). There are electron microscopy reports from researchers claiming that the mineralization process may involve the mobilization and translocation of insoluble mitochondrial calcium phosphate to the plasma membrane. According to this scheme, ions are ‘packaged’ and pinched off within trilaminar membrane-bound vesicles that are enriched and complexed with acidic phospholipid and contain NCP/proteolipid (Glinder et al., 1989). The phosphate-containing ALP within these new extracellular matrix vesicles is a species that is electrophoretically distinct from the form of the enzyme that is restricted to intracellular sites (Arsenis et al., 1976). Then, mineral formation penetrates the vesicle membrane and, in the presence of Ca+2, PO4\n\t\t\t\t\t-3, and pyrophosphate, serves as the nuclei for formation of needle-shaped apatite. Finally, proliferation of the apatite spreads outwards into the matrix, rupturing the matrix vesicle (Anderson et al., 1969).
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Figure 3.
Matrix vesicle secreted by osteoblasts (Left). Mineralized matrix vesicles (Right).
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3. Bone minerals
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The crystals of bone apatite are extremely small (crystallites). By x-ray diffraction, crystal size has been found to range in its long dimension (c-axis) from 10–25 nm (Boskey et al., 1985; Grynpas et al., 1986). By electron microscopy, bone crystal length has been found to vary from 30–70 nm (Landis et al., 1978). Therefore, bone mineral has a huge surface area of between 85 and 170 m2/g (Ortner, 2003).
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There are essentially five solid phases of calcium phosphate that have been linked to biological mineralization (Table 2). Of these, HAp (Ca10(PO4)6(OH)2) (Figure 4) is universally recognized as the final solid mineral phase of bone. All others have been implicated as minor or precursor phases; they are acid stable and will convert to the thermodynamically stable and insoluble HAp at a high pH. HAp alone is stable at neutral or basic pH. Tricalcium phosphate (Ca3(PO4)2, TCP) requires the presence of Mg for its formation at room temperature. Both dicalcium phosphate dihydrate (CaHPO4•2H2O, DCPD) and octacalcium phosphate (Ca8H2(PO4)6•5H2O, OCP) have acid phosphate groups (HPO4) and a structural plane on which HAp can be grown epitaxially (Neuman and Neuman, 1958). Studies suggest that platelets are the dominant morphology of bone apatite (Traub et al., 1989). The formation of plate-like crystals in the mineralized collagen fibrils is still not fully understood. One possible explanation for this mineral morphology in bone is that crystal growth occurs via an OCP intermediate (Brown et al., 1962; Weiner and Traub, 1992). OCP has nearly the same crystal structure as HAp but contains an extra hydrated layer that may be responsible for the observed plate-shaped crystals in natural bone. Amorphous calcium phosphate (ACP) was also found to spontaneously precipitate to apatite at physiological values in vitro (Eanes et al., 1965). However, Grynpas et al. could not detect the presence of ACP in young bone (Grynpas et al., 1984). Improved methods of imaging and structure determination have since led to the identification of stable and transient forms of amorphous precursors in biomineralization of calcium carbonate in sea urchin spines and spicules (Addadi et al., 2003; Politi et al., 2004; Politi et al., 2006). As a result, the role of amorphous phases in mineralization of HAp in biological tissues such as bone continues to be a subject of great research interest.
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Figure 4.
Hydroxyapatite crystal
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Phosphates (PO4) in the general formula of HAp can be CO3, SO4, VO4, AsO4, or SiO4. A variety of metals can take the place of Ca in the formula. In case of natural apatites, the main cation is Ca and Mg is secondary. The last group (OH)2 can be F2, Cl2, Br2, or CO3 (Zipkin, 1973). Chemical analysis has shown that in hard biological tissues, i.e., bone, enamel, and dentine, the biological apatites are not pure HAp, but contain a mixture of minor elements, including CO3, HPO4, F, Cl, Mg, and Na ions (Yoshikawa and Myoui, 2005). Based on the knowledge derived from biological mineralization systems, researchers, especially material scientists and chemists, are now seeking biomimetic apatite-related biomaterials.
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\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Name
\n\t\t\t\t\t\t
Formula
\n\t\t\t\t\t\t
Abbreviation
\n\t\t\t\t\t\t
Molar ratio
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Hydroxyapatite
\n\t\t\t\t\t\t
Ca 10 (PO 4 ) 6 (OH) 2
\n\t\t\t\t\t\t
HAp
\n\t\t\t\t\t\t
1.67
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Tricalcium phosphate
\n\t\t\t\t\t\t
Ca 3 (PO 4 ) 2
\n\t\t\t\t\t\t
TCP
\n\t\t\t\t\t\t
1.50
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Octacalcium phosphate
\n\t\t\t\t\t\t
Ca 8 H 2 (PO 4 ).5H 2 O
\n\t\t\t\t\t\t
OCP
\n\t\t\t\t\t\t
1.33
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Dicalcium phosphate dihydrate
\n\t\t\t\t\t\t
CaHPO 4 E 2H 2 O
\n\t\t\t\t\t\t
DCPD
\n\t\t\t\t\t\t
1.00
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Amorphous calcium phosphate
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
ACP
\n\t\t\t\t\t\t
1.30-1.50
\n\t\t\t\t\t
\n\t\t\t\t
Table 2.
Solid phases of biological calcium-phosphate
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4. In vitro approaches to fabricating biomimetic inorganic materials
Apatite powders can be synthesized via numerous production routes with a range of different reactants. Processing techniques include wet chemical methods (precipitation), hydrothermal techniques, hydrolysis of other calcium phosphates, and sol-gel methods. Since biological minerals, especially the apatite found in bone, are often ionically substituted apatite, apatite materials substituted by ions have been synthesized to control the characteristics of apatite materials. When HAp is synthesized in the presence of Mg, Fe, CO3, or F, these ions are readily and partly substituted at certain positions (e.g., Mg and Fe at the Ca site, CO3 at the PO4 site, and CO3 and F at the OH site) in HAp crystals. The ionically substituted HAp exhibits different characteristics than normal HAp. For example, the solubility of apatite containing Mg, Fe, or CO3 substitution increases with the increase in the concentration of the substitute ion (Gibson and Bonfield, 2002; Suchanek et al., 2004; Morrissey et al., 2005), whereas the stability of crystals increases and solubility decreases in apatite with F substitution (Okazaki et al., 1998; Okazaki et al., 1981). In addition to those, Sr- or Zn-substituted HAp crystals were synthesized by researchers. Sr-containing HAp enhanced the proliferation and differentiation of osteoblasts (e.g., MG63) (Capuccini et al., 2008). It also facilitated the nucleation of HAp, therefore, Sr-containing HAp is might be usable as a template for growing new bone (Pan et al., 2009). Zn-containing HAp increases the specific surface area (Tonegawa et al., 2007) and decreases the thermal stability of HAp (Li et al., 2008). Thus, ionic substitution, which occurs in natural apatite, is effective for controlling both material and biological characteristics of apatite.
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4.2. Apatite formation via biomimetic mineralization
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Researchers are also developing new synthetic, biomimetic systems to obtain apatite materials with biomimetic crystal morphology and size. Iijima et al. focused on the OCP crystal growth methods similar to the biological system. A collagen disk prepared from bovine Achilles tendon, which shows specific uniaxial alignment, was used as the template for OCP crystal formation. Consequently, the researchers were able to reproduce a ribbon-like OCP crystal formation morphologically close to the biological apatite precursors (Iijima et al., 1997b) (Figure 5a).
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Figure 5.
a) OCP crystals (Iijima et al., 2002) Copyright 2002 IADR, b) Apatite formation on metal substrate. Copyright 2008 Elsevier.
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Since simulated body fluid (SBF) containing inorganic ions similar to those in human plasma has been developed, SBF is considered to be a robust tool for reproducing biological apatite formation in vitro. Coating a bone-like apatite layer on substrate is expected to be a useful technique for inducing bioactivity on the substrate. The bone-like apatite layer can be formed on the surface of substrates in SBF solution when several specific functional groups are introduced to the substrates. Coating bone-like apatite layers through this biomimetic process has received much attention in the fabrication of novel bioactive composites (Kamitakahara et al., 2007). Often, the biomimetic apatite coating is developed on the surface of titanium and its alloys. Gu et al. developed a method for biomimetic deposition of apatite coating on surface-modified NiTi alloy. They prepared a TiO2 coating on NiTi alloy by heat treatment in air. The heat-treated NiTi alloy was then immersed in SBF for the biomimetic deposition of the apatite layer onto the surface of the TiO2 coating. XPS and Raman results showed that this apatite layer was a carbonated and non-stoichiometric apatite with a Ca/P ratio of 1.53, which is similar to human bone (Gu et al., 2005). Ohtsuki et al. reported in vitro formation of small crystallities of carbonate-containing apatite on the surface of Ceravital-type glass ceramics soaked in SBF (Ohtsuki et al., 1991).
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Moreover, there are reports about biomimetic methods of apatite formation using simpler solutions than SBF. For example, Bigi et al. reported a new fast method for the development of nanocrystalline HAp coatings on Ti6Al4V substrates using a slightly supersaturated Ca/P solution with an ionic composition simpler than that of SBF (Bigi et al., 2005). Shi et al. also followed the same biomimetic approach to synthesize an apatite layer on the surface of NaOH-modified titanium coatings in supersaturated solutions containing Ca2+ and HPO4\n\t\t\t\t\t2− ions. They observed that, depending on the ion composition and concentration of the solution, apatite layers were formed with preferred orientation and a composition similar to that found in bone (Shi et al., 2001) (Figure 5b).
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5. In vitro approaches to fabricate biomimetic organic/inorganic composite materials
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5.1. HAp containing organics
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Improvement of physico-chemical characteristics (e.g., crystallinity, solubility, adsorptive properties, etc.) of apatite is important for using apatite-based materials for biomedical applications such as bone regeneration. Since acidic molecules have a well documented affinity to HAp, researchers synthesized HAp in the presence of organics, including acidic molecules and sugars. Previous reports indicated that HAp synthesized with acidic amino acids (e.g., aspartic acid, glutamic acid) has decreased crystallinity and increased solubility (Kevin, et al., 2007; Matsumoto et al., 2002). FTIR analysis indicated that these HAp crystals contained acidic amino acids and showed selective loading capacity of positively charged molecules (Uddin et al., 2009) and enhanced osteogenic differentiation of cells (Boanini et al, 2006). Stupp et al. synthesized HAp using macromolecules such as poly(l-lysine) and poly(l-glutamic acid). Poly(l-lysine) generated large single crystals that were flat and thin, whereas poly(l-glutamic acid) generated nanoscale crystallites (Stupp et al., 1997). Stupp et al. also demonstrated biomimetic mineralization of bone apatite using self-assembling molecules known as peptide amphiphiles (Hartgerink et al., 2001). Since the peptide design is flexible, this approach would be robust for obtaining HAp crystals with desired structure and size.
