Drugs that have been withdrawn from international marketplaces between 1995 and 2005 due to associated hepatotoxicity.
\r\n\tThis book shall focus on these antisense guided sequence specific silencing molecules with different mechanisms and potency for gene silencing, providing the reader with a comprehensive overview of the current state-of-the-art in ASO based therapeutics, featuring the more recent developments in terms of clinical translation and the use of nanomedicine for the effective delivery of therapeutic nucleic acids towards precision medicine.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"96f256f5bb2e750c7496b3c0b62cb95a",bookSignature:"Prof. Pedro Baptista and Prof. Alexandra R Fernandes",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9571.jpg",keywords:"gene therapy, gene silencing, genome modulation, post-transcriptional modulation, modified oligonucleotides, PNAs, LNAs, siRNA, antisense nucleotides, vectorization of antisense nucleotides, nanotheranostics, clinical translation, nanoparticles for gene delivery",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 25th 2019",dateEndSecondStepPublish:"November 15th 2019",dateEndThirdStepPublish:"January 14th 2020",dateEndFourthStepPublish:"April 3rd 2020",dateEndFifthStepPublish:"June 2nd 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"82671",title:"Prof.",name:"Pedro",middleName:null,surname:"Baptista",slug:"pedro-baptista",fullName:"Pedro Baptista",profilePictureURL:"https://mts.intechopen.com/storage/users/82671/images/system/82671.jpg",biography:"Pedro Viana Baptista (b.1972) holds a degree in Pharmaceutical Sciences (1996) from the Universidade de Lisboa. He obtained his PhD in Human Molecular Genetics from the School of Pharmacy, University of London in 2000. In 2001 moved to FCT-NOVA where he created the Nanomedicine Group, which he leads. Currently, he is Full Professor of Molecular Genetics & Nanomedicine at the Department of Life Sciences, FCT-NOVA and responsible for the NanoImunoTech Group – Nanomedicine in the Applied Biomolecular Sciences Research Unit. His work focuses on the biomedical applications of nanoparticle-based strategies towards light-induced cancer therapy and as gene silencing platforms (including siRNA, antisense and nanobeacons). Coordinates several research projects focused on the use of nanotechnology for molecular diagnostics and nanotheranostics, including nanoparticles for diagnostics and therapy; biosensors (TFTs and ISFETs); medium-throughput SNP analysis platforms, and nanoparticle-based therapies (nanovectors for siRNA and antisense therapy, targeted combined therapies).",institutionString:"Universidade Nova de Lisboa",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Universidade Nova de Lisboa",institutionURL:null,country:{name:"Portugal"}}}],coeditorOne:{id:"253664",title:"Prof.",name:"Alexandra R",middleName:null,surname:"Fernandes",slug:"alexandra-r-fernandes",fullName:"Alexandra R Fernandes",profilePictureURL:"https://mts.intechopen.com/storage/users/253664/images/system/253664.jpg",biography:"Alexandra R. Fernandes is an Assistant Professor at the Department of Life Sciences, FCT-NOVA where she leads the group of Cancer Therapeutics dedicated to assessing novel compounds against tumor cells and elucidate the underlying molecular mechanisms. She has obtained her PhD in Biotechnology from IST-UL and, before joining FCT-NOVA, was responsible for setting up key molecular genetics diagnostics facilities in Portugal.",institutionString:"Universidade Nova de Lisboa",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Universidade Nova de Lisboa",institutionURL:null,country:{name:"Portugal"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270941",firstName:"Sandra",lastName:"Maljavac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270941/images/7824_n.jpg",email:"sandra.m@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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It is also one of the key requirements for any pharmaceutical organization that wishes to gain a competitive edge. The pharmaceutical industry is profit-driven because it has to fund its own drug innovation, which highlights why research and development (R&D) forms the backbone of this industry. According to the CEO of the Pharmaceutical Research and Manufacturers of America (PhRMA), John Castellani, member companies of PhRMA spent a record US$ 67.4 billion on R&D in 2011. This is approximately 20% of generated revenue, which is 5 times more than the average manufacturing firm invests into R&D [1]. The pharmaceutical sector was responsible for 20% of all R&D expenditures by U.S. businesses in 2011 [2]. The aforesaid figures do not describe global R&D expenditures, but serve to give some indication of the astronomical contributions that are annually devoted by the pharmaceutical industry to drug development.
Substantial fiscal investments are made against the backdrop of enormous investment risks. It is estimated that only 5 of every 10 000 compounds explored will make it to clinical trials [1]. Although the likelihood that an investigational new drug in clinical testing reaches the market has increased over the past couple of decades to 16%, the probability is still low. Furthermore, of those that do get approved, only 2 or 3 out of every 10 drugs recover their full pecuniary investment [1]. The stakes are incredible and the strain on the industry as a whole is overt. In 2011 the world\'s largest research-based pharmaceutical company, Pfizer, closed its R&D centre located in the U.K. owing to financial viability concerns. In an attempt to dissuade some of the financial pressures, many companies have opted for mergers to either maintain existing pipelines or acquire new development opportunities [3].
A fairly regular citation estimates the out-of-pocket, pre-approval cost per drug developed to be more than US$ 800 million [4]. Estimations reported in peer-reviewed literature ranges from US$ 391 million [5] to US$ 1.8 billion [6]. Evident from literature is the fact that the estimates increase over time, in other words, the cost of developing drugs is escalating, which implies ever-increasing financial pressures on industry.
Two of the most prominent concerns for the pharmaceutical industry are patent expirations and attrition rates. Patent expirations result in decreased revenue generation and, as stated, this industry is profit-driven, meaning that diminished earnings cripple the R&D of an organization. Not only does this predict deterioration for a pharmaceutical company, but decreased R&D output also slows the production of new drugs. This also has a major impact on healthcare. It is estimated that in the U.S. a new case of Alzheimer\'s develops every 68 seconds [7]. Using these figures, more than 460 000 new cases of Alzheimer\'s will develop each year the approval of an effective new drug is delayed. Whereas patent expirations prune generated revenues, attrition rates affect the opposite side of the equation, needlessly raising the cost of developing new drugs. Attrition rates are high (Figure 1). A chemical entity that reaches phase I clinical trials has a 71% chance of reaching phase II clinical trials. Those chemical entities that do reach phase II trials have only a 31% chance of entering phase III trials. Further compounding the issue are rising failure rates in phase III trials [4]. Attrition drives development costs for two reasons: 1) monetary investments into failed ventures are lost and 2) failing development programs occupy resources and time that could otherwise be spent on drug candidates that would eventually succeed to be approved for marketing.
The probability that a chemical entity under development will progress from one clinical phase to the next. Candidate drugs have only a 22% chance of completing clinical development prior to review by regulatory authorities [
Together, patent expirations and drug attrition add enormous strain on new drug development, in a cumulative way inhibiting productivity and output of the entire R&D process. An article recently published by Forbes offers some perspective on the impact of attrition on development costs [8]. According to this article, AstraZeneca has been plagued by development failures, which escalated their average cost to develop a new drug to US$ 12 billion. In comparison, for Eli Lilly the average cost of developing a new drugs is estimated at only US$ 4.5 billion. The difference in development cost between the two companies can be attributed to the difference in approval rates of new drug i.e. less failures [8].
The average times, from the start of a particular phase to entering the next phase, are 4.3 years for pre-clinical development and 1.0, 2.2 and 2.8 years for phase I, II and III trials, respectively. Regulatory perusal adds another 1.5 years to the entire process [4]. Collectively, the duration of drug development from initiation of clinical testing until drug approval is estimated at 7.5 years [4]. Including pre-clinical development, it takes, on average, 10 - 15 years to develop a new drug from its discovery to regulatory approval [1,4] (Figure 2). A study that investigated the reduction in costs associated with drug development with improved productivity of the process reported that a 5% reduction in total development time will decrease development costs by 3.5% [9]. Although this may not sound like much, 3.5% of US$ 1 billion is a substantial saving. The study also emphasized the reduction in costs if decisions to terminate unproductive development programs are shifted to earlier phases of the discovery process. For example, the study estimated that if a company manages to shift a quarter of its decisions to terminate from phase II to phase I, it would save US$ 22 million [9]. Again, it relates back to why attrition drives development costs. Making the decision to terminate (a development program) earlier would stop further investment into unfruitful programs and free resources to promote approval ratings.
