Matrix Metalloproteinases (MMPs) and their substrates (adapted from [24]).
\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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The extracellular matrix (ECM) is a network of proteins, fibrous and non-fibrous, which form a supporting architecture for the cells in cardiac tissues. Cardiomyocytes, fibroblasts, vascular cells, and inflammatory cells that are responsible for the synthesis and degradation of ECM proteins exist in and around the cardiac ECM. A unique hallmark of the cardiovascular (CV) system is that the tissue is subject to dynamic mechanical load from the pulsatile blood pressure and flow. A perturbation of the mechanical load will be transduced to and sensed by the cells via the ECM to trigger acute or chronic remodeling of the tissue, resulting in structural and mechanical changes in the ECM. The altered ECM biomechanical properties further change the behavior of the cells within the tissue. These aspects are known as mechanobiology. This chapter will focus primarily on the changes of the ECM in various cardiac diseases, the alterations in the mechanical properties of the myocardium as a result of the ECM remodeling, and the impact of these biomechanical factors on cellular and organ function in the progression of heart failure (Figure 1). Moreover, because collagen accumulation (fibrosis) is mostly investigated and contributes significantly to myocardial mechanical properties, we will limit our discussion on cardiac fibrosis as the main ECM remodeling event. Readers are referred to other extensive reviews that have summarized a broad category of ECM proteins during myocardial remodeling in different types of heart diseases [1, 2].
A schematic plot showing the relations between cardiac ECM remodeling (fibrosis), tissue mechanics and ventricular function.
Extracellular matrix (ECM) proteins found in biological tissue can serve structural or non-structural roles, depending on the location and composition of the protein. Glycoproteins primarily consist of structural ECM proteins, which include fibrillar collagen, elastin, fibronectin, and laminin [1]. These are often the main determinants of tissue’s passive mechanical properties. The non-structural ECM proteins are primarily categorized as proteoglycans, which are further distinguished as four subgroups—hyalectans, cell surface proteoglycans, basement membrane proteoglycans, and small leucine-rich proteoglycans (SLRP’s) [2]. These proteins play a key role in cell–cell or Cell—matrix interactions, interaction with growth factors, as well as binding to cell receptors to regulate cellular function [2].
Among the structural ECM proteins, collagen and elastin are mostly investigated in cardiovascular tissues. Collagen is the most abundant protein in the body and formed from the basic unit of tropocollagen [3]. Tropocollagens, made up of polypeptide chains, spontaneously twist together to form a triple helix structure, which form a newly synthesized procollagen fibril. Mature collagen fibers can then form via cross-linking of procollagen fibrils into bundles or sheets, conferring versatile mechanical properties in various tissues [3]. There are over 25 collagen types to date [2], each with different physical and mechanical properties [4]. For instance, type I collagen is a subtype that exhibits stiffer mechanical property and higher tensile strength compared to type III collagen. Collagen metabolism is maintained by the synthesis and degradation balance, and different tissues have different turnover rates [4, 5]. Higher turnover of collagen types I and III is observed in diseased tissues, and is also linked to the pathological state of the tissue such as inflammation and aging [4, 5]. Overall, fibrillar collagen contributes to CV tissue’s nonlinear elastic behavior at high strains due to the increased recruitment of fibers.
Elastin is another primary structural protein, contributing to the mechanical property of the CV tissue at low strains [6]. It is formed as sheets comprised of the base unit tropoelastin, which has the ability to stretch and recoil [6]. Compared to collagen fibers which have an average Young’s Modulus of 250–400 MPa [7], elastin fibers are more compliant with an average Young’s Modulus of 1 MPa [8]. Elastin is a highly stable protein that has very low turnover rate – once formed, it lasts almost for the entire lifespan [9]. Increased elastin degradation or damage is a sign of pathological remodeling of the tissue and is associated with aging and CV diseases [9].
In the myocardial tissue, the main ECM protein is collagen. Collagen is diffusively spread over in the myocardium—interstitial and perivascular collagen fibers have been revealed by histology. Collagen types I and III are the most prominent collagen types in the myocardium [10], making up 85% and 6–11% of the total collagen, respectively [11]. Other isoforms of collagen are also reported. Bashey et al. examined murine, canine, and nonhuman primate healthy hearts and found that type V collagen comprises 2 ~ 3% and type VI collagen comprises ~5% of the total collagen in the myocardium [11]. While the fractional content of type IV collagen was not evident, it appeared most prominent in the basement membrane and in the media [11]. A detailed summary of all fibrillar and non-fibrillar collagen and their roles in cardiac diseases can be found in a recent review [12].
Elastin content in the ventricle is not detailed in the same manner as collagen. The distribution of elastin is mainly limited to the epicardium, the outer layer of the ventricular wall [13, 14]. Biochemical measurements showed that elastin content is about one tenth of the collagen content in healthy heart. Furthermore, the left ventricle (LV) tended to have more elastin and collagen content (in μg/mg) than the right ventricle (RV) [15].
In heart valves, elastin is more abundant than in the myocardium. It is located primarily in the inflow layer and sparsely distributed in the outflow and central layers, comprising approximately 10% of total proteins in the tissue [16, 17]. Collagen type I is found primarily in the valve leaflets and the valve outflow layer, whereas collagen type III is distributed throughout the entire valve structure [16]. Collagen comprises approximately 60% of ECM proteins in human heart valves [17].
The cellular components responsible for the cardiac collagen synthesis include interstitial fibroblasts (in healthy hearts), transdifferentiated myofibroblasts and inflammatory cells (in diseased hearts), cardiomyocytes, and adventitial fibroblasts and smooth muscle cells (SMCs) in the blood vessels [18, 19, 20]. Several biological mediators such as pro-inflammatory cytokines, growth factors and hormones are also identified to participate in collagen synthesis, which are reviewed previously [4, 21, 22]. Among them, fibroblasts and transforming growth factor beta (TGF-β) are two main contributing factors. In cardiac remodeling, fibroblasts migrate to the injured region or to the area where ECM proteins are over-degraded and secrete new ECM proteins—primarily collagen types I and III [18]. Moreover, a “new” phenotype of cells myofibroblasts, emerge in injured myocardium, which is a key step to strengthen cardiac fibrosis in both infarcted and hypertensive myocardium. TGF-β is involved in signaling pathways of various cells (fibroblasts, cardiomyocytes, immune and vascular cells) to initiate fibrogenic action [19]. For a thorough review of current understanding of cardiac fibrosis in ischemic and non-ischemic heart diseases, the reader is referred to these references [12, 21].
Degradation of the ECM proteins is necessary for the turnover as well as normal protein function. Matrix metalloproteinases (MMPs) are the most significant molecules that contribute to this degradation and these enzymes are key in the CV tissue remodeling [10]. MMPs in the heart are primarily expressed by the fibroblasts and cardiomyocytes [20, 23]. Table 1 details various types of MMPs and the ECM proteins that they target. Insoluble fibrillar collagen such as collagen type I and III or more cross-linked collagen is difficult to be enzymatically degraded [11]. To prevent excessive degradation of ECM, tissue inhibitors of metalloproteinases (TIMPs) are secreted to bind to MMPs and limit the role of activated MMPs. Therefore, the overall balance between the activated MMPs and TIMPs determines the ECM remodeling and turnover rate.
MMPs | Substrate |
---|---|
MMP-1 | Collagens I, II, III, VII, X |
MMP-8 | Collagens I, II, III, V, VII, X |
MMP-13 | Collagens I, II, III, IV, fibronectin, laminin |
MMP-2 | Collagens, I, IV, V, VII, X, XI, fibronectin, laminin elastin |
MMP-9 | Collagens III, IV, V, VII, X, elastin |
MMP-3 | Collagens III, IV, V, IX, X, fibronectin, laminin |
MMP-10 | Collagens III, IV, V, IX, laminin, fibronectin |
MMP-11 | Collagen IV, fibronectin, laminin |
MMP-14 | Collagens I, II, III, fibronectin, laminin |
Matrix Metalloproteinases (MMPs) and their substrates (adapted from [24]).