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5.2. Biomimetic mineralization in organic gel to fabricate organic/inorganic composite material
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Basically, the methods originate from biochemical studies investigating the effect of matrix proteins on biomineralization. Silverman and Boskey developed a gel diffusion precipitation technique for growing large HAp crystals in collagen gel. This group has shown the inter alia promotion of HAp formation and growth by acidic phospholipids, biglycan, and BSP (Silverman and Boskey, 2004). On the other hand, inhibition of mineralization was observed for OP, dentin sialoprotein, aggrecan, and dentin matrix protein-1 (Tartaix et al., 2004). Hunter and Goldberg used a variation of the double diffusion gel method (using double diffusion of ions from opposite directions into a gel that contains the matrix molecule of interest) to explore apatite nucleation and inhibition by a number of matrix proteins (Hunter and Goldberg, 1993). Their system uses an agarose gel separated from calcium and phosphate reservoirs by diffusion membranes. SDS-polyacrylamide electrophoretic gel was also used as gel diffusion precipitation system. Calcium and phosphate ions were diffused naturally or propelled by electric potential. Calcium phosphate was precipitated in the gel. The precipitation was affected by proteins in the gel that had been separated by electrophoresis.
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From a different stand-point, gels containing precipitated minerals developed in these methods are considered to be organic/inorganic composite gel material. Yoh et al. performed in vitro fabrication of fibrin/apatite composite material by using gel diffusion systems at various pH conditions. The minerals generated in fibrin gel varied with the pH conditions: DCPD in the noncontrolled pH solution, a DCPD and OCP mixture at pH 7.4, and an OCP and HAp mixture at pH 9.0. The composition of minerals in the gel can be regulated by their reaction period or diffusion rate (Yoh et al., 2008, Figure 6). Watanabe et al. demonstrated anisotropic HAp formation in an agarose gel using an electrophoretic approach and an alternate soaking process to obtain the composite materials for bone regeneration (Watanabe et al., 2007).
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Figure 6.
Biomimetic mineralization of apatite in fibrin gel. Copyright 2008 Wiley.
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5.3. Cell based fabrication of organic/inorganic composite gel
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Synthesis of organic/inorganic composite materials generated by inorganic nucleation in a polymerized matrix is a unique system for obtaining biomimetic materials. Cells might also be great contributors to the synthesis of organic/inorganic composite material, because secreted proteins, especially those derived from osteogenic differentiated cells, supply regions where mineral crystals nucleate and grow. Our group demonstrated that culturing MSCs in three-dimensional (3D) gel matrix enhanced the precipitation of cell-derived matrix and minerals. The matrix and mineral content in the material can be regulated by cell culture conditions including cell number and period. Moreover, 3D cell patterning in the gel has been found to be effective in controlling the matrix and mineral position and distribution in the gel. Thus, this type of cell-based fabrication technique would be a new approach to fabricating more biomimetic materials (Figure 7).
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6. Conclusion
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Biological tissue shows amazing characteristics and has functions that cannot be easily reproduced by artificial synthesis. For example, bone tissue shows fracture toughness though it is soft in nature. Therefore, learning from biological systems gives us tremendous opportunities to fabricate materials that we have not yet been able to produce. The ionically substituted HAp materials or organic-containing HAp materials introduced in this chapter are good candidates for drug delivery carriers for bone regeneration or bone-related diseases. Organic/inorganic composite gel materials fabricated by self-precipitation or by a cell-based method would be neo-bone tissue that could shorten the bone regeneration period. Thus, apatite related biomaterials inspired by nature have potential for numerical biomedical applications.
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Figure 7.
Schematic illustration of biomimetic mineralization in fibrin gel culturing with MSCs.
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\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/10030.pdf",chapterXML:"https://mts.intechopen.com/source/xml/10030.xml",downloadPdfUrl:"/chapter/pdf-download/10030",previewPdfUrl:"/chapter/pdf-preview/10030",totalDownloads:4382,totalViews:383,totalCrossrefCites:3,totalDimensionsCites:11,totalAltmetricsMentions:0,impactScore:4,impactScorePercentile:92,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:null,dateReviewed:null,datePrePublished:null,datePublished:"March 1st 2010",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/10030",risUrl:"/chapter/ris/10030",book:{id:"3587",slug:"biomimetics-learning-from-nature"},signatures:"Mohammad Hafiz Uddin, Takuya Matsumoto, Masayuki Okazaki, Atsushi Nakahira and Taiji Sohmura",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Basics of biominralization of bones",level:"1"},{id:"sec_2_2",title:"2.1. Osteogenic differentiation of mesenchymal stem cells (MSCs):",level:"2"},{id:"sec_3_2",title:"2.2. Secretion of matrix proteins by osteoblasts",level:"2"},{id:"sec_4_2",title:"2.3. Nucleation and crystal growth of apatite minerals on matrix",level:"2"},{id:"sec_6",title:"3. Bone minerals",level:"1"},{id:"sec_7",title:"4. In vitro approaches to fabricating biomimetic inorganic materials",level:"1"},{id:"sec_7_2",title:"4.1. Biomimetic apatite: Ionically substituted apatite",level:"2"},{id:"sec_8_2",title:"4.2. Apatite formation via biomimetic mineralization",level:"2"},{id:"sec_10",title:"5. In vitro approaches to fabricate biomimetic organic/inorganic composite materials",level:"1"},{id:"sec_10_2",title:"5.1. HAp containing organics",level:"2"},{id:"sec_11_2",title:"5.2. Biomimetic mineralization in organic gel to fabricate organic/inorganic composite material",level:"2"},{id:"sec_12_2",title:"5.3. Cell based fabrication of organic/inorganic composite gel",level:"2"},{id:"sec_14",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAddadi\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeiner\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985 Interactions between acidic proteins and crystals: stereochemical requirements in biomineralization. Proceedings of the National Academy of Sciences USA, 82\n\t\t\t\t\t4110\n\t\t\t\t\t4114 .\n\t\t\t'},{id:"B2",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAddadi\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRaz\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeiner\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003 Taking the advantage of disorder: amorphous calcium carbonate and its roles in biomineralization. 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1. Introduction
Due to the significant population growth and the rising housing standards, the need to use structural wood products has been increasing [1]. At the same time, the timber industry must come up with solutions for ensuring the preservation of natural resources because of the growing demand for lumber and decreasing availability of large-diameter old-growth trees [2, 3]. Previously sawn from massive logs, structural lumber is now made from reconstituted wood in various shapes and sizes, which is classified as engineered wood products (EWPs). EWPs can maximize the use of wood and utilize small-diameter logs in comparison with conventional lumber [3, 4]. There are several types of EWPs in terms of the elements used, such as veneer-, strand-, fiber- and lumber-based EWPs, among which the veneer-based group is the oldest but still widely used.
The veneer-based EWPs, or called layered wood composites, are made of veneer sheets or veneer strands bonded with an adhesive [2], mainly including plywood, laminated veneer lumber (LVL), and parallel strand lumber (PSL), Figure 1. These products are largely made from peeled logs and reconstituted wood, which can then be fabricated into large sheets known as engineered panels [7]. The significant advantage of using veneer, as opposed to sawn lumber, is that it can increase the yield of wood materials from logs, particularly from small-diameter logs [8]. Veneer-based EWPs have a more homogeneous structure and uniform mechanical properties than solid lumber, making them a good candidate for building materials in construction.
Figure 1.
Veneer-based EWPs. Top left – plywood (source: photos obtained from Indiamart [5]) top right – thick plywood. Bottom left – LVL, bottom right – PSL (source: photos obtained from think wood [6]).
Veneer-based EWPs differ by wood species, adhesive type, as well as by layup structure. Figure 2 shows the cross-sections (i.e., the width-thickness plane, or x-y plane named here) of four widely used wood products in construction, i.e., solid wood/lumber, plywood, LVL, and PSL. In the y-axis, the dimensional change is similar between solid wood, plywood, and LVL due to limited efficacy of adhesive bonds in this direction, i.e., the radial direction of the wood. However, the dimensional change of PSL in the y-axis is smaller than that of the other three products because of its irregular arrangement of veneer strands in the x-y plane and application of an adhesive. On the x-axis, the dimensional change is largest in solid wood (Note: the x-axis is the tangential direction of the wood.) and smallest in plywood and PSL, with LVL being in between. In other words, solid wood has the largest variability in both x- and y-axes; plywood and LVL have the reduced variability in x-axes, and PSL has the smallest variability in both x- and y-axis.
Figure 2.
Cross-sections of solid wood and veneer-based EWPs.
The first type of veneer-based EWPs invented is plywood [9]. Later, modifications applied to the veneer layups resulted in LVL, and afterward, the long veneer strands were used to make PSL. The veneer-based EWPs have been widely used in construction nowadays [8]. Plywood is usually used as the sheathing material for walls, floors, and roofs, and the web stock for I-joists. LVL is commonly used as beams, columns, and the flange stock of I-joists. PSL is mainly used as columns and beams.
2. Plywood
2.1 Introduction
Plywood is a glued wood panel consisting of several thin layers of veneer with wood fibers in adjacent layers at right angles in most cases. Usually, a plywood sheet consists of an odd number of veneer layers [2, 3, 10]. Each layer is called ply, so the plywood can be deemed as a wood sandwich [7]. The cross lamination of adjacent plies in plywood contributes to improved mechanical properties and dimensional stability in both length and width directions [10].
Plywood is one of the oldest veneer-based EWPs. More than 3500 years ago, a type of plywood was found in ancient Egypt, which is part of the coffin, dating back to the third Egyptian dynasty [8]. Later, around 1500 BC, some images were discovered in which workers cut plywood with an axe-like tool. These images also show that the glue, apparently of animal origin, was prepared in a pot on fire [6]. Furniture constructed from overlapping sheets of wood and inlay had been discovered in Egyptian tombs. Hardwood veneer was preferred due to its attractive texture and shades [11]. The introduction of plywood was linked to the high cost of wood. Due to the shortage of available wood than supply, Egyptians had to import, by sea, ebony and mahogany from East Africa and cedar and pine from Lebanon at a very high price [12]. Later, the ancient Greeks and Romans started producing plywood. Plywood was primarily used for the manufacturing of furniture and household items [11]. Plywood production took off in the 1850s thanks to the Swedish inventor Emmanuel Nobel, who created a model of a rotary lathe [8]. This model made it possible to remove the veneer in a certain and constant thickness from a wooden block. It gave the plywood a uniform thickness and structure [8].
Despite the fact that plywood is now widely used for sheathing in residential and commercial construction, early builders were hesitant to use the newly-born plywood panels because the blood and soybean protein-based glues used were not waterproof, and some panels delaminated when they got wet [13]. In 1934, waterproof synthetic wood adhesives were introduced, which solved the problem and eased builders’ concerns [8, 13]. During World War II, the use of plywood was exploded in many industries such as boats, aircrafts, footlockers, crates, and buildings [13]. It led to the post-war boom in plywood production [8], which was adopted for structural and exterior applications. One notable example of using plywood is the construction of the legendary bomber Mosquito [14]. This aircraft was introduced during the World War II. Spruce wood, birch plywood, and balsa wood were used in the construction of aircraft, which made it possible to achieve the necessary strength with a low weight structure [15]. Plywood and other structural panels have changed the way of constructing light wood-frame houses and buildings [11, 16]. Since the middle of the past century, usage of structural panels has expanded from a few niche applications to a popular commodity such as subflooring, roof and wall sheathing, corner bracing, and concrete forming [16]. Initially concentrated in the Pacific Northwest of the United States, where old-growth, large-diameter Douglas-fir was mostly used the plywood business therefrom expanded into the southeastern regions in the 1970s as the technological barrier of bonding southern yellow pine veneer was removed [13]. As seen from Figure 3, plywood consumption in Canada was rather stable in the last 15 years or so despite the emergence of other new types of building materials. However, Canada also imports plywood from other countries to meet its increasing demand in construction and other industries such as furniture [17].