Average duration (in years) of different phases of drug development [
Industry continuously struggles to bring new drugs to the market, despite the process being overextended, costly and particularly uncertain of success. Over the last decade, overall drug development time has increased by 20% and the rate of approval of new chemical entities has dropped by 30% [10]. There is a mounting need to nurture output from the drug development process. Minor restructuring and streamlining of this process is required to increase its productivity and alleviate some of the financial pressures that drug developers experience. One area in particular where pruning of this process is overdue is the early pre-clinical detection / prediction of potential hepatotoxic chemical entities.
Drug-induced liver injury (DILI) is a challenge for both the pharmaceutical industry and regulatory authorities. The most severe adverse effect that DILI may lead to is acute liver failure, resulting in either death or liver transplant. Of all the cases of acute liver failure in the U.S., between 13% and 50% can be attributed to DILI [11,12]. Without a doubt there is great concern for the safety of consumers exposed to drugs that may cause DILI because patients have only one liver. For this reason, government and the public put pressure on regulatory authorities to establish safer drugs [13]. However, if regulatory authorities unnecessarily raise safety standards without scientific evidence, this will discourage drug development because of attrition, which is predominantly unwanted when considering the current scenario where fewer antimicrobials are being developed alongside increased antibiotic resistance.
A prevailing issue in drug development is the attrition of new drug candidates. Between 1995 and 2005, a total of 34 drugs were withdrawn from various markets (Table 1) and the reason for withdrawal in the majority of cases was hepatotoxicity [14]. Hepatotoxicity is the leading cause of drug withdrawals from the marketplace [15-17]. Examples include the monoamine oxidase inhibitor, iproniazid, the anti-diabetic drug, troglitazone, and the anti-inflammatory analgesic, bromfenac, all of which induced idiosyncratic liver injury. Iproniazid, the first monoamine oxidase inhibitor released in the 1950\'s, was probably the most hepatotoxic drug ever marketed [16]. Troglitazone was available on the U.S. market from March 1997. By February 2000, 83 patients had developed liver failure, of which 70% died. Of the 26 survivors, 6 required liver transplants [18]. While on the market, troglitazone accrued approximately US$ 700 million per year [14]. Withdrawals of lucrative drugs like troglitazone diminish return on investments and threaten further R&D.
Of all classes of drugs, non-steroidal anti-inflammatory drugs (NSAIDs) have had one of the worst track records regarding hepatotoxicity. Benoxaprofen and bromfenac are two NSAIDs that were withdrawn from public use after reports of hepatotoxicity [16,19]. Benoxaprofen was withdrawn in 1982, the same year that it was approved [16]. Bromfenac was predicted to earn around US$ 500 million per year [14].
Although diclofenac is widely used to treat rheumatoid disorders, approximately 250 cases of diclofenac-induced hepatotoxicity have been reported. In perspective, DILI caused by diclofenac has an incidence of 1-2 per every million prescriptions [20,21], being high enough that a considerable amount of literature has been generated warning against diclofenac-induced hepatotoxicity. Between 1982 and 2001 in France, more than 27 000 cases of NSAID-induced liver injuries were reported. Clometacin, and silundac were the NSAIDs with the highest risk of DILI. Over the same peroid approximately 2100 cases of NSAID-induced liver injuries were reported in Spain, with the main culprits being droxicam, silundac and nimesulide [22]. Acetaminophen (a.k.a. paracetamol) must be the most notorious of all the NSAIDs, if not all drugs, when it comes to DILI. Its mechanism of hepatotoxicity is better understood than its therapeutic mechanism of action. Fortunately, acetaminophen has a substantial therapeutic index and copious amounts need to be administered before the liver will not be able to manage its onslaught anymore [23].
Troglitazone was available on the U.S. market for three years before withdrawal, during which time it was used by almost 2 million patients, realising some return on investment [18]. Ximelagatran, on the other hand, was in the very late stages of development when its fate was sealed. In fact, AstraZeneca had already applied at the EMEA for marketing approval when the company withdrew all applications due to concerns over the hepatotoxic potential of the drug [24]. Although this drug did reach the market in France, the U.S. FDA was not prepared to grant approval and the drug was never marketed in the U.S. [25]. Ximelagatran, which was the first orally available thrombin inhibitor that would have replaced the troublesome warfarin as an oral anticoagulant, serves as a good example where huge investments were made to get the drug to market, but a return on investment was never realised. This example emphasizes the necessity for improved methodologies to predict intrinsic hepatotoxicity more accurately during the initial phases of the drug development process.
Alpidem Bendazac Benoxaprofen Bromfenac Clormezanone Dilevalol | \n\t\t\tEbrotidine Fipexide Iproniazid Nevazodone Pemoline Perhexilene | \n\t\t\tTroglitazone Temafloxacin Tolcapone Tolrestat Trovafloxacin Ximelagatran | \n\t\t
Drugs that have been withdrawn from international marketplaces between 1995 and 2005 due to associated hepatotoxicity.
Examples of other drugs that were never marketed in the U.S. because of hepatotoxicity include drugs such as ibufenac, perhexilene and dilevalol. There are also drugs for which the use / application has been limited because of possible DILI. These include the drugs isoniazid, pemoline, tolcapone and trovafloxacin [15]. A big question that remains a challenge for regulatory authorities is how rare or mild does hepatotoxicity have to be for a drug to be approved and to remain on the market? [13] Undoubtedly, DILI has a sizeable influence on drug development output. Pre- and post-marketing attrition as a result of DILI causes further financial stresses for those in the industry. Limiting attrition to the early phases of drug development can only be beneficial. Both the pharmaceutical industry and regulatory authorities agree that there is a great need for improved methodologies and strategies to accurately assess the hepatotoxic potential of compounds, earlier in the drug development process [13,26].
Distinct from pharmacology proper, which examines the desired effects and kinetics of a particular drug, safety pharmacology identifies and characterises secondary adverse pharmacological and toxicological effects of potential drugs, mainly through the use of established animal models [27]. Regulatory authorities require that certain minimal safety pharmacology examinations be completed before a new investigation drug application will be approved. These international regulatory guidelines were compiled by the International Committee for Harmonization (ICH) in the documentation covering topic S7. The ICH S7A and ICH S7B guidelines have been in effect since 2000 and 2001, respectively [27].
At present, the attention of pre-clinical safety pharmacology investigations is drawn to three physiological systems: the cardiovascular system, the respiratory system and the central nervous system (for compounds that may cross the blood-brain barrier). Effects on the cardiovascular system are of great concern because 1) it is a system often found to be affected and 2) due to its redundancy (organisms relevant to drug development have only one heart). Like the heart, the respiratory system is of concern because it is essential to the immediate survival of the organism.
Hepatic safety does not form part of the core battery of pre-clinical tests performed for initial safety pharmacology. The EMEA have published draft guidance on the non-clinical assessment of hepatotoxic potential [28]. This draft amounted to a clinical white paper [29], however, no regulations are set in place yet. This initial draft may demonstrate the future intent of regulatory authorities. If this is the case, not only is it worthwhile for the pharmaceutical companies to consider improved pre-clinical evaluation of hepatotoxic potential for their own profit, but it may soon be required as part of their investigational drug applications before first-in-human trials.
Currently,
Elevations of > 3 × ULN are considered a sensitive signal of a potential hepatotoxic test compound. Data from 28 clinical trials (phases II - IV) conducted by GlaxoSmithKline between 1995 and 2005 found elevations in ALT of > 3 × ULN at baseline to be rare, with a prevalence of 6.265% [36]. A study of Merck clinical trial databases, reported that elevations of ALT or AST > 3 × ULN had an 83% sensitivity to detect serious liver disease [Senior, 2003]. ALT > 3 × ULN has proved a useful threshold for screening for clinically significant DILI from various hepatotoxic substances. This includes drugs that have been withdrawn from the market due to hepatotoxicity, such as troglitazone and bromfenac [15]. However, this is not a very specific signal as increases in aminotransferase levels can also be induced by drugs that do not cause DILI such as aspirin, statins and heparin [17]. Indeed, the Merck study showed that the predictive power of elevations of ALT or AST > 3 × ULN, was only 11% [37]. A separate manuscript also reported high sensitivity and specificity when using ALT > 3 × ULN, but again with very low predictive power (only 6%) [38]. Serum ALT or AST levels are therefore a sensitive screen for possible hepatotoxic side-effects, but not definitive enough to terminate a drug development program.