There is increasing agreement that the ECM is not a passive biological component but actively interferes with cellular and organ function in the dynamic remodeling process. Thus, the measurement of ECM proteins is critical to study their roles in tissue biomechanics and remodeling in various diseases. The existing measurement methods can be classified into these categories: medical imaging techniques, optical imaging techniques, biochemical and biological methods.
Medical imaging techniques are generally noninvasive because they can be performed on a live subject with negligible risks; they are sometimes referred to as organ-scale imaging [25]. Primary medical imaging techniques include Magnetic Resonance Imaging (MRI), ultrasound and nuclear imaging. These techniques could measure bulk quantities of the materials—concentration, volume fraction and distribution of proteins.
MRI is the most common imaging method for collagen detection because of its higher sensitivity to specific molecular probes to target specific ECM proteins [26]. For example, the feasibility of detection of collagen (predominantly collagen type I) using a gadolinium-containing molecular contrast agent (delayed or late gadolinium enhancement) has been demonstrated in preclinical animal studies [27, 28]. The technique is valuable in the detection of fibrosis in ventricles [29, 30]. Recently, T1 mapping technique has emerged as a more useful technique for diffuse interstitial fibrosis measurement [31, 32]. In addition, a particular mode of MRI, tagging and feature tracking, enables clinicians to measure tissue strain from which collagen measurements can be indirectly deduced [33]. Elastin content can be quantified directly by molecular MRI as well [34].
Ultrasound technique is another imaging method to quantify collagen or elastin. Strain elastography measures elasticity of the myocardium, from which properties of the structure and content of collagen and elastin are indirectly derived [35, 36]. This method is sensitive to the fiber angle and density, both of which give light to the health status of the tissue [35]. Using the known mechanical properties of elastin and collagen (i.e., Young’s Modulus), one can distinguish the relative contributions of ECM proteins to the tissue. Finally, cardiac nuclear imaging, including single-photon emission computed tomography (SPECT) and positron-emission tomography (PET), has been used to quantify the ECM content [25]. Radioactive molecular probes are used in these techniques. The common targets include collagen type I, II and IV, as well as MMPs [37, 38].
Optical imaging techniques are often used to provide the images of collagen fibers including their content and fiber orientation in intact, fresh tissues using physical properties of photons [39]. Two primary optical imaging techniques are the Second-harmonic Generation (SHG) and Small Angle Light Scattering (SALS). SHG imaging is a form of nonlinear optical microscopy. It can be applied to fresh or fixed tissues at varying depths (optical section), thus revealing the 2D or 3D structure of the collagen fibers [40]. This technique is advantageous due to its high resolution and specificity for the microstructure of collagen fibers [41]. However, it only allows the imaging of samples to a certain distance (depth), and deep tissue imaging systems are currently under development to enable larger length of penetration [42]. SALS is another method to measure fiber orientation when a polarized light beam is passed through a specimen—biological or nonbiological [43, 44]. The distribution of the scattered light is used to identify fiber orientation and alignment [43]. The gross/average collagen fiber orientation can be obtained in tissues with a thickness of at least 500 microns [45]. The advantage of this technique is the capability to measure in thicker tissues than SHG; but the disadvantage is that only an average of planar (2D) fiber orientation is derived, and the information along the depth direction is unavailable.
Direct measurements of collagen can be obtained using a long-established biochemical measurement – hydroxyproline assay, which quantifies the hydroxyproline content in digested samples. Hydroxyproline is a main molecular component of collagen and its amount can indirectly reflect the collagen content or is converted to collagen content with assumed collagen to hydroxyproline ratio [46]. Different methods have been established to measure hydroxyproline including colorimetric methods, high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC–MS) [47].
In addition, tissue staining protocols—histology methods—are convenient to examine the ECM protein content and structure without losing the local distribution information. The common staining methods for collagen are Masson’s Trichrome stains [35, 48] and Picrosirius Red stains [49]. Because mature collagen is birefringent and the Picrosirius Red stain can enhance the birefringency of collagen, collagen fibers can be visualized better and in more details under polarized light. It also enables a quick examination of types I and III collagen in CV tissues due to the different fiber thickness [50, 51]. Alternatively, the elastin is often examined by the Verhoeff-Van Gieson (VVG) stain [52] and the glycosaminoglycans (GAGs) and proteoglycans are examined by the Alcian blue stain [53]. Moreover, immunohistochemistry (IHC) employs the use of antibodies to quantify the specific protein of interest [10, 11].
Non-microscopic measurement methods include enzyme-linked immunosorbent assay (ELISA) and other standard biological methods. ELISA has been applied to detect collagen types I and III, as well as elastin and cross-linking of collagen [54, 55]. Finally, like all other proteins, the ECM proteins can be quantified by the protein expression using Western blot (immunoblotting) or by the mRNA or DNA expression using qPCR (quantitative Polymerase Chain Reaction) [6, 56].
Heart failure (HF) affects approximately 6.2 million adult Americans [57]. The main causes of HF are myocardial infarction, pressure-overload (hypertension), volume-overload, arrhythmia, valve stenosis or regurgitation, etc. Ventricular dysfunction is the most common type of HF including left-sided HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), as well as right-sided HF secondary to pulmonary hypertension and congenital heart disease [58, 59, 60]. The malfunction of the myocardium can occur in the LV, RV, or both ventricles (biventricular HF).
As shown in the overall scheme (Figure 1), the cardiac ECM remodeling is an interactive, dynamic procedure that brings the cellular function, tissue mechanical behavior and organ function into one scenario. The ECM remodeling leads to both biological (structural) and mechanical (functional) changes of the tissue, which in turn regulates cell behaviors and alters the hemodynamics and cardiac performance. It is accepted that the remodeling often starts with an attempt to maintain the homeostasis environment of the cells and organ. This is referred to as adaptive remodeling (compensation). However, when the remodeling cannot achieve a ‘stable’ status of the new homeostasis but continues to deteriorate, impairments of the cells and organ will occur. This is known as adverse or mal-adaptive remodeling (decompensation). The mechanism of transition from compensation to decompensation remains a key knowledge gap. In almost all types of HF, cardiac fibrosis plays an important role in the pathogenesis; but its effects on mechanical changes of the myocardium and the physiological function are less noted. Hence, our discussion here will focus on the maintenance of the biomechanical homeostasis in common types of HF involving both LV and RV.
Hypertension is defined as chronically elevated blood pressure in the systemic circulation, with a systolic blood pressure greater than 120 mmHg, and/or a diastolic blood pressure greater than 80 mmHg [61]. It is one of the most prevalent pathologies in the United States, affecting approximately one in three adults. Hypertensive heart disease (HHD) accounts for approximately a quarter of all causes of heart failure [61]. In response to the pressure overload, cardiac hypertrophy and fibrosis are the most prominent events observed. The increased interstitial and perivascular collagen is originated from several cell types including cardiac fibroblasts, activated macrophages [62], cells derived from EndMT (or epithelial-to-mesenchymal transition (EMT)) or myofibroblasts, which are transdifferentiated from EndMT and EMT [21, 63].
In preclinical animal models, HHD can be induced by aortic banding [64, 65], genetic alteration (e.g. spontaneous hypertensive rates (SHR)) [66], or other methods that overlap with the models of systemic hypertension (e.g. high-salt diet or angiotensin II infusion) [63]. From both clinical and animal studies, various fibrillar collagen types such as I, III, IV, and V were reported to increase in the hypertensive LV [12, 64, 65, 67, 68]. The regulation of collagen turnover is dynamic. For instance, collagen types I and III increased within a day after hypertension was induced [64, 65]. Collagen types I and III reached a peak content (fivefold and 1.7-fold, respectively) at day 3, then decreased at day 7 and plateaued four weeks after the aortic banding. In contrast, collagen type IV reached its peak one day after the banding, and then began to decline at day 3 and plateaued at day 7 [65]. A similar trend of an initial elevation followed by a decline of collagen types I, III and IV has been reported by Jalil et al. in a rat aortic banding model [64]. The time-dependent change has been suspected to be associated with the transition from compensative hypertrophy to decompensation. The overall ECM degradation in later stages of HHD is speculated to disrupt the mechanical support and electrical conduction for myocardial contraction and promote cardiomyocyte apoptosis, which results in impairments of cardiomyocyte contractility and organ failure [12, 69].