Figure 3.
Plywood production and consumption in Canada [17].
2.2 Manufacturing
Figure 4 illustrates the key processes of manufacturing three major veneer-based EWPs, i.e., plywood, LVL, and PSL. An example of manufacturing Canadian softwood plywood is given below, which is used for structural applications. Specially chosen peeler logs are transported to a barker, where they are rotated against a steel claw, which removes the bark [18]. Then debarked logs are cut into peeler blocks. A block is placed on a massive lathe, rotating against a sharp knife. When the block turns, a continuous thin layer of wood, i.e., veneer is peeled off, similar to how paper unwinds from a roll.
Figure 4.
Processes of manufacturing veneer-based EWPs.
The whole block is tried to use with an aim to generate a high yield of good quality wood material. The leftover small spindles are used to make other wood products. The long ribbon of the veneer is then cut with clippers into desired widths and sorted. It is also possible to remove defective pieces of veneer. Subsequentially, the veneer is dried to a moisture content of 5% or so in steam- or gas-heated ovens [18]. Depending on its intended use, the veneer may range in thickness from 0.3 mm (0.01 in) to 6.3 mm (0.25 in) [11]. After drying and sorting, the veneer is fed by glue spreaders, which apply an adhesive layer of uniform thickness. Phenol-formaldehyde (PF) adhesives are usually used in the manufacturing of plywood for structural and outdoor applications when exposed to the weather in its service [3]. Veneer sandwiches are sent to the hot press, which is a key step in the production process of curing the adhesive, subjected to a temperature of 150°C (300°F), and a pressure of 1.38 MPa (200 psi). After the press panels are cut to required dimensions, sanded, and graded [18].
In the fabrication of plywood for non-structural uses, such as furniture, cabinets, and indoor decoration, water-resistant urea-formaldehyde (UF) adhesives are used. The UF adhesives can be cured at a temperature of about 120°C (250°F) during hot-pressing, which can also be cured with high-frequency heating system with an aim to reduce the hot-pressing time and increase the production efficiency [3].
Quality control, which includes incoming management of raw materials, such as wood and glue, and manufacturing parameters at all stages of the production, must be applied in order to produce good quality plywood products. Acceptance quality control is the final stage of the manufacturing process. Many plywood manufacturers in western Canada produce structural plywood under the supervision of the British Columbia Council of Forest Industries (COFI), which constantly checks glue bond strength and other properties to guarantee that the products satisfy the Canadian Standards Association (CSA) standard [18].
2.3 Typical species and sizes
Plywood can be made from various types of wood. Softwoods are commonly used to make veneer for plywood in North America, containing Douglas fir, western hemlock, spruces, pines, and firs [14]. These wood species can be divided into various categories based on their strength and use within the plywood structure. Spruce is used to make the majority of construction-grade softwood plywood in Canada [7]. More discussion on softwood plywood is given through the text in following sections.
Of hardwoods, birch, alder, linden, and lauan (“Philippine mahogany”) are most popular for veneer production [7, 10]. These species do not have distinguished earlywood and latewood zones, which are characterized by uniform density and structure, making them easy to be peeled to produce thin and durable veneer.Beautifully grained hardwoods are often combined in several ways to make a unique face pattern [7].
The first standard plywood sheet had a width of 1.22 m (4 ft) and a length of 2.44 m (8 ft), which appeared in 1928 [19]. Such a standard size for plywood sheets has, since then, almost not been changed. The common thickness of plywood varies from 3.2 mm (1/8 in) to 76 mm (3 in) [10]. It depends on the thickness of the veneer and the number of layers. The most common plywood contains 3, 5, or multiple layers. With a three-layer, the plywood is 2–3 mm (0.08–0.12 in) in thickness, which can be used as an underlayment between the subfloor and the tile. Hardwood decorative plywood is often uniformly selected for grain texture, which is widely employed for indoor uses. The universal hardwood plywood has five layers, resulting in a thickness of 4 mm (0.16 in) or so, which can be used for multiple outdoor and indoor applications. Multiple layer plywood with more than seven layers can be classified as thick plywood, which is widely used for structural purposes, requiring acceptable strength and durability under the loading condition [11]. The thick plywood needs a sub-floor or structural sheathing attached to the framing elements of a new canopy.
Hardwood can be peeled or sliced for the production of decorative veneer for making furniture, cabinets, and interior decoration. Slicing results in more loss in raw materials and more intensiveness in labor [16]. Hardwood veneer, such as birch, usually has a thickness of 1.5 mm (0.06 in), whereas softwood veneer is often cut to a thickness of 3 mm (0.12 in) for plywood and LVL production [8].
2.4 Grading
Plywood comes in a range of appearance grades, from flat natural surfaces suitable for finishing to cost-effective unsanded grades suitable for sheathing. More than a dozen typical thicknesses and over twenty different grades of plywood are available [14]. The plywood is usually graded based on the appearance quality of veneer in North America. There are commonly two classes of plywood, each of which has its own set of standards: (a) construction and industrial plywood and (b) hardwood and decorative plywood [3].
In Canada, the two most popular types of softwood plywoods are unsanded sheathing grade Douglas Fir Plywood (DFP), which conforms to CSA O121 “Douglas fir plywood”, and Canadian softwood plywood (CSP), which conforms to CSA O151 “Canadian softwood plywood”. The poplar plywood, which conforms to CSA O153 “Poplar plywood”, is also designated but less uses in construction [14]. The group of DFP can include other species in addition to Douglas fir. For example, the front and back faces are made of Douglas fir, but the inner plies can be made from any of the specified species, including Douglas fir, western hemlock, and the majority of spruce, pine, and fir species in Canada [14]. Plywood that contains other selected Canadian wood species in the face and back plies is labeled CSP. Most species that are only allowed as inner plies for DFP may also be used as the face or back plies for CSP. Three hardwood species, i.e., balsam poplar, trembling aspen, and cottonwood, are restricted to use as inner plies in DFP and CSP [14]. The sizes, grades, specialty panels, manufacturing tolerances, and glue bond quality of plywood are all stipulated in the standards CSA O121, CSA O151, and CSA O153. The structural plywood is put with a legible and durable stamp showing the manufacturer, the bond style (EXTERIOR), the species (DFP or CSP), and the grade [14]. DFP and CSP are both made in a variety of grades based on the appearance and quality of the veneer used for making the outer plies.
Many plywood mills are members of the associations, which are responsible for inspecting, testing, and certifying the products with stamps. These stamps indicate that the stamped products meet the standards accepted by the associations. One of the largest associations in North America is APA – The Engineered Wood Association (formerly American Plywood Association) [20]. There are usually two letters on a stamp, the first indicating the quality of one surface, while the second showing the quality of the opposite surface, Figure 5 [7]. This stamp ensures the customer that this product has followed the association’s stringent quality and efficiency standards [3]. In Canada, the CertiWood™ Technical Center (formerly CANPLY– the Canadian Plywood Association), a non-profit, industry-funded association, represents manufacturers of EWPs [21]. Those mills, being the members of CertiWood™ Technical Center, can put the stamp with the trademark CANPLY on their products [7, 21].
Figure 5.
A sample stamp on plywood: 1- panel grade - panel grades are generally identified in terms of the veneer grade used on the face and back of a panel (e.g., A-B, B-C); 2- bond classification - exposure ratings for APA wood structural panels may be exterior or exposure 1; 3 - decimal thickness declaration; 4 - mill number - manufacturing mill identification number; 5- species group number - classified according to strength and stiffness under manufacturing standard; 6 - product standard [20] (source: photos obtained from APA – the Engineered Wood Association [20]).
The vast majority of construction and industrial plywood is used in applications where structural performance surpasses appearance. Some construction and industrial plywood are manufactured with faces chosen mainly for appearance of either plain natural finishes or lightly pigmented finishes [3]. Structural plywood is available in two exposure durability classes: interior and exterior [13]. INTERIOR plywood is only intended for use in dry indoor applications where the panels should be protected from moisture permanently; which is even glued with a water-resistant interior-use adhesive [13]. EXTERIOR plywood is the only panels suitable for outdoor exposure. They are bonded with a waterproof exterior-use adhesive [13], including EXPOSURE 1 and EXPOSURE 2. EXPOSURE 1 panels are waterproof and designed for applications where long construction delays or exposure to high moisture in service are possible [13]. EXPOSURE 2 panels are water-resistant and designed for protected applications, where only minor construction delays are expected since they are mainly developed for interior use [13]. Sheathing grades that are not listed for appearance usually have the grading stamp on one of the faces, whereas grades such as Good Two Sides are stamped on the edge to avoid affecting the appearance. The strength values stipulated in CSA O86 “Engineering design in wood” [22] are used for Sheathing grade panels based on layups containing only C-grade veneer. Typical DFP and CSP grades include Sanded grades, primarily used in concrete formwork or non-structural applications, and Select and Select Tight Face grades, which are primarily used in floor underlayment applications requiring a smooth and solid surface [14].
Chemical treatments can be applied to plywood to increase its resistance to decay and fire. In Canada, the preservative-treated plywood must be made following CSA O80 “Wood preservation” [23]. To assess the effects of fire retardants or some other potentially strength-reducing compounds, plywood producers shall conduct tests following ASTM D5516 “Standard test method for evaluating the flexural properties of fire-retardant-treated softwood plywood exposed to elevated temperatures” [24] and ASTM D6305 “Standard practice for calculating bending strength design adjustment factors for fire-retardant-treated plywood roof sheathing” [14].
2.5 Properties
The density of plywood depends on the wood species and thickness used, which varies from 400 kg/m3 (25 lb./ft3) to 800 kg/m3 (50 lb./ft3) [3]. This is compared to the density of oven-dry wood, ranging from approximately 320 kg/m3 (20 lb./ft3) to 720 kg/m3 (45 lb./ft3) [3]. Plywood has good machining properties; thus, it is possible to work with it just like with ordinary wood, such as sawing, nailing, and gluing. However, the cross-lamination design of plywood, in contrast to wood that is broken down the grain, prevents it from splitting readily in the grain direction. As a result, screws and nails can be used in structural applications near the edges of plywood panels.
Plywood has exceptional built-in resistance to raking, twisting, or distortion, which is especially crucial when care is taken for transferring large shear stresses generated by powerful winds or earthquakes [11]. Many strength properties are equalized by changing the direction at 90 degrees to the grain with each consecutive wood layer of veneer. This provides plywood with a two-way capacity, i.e., the properties in the width direction are approximately equal to those in the length direction. For example, 6 mm (1/4 in) sheathing plywood on a typical framed construction wall with doors and windows delivers double the rigidity and strength furnished by 19 mm (3/4 in) thick boards laid diagonally. When glued to the framework, the strength values for plywood walls are raised even further [11].
Because structural plywood uses waterproof resins, a weather-resistant panel can be obtained if the edges are properly sealed [10]. Awareness of the allowable design values of a plywood panel is not required except in special engineering applications such as diaphragms and earthquake-resistant shear walls. When properly fastened to framing at the correct spacing, the span ratings alone ensure that the panels can work well under the roof and floor loadings stipulated in the building code. In North America, the design values can be found in CSA O86 “Engineering design in wood” [22], Wood Design Manual [25], and APA – Plywood Design Specification [20] or in its Design Capacities of APA Performance-rated Structural-Use Panels Technical Note N375 [26]. For engineering applications, STRUCTURAL I panels are typically the best choice. The typical values of sheathing grades are listed in Table 1. The properties of plywood vary with the quality of the constituent layers.