Even though it was originally not intended as such, the most successful predictor of hepatotoxicity is “Hy’s law”, which is based on the original observations made by Dr. Hyman Zimmerman. It was described by Dr. Zimmerman as "clinical jaundice" and its modern application has proved valuable in being able to predict idiosyncratic hepatotoxicities brought about by drugs / potential drugs such as troglitazone and dilevalol. A more recent description is a state of drug-induced jaundice caused by hepatocellular injury, without any significant obstructive component [17,35]. Therefore, Hy’s Law is met when:
There exists the possibility that a drug (or potential drug) can induce hepatocellular damage as evident from elevations in serum aminotransferase levels of ≥ 3 × ULN and
These elevations are accompanied by elevations in total bilirubin of ≥ 2 × ULN with no evidence of intra- or extra-hepatic obstruction (elevated ALP) or Gilbert’s syndrome.
It is worth noting that Dr. Zimmerman himself placed some weight on the degree of jaundice as it often served to predict a negative outcome [35]. Hy\'s Law is, however, not exclusive to DILI and if it is met, it is of utmost importance that any other condition(s) that may also cause these symptoms be excluded before any conclusions are drawn about a potential intrinsic hepatotoxin. Such conditions may include viral hepatitis, hypotension or congestive heart failure [17]. Obviously, the possibility of DILI caused by concomitant drugs should also be excluded.
The incidence of idiosyncratic DILI is generally 1 per 10 000 or less. This makes it exceptionally difficult to detect idiosyncratic hepatotoxicity due to an investigational drug during clinical testing, even if several thousands of subjects are studied [39]. Generally, an investigational drug does not get administered to more than 2000 subjects [33], which makes it unlikely to detect a single incidence in 10 000. Although it portrays the role of the key predictor of the hepatotoxic potential of an investigational drug during drug development, Hy\'s Law falls short of constituting a "gold standard\'" and validation of Hy\'s Law is much needed, chiefly with regards to its sensitivity and specificity [35]. Moreover, for the purposes of detecting potential intrinsic hepatotoxins as early as possible during drug development, the foremost drawback of Hy’s law is that it requires
The ultimate goal of research into this field is to establish an
Cell-based models are increasingly used as there is a growing pressure to reduce, refine and replace the use of animals from organisations such as the European Centre for the Validation of Alternative Methods (ECVAM). The three basic types of cells used for
The use of immortalized human hepatocytes cell lines, like HepG2 cells, were proposed to overcome limitations of primary human hepatocytes including the scarce availability of fresh human liver samples, complicated isolation procedures, short life-span, inter-donor variability, and cost. HepG2 cells display morphological features similar to that of liver parenchymal cells and maintain many functions of
The chief advantage that primary cell cultures have over most perpetual cell lines is that they are the closest
Two techniques have received attention over the years to try and improve the life-span of primary hepatocytes in culture. These are sandwich culturing techniques and special medium formulations. Sandwich culturing techniques address the conformational / spatial discrepancies between the 2D
The problems of low levels of enzyme expression in HepG2 cells and limited life-span of primary hepatocytes was overcome with the emergence of the HepaRG cell line. These cells express higher levels of CYP\'s than HepG2 cells and respond acutely to induction of these enzymes [50]. HepaRG cells maintain hepatic functions of primary hepatocytes and express normal levels of liver-specific genes while lacking the inter-donor variability observed with primary hepatocytes [50,54]. A lot of literature praises HepaRG for the increased metabolic activity, which allows the
Researchers at Pfizer postulate that the poor predictive power of conventional cytotoxicity assays is related to the endpoint being measured [57]. Cytotoxicity endpoint assays only assess the final extreme from a series of pathological events that lead to cellular death. Assays that target such late events are likely to fail in detecting more subtle types of toxicity that develop after chronic, low-dose exposure to manifest as non-lethal, but definite adverse, complications [46]. In addition to this, the liver is the only organ in mammals that can fully regenerate after injury [58], making testing for adaptive changes even more relevant and applicable. An example of this scenario of subtle toxicity can be found in troglitazone, which exerts sub-acute hepatotoxicity by acting on a sub-cellular level, disrupting mitochondrial homeostasis. The mechanism of toxicity of troglitazone was investigated by means of
An important tool that was used in the MEIC study, and remains relevant to current methodologies, is that of mathematical modelling. In the MEIC study, researchers employed partial least squares regression [42]. Mathematical modelling provides a way in which researchers can combine data from different endpoint assays, thereby allowing them to piece together underlying associations and correlations observed when drugs (or groups of drugs) affect normal cellular function. Previous research illustrated how mathematical modelling of multiparametric data can aid prediction [64]. Seventeen compounds (7 known hepatotoxins and 10 "unknowns") were subjected to testing using 6 separate endpoint assays monitored with a fluorescent plate reader. The data was then used to develop 5 prediction models. Modelling techniques included logistic regression, support vector machines (using several different kernel functions), decision tree, quadratic discriminant analysis and neural networks. Discriminant analysis was found to yield the best positive and negative predictive values [64]. In addition, the study highlighted the significance of adequate sample size and careful consideration and defining of positive and negative test values in the training data set. It is important to realise that the task of predicting DILI from
Sequenced outcomes that can be considered for endpoint assays in pre-clinical
As with the study by Flynn and Ferguson [64], high content screening (HCS), which is based on automated microscopy, also employs fluorescent probes. HCS is one cell-based methodology that has shown promising results in predicting DILI. This methodology has three key strengths: 1) the ability to simultaneously examine multiple parameters of cellular function, 2) all parameters can be examined in individual cells, and 3) it has the potential for high-throughput screening since it is based on a microplate format. Combined, these features culminate in powerful technology. Testing more than 240 drugs using an HCS platform, researchers at Pfizer demonstrated that this methodology had overall sensitivity and specificity of 90% and 98%, respectively, for predicting
Another fluorescence detection method that has a potential role in early pre-clinical assessment of intrinsic hepatotoxicity is flow cytometry. Essentially, this method of detection can analyse the same parameters as fluorometry and fluorescence microscopy. It has not been explored in as much detail as HCS, but initial reports are positive [65]. There is room for research comparing these different methods of detection and the verdict is still out on which platform outperforms the rest.
Virtually all responses to toxic insults are accompanied by differential gene expression [66]. Differential gene expression is likely to be accompanied by differential transcription and differential protein expression (adaptive responses in Figure 3). On this conceptual basis, researchers have tried to use profiling technologies such as genomics / transcriptomics and proteomics to discern between compounds that may or may not induce liver injury and even between subsets of chemical entities that cause different types of hepatotoxicity like necrosis, steatosis and cholestasis [67].
The sensitivity of genomics experiments is high enough to detect subtle changes in gene expression profiles. For this reason, it is argued to be more sensitive than conventional methodologies aimed at detecting toxicity [68]. Indeed this was demonstrated in rats exposed to sub-toxic doses of acetaminophen, where subtle changes in gene expression profile were observed although no histological changes manifested [69]. This boasts well for toxicogenomics as being able to identify the most sensitive signals of potential hepatotoxicity. The authors did however emphasise the weight of demarcating toxic events, sub-toxic / adverse events, and adaptive responses as this will have great influence on the outcomes of toxicogenomic studies. The ability to detect responses at a molecular level that are not necessarily revealed at phenotypic level makes it possible to address questions about linearity of the dose-response curve at low exposure levels and allows for more accurate determination of inflection points along to dose-response curve and threshold exposure levels [68]. These determinants can play pivotal roles in safety pharmacology when selecting dosages for clinical studies. Regarding the predictive power of genomics, Zhang
Unlike the genome, the proteome is a dynamic entity that changes as gene activation and epigenetic factors alter protein expression due to endogenous and exogenous signals and factors. Studying the proteome allows the surveillance of current cellular events, which can only be deduced from genomics data. This is probably the greatest disadvantage of toxicogenomics compared to toxicoproteomics; there are many splice variants, post-translational modifications and subcellular localizations of the final products originating from genes [72,73] implying that some degree of extrapolation is necessary when predicting cellular events from genomics data. When studying the proteome, differential expression such as this can be detected and this may in fact form part of the solution, rather than part of the problem.
