Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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The field has recognized that climate is something that changes continually under the influence of physical and biological forces and so, cannot be understood in isolation but rather, is one that includes diverse scientific disciplines that play their role in understanding a highly complex coupled "whole system" that is the earth\'s climate. The modern era of climatology is echoed in this book. On the one hand it offers a broad synoptic perspective but also considers the regional standpoint, as it is this that affects what people need from climatology. Aspects on the topic of climate change - what is often considered a contradiction in terms - is also addressed. It is all too evident these days that what recent work in climatology has revealed carries profound implications for economic and social policy; it is with these in mind that the final chapters consider acumens as to the application of what has been learned to date.',isbn:null,printIsbn:"978-953-51-0095-9",pdfIsbn:"978-953-51-4959-0",doi:"10.5772/2014",price:139,priceEur:155,priceUsd:179,slug:"modern-climatology",numberOfPages:400,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"1ff6285db485c8ded3e5a29b2f721f6d",bookSignature:"Shih-Yu (Simon) Wang and Robert R. 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His research\ninterests cover climate diagnostics and prediction, as well as severe\nweather systems. He is particularly interested in connecting the\nweather and climate processes. Dr. Wang obtained Ph.D. in Meteorology\nfrom Iowa State University, USA. He has worked as research associate\nin the Utah Climate Center with a research focus on regional climate\nvariability.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Utah State University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"106232",title:"Dr.",name:"Robert",middleName:null,surname:"Gillies",slug:"robert-gillies",fullName:"Robert Gillies",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Dr. Robert R. 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1. Introduction
Advances in biomaterials are implicated in the huge results as the artificial support matrices penetrate the barrier of all physicochemical properties in clinical tissue implantation, an artifact of regenerative tissue engineering applications. Unlike traditional tissue grafting, the artificial implanting process involves the replacement of any damaged tissues irrespective of age, diseases, and kinds of trauma. Based on the potential requirements, efforts in different fields that include material science, cell biology, medicine, theory and computational studies represent a versatile contribution in regenerative medicine to save thousands of lives. The preliminary idea of tissue engineering is to reconstruct the traditional surgical or mechanical device-related techniques; those though significantly prevented the untimely demises of lives. The time on demand of available organ donors and appropriate complimentary biological environments are implemented in the term ‘Tissue Engineering’ (TE) in 1933 by Langer and Vacanti [1]. TE is the versatile gift of scientists who have greatly remodeled and mimicked the in vivo biological niche through a combination of engineered biomaterials, cells of interest and biochemical factors, which are important factors for tissue development. The manufacture of the implantation of the desired shape is the key factor in TE, which could support seeding of isolated cells, cell–cell interaction, and its proliferation and migration. The cell adhesion and secretion of extracellular matrixes (ECM) are switched through growth factor-mediated signaling pathways [2]. The growth factors are the class of cytokines, at the basis of cell attachment, proliferation and migration in tissue regeneration, remodeling and other various cellular functions [3, 4]. Epithelial growth factors (EGFs), platelet-derived growth factors (PDGFs), insulin-like growth factors (IGFs), and hematopoietic cell growth factors (HCGFs) are promising types of cytokines that have played a significant role in tissue engineering.
The new generation of biomaterials has revolutionized the fields of regenerative medicine while, the development of 3D architecture could enable us to mimic the ideal in vivo tissue organoid. Other important parameters of the supporting scaffolds include the porosity, biodegradability, biocompatibility and good carrier of the therapeutic molecules, immobilized onto the matrixes. Due to intrinsic biological characteristics, both synthetic and natural materials have been investigated to formulate the three-dimensional support structure, but the requirements related to microbial resistance, genotoxicity, and mechanical strength remain to be questioned. Collagen, gelatin, hyaluronic acid, alginate, guar gum, chitosan, polyhydroxyalkanoates are the well-known naturally originated, biocompatible and biodegradable polymers, which have emerged as a bio-mimicking matrixes in the development of artificial 3D construct, but their mechanical as well as hydrophilicity limited its unique usages. The drawback is significantly erased by the appearance of biosynthetic technology. In particular, the discovery of carbon compounds such as carbon nanotubes, graphene oxide nanoparticles, etc., has revolutionized the fields of tissue engineering. The additional biocompatibility, antimicrobial activity and mechanical stability of such compounds are considered to fabricate the bioimitating 3D construct. Furthermore, synthetic materials such as poly (lactide-coglycolide) and poly (ethylene glycol) play an important role in the construction of the ideal scaffold [5, 6].
The challenge in tissue regeneration is the seeding of cells. The risk factors such as in vivo immune-rejection, viral or microbial contaminations, processing of clean healthy cells are the main obstacles in choosing of the desired cells. Keeping in mind, the allogeneic cells, i.e., cells from a healthy person is considered for the several tissue regeneration systems. A variety of stem cells has been an essential and elementary option for the in vitro cell growth in the regeneration of cartilage tissues [7]. Nevertheless, an ideal scaffold with interconnected porous networks, proper mechanically and biologically appropriate engineering should lead to ECM secretion with prominent adhesion, and cell transduction and proliferation are best suited for tissue engineering applications.
This chapter will explore the sources of the 3D polymer construct and its validity in the biological niche, i.e. biocompatibility and cell motility through different growth factors.
2. Why is the 3D construct in tissue regeneration (TE)?
In tissue engineering, the assessment of cell compatibility is evaluated in a “in vitro” model of either 2D or 3D based on the results of optimal support arrays in which cells must continually increase their colonies as the native tissue environment as shown in Figure 1. The trafficking of therapeutic delivery in several cases is to get rid of all kinds of forthcoming issues. Therefore, it must circumvent these obstacles by taking into account various facts such as the extracellular matrix density, the nature of the cell-tissue interaction, and the penetration of nano carriers through tissue layers, etc. In 2D cell culture, the cells are grown, adhered to flat polystyrene surfaces in a thin monolayer’s manner. The proliferation, migration, epigenetic and genetic expressions are varied as compared to in vivo tissue regeneration. Cell attachments and motility also constraint within monolayer frames and are exposed to unlimited nutrient sources. The two-dimensional culture is related to an easy and cost-effective process. However, it deprives the study of cell–cell interaction, cell-matrix interaction, cell signaling, and the nature of cell elasticity, which promotes the usefulness of the biological niche, i.e. the 3D construct.
Figure 1.
Schematic comparison of 2D and 3D cell culture model.
Unlike 2D model, 3D constructs regulate the cell growth and proliferation in heterogeneity similar to in vivo tissue as the exposure of growth factors, oxygen, nutrients distributed unevenly in the scaffold or any other 3D construction. The cell morphology as well as the cell polarity is maintained because it greatly controls the cell-signaling, cell topology and various metabolic activities [8, 9]. However, culturing in 3D models is a lengthy and expensive process and is formulated in several ways: 3D spheroid where cells spend their survival time in layers, mimicking the correct cell–cell and cell-matrix interaction as in the environment of native tissue. The identification of biomarkers and the expression of genes that are involved in topological processes as well as the polarity changes of cancer cells are examined in the spheroid models [10]. Furthermore, it is expected that the adherence and proliferation of primary cells follow all the characteristics of in vivo tissue processes [11]. The 3D scaffolding systems, made of biodegradable and biocompatible materials, have demonstrated superior cell migration, proliferation through a network of porous 3D microenvironments [12]. In view of the significant advantages, the utility of bio-imitating 3D constructs is however encompassed in the niche of tissue regeneration though; 2D cell culture is still used as a reliable method before initiating the animal studies.
3. Choice of material in artificial supporting matrixes
The involvement of suitable materials, whether synthetic or naturally extracted in the fabrication of the artificial tissue environment, remains a challenge. The prerequisite in the development of 3D constructs includes biocompatibility, biodegradability, mechanical strength, interconnected and antimicrobial porous mechanical strength, antimicrobial and interconnected porous networks in which cellular activities could be performed analogously to their native tissue domicile. Taking into account the fact that biomaterials that actually contain the structural component or similar biochemical and physicochemical identity of native tissue have been granted for the processing of the platform in support of artificial cells. Meanwhile, the involvement of any unique material may or may not be able to create the imitation of equivalent tissues requires a broad understanding of the cell-matrix interaction. Therefore, the role of the combination of materials is considered as the essential means to overcome all the barriers that include bioactivity, biodegradability, microbial contamination and maximum mechanical flexibility which contribute as a key to tissue engineering.
3.1 Impact of naturally sourced biomaterials on cell-cell cross-talk
Mimicking of biological tissue environment using collagen is an attractive theme, which is due to the inherent features such as fibrous structure, biocompatibility and low antigenicity. However, the improvement of mechanical stability and biodegradability requires additional treatment that includes cross-linking or chemical modification in the presence of second party molecules. The approaches of modification of different natural biopolymer and its tuning into desired artificial tissue architecture that support the adhesion, proliferation, and migration of cells in biological niche are discussed here.
3.1.1 Collagen as base material and its derivatives
Collagen is a key component in extracellular matrixes and composed of RGD (arginine−glycine−aspartic acid) domains that plays a potential role in cell adhesion, growth and motility through its interaction with cells. But, the drawback due to poor mechanical stability and biodegradation is overcome by the modification with various natural polymers or synthetic polymers. In one approach, collagen molecules were chemically conjugated with oxidized guar gum to immobilize platelet-derived growth factor [13]. The guar gum which is a water soluble and ionic polysaccharide was oxidized to poly(dialdehyade) guar gum in presence of sodium periodate. The resultant oxidized guar gum not only promoted the crosslinking of collagen molecules but also helped to immobilize the platelet-derived growth factor, enabling the formation of biologically active hybrid 3D scaffolds with excellent swelling, thermal and biodegradable properties. FTIR, SEM analysis was performed to confirm the synthesis of the hybrid structure. SEM morphology revealed the interconnected 3D porous honeycomb structure with an average pour size of 15 ± 7 μm. The hybrid scaffold was shown to promote the release of growth factors with the increase of NIH 3 T3 cell density and proliferation and was seen as a promising candidate for tissue engineering applications.
