Summary of changes in vitamin-k dependent proteins.
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",isbn:"978-1-83969-558-2",printIsbn:"978-1-83969-557-5",pdfIsbn:"978-1-83969-559-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"97b6de623f15598880112f6bafedc3e1",bookSignature:"Dr. Robert M.X. Wu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11916.jpg",keywords:"Business Models, E-commerce Marketing Strategy, E-commerce Business Models, Digital Transformation, Business Intelligence, E-business Applications, Research, Information System Management, Marketing Management, Electronic Commerce, Internet Marketing, Information Systems",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 26th 2022",dateEndSecondStepPublish:"May 24th 2022",dateEndThirdStepPublish:"July 23rd 2022",dateEndFourthStepPublish:"October 11th 2022",dateEndFifthStepPublish:"December 10th 2022",remainingDaysToSecondStep:"4 hours",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:'Dr. Wu holds a Ph.D. in e-Commerce, lectures at the School of Engineering and Technology in Australia, and is a Distinguished Professor at Shanxi Normal University, China. In 2011, Dr. Wu was recognized as a ‘Top 100 Outstanding Academic Leader for China’s Informatics’ by the China Informatics Society. He was awarded "Outstanding Contribution in Reviewing" by Q1 Journals such as Electronic Commerce Research and Applications (Elsevier).',coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"190913",title:"Dr.",name:"Robert M.X.",middleName:null,surname:"Wu",slug:"robert-m.x.-wu",fullName:"Robert M.X. Wu",profilePictureURL:"https://mts.intechopen.com/storage/users/190913/images/system/190913.jpg",biography:"Robert M.X. Wu has a diploma in Computer Science, a bachelor’s degree in Economics, and master’s and doctorate degrees in e-Commerce. He is currently lecturing e-commerce / Information Systems at Central Queensland University Australia (CQU). He has led more than ten industry-based research projects since 2012 and contributes to reviewing five A-level Australian Business Deans Council (ABDC) journals and Q1 journals.\r\nIn July 2011, Dr. Wu was recognized as a ‘Top 100 Outstanding Academic Leader for China’s Informatics’ by the China Informatics Society. In 2017 he was appointed Distinguished Professor at Shanxi Normal University, China. He was also awarded ‘Outstanding Contribution in Reviewing’ in 2016 and 2018 by the Electronic Commerce Research and Applications journal (Elsevier) and ‘Student Voice Commendation – EDUCATORS of THE YEAR 2020’ for Emerging Technologies in E-Business, CQU.",institutionString:"Central Queensland University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Central Queensland University",institutionURL:null,country:{name:"Australia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440204",firstName:"Ana",lastName:"Cink",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440204/images/20006_n.jpg",email:"ana.c@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Is There Any Evidence about Its Impact on Coronary Artery Disease?",doi:"10.5772/intechopen.99335",slug:"vitamin-k-deficiency-and-vascular-calcification-is-there-any-evidence-about-its-impact-on-coronary-a",body:'Cardiovascular diseases are the leading cause of mortality worldwide. Their constant increasing rate is attributed to many factors as the adoption of poor dietary habits and sedentary lifestyle accompanied in some cases with hereditary background. The so-called Western way of living has led also to the rise of other diseases such as dyslipidemia, hypertension, obesity, diabetes mellitus and chronic kidney disease, which are the main risk factors of CVD. Those conditions are mainly responsible for the rapid progression of vessel’s atherosclerosis and plaque formation. Intimal calcification of large vessels is the main effect of those disorders responsible for plaque’s progression. However, atherosclerosis is not the only factor. Vascular calcification is another major and independent risk factor strongly related with the development of vessel plaque leading to CVD [1]. It is a chronic and multi-factorial procedure related mainly with disorders such as chronic kidney disease and diabetes mellitus [2]. The metabolic pathways which are responsible for the progression of vascular calcification is not well-established and consequently treatment remains a challenge. Media arterial layer is the target area of calcification and can involve all vessel sizes regardless of the concurrence of atheromatic plaque [3]. The negative effect of this procedure can gradually lead to the development of valvural heart disease and coronary artery disease (CAD).
Matrix degradation and modification is the main reason of medial arterial calcification. Matrix Gla protein (MGP), Gla rich protein (GRP) and growth arrest specific gene-6 (Gas-6) are a group of vitamin-k dependent proteins that is considered to effectively inhibit the progression of vascular calcification. For example, in cases of vitamin-k deficiency, glutamic acid residues do not convert to the amino acid γ-carboxyglutamic acid residuals (Gla) which is a vital part for the normal function of MGP. Consequently, inactive forms of MGP (dp-ucMGP) accumulate in calcified tissues such as the blood vessels. Past studies have proposed ucMGP as a potential marker of vitamin-K deficiency, vascular calcification and cardiovascular disease [4]. Other trials have showed that patients under treatment with vitamin-k antagonists (VKAs) had higher scores of vascular calcification compared to a group of controls. Animal trial connected the administration of VKAs with an accelerated progression of medial calcification. On the other hand, when high doses of vitamin-K were administered, calcification lesions started slowly to improve [5]. Perspectives about the benefit of vitamin-K administration in specific population remain controversial, and therefore further research is required in this domain.