There is no consensus on whether type I or type III collagen plays a more significant role in the LV hypertrophy. Some studies have indicated a predominance of type I collagen accumulation [70, 71], but others reported equivalent elevations of type I and III [72]. In a patient study that examined the collagen type I and III mRNAs expression in dilated cardiomyopathy, it was shown that the collagen type III/I ratio was higher in dilated cardiomyopathy patients (idiopathic, hypertensive and alcoholic) than the healthy controls [73]. This suggests an important role of collagen type III in the hypertensive LV fibrosis. The metabolism of the two collagen isoforms may not be independent since it has been shown that type III collagen is crucial for collagen I fibrillogenesis during the normal development of cardiovascular system [74]. Therefore, a further understanding of the role of collagen isoforms in fibrosis is needed.
In the RV, similar fibrotic remodeling occurs in response to pulmonary hypertension (PH), which is defined as a mean pulmonary arterial pressure (mPAP) exceeding 20 mmHg [75]. Increases in total collagen content or collagen synthesis were consistently reported in hypertensive RVs, from clinical to preclinical studies, from large to small animals, as well as from early to late stage of RV failure [50, 76, 77, 78]. The types of collagen upregulated in the RV has been investigated but inconsistent findings are reported. In a mouse model of PH (Sugen+hypoxia), the ratio of collagen type I/III was increased in the diseased RV and it was mainly attributed to the increase in type I collagen [78]. But in a recent ovine model of PH, type III collagen rather than type I collagen was found to be increased more significantly in the RV [51]. While both studies used Picrosirius Red stained histology samples to quantify collagen isoforms in the RV, these results need to be confirmed by other quantitative methods in future studies.
Finally, not only is there a change of the collagen content, but the morphology, cross-linking, and alignment are altered in the remodeling process. First, in the hypertensive LV, collagen type I became thicker and denser, creating a tighter mesh of fibers [64]. Second, the increase in collagen content is accompanied with an increase in cross-linking as this is part of the maturation of new collagen. Cross-linking is an enzymatic driven event and two types of enzymes—the LOX (lysyl oxidase) family and TG (tissue transglutaminase)—have been found to be upregulated in hypertensive myocardium [79, 80]. It has been shown that the collagen cross-linking, not content, was associated with the LV chamber stiffness and filling pressure [80, 81]. Collagen cross-linking was also associated with a higher incidence of hospitalization in HHD patients [82]. On the other hand, the cardiac remodeling requires degradation of insoluble collagens to enable rearrangement of cells and matrix proteins, and reduction in collagen cross-linking was reported as well [70]. Therefore, the role of cross-linking has not been fully understood in HHD. Third, collagen fibers became more aligned in the hypertensive LV [65]. Similarly, enhanced fiber alignment has been reported in the RV. In rat PH RVs, the myo-fibers and collagen fibers were more strongly aligned in the longitudinal (apex-to-outflow) direction so that the tissue became more anisotropic in mechanical behavior [83].
Myocardial stiffening is widely evident in HHD patients, particularly revealed by the increase in diastolic (passive) stiffness of the LV [65, 67]. The reduced mechanical strain is a surrogate of myocardial stiffening and became noticeable in hypertensive LVs even when the contractility was preserved [32, 84]. This indicates that the stiffening occurs in the early stage of HHD. Increased myocardial stiffness is thought to predominantly contribute to the diastolic dysfunction, which is evident by increases in isovolumetric relaxation time (IVRT), and end-diastolic volume or diameter (EDV or EDD) [85, 86]. Moreover, the persistent diastolic dysfunction with a dilatation/thinning of the myocardium is associated with impaired contractile (systolic) function, which was revealed by changes in dP/dtmax, dP/dtmin, end-systolic pressure-volume relations (ESPVR), fractional shortening (FS), ejection fraction (EF), stroke volume (SV), or cardiac output (CO) [87]. The mechanical changes are of high clinical relevance as the myocardial stiffness is significantly greater in the high-risk patients than in healthy controls, which may indicate a transition to heart failure with preserved ejection fraction (HFpEF) [88]. However, what initiates the transition from adaptive to maladaptive remodeling remains unclear.
Like the LV, the RV myocardium stiffens under chronic pressure overload [83, 89, 90]. The clinical evidence of RV stiffening in PH patients has been reported via the myocardial strain or strain rate measurements [91, 92]. Compared with the LV, the RV passive mechanics seem to play a more important role in physiological function, which is supported by the findings that the RV elasticity is more closely associated with the severity of RV failure and is better related to prognosis than the RV systolic function [93, 94, 95]. The RV stiffening is also evident from
The potential clinical significance of RV stiffening has been explored in a few studies. Jang et al. found that in PH rats, the RV longitudinal elastic modulus (EM) derived at low strains was correlated with RV diastolic function (end-diastolic elastance). This is the first report on the linkage of RV tissue mechanics and in vivo hemodynamics [90]. Recently, from an ovine model of PH, the RV longitudinal stiffness was significantly increased and correlated with the long-axis end-diastolic or end-systolic diameter or area. Moreover, in the longitudinal (apex-to-outflow tract) direction, there were trends of correlations between the low-strain EM and the acceleration time, as well as between the high-strain EM and the deceleration time. These findings indicate the critical role of the RV passive mechanical properties in the organ function [98]. Nevertheless, the question remains as to how exactly the mechanical changes affect the transition from adaptive to maladaptive remodeling.
Finally, the role of RV fibrosis in PH development may be different than the fibrosis in the hypertensive LV. For instance, RV fibrosis occurs early with the pressure overload and no report of collagen degradation has been noted in failing RVs. In contrast, collagen degradation has been documented in the late stage of LV failure (see Figure 3 below). Second, the RV fibrosis measured by T1 mapping was correlated with pulmonary arterial stiffness and RV RAC (relative area change), but not correlated with pulmonary pressure, RV mass or ejection fraction in PH patients [99]. This indicates that the RV fibrosis may be an early marker of maladaptive RV remodeling before the deterioration in the functional metric [99]. Such prognostic role has not been reported in LV fibrosis. Third, different outcomes of anti-fibrotic treatment were found between LV and RV. In the LV, treatments that induced reduction of fibrosis had led to regression of chamber stiffness and function improvement [71, 100, 101, 102, 103]. The beneficial outcomes of anti-fibrotic treatment are convincing and recently reviewed [104]. But interestingly, interruptions of collagen accumulation in RV had led to various consequences. The restriction of collagen accumulation using a transgenic mouse model resulted in limited RV hypertrophy and preserved RF function in PH development, indicating a protective role of anti-fibrosis therapy for the RV [78]. Other drug studies that demonstrated reduced RV fibrosis and improved RV function are briefly summarized by Bogaard et al. [105]. But recently, an anti-fibrotic intervention via suppressed Gelectin-3 expression (knock-out mice) or pharmaceutical inhibitors was insufficient to improve RV function in PH mice, despite an improvement in RV fibrosis [106]. These results raise more questions about the role of RV fibrosis in its function. Therefore, whether and how the fibrotic event precedes the functional decline in the RV may be organ specific and remains to be elucidated. Other different responses of the LV and RV to pressure overload are listed in Table 2.