Through thickness (edgewise shear) ASTM D2719 [32]
Table 1.
Mechanical properties and testing standards of plywood (source: Wood Engineering Handbook [27]).
2.6 Applications
Plywood is widely employed in structural and non-structural applications [3], which can be an ideal option for use in both wet and dry environments [14]. It was reported that plywood took about 54.8% of the market share in 2017 in the construction sector in North America Figure 6 [21].
Figure 6.
North America plywood market share by segment in 2017 (source: Figure obtained from BCC research, FAO, RAUTE, IMF, National Statistics Offices [33]).
In construction, plywood is mainly used as a load-bearing element in platform-frame structures, including single-family and multi-family housing, such as sheathing and underlayment, since it has good dimensional stability and does not crack, cup, or twist [18]. Plywood panels are used as wall sheathing materials, providing high lateral resistance to shear walls and high racking strength, and assisting in achieving the overall thermal efficiency of walls [16, 18]. Roof sheathing is frequently made of plywood. The stiffness of which constitutes diaphragm action when using prescribed framing and nailing patterns [18]. Also, plywood often finds its uses in the fabrication of I-joists as web stocks, marine applications, pallets, industrial containers, and furniture, Figure 7. Extra thick plywood with special surface treatment can be used for facing concrete formwork in concrete structures [7, 10, 14].
Figure 7.
Plywood applications [20, 34, 35, 36].
3. Laminated veneer lumber (LVL)
3.1 Introduction
Laminated veneer lumber (LVL) is a type of structural composite lumber (SCL) made by gluing several layers of veneer in the longitudinal direction of the wood, which differs from plywood that has the veneer layers cross-laminated. LVL is one of the most important members in the family of veneer-based EWPs [8]. This material was initially used to produce aircraft propellers and other high-strength aircraft components during World War II [18, 37]. The research and development of LVL can be dated back to the 1940s with an aim at making high-strength parts for aircraft structures out of Sitka spruce veneer [3]. LVL was used as a building material since the mid-1970s [18, 37, 38] when the research was focused on examining the effects of manufacturing variables on LVL with a thickness being up to 12.7 mm (1/2 in) [3]. LVL is now widely used as building and packaging materials [18].
3.2 Manufacturing
The veneer manufacturing and drying processes are almost the same as those used in making plywood. Figure 4 illustrates the different processes in the manufacturing of LVL from plywood, largely including veneer orientation during layup, hot press type, and end cutting to produce the length required.
To make veneer sheets, the logs are usually peeled in a lathe. The thickness of veneer sheets in 1.5 mm (0.06 in) up to 6.4 mm (0.25 in) [16, 38], the length is 2640 mm (104 in), and the width is 1320 mm (52 in) or 660 mm (26 in) [18]. The veneer is dried to a moisture content of 6–10%, ideally 6–8% [38]. The veneer is clipped to remove any strength-reducing defects and graded. The veneer sheets are cut to the desired width for billet production [18]. The individual veneer sheets are then joined, with the grain of all veneers running in the direction of a billet’s length direction. End joints between different veneer pieces are staggered along the length of the billet to distribute any defects that could reduce strength. To effectively transmit load, the joints might be scarf joined or overlapped for some distance [18]. Then the veneer sheets are covered with a waterproof phenol-formaldehyde adhesive [18, 37, 38] or phenol-resorcinol-formaldehyde or polyurethane adhesives [39].
The veneer layup of LVL differs from that of plywood. In the production of LVL, the veneer is oriented in the same direction, i.e., the longitudinal grain direction of the wood, providing the super strength in this direction, which is similar to or larger than solid lumber, Figure 8. Thus, LVL is commonly used for beams and columns in the construction of buildings [8, 10]. Veneer sheets in plywood are cross-laminated, making it possess two-way properties, i.e., similar properties in both major and minor directions, as mentioned in Section 2, suitable for sheathing materials.
Figure 8.
Layups of LVL and plywood (source: image obtained from Gong [39]).
The pre-pressing of LVL billets could be carried out in a single-opening cold press or a short continuous cold press [38]. The completed billets are simultaneously exposed to pressure to consolidate the veneer and heat to accelerate the curing of the glue [18]. In general, the press temperature used to produce LVL is rarely higher than 175°C (350°F). For the batch type presses, it is usually 160°C (320°F). For the continuous presses, the temperature might be significantly higher since there is a pre-heating zone. As veneer sheets are relatively low in permeability, it is recommended to avoid using a high press temperature, especially when combined with a long press time [38]. This process is similar to used in manufacturing of plywood, except that instead of being formed into thin flat panels, the veneer sheets for making LVL is formed into long billets up to 25 m (80 in) in length. After curing, the billets are sawn to specific lengths and widths for the target application(s) of a LVL product [18].
During the manufacturing of LVL, the selection of veneer is, in terms of thickness and grade, of great importance. The right veneer thickness can help balance LVL properties and manufacturing costs in the production. The veneer used in the manufacture of LVL must be carefully selected in order to obtain the desired engineering properties. Ultrasonic scanning is often used to sort veneer sheets to ensure that the final product has the desired engineering properties [37]. The individual veneer is typically graded so that the strength characteristics of each LVL can be customized [10]. For esthetic reasons and superior flatwise bending properties, the best veneer sheets are usually used as surface plies, while lower-grade sheets are used for the inner plies [38]. For example, if the final use of LVL is scaffold planks, the higher grade veneer will be put on the plank’s outer sides [18].
With decreasing veneer thickness, the number of veneer sheets required increases for the same density, thickness, and layout technique of an LVL product. As a result, defects in LVL with thinner veneer will disperse more defects than in LVL with thicker veneer. Because of this, as the veneer thickness decreases, the variation diminishes, and the strength values increase. However, as veneer thickness decreases, resin content, press cycle time, and production cost increase [38].
The strength properties of veneer are more critical for LVL than those in plywood in general. As a result, it is highly desirable for LVL producers to avoid using the veneer sheets with deep lathe checks that cause a reduction in veneer strength. Deep lathe checks can decrease LVL’s shear strength and stiffness while having little effect on its MOE. Low shear rigidity can reduce LVL’s MOE rating [38].
3.3 Typical species and sizes
LVL can be made from different softwood and hardwood species; however, in North America, Douglas-fir, larch, southern yellow pine, hemlock, aspen, and yellow poplar are the most widely used wood species for producing LVL [18, 37, 40].
LVL is available in thicknesses ranging from 19 mm (3/4 in) to 89 mm (3–1/2 in) and likely to 178 mm (7 in) [18, 41]. The most typical thickness of LVL used in construction are 38 mm (1–1/2 in) [3] and 45 mm (1–3/4 in) [18], from which broader beams can be conveniently assembled on a job site by fastening several LVL plies [18]. The typical depth is from 140 mm (5–1/2 in) to 508 mm (20 in). Different manufacturers can also provide different widths and depths. At the job site, LVL can easily be cut to a length required [37]. Typical lengths of LVL are 14.6 m (48 in), 17 m (56 in), 18.3 m (60 in), 20.1 m (66 in), and 24.4 m (80 in) [10, 37, 41]. LVL is manufactured in the form of billets with widths of 610 mm (24 in) or 1220 mm (48 in). The required depth of LVL can be cut from these billets [18].
3.4 Grading
LVL is a proprietary product; therefore, its engineering properties and sizes can differ from one manufacturer to another. As a result, there is no general production standard or design values in the LVL industry [37]. However, the Canadian Construction Materials Centre (CCMC) reviews and approves the design values, which are derived from test results following CSA O86 “Engineering design in wood” and ASTM D5456 “Standard specification for evaluation of structural composite lumber products” [37]. Each manufacturer develops the characteristic properties of its LVL products by in-grade testing. The manufacturer is also responsible for checking the properties of its products by constant monitoring and quality management. Each manufacturer publishes its own list of design properties, resulting in a unique grade for a given LVL product [42]. Products that satisfy the CCMC criteria are assigned an Evaluation Number and an Evaluation Report that describes the design strengths. They are then entered into the CCMC’s Registry of Product Evaluations. The manufacturer’s name or product marking, as well as the stress grade, are stamped on the material at different intervals, although this may not be present on every piece due to end cutting [37].
Figure 9 presents a stamp of LVL from APA – The Engineered Wood Association, which shows a qualified LVL grade (e.g., 3100Fb-2.0E), product evaluation reports, the treatment facility, and standard specifications for SCL.
Figure 9.
LVL stamp: 1 – qualified LVL grade (usually represented by design values; 2 – APA mill number; 3 – product evaluation reports; 4 – standard specification for structural composite lumber (source: photo obtained from APA – the Engineered Wood Association).
3.5 Properties
The density of LVL is about 480–510 kg/m3 (30-32 lb./ft3) [43], which is similar to that of the wood made from. Compared to solid wood, LVL has more stable characteristics than solid timber. This is due to the fact that natural defects, such as knots, splits and slope of grain, are dispersed throughout the material or completely removed during the manufacturing, and dried veneer and adhesives are employed [37].
LVL can easily absorb water, resulting in the change in dimensions, in particular in the thickness direction since there are almost no adhesive restrictions. Therefore, LVL should be protected from the weather during job site storage and after installation [3, 37]. Wrapping the LVL materials for shipping to the job site is also critical for minimizing the moisture effect. End and edge sealing are the commonly used approach to avoid moisture penetration and protect LVL products in their services [37].
Both special cutting, notching, or drilling should be performed according to the manufacturer’s instruction. LVL acts similarly to solid sawn timber or glue-laminated beams of equal height, which requires the same fastening and connection requirements as solid lumber [40]. The primary sources of knowledge for design, standard installation descriptions, and performance characteristics are provided in the manufacturer catalogs and inspection reports [37].
3.6 Applications
LVL is mainly used as structural framing in residential and industrial buildings. In the building industry, LVL is widely used for beams or headers over windows and doors on the edge, for hip and valley rafters, scaffold planking, and the flange material of I-joists [3, 10]. LVL may also be used as truck bed decking and road signposts. LVL is chiefly used as a structural component, most commonly in hidden spaces where esthetics is not a concern. Certain manufacturers offer a finished or architectural grade look, but it typically comes at a cost. When using LVL in applications where esthetics is significant, standard wood finishing techniques may be used to accent the grain and preserve the surface layer. The finished wide outer layer of LVL looks like plywood [37]. Figure 10 shows such a complex curved structure constructed Burnaby, British Columbia, Canada, which was designed and built with 53 parallel CNC-cut spruce LVL sections [44]. Each curved structure was panelized into six segments, shipped to the construction site, and assembled into one piece [44].
Figure 10.
Curved LVL structures at Simon Fraser University (Canada) - Ripple Cone Canopy (source: photos obtained from StructureCraft [44]).
Veneer-based EWPs have also been used in the windmill industry, in which wood veneer sheets are used to make windmill blades [45]. Previously, the size of the wooden blade was constrained by the availability of large, consistent-quality tree trunks. Veneering, on the other hand, spreads out defects like knots, resulting in more substantial and more predictable stiffness properties. This makes it possible to make larger wooden blades. When compared to fiberglass, wood laminates provide substantial cost and reduced weight. There are examples of blades made primarily of LVL reinforced with carbon composite spars and coated with a fiberglass composite outer layer [46]. One of the largest windmill blades is 107 meters long (351 ft), which is longer than a football field, produced in Cherbourg, France. It was made from a high-tech sandwich structure consisting of thin layers of glass and carbon fibers and balsa wood veneer [47].