Recently, Diogo et al. developed a method of fabrication of ‘in situ’ mineralized collagen based 3D printed hydrogel. As an alternative to various traditional approaches, Co-precipitation method is used to mineralize the collagen fiber in presence of calcium chloride (CaCl2) and ammonium hydrogen phosphate [(NH4)2HPO4]. To prepare the cell laden 3D printed hydrogel, variuos raio’s of mineralized collagen and alginate (a biocompatible and degradable natural polymer) mixture was treated with incubated L929, mouse fibroblast cell line and printed using a bioprinter V1 (REGEMAT 3D, Granada, Spain), resulted the cell laden 3D printed bi-oink. The cell-laden scaffold was shown to support the adhesion, growth and survival of mouse fibroblast cell line [14]. The similar kind of the cell-laden-collagen core and alginate-polyethylene oxide shell based 3D porous structure was developed using microfluidic channel and at low temperature working condition for cryopreservation (Figure 2A) which is subjected to maintain the shortage of cells, tissue and organs. The in vitro assays of two days cryo-preserved osteoblast cells or human adipose stem cells demonstrated good cell viability and steady growth similar to conventional 3D scaffold based cell treatment as shown in Figure 2B, which would bring the potential application in tissue engineering [15]. In a report, the mixture of neonatal chicken bone marrow cells (cBMCs) derived bioactive component and collagen was used to prepare the cell supporting bioink, which was further printed with human adipose tissue-derived stromal cell (hASC) lines to formulate the hASC-laden 3D scaffold [16]. The ‘in vitro’ study using 3D architecture was shown to promote the growth, proliferation and osteogenesis of hASC cells. The system was further implanted in a rat mastoid obliteration model to monitor the potential effect of cBMCs derived bioactive component on the osteogenic differentiation in new bone regeneration. After 12 weeks of post transplantation, experimental groups showed excellent bone formation as compared as shown in Figure 2C. The modification of collagen fiber with synthetic polymer such as polycaprolactone or polylactic acid also resulted the mechanically and biologically active 3D porous cell supporting materials and which was confirmed by SEM, FTIR and proton NMR studies. In skin tissue engineering, the 3D scaffold was shown to increase the adipose tissue derived mesenchymal stem cell (AT-MSC) adhesion and growth with the formation of a tissue environment compared to only PCL or PLA-based scaffolds [17].
Figure 2.
(A) Application of cryopreservation/cell-printing process to tissue engineering processes. [Ref: [15], reproduced with permission from publishing authority]. (B): (a) Optical and SEM images of final scaffold with core/shell mesh structure. (b) Optical images of final scaffold before/after EDTA treatment and fluorescence images of live cells and collagen fiber in core strut after EDTA treatment. [Ref: [15], reproduced with permission from publishing authority]. (C): Osteogenic differentiation of human adipose-derived stromal cell (hASC)-laden structures with (experimental) or without (control) chicken bone marrow cell-conditioned medium. (i) Optical microscopy images of alkaline phosphatase (ALP) staining (at 7 days) and relative ALP activity (at 3, 7, and 14 days) of hASCs in the control and experimental structures. The experimental structure reached maximum ALP activities at 7 days (significantly higher than those of control) and then decreased at 14 days, whereas the ALP activities of the control group continued to increase at 14 days (n = 6, *p < 0.05). Decreased gray values of the magnified ALP staining, indicating that the proliferating cells in the pore were effectively mineralized. The image was captured in the pore of the experimental structure. (ii) Optical microscopy images of Alizarin Red S staining (at 14 days) and relative calcium deposition of the scaffolds (at 7 and 14 days). Calcium deposition levels of the experimental scaffolds were significantly higher than those of the control scaffolds (n = 6, *p < 0.05). Increased red staining was observed in the pore region in the experimental scaffold. (iii) Expression levels of runt-related transcription factor 2 (Runx2), collagen type I alpha chain 1 (Col I), Alp, bone morphogenic protein 2 (Bmp-2), osteocalcin (Ocn), and osteopontin (Opn) at 14 days of culture. Significantly increased expression levels of Runx2, Bmp-2, Ocn, and Opn were detected in the experimental structure (n = 6, *p < 0.05). All values are expressed as mean ± SD. [Ref. [20], reproduced with the permission from publishing authority]. [Ref: [16], reproduced with permission from publishing authority].
3.1.2 Hyaluronic acid as base material and its derivatives
As like collagen, hyaluronic acid (HA) is also a part of extracellular matrix and shown to have a potential role in modulating inflammation, cell attachment, and migration as well as tissue morphogenesis, owing to the biodegradable, biocompatible, non-immunogenicity and anti-inflamatory properties. An attempt by Gao et al. was initiated to develop the self-crosslinked hyaluronic acid-grafted collagen-I hydrogel using EDAC/NHS reaction method. Further, chondrocytes was encapsulated into the hydrogel to verify the cell-matrix interaction and which had a significant effect on the secretion of cartilage-specific matrices to promote the migration, proliferation and gene expression of chondrocytes cells. The in-vivo cytocompatibility and biodegradation studies on Sprague–Dawley (SD) rats (~200 g) showed the gradual decrease of the assembled nanofibre bundle and weight of the hydrogel after prolonged subcutaneous implantation [18]. Therefore, the manufactured self-crosslinking hydrogel could find significant application in tissue engineering applications.
In an approach, the injectable HA-SH/peptide hybrid hydrogels was developed based on the covalent/noncovalent supramolecular interaction between thiolated hyaluronic acid (HA-SH) and BPAA-AFF-OH short peptide to regulate the chondrogenic expression both in vitro and in vivo environments in the cartilage tissue engineering [19]. The prepared hydrogel confirmed by proton NMR, FTIR and SEM analysis was then employed to explore the cytocompatibility of chondrocyte cells. The chondrocyte cells laden hybrid scaffolds demonstrated the significant adhesion, proliferation of chondrocyte with the expression of chondrogenic specific genes such as Col II, Sox9 and AGG. The in vivo study based on the subcutaneous implantation of chondrocyte cells encapsulated hydrogel in New Zealand rabbit’s models also revealed the abundant aggregation and proliferation of cells with the secretion of matrix after 4 weeks of post implantation period, resulting in the inhibition of hypertrophy trend of chondrocytes and tunable hyaline cartilage formation.
In order to improve the mechanical properties, methacrylated HA was modified with elastin-like polypeptide (ELP, consists of 70 repeats of the pentapeptide VPGVG) through free radical photopolymerization technique. The hydrogel made from the combination of MeHA/ELP revealed the tunable physicochemical and mechanical properties which is comparable to native tissue structure. Further, incorporation of zinc nanoparticles into the hydrogel had resulted an excellent antimicrobial platform for cell adhesion, growth, and proliferation phenomena (See Figure 3A). The ‘in vivo’ cytocompatility experiment via subcutaneous implantation of MeHA/ELP hydrogel demonstrated that the weight of the hydrogel was significantly decreased with the generation and growth of autologous tissue without any inflammatory action [20]. This was due to the biodegradation of the transplanted hydrogel that led to the new space for the spreading and infiltration of the proliferated cells. The immunofluroescent staining study also exhibited the minor invasion and infiltration of lymphocyte and macrophages cells, assigning the potential application of the engineered hydrogel in various artificial tissue regeneration processes.
Figure 3.
(A)(i) In vitro cytocompatibility of MeHA/ELP and MeHA/ELP-ZnO hydrogels. Representative live/dead images from hMSCs seeded on (a) MeHA/ELP and (b) MeHA/ELP-ZnO hydrogels after 5 days of seeding. Representative phalloidin (green)/DAPI (blue) stained images from hMSCs seeded on (c) MeHA/ELP and (d) MeHA/ELP-ZnO hydrogels at day 5 post culture. Quantification of (e) viability and (f) metabolic activity of hMSCs seeded on hydrogels after 1, 3, and 5 days of culture. Hydrogels were formed by using 2% MeHA and 10% ELP with 0 and 0.2% (w/v) ZnO nanoparticles at 120 s UV exposure time (* p < 0.05, ** p < 0.01, *** p < 0.001). [Ref: [20], reproduced with permission from publishing authority]. (ii) In vitro antimicrobial properties of MeHA/ELP-ZnO hydrogels with different ZnO concentrations. Representative SEM images of methicillin-resistant Staphylococcus aureus (MRSA) colonization on hydrogels containing (a, b) 0% ZnO, (c, d) 0.1% ZnO, and (e, f) 0.2% ZnO. Clusters of bacteria are shown in dashed circles. [Ref: [20], reproduced with permission from publishing authority]. (B): (i/a) Schematic Diagram of Salivary Gland Damage and Tissue Engineering-Based Therapeutic Approach; (i/b) Schematic Diagram of Mimicking Mesenchymal HA of Developing eSMG on Material Surfaces by Using Adhesive HACA. [Ref: [21], reproduced with permission from publishing authority]. (ii) NiCHE coating platform enhances growth of eSMGs on various substrates. (b) Bright field images and budding levels of eSMGs cultured either on bare or HACA-coated materials after 48 h-culture. Average bud count of eSMGs freshly isolated from TP15 mouse fetus is considered as 100%. Scale bar = 200 μm. (iii) Apoptotic activity, VE structure, and mitotic activity of progenitor cells of eSMGs cultured either on bare or HACA-coated materials after 24 and 48 h-culture, respectively. White scale bar = 200 μm, red scale bar = 500 μm, yellow scale bar = 100 μm. [Ref: [21], reproduced with permission from publishing authority]. (C) (i) Gross view and histological evaluation of repaired region at 6 and 12 weeks postsurgery. Macroscopic images of cartilage defects regions at 6 weeks (A−C) and 12 weeks (D−F) postsurgery. (ii) Biomechanical and biochemical analyzes of the engineered cartilage tissue in vivo. Young’s modulus (A), wet weight (B), thickness (C), DNA qualification (D), GAG qualification (E), and collagen qualification (F) of the in-vivo-engineered cartilage tissue. Values are expressed as mean ± SD, n = 3, *p < 0.05. [Ref: [23], adapted with permission from publishing authority]. (D) (i): (A1-A3) Spatial distribution of the purple formazan crystal inside the 5 L implant at day1(A1), 3(A2) and 5(A3). The scale bars represent 5 mm. Distribution profile of purple formazancrystal indicates an in-growth of cells inside the implant. (B1–5) Presence and distribution of MTT crystals on each bead layer. (ii) Study of the osteogenic properties of the implant in vitro. The study was carried out using human mesenchymal stem cells (hMSC). (A) Time dependent variation of alkaline phosphatase expression. ALP activity was measured in the supernatant of the culture. (B) Study of the expression of osteogenic marker through RT-PCR. The study was carried out after culturing the hMSC on different substrates in presence of osteogenic media for 14 days. (C) Fluorescent micrographs of the replated partially differentiated hMSC stained with FITCPhalloidin(green) and DAPI (blue). The cells were initially cultured on implant and control substrates. They were then trypsinized and replated on tissue culture plate. Imaging was done after 3 days of replating. [Ref: [26], reproduced with permission from publishing authority].
Like various tissue regeneration processes, utilizing of HAbased cell supporting materials explicated the significant output in artificial salivary gland repairing and remodeling. In an experiment, Lee et al. demonstrated the synthesis of hyaluronic acid−catechol (HACA) conjugates based platform named as NiCHE (nature-inspired catechol conjugated hyaluronic acid environment) to mimic the mesenchyme of embryonic submandibular glands (eSMGs) as shown schematically in Figure 3B(i) [21]. The NICHE was developed by the coating of HACA conjugates on the various polymeric scaffolds such as polycarbonate membrane, stiff agarose hydrogel, and polycaprolactone that led to cell adhesion and growth, vascular endothelial and proliferation of progeniotor of eSMGs cells isolated from ICR mice fetus [See Figure 3B(ii&iii)].