RV | LV | |
---|---|---|
Fibrosis | Persistent in all stages | Mostly in early stage; degradation occurs in late stage |
Cardiomyocytes | ↓ α-MHC and ↑β-MHC (fetal gene expression); no atrial natriuretic peptide (ANP); inefficient energy metabolism | ↑β-MHC only; ↑ ANP; Improved energy metabolism |
Collagen isoforms | Type I and III | Type I, III, V, IV, VIII, and more |
Collagen fiber | More aligned fibers into apex-to-outflow tract direction | Thicker, denser collagen type I, more cross-linking & aligned fibers |
Dilatation | Occurs acutely in early stage | Occurs in late stage |
Capillary rarefaction? (↓ blood perfusion) | Yes | No |
Inflammatory response involved? | Yes (macrophages, TNF-α, IL-1β) | Yes (T lymphocytes, TNF-α, IL-1β) |
Response to anti-fibrosis treatment | Discrepant findings on function improvement | Mostly effective |
Volume overload is initially learned as physiological responses of myocardium because of the reversible myocardial remodeling observed in athletes and women in pregnancy. But pathological responses are also found in patients with heart valve disease (regurgitation) and congenital heart disease, which alternatively lead to heart failure. As a result, different views form regarding whether the remodeling from volume overload is adaptive and irreversible [110, 111]. In contrast to pressure overload, volume overload is often treated as another type of mechanical ‘insult’ in which the tissue is stretched beyond its normal state during diastole [112, 113, 114]. Under this type of mechanical load, collagen loss and chamber dilatation occurred since the early stage and these changes persisted, leading to an overall decrease in cardiac ECM [112, 113, 114, 115]. Such remodeling was attributed to an increase in MMP activity [113]. But elastin showed biphasic changes in the progression of ECM remodeling. Ruzicka et al. reported an initial (within one week of induced volume overload) increase in elastin concentration but then a decrease of elastin concentration below control levels 10 weeks after induced volume overload [114]. The reduction of ECM turnover in volume overloaded LV was related to a phenotype change of fibroblasts into hypofibrotic type [116] and increased MMP expressions from macrophages or mast cells [117, 118, 119]. An increased collagen III/I ratio was also noted in the compensated stage of the remodeling [114]. The elevated ECM degradation in volume overloaded LV seems to share common pathways as seen in late stage of HHD—to enable ventricle dilatation and thinning and weaken the cell-matrix connections, which impairs contractile function.
The RV did not undergo initial remodeling to the same extent of the LV. It is well known that the RV is better in adaptation of the volume overload whereas the LV is better in adaptation of the pressure overload [107, 120]. The chamber difference also lies in the fact that LV alterations are more widely reported on than those of the RV and that the RV has exhibited milder remodeling than the LV [121]. The less pronounced remodeling including the ECM alteration of the RV may be explained by the different origins and contractile behaviors of cardiomyocytes [120, 122] and, thus, different responses to the mechanical stimulations.
Like in pressure overloaded HF, myocardial stiffening also arises in response to volume overload and eventually leads to heart failure [123, 124]. For instance, Emery et al. reported a 10-fold increase in LV mid-wall stiffness along the fiber direction and the cross-fiber direction six weeks after volume overload induction [125]. The underlying cause of the myocardial stiffening is investigated by collagen measurement. Interestingly, despite the decrease in the relative collagen content, there was an upregulation of collagen cross-linking [115]. A similar finding was identified using hydroxylysylpyridinoline (HP) assay in minipig LVs [126]. Therefore, despite a decrease in total collagen content, the tissue stiffening occurs due to elevated cross-linking in these ventricles [115, 125, 126].
Myocardial compliance, however, showed different trends of changes than the intrinsic (material) mechanical property of the myocardium. This is because the chamber compliance is a measurement of overall stiffness that incorporates changes in the intrinsic mechanical property, the geometry of the wall (dilatation and thinning) and the contractility of the heart (ventricular pressure). In the acute stage, the LV wall dilated and the compliance increased 2 days after induction of volume overload [112]. Similar findings are reported in the compensated stage. A significant decrease in the end-diastolic pressure-volume relationship (EDPVR) and a right shift of the pressure-volume loop were seen in the group with 8-week volume overload [127]. This indicated increased compliance and chamber dilatation. But at 15–21 weeks of volume overload, there was no significant change in the EDPVR compared to that at week 8 [127]. Thus, the maintained compliance may be a combined results of increased intrinsic stiffness and decreased myocardial thickness.
Both pressure overload and volume overload are categorized as the hemodynamic (mechanical) ‘insult’ of the myocardium. The pressure overload is considered as an afterload increase whereas the volume overload is considered as a preload increase. Therefore, the main mechanical stimulus difference lies in the ‘phase’ – systolic phase for pressure overload and diastolic phase for volume overload, during which the cells sense increased wall stress or stretch. The comparison of physiological changes and cellular responses are reviewed previously [110, 111, 128], and temporal myocardial responses to pressure overload and volume overload are summarized in Figures 2 and 3.
Temporal changes in myocardial fibrosis, wall stiffening and physiological function in pressure overload induced heart failure progression.
The initial (early) remodeling of these two types of overload is different, leading to concentric remodeling (reduced volume and increased wall thickness (h) to radius (r) ratio) in pressure overload and eccentric remodeling (increased volume and reduced h/r ratio) in volume overload. Sometimes these changes are considered as ‘adaptive’ since the wall stress was normalized by the remodeling (according to Law of Laplace). However, at the cellular level, the ‘growth’ of cardiomyocytes is in width (pressure overload) and in length (volume overload), respectively. Interestingly, it remains unclear why and how the cardiomyocytes respond to the higher stress at passive and active states differently [129]. Furthermore, as pointed by Pitoulis et al., the late remodeling of these two types of overload ‘converges’, indicating some common pathways shared in the decompensation stage [128]. The convergence could be caused by a co-existence of these mechanical overloads in the same patient or by the key shared pathways that lead to irreversible remodeling at the late stage of heart failure. These are important questions that remain to be investigated to further improve the clinical management of non-ischemic heart failure patients.
Temporal changes in myocardial fibrosis, wall stiffening and physiological function in volume overload induced heart failure progression.
Myocardial infarction (MI) is caused by a reduction of blood perfusion in coronary arteries and necrosis—cardiomyocyte cell death [130]. This is the most studied type of heart failure, and there are numerous reviews on ECM changes in MI [1, 2, 21]. Acute and chronic MI lead to significant inflammatory and fibrotic responses by recruitment and activation of neutrophils, macrophages and (myo)fibroblasts. Interstitial and perivascular fibrosis from both replacement and reactive types of collagen accumulation greatly reduces the cardiomyocyte population and muscle contractility. The failure to resolve the fibrotic region (scar) results in a continuous stiffening and dilatation of myocardium and irreversible HF [105]. Compared to the LV, the RV is less susceptible to ischemic injury and it can recover after prolonger coronary occlusion [131, 132]. Therefore, our discussion below is mainly focused on the LV.
The initial response of MI is a cascade of events including the release of MMPs and proteases, which is thought to trigger the post-MI inflammatory response and to degrade the ECM following proliferative phase [12]. Then, collagen deposition is seen most prevalently in the infarcted region, creating a fibrotic scar [133]. The injured region can be clearly identified, with a high-density mesh of small diameter, aligned collagen fibers [134]. Both collagen types I and III were increased in infarcted LVs [134, 135]. Cleautiens et al. found that type I procollagen expression was increased and peaked by 10-fold four days post-MI, and the elevation remained 90 days after infarction. A similar trend was seen in type III procollagen, however its levels reached a peak later at day 21 post-MI [135]. Alternatively, experimental work also shows that the procollagen type III induction occurs earlier than that of procollagen I [136]. Other fibrillar collagen, such as types V and VI, increased in infarcted areas; for instance, the content of type VI peaked two weeks post-MI [137]. Elastin content was found to increase initially, but it rapidly decreased to values lower than the healthy tissue [134].