The correlation between low vitamin-K levels and rapid progression of vascular mineralization is supported by researchers in the past [6]. The pathophysiological pathways that justify such claims involve a group of vitamin-K dependent protein and calciprotein particles. Those proteins are the matrix Gla protein (MGP), gamma-carboxylated Gla-rich protein (GRP) which are both considered as strong inhibitors of vascular calcification and the growth specific arrest gene-6. Matrix Gla protein (MGP) is a vitamin-k2 dependent protein which is secreted by many cells, including the vascular smooth muscle cells (VSMC) and has high affinity to calcium crystals. Its effect on atherosclerotic plaque may probably derive from the blocking of calcium accumulation. It’s present in bones and cartilage, in kidneys but also in blood vessels, endothelium and coronary artery. Matrix Gla protein prevents from the calcification development in soft tissues such as the blood vessels. Additionally, its preventive effect is exerted by inhibiting the bone morphogenetic protein-2 and 4 (BMP-2, BMP-4). This effect is of outmost importance because it prevents the VSMC from the transdifferentiation into osteoblasts like-cells which lead into progressive calcification of atherosclerotic plaques. In order to exert its effect, MGP has to be synthesized locally in the VSMCs. Vitamin-k2 is used as co-factor to its formation through the post-translational γ-carboxylation and phosphorylation of inactive MGP [7]. Carboxylated MGP (cMGP) is the active protein form responsible for the prevention of the calcification of the arterial wall [8]. MGP’s expression from the VSMCs and the endothelium may give us the opportunity to measure its circulating levels. As it was mentioned before, cMGP has high affinity to calcium crystals and binds strongly to them preventing from their accumulation into the arterial wall. Considering that cMGP could evolve into a very promising biomarker for the prognosis and the progression of calcification as well as a prognostic factor to severe cardiovascular outcomes [9]. On the other hand, it should be mentioned that inactive forms of MGP have been associated with accelerated rate of vascular calcification but also with increased mortality [10]. Whereas the active form of MGP is both carboxylated and phosphorylated, the inactive forms have not undergone one of those two metabolic steps or both of them (uncarboxylated, dephosporylated MGP, dp-ucMGP). cMGP is the only factor that under specific conditions may promote the reversal of vascular calcification [11]. It is worth mentioning that calcified arteries have high concentrations of MGP and the severity of such lesions was related to MGP serum levels [12]. Gla rich proteins is another vitamin K dependent protein which is present in both bone and cartilage and also has high affinity to calcium. High concentrations of γ-carboxylated GRP have been observed in individuals with increased vascular calcification. However, suggested data derive mainly from animal studies and its functionality in humans is not well established. Calciprotein particles are particles that prevent from vascular calcification by blocking the formation of the calcium/phosphate crystals. These particles also contain high levels of MGP and GRP, so in cases of vitamin-k deficiency, their effect may be impaired. Vascular smooth muscle cells excrete also the growth arrest specific gene 6 protein (Gas-6) which is one of the stimulating factors of their growth. It exerts its preventive effect through several pathways. Initially it stimulates the bcl-2 anti-apoptotic protein which is responsible for the inhibition of caspase-3. Caspase-3 is a crucial protein for the pro-apoptotic cell procedure, so through that way Gas-6 protects VSMCs from transdifferentation into cells with osteoblast-like effects. Apoptotic cells could be used as substrate for the development of constant inflammation and excessive calcification. Thus, Gas-6 through this way Gas-6 prevents the arterial from this process. However, in order to exert its effects Gas-6 needs γ-carboxylation a process in which vitamin-k is a necessary co-factor [13]. Taking all that into consideration, Gas-6 is vitamin-K dependent and very important factor, against the VMSCs apoptosis and the progression of calcified plague. In cases of vitamin-k deficiency the lack of Gla proteins affect negatively the growth of VSMC [14] (Figure 1).
Summary of the effect of vitamin K deficiency on vascular calcification. Abbreviations: BMP-2, bone morphogenetic protein-2; VSMCs, vascular smooth muscle cell.
In past studies it was also observed that post-menopausal women with osteoporosis had increased rates of arterial calcification [15]. Based on that, researchers have investigated the potential correlation of vitamin-k status, bone formation rate and vascular calcification of post-menopausal women. Initially, lower bone formation rate in parallel correlation with low levels of serum vitamin-k. The same also applies for the increased frequency of vascular calcification observed in post-menopausal women [16]. Concerning, the lower bone mass of post-menopausal women, it seems that vitamin-k levels and osteocalcin induced remodeling bone process are closely related. Though not with the same metabolic way to vascular calcification but in both situations vitamin-k is necessary [17]. It is important to mention that few trials, evaluated the potential benefit of vitamin k2 supplementation in post-menopausal women with aortic calcification and osteoporotic lesions. According to the authors, calcified lesions were at least sustained or in some cases decreased. However, these beneficial effects were observed in individuals that received vitamin-k2 supplementation but not vitamin-k1 [18]. Finally, results from the study of Gast et al. in this group of patients, have showed that vitmamin-k2 had the greatest preventive effect in CAD [19]. There are data that suggest that osteoporotic women are on higher risk of cardiovascular disease compared to match-aged non-osteoporotic individuals. These evidence imply that this difference occurs due to increased vascular calcification of both large vessels and coronary artery in those patients. Vitamin-k2 may have an essential role both to bone formation via its effect on osteocalcin as well as to the reduction of vascular mineralization. Further and larger studies are needed in order to assess the potential benefit of vitamin-k2 supplementation in both bone mass loss, atherosclerotic progression and prevention of cardiovascular disease in this specific population [20].