Studying the proteome provides a direct description of cellular functions [74]. Thus far, toxicoproteomic attempts to predict DILI have demonstrated limited efficacy when performed
Perhaps a more integrated approach would eventually prove more fruitful. Researchers conducted a study in which they characterised methapyrilene-induced hepatotoxicity in rats employing three profiling technologies simultaneously: genomics, proteomics and metabolomics [77]. The report demonstrated the possibility and great value of these technologies when used in an integrative manner, where responses to the toxic insult could be followed from genetic expression changes, to protein up- / down-regulation, through to changes in the metabolite profile, which gave a very good indication of where and how the chemical entity may exert its biochemical action(s). Conducting this type of study on a substantial number of compounds, both hepatotoxic and not, will yield a vast amount of data on how hepatocytes react toward challenges with different types of chemical entities and provide insight into which responses should raise concern and which are harmless. It may also deliver further understanding of the mechanisms by which hepatocyte injury occurs.
One major drawback of all the profiling technologies is that most of the current research has been carried out
The main reason for a lack of
As all physiological processes take place in a cellular setting, the highest quality of cells should be used to determine safety and efficacy. This led to the use of stem cells. Stem cells are classified as embryonic or adult, which is distinguished by developmental status. Where adult stem cells are multipotent (yield the cell type from the tissue from which they originate), embryonic stem cells are pluripotent (can give rise to differentiated cell lineages of all three germ layers). Stem cells that originate from embryos have a normal diploid karyotype and do not exhibit donor-dependent variability. The advantage of these cells compared to primary cells are that they can be maintained in culture for a longer period of time and can be grown up in large scale, producing high volumes.
The implementation of murine embryonic cells to predictably identify human developmental toxins, allowing for early identification of toxicity or candidate compounds in the discovery pipeline was initiated by ECVAM. Mouse hepatocyte-like cells, which were established from embryonic stem cells were the first to be used in hepatotoxicity models. The efficacy of cell differentiation and maturation was improved, where the cells generated alpha fetoprotein and albumin [78]. Cell characteristics included: 70% expressed the phenotypical marker albumin, they metabolized ammonia, lidocaine and diazepamat nearly two-thirds the rate of primary mouse hepatocytes. However, the difference in metabolism between humans and mice is considerable leading to interspecies extrapolation problems. Subsequently hepatocyte-like cells were differentiated from hESC [79]. These cells contained liver-related characteristics such as; expression of α-fetoprotein, production of albumin, hepatocyte nuclear factor 4α and induction of CYP450 enzymes, stored glycogen and showed uptake of idocyanine green. This was followed by more differentiated hepatocyte-like cells which additionally express functional glutathione transferase activity at levels comparable to human hepatocytes [80].
The advantages of stem cells in relation to transformed/tumour or primary cells are that the former possesses normal growth, genetic transformation and genetic composition as well as uniform physiology and pharmacology [81]. Since stem/progenitor cells can differentiate into clinically relevant cell types, but still maintain functional similarities to their
As with all technologies, there are still hurdles to overcome with stem cell technology. Many clinically relevant cell types cannot be efficiently differentiated, purified and isolated [82]. Human stem cells that reproducibly deliver hepatocytes with predictive pharmacology results for high-throughput safety screens are limited. Although progress has been made in the differentiation protocols, scaling cell growth and plating for cell-based assays, as well as refining of these protocols in order to ensure homogeneous preparations will continue. Currently, panels of human embryonic stem cells which reflect the wide variation in the population are not available.
Although these hurdles exist, stem cells hold the potential for investigation into metabolic competence, biotransformation capacity and transformation of exogenous compounds. Also, the ability to determine human inter-individual differences due to genetic polymorphisms.
Although 2D techniques have the advantages of being relatively inexpensive, reproducible, robust and convenient, they have the chief disadvantage of loss of much of the functionality of native hepatocytes [84], which raises the question of the relevance of such a model in predicting DILI. Three-dimensional culturing of hepatocytes is an attempt to imitate an
The sandwich configuration of 3D culturing is frequently used when propagating primary hepatocytes as it has been shown that maintaining these cells in this configuration prolongs their
A manuscript that unmistakeably illustrates the important role that 3D culturing techniques can play in drug development is Lee
It is difficult for nutrients to reach, and for waste products to be removed from hepatocytes in a traditional sandwich configuration because the cells are entrapped in a thick extracellular matrix. The perfusion sandwich culture [91] and entrapment between ultra-thin porous silicon membranes technologies [92] were developed to surmount these complications. In addition to maintaining hepatobiliary function, both these methods claim added predictive capabilities for DILI as demonstrated through increased sensitivity to acetaminophen toxicity due to preserved metabolic enzyme functionality. Still, even with these improved methods, the life-span of these primary hepatocytes remains limited, which restricts the use of such methods on a large scale.
Other 3D culturing methods are mainly based on bio-artificial liver bioreactors that are aimed at developing extracorporeal liver support systems for patients with acute liver failure. In the past, such bioreactors were based on adult hepatocytes and proved unsuccessful because the hepatocytes failed to proliferate [93]. The latest of these that are being explored for its use in drug toxicity testing is the four-compartment perfusion model. Cells are contained in one of the four compartments, the remaining three compartments comprises three independent but interwoven artificial capillary bundles that form the capillary bed in which the cells are housed. Cells are derived from hESCs and currently research is being carried out to obtain the optimal protocol for differentiating these cells into mature hepatocytes that closely resemble innate hepatocytes. This research project is headed by the EU Vitrocellomics project [94].
Anchorage-free 3D culturing methods result in the formation of small hepatocyte aggregates known as spheroids. There are different ways to induce the formation of spheroids including continuously-stirred bioreactors [94], the rocked suspension technique [95] and rotating wall bioreactors [96]. Initial experimentation demonstrated that, between spheroids and monolayers, there was indeed differential toxicity induced by 7 day methotrexate exposure. It was thought that this was due to preservation of hepatocyte functionality, but could also have been due to lack of the test compound to penetrate the spheroidal structure [97]. More than a decade later it is well known that liver-specific functions like albumin and urea synthesis and metabolic activities are maintained for prolonged periods of up to 21 days [94]. In time, spheroids deposit an extracellular matrix consisting of laminin, fribronectin and collagen, which encapsulates each individual spheroid. These structures also preserve histotypical cytarchitechture, intercellular contacts (gap junctions) and biliary canaliculi [98]. Moreover, when hepatocytes grown under these conditions are encapsulated in alginate polymers, albumin and urea synthesis doubles and phase I and II metabolic activities are also elevated. This may be attributed to the bulk added to the extracellular matrix, provided by the alginate polymers, which protects the hepatocytes from shear stresses under hydrodynamical conditions [94]. A setback of this technique is the difficulty of obtaining spheroids that are of a specific mean diameter (100 μm) and batches of spheroids that are all similar in size. This is necessary as necrotic cell death may occur at the centre of spheroids if the diameter of these aggregates exceeds approximately 300 μm. The reason for this is lack of oxygen perfusion to cells located in the central region of spheroids that are too large in size [99].
Recently researchers attempted to predict hepatotoxicity employing hepatocyte spheroids developed from an immortalised cell line, a HepG2 derivative (C3A), instead of primary hepatocytes [96]. The study emphasizes the value of proper dosing during toxicity testing. In the study spheroids were not exposed to a set concentration of drug in the culture medium for individual experiments. Rather, the concentration of drug in the culture medium was adjusted with each experiment to mimic
It would be fair to say that 2D culturing techniques have predominated since the inception of research on artificially cultured cells and as such numerous ways have been developed to analyse cells in the 2D format. Amongst others, this is one of the key advantages that 2D culturing techniques have over 3D culturing techniques, demonstrated by the multiple parameters that can be simultaneously assessed using HCS. Currently, this is not possible when using 3D cultures as all cells are not in the same pane and cannot be examined individually. On the other hand, the relevance of 2D culture models is questionable when compared to 3D models that more closely resemble their native counterparts. Various reports have shown that 3D culturing methods are superior to 2D cultures in detecting or predicting certain types of DILI, especially cholestatic injury as 2D models do not express the necessary morphology to study this. Profiling technologies may be able to breach the chasm between 2D and 3D culture models because it is applicable to both scenarios and have been shown to distinguish cholestatic hepatotoxins even when applied to 2D cultures.