Moreover, regional changes occur in the non-infarcted zones. In the rat LV, collagen concentration increased by 50% in the infarcted region, whereas only a 27% increase was reported in the remote region [138]. Furthermore, collagen cross-linking only occurred in the infarcted zone and not in the remote region [138]. Similarly, there was a gradient of changes in the mechanical properties in different regions. The infarcted region showed mechanical alterations to the highest degree; the border zone showed moderate changes, and the remote region showed little to no change [139]. ECM remodeling also arises in the septum and RV with infarcted LV [135]. A 4–5 folds increase in expression of procollagen types I and III mRNA was observed in the septum within three weeks post-MI, followed by a decline to control levels. A less but significant elevation of collagen types I and III also occurred in the RV, with levels of type III remaining elevated 90 days post-MI [135].
The injured area post-MI is predominantly a fibrotic scar with time-dependent changes in mechanical properties. Torres et al. found that the myocardial stiffness increased initially in the MI region, then in the border zone and the remote region. At 28 days post-MI, the myocardial longitudinal stiffness in all three regions decreased, and the reduction was most notable in the MI region with a 40% decrease [139]. Decreases in stiffness in the infarcted zone in late MI have been documented in other studies: the tissue becomes more compliant and more isotropic compared to the healthy tissue [140]. The initial increase in stiffness can be attributed to deposition of collagen and increased collagen isotropy [141]. At later stages, tissue became softer (e.g., 6–8 weeks post-MI) due to collagen degradation [131, 132, 140, 141]. These biomechanical changes are speculated to contribute to the further thinning and dilation of the myocardium leading to irreversible HF. Thus, the end-stage of HF due to MI, pressure overload and volume overload seem to share some common pathways associated with similar biomechanical alterations.
Heart valve disease can occur as a result of various causes such as aging, birth-defects, or infections. Depending on the mechanical abnormalities, the heart valve disease can be categorized into two types—stenosis (with reduced opening of valves) and regurgitation (with incomplete closure of valves). These mechanical changes will increase the mechanical load of the ventricle and reduce cardiac output. Often the disease progression involves a mix of pressure and volume overloads and biventricular dysfunction. Aortic valve disease (AVD) is the most studied heart valve disease and involves high levels of ECM degradation and calcification. For instance, collagen I and III decreases resulted in decreased valve stiffness [142]. But the aggregation of calcium hydroxyapatite (calcification) that replaces degraded collagen can lead to an ultimate stiffening of the valve leaflets. We recommend the reader to these thorough reviews of the biomechanical changes of heart valves in heart valve disease [143, 144, 145].
In healthy valve leaflets, collagen makes up ~90% of the ECM and thus is the main load-bearing component. Elastin, proteoglycans, and GAGs also contribute to the mechanical properties of the heart valves. This dense connective tissue is highly organized and present special viscoelastic mechanical behavior (minimal creep but significant stress relaxation) [146]. Therefore, any changes in the collagen fiber orientation or ECM proteins will induce mechanical dysfunction and thus abnormal opening/closing of the valves. The necessity of investigation of valve ECM is recently reviewed [143]. Furthermore, for the atrioventricular valve (i.e., mitral valve or tricuspid valve), the additional connection of the leaflets (LL) to the chordae tendineae (CT) and then further to papillary muscles (PM) has extended the research into transition regions of LL-CT and CT-PM. Because CT rupture is the primary cause of valve regurgitation, the mechanical properties of these regions are critical to delineate the pathology. Advanced methodologies on collagen fiber quantification (e.g., X-ray diffraction) and computational models were recently adopted to investigate the macro- and micro-mechanical properties of these transition regions [147, 148], although the research has been mostly focused on healthy tissues. A nice review of the microstructural mechanical characterization on CT of valves is referred here [149].
Collagen fibers in the CT contribute greatly to the overall function of the valve [147]. From the mitral valve (MV), collagen fibers found in the CT form a ‘core’ that are oriented longitudinally, with another group of collagen fibers that wrap around the core, offset from the primary axis [150]. Conversely, it has been observed that the CT extending from the tricuspid valve (TV) consists of smaller diameter of fibers but in higher densities than the MV [151]. This difference in collagen formation is a result of the mechanical needs of each CT, as the TV experiences lower loading than the MV. In diseased valves such as myxomatous degeneration of the mitral valve (MDMV), collagen deposition and myofibroblasts activation are observed. Although accumulation of collagen fibers is often associated with increased stiffness, the CT in MDMV actually becomes more compliant. Barber et al. found that the elastic modulus (EM) of healthy CT (132 ± 15 MPa), as well as the failure strength (25.7 ± 1.8 MPa), were significantly higher than those of diseased CT in MDMV (40.4 ± 10.2 MPa and 6.0 ± 0.6 MPa, respectively) [152]. A similar finding was also observed in other valve diseases: myxomatous degeneration of the tricuspid valve by Lim et al. [153], as well as by Casado et al. in the calcified mitral valve CT [154]. In such cases, the collagen fibers in the center core of the CT became disorganized and were no longer formed in tight bundles as they do in healthy CT [153]. Therefore, the altered alignment and dis-organization of the collagen fibers reduce the overall stiffness as well as the tensile strength of the CT.
As we discussed above, ECM remodeling is a critical part of tissue’s response to altered mechanical loads or other pathological stimulations (e.g., ischemia) [112, 113, 114, 155, 156, 157, 158, 159, 160]. This leads to dynamic alterations of the myocardial mechanical properties including the anisotropic, nonlinear elastic behavior as well as the viscoelastic behavior. The clinical relevance of ventricular mechanical behavior has been recently reviewed by our group [76]. In this chapter, we will focus on another impact – the cellular response to substrate biomechanical properties. Because of the prominent role of fibrillar collagen in myocardial mechanical behavior (especially in diseased tissues), we will mainly discuss the cellular response caused by fibrillar collagen deposition. The influence of other ECM proteins on cardiac cells during HF progression is reviewed in these references [12, 161].
The cardiac cell’s response to mechanical factors has been mostly investigated by exposing cells to steady or cyclic stretches to mimic myocardial contraction. Compared to the unstretched condition, there was significant increase in procollagen type I activity in cultured fibroblasts under cyclic stretching [156, 157]. Alternatively, Carver et al. evaluated the change in collagen III/I ratio in isolated cardiac fibroblasts. After 12 hours of cyclic loading, there was a 70% increase in the ratio of type III to type I collagen compared to unstretched cells [158]. Not only the collagen synthesis but also the degradation signaling pathway are upregulated by the mechanical loads. Multiple studies have found an upregulation of MMPs, particularly MMP-2 and MMP-9, in response to mechanical stretches compared to unstretched conditions [113, 155, 159]. Since the expression of collagen or procollagen was greater than that of MMP’s, a net increase in collagen was observed [155]. This mechanical regulation can be attributed to higher levels of transforming growth factor beta 1 (TGF-β1), which stimulates fibroblast’s growth and transdifferentiation and ECM protein synthesis [155, 160]. However, while these findings strongly advocate the mechanical regulation of cardiac fibroblasts and fibrogenesis, the unstretched condition is non-physiological and thus it is difficult to directly translate the findings into pathogenesis of fibrosis and heart failure.
More in-depth investigation of the substrate’s mechanical regulation is performed by varying the magnitudes of mechanical strains or comparing the effects of tensile stretch and compression. For example, after 24 hours of culture of cardiac fibroblasts, Lee et al. found that the expression of collagen type I mRNA significantly increased at uniaxial strain of 10% but showed no change at 20% strain. In contrast, type III collagen mRNA expression significantly increased at 10% strain but decreased at 20% strain. The response of collagen type III was more prominent than collagen type I [160]. In compression though, no significant change was noted in type I or III collagen mRNA. The different response between stretch and compression is intriguing as it implies that it is the mechanical signal in diastole (stretching of wall), not in systole (compression of wall), that stimulates the fibrotic response in fibroblasts. But a discrepant result is also reported. Kong et al. observed at compressive cyclic loading (5–20% strain) an upregulation in collagen type I and TGF-β1 expression [155], whereas Lee et al. reported significant increases only in TGF-β1 expression and no notable changes in collagen type I at 6% compressive strain compared to unstretched cells [160].