Vitamin-k antagonists are oral anticoagualants that reduce the levels of vitamin-k by interfering in vitamin’s recycle. They essentially inhibit vitamin-k reductase complex-1 and consequently reducing active vitamin-k reserves. Thus, they prevent from the formation of blood clots. Nevertheless, vitamin-k depletion in serum has some detrimental effect on many sequences of steps in metabolic pathways like those mentioned before. Taking that in mind, previous studies have demonstrated the negative effect of VKAs on the progress of vascular calcification [5]. Win et al. examined the potential benefit of apixaban administration in patients with atrial fibrillation in terms of the atherosclerotic plaque progression. Study results showed that apixaban administration was associated with slower plaque progression as well as lower calcium scores compared to warfarin treated group. Taking into consideration the usual co-existence of atrial fibrillation and coronary artery disease, apixaban could be a preferable choice in patients with atrial fibrilation not only for the prevention of thromboembolic events but also to slow down coronary plague progression and prevent from fatal cardiovascular events [21]. Accordingly, outcomes from a trial that compared the use rivaroxaban against warfarin have also indicated the beneficial effect of NOAGs into the slower plaque progression arterial calcification [22]. Therefore, in cases of individuals with established CAD or high level of vascular atherosclerosis in need for anticoagulation, the physician should choose wisely the appropriate treatment. These data suggest the preferable choice of NOACs instead of VKAs though further studies are needed for more robust results. However, what about patients that are in need for VKAs coagulation, or the use of NOACs is contraindicated? Such dilemmas are common in clinical practice and therefore the presence of clearly defined guidelines is essential.
Chronic kidney disease is strongly associated with the presence of increased cardiovascular risk. The most frequent cause of death in this population is coronary artery disease as well as stroke events. Hypertension, dyslipidemia, diabetes mellitus, which are common comorbidities in patients with renal failure, are important factors that can lead to excessive atherosclerosis and the development of CVD. Moreover, vascular calcification is also excessive in patients with chronic kidney disease (CKD) and so it constitutes an independent risk factor for the development of CVD [23]. Age, time on hemodialysis, persistent hyperphospahetamia and hypercalciemia are some of the causes of accelerated vascular calcification. High calcium and phosphate levels are associated with the deposition of hydroxyapatite into the arterial wall [24]. Whereas the presence of intimal calcification, which is related mainly to large vessels, is almost the same between individuals with or without end-stage renal disease, this is not the case for median calcification of the arterial wall. For example, aorta calcification is worse in patients with renal disease compared to those without. Aorta calcification increases arterial stiffness, which consequently aggravates the present hypertension and finally contributes to the development or the deterioration of a pre-existing left ventricular hypertrophy and left ventricular insufficiency. Patients with end-stage renal disease have increased vascular calcification compared to non-CKD individuals, especially those that are under hemodialysis [25]. Coronary artery calcification is common among older patients with CKD. However past studies have also showed that younger individuals with end-stage renal disease have also a high percentage of vascular calcification as well as coronary artery calcification [26]. Using high resolution computed tomography; researchers have proved that coronary calcification was higher in young adults that were on dialysis compared to those that were not. At this moment, the main treatment approach against the vessel mineralization of CKD patients is the strict regulation of calcium and phosphate balance. Additionally, clinician focus their attention to better treatment management of concomitant disorders that affect atherosclerotic plaque, such as diabetes, dyslipidemia and smoking cessation. Even though there is no strong evidence that support the administration of agents that inhibit calcification, it is easy to understand that those interventions might play a crucial role to the prevention of CVD in CKD-individuals. In a microenvironment of constant inflammation, vascular smooth cells are gradually transformed in osteoblasts like-cells promoting then the development of medial artery calcification. This process is mediated by multiple proteins and is facilitated by the presence of systemic or local inflammation. The latter is of outmost importance for the reason that macrophages excrete among others, matrix-metalloproteinase which lead to the apoptosis of elastic fibers and thus promote vascular calcification. In addition, vitamin k-dependent matrix Gla protein and Gia-rich protein are both important for vascular calcification. As it was mentioned before, low levels of those proteins have been associated with increased rate of calcification and development of cardiovascular disease. Several studies in the past have proved the increased coronary artery calcification in CKD-individuals by calculating the number of vessel calcifications using high resolution computed tomography. According to the study of Holden et al. in patients with CKD and/or end-stage renal disease vitamin-K deficiency is very common. It is possible that this outcome has some extra effect on the progressive calcification of these patients [27]. At this point, treatment in order to delay the progression of vascular calcification in ESRD and CKD patients targets to the regulation of calcium and phosphate. However, dietary advice in order to prevent hyperkaliemia or hyperphospatemia leads to the avoidance of food rich in vitamin k, inducing the existing deficiency. A recent study with hemodialysis patients have studied the ffect of vitamin-k supplementation on the plasma levels of ucMGP, uncarboxylated osteocalcin and PIVKA-II. The results were very promising, because have showed a significant decrease of the inactive form of MGP and also proved the vitamin-k deficiency in this specific population. The outcomes of this study may be the beginning of future randomized controlled trials that will evaluate the effect of vitamin-k supplementation on vascular calcification of CKD patients [28]. Respectively, another study by Oikonomaki et al. in hemodialysis patients have demonstrated the reduction in uc-MGP levels after 1-year of vitamin-k2 supplementation but the progression of vascular calcification remained the same between studied groups [29]. It is possible that only vitamin-k supplementation is not enough in order to overt calcification. This process in such individuals is so multi-factorial that need a comprehensive treatment approach that will slow the progression. Further studies are needed in order to clarify the benefits of vitamin-k supplementation in ESRD or CKD patients.