The proteome represents current events on a cellular level and 3D cultures are better depictions of innate hepatocytes. Therefore, proteomic investigations that are based on 3D cultures, dosed using
What is missing from current literature is the assessment of 3D cultures to express / secrete biomarkers that are currently used in the clinical setting, i.e. ALT, AST, ALP and bilirubin, and how these respond following challenge with various drugs. Research into this area may uncover possible accurate extrapolations that can be validated for use in predicting DILI. For instance, it is possible that 3D cultures secrete sufficient quantities of ALT and bilirubin to be measured in the surrounding culture medium. Maybe these markers will fluctuate in a way similar to what would occur in the
The
Work is necessary to incorporate the available methods into a standard set of tests, comprising of different tiers, which generate data that can be interpreted as a whole, to aid the critical ‘go’ / ‘no-go’ decision (the earlier, the better). Such a set of experiments will greatly improve lead prioritization before astronomical amounts of funds are invested into a particular potential drug. In the long run this will increase the productivity of the entire drug development process by alleviating some of the financial pressures and improving time-scales from drug discovery to marketing as less time is spent on candidates that will eventually fail in the clinical phases. Finally, it should aid regulatory authorities in granting approval and provide safer drugs for consumers.
European Centre for the Validation of Alternative Methods (ECVAM); Drug metabolism and pharmacokinetic (DMPK); Drug-induced liver injury (DILI); High content screening (HCS); International Committee for Harmonization (ICH); Multicentre evaluation of
Nanocomposite materials can be obtained through the crystallisation of the grain-boundary glass phase in a ceramic matrix; the electrical and structural properties are improved with glass additives [1]. Over the last few decades, the field of electronic ceramics applications has been progressing. Some newer applications, such as in low temperature co-fired ceramics (LTCCs) and dynamic random access memories (DRAMs), utilise the material’s dielectric properties. LTCC applications require the sintering temperature to be below the melting point of the electrode materials [2]. The chemical processes of adding glass and using starting materials with ultra-fine particle sizes improve the characteristics of ceramics at low sintering temperatures [3]. Glass additives can have useful effects on the dielectric constant due to their effect in broadening the diffusive phase transition at the Curie temperature, something that is desirable in the application of multilayer ceramic capacitors [4].
Glass–ceramics are ceramic materials that are produced through the controlled nucleation and crystallisation of glass through thermal treatment. Depending upon the chemical composition and microstructure of glass–ceramics, they can exhibit useful thermal, optical, chemical, mechanical, electrical, and magnetic properties. Useful composite materials can be produced by combining glass–ceramics and other materials, such as metals [5]. Low sintering temperatures and high relative permittivity are of primary importance in the manufacture of ferroelectric ceramics. Typical dielectric ceramic materials, such as barium titanate (BaTiO3) and lead titanate zirconate (PZT), have found many applications in the electronics industry. Certain additives for BaTiO3 and PZT, such as LiF and PbO-B2O3-SiO2, can reduce their sintering temperatures to around 900°C and improve their ferroelectric properties, making them suitable for a range of different electronic applications [6, 7].
It is known that the functional properties of ceramic materials are strongly dependent on microstructure, which provides opportunities to develop new or improved ceramic materials through microstructural engineering. One of these approaches involves combining ferroelectric perovskite with glass-forming oxides in order to form ferroelectric glass–ceramics [5, 8]. The microstructure of such materials comprises ferroelectric nanocrystals dispersed within a glass matrix [9], giving rise to novel materials having pore-free, fine-grained microstructures, low thermal expansion coefficients, high mechanical strength, high chemical stability and good dielectric properties [10]. Such materials have potential applications in high energy density capacitors [11], as well as piezoelectric [12] and electro-optic devices [10, 13]. The glass–ceramic processing route can provide well-controlled microstructure, formed by the crystallisation of chemically and microstructurally homogeneous glasses, at relatively low cost [5, 8].
Ferroelectrics are insulating solids that have spontaneous polarisation. This means that they contain a permanent polarisation at the unit cell level, even in the absence of external electric fields. Additionally, ferroelectric materials exhibit the ability to alter the orientation of their polarisation between two or more directions when under the influence of external electric fields. In order to exhibit spontaneous electric polarisation, there must be a noncentrosymmetric arrangement of the ions and their electrons in these materials. Many ferroelectric materials have perovskite structures with a general chemical formula of ABO3 ABO3-type oxides are known to stabilise with a wide range of A (Pb, Ba, Ca, Sr) and B (Ti, Zr, Sn) ions, with A ions having larger ionic radii than B ions.
Ferroelectrics have typical properties which are essential for their use in electronic devices. High relative permittivity and low-loss dielectric characteristics are most important in multilayer ceramic capacitors (MLCC), which are widely used in electronic devices. There have been progressive developments in the manufacture of MLCCs to increase both the relative permittivity and the number of layers, as well as decreasing the layer thickness, t, according to the equation below [14, 15].
where ԑr is the relative permittivity or relative dielectric constant. The capacitance itself is dependent upon ԑr, the area of the parallel plates, A, and the thickness of the dielectric material, t.
Ferroelectrics are polar crystals with the ability to alter their polarisation direction upon the application of an external electric field. They exhibit spontaneous polarisation, even in the absence of external electric fields. In the unit cell, net permanent dipole moments are present in ferroelectric materials. In polycrystalline ceramics, the orientation of the dipole moments are random and therefore a net polarisation is not normally present after cooling through TC in the absence of an external electric field. The overall orientation of the dipole moments in polycrystalline and single crystal ferroelectrics are not completely random at the scale of the unit cell, since they form ordered groups, referred to as domains. Within the domains, there is a uniform alignment of dipoles, with neighboring domains being separated by boundaries known as domain walls.
The direction of spontaneous polarisation in ferroelectrics can be altered through an applied electric field, as shown in Figure 1. With the increase of the electric field, the domains begin to align, giving rise to an increase and saturation in the polarisation at high field. In the absence of an external electric field, some of the domains remain aligned. Thus, the crystal displays remnant polarisation. If the field is reversed, the domains change direction. The direction of polarisation flips and produces a hysteresis loop when the external electric field alternates between negative and positive [16, 17].
Illustration of the polarisation-electric field relation, P-E hysteresis loop, for a typical ferroelectric crystal [
Significant improvements over the last couple of decades in both the energy storage density and reliability of capacitors have been achieved through a combination of novel materials, diagnostic methods, and manufacturing techniques. Capacitors, inductors, and batteries are means through which electrical energy is stored. Figure 2 depicts a graph of the specific energy for different energy conversion and storage devices plotted against their specific powers [18].
Diagram of power density as a function of energy density in different energy-storage devices [
The characteristics of energy-storage in four types of the most highly studied dielectric materials, namely, relaxor ferroelectrics, polymer-based ferroelectrics, antiferroelectric, and dielectric glass–ceramics were reviewed by Hao [19].
The changes in polarisation upon the application of an electric field are a critical aspect of energy storage dielectrics. This response can be used to estimate the stored energy, which should exclude hysteresis losses. Dielectrics may be grouped into being either linear or non-linear, according to the relationship between the applied electric field and the polarisation. A simple equation (below) may be used to describe their behavior [20].
Therefore:
where χ is dielectric susceptibility and D is the dielectric displacement.
Energy density, U, is a measure of the energy stored per unit volume. For dielectrics, this can be obtained by the following relationship:
Using formula above (Eq. (4)), the U values of the dielectrics can be obtained through the numerical integration of the area between the polarisation and curves for the electric-field polarisation (P-E) loops. Figure 3, shows that upon reaching the maximum electric field strength (Emax), the polarisation approaches its maximum (Pmax) and the capacitor holds the electrical energy (Ustore), as illustrated by the red and green areas.
The typical dependence of (a) polarisation and (b) relative permittivity on the electric field of ferroelectrics in the first quarter shows the charge–discharge cycle. The area I (green shaded area) corresponds to the discharged or recoverable, energy density and area II (red shaded area) correspond to the energy density loss [
The recoverable electrical energy density (Urec) is released during the discharge process when the electrical field reduces from Emax to zero. This is represented by the green area in Figure 3. Therefore, an amount of the stored energy (the red segment surrounded by the loops) is dissipated during the process of depolarisation, denoted the hysteresis loss, Uloss [19, 21].