Besides the mechanical forces, it is also critical to investigate if and how the mechanical stiffness of the substrate affects cellular function. To date, a few
Biomechanical Cue | Cell Type | Main Finding | Ref |
---|---|---|---|
Polyacrylamide gel with varying stiffnesses: 8 kPa, 15 kPa, 50 kPa, 100 kPa (stiffness range from healthy to diseased heart | Adult Rat Cardiomyocytes (CM) | Contracting force of the CM tends to increase with matrix stiffness. Contractile function, though, is normalized when the matrix stiffness was returned to healthy levels | [165] |
PDMS surfaces with varying stiffnesses: 1 kPa, 6 kPa, 20 kPa, 130 kPa (embryonic stiffness to fibrotic heart stiffness) | Adult Rat Cardiomyocytes (CM) | On soft surfaces, CM exhibits greater contraction than those on stiff surfaces. Sarcomeres show faster shortening speeds on soft surfaces. TGF-β1 is more prevalent on stiffer surfaces | [166] |
PEG hydrogels with varying stiffnesses: 10 kPa (healthy neonatal heart), 35 kPa (diseased neonatal heart) | Neonatal Rat Ventricular Cardiomyocytes (CM) | Regardless of matrix stiffness, myocytes spontaneously contract and form healthy, organized sarcomeres. However, fractional shortening increased only on soft gels | [167] |
Collagen type I matrix morphology (fibrous vs. non-fibrous) and stiffness (48–170 kPa) | Alveolar-like Macrophages | Non-fibrous collagen leads to cells with higher filopodia (actin-rich protrusions) and higher CD206 expression, whereas stiffness has no significant impact on cell behavior | [168] |
Fibronectin coated polyacrylamide gels with varying stiffness: soft (1–5 kPa) to represent healthy artery and stiff (280 kPa-70 GPa) to represent atherosclerotic plaque | Human Macrophages | Stiffer substrates leads to larger cell spread area, faster migration speed, less dense but more organized F-actin, and increased proliferation rate | [169] |
Polyacrylamide Gel with varying stiffness: 1.2 kPa to represent normal lungs and 150 kPa to represent fibrotic lungs | Mouse macrophages | Cell elasticity increases with increased matrix stiffness; and cell elasticity is a major determinant of innate macrophage function | [170] |
PEG-RGD hydrogel with tangent (compressive) modulus from 130 kPa to 840 kPa | Mouse macrophages | Stiffer hydrogel leads to larger cell spread area and more extended branches of actin, activation of pro-inflammatory cytokines, and more severe foreign body response | [171] |
Summary of
The cardiac ECM is critical in maintaining cardiac tissue structure and function. Many studies have been conducted to measure ECM proteins in healthy and diseased myocardium to better understand their roles in cardiac remodeling – including the biomechanical changes. Our review shows that the ECM remodeling (particularly collagen accumulation) in HF is both spatially and temporally dependent. We have compared the myocardial collagen deposition, wall stiffening and systolic and diastolic dysfunction between early and late stages of various types of HF. While the initial remodeling events being quite different among these diseases, common biomechanical changes are shared in the end-stage of HF – ECM degradation with persisted cross-linking, which are associated with thinning and dilatation of the myocardial wall. However, the relation of cardiac fibrosis to the transition from compensation to decompensation remains to be elucidated. Furthermore, we have high-lighted different responses of the LV and RV to ‘identical stimulus’ (pressure overload, volume overload and ischemia). The interventricular difference should be another important future direction of research, which may help to bring new insights into the pathogenesis and treatment for ventricular failure.
The authors declare no conflict of interest.
Estuaries are places where silting-up events usually occur. Different processes are the root of particle sedimentation on the bed, which contributes to the filling process of estuaries. Flocculation processes (aggregation and break up), erosion, deposition and compaction are major phenomena that must be considered in order to predict the long term behaviour of estuarine sedimentary dynamic. So, in sedimentary transport, as well as other problems with particulate flows, the complex dynamics is not well described [1].
Most of the study had been realised at macro-scales, due to the huge number of particles that constitute these particulate systems, where the fluid and the particles can be considered as a mixture. So it is of single-phase models at large scale without [2] or with sedimentation consolidation model [3]. They can simulate the behaviour of large-scale systems such as estuaries or ports. At smaller scale, Euler–Euler two-phase flow models have been used with success [4, 5, 6, 7, 8, 9, 10]. The predictive ability and accuracy of theses codes depend essentially on the quality of the closure equations that model phenomena at smallest scales. Processes such as drag or lift forces acting on a suspension are not well established, and there is clearly a need to better understand smallest-scale phenomena in order to better formulate these constitutive relations.
Direct numerical simulation models for particulate flows have received a great attention for 20 years. In these methods, the fluid phase is governed by the Navier–Stokes equations, and the rigid inclusions are governed by Newton’s laws. The flow field around each particle is resolved, and hydrodynamic interactions are results of simulations. Such a model was proposed by Glowinski et al. [11], Peskin [12], Yu and Shao [13], Wachs [14].
Natural sediments responsible for the morphodynamic of the estuaries and coast are of different sizes and densities. Some are cohesive and some are non-cohesive. The transport in suspension and their sedimentation of such a polydisperse suspension are different than the ones for a monodisperse suspension [15]. Thus, the complex behaviour of such particulate systems is not well understood and not really explored by numerical investigations.
We propose here to examine the sedimentation of a polydisperse suspension by the use of a two-dimensional fully resolved model that we developed and validated with monodisperse suspensions in water column. Section 2 briefly describes the mathematical and numerical background of the model. Section 3 presents a validation of the model. Simulation results on the sedimentation of monodisperse and polydisperse particle systems are discussed in Section 4. Finally, Section 5 presents the conclusions and perspectives of the work.
In the direct numerical simulation models for particulate flows, the fluid phase is governed by the Navier–Stokes equations, and the rigid inclusions are governed by Newton’s laws. The flow field around each particle is resolved, and hydrodynamics interactions are results of simulation. The model presented here is based on the ‘Direct-Forcing/Fictitious Domain’ method of Yu and Shao [13] and the Direct Numerical code of Guillou and Makhloufi [16]. Herein we briefly recall the basic equations with special closure laws. More details can be found in Verjus [17] and Verjus et al. [18].
Let consider a Newtonian fluid and one rigid cylindrical particle. Let
where
A fractional-step method is used in order to decouple the problem described by the Eqs. (1)–(5). For a time instant, three major steps are written: one for the prediction of the fluid velocity (and pressure) (Eqs. (6) and (7)); one for the calculation of the particle’s motion and the interaction with the fluid (Eqs. (7)–(9)); and the last one to correct the fluid’s velocity (Eq. (10)). The present model is an extension of the SUDRES code [16] for the DNS of the fluid flow in two dimensions. A Finite Difference Method on a staggered grid and a projection technique are used to solve the fluid problem. Finally, the time marching-algorithm used is as follows:
• Step 1: Calculation of the fluid velocity and pressure with a projection method
• Step 2: Calculation of the particle subproblem for
◦ Step 2.1: Calculation of
◦ Step 2.2: Calculation of
• Step 3: Correction of the fluid velocity
The discretization of the particle (Lagrangian mesh associated to the particle) is still an open question. In the Distributed Lagrangian Multiplier Method, different techniques are used to discretize the particle [19], but the Collocation Element Method is often used. In the present study, a structured meshing strategy is used to discretize the particle (Figure 1). So for the solid problem, the particle is dicretized with the Collocation Point Method. The arrangement of the Lagrangian points is presented in Yu and Shao [13]. Special attention is dedicated to the space between particle nodes: it is greater than the fluid nodes space as suggested by Glowinski et al. [11]. Bilinear interpolations are used to interpolate quantities defined on the fluid’s mesh (Eulerian) on the particle’s mesh (Lagrangian) and vice versa. A trapezoidal rule is used to perform integrals. The collision strategy employed in this code is based on a normal repulsive force acting when two particles are too close each other [11].