3.1.3 Gelatin as base material and its derivatives
Owing to the excellent biocompatibility, biodegradability and water solubility, gelatin has emerged tremendous interest for the formation of 3D hydrogel in tissue engineering application. Song et al. developed an injectable 3D printed gelatin hydrogel composed of continuous phase gelatin and gelatin microgels. The two-step cross-linked injectable gelatin was shown to exhibit the biocompatible lattice, cup-shaped, tube-shaped and rheological modified structure analogous to human anatomical features. The biocompatibility of the microgel led to the spread and expression of metabolic activities in mouse fibroblast cells, which can be attributed to the good cell-matrix interaction such as in vivo remodeling stages [22].
Due to the limited clinical success in repairing defective cartilage, unlike conventional surgery, the biopolymer-based tissue engineering approach such as the production of gelatin-linked electrospun, gelatin-polycaprolactone (gelatin-PCL) nanofiber-filled decellularized extracellular matrix has been investigated to monitor biological functions. The decellularized composite has shown to exhibit the excellent mechanical property and promoted the cartilage regeneration with the secretion of collagen and glycosaminoglycan as shown in Figure 3C [23].
The development of gelatin methacrylate (GelMA) and poly (ethylene glycol) diacrylate (PEGDA) printed three layered scaffold, modified by lysine functionalized rosette nanotubes (RNTK) significantly improved the adhesion, growth and differentiation of adipose-derived mesenchymal stem cells (ADSCs). The RNTK not only acted as a potential biomimetic layer, its presence dramatically increased the secretion of collagen II, glycosaminoglycan, and total collagen as compared to native GelMA-PEGDA scaffolds, and have an potential impact on cartilage regeneration [24].
To improve wound repair caused by burns or accidental injuries, a versatile approach has been shown to fabricate the skin tissue analogue of a mechanically stable acellular elastomeric scaffold in the presence of biodegradable polyurethane and gelatin composite. The Gel-20%PU showed the best cell infiltration and biodegradation in a mouse in vivo experiment. Also, it reveals negligible immunogenicity and could be accepted as a substitute for new generation tissues [25].
3.1.4 Sodium alginate as base material and its derivatives
The implementation of the osteogenic microenvironment loaded with therapeutic agents has emerged as the key pathway for bone tissue engineering in recent decades. Like various biopolymers, the utility of alginate, which is a polyionic-polysachharide comprising units of mannuronic acid and guluronic acid, has strengthened the field of next-generation polymer remodeling. The fabrication of calcium alginate bead based 3D implant made by the stacking of hexagonal closed pack (HCP) layers (Figure 3D(i)) in presence of glutaraldehyde crosslinker facilitated the spatiotemporal drug release in the artificial matrixes through the changes of the spatial coordinates of the drugs loaded layers. The supporting scaffold promoted the growth, progression and cytosketal reorganization of the osteoblast cells and triggered the expression of the alkaline phosphatase, runx2 and collagen type1 in human mesenchymal stem cells, attributed to the osteoconductive and osteogenic nature of the implant [26]. The in vivo assessment of the VEGF loaded implant was conducted in mice model and it revealed the regeneration of tissue with prominent existence of neovascularization as shown in Figure 3D(iii), due to cohesive interaction between supportive implant and native tissue environment. A recent report [27] demonstrated the formation of mechanically stable alginate-gelatin (ALG-GEL) hydrogels, resembling the comprehensive nonlinear and complex mechanical features of brain soft tissues. The rheology analysis also indicated that the stiffness of the hydrogel is solely dependent on the blending concentration and incubations times of the composites, assigning for the potential application in the fabrication of brain tissue supporting matrixes. Another report, where, (2, 2, 6, 6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl [TEMPO] oxidized cellulose nanofibre incorporated alginate scaffolds was investigated to enhance the biodegradability, sustainability and mechanically strengthened reactive surface area. The rheology study resulted in the recovery of 60% viscosity than that of native alginate scaffolds. The simulated body fluid (SBF) mediated mineralization evolved the nucleation of the hydroxyappetite into the hydrogel [28]. The combinatory efforts including direct writing 3D printing and freeze-drying techniques were carried out to develop the dual porous mechanically and dimensionally stable cellulose based 3D scaffolds. The dehydrothermal treatment displayed the increased surface hardness, indentation modulus and compression strength, should opened the new glimpse toward the decoration of bio-mimetic bone tissue engineering [29]. Furthermore, several studies have been conducted using cellulose or different derivatives to present an active tissue engineering tool and revealed the positive result in terms of cytocompatibility, biodegradability and flexibility of the scaffolds [30]. Similarly, Suneetha et al. [31] described the synthesis of mussel inspired polydopamine (PDA) filled sodium alginate (SA) − polyacrylamide (PDA − SA − PAM)-based hydrogel for skin tissue regeneration. The in situ synthesis process was conducted via two consecutive reaction steps. Initially, the dopamine molecules in the dopamine and sodium alginates blend was polymerized through alkali-induced polymerization and secondly, free radical polymerization technique was used to polymerize the acrylamide part in the processing of mechanically and biologically supporting adhesive hydrogel. The cytocompatibility assessment of the human skin fibroblasts (SFs) and keratinocytes (KTs) seeded PDA − SA − PAM-based hydrogel exhibited the higher cell adhesion, proliferation and spreading into the 3D microenvironment as compared PDA-free or 2D polystyrene plate and which is confirmed by fluorescence based live-dead assays or SEM morphology analysis as shown in Figure 4A(i&ii). In addition, the effect of PDA molecules on the platelet adhesion was evaluated by the processing of porcine whole blood and it showed the higher adhesion of the platelet on the hydrogel as shown in SEM images, attributing to the potential effect of PDA in the regulation of fibrous network and adhesion of bioactive molecules.
Figure 4.
(A) (i) Schematic Representation of the Formation of Adhesive Hydrogels for Tissue Engineering Applications. (ii) SEM images of cell attachment of SF and KT cells on hydrogels in different culture conditions (3 and 7 days). (iii) MTT assay cell proliferation of hydrogels for (a) SF and (b) KT. (iv) live/dead assay fluorescence images of SF and KT cells on hydrogels under 10× magnification (scale bar 200 μm) (*p < 0.05). [Ref: [31], reproduced with permission from publishing authority]. (B) Schematic presentation of Chitosan-Lysozyme Conjugates for Enzyme-Triggered Hydrogel Degradation in bone Tissue Engineering Applications. [Ref: [33], reproduced with permission from publishing authority]. (C) (i) SEM images of the cell seeded scaffold of pure CHT and its nanohybrid. Red arrow indicates the position of the cells. Scale bar = 60 μm; (ii) (a) X-ray photographs of rat femur bone defects of control (devoid of any material), CHT (filled with pure CHT scaffold), and CHT-L (filled with nanohybrid scaffold, CHT-L) after one day, four weeks and eight weeks of implantation. Blue and cyan arrows indicate osteocyte and osteoblast cell, respectively; (iii/a) H & E stained histopathological section of the rat femur bone defects after eight weeks of implantation, inset figure of each image indicates that the section were taken from that part (indicated by dotted red lines). Scale bars represent 100 μm; (iii/b) Histopathological section of connective tissue attached with the bone, stained using H & E. Scale bar is 100 μm. [Ref: [35], reproduced with permission from publishing authority].
Figure 5.
(A) (i) (a) 3D model of the designed octahedral type of scaffold with marked dimensions; (b) scaffold was loaded on the compression platform; (c) strain–stress curves; (d) elastic moduli for three groups of homogeneous scaffolds; (ii) (a-i) Fluorescent microscope images taken with a 4 × objective to show the 3 T3 fibroblasts distribution in the scaffold. (a-ii) Interaction of 3 T3 fibroblasts with the joint of scaffold. (b-i) optical and fluorescent microscope images taken with a 10× objective. (b-ii) Fibrous-like cell layer formed on the frame surface of scaffold. [Ref: [54], reproduced with permission from publishing authority]. (B) Interaction of A10 VSMCs with D-PHI porous scaffolds. SEM (a-h) and live-dead (i-viii) images of D-PHI-0 (a-d and i-iv) and D-PHI-5 (e-h and v-viii) porous scaffolds in the absence of cells and following a 3 day, 1 week, and 2 week culture period with A10 VSMCs at 0 μm depth (scaffold surface). Cell-free scaffolds (i and v) fluoresce red under the microscope. All SEM images were taken at 500 × original magnification. [Ref: [55], reproduced with permission from publishing authority].
3.1.5 Chitosan as base material and its derivatives
Chitosan, a polysaccharide with various functional groups has increased tremendous interest in biomedical applications such as tissue engineering. But, major problems due to poor solubility and biodegradability limit its monopoly use in the processing of cell supporting materials. This is avoided by the stacking or modifying with various synthetic or natural biomaterials. In a report, Li et al. developed the oxidized alginate hydrogel crosslinked with N, O-carboxymethyl chitosan with moderate swelling, degradation and porosity. The chitosan modified alginate scaffold revealed improved biocompatibility, as the number of free aldehyde groups in the oxidized alginate is reduced after crosslinking [32].
In another report [33], the methacrylated chitosan molecules were conjugated with lysozyme (an endo-carbohydrase) via riboflavin initiated photo-cross-linking to a constructed biodegradable and biocompatible hydrogel. The in vitro biodegradation study of the hydrogel revealed the increase of the pore size and larger fraction of outliers in cryo-SEM micrographs. Further, the mouse bone marrow stromal cell line (BMSC) loaded hydrogel exhibited the adhesion, proliferation and spreading of BMSCs with the expression of the osteogenic-specific markers throughout various layers of hydrogel as compared to chitosan based hydrogel. This may be attributed to the lysozyme mediated breaking of chitosan chains, thereby helping the penetration of cells through the disintegrated hydrogel networks. Also, as shown in Figure 4B, the in vivo bone regeneration experiment demonstrated the significant recovery of the defected bone with new bone tissues after six weeks of hydrogel post-implantation in a nude mice model with the recruitment of cells to the damaged zone. Similarly, the mechanically stable and tunable porous graphene oxide incorporated alginate-chitosan-collagen (GO/SA-CS-Col) based composite scaffolds was fabricated via Ca2+ mediated crosslinking and freeze-drying techniques. The composition and surface morphology were confirmed by FTIR, Raman spectra, SEM and XRD analysis. In vitro study of the osteoblast cell encapsulated scaffold revealed the adhesion, proliferation of the cells and osteogenic differentiation [34]. In an approach, the sulfonated graphene oxide functionalized chitosan based hybrid scaffold was prepared and FTIR, SEM, TEM and XRD analysis confirmed the synthesis of the interconnected porous chitosan/GO nanohybrid scaffolds [35]. The in vitro drug release assay at phosphate buffer solution at 37°C exhibited the sustained release of the drug molecules, may be due to the noncovalent interaction between drug and composites that triggering the slow diffusion of the drug molecules. The hybrid scaffold also revealed the high cell growth and spreading into the deep part of porous scaffold as compared to GO-free chitosan scaffold which was observed by fluorescence and SEM analysis as shown in Figure 4C(i). Further, the in vivo experiment using cell laden scaffold in rat model was investigated and the 75 days of post-implantation result demonstrated the faster healing of the defected area with significant proliferation of the osteoblast cells as compared to pure chitosan scaffold (see in Figure 4C(ii)). Intertestingly, Zao et al., developed a glucono δ-lactone (GDL) incorporated and carboxymethyl chitosan (CMCh) stabilized calcium phosphate (ACP) (designated as CMCh-ACP hydrogel) bioactive hydrogel using freeze-drying process for mesenchymal stem cells [MSCs] based bone regeneration [36]. FTIR analysis exhibited the characteristics peaks at 1064and 547 cm−1 due to the presence of phosphate (PO43−) group of spherical particles with average size of 80 nm. Next, the cytocompatability of the MCSs laden (iMAD cell line) CMCh-ACP hydrogel revealed the time dependent increase of cell density with negligible apoptotic cell morphology as in Hoechst 33258 stained, indicating the biocompatibility of the hydrogel for long-term cell friendly growth microenvironment. Like, in vitro assays, the in vivo bone regeneration experiment in presence of BMP9-(potent bone-forming factor) induced iMAD cells/CMCh-ACP hydrogel demonstrated the efficient new bone formation with the extensive vascularisation on the surface of the masses, attributing to the upregulation osteogenic-specific biomarkers and regulars, thereby enabling the BMP9 induced osteogenesis. In our several works, we demonstrated the modification of chitosan with different biomaterials such as montmorillonite clay (OMMT), hydroxyapatite, poly (ethylene glycol), polymethylmethacrylate-co-2-hydroxyethyl-methacrylate and polyvinyl alcohol. The formulated porous scaffolds were made with improved mechanical, antibacterial and biocompatible for application in bone tissue engineering [37, 38, 39, 40].