Vascular calcification and especially coronary calcification is a strong predictor of coronary events and this is a process that is regulated actively by vitamin K dependent proteins which are called matrix Gla proteins. There are currently no pharmacological means to improve vascular stiffness and vascular calcification. There is growing evidence that vitamin K, a cheap and safe intervention that can have beneficial effects on cardiovascular health. Vitamin K straightforward administration can reduce the progression of vascular calcification. The biological rationale is that supplementation with vitamin K will carboxylate (activate) Gla proteins, whose role, among others, is to reduce the progression of vascular calcification [30]. Coronary artery calcification which is a significant marker of cardiovascular disease is affected by these dependent vitamin K proteins. As it was mentioned before vitamin-K deficiency promotes coronary artery calcification [6]. In animal studies, MGP removal showed severe progression of vessel calcification and this empowered the theory about vitamin K role in this process [31]. The most of the clinical trials showed that supplementation with Vitamin K2 (menaquinone) had beneficial effects in cardiovascular calcification. But a clinical trial from Shea et al. showed that also supplementation with vitamin K1 (phyloquinone) slowed the progression of coronary artery calcification. Though its effect was enhanced by the parallel administration of vitamin-D and calcium supplements [32]. On the other hand, Beulens et al., with a cross-sectional study among 564 post-menopausal women reached the conclusion that only high intake of menaquinone is associated with reduced coronary calcification, as it was measured via computed cardiac tomography [31]. Also Vossen et al. wanted to study a sample of patients with coronary artery disease and follow them up via Agatston calcium score about the progression of coronary calcification as long as the individuals were under vitamin-k supplementation [33]. The Roterdam Study, a prospective population-based study, showed in a sample of 7983 men and women aged 55 y and over in a follow up to 10 years, that dietary intake of menaquinone had a protective effect against coronary heart disease [18]. Also a meta analysis of 3 US Cohorts, among 3891 patients, who measured fasting circulating phyloquinone levels, showed that low phyloquinone levels was associated with increased all – cause mortality but not of CVD [32]. Many clinical trials as referred above showed a possible correlation between vitamin K and increased artery calcification mainly in high risk patients. A systematic review from Hartley et al. tried to show if there is primary prevention from CVD in healthy individuals who received supplementation with vitamin K. They only found a small clinical trial with only 60 patients that fulfilled their criteria and there was no significant impact in primary prevention of CVD and other CVD factors such as blood pressure and plasma lipids level (Hartley). However, this was a small clinical trial with short duration. Further studies are necessary about the benefit of vitamin-k supplementation in the primary prevention of CVD.
Valvular calcification is a common degenerative disease characterized by progressive valvurar calcification. Nowadays the incidence of valvural disease is higher probably due to increased life expectancy. The most commonly calcified valves is aortic valve followed by mitral valve. Based on the role of vitamin K as protective agent for cardiovascular health and especially as a protector against vascular calcification, some trials evaluated the potential effect of vitamin-k as a protective factor against the development of valvular calcification. Bradenburg et al. with a small prospective, open label clinical trial with 99 patients, selected individuals with asymptomatic or mild symptoms with aortic calcified valve and separated them in two study arms with vitamin-k1 supplementation and placebo. Then, they calculated the amount of calcification of the valve via cardiac computed tomography, at the beginning of the trial and after 12 months. Also they measured the dephosphorylated undecarboxylated MGP as a circulating marker for vitamin-k deficiency. Over the 12 month period, aortic valve calcification volume score progressed 10% in the arm with vitamin K supplementation compared with 22% in the placebo group. Also plasma dp-ucMGP were significantly reduced by 45% in the vitamin K group. On the other hand, this trial had many limitations such as the small sample, the short duration of follow up, the open-label design and the broad spectrum of severity of valvural disease at baseline [34]. Another clinical trial that is planned and want to study the effect of vitamin K in aortic calcification is from Peeters et al. concerning especially the calcification progress of bicuspid aortic valve. Bicuspid aortic valve, a common congenital abnormality, occurring in 13,7 per 1000 people in general population is associated with early development of calcific aortic valve stenosis. In this double-blind study they will supply vitamin K2 and follow up 44 people in a period over 18 months. The follow up of the sample will be every 6 months with PET/cardiac MRI, cardiac CT and echocardiography. This trial will provide us with more information for calcium activity on aortic valve and the potential effect of vitamin K. It will also open the way for large scale randomized clinical trials in order to develop potential treatment option against the progression of calcific aortic valve stenosis [35].