Meshes of the fluid and solid domains.
The numerical model is validated by three cases: the simulation of the flow around a fixed particle, the sedimentation of one particle and the sedimentation of two particles.
The first test case is the fixed cylinder (circular particle) in Poiseuille flow. A cylinder is placed at the centre of a channel of width
Flow past a circular cylinder (vorticity on the left and stream line on the right) in a channel (width/diameter = 4) for
Rep | 0.5 | 1 | 5 | 10 | 20 | 0 | 100 |
---|---|---|---|---|---|---|---|
Present | 93.00 | 46.68 | 10.28 | 6.05 | 3.96 | 2.84 | 2.16 |
Present | 90.34 | 46.68 | 10.01 | 5.89 | 3.85 | 2.75 | 2.08 |
Present | 89.11 | 44.73 | 9.88 | 5.83 | 3.80 | 2.72 | 2.06 |
Yu and Shao [13] | 87.95 | 44.16 | 9.95 | 5.75 | 3.76 | 2.68 |
Drag coefficients for several Reynolds numbers and for several mesh sizes (
The second test case concerns the sedimentation of circular particle in a fluid at rest. The gravity is along the channel axis. The domain and numerical parameters are identical to the ones used for the first case. The Froude and Reynolds numbers are based on an estimation of the settling velocity
Sedimentation of a circular particle (
This test concerns the sedimentation of two particles in a close domain. The simulations for
Sedimentation of two particles: (a) trajectories of the particles; (b) equilibrium positions of the particles; (c) time evolution of the dimensionless rotation velocity.
This configuration corresponds to the experiment of Jayaweera and Mason [21]. As described by Feng et al. [22], the trailing cylinder accelerates in the wake of the leading one and then turns around this one until the centre of the cylinders is horizontally aligned. Afterwards, the two particles move apart on the horizontal direction. This phenomenon is found in the simulation. As Feng et al. [22] showed the trailing particle oscillates around the channel axis, whereas the leading one oscillates with smaller amplitude around an axis close to wall. Figure 4c shows that the rotation of the particles is accounted for. The rotational velocity is quite small but not nil. More details about the chaotic sedimentation of two particles at low Reynolds number were presented in Verjus et al. [17].
In this section, the sedimentation of a great number of particles is considered. The settling velocity depends on the number of particles. The more there are, smaller is the velocity. In such a case, the terminal velocity formulation is close to the one proposed by Richardson-Zaki [23]:
The problem concerns the sedimentation of
Snapshot of the sedimentation of an initially homogeneous suspension of 785 particles (
A comparison with macroscopic parameter such as the settling velocity of Richardson-Zaki can be made. But a control surface (volume in 3
In Figure 6 (left), the clear water interface is drawn for several solid volume fractions. At the beginning of the motion, the interface settles with a constant velocity and then reaches a regime for which the evolution slows down. This is hindered settling regime. After a while, there is no motion. It corresponds to the gel point. The hindering regime depends on the number of particles, so its time duration is longer for the higher initial solid volume fraction. The right picture presents the evolution of the dimensionless settling velocity versus the solid volume fraction (0.026, 0.058, 0.103, 0.136, 0.233 and 0.32 which correspond to 136, 306, 544, 850, 1204 and 1666 particles) for
Left: Time evolution of the clear water-suspension interface (settling curve) for three initial solid volume fractions 0.32, 0.162, 0.058 (
In this section, we consider the sedimentation of a poly-disperse suspension. The simulations are two dimensional, and particles are represented by discs with three different diameters:
Snapshots of the sedimentation of tri-disperse particles in a closed box (grey particles for diameter
Figure 7 presents the motions of particles and the fluid flow for various instants. At the beginning of simulation, the suspension is homogeneous in the domain. After few seconds, most of smallest particles are expulsed upwards, whereas the two other kinds of particles fall on the bottom. However, the biggest particles fall faster than medium ones and then reach the bottom first. In the suspension, two different areas appear: one which is essentially composed of smallest particles in the upper part and a second one constituted with a non-homogeneous mixture of small and medium particles. The bed is constituted in majority of big particles. At the end of simulation, particles are fully segregated, and the bed is composed of three layers filled mainly with respectively one class of particle.
Figure 8 presents the vertical evolution of the net pressure at different instants. This pressure corresponds to the total pressure less the hydrostatic pressure in that case. At the beginning of the simulation, the pressure gradient is constant. Two areas appear at instant
Net pressure versus height at different instants. Right figure is the simulation with the parameters presented in the article. Left figure, the simulation case differs by the number particles by species (114 particles of diameter
Where
Particles arrangement in the bed at the end of the simulation. Velocity vectors and contours are plotted (unity: cm/s).
A fully resolved model based on the Direct-Forcing/Fictitious Domain method (DF/FD) was developed to study the sedimentation of particles. It was validated on simple cases and applied to the sedimentation of mono-disperse particles. The macroscopic behaviour of the solution corresponds to experimental results and average settling velocities follow a Richardson-Zaki type law. The application of the model to a poly-disperse suspension leads to the apparition of a natural segregation of the particles on the bed. As the pressure is computed by the model, the pressure between the grains can be extract. So the excess pore pressure along the vertical is extract. It appears that at the end of the simulation, but not of the rearrangement of the bed, the pressure profile approaches the law proposed by Guazzelli and Morris [24].
The results presented here are limited to low Reynolds numbers, so we will explore other range of Reynolds numbers. The simulation of sedimentation of particles with complex shapes is possible, but a supplementary work is necessary concerning the collision strategy.
We would like to thank the Syndicat Mixte du Cotentin for financing the computational resources.