3.1.6 Polyhydroxyalkanoates (PHA) as base material and its derivatives
Unlike different biomaterials, polyhydroxyalkanoates (PHA) are the class of biodegradable biopolymer extracted by the harvesting of microbial cells. Despite the cost-effective synthesis and ease of processing, the hydrophobicity, brittleness and lack of antibacterial limits it random uses in biomedical applications such drug delivery, surgical suture and supporting matrices for tissue regenerations. Efforts are being made to improve its biocompatibility, mechanical strength and antimicrobial properties by blending or modifying the surface with bioactive and high-strength nanomaterials. One approach was used to develop the biocompatible collagen-immobilized porous 3D scaffold based on poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [collagen/PHBV], which allows better growth and proliferation of the rat osteogenic cell line (UMR-106 cell line) than native PHBV scaffold [41]. A similar trend was also observed when hydroxyappetite was further incorporated into the collagen grafted PHBV composite. The modified scaffolds revealed better adhesion and growth of osteoblast cells [42]. In another study, a hyaluronic acid immobilized chitosan-grafted porous PHA membrane was fabricated and it exhibited better protein adsorption and improved adhesion and proliferation of L929 fibroblasts. The supportive matrix also showed excellent antibacterial activity against several bacterial strains [43]. The mechanically and biocompatibility challenged porous PHH-mixed PHB [PHBHHs] scaffolds showed significant growth and proliferation of chondrocytes isolated from rabbit articular cartilage (RAC) as compared to only PBHs or PHB scaffolds. With the increase of the PHBHH content in the mixture, both the mechanical and the cell compatibility increased dramatically, they have a potential impetus in tissue engineering applications [44]. Recently, a group of researchers has potentially formulated the carbonaceous or conductive nonmaterial such as polyaniline, graphane oxide modified PHA based 3D porous scaffolds for tissue engineering applications. The antimicrobial and cell-stimulated active 3D constructs not only improved cell attachment, proliferation, but migratory behaviors were observed through interconnected porous networks. The magnetically active MRI scaffolds have tissue engineering applications controlled by significant bioimaging [45, 46, 47].
3.1.7 Silk as base material and its derivatives
Silk is a naturally occurring fibrous protein with biodegradability, biocompatibility, and mechanical durability that has utility in tissue engineering applications. In one study, silk fibroin-grafted polycaprolactone nanofibers were able to deliver dual growth factors such as bone morphogenetic protein-2 (BMP-2), transforming growth factor-beta (TGF-β), in the regeneration of bone tissue [48]. Li et al. also presented a similar type of biocompatibility while a PCL/silk 3D bioprinting scaffold was imposed to regenerate the meniscus tissue [49]. The computer-assisted 3D printed silk matrices have attracted significant attention and found to be improved the cell–cell and cell-matrix interaction and enable their activity in patient specific tissue architecture [50]. Similarly, the gelatin-silk composite was subjected to the fabrication of 3D bioprinting for cartilage tissue engineering in rabbit model [51].
The novel development of 4D printing hydrogel has gained significant attention in next generation biofabrication. The fabrication of 4D printing from 3D printing hydrogel was regulated by the modulation their interior or exterior properties with the proper controlled of expansion rate of the hydrogel in distilled water and salt water. The biocompatibility of assessment of the 4 D printing hydrogel was conducted in culture medium by shape change method as mentioned earlier. The results revealed the adhesion and growth of the PKH127 (green)-labeled human chondrocyte (hTBSCs) along with the deposition of cartilage extracellular matrix in the side of the construct. To verify the clinical applicability of the construct, the rabbit TBSC and chondrocytes-laden artificial 4D construct was implanted into the site of the rabbit trachea and the results of 8 weeks post-implantation revealed the regeneration of the respiratory epithelial layer and formation of neocartilage around the perichondrium. This findings proved the potential application of the cell laden 4D hydrogel in the recovery of respiratory organ, trachea regeneration [52]. A very recently, the approach of development of electrical simulation modulated polypyrrole/silk fibroin (PPy/SF) based conductive composite scaffold has been opened up the new avenue in the neuronal tissue regeneration [53]. The 3D printing electrospining method was used to fabricate for the alignment of silk fibrous, followed by the coating of polypyrrole (a mechanically stable conductive material) to get the desired silk fibroin (PPy/SF) composite scaffold as nerve guidance conduits (NGCs). Morphological tracking by SEM analysis exhibited the core-shell structure having interpenetrating PPy fibers on the smooth SF nanofibers with average diameter of 0.427 ± 0.083 μm. Resultant physicochemical properties such as mechanical stability (0.059 MPa) and conductivity (0.11446 ± 0.00145 mS/mm) of composite were comparable to ideal working in NGCs system, indicating the increase of mechanical property of the conduit by the coating of PPy. The ES controlled cell compatibility of the NGCs was evaluated with the seeding of Schwann cells (SCs) and it showed the significant growth, proliferation and migration of the cells with the expression of neurotrophic factors. Further, to investigate the effect of artificial NGCs on in vivo nerve tissue regeneration, the composite was implanted in defected sciatic nerve of rat and monitored for six months under ES regulation. Histochemical and microscopic analysis revealed the densely regenerated myelinated fibers and mylinated axon dispersed in the fibrous networks that promoted the regeneration of the pheripheral injured nerve. Since, the cellular activities in nervous system are regulated by the expression of various neurotrophic factors (BDNF and NT-4/5) and signaling pathways. The ES modulation may activate the MAPK in the cell microenvironment and promoted the growth of the axon, correlated with nerve regeneration. Therefore, although several reports have been undergone using silk for the construction of different tissue architectures but intensive research must be conducted to find potential validity in clinical trials.
3.1.8 Different synthetic materials and their combination
The synthetic materials based 3D hydrogel have also shown to mimic the native tissue stiffness while the optimum conditions for the 3D constructions are digitally controlled. The digital light processing (DLP) based printed poly(ethylene glycol)diacrylate (PEGDA) hydrogels exhibited nearly 60% of enhanced elastic modulus, suited for the support of 3 T3 cells adhesion and proliferation as shown in Figure 5A [54]. In one study, degradable, polar hydrophobic and ionic porous polyurethane scaffolds were synthesized using a lysine-based crosslinker. The scaffolds demonstrated (see Figure 5B) the comprehensive mechanical, swelling and biocompatible properties that support the adhesion and growth of muscle cells in vascular tissue engineering [55]. Apsite et al., reported the design and fabrication of polycaprolactone and poly(N-isopropylacrylamide) based multilayerd porous electrospun mats. The self-folding 4D bio-fabrication was found to act as good cells adhesion and viability, assigning as a new perspective in new generation tissue engineering [56]. In a paper, Kutikov explained how the integration of hydrophilic polyethylene glycol into hydrophobic polyester block copolymers changes the physicochemical properties of 3D matrices. The incorporation also demonstrated the different types of cell adhesion, growth, and tissue regeneration both in vitro and in vivo experiment [57]. Therefore, the deviations in the fabrication of 3D artificial support matrices using natural biopolymer or synthetic materials individually must be compensated by the chemistry of piling or surface modification to increase any physical properties that would satisfactory fill the gaps to improve the clinical applications.
4. Effect of growth factors on cell-matrix interaction
Enormous studies have been thoroughly investigated on the interaction between cellular and bio-mimetic 3D matrices in vitro and in vivo tissue generation experiments that demonstrated the phenomena of adhesion, growth and differentiation of different cells. But, most of the study doesn’t meet the pre-requisite for the successful clinical application due to the insufficient secretion of protein molecules that responsible for the biological and biochemical signaling between cell–cell and cell matrix cross-talk. The prominent small proteins that induce cell growth, proliferation, differentiation and regulate angiogenesis are encoded as growth factors. The emergence of versatility of different growth factors related to the reported mediated repair of damaged tissue tends to fall into various categories based on their functionality in tissue engineering. EGFs, NGFs, IGF, FGFs, PDGFs, interleukins etc. are the class of growth factors mainly disclosed for the cell–cell medicated trafficking of proliferation and actin-cytoskeleton in living tissue regeneration process.
Mechanically, the function of growth factors is to drive progenitor cells to its damaged target tissues by extracellularly mediated signaling pathways. In fact, therapeutic molecules bind to the cell surface transmembrane receptor and then to the internalized receptor-protein complex through phosphorylation-mediated signal transduction that triggers down-regulation of cells, followed by reduction of overwhelming responses and stimulation at the cellular level to carry out biological functions. Furthermore, the non-diffusible method leads to the binding of growth factor to the cell surface without any major internalization or downregulation in the results of long-term biological activities, as shown in Figure 6A(i&ii) [58]. Mimicking the in vivo tissue environment, various approaches have been implicated using growth factors loaded 3D biocomposite for sustained release without any dysfunction of the protein molecules. Bone morphogenesis protein-2 and 7 (BMP-2 & BMP-7) are the part of transforming growth factors enable the proliferation and osteogenic differentiation of bone marrow derived mesenchymal stem cells. The removal of bio-signaling molecules has demonstrated the deregulation of cell proliferation, differentiation and alteration of bone tissue formation [59, 60]. Co-administration of TGF-b3 and BMP-2 via alginate-based scaffolds revealed a tendency for increased osteogenesis in in vivo bone formation tests. A similar type of output has been observed while TGF-1 and IGF-1 are used simultaneously for bone tissue engineering [61, 62]. In a study, Kim et al., demonstrated that the inhibition of epithelial growth factor predominantly affects the cell–cell and contact based cell proliferation. In addition, over-expression of cadhreine, a transmembrane-type cell surface protein limited cell-to-cell contact with the arrest of cell cycle, resulted in spatial cell rearrangement tuned to tumor formation. Therefore, the epithelial growth factor plays an active function towards the formation of epithelial cells in tissue engineering [63].