4. Parallel strand lumber (PSL)
4.1 Introduction
Parallel strand lumber (PSL) is known as a composite of veneer strands with wood fibers aligned primarily along the length of the member, i.e., the longitudinal direction of wood [3]. PSL is overall similar to laminated strand lumber (LSL) and oriented strand lumber (OSL) but is made up of veneer strands (sometimes called veneer strips). The length of veneer strands used in PSL is longer than the strands used in LSL and OSL, with a length-to-thickness ratio of around 300.
PSL was invented in 1975 by MacMillan Bloedel Ltd., in Vancouver, Canada, who set out to create a high-strength wood-based material [13]. The first PSL plant was opened in 1982, and its products were first commercially sold for Expo ‘86. MacMillan Bloedel, which is now called Weyerhaeuser, commercialized and patented its PSL products with the brand name Parallam®. The process has been improved over time to produce relatively giant and long beams, and the production and sales have steadily increased [48].
4.2 Manufacturing
The process of manufacturing PSL allows prominent members to be built from small trees, resulting in the more efficient use of forest resources [49]. The first stages in the production of PSL are similar to those used in the production of plywood or LVL. Figure 4 illustrates the unique processes employed in the manufacturing of PSL, differentiating from those in plywood or LVL. To make veneer, logs are turned on a lathe [18]. The thickness of veneer is from 3 mm (1/8 in) to 6.4 mm (1/4 in) [3]. The veneer sheets are then dried to a moisture content of 2–3% before being sliced into long thin veneer strands parallel to one another [9]. After that, the veneer sheets are clipped into long, narrow veneer strands with a length of 2.4 m (8 feet), a width of 13 mm (1/2 in) [18], and a thickness from 2.54 mm (1/10 in) to 3.175 mm (1/8 in) [38].
The production process is designed to use materials from the log roundup and other less than full-width veneer in the veneer cutting stage. As a result, the process uses waste materials from a plywood or LVL operation [3]. The veneer strands are oriented to the length direction of a continuous billet using special equipment (Figure 11) and mixed with a waterproof exterior structural adhesive, such as phenol-formaldehyde, prior to hot-pressing.
Figure 11.
Orientation of veneer strands in PSL (source: photos obtained from WorldPress.com [50]).
The pressing process densifies the veneer strands to some degree, and the adhesive is cured with the aid of microwave technology [18, 49]. A continuous press is employed to produce PSL, which theoretically produces an unlimited length but is constrained only by transportation restrictions [3].
4.3 Typical species and sizes
Douglas fir is used to produce PSL in Canada, and southern yellow pines are employed in the USA. In addition to this, western hemlock and yellow poplar are also used [3, 49, 51]. In general, there are no restrictions on the use of other wood species.
The available stock sizes for PSL have to be compatible with existing wood framing materials and standard dimensions [18]. PSL beams are available in thicknesses from 89 mm (3–1/2 in) to 178 mm (7 in), and in-depth from 235 mm (9–1/4 in) to 457 mm (18 in) [41]. PSL columns come in square and rectangular shapes of a dimension of 89 mm (3–1/2 in), 133 mm (5–1/4 in), or 178 mm (7 in) [41]. Smaller thicknesses can also be used, either individually as single plies or in combination for multi-ply applications [18, 49]. Steel connectors are usually required for larger dimensions [51]. PSL is available in lengths up to 20 meters (66 ft) [41].
The beam-like PSL products can be also ripped into thin boards, Figure 12, which opens a window for non-structural applications [18].
Figure 12.
Boards ripped from PSL (source: photos adopted from Goulddesigninc.com [52]).
4.4 Grading
PSL is a proprietary product, the same as LVL. Therefore, specifications and dimensions are unique to each manufacturer. In North America, both PSL and LVL are treated as the same structural composite lumber [18]. The evaluation procedure and grade determination of PSL are the same as LVL (refer to Section 3.4). Figure 13 presents a stamp of PSL (Parallam® Plus), including a description of the product and uses, the type of treatment, and the treatment facility. The treatment stamp can also reference the treating standards (such as AWPA U1/UC4A by the American Wood Protection Association) and third-party quality program monitor (SPIB - Southern Pine Inspection Bureau) [53].
Figure 13.
Stamp on PSL (Parallam® plus) (source: image obtained from Weyerhaeuser [53]).
4.5 Properties
Since natural defects such as knots, the slope of grain, and splits have been scattered across the material or eliminated during the manufacturing process. The combination of a structural adhesive used with dried wood veneer strands, heat, and pressure employed during pressing makes PSL less warping than solid timber. Therefore, PSL is a type of highly consistent, uniform EWPs [49], which exhibits much less variability and larger load-bearing capabilities than solid lumber [51]. The density of PSL is 720 kg/m3 (45 lb./ft3) [54], which is similar to that of the wood used. Other advantages of PSL are given to its high strength, stiffness, and dimensional flexibility [49]. PSL is less susceptible to shrinkage, warping, and splitting as it has a moisture content of 11% [49].
The texture of PSL is rich due to the grain of wood veneer strands and dark glue lines. PSL is a visually appealing construction material that fits well to the applications that require a high level of finished appearance [49]. The techniques applicable to sawn lumber can be used to machine, stain, and finish PSL. At the end of the manufacturing period, PSL is sanded to ensure exact dimensions and a high-quality appearance. Stain can be used to emphasize the warmth and texture of the wood [49]. It should be pointed out that the special cutting, notching, or drilling of PSL shall be performed in compliance with the manufacturer’s instruction.
As mentioned above, both PSL and LVL are treated as the same SCL in Canadian practices; therefore, their design values are the same. Table 2 lists the key strength properties of sample SCL. Some specific design values can be obtained from manufacturers [41].
Property
Value (MPa)
Modulus of elasticity, E
13,800
Allowable bending stress, fb (300 mm depth)
37.0
Allowable shear stress, fv (perpendicular to glue line or wide face of the strand)
3.7
Allowable bearing stress, fcp (parallel to glue line or wide face of the strand)
9.4
Table 2.
Major strength properties of SCL (source: Canadian Wood Council [41]).
4.6 Applications
PSL is mainly used in residential, commercial, and industrial construction as structural framing components, such as beams and columns in the post-and-beam construction, and headers, pillars, and lintels in the light-frame construction [18]. According to Part 3 of the National Building Code of Canada, CCMC has approved PSL for use as heavy timber construction [51]. Due to the excellent strength characteristics of PSL, it is possible to use it in the design of the roofs with a large span and rooms with open spaces. Figure 14(left) presents PSL beams that are used for an open floor plan at Vancouver Firehall No.15, Vancouver, Canada. Another example is presented in Figure 14(right), showing a portable Concord Pacific Display Pavilion at Vancouver, Canada, which uses a glass-enclosed superstructure made of exposed PSL columns. In addition, PSL is a visually attractive material; thus, it is well suited to applications where the finished look is essential. It can be also appropriate for hidden structural applications where appearance is unimportant [18].
Figure 14.
Floor and columns made of PSL in Vancouver Firehall No.15 (left) and Concord Pacific display pavilion (right), respectively (source: photos obtained from StructureCraft [55]).
5. Endnotes
EWPs are relatively recent structural members that have been widely incorporated in the building industry in North America and beyond. They have been invented and used for making timber buildings and furniture. The family of veneer-based EWPs mainly has three major members, i.e., plywood, LVL, and PSL. Because the majority of veneer-based EWPs are designed to handle relatively large loads, they must be manufactured in accordance with recognized standards or technical guides to ensure that the required engineering design values and applications are met. Veneer-based EWPs have been accepted and acknowledged in the building industry as premium structural materials. It is possible to make these products considerably large from small-diameter logs. The only restriction can be the length of LVL and PSL during transportation [38].
Non-traditional resources (such as under-utilized wood species) can be used to manufacture veneer-based EWPs of better physical and mechanical properties than other traditional structural products (such as solid timber products) [1]. Due to engineering design, removal of defects, drying of wood materials, application of adhesive, and layer-by-layer bonding, the veneer-based EWPs are stronger and more durable than solid wood of the same size. This is an outstanding advantage for constructing a building requiring high strength without a bulky appearance. Typically, LVL and PSL have about three times larger bending strength and 30% larger stiffness than the lumber products of comparable sizes [41].
Interest in veneer-based EWPs products will continue to grow for ecological reasons. For example, restrictions have been introduced in many countries on deforestation of large-diameter old-growth trees. Due to the needs in the construction market, alternative materials must be further developed. The rapid advancement in technology, along with the available raw materials, i.e., small-size fast-growth trees, would inevitably accelerate the development of EWPs [2]. Also, in recent years, the minimization of carbon footprints in construction has reached a consensus. Many architects and engineers have been designing and constructing buildings with 100% solid wood and EWPs. Meanwhile, research on the standardization of the veneer-based EWPs and expansion of their uses is no doubt required. Modernization of existing equipment and improvement of the gluing systems will allow the creation of innovative designs and special shapes that are currently not available for wood products. This will certainly expand the matrix of applications for veneer-based EWPs, as well as making them become more competitive in the market of building materials.
Acknowledgments
This piece of work was financially supported by the New Brunswick Innovation Research Chair Initiative Program by the New Brunswick Innovation Foundation (Canada) and the Collaborative Research and Development Grants by Natural Sciences and Engineering Research Council of Canada (CRDPJ 523922-18).