The above analysis indicates that there are three prerequisites to designing an effective dielectric material for practical use with high efficiency and high recoverable energy-storage density. These three requirements need to be satisfied simultaneously and are small remnant polarisation, large saturation polarisation, and a high electric breakdown field [22].
Figure 4(a)-(d) depicts typical P-E loops and an illustration of the energy-storage of four types of dielectrics: (a) linear dielectric with constant permittivity (e.g. Al2O3, glass), (b) antiferroelectric with zero net remnant polarisation (e.g. PbZrO3), (c) ferroelectric with spontaneous polarisation (e.g. PbTiO3, BaTiO3), and (d) relaxor ferroelectrics with nanosized domains, e.g. (Pb,La)(Zr,Ti)O3.
Schematic description of the energy storage characteristics of (a) linear dielectrics, (b) antiferroelectrics, (c) ferroelectrics, and (d) relaxor ferroelectric ceramics [
Even though linear dielectrics often have lower energy losses and higher breakdown fields, small polarisation values resulting from the use of low-permittivity dielectrics can reduce their effectiveness for high-energy storage purposes, unless very high breakdown fields can be achieved. Ferroelectrics generally have moderate electric field endurances and larger saturated polarisations, however, due to their larger remnant polarisations, they are often less efficient and have smaller energy-storage densities. Figure 4 demonstrates that antiferroelectrics and relaxor ferroelectrics are more attractive for high energy storage due to their relatively moderate breakdown fields, smaller remnant polarisations, and larger saturated polarisations.
Novel manufacturing processes, such as the use of composite technology and glass-crystallisation techniques, have allowed for the production of ceramic-polymer composites and glass–ceramics. These materials could potentially combine the larger polarisations of ferroelectrics and the higher breakdown fields of linear dielectrics. Therefore, amongst the aforementioned four groups of dielectrics, namely, relaxor ferroelectrics, ceramic-polymer composites, glass–ceramics, and antiferroelectrics, the former two are generally thought to be the most useful for high energy storage purposes and therefore much research has been conducted on these two types of material [19, 23].
Pb(Zr,Ti)O3 (PZT) based materials have been widely used in energy storage applications because of their high dielectric constant. However, the environmental issues derived from the use of lead have encouraged many searches for more environmentally friendly materials.
The perovskite structure of BaTiO3, capable of high dielectric constant values, spontaneous polarization, low dielectric loss and ferroelectricity offers an alternative for lead-based capacitors. As mentioned earlier on, for energy storage applications a high dielectric breakdown strength is required to allow device miniaturization. It is well known that the energy storage properties of BaTiO3 based ceramics can be improved by reducing the porosity [24], tuning the grain size [25], the addition of glass additives [26], presence of secondary phases, etc. For example, the relative permittivity of BaTiO3 increases as the grain size decreases [27], reaching a maximum of 5000 at grain sizes of about 0.8 to 1.1 μm [28]. This was attributed to domain size and stress effects. Further reductions in the grain size resulted in a rapidly decreased permittivity. Furthermore, the dielectric breakdown strength increases with decreasing grain size [29], being about 8.5 kV mm−1 when the grain size is 3.5 μm [30].
The addition of glass additives to induce liquid phase sintering is a widely used technique to improve the energy storage capabilities of BaTiO3 based ceramics. During the liquid phase sintering, a thin layer of the fluxing agent coats the BaTiO3 grains leading to improved relative densities and reduced sintering temperatures. Until now, the use of several glass additives in BaTiO3 ceramics has been proved to show promising results for energy storage applications. For example, Sarkar and Sharma [31] demonstrated that the addition of B2O3 and PbB2O4 to BaTiO3 significantly reduced the sintering temperature to about 800°C, which is suitable for commercial applications as multilayer capacitors. Moreover, they doubled the dielectric breakdown strength of BaTiO3 by the addition of 10 mol% of PbB2O4 [31]. However, this improvement in the dielectric breakdown strength was accompanied by a small decrease in the dielectric constant.
The aliovalent substitution at the Ba2+ and/or Ti4+ sites in the perovskite structure of BaTiO3 has been demonstrated [32] to be an effective approach to tailor the energy storage properties of BaTiO3 to meet industrial application requirements. Recently, Puli et al. [33] investigated the dielectric, ferroelectric and energy density properties of (1-x){BaZr0.2Ti0.8O3}˝-(x){Ba0.7ZCa0.3TiO3} where x = 0.1, 0.15 and 0.20, hereinafter denoted BCZT. They reported a dielectric of the permittivity of 8400 when x = 0.15 and a low loss (tan
(a) Composition dependence of recoverable energy density (Urec), stored energy density (Ustor), and energy storage efficiency (ƞ %) of (1-x){BaZr0.2Ti0.8O3}-(x){Ba0.7ZCa0.3TiO3} where x = 0.1, 0.15 and 0.20 (b) Weibull plots of the breakdown strength of BCZT ceramics sintered at 1600°C [
Wang et al. [34] achieved an energy density of 0.52 J cm−3 in a (Ba0.85Ca0.15)(Ti0.9Zr0.1)O3 ceramic prepared by the sol–gel method. They attributed it to the improved microstructure compared to that obtained by the conventional solid-state reaction method. In order to simultaneously attain high dielectric breakdown strength, high energy density and a high dielectric constant in a material, the glass–ceramic concept has been devised. Here, the high dielectric breakdown of the linear dielectric (glass) and the high dielectric constant/large polarization typical of ferroelectric ceramics are combined in a nanostructured composite-type material. Puli et al. [35] followed the glass–ceramic approach to improve the energy storage properties of BCZT ceramics. They added 15 wt% of two different alkali-free glass compositions, namely 0.1BaO + 0.4B2O3 + 0.5ZnO and 0.3BaO + 0.6B2O3 + 0.1ZnO, to BCZT, they reported a slight improvement in the dielectric breakdown field to about 28 kV mm−1 but a lower energy density compared to glass-free BCZT. The low energy density values reported were attributed to the low relative permittivity values (≈ 270) for glass–ceramic composition.
Another lead-free perovskite material that exhibits useful ferroelectric properties is the solid solution system potassium-sodium niobate (KNN). The solid solution in the binary system KNbO3-NaNbO3 crystallises as an orthorhombic perovskite, [36], with the composition around K0.5Na0.5NbO3 being the most popular due to its closeness to the morphotropic phase boundary (MPB) which occurs at about 52.5% Na [37]. The solid solution (K,Na)NnO3 exhibits ferroelectric behaviour which diminishes at high sodium additions until it completely disappears due to the nonpolar, antiferroelectric end-member NaNabO3 [38, 39]. The dielectric constant of K0.5Na0.5NbO3 at room temperature is about 290 [38] and reaches 990 at 473 K. The use of additives to reduce the grain size and to improve the energy storage abilities of KNN ceramics has shown promising results. Qu et al. [40] achieved an energy storage density of 2.48 J cm−3 and a breakdown strength of 29.5 kV mm−1 by reducing the grain size of KNN to 0.5 μm through the addition of Sr.(Sc0.5Nb0.5)O3 (SSN), although they reported the presence of porosity at the grain boundaries. Highly dense KNN-SNN samples were achieved through the addition of 0.5 mol% ZnO, leading to a breakdown strength of 40 kV mm−1 and an energy storage density of 2.6 J cm−3 [41].
Glass-ceramics are classified as ceramic materials. They are polycrystalline materials that are formed by controlling the crystallisation of an amorphous glass. These materials are an important type of electroceramic and were successfully developed during the 1940 and 1950s. During this period, S. D. Stookey (Corning, USA) successfully used glass–ceramics as electrical insulators in electronics technology [5, 20]. The fundamental patent of Stookey was based on the concept that the TiO2 works as a nucleating agent in a glass system. Additionally, ZrO2 was used by Tasiro and Wada [5], in 1963 as a nucleating agent. Another discovery was made in the 1950s by Hummel, who discovered the crystal arrangement of the Li2O-Al2O3-2SiO2 system [42].
Figure 6 shows three types of an atomic structure with different atomic arrangements. A crystalline solid is one which has a long-range order in its atomic structure; an amorphous solid is one in which there is no long-range order in its atomic structure. Crystalline solids have two subdivisions, single crystal and polycrystalline. A single crystal has a periodic atomic arrangement. In this case, there are no grain boundaries. A polycrystalline solid contains many grain boundaries in the structure due to the differences in the orientations of the grains (that have a short-range order) [43].