Figure 6.
(A) (i) Modes of action of growth factors. Growth factors interact with their receptors in a diffusible manner (e.g., by endocrine, paracrine, autocrine and intracrine pathways) or in a non-diffusible manner (e.g., by juxtacrine and matricrine pathways). Some growth factors are known to act in both ways. (A) (ii) Three main factors in tissue engineering: cells, growth factors and matrices (scaffolds). The conjugation of growth factors and matrices provides a new approach for generating biofunctional substrates for regenerative medicine [Ref-58, reproduced with the permission from publishing authority]. (B) (i/a): Schematic representation of proposed mechanisms for enhanced bone regeneration in vivo. (i/b): Optical images of retrieved specimens from representative critical-sized bone defects at 4 and 8 weeks. (i/c) Micro-CT analysis. (i/d) Quantitative analysis of bone regeneration. (i/e) Fibrous tissue thickness at the defect site at 4 and 8 weeks (*P < 0.05; **P < 0.01; ***P < 0.001). [Ref. [66], adapted with permission from publishing authority].
It has been a challenge to meet the need to develop a bio-mimetic tool for vascular tissue engineering. In contrast to various soft tissues, vascular tissue controls the supply of oxygen, essential cellular nutrients, the transport of waste products and stem cells as well as progenitor cells. Therefore, it is urgent to reconstruct the network of the neovascularization process with the initiation of adhesion, growth and differentiation of cells as a native tissue environment in artificial tissue engineering. Cao et al. demonstrated the therapeutic approaches of growth factors and their signal cascade that control neovascularization and the formation of neovessels using the spatiotemporally controlled 3D construct both in vitro and in vivo pathways. The literature also explained how vascular epithelial growth factor (VEGF) plays a critical role in vasculogenesis in stages of embryonic development from pre-existing blood vessels through consecutive signaling pathways [64, 65]. The multifunctional triple layered chitosan/poly (gamma-glutamic acid)/hydroxyapatite (CPH) hydrogels was formulated to regulate the release of platelet-rich fibrion (PRF) which was extracted from rat abdominal arota, into the site of damaged bone tissues. The PRF entrapped composite hydrogel was prepared through noncovalent electrostatic interaction and lyophilization technique to promote the osteoconductive mediated new bone tissue formation. The PRF entrapped composite hydrogel was prepared through noncovalent electrostatic interaction and lyophilization technique to promote the osteoconductive process in the formation of new bone. PRF is a combination of different growth factors such as TGF-β, PDGF, and IGF that have an abiity to induce the mineralization and the upregulation of various osteogenetic biomarkers in order to activate the osteoblast as seen in vitro and in vivo experiments. As a part of ‘in vivo’ tissue regeneration study, rat calvarial defect models demonstrated the superior healing of the calvarial defect after 8 weeks post implantation period in presence of PRF/CPH composite than that of control experiment (see Figure 6B) [66]. In summary, the combined growth factors entrapped 3D supporting matrixes would bring a new avenue towards the cell–cell cross-talk mediated tissue generation with the advancement of bio-mimetic tools in finding the arrays of the artificial tissue engineering in the future.
5. Conclusions
Understanding the mechanism and basic criteria in the process of tissue regeneration has unveiled the secret of the communication involved in cell–cell, cell-matrix interaction that enables healing in an artificial tissue environment such as native tissue repair processes. In fact, the biocompatibility of any fabricated 3D architecture plays an important role in adhesion, proliferation, migration, and differentiation of the cells of interest to biologically mimic the signaling cascade that triggers cellular activities. Several investigations have shown that 3D constructs comprising naturally extracted and synthetic materials having a porous and mechanically stable geometry promoted integrin ligand-mediated differentiation and tailored actin-cytoskeletal cell morphology in a better way. The studies also explained how the biological and biochemical performances of cells are influenced by the different growth factors mediated signaling pathways and the active function of the ECM components. Therefore, present review provided the core thinking behind the physicochemical features of supporting matrixes that significantly control the cell–cell and cell-matrix interaction towards the implementation of clinically approved artificial 3D biocomposite for the successful clinical tissue engineering applications.
Acknowledgments
Dr. Nilkamal Pramanik and Dr. Tanmay Rath acknowledge UGC, DST, SERB- DST (NPDF), Govt. of India, for their financial supports. Dr. Nilkamal Pramanik also gratefully acknowledges Dr. Tanmay Rath, Prof. Patit Paban Kundu (Department of Polymer Science and Technology) and Dr. Ranjan Kumar Basu (Department of Chemical Engineering), University of Calcutta for their kind guidance to carry the biomaterials based tissue engineering works.
Conflict of interest
No conflict of interest is a declaration.
Acronyms and abbreviations
TE
Tissue Engineering
ECM
Extracellular matrixes
EGFs
Epithelial growth factors
PDGFs
Platelet derived growth factors
IGFs
Insulin like growth factors
HCGFs
Hematopoietic cell growth factors
AT-MSCs
Adipose tissue-derived mesenchymal stem cells
GelMA
Gelatin methacrylate
PEGDA
Poly (ethylene glycol) diacrylate
HCP
Hexagonal closed pack
TEMPO
(2, 2, 6, 6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl
SBF
Simulated body fluid
hBMSCs
Human bone marrow derived mesenchymal stem cells
OMMT
Montmorillonite clay
HA
Hyaluronic acid
IPN
Interpenetrating network based
BMP-2
Bone morphogenetic protein-2
PEGDA
Poly(ethylene glycol)diacrylate
VEGF
Vascular epithelial growth factor
\n',keywords:"biomaterials, biocompatibility, extracellular matrix, therapeutic molecules, regenerative medicine",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74302.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74302.xml",downloadPdfUrl:"/chapter/pdf-download/74302",previewPdfUrl:"/chapter/pdf-preview/74302",totalDownloads:128,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:0,impactScoreQuartile:0,hasAltmetrics:0,dateSubmitted:"September 20th 2020",dateReviewed:"November 4th 2020",datePrePublished:null,datePublished:"November 24th 2021",dateFinished:"December 3rd 2020",readingETA:"0",abstract:"Impairment of the clinical tissue-implantation is due to the lack of a suitable organ donor and immunogenic rejection, which leads to the cause for the enormous loss of human life. The introduction of artificial regeneration of tissues by Langer and Vacanti in 1993, has revolutionized in the field of surgical organ transplantation, to alleviate the problem of tissue injury-related death. There is no doubt that the term “regenerative medicine” to open a new space of tissue reconstruction, but the complications that arise due to the proper machinery of the cell, supporting biomaterials and growth factors has yet to be resolved to expand its application in a versatile manner. The chapter would provide a significant overview of the artificial tissue regeneration while a triangular relationship between cells, matrixes, and growth factors should be established mentioning the necessity of biomedical tools as an alternative to organ transplantation.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74302",risUrl:"/chapter/ris/74302",book:{id:"10301",slug:"biomechanics-and-functional-tissue-engineering"},signatures:"Nilkamal Pramanik and Tanmoy Rath",authors:[{id:"187357",title:"Dr.",name:"Tanmoy",middleName:null,surname:"Rath",fullName:"Tanmoy Rath",slug:"tanmoy-rath",email:"tanmayrath@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Central Institute of Plastics Engineering and Technology",institutionURL:null,country:{name:"India"}}},{id:"327038",title:"Dr.",name:"Nilkamal",middleName:null,surname:"Pramanik",fullName:"Nilkamal Pramanik",slug:"nilkamal-pramanik",email:"nilkamal.can@rediffmail.com",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. Why is the 3D construct in tissue regeneration (TE)?",level:"1"},{id:"sec_3",title:"3. Choice of material in artificial supporting matrixes",level:"1"},{id:"sec_3_2",title:"3.1 Impact of naturally sourced biomaterials on cell-cell cross-talk",level:"2"},{id:"sec_3_3",title:"3.1.1 Collagen as base material and its derivatives",level:"3"},{id:"sec_4_3",title:"3.1.2 Hyaluronic acid as base material and its derivatives",level:"3"},{id:"sec_5_3",title:"3.1.3 Gelatin as base material and its derivatives",level:"3"},{id:"sec_6_3",title:"3.1.4 Sodium alginate as base material and its derivatives",level:"3"},{id:"sec_7_3",title:"3.1.5 Chitosan as base material and its derivatives",level:"3"},{id:"sec_8_3",title:"3.1.6 Polyhydroxyalkanoates (PHA) as base material and its derivatives",level:"3"},{id:"sec_9_3",title:"3.1.7 Silk as base material and its derivatives",level:"3"},{id:"sec_10_3",title:"3.1.8 Different synthetic materials and their combination",level:"3"},{id:"sec_13",title:"4. Effect of growth factors on cell-matrix interaction",level:"1"},{id:"sec_14",title:"5. 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Centre for BioSystems Science and Engineering, Indian Institute of Science, India
Cardiovascular disease is the leading cause of death in men and women in the United States and throughout the world [1]. Current efforts are focused on decreasing the burden of death due to atherosclerosis and cardiac disease overall. Increased attention has been placed on the activation of the renin-angiotensin-aldosterone system (RAAS) and pathogenetic mechanisms in cardiovascular disease. The RAAS system effects blood pressure control and electrolyte and fluid balance and therefore plays a significant role in cardiovascular hemodynamics [2, 3, 4].
Classically, it is known that angiotensinogen is cleaved by renin to form angiotensin-I (Ang I), which is then converted to angiotensin-II (Ang II) by angiotensin converting enzyme (ACE), however other peptides and products of this axis have been shown to play a role in the development of cardiovascular disease [3, 4]. It is thought that two of these products (angiotensin 1-7 and angiotensin 1-9) may have counterregulatory effects on the development of atherosclerosis and cardiovascular disease [4]. Although the role of angiotensin II is understood more clearly, these peptides provide other targets by which the RAAS system can be utilized to prevent atherosclerosis.
Overactivation or pathologic activation of the RAAS system, specifically angiotensin II, has been shown to play a specific role in endothelial dysfunction, inflammation, intense vasoconstriction, increased vascular and cardiac hypertrophy, fibrosis and the development of atherosclerosis [2, 3, 4, 5]. Multiple large investigations have shown that direct inhibition of the effects of angiotensin II via angiotensin converting enzyme inhibitors (ACE-I) and angiotensin-receptor blockers (ARB) improve mortality, prevent renal disease and decrease cardiovascular events in this subset of patients. Additionally, some studies have shown that utilization of both ARB and ACE-I may have cumulative effects on inhibiting the adverse effects of an overactivated RAAS system [6, 7].
We aim to highlight the known role of the activated RAAS and provide an updated description of the mechanisms by which overactivation of RAAS promotes disease and provide a summary of the clinical implications of RAAS inhibition in cardiovascular disease.