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"veneer-based engineered wood products, plywood, laminated veneer lumber, parallel strand lumber, adhesives, engineering properties, structural uses",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80677.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80677.xml",downloadPdfUrl:"/chapter/pdf-download/80677",previewPdfUrl:"/chapter/pdf-preview/80677",totalDownloads:67,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 18th 2021",dateReviewed:"December 15th 2021",datePrePublished:"March 2nd 2022",datePublished:"April 28th 2022",dateFinished:"March 2nd 2022",readingETA:"0",abstract:"Veneer-based engineered wood products (EWPs) are widely used in construction. Veneer-based EWPs are made of thin veneer sheets or veneer strands with adhesives, mainly including plywood, laminated veneer lumber (LVL), and parallel strand lumber (PSL). This chapter first discusses veneer-based EWPs in terms of their manufacturing, properties, and applications. Secondly, it introduces how veneer sheets or veneer strands intersect with each other in these products, providing additional strength and stable dimensions. Thirdly, this chapter overviews the effects of element dimensions, basic structure, veneer grade, adhesive type, and processing parameters on the properties of these products. Finally, it illustrates the uses of veneer-based EWPs through examples with a focus on their construction applications.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80677",risUrl:"/chapter/ris/80677",signatures:"Elena Vladimirova and Meng Gong",book:{id:"10584",type:"book",title:"Engineered Wood Products for Construction",subtitle:null,fullTitle:"Engineered Wood Products for Construction",slug:"engineered-wood-products-for-construction",publishedDate:"April 28th 2022",bookSignature:"Meng Gong",coverURL:"https://cdn.intechopen.com/books/images_new/10584.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83962-772-9",printIsbn:"978-1-83962-771-2",pdfIsbn:"978-1-83962-790-3",isAvailableForWebshopOrdering:!0,editors:[{id:"274242",title:"Dr.",name:"Meng",middleName:null,surname:"Gong",slug:"meng-gong",fullName:"Meng Gong"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"274242",title:"Dr.",name:"Meng",middleName:null,surname:"Gong",fullName:"Meng Gong",slug:"meng-gong",email:"meng.gong@unb.ca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274242/images/system/274242.jpg",institution:{name:"University of New Brunswick",institutionURL:null,country:{name:"Canada"}}},{id:"349598",title:"Mrs.",name:"Elena",middleName:null,surname:"Vladimirova",fullName:"Elena Vladimirova",slug:"elena-vladimirova",email:"evladimi@unb.ca",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Plywood",level:"1"},{id:"sec_2_2",title:"2.1 Introduction",level:"2"},{id:"sec_3_2",title:"2.2 Manufacturing",level:"2"},{id:"sec_4_2",title:"2.3 Typical species and sizes",level:"2"},{id:"sec_5_2",title:"2.4 Grading",level:"2"},{id:"sec_6_2",title:"2.5 Properties",level:"2"},{id:"sec_7_2",title:"2.6 Applications",level:"2"},{id:"sec_9",title:"3. Laminated veneer lumber (LVL)",level:"1"},{id:"sec_9_2",title:"3.1 Introduction",level:"2"},{id:"sec_10_2",title:"3.2 Manufacturing",level:"2"},{id:"sec_11_2",title:"3.3 Typical species and sizes",level:"2"},{id:"sec_12_2",title:"3.4 Grading",level:"2"},{id:"sec_13_2",title:"3.5 Properties",level:"2"},{id:"sec_14_2",title:"3.6 Applications",level:"2"},{id:"sec_16",title:"4. Parallel strand lumber (PSL)",level:"1"},{id:"sec_16_2",title:"4.1 Introduction",level:"2"},{id:"sec_17_2",title:"4.2 Manufacturing",level:"2"},{id:"sec_18_2",title:"4.3 Typical species and sizes",level:"2"},{id:"sec_19_2",title:"4.4 Grading",level:"2"},{id:"sec_20_2",title:"4.5 Properties",level:"2"},{id:"sec_21_2",title:"4.6 Applications",level:"2"},{id:"sec_23",title:"5. Endnotes",level:"1"},{id:"sec_24",title:"Acknowledgments",level:"1"},{id:"sec_27",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Thelandersson S, Larsen HJ. Timber Engineering. New York, USA: Wiley; 2003'},{id:"B2",body:'Bodig J, Jayne BA. Mechanics of Wood and Wood Composites. Reprint edition. Malabar, FL: Krieger Pub Co; 1993'},{id:"B3",body:'Forest Products Laboratory (FPL). WoWood Handbook-Wood as an Engineering Material. General Technical Report FPL-GTR-190. Madison, WI: U.S. Department of Agriculture, Forest Service, Forest Products Laboratory; 2010'},{id:"B4",body:'Gong M. Lumber-Based Mass Timber Products in Construction. London, UK: IntechOpen; 2019. pp. 7-16. DOI: 10.5772/intechopen.85808'},{id:"B5",body:'Wooden Plywood Board. IndiamartCom 2021. https://www.indiamart.com/proddetail/wooden-plywood-board-14009756373.html [Accessed: June 16, 2021]'},{id:"B6",body:'ThinkWood CEU. Design and Construction of Taller Wood Buildings. 2021. https://www.thinkwood.com/wp-content/uploads/2019/09/ThinkWood-CEU-Design-and-Construction-of-Taller-Wood-Buildings.pdf [Accessed: June 3, 2021]'},{id:"B7",body:'Vogt F, Nauth M. Carpentry. Toronto, Canada: Nelson Education Limited; 2015'},{id:"B8",body:'Ansell MP. Wood Composites. Cambridge, United Kingdom: Elsevier Science & Technology; 2015'},{id:"B9",body:'Porteous J, Kermani A. Structural Timber Design to Eurocode 5. Hoboken, United Kingdom: John Wiley & Sons, Incorporated; 2013'},{id:"B10",body:'Canada NR. Plywood 2014. https://www.nrcan.gc.ca/our-natural-resources/forests-forestry/forest-industry-trade/forest-products-applications/taxonomy-wood-products/plywood/15855 [Accessed: March 24, 2021]'},{id:"B11",body:'Sellers T. Plywood and Adhesive Technology. Forest Products Utilization Laboratory, Mississippi State University, Mississippi, USA: CRC Press; 1985'},{id:"B12",body:'Filippovich A. Plywood history. From ancient Egypt to mid-twentieth century, part 1. Saint-Petersburg, Russia: Lesprominform. 2018;3:104-113'},{id:"B13",body:'Smulski S, editor. Engineered Wood Products: A Guide for Specifiers, Designers & Users. Madison, WI: Pfs Research Foundation; 1997'},{id:"B14",body:'Plywood - Sizes - Grades. The Canadian Wood Council - CWC 2021. https://cwc.ca/how-to-build-with-wood/wood-products/panel-products/plywood/. [Accessed: March 24, 2021]'},{id:"B15",body:'McIntyre RB. Design Features of the Mosquito. Aircraft Engineering and Aerospace Technology Emerald Insight, United Kingdom. 1944;16:64-67. DOI: 10.1108/eb031101'},{id:"B16",body:'Bowyer JL, Shmulsky R, Haygreen JG. Forest Products and Wood Science: An Introduction. 5th Ed. Oxford, UK: Wiley-Blackwell; 2007'},{id:"B17",body:'FAO. Yearbook of Forest Products 2000,2005,2010,2015,2019. Rome, Italy: FAO; 2021. DOI: 10.4060/cb3795m'},{id:"B18",body:'Canadian Wood Council. Wood Reference Handbook. Ottawa, Ontario, Canada: Canadian Wood Council; 1997'},{id:"B19",body:'Plywood. Wikipedia 2021. https://en.wikipedia.org/w/index.php?title=Plywood&oldid=1028259276 [Accessed: June 17, 2021]'},{id:"B20",body:'APA – The Engineered Wood Association. 2021. https://www.apawood.org/ [Accessed: April 14, 2021]'},{id:"B21",body:'certiWood™ Canply plywood. Plywood Design Fundamentals Canadian Plywood Association 2021. https://tolko.com/wp-content/uploads/2020/05/Plywood-Design-Fundamentals-Canadian-Plywood-Association.pdf [Accessed: May 18, 2021]'},{id:"B22",body:'CSA Group. CSA 086:19 Engineering Design in Wood. National Standard of Canada. Toronto, Canada: CSA Group; 2021'},{id:"B23",body:'CSA Group. CAN/CSA-O80 SERIES-15 (R2020) Wood Preservation. National Standard of Canada. Toronto, Canada: CSA Group; 2020'},{id:"B24",body:'ASTM International. D5516-18 Standard Test Method for Evaluating the Flexural Properties of Fire-Retardant Treated Softwood Plywood Exposed to Elevated Temperatures. West Conshohocken, PA: ASTM International; 2018. DOI: 10.1520/D5516-18'},{id:"B25",body:'Wood Design Manual 2017. Ottawa, Ontario, Canada: Canadian Wood Council Webstore; 2017'},{id:"B26",body:'APA. Design Capacities of APA Performance-Rated Structural-Use Panels Technical Note N375. Tacoma, Washington, USA: APA The Engineered Wood Association; 1995'},{id:"B27",body:'Wood Engineering Handbook. Second ed. Englewood Cliffs, NJ: Forest Products Laboratory; Prentice Hall; 1990 http://www.matweb.com/search/datasheet_print.aspx?matguid=bd6620450973496ea2578c283e9fb807 [Accessed: May 31, 2021]'},{id:"B28",body:'ASTM International. D3500-20 Standard Test Methods for Wood Structural Panels in Tension. West Conshohocken, PA: ASTM International; 2020. DOI: 10.1520/D3500-20'},{id:"B29",body:'ASTM International. D3043-17 Standard Test Methods for Structural Panels in Flexure. West Conshohocken, PA: ASTM International; 2017. DOI: 10.1520/D3043-17'},{id:"B30",body:'ASTM International. D3501-05a (2018) Standard Test Methods for Wood-Based Structural Panels in Compression. West Conshohocken, PA: ASTM International; 2018. DOI: 10.1520/D3501-05AR18'},{id:"B31",body:'ASTM International. D2718-18 Standard Test Method for Structural Panels in Planar Shear (Rolling Shear). West Conshohocken, PA: ASTM International; 2018. DOI: 10.1520/D2718-18'},{id:"B32",body:'ASTM International. D2719-19 Standard Test Methods for Structural Panels in Shear through-the-Thickness. West Conshohocken, PA: ASTM International; 2019. DOI: 10.1520/D2719-19'},{id:"B33",body:'BBC Research. MFG058A Plywood Manufacturing: Global Markets to 2022. Wellesley, Massachusetts, USA: BCC Publishing; 2018'},{id:"B34",body:'Georgia-Pacific Building Products. Plytanium Sturd-I-Floor Plywood Subfloor Panels. Atlanta, Georgia, USA: Georgia-Pacific Building Products; 2021. https://buildgp.com/product/plytanium-sturd-i-floor/ [Accessed: May 22, 2021]'},{id:"B35",body:'Georgia-Pacific Building Products. Plywood Roof Sheathing, OSB Roofing Boards. Atlanta, Georgia, USA: Georgia-Pacific Building Products; 2021. https://buildgp.com/wood/roof-sheathing/ [Accessed: May 22, 2021]'},{id:"B36",body:'American Wood Council. Visual Guide to Floor, Roof, and Wall Systems. Washington, DC, USA: American Wood Council; 2021'},{id:"B37",body:'Laminate Veneer Lumber. The Canadian Wood Council - CWC 2021. https://cwc.ca/how-to-build-with-wood/wood-products/structural-composite/laminate-veneer-lumber/ [Accessed: April 14, 2021]'},{id:"B38",body:'Hsu WE. Structural Composite Lumber Manufacturing. Scotts Valley, California, USA: CreateSpace Independent Publishing Platform; 2016'},{id:"B39",body:'Gong M. Wood Technology, Lecture on Wood Products. Fredericton, Canada: University of New Brunswick; 2021'},{id:"B40",body:'Natural Resources Canada. Laminated veneer lumber. Ottawa, ON, Canada: Natural Resources Canada; 2014. https://www.nrcan.gc.ca/our-natural-resources/forests-forestry/forest-industry-trade/forest-products-applications/taxonomy-wood-products/laminated-veneer-lumber/15795 [Accessed: April 14, 2021]'},{id:"B41",body:'Introduction to Wood Design 2018. Canadian Wood Council; 2018'},{id:"B42",body:'Structural Grading. WoodSolutions; 2021 https://www.woodsolutions.com.au/articles/structural-grading [Accessed: April 14, 2021]'},{id:"B43",body:'Stora Enso Wood Products GmbH. LVL by Stora Enso Technical brochure. Helsinki. Finland: Stora Enso; 2021. https://www.storaenso.com/-/media/documents/download-center/documents/product-brochures/wood-products/lvl-by-stora-enso-technical-brochure-en.pdf [Accessed: June 4, 2021]'},{id:"B44",body:'Laminated Veneer Lumber | Engineered Wood | StructureCraft. StructureCraft Builders. 