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extensive scientific interest during the last decades, due to their ability to directly convert the thermal energy to electricity. This is described by the well-known “Seebeck effect”. TE materials can convert also electricity into cooling through the “Peltier effect”. As such, TE materials and thermoelectric generator (TEG) devices can be utilized for potential applications including (i) thermal energy harvesting, (ii) local cooling and (iii) temperature sensing. The direct conversion of heat into electricity has been one of the most attractive solutions to the severe environmental and energy issues the humanity is coming across. This chapter covers the fundamental working principle of TE materials, the synthetic protocols for inorganic and organic thermoelectric materials, techniques and technologies for the fabrication of thermoelectric generators (otherwise defined as thermoelectric module devices) and a number of applications. Finally, future aspects and outlooks for further advancements at the “material” or “device” level for efficient power generation are remarked.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Lazaros Tzounis",authors:[{id:"288931",title:"Dr.",name:"Lazaros",middleName:null,surname:"Tzounis",slug:"lazaros-tzounis",fullName:"Lazaros Tzounis"}]},{id:"11874",doi:"10.5772/10128",title:"Some Chaotic Points in Cuprate Superconductors",slug:"some-chaotic-points-in-cuprate-superconductors",totalDownloads:2130,totalCrossrefCites:2,totalDimensionsCites:3,abstract:null,book:{id:"3573",slug:"superconductor",title:"Superconductor",fullTitle:"Superconductor"},signatures:"Özden Aslan Cataltepe",authors:null}],mostDownloadedChaptersLast30Days:[{id:"67825",title:"Organic Thermoelectrics and Thermoelectric Generators (TEGs)",slug:"organic-thermoelectrics-and-thermoelectric-generators-tegs-",totalDownloads:1291,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Inorganic and organic thermoelectric (TE) materials have received an extensive scientific interest during the last decades, due to their ability to directly convert the thermal energy to electricity. This is described by the well-known “Seebeck effect”. TE materials can convert also electricity into cooling through the “Peltier effect”. As such, TE materials and thermoelectric generator (TEG) devices can be utilized for potential applications including (i) thermal energy harvesting, (ii) local cooling and (iii) temperature sensing. The direct conversion of heat into electricity has been one of the most attractive solutions to the severe environmental and energy issues the humanity is coming across. This chapter covers the fundamental working principle of TE materials, the synthetic protocols for inorganic and organic thermoelectric materials, techniques and technologies for the fabrication of thermoelectric generators (otherwise defined as thermoelectric module devices) and a number of applications. Finally, future aspects and outlooks for further advancements at the “material” or “device” level for efficient power generation are remarked.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Lazaros Tzounis",authors:[{id:"288931",title:"Dr.",name:"Lazaros",middleName:null,surname:"Tzounis",slug:"lazaros-tzounis",fullName:"Lazaros Tzounis"}]},{id:"11871",title:"X-ray Micro-Tomography as a New and Powerful Tool for Characterization of MgB2 Superconductor",slug:"x-ray-micro-tomography-as-a-tool-for-quantitative-characterization-of-mgb2-superconducting-materials",totalDownloads:2837,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"3573",slug:"superconductor",title:"Superconductor",fullTitle:"Superconductor"},signatures:"Gheorghe Aldica, Ion Tiseanu, Petre Badica, Teddy Craciunescu and Mattew Rindfleisch",authors:null},{id:"66134",title:"Heat Recovery and Power Generation Using Thermoelectric Generator",slug:"heat-recovery-and-power-generation-using-thermoelectric-generator",totalDownloads:1291,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"In this chapter, experimental analysis of the direct conversion of thermal energy into electric energy was carried out, in order to encourage the conscious use of energy and to reduce waste. The conversion of thermal energy into electrical energy occurs in a thermoelectric generator through the Seebeck effect. This effect is associated with the appearance of an electric potential difference between two different materials, placed in contact at different temperatures. This relation between temperature and electrical properties of the material is known as thermoelectricity. This experimental study has as objective the obtaining of operating characteristic curves of the thermoelectric generator TEG1-12611-6.0, for different temperature gradients and under constant pressure between the heater plate and the heat sink. Resistors were used to heat the thermoelectric generator, which simulates the residual heat, and insulation material to minimize the dissipation of heat to the environment. For cooling, a heat exchanger was used in order to maximize the temperature difference between the sides of the thermoelectric generator. In this way, it was possible to perform an experimental analysis of the obtained electric power for different temperature ranges between the faces of the generator and, with this, verify the applicability in real systems.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Luis Vitorio Gulineli Fachini, Pedro Leineker Ochoski Machado, Larissa Krambeck, Romeu Miqueias Szmoski and Thiago Antonini Alves",authors:[{id:"227996",title:"Prof.",name:"Thiago",middleName:null,surname:"Antonini Alves",slug:"thiago-antonini-alves",fullName:"Thiago Antonini Alves"},{id:"229395",title:"MSc.",name:"Larissa",middleName:null,surname:"Krambeck",slug:"larissa-krambeck",fullName:"Larissa Krambeck"},{id:"286032",title:"Mr.",name:"Luis Vitorio",middleName:null,surname:"Gulineli Fachini",slug:"luis-vitorio-gulineli-fachini",fullName:"Luis Vitorio Gulineli Fachini"},{id:"293535",title:"Mr.",name:"Pedro Leineker",middleName:null,surname:"Ochoski Machado",slug:"pedro-leineker-ochoski-machado",fullName:"Pedro Leineker Ochoski Machado"},{id:"293537",title:"Prof.",name:"Romeu",middleName:null,surname:"Miqueias Szmoski",slug:"romeu-miqueias-szmoski",fullName:"Romeu Miqueias Szmoski"}]},{id:"66622",title:"Thermoelectric Generator Using Passive Cooling",slug:"thermoelectric-generator-using-passive-cooling",totalDownloads:912,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter presents an analysis of a point-of-use thermoelectric generator that is patented by one of the authors. The design, implementation and performance of the generator for powering electronic monitoring devices and charging batteries is discussed. This passive generator has no moving parts and relies on ambient air cooling. In one iteration it produces 6.9 W of steady state power using six Laird thermoelectric modules (Laird PB23 Series, HT8, 12) when placed on a 160°C steam pipe with a 30°C ambient environment (\n\nΔ\nT\n\n of 130°C). The generator produced 31.2 volts (V) open circuit and 0.89 amperes (A) short circuit. It successfully powered two microcontroller-based security cameras, one with a wireless Local Area Network (LAN) and another with cellular connectivity. In another scenario, the generator produced approximately 6 W with a steam pipe temperature of 140°C and an ambient of 25°C (\n\nΔ\nT\n\n of 115°C). This second system powered LED lights, a cellular-interfaced video surveillance system, and monitoring robots, while simultaneously trickle charging batteries. A third installation totally powered a stand-alone 3G web security camera system.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Robert Dell, Michael Thomas Petralia, Ashish Pokharel and Runar Unnthorsson",authors:[{id:"86966",title:"Dr.",name:"Runar",middleName:null,surname:"Unnthorsson",slug:"runar-unnthorsson",fullName:"Runar Unnthorsson"},{id:"285210",title:"Prof.",name:"Robert",middleName:null,surname:"Dell",slug:"robert-dell",fullName:"Robert Dell"},{id:"294487",title:"MSc.",name:"Michael Thomas",middleName:null,surname:"Petralia",slug:"michael-thomas-petralia",fullName:"Michael Thomas Petralia"},{id:"294497",title:"BSc.",name:"Ashish",middleName:null,surname:"Pokharel",slug:"ashish-pokharel",fullName:"Ashish Pokharel"}]},{id:"67254",title:"Quantum Theory of the Seebeck Coefficient in YBCO",slug:"quantum-theory-of-the-seebeck-coefficient-in-ybco",totalDownloads:755,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The measured in-plane thermoelectric power (Seebeck coefficient) \n\n\nS\nab\n\n\n in YBCO below the superconducting temperature \n\n\nT\nc\n\n\n (\n\n∼\n\n94 K) \n\n\nS\nab\n\n\n is negative and \n\nT\n\n-independent. This is shown to arise from the fact that the “electrons” (minority carriers) having heavier mass contribute more to the thermoelectric power. The measured out-of-plane thermoelectric power \n\n\nS\nc\n\n\n rises linearly with the temperature \n\nT\n\n. This arises from moving bosonic pairons (Cooper pairs), the Bose-Einstein condensation (BEC) of which generates a supercurrent below \n\n\nT\nc\n\n\n. The center of mass of pairons moves as bosons. The resistivity \n\n\nρ\nab\n\n\n above \n\n\nT\nc\n\n\n has \n\nT\n\n-linear and \n\nT\n\n-quadratic components, the latter arising from the Cooper pairs being scattered by phonons.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Shigeji Fujita and Akira Suzuki",authors:[{id:"82812",title:"Prof.",name:"Shigeji",middleName:null,surname:"Fujita",slug:"shigeji-fujita",fullName:"Shigeji Fujita"},{id:"87760",title:"Prof.",name:"Akira",middleName:null,surname:"Suzuki",slug:"akira-suzuki",fullName:"Akira Suzuki"}]}],onlineFirstChaptersFilter:{topicId:"736",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"28",type:"subseries",title:"Animal Reproductive Biology and Technology",keywords:"Animal Reproduction, Artificial Insemination, Embryos, Cryopreservation, Conservation, Breeding, Epigenetics",scope:"The advances of knowledge on animal reproductive biology and technologies revolutionized livestock production. Artificial insemination, for example, was the first technology applied on a large scale, initially in dairy cattle and afterward applied to other species. Nowadays, embryo production and transfer are used commercially along with other technologies to modulate epigenetic regulation. Gene editing is also emerging as an innovative tool. This topic will discuss the potential use of these techniques, novel strategies, and lines of research in progress in the fields mentioned above.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11417,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). She is the head of the Reproduction and Embryology Laboratories and was lecturer of Reproduction and Reproductive Biotechnologies at Veterinary Medicine Faculty. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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