Vitamin-K deficiency is associated with low-levels of MGP and Gas-6 and the accumulation of GRP, ucMGP and dpMGP forms in soft tissues and vessels. As it was described before, vitamin-K is used as co-factor for the post-translational γ-carboxylation of MGP and Gas-6 in order to maintain preventive effect on vessels and VSMCs respectively. In addition, vitamin-k deficiency is associated with higher circulating levels of uncarboxylated or dephosphorylated forms of MGP. A three arm randomized controlled trial assessed the levels of deposhpo-carboxylated MGP levels after 12 weeks of menaquinone-7 supplementation. The dp-ucMGP levels were reduced significantly. It is important to mention that according to the authors the outcome was dose-dependent and increased in time [4]. In a systematic review meta-analysis of trials with different study-design by Lees et al., dp-ucMGP levels were significantly reduced with the administration of vitamin-k. However, that effect did not lead to the improvement of vascular calcification with the exception of a small number of studies. Concerning the use of dp-ucMGP as biomarker of CVD the results are controversial and so that is not suggested. It is important to mention that the greater efficacy was achieved with vitamin-k2 supplementation rather than k1 [30]. These data suggest that dp-ucMGP could be an important marker of vitamin-k status. It is worth mentioning that the co-administration of vitamin-k and vitamin-D have showed some promising results concerning the prevention of fatal CVD. However, larger randomized controlled trials are needed in order to delineate if vitamin-k supplementation alone or in combination with vitamin-D could benefit patients with progressive vascular calcification [36] (Table 1).
Vitamin-K sufficiency | Vitamin-K deficiency (ex. Inadequate intake, VKAs administration) | |
---|---|---|
MGP (vitamin-K dependent carboxylation) | ↑ active cMGP prevents: The hydroxyapatite formation The accumulation of calcium crystals Transdifferentiation of VSMCs into osteoblast like-cells Decreased BMP-2 activity | Significantly lower levels of MGP-2 and accumulation of its inactive forms (dp-uc MGP) with devastating impact on VC |
Gas-6 protein (γ-carboxylation with vitamin-K as co-factor) | Activation of anti-apoptotic protein Bcl-2 Inhibition of pro-apoptotic protein Caspase-3.* | ↓Gas-6 levels, inhibition of VSMCs growth and increased apoptosis |
VSMCs | Inhibition of apoptosis and transdifferention into osteoblast like-cells | Increased apoptosis and transdifferention into osteoblast like-cells |
Vascular Calcification | Suspended and possibly reversed medial VC** | Increased medial VC |
Summary of changes in vitamin-k dependent proteins.
Apoptotic cells are used as substrate for accumulation of calcium crystals.
Observed in small trials with co-administration with vitamin D. Further studies are needed.
VSMCs status and progression of vascular calcification depending on vitamin-k serum levels. Abbreviations: MGP, matrix GIa protein; Gas-6 protein, growth arrest specific gene 6 protein; VSMCs, vascular smooth muscle cell; VC, vascular calcification.
Vitamin-k is a fat-soluble vitamin mostly known for its significant role in the coagulation sequence of steps. However, vitamin-k is also important to other also important metabolic pathways. Vascular calcification has proved to be a multi-factorial procedure that leads to the transdifferentation of VSMCs into osteoblast phenotype like-cells and a vicious circle of arterial wall calcification. Vitamin-K dependent proteins MGP, GRP and Gas-6 play an important role in the regulation of this constant progressive process. In cases of vitamin-k deficiency, the preventive effect of those Gla proteins on the arterial wall declines and consequently the process of vascular calcification is enhanced. The calculation of the uncarboxylated and dephosphorylated forms of those proteins are considered a marker of vitamin-k deficiency. However, existing data do not suggest the use of dp-ucMGP as predicting factors of cardiovascular disease. Vitamin-k supplementation have been associated with a significant reduction in the dp-uc MGP circulating levels, although this reduction was not related with a reduction in the process of vascular calcification. Due to the multi-factorial process for the formation of calcified plagues, it cannot be suggested at this point that vitamin-k supplementation alone will reverse those lesions. Emerging evidence support the co-administration of vitamin-D and vitamin-K has a greater effect against the progression of vascular calcification. Concerning the effect of vitamin-k deficiency and cardiovascular health, evidence remains controversial. It is a given that more studies are needed in this area in order to draw safe and robust conclusions. Vascular calcification and atherosclerotic plaques are strongly related with arterial stiffness, hypertension and impaired cardiac function. It is of outmost importance to find solution of this degenerative procedure in order to develop additional preventive and therapeutic strategies against the development of cardiovascular diseases.
Terahertz radiation generally accounts for the photons of energy ranging from 414 μeV to 41.4 eV. This energy spectrum corresponds to the frequencies of 0.1–10 THz in the electromagnetic spectrum. In the past, it has been referred to as the ‘terahertz gap’ primarily due to the inefficient methods for generation and detection of waves in the frequency range [1, 2]. The major reason for the complexity in the designing of efficient THz systems was the presence of background noise sources in incoherent light (room temperature is 25 meV, or 6 THz) [2, 3, 4]. Over the past few decades, due to the advancement in the nanoscale fabrication, there has been a significant surge of progress in enabling integrated, compact and efficient chip-scale solid-state semiconductor technology that can operate at room temperature and can be manufactured at a low cost, exploiting economies of scale. Considerable work has been directed towards miniaturized technologies demonstrated with quantum-cascade lasers [5], microbolometers [6], nanowires [7], novel plasmonic nanostructures [8], metamaterials [9] and ultrafast conductive semiconductor materials [10]. This progress has resulted a major step towards a more holistic approach for realizing the development of THz systems for applications in communication, spectroscopy and hyperspectral imaging [11].