2021. https://structurecraft.com/materials/engineered-wood/laminated-veneer-lumber [Accessed: May 21, 2021]'},{id:"B45",body:'Moretti PM, Divone LV. Modern windmills. Scientific American. 1986;254:110-119'},{id:"B46",body:'Decker KD. Reorienting the economy to the rhythms of nature: Learning to live with intermittent energy supply. American Journal of Economics and Sociology. 2020;79:877-905. DOI: 10.1111/ajes.12333'},{id:"B47",body:'Extreme Measures: At 107 Meters, The World’s Largest Wind Turbine Blade Is Longer Than A Football Field. Here’s What It Looks Like | GE News. 2019. https://www.ge.com/news/reports/extreme-measures-107-meters-worlds-largest-wind-turbine-blade-longer-football-field-heres-looks-like [Accessed: May 30, 2021]'},{id:"B48",body:'Weyerhaeuser Uses Strong Scraps. Wood Business. 2014. https://www.woodbusiness.ca/weyerhaeuser-strong-scraps-1859/ [Accessed: April 24, 2021]'},{id:"B49",body:'Parallel Strand Lumber. The Canadian Wood Council – CWC. 2021. https://cwc.ca/how-to-build-with-wood/wood-products/structural-composite/parallel-strand-lumber/ [Accessed: April 16, 2021]'},{id:"B50",body:'Waste not Cambodia: Image. 2021. https://wastenotcambodia.files.wordpress.com/2012/05/parallam1.jpg [Accessed: June 16, 2021]'},{id:"B51",body:'Canada NR. Oriented Strand Lumber. 2014. https://www.nrcan.gc.ca/our-natural-resources/forests-forestry/forest-industry-trade/forest-products-applications/taxonomy-wood-products/oriented-strand-lumber/15827 [Accessed: April 24, 2021]'},{id:"B52",body:'Gould-Design-Inc. Parallel-strand-lumber. Gould Design, Inc. 2013. https://goulddesigninc.com/2013/11/14/the-abcs-of-ewp-engineered-wood-products/parallel-strand-lumber/ [Accessed: June 16, 2021]'},{id:"B53",body:'How can I be sure that I have genuine Parallam® Plus PSL? Trus Joist Technical Support. 2021. https://www.techsupport.weyerhaeuser.com/hc/en-us/articles/205173710-How-can-I-be-sure-that-I-have-genuine-Parallam-Plus-PSL [Accessed: May 30, 2021]'},{id:"B54",body:'Parallam® PSL Deep Beam Specifier’s Guide. 2015'},{id:"B55",body:'Parallel Strand Lumber. Engineered Wood. StructureCraft. StructureCraft Builders. 2021. https://structurecraft.com/materials/engineered-wood/parallel-strand-lumber [Accessed: May 21, 2021]'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Elena Vladimirova",address:"evladimi@unb.ca",affiliation:'
'}],corrections:null},book:{id:"10584",type:"book",title:"Engineered Wood Products for Construction",subtitle:null,fullTitle:"Engineered Wood Products for Construction",slug:"engineered-wood-products-for-construction",publishedDate:"April 28th 2022",bookSignature:"Meng Gong",coverURL:"https://cdn.intechopen.com/books/images_new/10584.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83962-772-9",printIsbn:"978-1-83962-771-2",pdfIsbn:"978-1-83962-790-3",isAvailableForWebshopOrdering:!0,editors:[{id:"274242",title:"Dr.",name:"Meng",middleName:null,surname:"Gong",slug:"meng-gong",fullName:"Meng Gong"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"344364",title:"Mr.",name:"Simon",middleName:null,surname:"Davies",email:"Simon.Davies@bausch.com",fullName:"Simon Davies",slug:"simon-davies",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{id:"76356",title:"The Safe Evolution of Liposuction into Liposculpture",slug:"the-safe-evolution-of-liposuction-into-liposculpture",abstract:"Liposuction was described in the 1920s & popularised in 1977 by Illouz. He developed smaller diameter blunt cannulas. To add safety he also developed the wet technique to reduce blood loss. Tumescent anaesthesia described by Klein in 1987 made large volume liposuction safer allowing for more refined body contouring through significantly minimising blood loss. Liposuction journey started as mechanical debulking that evolved over the last 4 decades into a refined high definition body contouring and proportioning surgery, thus making sculpturing a shape of figurine possible. To achieve such high definition body sculpting technology including Laser, and Vaser not only added safety, however, they also achieved outcomes that cannot be matched with the older methods of liposuction, under local anaesthesia. In this chapter we aspire to discuss the journey of how liposuction evolved into body contouring surgery with large volume lipo-aspirates yet more safely.",signatures:"Ali Juma, Jamil Hayek and Simon Davies",authors:[{id:"343918",title:"Dr.",name:"Jamil",surname:"Hayek",fullName:"Jamil Hayek",slug:"jamil-hayek",email:"plasticsurgeonjamilhayek@gmail.com"},{id:"344364",title:"Mr.",name:"Simon",surname:"Davies",fullName:"Simon Davies",slug:"simon-davies",email:"Simon.Davies@bausch.com"},{id:"351015",title:"Dr.",name:"Ali",surname:"Juma",fullName:"Ali Juma",slug:"ali-juma",email:"alijuma@me.com"}],book:{id:"10351",title:"Enhanced Liposuction",slug:"enhanced-liposuction-new-perspectives-and-techniques",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"73035",title:"Prof.",name:"Ercan",surname:"Karacaoglu",slug:"ercan-karacaoglu",fullName:"Ercan Karacaoglu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/73035/images/322_n.jpg",biography:"E R C A N K A R A C A O G L U\r\n\r\n\r\n\r\n\r\n\r\n\r\nAcademic Title: Associate Professor of Plastic Surgery\r\n\r\nSpeciality: Plastic, Aesthetic and Reconstructive Surgery\r\n\r\nMinor Speciality: Aesthetic surgery, Aestehetic Breast Surgery, Reconstructive Breast surgery\r\n\r\nPlace of Birth : Tekirdag, Turkey\r\nDate of Birth : December 18, 1967\r\n\r\nGraduated Faculty and Year: GATA School of Medicine, 1992 \r\n\r\nPlace and date of Speciality: GATA Haydarpasa Training Hospital\r\nIstanbul, Turkey, 2000\r\n\r\nPlace and date of Minor Speciality: 1.Brown University, School of Medicine, Department of Plastic surgery, Providence, Rhode Island, U.S.A., 2001\r\n\t\t\t\t 2. Brown University, School of Medicine, Department of Plastic surgery, Providence, Rhode Island, U.S.A., 2004\r\n\r\n\r\nForeign Languages: English\r\n\r\nVocational Awards: \r\n\r\nGrants: LifeCell Corporation\r\nAssessment of In-Vivo Integration of Allograft around implants\r\nPrinciple Researcher.\r\nAward: $30,000 (2004)\r\nHonors and Awards: The second best scientific presentation award in 22nd National Congress of Turkish Plastic and Reconstructive Surgery Society (Sept 2000).\r\n\r\n-The best grade of graduation in 1990-1991 Training Year, Gulhane Military Medical \r\n Academy, School of Medicine (1991)\r\n\r\n\r\nVocational Publications: \r\n\r\n\tNumber of Foreign Publications: 26\r\n\r\n\tNumber of Turkish Publications: 14\r\n\r\n\tNumber of National Congress Presentations: 35\r\n\r\n\tNumber of International Congress Presentations: 32\r\n\t\r\n\tNumber of Book/ Chapters: 3\r\n\r\nSummary of the Career: \r\n\r\n-Since June 2009: Associate Professor of Plastic Surgery in Yeditepe University, School of Medicine, Dept of Plastic Surgery\t Istanbul, Turkey.\r\n-March 2005- June 2009: Assistant Professor \r\n-Oct 2003- Dec 2004: Fellowship in Breast Surgery (Teaching and Clinical Fellow) Brown University, School of Medicine\r\nRI Hospital, Div of Plastic Surgery Providence, RI U.S.A. \r\n-Jun 2003- Sept 2003 : Private Practicing, Istanbul, Turkey. \r\n-Sept 2001- Jun 2003 : Chief (Captain, M.D), Plastic Surgery Service Golcuk 600-Bed Naval Hospital, Golcuk, Kocaeli Turkey. \r\n-Dec 2000- Aug 2001 : Fellowship in Aesthetic and Reconstructive Breast Surgery Brown University, School of Medicine RI Hospital, Div of Plastic Surgery Providence, RI, U.S.A. \r\n-Nov 2000 : Chief (Captain, M.D), Plastic Surgery Service Golcuk 600-Bed Naval Hospital, Golcuk, Kocaeli Turkey. \r\n-Sept '95-Oct 2000 : Residency in Plastic and Reconstructive Surgery. GATA Military Medical Academy, Haydarpasa Training Hospital, Kadikoy, Istanbul Turkey. \r\n-May.’94-Sept ’95 : Chief of Emergency Medical Care Service Turkish Navy, Heybeliada Naval Hospital, Heybeliada, Istanbul Turkey. \r\n-June’93-May.’94 : Emergency Care Staff and Destroyer Doctor, Turkish Navy, Golcuk 600-Bed Naval Hospital, 41657 Golcuk, Kocaeli Turkey. \r\n-Sept ’92- June ’93 : Postgraduate Internship \r\nGATA 1200-Bed Military Medical Academy Hospital Etlik, Anakara Turkey\r\n\r\n\r\nMemberships in Associations/Clubs: \r\n\r\nSince 2006: Fellow, EBOPRAS Board Certificate (EBOPRAS, European Board of Plastic, Reconstructive and Aesthetic Surgery)\r\n\r\nSince 2006: ASPS (American Society of Plastic Surgeons)\r\n\r\nSince 2004: ISAPS ( International Society of Aesthetic Plastic Surgery)\r\n\r\nSince 2004: TASSSA (Turkish American Scientists Scholars Association)\r\n\r\nSince 2007: Society of Turkish Aesthetic Surgeons\r\n\r\nSince 1995 : Society of Turkish Plastic and Reconstructive Surgeons \r\n\r\nSince 1992 : Association of Turkish Medical Doctors \r\n\r\n\r\n\r\nE-Mail: drercanka@yahoo.com",institutionString:null,institution:{name:"Yeditepe University",institutionURL:null,country:{name:"Turkey"}}},{id:"342452",title:"Dr.",name:"Roger E.",surname:"Amar",slug:"roger-e.-amar",fullName:"Roger E. 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Doolabh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/344573/images/15430_n.jpg",biography:null,institutionString:null,institution:null},{id:"347622",title:"Ph.D.",name:"Michael",surname:"Kreindel",slug:"michael-kreindel",fullName:"Michael Kreindel",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"351015",title:"Dr.",name:"Ali",surname:"Juma",slug:"ali-juma",fullName:"Ali Juma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"open-access-funding",title:"Open Access Funding",intro:"
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In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
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Does your institution already have a budget for covering Open Access publication costs?