2. Overview of the RAAS system
The RAAS system has several moving parts, with different organ systems stimulating its activation and suppression. Renin, the active form of prorenin, is secreted by the granular cells of the kidney. Although renin’s role is that of an enzyme, its means of expression are more hormonal. Renin’s production is stimulated by hypotension, hyponatremia, and decreased sympathetic activity. Renin is responsible for cleaving angiotensinogen, a protein produced in the liver. Angiotensinogen is regulated via thyroid hormone, steroids, and levels of circulating angiotensin II. Angiotensinogen is cleaved into angiotensin I, which is further converted into angiotensin II by angiotensin converting enzyme [3, 4].
RAAS key players are composed of renin, angiotensin I & II, and angiotensin converting enzyme located in the heart atria, conduction system, valves, ventricles, coronary vessels, fibroblasts and myocytes [8, 9]. Ang II is the effector hormone playing a pivotal role in the cardiac RAAS and has a widespread effect throughout the body, targeting different mechanisms of action.
Ang II acts via the angiotensin receptors mediating the following actions [9, 10]:
Cardiovascular system - vasoconstriction, increased blood pressure, increased cardiac contractility, vascular and cardiac hypertrophy
Renal system - tubular sodium reabsorption, inhibition of renin release
Sympathetic nervous system stimulation
Aldosterone synthesis through adrenal cortex
Cell growth and proliferation, inflammatory response, and oxidative stress.
Angiotensin converting enzyme 2 (ACE 2) is involved in the degradation of Ang II to Ang (1-7) and Ang (1-9), which provide a relative vasodilatory effect as outlined in Figure 1. ACE 2 is restricted to vascular endothelial cells, arterial smooth muscle cells, myofibroblasts, carotid arteries and renal tubular epithelium [8, 9, 10]. The effects of Ang II, Ang (1-7) and Ang (1-9) have been uncovered in the past several years, specifically their role in hypertension, endothelial damage, and cardiovascular disease [5, 6, 9, 12]. The role of Ang (1-7) and Ang (1-9) is further outlined in Figure 1 as they pertain to the pathophysiologic changes in the cardiovascular system.
Figure 1.
Schematic of the RAAS as it pertains to angiotensin II and angiotensin (1-7) (Ang-(1-7)) and their counter-regulatory effects via angiotensin receptors 1 and 2 (AT1-R and AT2-R respectively) and MAS receptor (MAS) [5, 6, 11]. Abbreviations: ACE-I (angiotensin converting enzyme inhibitor), ARB (Angiotensin-II receptor blocker), Ang (1-9) (angiotensin 1-9), ACE (angiotensin converting enzyme).
3. Pathogenic insights
3.1 Atherosclerosis and endothelial dysfunction
Endothelial dysfunction is thought to be a precursor to atherosclerosis, or the thickening and stiffness of vessels. This damage often cultivates in an atherosclerotic plaque, which is a fibrin and cholesterol contained structure that deposits on the inner lumen of blood vessels and can impede oxygen delivery to tissues and organs. Endothelial damage and inflammation allow for the migration of monocytes and macrophages to the site of injury and the formation of foam cells [13, 14, 15]. Additionally, stimulation of inflammatory mediators also promotes smooth muscle cell (SMC) thickening, stiffness of vessels and forms a fibrous cap on the atherosclerotic plaque (Figure 2) [16]. The pathophysiology of plaque development is very closely tied to RAAS as Ang II plays a key role in these pathophysiologic changes.
Figure 2.
A schematic depicting the dynamic changes involved in the formation of an atherosclerotic plaque [16]. Abbreviations: ROS, reactive oxygen species; ICAM-1, intracellular adhesion molecule 1; IFN-c, interferon-gamma; IL, interleukin; LDL, low-density lipoprotein; M-CSF, macrophage colony-stimulating factor; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; oxLDL, oxidized LDL; SR-A, scavenger receptor A; TGF-b, transforming growth factor beta; VCAM-1, vascular adhesion molecule 1; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cells. Reproduced with permission from Mary Ann Liebert, Inc.
Ang II acts on the AT1 and AT2 receptors (AT1-R and AT2-R) causing arteriolar vasoconstriction, and inflammation through generation of reactive oxygen species (ROS), proinflammatory transcription factors such as nuclear factor kB (nf-kB), and the proliferation of smooth muscle cells contributing to atherogenesis [17, 18]. Activated nf-kB increases inflammatory mediators including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and platelet derived growth factor (PDGF), all of which mediate inflammation, endothelial damage and monocyte migration and adhesion leading to fibrosis [6, 18].
Ang II induces NF-kappaB (NF-kB) and inflammation through its binding to AT1-R. This has been demonstrated extensively as AT1-R blockers have shown to significantly decrease inflammation. Induction of NF-kB leads to the expression of pro-inflammatory cytokines such as IL-6 and TNF-alpha [19, 20]. Additionally, IL-6 itself can activate AT1-R resulting in overexpression and production of reactive oxidative species (ROS) when RAAS is overstimulated [19]. The RAAS is also a potent oxidant stimulator, as it activates the NADH/NADPH oxidase signaling pathway, and thereby produces superoxide anions and other ROS. TNF-alpha impairs endothelial nitric oxide (NO) production in coronary arteries thereby causing vasoconstriction. Additionally, ACE plays a role in the degradation of bradykinin, which depletes NO formation as well [6, 18, 19, 20]. Overall, we have a RAAS mediated expression of ROS, inflammatory mediators, and depletion of vasodilatory NO.
This inflammation mediated cellular injury and production of ROS, activates the endothelium and increases expression of intercellular adhesion molecules (ICAM-1) and vascular cell adhesion molecules (VCAM-1), which promote endothelial damage and make cells leaky [9, 21, 22]. The endothelial damage promotes further migration of leukocytes, production of inflammatory cytokines and chemokines.
Finally, RAAS promotes thrombosis through Ang II receptors located on human platelets. Through these receptors Ang II promotes the release of thromboxane A2 and platelet derived growth factor, which promote atherosclerotic plaque formation and thrombus formation [22, 23]. Ang II involvement in endothelial dysfunction and atherosclerotic plaque formation is summarized in Figure 3.
Figure 3.
Summarized effects of Ang II as it is known to cause endothelial damage, inflammation, migration and adhesion of monocytes, proliferation of vasculature and platelets and formation of atherosclerotic plaque and thrombus [6, 18, 19, 20, 21, 22, 23].
4. Hypertension
Hypertension, defined as a systolic blood pressure greater than 120 and diastolic pressure greater than 80, affects a quarter of the world’s population. When the etiology of hypertension is unknown, it is termed essential hypertension. When the cause of hypertension is known, by way of underlying metabolic, hormonal, neurogenic, or cardiovascular dysfunction, it is deemed as secondary hypertension [24]. As we have reviewed thus far, RAAS is responsible for maintaining sodium concentration in the blood, fluid status, and hemodynamic stability and therefore has a significant effect on blood pressure. Overactivation of RAAS can perpetuate unwanted elevations in blood pressure.
Increased levels of Ang II and subsequently aldosterone cause increases in vascular tone and hypertension. Aldosterone, a mineralocorticoid, takes its effect by binding to mineralocorticoid receptors (MR) and translocating into nucleus. Here, it integrates with cellular DNA and induces transcription of genes that regulate electrolytes and fluid balance. An over expression of aldosterone causes an elevated aldosterone-renin ratio which leads to systemic complications [4].
Patient’s with primary aldosteronism (PA) and increased aldosterone levels are at higher risk for cerebrovascular complications. Although PA is not a common diagnosis, fifteen percent of patients with essential hypertension have higher than normal levels of circulating aldosterone. We can conclude that this sub-set of essential hypertension patients will have similar end-organ effects of elevated aldosterone as do patients with PA [4].
Hypertension itself can cause endovascular injury, which leads to increased production of ROS and inflammatory mediators ultimately contributing to atherosclerosis [25, 26]. The result of such endothelial injury is worsening cardiovascular disease, hypertension, and renal dysfunction. We see this manifest in the kidney with proteinuria and collagen deposition. Eventually, healthy kidney parenchyma is replaced with fibrotic tissue, leading to even more dysregulation with blood pressure homeostasis. In the cardiovascular system, inflammatory damage from overactivation of RAAS and hypertension causes calcifications and fibrosis. As such, inhibition of the RAAS system with ACE-I and ARB has become a cornerstone in therapy for hypertensive patients, particularly those with evidence of diabetes, microalbuminuria and in CAD patients overall [15, 25, 26, 27, 28]. The details of some of the landmark clinical trials contributing to the guidelines in treatment with ACE-I and ARB are further discussed in this chapter.
5. Ischemic heart disease
Coronary artery disease (CAD) or Ischemic heart disease (IHD), develops when there is a limitation of blood flow within the coronaries. It occurs due to the gradual buildup of atherosclerotic plaque within the wall of arteries leading to reduced oxygen delivery to cardiac myocytes. It comprises a clinical spectrum based on the degree of luminal narrowing and the activation of the atherosclerotic plaque [13, 14]. The RAAS plays a vital role in the pathogenesis of CAD. Evidence supports that RAAS controls atherosclerosis through intracellular signaling pathways by mediating endothelial function, inflammation, fibrinolytic balance, growth, lipid-glucose metabolism, and its vasoconstrictor function.
Ang II has growth promoting effects by regulating growth of vascular smooth muscle cells and activating the growth associated kinase pathways. In states of ischemia, there is increased vascular endothelial growth factor (VEGF) expression. In vascular smooth muscle cells, transforming growth factor B1, platelet derived growth factor causes fibrosis and cellular hypertrophy. These angiogenic factors lead to the formation of new cells, fibrin, and collagen deposition leading to growth of the plaque and thickening of vessels [20, 21].
RAAS plays a role in altering the fibrinolytic balance as well by inhibiting fibrinolysis and enhancing thrombosis. Within the vessels, Ang II stimulates the release of plasminogen activator inhibitor - I (PAI-I) thereby reducing the fibrinolytic activity. It activates tissue factor which acts as a cofactor for factor VII, potentiating the coagulation cascade [22, 23]. The above mechanism increases the thrombogenic activity.
Ang II overexpression causes endothelial inflammation and activation of cytokine cascade thereby causing progression of atherosclerotic plaque. The silent plaque ruptures when the inflammation overwhelms the stable fibrous cap causing thrombosis and acute ischemia [13, 14].
6. Heart failure
Heart failure is a clinical syndrome categorized based on clinical signs and symptoms and further subclassified by echocardiography findings. As per the American College of Cardiology, left ventricular ejection fraction (LVEF) of ≥50% is defined as heart failure with preserved ejection fraction (HFpEF), LVEF 41-49% as heart failure with mid-range ejection fraction (HFmrEF), LVEF≤40% as heart failure with reduced ejection fraction (HFrEF). HFrEF particularly occurs after an inciting event like myocardial injury, arrhythmias, cardiomyopathies, substance abuse, infections or genetic diseases which put the heart in a state of stress leading to contractile dysfunction and cellular remodeling [29]. The circulatory changes arising from heart failure are sensed by the peripheral baroreceptors and chemoreceptors, thereby activating a sequalae of compensatory neurohormonal mechanisms. The compensatory mechanisms include activation of sympathetic nervous system (SNS) and RAAS. RAAS plays an integral role in cardiac contractility, homeostatic control of blood pressure and electrolyte-fluid balance [30, 31].