The structure of ceramics [
It is difficult to specifically define a glass since the behaviour of a glass alters with changes in temperature. There are two points at which a glass can be defined; the first is at high temperature, when the glass is a liquid, while the second is at a lower temperature when the glass is considered as a supercooled liquid. Although there are important structural differences between glasses and polycrystalline ceramics, their mechanical and functional properties at room temperature can be similar.
The traditional definition of glass is that it is a supercooled liquid. According to the American Society for Testing and Materials (ASTM), the definition of glass is that it is an inorganic product of fusion which has cooled to a solid state without being crystallized. However, there are alternate definitions for glass, one being that glass is a type of amorphous solid material that lacks long-range order (not a random arrangement) in its atomic structure. Another definition, also put forward by ASTM, it that a glass is a liquid that has lost its ability to flow [5, 16].
The heat treatment of glass leads to the occurrence of many transitions. Differential scanning calorimetry (DSC) is a form of thermal analysis that depends upon the change in a material’s physical properties [42]. In DSC, there is a difference in temperature (ΔT) that is seen between the sample and the reference. Here ΔT represents differences in heat flow as ΔQ. The two quantities, ΔT and ΔQ, are functions of thermal resistance (R), as shown in equation below.
In the first step of the glass transition, some of the physical properties change for amorphous materials. This change occurs in the heat capacity, which can be measured by DSC as an endothermic change in the sample. The transitions in glass due to the effects of temperature occur in the range of temperature which is known as the glass transition temperature (Tg). Therefore, below Tg, materials display a rigid glassy structure. When the temperature is increased above Tg, these materials display a flexible structure.
Another transition which occurs due to changing temperature is crystallisation. In this case, the amorphous materials are transformed into a crystalline structure. With an increase in temperature, the next conversion is melting. At this point, the crystalline structure converts to a viscous amorphous structure. The melting point is dependent upon the chemical impurity of the materials. After the melting stage, a reaction inside the material causes an increase in the density of the material [5, 42].
Generally, since 1960, there has been much research undertaken regarding glass systems in the field of glass–ceramics. Glass–ceramics are very important in many fields of application. They have demonstrated many desirable thermal, optical, biological, chemical, and electrical properties. Some of these properties provide advantages to glass–ceramics over more traditional materials. A glass–ceramic is a polycrystalline material formed by controlling the crystallization of glass. Therefore, in order to make glass–ceramics from glass, the main manufacturing process needs to be a thermal one. Figure 7 shows the steps of glass transforming into glass–ceramic. These steps begin at a low temperature with the formation of nuclei, then at higher temperatures crystallisation occurs by growth of the nuclei; this continues to produce the polycrystalline a glass–ceramic microstructure [5, 43].
Schematic representation of glass–ceramic processing [
Microstructural control is said to be easier when the temperature required for crystallisation lies between but is significantly different from both the glass transition temperature and that of matrix devitrification. In such a case, the desired crystalline phase can be induced to form without devitrification of the glass matrix. The crystallite size generally increases with increasing temperature, as shown by the micrographs in Figure 8 [44].
TEM micrographs showing Nanoscale crystallites precipitated from a glass matrix of SiO2/Lu2Si2O7 heat-treated at 1100°C (a), 1200°C (b) and 1300°C (c) [
In Figure 9, the typical thermal preparation of glass–ceramic can be seen. In this case, the raw materials, Li2CO3 and SiO2, are used to create lithium disilicate. There are two main stages in obtaining glass–ceramics: glass formation and glass crystallisation. In each stage, there are many steps which depend upon both temperature and time. The first stage begins by melting the components and then quickly cooling them. The nucleation and crystal growth occurs in the second stage. During this stage, controlled crystallisation of the glass produces nanoscale crystals [5].
Schematic of glass processing in the formation of a glass ceramic [
Glass-ceramics can be containing a substantial glassy phase if the range is highly crystalline. As a result of that, glass–ceramics can contain grain boundaries as well as it can range from transparent to opaque. Therefore, the properties of glass–ceramics depending on the microstructure and the chemical composition, which can be tuned to meet demanding requirements. In general, the most important of glass–ceramics properties that can be exhibited is about zero thermal expansion with high toughness. as well as, have a high impact resistance with resistant to thermal shock [5, 8].
The potential applications of glass–ceramics in energy storage capacitors was investigated by Du et al. [11]. Here, the Na2O-PbO-Nb2O5-SiO2 glass–ceramics system achieved a highest relative permittivity of >600 after heated the sample at 850°C. The results given by Gorzkowski et al. [46] shown that the interfacial polarization due to the difference in the dielectric and conductivity of glass phase and ceramic phase large hysteresis loss, led to low energy density (Max. 0.9 J cm−3) and breakdown strength (Max. 800 kV cm−1) of the BST glass–ceramics that expected much higher energy density (≈ 3.5 J cm−3 in case assuming is it ideal linear dielectric behavior) [46].
As the energy crisis intensifies, the search for novel, high performance and environmentally friendly energy storage devices have attracted wide attention. For a material to possess high energy density capabilities, a high relative permittivity and dielectric breakdown strength are needed; this is a challenging task since theoretical and experimental studies on crystalline materials usually show a contrary relationship between these properties [47]. Compromises between relative permittivity and dielectric breakdown strength have encouraged the search for more efficient materials such as polymers and glasses. Recently, a high relative permittivity and a high dielectric breakdown strength were found in fluoropolymers, with energy density values up 25 J cm−3 being reported [48]. A high dielectric breakdown of ≈ 12 MV cm−1 (1.2 MV mm−1) was also reported [49] in a low relative permittivity (εr ≈ 6) alkali-free glass, showing the possibility to reach an energy density of 35 J cm−3. These results are very promising since the relationships between relative permittivity and dielectric breakdown strength in inorganic glasses are not well established.
Xue et al. [38] studied the effect of glass concentrations on the energy storage capabilities of niobate glass ceramics (100-x)(40BaO-10Na2O-50Nb2O5)-x(63SiO2-12BaO-16B2O3-9Al2O3) prepared via controlled-crystallization. They achieved dielectric breakdown strength of about 130 kV mm−1 and a charge–discharge efficiency of 92.5%, with a relative permittivity of about 50, see Figure 10 below.
Relative permittivity versus temperature curves of niobate glass–ceramics prepared via the controlled-crystallisation route, samples were annealed at 1100°C. When the glass content was 30–60%, the samples were labelled G30 to G60, respectively [
Glass-ceramics are amongst the most important hosts for transition metal ions [51]. There are several benefits of adding glass to ceramics, such as improving their dielectric properties and reducing both the sintering temperature and the porosity [6]. In glass–ceramics, the ferroelectric and dielectric properties are highly dependent on the characteristics of the glass matrix as well as the crystal volume fraction and crystal size [52]. Glass-ceramics are crucial in the development of more efficiently produced and controlled energy. They are thought to be efficient cathodes or solid electrolyte materials when used in lithium batteries. Dielectric glass ceramics are also of interest due to their uses in high-power microwave systems, distributed power systems, power electronics, and pulsed power.
To decrease the thickness of the dielectric layers in a capacitor and reduce the weight of portable pulsed power systems, it may be necessary to have high dielectric breakdown strength in the materials. In any case, improved control of the porosity, along with enhanced energy storage capabilities, are important aspects of improving the performance of glass–ceramics [53]. The significance of glass–ceramics in many applications lies in the possibility of utilizing key properties such as transparency, strength, resistance to abrasion, and the controlled coefficient of thermal expansion. All these properties can be manipulated by the controlling the composition, extent of crystallisation, crystal morphology, crystal size, and aspect ratio of the materials [54]. Glass-ceramics are used in a range of applications across different fields such as telecommunication, radar, and navigation. With respect to the use of high-density electron device packages, the materials which are used in LTCC applications need to have good dielectric properties and a large coefficient of thermal expansion (CTE). These characteristics are important in order to achieve thermal matching between the components of the package [55, 56].