Interaction of the terahertz radiation with matter provides a vital low-energy probe to the electronic nature of doped semiconductors by generating carriers optically with a fraction of laser beam [12, 13], this technique is known as Optical Pump Terahertz Probe Spectroscopy (OPTPS). This technique has the benefit of allowing the carrier density to be readily controllable, and also allows the photoconductivity to be measured on picosecond time scales after photoexcitation. A detailed description of the OPTPS is presented by the authors of paper; [14], and further, the authors discussed the terahertz spectroscopy method to measure transient variation in the photoconductivity of bulk and nanostructured semiconductors. There are a number of terahertz spectroscopic techniques and applications which have been presented and discussed from various scientists around the world. The studies based on the terahertz spectroscopy of polymer-fullerene based hetrojunctions are reviewed by the authors of [15] and the utilization of near-field terahertz for ultrafast imaging is explained in depth by the authors of [16].
On the electronics front for the development of terahertz-based devices and integrated circuits (ICs), researchers across various disciplines have converged to address the technological challenges in the field. Scientists have made numerous efforts in engineering the fabrication of novel nanomaterials, and most importantly, in the development of theoretical framework to optimize the design parameters of the devices and ICs. The main result of this effort is reflected in the ability of various technologies to generate terahertz signals with sufficient power levels. Particularly in frequencies beyond 1 THz, the semiconductor technologies based on III–V group elements such as InP heterojunction bipolar transistors (HBTs), high electron mobility transistors (HEMTs) and GaAs-based Schottky diodes are now capable of generating power levels almost two to five times higher than a decade ago [17, 18]. Silicon-based integrated technology, providing a platform for massive integration has demonstrated complex phased array, imaging and communication systems with output power reaching up to the 100 μW at the terahertz frequency range [19, 20].
Semiconductor device modeling represents a physics-based analytical modeling approach to predict device operations at specific conditions such as applied bias (voltages and currents), environment (temperature and noise) and physical characteristics (geometry and doping levels). The fundamental understanding of the charge carrier dynamics plays a crucial role in the formulation of numerical models by implementing mathematically fitted conductivity equations. Numerical models are primarily used as virtual environments for device optimization to directly estimate the conductivity providing insight into the nature of charge carriers, their mobility and its dependence on time. In this chapter, the focus is on the conductivity at terahertz frequencies of bulk and nano-structured solid state materials. A variety of theoretical formalisms that describe the terahertz conductivity of bulk, mesoscopic and nanoscale materials are explained in the chapter (Section 2). The validity and limitations of the respective formulations are discussed to highlight the boundary of implementation for accurate calculations. The chapter starts with the definition of the complex conductivity (Section 3) and then the experimental method (Section 4) to obtain complex conductivity is described to develop the understanding of practical implementation. Finally, the effectiveness of surface passivation using hydrogenated amorphous silicon is quantified through time resolved terahertz spectroscopy and the results of the measurements are presented in the form of change in photoconductivity upon excitation from terahertz electric field (Section 6). Further, in the section, the results of Fourier transform infrared spectroscopy are discussed to comment upon the nature of bond formation in the amorphous silicon passivation layer.
The complex conductivity (
where
The response of a material to an electromagnetic wave is generally described by the dielectric constant of the material. Fundamentally, the refractive index of a material quantifies the combined response of a material to a electric and magnetic field which is given by the following equation,
where the dielectric function or electrical permittivity (
where
where
Generally, a valid assumption for the equations derived from Maxwell’s equation is the excitation from a conventional monochromatic plane wave propagating in the
where
In this chapter, various models for the terahertz conductivity are compared and outlined in sequential manner, initially the basic fundamental physics of charge transport is described to develop the understanding of terahertz conductivity in a homogeneous media. The chapter starts with the description of Drude-Lorentz model which is applicable in classical domain of charge transport and further discussed about the limitation in the applicability of the model. Further, the chapter provides the discussion of the models that functions effectively at the quantum mechanical domain and elucidates the mathematical expressions for the terahertz conductivity. The relationship between the length scale and the applicability of various conductivity models is demonstrated with the help of a schematics shown in Figure 1, it clearly separates the quantum and classical conductivity models based on the length scale of electrons mean free path in the semiconductor. The schematics also shows the conductivity models namely Drude-Smith and Plasmon model which consider the interfacial scattering of electrons into account for the sub-micrometer length scale of the semiconductor material.
The relevant terahertz conductivity models of blends and micro/nano-materials at different length scales.
A classical circuit theory forms a simple analog to examine the complex conductivity
Drude-Lorentz model provides the simplest approach to mathematically interpret the frequency-dependent conductivity of metals and semiconductors. This model considers the charge carriers i.e. electrons and holes transportation as a non-interacting gas plasma. It is assumed in the model that the charge carriers undergo random collisions at a rate
where at normal incidence the local electric field
It should be noted form the equation that the real part (
The plasmon model is a straightforward extension to the Drude-Lorentz model, in this model a restoring force with an external electromagnetic wave derives the motion of electrons which is governed by the equation of motion of a damped, driven simple harmonic oscillator [22]. The restoring force can be provided by electromagnetic or for instance electrostatic, by a surface depletion layer or accumulation layer, which is often the case when calculating for the charge transportation at the interface of semiconductors. Hence, the plasmon model is mostly applicable to model the terahertz conductivity of semiconductor nanomaterials. A mathematical term
A larger restoring force requires a greater value of
The oscillation frequency (
and
The equations are valid for the assumption that the charges are located on the surface of a small spherical particle which has the geometric factor
Conduction bands with normal metals can be significantly different from the ideal spherical energy band (that assumes an effective electron mass,
Scattering relaxation time is assumed to be independent of energy
A local-response regime is assumed.