In an adult with normal circulation, the baroreceptors located in the carotid sinus and aortic arch balance the sympathetic and parasympathetic outflow from the central nervous system. Alterations in the cardiac output change the effective arterial blood volume resulting in inhibition of parasympathetic response and a reflux increase in the sympathetic vascular tone. The increased sympathetic activity leads to vasoconstriction of the renal afferent arteriole and decreases blood flow to the kidney [29, 32]. This activates renin secretion and thereby RAAS.
Renin is secreted in response to 4 main stimuli [10, 33]:
Decreased renal perfusion pressure sensed by baroreceptor cells in the arterial vessel wall
Sympathetic nerve stimulation via beta-1 adrenergic receptors
Negative feedback by a direct action of Ang II
The pathophysiology of heart failure allows for decreased renal perfusion and increased sympathetic response, both of which cause an overactivation of the RAAS [34]. The overstimulation of RAAS in heart failure is further depicted in Figure 4.
Figure 4.
The regulatory effects of RAAS as it pertains to heart failure mechanics [34]. Reproduced with permission from McGraw Hill LLC.
In pathological states like pressure or volume overload, cardiac tissues exhibit elevated levels of renin and Ang II levels leading to cardiac hypertrophy, myocardial fibrosis, hypertensive heart disease and chronic heart failure through mechanics explained earlier. Additionally, post-infarction levels of ACE-2 have been shown to be elevated, which may explain a counter-regulatory mechanism to protect against the Ang-II mediated myocardial damage. When this natural counter-regulatory mechanism is lost in ACE-2 knockout animal models the levels of dilated cardiomyopathy were much more pronounced. Several trials have also looked at specific levels of plasma renin and HFrEF and have found that those with elevated levels had an associated worse outcome than their counterparts. In patients with advanced heart failure, baseline levels of plasma renin and plasma aldosterone are persistently high, which further exemplifies the role of RAAS in cardiac remodeling and heart failure [35, 36, 37].
Innovative studies have discovered that a particular breakdown product of Ang 1-7, also known as Alamandine, has shown to prevent ventricular and vascular remodeling in animal models [11]. Studies of by-products offer areas of potential research as we grow to understand the intricacies of the molecular pathways that play a role in the development of heart failure.
7. Clinical implications
The overactivation of RAAS and its effects on the pathophysiology of hypertension, vascular stiffness, ischemia, thrombosis, and left ventricular (LV) remodeling has been well documented. As such, several medications that impede the harmful effects of the overactivation of RAAS have been shown to prevent the negative clinical outcomes. Here we review some of the landmark clinical trials that have contributed to the current guidelines and recommendations for the treatment of hypertension, ischemic heart disease and heart failure (Table 1).
Age over 55 years with CAD, PAD, CV disease or high-risk DM
Telmisartan VS Ramipril VS Telmisartan and Ramipril
25,620/56 months (about 4 and a half years)
Patients with CV disease or DM with complications telmisartan was as good as Ramipril in preventing death, MI, and stroke. The combination of both however had no increase in benefit and was associated with more adverse events.
CV mortality, aborted cardiac arrest, or HF hospitalization
Age > 50 years, LVEF >45%, SBP <140 or < 160 if on 3 anti-hypertensives, serum potassium <5, elevated BNP in last 60 days, or HF hospitalization in last 12 months
Spironolactone VS placebo
3,445/3 years
Spironolactone did not reduce CV mortality however did result in a small reduction in HF hospitalizations
Age > 18 years, NYHA class II-IV, EF <35%, if no HF hospitalizations in last year BNP >150 pg./mL, ACE, or ARB and BB with stable dose, If HF hospitalization in last year BNP >100 pg./mL
ARNI VS enalapril
8,399/27 months (about 2 and a half years)
ARNI reduces CV mortality or HF hospitalizations when compared to enalapril. Also reduces all-cause mortality
HF hospitalizations and CV mortality, change in NYHA class at 8 months, all-cause mortality
>50 years of age, LVEF>45%, NYHA II-IV, and at least one of the following: HF hospitalization with NT-proBNP>200 (no AFIB) or > 600 (AFIB) or NT-proBNP>300 (no AFIB) or > 900 (Afib) on screening visit ECG
ARNI VS valsartan alone
4,822/35 months (about 3 years)
ARNI did not lower hospitalizations or death from CV causes, however there was a modest improvement in NYHA class and a slower decline in renal function than what was seen in valsartan alone
Time-averaged change in NT-proBNP concentration from baseline through weeks 4-8
Age > 18 years, LVEF<40%, NT-proBNP of 1600 pg./mL or more, or BNP of 400 pg./mL or more, receiving diagnosis of acute decompensated HF up to10 days after presentation
ARNI versus enalapril
881/2 years
ARNI decreased NT-proBNP compared to enalapril therapy without significant change in rate of adverse events
Death from CV causes, nonfatal MI, nonfatal stroke, ESRD, death attributable to kidney failure, or the need for RRT
35 years or older with type 2 diabetes and evidence of microalbuminuria, macroalbuminuria, or cardiovascular disease
Aliskiren VS placebo
8,561/32 months (about 2 and a half years)
The addition of aliskiren to standard therapy in patients with type 2 diabetes who are at elevated risk for CV and renal events is potentially harmful
Table 1.
Trials documenting improvement in cardiovascular outcomes and reduced cardiovascular mortality with renin-angiotensin-aldosterone system inhibition.
Summarized landmark clinical trials depicting the benefits of RAAS inhibition in cardiac and renal patients. Abbreviations: CKD: Chronic kidney disease, AA: African American, SBP: systolic blood pressure, DBP: diastolic blood pressure, CV: cardiovascular, EF: ejection fraction, LV: left ventricular, MI: Myocardial infarct, ESRD: End stage renal disease, RRT: renal replacement therapy.
In the treatment of hypertension, the patient’s specific co-morbidities must be considered prior to initiating therapy including, race, diabetes, kidney function and other high-risk pre-existing conditions that may predispose to CV outcomes. One landmark trial, the AASK trial (2002), studied African Americans with hypertension and kidney disease and compared intensive blood pressure control versus conservative blood pressure control with ACE-I, metoprolol, and amlodipine. The two groups had no difference in the progression to CKD, however patients on ACE-I had less chronic kidney disease events and death, which solidified the use of ACE-I in patients with CKD [38].
The mainstay of treatment in patients with heart failure and CAD is blockade of the RAAS. Multiple trials highlighted in Table 1 have been performed showing improvement in cardiovascular (CV) outcomes and reduced CV mortality.
The first trial to demonstrate improved CV outcomes with HFrEF is the CONSENSUS (1987) trial conducted among New York Heart Association (NYHA) Class IV HF and cardiomegaly patients which compared enalapril and placebo. Six-month mortality with enalapril was 26% as opposed to 44% with placebo [39]. The SOLVD (1991) treatment trial chose patients with HF and LVEF ≤35%, NYHA II-IV, with similar randomization, showing mortality reduction by 16% due to reduction of death in patients on enalapril versus placebo. This study also showed a decrease in CV related hospitalizations [40]. Further research with the V-HeFT II (1991) trial showed that ACE-I was superior in improving survival to vasodilators such as isosorbide dinitrate and hydralazine [41]. Additionally, use of ACE-I as a disease modifying drug was established post-MI in the SAVE trial (1992), which is further discussed in Table 1 [42].
Additional studies looked to compare the effects of ACE-I versus ARB. These trials were the VALIANT (2003) trial and the OPTIMAAL (2002) trial. The VALIANT trial showed that valsartan was as effective as captopril in improving survival among patients with HF and/or LV disfunction in the post-MI period [43]. The OPTIMAAL trial compared losartan and captopril in high-risk patients after acute myocardial infarction with LV-dysfunction and heart failure and found no difference in mortality outcomes [44]. Similar studies in patients with HFpEF were conducted, including the CHARM-Preserved trial (2003) and the I-PRESERVE trial (2008). CHARM- Preserved showed that candesartan modestly reduced HF-related hospitalizations however had no effect on mortality [45]. I-PRESERVE used Irbesartan in HFpEF patients and similarly found no reduction in mortality [46].
The thought that the addition of an ARB to an ACE inhibitor could inhibit RAAS more significantly was established. This was compared in two large significant trials. The CHARM-added trial compared symptomatic HF patients with LVEF ≤40% who were already on an ACE inhibitor with either addition of candesartan or placebo. This trial showed a reduction in CV mortality and HF hospitalizations; however, it was accompanied by a significant increase in hyperkalemic events [47]. The Val-HeFT (2001) compared patients with symptomatic HF, LVEF <40% with LV dilatation and on ACE inhibitors by adding either valsartan or placebo. There was no effect on mortality however, there was a 23% reduction in HF hospitalization in the treatment group [48]. Finally, the ONTARGET trial (2008) compared ramipril to telmisartan to a combination of both in patients with CV disease or diabetes with complications and found that the combination of telmisartan plus ramipril had no increase in benefit and was associated with more adverse events [49].
Several trials looking at the effects of aldosterone antagonists and heart failure patients were conducted with overall favorable results. Patients benefit from reduced sympathetic stimulation and alleviate fluid overload from sodium and water retention through aldosterone blockade. The RALES trial (1999) studied the role of spironolactone in patients with LVEF≤35% and NYHA class III-IV, which showed that Spironolactone, along with ACE-I (as most patients were already on ACE-I) showed a 11% reduction in CV mortality compared to placebo [50]. The TOPCAT trial (2014) done in patients with HFpEF and controlled blood pressures to receive spironolactone or placebo. This study conversely showed that spironolactone did not reduce CV mortality however did result in a small reduction in HF hospitalizations [51]. Another trial, the EMPHASIS-HF trial (2011), looked at Eplerenone versus placebo in HF patients, NYHA class II, showed that Eplerenone reduced the risk of death and hospitalizations in patients with HF [52].
A newer group of RAAS inhibition medications combining an ARB and neprilysin inhibitor (ARNI) was studied in 2014 in the PARADIGM-HF trial. Neprilysins are key enzymes in the degradation of natriuretic peptides. They increase endogenous natriuretic peptide levels including bradykinin, thereby promoting vasodilation and natriuresis. Neprilysins were initially attempted with an ACE inhibitor combination however this led to incidences of angioedema given increased levels of bradykinin. PARADIGM - HF trial was conducted in patients with symptomatic HF and LVEF ≤40% assigned to enalapril alone or valsartan-sacubitril combination. This showed significant reduction in CV mortality, all-cause mortality, and HF hospitalizations with no increase in angioedema events [53]. The PARAGON-HF trial (2019) studied ARNI versus valsartan alone in HFpEF patients with EF > 45% and NYHA II to IV and showed that ARNI did not lower hospitalizations or death from CV causes, however there was a modest improvement in NYHA class and a slower decline in renal function than what was seen in valsartan alone [54]. The PIONEER-HF trial (2019) showed that initiated of ARNI versus enalapril in acute diastolic heart failure patients allowed for significant reductions in HF biomarker, NT-proBNP, without significant change in adverse effects [55].