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If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
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Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at funders@intechopen.com
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Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
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Polymorphism at the DNA level includes a wide range of variations from single base pair change, many base pairs, and repeated sequences. Genomic variability can be present in many forms, including single nucleotide polymorphisms (SNPs), variable number of tandem repeats (VNTRs, e.g., mini- and microsatellites), transposable elements (e.g., Alu repeats), structural alterations, and copy number variations. Different forms of DNA polymorphisms can be tracked using a variety of techniques; some of these techniques include restriction fragment length polymorphisms (RFLPs) with Southern blots, polymerase chain reactions (PCRs), hybridization techniques using DNA microarray chips, and genome sequencing. During the last years, the recent advance of molecular technologies revealed new discoveries of DNA polymorphisms. DNA polymorphisms are endless, and more discoveries continue at a rapid rate. Mapping the human genome requires a set of genetic markers. DNA polymorphism serves as a genetic marker for its own location in the chromosome; thus, they are convenient for analysis and are often used as in molecular genetic studies.",book:{id:"6719",slug:"genetic-diversity-and-disease-susceptibility",title:"Genetic Diversity and Disease Susceptibility",fullTitle:"Genetic Diversity and Disease Susceptibility"},signatures:"Salwa Teama",authors:[{id:"249329",title:"Dr.",name:"Salwa",middleName:null,surname:"Teama",slug:"salwa-teama",fullName:"Salwa Teama"}]},{id:"58467",title:"Generation of Antibody Diversity",slug:"generation-of-antibody-diversity",totalDownloads:3111,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Because of the huge diversity, the immunoglobulin repertoire cannot be encoded by static genes, which would explode the genomic capacity comprising about 20,000–25,000 human genes. The immunoglobulin repertoire is provided by the process of somatic germ line recombination, which is the only controlled alteration of the genomic DNA after meiosis. It takes place in mammalian B lymphocyte (B cells) precursors in the bone marrow. The genome germ line sequence of undeveloped B cells is organized in gene segments and compromise V (variable), D (diversity), and J (joining) gene segments constituting the variable domain of the heavy chain and only V and J genes for building up the variable domain of the light chain. The rearrangement of the variable region follows a strict order. The following processes that participate in the generation of antibody diversity were summarized—allelic, combinational, and junctional diversity, pairing of IgH and IgL, and receptor editing—which all together produce the primary antigen repertoire (pre-antigen stimulation). When a B cell encounters a foreign antigen, affinity maturation and class switch are induced. Thereby the antibody repertoire increases. The resulting secondary immunoglobulin repertoire reveals in humans at least 1011 specificities for different antigens.",book:{id:"5784",slug:"antibody-engineering",title:"Antibody Engineering",fullTitle:"Antibody Engineering"},signatures:"Oliver Backhaus",authors:[{id:"177685",title:"M.Sc.",name:"Oliver",middleName:null,surname:"Backhaus",slug:"oliver-backhaus",fullName:"Oliver Backhaus"}]},{id:"61204",title:"Polymorphisms",slug:"polymorphisms",totalDownloads:2005,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Polymorphism or variation in DNA sequence can affect individual phenotypes such as color of skin or eyes, susceptible to diseases, and respond to drug, vaccine, chemical, and pathogen. It occurs more often than mutations (frequency ≥ 1%). The common polymorphism is single nucleotide polymorphism (SNP) which is a single base change in a DNA sequence that occurs most commonly in the human genome. SNPs have been used as molecular markers in a wide range of studies. Genome-wide association studies (GWAS) searches for SNPs that occur more frequently in person with a particular disease than in person without the disease and pinpoint genes or regions that may contribute to a risk of disease. This topic describes about polymorphisms, SNPs, GWAS, linkage disequilibrium (LD), minor allele frequency, haplotype, method for SNP genotyping, and application of SNPs and genome-wide association study in human diseases and drug development.",book:{id:"6719",slug:"genetic-diversity-and-disease-susceptibility",title:"Genetic Diversity and Disease Susceptibility",fullTitle:"Genetic Diversity and Disease Susceptibility"},signatures:"Wasana Sukhumsirichart",authors:[{id:"238537",title:"Associate Prof.",name:"Wasana",middleName:null,surname:"Sukhumsirichart",slug:"wasana-sukhumsirichart",fullName:"Wasana Sukhumsirichart"}]},{id:"21711",title:"Screening of Bacterial Recombinants: Strategies and Preventing False Positives",slug:"screening-of-bacterial-recombinants-strategies-and-preventing-false-positives",totalDownloads:28414,totalCrossrefCites:1,totalDimensionsCites:5,abstract:null,book:{id:"375",slug:"molecular-cloning-selected-applications-in-medicine-and-biology",title:"Molecular Cloning",fullTitle:"Molecular Cloning - Selected Applications in Medicine and Biology"},signatures:"Sriram Padmanabhan, Sampali Banerjee and Naganath Mandi",authors:[{id:"46458",title:"Dr.",name:"Sriram",middleName:null,surname:"Padmanabhan",slug:"sriram-padmanabhan",fullName:"Sriram Padmanabhan"},{id:"136523",title:"Prof.",name:"Sampali",middleName:null,surname:"Banerjee",slug:"sampali-banerjee",fullName:"Sampali Banerjee"},{id:"136524",title:"Prof.",name:"Naganath",middleName:null,surname:"Mandi",slug:"naganath-mandi",fullName:"Naganath Mandi"}]},{id:"49200",title:"Human Embryology",slug:"human-embryology",totalDownloads:3523,totalCrossrefCites:5,totalDimensionsCites:7,abstract:"The study of human embryology has a very long history. Modern embryology owes its initial development to the key embryo collections that began in the 19th century. The first large collection was that of Carnegie, and this was followed later by the major 7 collections. The second role of the Carnegie collection was for researchers to establish a defined set of Carnegie stages based on embryo morphological features. Today, embryos are imaged three-dimensionally (3D) by a range of imaging modalities including, magnetic resonance microscopy (MRM), episcopic fluorescence image capture (EFIC), phase-contrast X-ray computed tomography (pCT), and optical projection tomography (OPT). Historically, embryo serial images were reconstructed using wax-plate and model techniques. The above new 3D imaging techniques now allow 3D computer reconstructions, analysis, and even 3D printing. This chapter will describe how the classical embryology collections and techniques have developed into today’s imaging and analysis techniques, giving new insights to human embryonic development.",book:{id:"4588",slug:"new-discoveries-in-embryology",title:"New Discoveries in Embryology",fullTitle:"New Discoveries in Embryology"},signatures:"Shigehito Yamada, Mark Hill and Tetsuya Takakuwa",authors:[{id:"49486",title:"Prof.",name:"Shigehito",middleName:null,surname:"Yamada",slug:"shigehito-yamada",fullName:"Shigehito Yamada"},{id:"90205",title:"Prof.",name:"Tetsuya",middleName:null,surname:"Takakuwa",slug:"tetsuya-takakuwa",fullName:"Tetsuya Takakuwa"},{id:"175453",title:"Dr.",name:"Mark",middleName:null,surname:"Hill",slug:"mark-hill",fullName:"Mark Hill"}]}],onlineFirstChaptersFilter:{topicId:"54",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:286,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"22",title:"Business, Management and Economics",doi:"10.5772/intechopen.100359",issn:null,scope:"
\r\n\tThis series will provide a comprehensive overview of recent research trends in business and management, economics, and marketing. Topics will include asset liability management, financial consequences of the financial crisis and covid-19, financial accounting, mergers and acquisitions, management accounting, SMEs, financial markets, corporate finance and governance, managerial technology and innovation, resource management and sustainable development, social entrepreneurship, corporate responsibility, ethics and accountability, microeconomics, labour economics, macroeconomics, public economics, financial economics, econometrics, direct marketing, creative marketing, internet marketing, market planning and forecasting, brand management, market segmentation and targeting and other topics under business and management. This book series will focus on various aspects of business and management whose in-depth understanding is critical for business and company management to function effectively during this uncertain time of financial crisis, Covid-19 pandemic, and military activity in Europe.
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His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,annualVolume:11975,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. She serves as an Associate Editor for the International Journal of the Analytic Hierarchy Process. She is a member of AHP Academy and a member of several editorial boards. 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Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. 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He holds a Master’s Degree in Urban Development Planning from the University College of London (UCL), and a Ph.D. in Urban Planning & Engineering from TU Berlin. He has conducted applied research on urban planning and infrastructure issues in over 20 countries in Africa and Asia. In 2005 he joined Eawag-Sandec as Leader of the Strategic Environmental Sanitation Planning Group. Since 2015 he heads the research department Sanitation, Water and Solid Waste for Development (Sandec) at the Swiss Federal Institute of Aquatic Research and Technology (Eawag).",institutionString:"Swiss Federal Institute of Aquatic Science and Technology, Switzerland",institution:null},editorTwo:{id:"290571",title:"Dr.",name:"Rui Alexandre",middleName:null,surname:"Castanho",slug:"rui-alexandre-castanho",fullName:"Rui Alexandre Castanho",profilePictureURL:"https://mts.intechopen.com/storage/users/290571/images/system/290571.jpg",biography:"Rui Alexandre Castanho has a master\\'s degree in Planning, Audit, and Control in Urban Green Spaces and an international Ph.D. in Sustainable Planning in Borderlands. Currently, he is a professor at WSB University, Poland, and a visiting professor at the University of Johannesburg, South Africa. Dr. Castanho is a post-doc researcher on the GREAT Project, University of Azores, Ponta Delgada, Portugal. He collaborates with the Environmental Resources Analysis Research Group (ARAM), University of Extremadura (UEx), Spain; VALORIZA - Research Center for the Enhancement of Endogenous Resources, Polytechnic Institute of Portalegre (IPP), Portugal; Centre for Tourism Research, Development and Innovation (CITUR), Madeira, Portugal; and AQUAGEO Research Group, University of Campinas (UNICAMP), Brazil.",institutionString:"University of Johannesburg, South Africa and WSB University, Poland",institution:{name:"University of Johannesburg",institutionURL:null,country:{name:"South Africa"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:2,paginationItems:[{id:"81644",title:"Perspective Chapter: Ethics of Using Placebo Controlled Trials for Covid-19 Vaccine Development in Vulnerable Populations",doi:"10.5772/intechopen.104776",signatures:"Lesley Burgess, Jurie Jordaan and Matthew Wilson",slug:"perspective-chapter-ethics-of-using-placebo-controlled-trials-for-covid-19-vaccine-development-in-vu",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"SARS-CoV-2 Variants - Two Years After",coverURL:"https://cdn.intechopen.com/books/images_new/11573.jpg",subseries:{id:"6",title:"Viral Infectious Diseases"}}},{id:"80546",title:"Streptococcal Skin and Skin-Structure Infections",doi:"10.5772/intechopen.102894",signatures:"Alwyn Rapose",slug:"streptococcal-skin-and-skin-structure-infections",totalDownloads:48,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Streptococcal Infections",coverURL:"https://cdn.intechopen.com/books/images_new/10828.jpg",subseries:{id:"3",title:"Bacterial Infectious Diseases"}}}]},overviewPagePublishedBooks:{paginationCount:13,paginationItems:[{type:"book",id:"6667",title:"Influenza",subtitle:"Therapeutics and Challenges",coverURL:"https://cdn.intechopen.com/books/images_new/6667.jpg",slug:"influenza-therapeutics-and-challenges",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Shailendra K. Saxena",hash:"105e347b2d5dbbe6b593aceffa051efa",volumeInSeries:1,fullTitle:"Influenza - Therapeutics and Challenges",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:null,institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7064",title:"Current Perspectives in Human Papillomavirus",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7064.jpg",slug:"current-perspectives-in-human-papillomavirus",publishedDate:"May 2nd 2019",editedByType:"Edited by",bookSignature:"Shailendra K. Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:null,institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",slug:"current-topics-in-neglected-tropical-diseases",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Alfonso J. Rodriguez-Morales",hash:"61c627da05b2ace83056d11357bdf361",volumeInSeries:3,fullTitle:"Current Topics in Neglected Tropical Diseases",editors:[{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",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. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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