The above reasons highlight the importance to achieve even better modeling accuracy and therefore it is necessary to move towards the more complicated semiclassical treatment of terahertz conductivity of materials.
In the Drude-Lorentz model, it is assumed that the charge carriers are propagating in the bulk of the material which means that the carrier displacement is less than the largest dimension
The conductivity of charge carrier undergoing restricted motion is derived from an extension of the Drude-Lorentz model, in which the charge carrier conserves a part of its initial velocity upon scattering from a boundary layer energy barrier [25]. It is assumed that the collisions are randomly distributed in time and
The subscripts DS and SP are used to distinguish the scattering times denoted in the Drude-Smith model and surface plasmon model. There is an alternate approach to simulate the conductivity of materials with length scales comparable to the mean free path which includes the effect of non-uniformity on the electronic states. The non-uniformity of the electronic states is the result of disordered materials for which long-range delocalized eigen states such as Bloch functions cannot be used to describe the electronic wavefunctions. Tight-binding approach more appropriately describes the localized states of disordered material [26]. The first order correction to the Drude-Lorentz model take the following form in the limit of weak disorder [26, 27, 28, 29],
where
Drude-Lorentz model is attempted to provide another extension which include the influence of an energy dependent
where the Cole-Cole (
A classical approach has been used to model the terahertz conductivity where quantum mechanical effects such as a finite density of energy states, or an energy dependent
The electron distribution function in equilibrium at temperature
where the chemical potential
where
Skin depth is much less than linear dimensions of metal, thus regarding it as planar and infinite in extent.
Normal incidence of propagation, thus simplifying to a one-dimensional problem.
Conduction electrons are quasi-free, having a kinetic energy
Collision mechanism is always described in terms of
A fraction p of electrons arriving at the surface is scattered specularly, while the rest are scattered diffusely.
This one-band free-electron model does not apply to multivalent metals, in which the electrons occupy more than one energy band (e.g., aluminum or tin).
While the semiclassical treatment takes into account partially-filled conduction band energy dispersion,
These assumptions laid the foundation of a more accurate theoretical framework which considers the quantum behavior of electrons for the purpose of calculating the charge carrier dynamics inside the semiconductor materials.
The conductivity associated with interband and intraband transitions can be determined accurately from the linear response theory or Kubo-Greenwood theory. The transition rate of electrons denoted by
where
where
The most prominent systems to form excitons from the binding of electrons and holes together, are the ones which exhibits quantum confinement and where the excitonic binding energy is enhanced by the quantum effects. The model of hydrogen atom can be used to derive a comparison for the eigen states of an exciton, where 1s, 2s, 2p, 3s,… are in spectroscopic notation. It is important to highlight the difference between the classical approach and the current approach, for the hydrogen atom, the lowest order electric dipole allowed transition (1s-2p) falls in the ultraviolet range while for GaAs quantum wells due to the lower effective masses of electrons and holes, and high dielectric constant, 1s-2p transition results in the excitons of terahertz frequency range. The expression of frequency dependent complex conductivity is yielded from the Fermi’s golden rule,
where
Further, for superconducting materials, Mattis-Bardeen theory provides the quantum mechanical expression for the conductivity. When the terahertz photon energy exceeds the Cooper pair binding energy
where
The extended Drude model provides an additional accurate approach to simulate the terahertz conductivity in quantum materials [30, 31]. It has been extensively applied to the visible and infrared conductivity of metals and superconductors, and is applicable for Fermi liquids with strong electron–electron interactions, rather than the weaker interaction of a Fermi gas. In this model, the single-particle effective mass (
and the energy-independent scattering time
Generally, the studies based on broadband spectroscopy are obtained from a method known as terahertz-time domain spectroscopy (THz-TDS) which measures the electric field of pulses of electromagnetic radiation directly in the real time after the interaction of radiation with the sample material. Short pulses (
Now, lets discuss about the detection methods, there are generally two competing technologies that are being used for the coherent detection of THz pulses which are as follows,
The first detection method is based on the change in the polarization state of an IR gate pulse due to the interaction with the electric field of THz pulse, this is known as electro-optic sampling [38, 39]. The polarization state of the pulse is often analyzed by a Wollaston prism and balanced photodiodes, and the electric field of THz pulse can be directly calculated from the experimental signals using known parameters of the electro-optic crystal [40].