Direct renin inhibitors have been attempted with the goal of reducing renin and thereby the entire RAAS cascade. The ALTITUDE trial (2012) added aliskiren to patients with diabetes type 2 in order to prevent kidney disease and CV outcomes. These patients were on ACE-I however the addition of aliskiren led to an increase in CV mortality, hypotension, and adverse hyperkalemic events. The trial was stopped early due to higher mortality findings [56].
8. Summary and conclusions
RAAS is a complex and evolving pathway that has been implicated in the pathogenesis of endothelial damage, atherosclerosis, and cardiac remodeling. Inhibition of the negative effects of overactivated RAAS has shown to cause morbidity and mortality benefits in cardiovascular disease outcomes. Significant research has yet to be performed on the possibility of stimulating the counter-regulatory effects of RAAS through AT2-R and MAS-R. Such mechanisms are still being studied in animal models; however, the effects of AT2-R and MAS-R offer potential areas of continued research and potential targets for future therapy.
Conflict of interest
No conflicts of interest exist for this work by any of the authors.
\n',keywords:"cardiovascular disease, coronary artery disease, heart failure, hypertension",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75639.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75639.xml",downloadPdfUrl:"/chapter/pdf-download/75639",previewPdfUrl:"/chapter/pdf-preview/75639",totalDownloads:286,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 19th 2021",dateReviewed:"February 4th 2021",datePrePublished:"March 26th 2021",datePublished:"November 24th 2021",dateFinished:"March 10th 2021",readingETA:"0",abstract:"Increased attention has been placed on the activation of the renin-angiotensin-aldosterone system (RAAS) and pathogenetic mechanisms in cardiovascular disease. Multiple studies have presented data to suggest that cardiac and arterial stiffness leading to adverse remodeling of both the heart and vasculature leads to the various pathological changes seen in coronary artery disease, heart failure (with preserved and reduced ejection fractions), hypertension and renal disease. Over-activation of the RAAS is felt to contribute to these structural and endocrinological changes through its control of the Na+/K+ balance, fluid volume, and hemodynamic stability. Subsequently, along these lines, multiple large investigations have shown that RAAS blockade contributes to prevention of both cardiovascular and renal disease. We aim to highlight the known role of the activated RAAS and provide an updated description of the mechanisms by which activation of RAAS promotes and leads to the pathogenesis of cardiovascular disease.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75639",risUrl:"/chapter/ris/75639",signatures:"Violeta Capric, Harshith Priyan Chandrakumar, Jessica Celenza-Salvatore and Amgad N. Makaryus",book:{id:"10488",type:"book",title:"Renin-Angiotensin Aldosterone System",subtitle:null,fullTitle:"Renin-Angiotensin Aldosterone System",slug:"renin-angiotensin-aldosterone-system",publishedDate:"November 24th 2021",bookSignature:"Samy I. McFarlane",coverURL:"https://cdn.intechopen.com/books/images_new/10488.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-287-2",printIsbn:"978-1-83968-286-5",pdfIsbn:"978-1-83968-458-6",isAvailableForWebshopOrdering:!0,editors:[{id:"53477",title:"Prof.",name:"Samy I.",middleName:null,surname:"McFarlane",slug:"samy-i.-mcfarlane",fullName:"Samy I. McFarlane"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"106536",title:"Dr.",name:"Amgad N.",middleName:null,surname:"Makaryus",fullName:"Amgad N. Makaryus",slug:"amgad-n.-makaryus",email:"amakaryus@gmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/106536/images/8468_n.jpg",institution:{name:"North Shore University Hospital",institutionURL:null,country:{name:"United States of America"}}},{id:"345779",title:"Dr.",name:"violeta",middleName:null,surname:"capric",fullName:"violeta capric",slug:"violeta-capric",email:"violeta.capric@downstate.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"346171",title:"Dr.",name:"Harshith",middleName:null,surname:"Priyan Chandrakumar",fullName:"Harshith Priyan Chandrakumar",slug:"harshith-priyan-chandrakumar",email:"priyan.chandrakumar@downstate.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"SUNY Downstate Medical Center",institutionURL:null,country:{name:"United States of America"}}},{id:"346172",title:"Dr.",name:"Jessica",middleName:null,surname:"Celenza-Salvatore",fullName:"Jessica Celenza-Salvatore",slug:"jessica-celenza-salvatore",email:"jessica.salvatore@downstate.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"SUNY Downstate Medical Center",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Overview of the RAAS system",level:"1"},{id:"sec_3",title:"3. Pathogenic insights",level:"1"},{id:"sec_3_2",title:"3.1 Atherosclerosis and endothelial dysfunction",level:"2"},{id:"sec_5",title:"4. Hypertension",level:"1"},{id:"sec_6",title:"5. Ischemic heart disease",level:"1"},{id:"sec_7",title:"6. Heart failure",level:"1"},{id:"sec_8",title:"7. Clinical implications",level:"1"},{id:"sec_9",title:"8. Summary and conclusions",level:"1"},{id:"sec_13",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'WHO’s Global Health Estimates (2020, December 9). The top 10 causes of death. Retrieved December 24, 2020, from https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death'},{id:"B2",body:'Ferrario, C. M. Role of Angiotensin II in Cardiovascular Disease Therapeutic Implications of More than a Century of Research. J. 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Curr Diab Rep (2009) 9(3):229-37'},{id:"B29",body:'Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017 Aug 8;136(6):e137-e161. doi:10.1161/CIR.0000000000000509. Epub 2017 Apr 28. PMID: 28455343'},{id:"B30",body:'Dostal DE, Baker KM. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res. 1999 Oct 1;85(7):643-50. doi: 10.1161/01.res.85.7.643. PMID: 10506489'},{id:"B31",body:'Ruzicka M, Leenen FH. Relevance of blockade of cardiac and circulatory angiotensin-converting enzyme for the prevention of volume overload-induced cardiac hypertrophy. Circulation. 1995 Jan 1;91(1):16-9. doi: 10.1161/01.cir.91.1.16. PMID: 7805197'},{id:"B32",body:'Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol. 2017 Jan;14(1):30-38. doi: 10.1038/nrcardio.2016.163. Epub 2016 Oct 6. PMID: 27708278; PMCID: PMC5286912'},{id:"B33",body:'Verbrugge FH, Tang WH, Mullens W. Renin-Angiotensin-aldosterone system activation during decongestion in acute heart failure: friend or foe? JACC Heart Fail. 2015 Feb;3(2):108-11. doi: 10.1016/j.jchf.2014.10.005. Epub 2014 Oct 31. PMID: 25543974'},{id:"B34",body:'Mann DL, Chakinala M. Heart Failure: Pathophysiology and Diagnosis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison\'s Principles of Internal Medicine, 20e. McGraw-Hill; Accessed December 22, 2020'},{id:"B35",body:'Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 1990 Nov;82(5):1724-9. doi:10.1161/01.cir.82.5.1724. PMID: 2146040.'},{id:"B36",body:'Kostin S, Hein S, Arnon E, Scholz D, Schaper J. The cytoskeleton and related proteins in the human failing heart. Heart Fail Rev. 2000 Oct;5(3):271-80. doi: 10.1023/A:1009813621103. PMID: 16228910'},{id:"B37",body:'Mentz RJ, Stevens SR, DeVore AD, Lala A, Vader JM, AbouEzzeddine OF, Khazanie P, Redfield MM, Stevenson LW, O\'Connor CM, Goldsmith SR, Bart BA, Anstrom KJ, Hernandez AF, Braunwald E, Felker GM. Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure. JACC Heart Fail. 2015 Feb;3(2):97-107. doi: 10.1016/j.jchf.2014.09.003. Epub 2014 Oct 31. PMID: 25543972; PMCID: PMC4324057'},{id:"B38",body:'Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002 Nov 20;288(19):2421-31. Erratum in: JAMA. 2006 Jun 21;295(23):2726'},{id:"B39",body:'CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. (1987) Jun 4;316(23):1429-35'},{id:"B40",body:'SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. (1991) 325(5):293-302'},{id:"B41",body:'Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. (1991) 325(5):303-10'},{id:"B42",body:'Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992 Sep 3;327(10):669-77. doi: 10.1056/NEJM199209033271001. PMID: 1386652'},{id:"B43",body:'M. A. Pfeffer, J. J. McMurray, E. J. Velazquez et al., Valsartan in acute myocardial infarction trial investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. The New England Journal of Medicine (2003) 349:1893-1906'},{id:"B44",body:'Dickstein K, Kjekshus J. the OPTIMAAL Trial Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. Lancet. 2002; 360: 752-760'},{id:"B45",body:'Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. (2003) 362(9386):777-81'},{id:"B46",body:'Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. (2008) 359(23):2456-67'},{id:"B47",body:'McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. (2003) 362(9386):767-71'},{id:"B48",body:'Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. (2001) 345(23):1667-75'},{id:"B49",body:'ONTARGET Investigators: Yusuf S, Teo KK, et al.: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med (2008) 358:1547-1559'},{id:"B50",body:'Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. (1999) 341(10):709-17'},{id:"B51",body:'Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O\'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. (2014) 370(15):1383-92'},{id:"B52",body:'Zannad, F., McMurray, J. J. V., Krum, H., van Veldhuisen, D. J., Swedberg, K., Shi, H., … Pitt, B. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. New England Journal of Medicine (2011) 364(1), 11-21'},{id:"B53",body:'McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. (2014) 371(11):993-1004'},{id:"B54",body:'Solomon, Scott D., et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction: NEJM. N Engl J Med (2019) 381:1609-1620'},{id:"B55",body:'Velazquez, Eric J., et al. Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure: NEJM. N Engl J Med (2019) 380:539-548'},{id:"B56",body:'Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 6;367(23):2204-13'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Violeta Capric",address:null,affiliation:'
Department of Medicine, State University of New York-Downstate, Downstate-Health Science University, United States
Department of Medicine, State University of New York-Downstate, Downstate-Health Science University, United States
'},{corresp:"yes",contributorFullName:"Amgad N. Makaryus",address:"amakaryu@numc.edu",affiliation:'
Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, United States
Department of Cardiology, Nassau University Medical Center, United States
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. Anderson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"
\r\n\tIf we aim to prosper as a society and as a species, there is no alternative to sustainability-oriented development and growth. Sustainable development is no longer a choice but a necessity for us all. Ecosystems and preserving ecosystem services and inclusive urban development present promising solutions to environmental problems. Contextually, the emphasis on studying these fields will enable us to identify and define the critical factors for territorial success in the upcoming decades to be considered by the main-actors, decision and policy makers, technicians, and public in general.
\r\n
\r\n\tHolistic urban planning and environmental management are therefore crucial spheres that will define sustainable trajectories for our urbanizing planet. This urban and environmental planning topic aims to attract contributions that address sustainable urban development challenges and solutions, including integrated urban water management, planning for the urban circular economy, monitoring of risks, contingency planning and response to disasters, among several other challenges and solutions.
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