The second method is the photoconductive detection of THz radiation pulses which is basically a inverse process of emission [34]. A photocurrent created by a gate beam flows between two contacts under the influence of the THz electric field, producing a signal that is proportional to
Commonly, a THz-TDS setup contains a photoconductive antenna which generates and detect THz radiation. The emitter chip generates a burst of terahertz radiation when excited by the photons of a subpicosecond laser pulse of average beam power in the range of few mW. A silicon lens is generally included in the setup which collimates the excited THz pulse for parallel free space propagation before reflecting from a parabolic mirror. A second mirror reflects the THz pulse onto the detector, and the time-dependence of the THz pulse is obtained by scanning the relative time delay between the emitter excitation pulse and the detection pulse. The conductive sample which is located between the parabolic mirrors, causes a time delay and a reduction in the amplitude of the THz pulse which can be compared with the reference THz pulse measured without the sample. This comparison gives the information about the magnitude and phase of the spectra and hence results in the numerical calculation of absorption coefficient and refractive index. Hence, the conductivity (
Compared with the THz-TDS method, Time-Resolved Terahertz Spectroscopy (TRTS) is an another important method to probe the conductivity at higher frequencies and is therefore sensitive to THz conductivity instead of static conductivity of materials. The sub-picosecond time resolution is suitable to study the ultrafast dynamics of carriers. The complex photoconductivity is calculated from the real time monitoring of amplitude and phase of emitted THz wave which is excited by the optical pump probe. For THz-TDS, electric field waveforms transmitted through the unexcited sample,
where the substrate is defined as the unexcited portion of the sample and the superscripts
Solar energy is one of the clean source of technology that has the potential to reduce the anthropogenic damage to the earth and its ecosystem. This puts the photovoltaic materials that make up solar cell as the subject of intensive study and scientists all around the world are analyzing the photovoltaic properties of novel materials to discover the true potential of solar energy [45, 46]. Time Resolved Terahertz Spectroscopy is one of the methods to analyze the conductivity of photovoltaic materials where spectroscopy, in general defines the study of interactions between matter and electromagnetic radiation. The sentence has been corrected. Generally, the field of spectroscopy plays an important role in the study of photovoltaic materials which is necessary for the efficient designing of solar cells. The investigation of early-time film dynamics offers unique opportunities to improve the photoconductive characteristics of the active materials by better understanding the carrier evolution properties.
Terahertz spectroscopy uses ultrashort pulse lasers to study the charge carrier dynamics of matter and electromagnetic radiation within extremely short time scales (nanoseconds to picoseconds). The lasers excite the specimen material in short pulses, which initiates the generation of charge carriers in the materials. Hence, provides a non-contact and accurate method to measure the photo conductivity of the material providing insight into the nature of charge carriers, respective mobility and time dependence of the conductivity. Hydrogenated amorphous silicon (a-Si:H) thin films are attracting increasing attention for their applications to silicon hetrojunction solar cells in surface passivation [47]. The state-of-art deposition method of intrinsic a-Si:H thin films is plasma enhanced chemical vapor deposition (PECVD), in this section we test the passivation capabilities of a-Si:H films on n-type silicon (Si) surface by measuring the change in conductivity (
where
Intrinsic a-Si:H films are deposited by an oxford instruments PECVD system using a source of silane gas (SiH4), where the hydrogenation of films is achieved by providing hydrogen gas (H2) for the generation of plasma in the deposition chamber. The total pressure inside the chamber is maintained around 400 mTorr with the partial pressure of SiH4 and H2 in the ratio of 5:4, which is determined experimentally for the optimum hydrogenation of amorphous silicon. Firstly, the samples are RCA cleaned and then, a dry oxidation of the sample is performed to grow a 100 nm double-sided layer of silicon dioxide (SiO2) on the silicon sample. Secondly, a forming gas annealing at 300°C is performed followed by the conductivity measurement to determine the reference measurements for the comparison purposes. Thirdly, a wet etching procedure using HF is performed to remove the top-layer of SiO2 and lastly, the sample is immediately placed in the chamber for the deposition of 30 nm of a-Si:H for surface passivation. The thickness of deposited amorphous silicon films are measured using a J.A. Woollam N-2000 spectroscopic ellipsometry system.
The schematic of the experimental setup is shown in Figure 2 and the results prepared for the measurements performed are shown in Figure 3. A pump probe delay time is varied in order to obtain the photoconductivity kinetics while the gating delay time is fixed at the peak of the terahertz electric field (
Schematic diagram of the terahertz setup used in probing charge carrier dynamics in hydrogenated amorphous silicon passivation layer. The transmitted electric fields,
Surface passivation effectiveness of a layer of hydrogenated amorphous silicon (a-Si:H). (a) Schematic of the double-layered sample under observation, it consists of one-sided growth of 100 nm SiO2 and on the other side 30 nm a = Si:H is deposited through PECVD process. (b) Scanning Electron microscopy (SEM) image of the top surface of the sample where an uniform layer of a-Si:H is clearly visible due to contrast difference between Si and a-Si:H. (c) the photoconductivity kinetics of the sample under study normalized to the excitation density where
Terahertz radiation, in particular the theoretical framework, has become a requirement to design faster and energy efficient devices. Successful first-pass design of components of a system requires the ability to accurately predict the dissipative losses due to charge-carrier scattering in semi-conductor and metallic materials used in waveguides, filters, antennas and optics. A comprehensive description of different formalisms was presented that allows the complex conductivity of semiconductor materials to be calculated at terahertz frequencies by including the energy dependence of the scattering rate. The generalized conductivity reduces to the Drude model in the limit of zero temperature or an energy independent scattering rate. Terahertz time-domain spectroscopy was used to determine the conductivity and the photoconductivity of hydrogen-doped amorphous silicon, which was semi-quantitatively accounted for by the generalized conductivity model. The breadth and depth of the studies of conductive solid state materials using terahertz radiation continues to advance and as the field is very broad, it is very important to understand the fundamental models to better utilized materials for future. Terahertz based spectroscopy methods can be valuable to not only in revealing fundamental processes or micro/nano strategies but also in providing insights for possible optimization of manufacturing procedures for solar cell industry.
Rahul Goyal would like to thank Ministry of Human Resource and Development, Government of India, for providing financial support and Centre for Nanoscience and Engineering for the research facilities.
The authors declare no conflict of interest.
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
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\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
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