Silicates are salts of silicic acid, H4SiO4. Most of the silicates contain SiO2, while in the case of SiO2 or quartz glass, only SiO2 is present. For all other types of glass, additional oxides, such as: Li2O, BaO, B2O3, Na2O, K2O, MgO, CaO, or Al2O3 are employed as network formers or modifiers. Alkaline and alkaline earth oxides are important in glass due to their effects on the network. Therefore these additives work as effective network modifiers [57]. The alumina-silica system, Al2O3-SiO2, is amongst the most important binary oxides and ceramic systems. Figure 11 shows the phase diagram of the binary Al2O3-SiO2 system. The low solid solubility for SiO2 in Al2O3, and vice versa, can be seen in this diagram. At a high temperature below 1890°C, part of the Al2O3 component is transformed to a molten state, while the other part remains solid. This also occurs with SiO2 at a temperature below 1600°C. The effect of the SiO2 ratio in reducing the melting point of Al2O3-SiO2, can be seen [58].
Phase diagram of the binary alumina-silica system [
Figure 12 shows the silica structure as a network. In Figure 12-A the basic units for silica are represented; these are Si4+ with O2-. The network of pure silica, also known as quartz, is presented in Figure 12-B, while Figure 12-C shows the structure of this 2D network with the addition of some alkaline additives as modifiers [57].
Silica network structure: (A) silica tetrahedron, (B) pure silica quartz, (C) and a soda lime silicate [
Glass-ceramics can be modified by a formulation process. Alkaline and alkaline earth oxides are modifiers of glass networks and act to decrease the connectivity of the glass network, effecting changes in the properties of the glass. There are many oxides that are used to modify glass-ceramics, such as: Ba, Li, B, Ca, Na, etc. [57]. These glass-ceramic systems contain binary and ternary systems. Both types of systems contain oxides, such as: BaO, B2O3, MgO, CaO, PbO, ZnO, Al2O3, SiO2, and SrO [5]. Some of the oxides contained within the glass are popular as sintering aids for ceramics. This is because of the high stability of their structures and the low glass transition temperatures, in addition to their thermal and electrical properties. The systems of PbO-containing glasses (e.g. PbO-B2O3-SiO2 and PbO-B2O3-ZnO) are important due to the aforementioned reason [59, 60].
Other glass systems include Bi2O3-B2O3, BaO-CaO-Al2O3-B2O3-SiO2, CdO-Bi2O-PbO-B2O3, and BaO-B2O3-SiO2 which have all been used to reduce the sintering temperature [3, 61]. The structure of PbO is not easy to crystallise, even with a high percentage of it within the glass, because PbO4 is formed within the glass system. Recently, many glass systems have been developed as alternative lead-free materials. In this research, BaO, ZnO, and Bi2O3 are used instead of PbO [61]. Most glasses containing a high proportion of PbO are undesirable due to the toxicity of lead oxide causing environmental problems during or after production. Therefore, most researchers focus on decreasing the PbO content or replacing it with other oxides. This issue was addressed by Bobkova and Khot’ko [62], who were studied the ZnO-SrO-B2O3 system. They found that the optimum glass was produced when it contained a high ZnO and low B2O3 content. In addition, two ternary systems, B2O3-CaO-SiO2 and B2O3-CaO-Al2O3, have been studied by Vartanyan et al. [63]. They found that these two systems successfully produced lead-free materials for low-temperature simultaneously fired ceramics (LSCs).
Glass manufacturing processes can be generally complex due to the materials which undergo different changes during the melting and cooling. The ternary systems of B2O3-CaO-Al2O3, B2O3-CaO-SiO2, and B2O3-ZnO-SiO2–BaO were developed at low melting points below 1000°C then used as sintering aids with ceramics at low sintering temperatures [62, 63]. Consequently, these systems (BaO-B2O3-SiO2) and (BaO-B2O3-SiO2- Al2O3) possess their own particular thermal physical properties, where achieved a coefficient of thermal expansion (11–17 ppm °C−1) and low permittivity (≈7) [64]. B2O3-Bi2O3-SiO2-ZnO (BBSZ) is commonly used as an appropriate additive to reduce the sintering temperature of many dielectric materials and make them suitable for LTCC applications [65, 66]. Therefore in order to improve the electromagnetic properties of Ni–Cu–Zn ferrite (NCZF) and BaTiO3, the BBSZ glass was chosen as a melting agent [67]. Glass-ceramics based on the CaO–MgO–SiO2 system has been studied with the additives B2O3, P2O5, Na2O, and CaF2. The results showed that these systems required high melting points and the final crystallisation of the glass-ceramic occurred with temperatures of 900°C, producing high levels of density [68].
The binary system of BaO-B2O3 is used in a wide range of glass ceramic production, oxide cathodes and the coloured materials in paints. In addition, these systems are used as sintering aids for low temperature co-fired ceramic applications due to the low softening temperature of the B2O3 [69]. Figure 13 shows the phase diagram for the binary system of BaO-B2O3 [70]. The procedures of melting and cooling the BaO-B2O3 systems lead to glass formation. In the phase diagram, it can be seen that the lowest melting point with high stability for these systems occurs with approximately 60 to 80% B2O3. In practise, the optimum ratio also depends upon the rate of cooling of the glass [70].
Phase diagram of the BaO-B2O3 system [
The binary system of BaO-B2O3 was modified by SiO2 or Al2O3 as a network modifier. Therefore, it was expected that the mineral phase with odd physical characteristic would be obtained. Therefore, glass ceramics are prepared with low sintering temperatures [64]. It should be noted that the melting point of B2O3 is around 450°C, which is much lower than SiO2, which has a melting point of around 1710°C. However, the crystalline glass of B2O3 is much more difficult to produce than that of SiO2 [70].
SiO2 added to borate glasses generally leads to an improvement in the density of the glass and an increase in its Tg and chemical durability [71]. The effect of the Al2O3 on the characteristics of BaO-B2O3-SiO2 was reported by Lim et al. [72]. It was found that the crystallisation temperature, sintering temperature, and glass transition temperature increased with increased amounts of Al2O3 in the glass systems. The ternary glass system BaO-B2O3-SiO2 was studied by Lim et al. [61, 69]. The SiO2 ratio was fixed at 10% and the effects of the amount of BaO/B2O3 on the thermal and physical properties of the glass system were studied. Increasing B2O3 content gave rise to a clear increase in the dielectric properties. The electrical conductivity of solid silicates shows a complex dependence on glass formation processes, devitrification, and temperature. Here, a slight change in the composition of the glass can lead to marked differences in the electrical conductivity values. In spite of the fact that most studies are about the binary systems, however, there is a scarcity of experimental data on the electrical conductivity of the glasses. Accordingly, the study of the influence of the metal oxide on the electrical conductivity is important for the multicomponent silicate glasses for electrical purposes [73, 74].
It was reported that the electrical conductivity is decreased by the presence of the K+ ions in the alumina-silica glasses while the glass transition temperature increased [73]. Wang et al. noted that the addition of Na2CO3 into Ba0.4Sr0.6TiO3 (BST) ceramics caused a decrease in the room temperature dielectric constant of BST, while the highest Na + and K+ content produced an increase in the energy storage density [75].
The following sections summarise the results of previous research on the use of glass additives into ferroelectric ceramics, producing ferroelectric glass-ceramic and composites, and on the heat treatment of amorphous glasses to produce glass-ceramics containing nanocrystalline ferroelectric phases. The emphasis of the present research is on lead-free ferroelectric materials and therefore previous work on lead titanate and PZT-based glass-ceramics is not included here.
BaTiO3-based ceramics have been widely used in a number of electronics and electrical industries, due to their excellent dielectric properties [76]. Glass additives have been used during the sintering process of ceramic materials to form a liquid phase to improve the sintering behaviour of well-known ferroelectric ceramics such as BaTiO3, PZT and KNN. During this process, the reactive liquid formed by the glass additives wets the solid particles and facilitates their rearrangement. This rearrangement of particles gives more effective packing and higher densities, desirable for ferroelectric applications. Furthermore, the capillary pressure developed at each inter-particle space provides an additional driving force for particle rearrangement and re-shaping during sintering, inducing densification.
The pioneering work of Stookey in 1949 [77] on photosensitive glasses led to the discovery of methods for heterogeneous nucleation, where crystal growth takes place from many nuclei dispersed in the glass matrix after the glass has been formed [78]. Later on, Herczog [79] studied the properties and composition of glasses suitable for crystallization of BaTiO3 from glasses. Perovskite BaTiO3 with a minor amount of BaAl2Si2O8 was obtained by heat treating glasses of compositions corresponding to (x)(BaTiO3) + (100-x)(BaAl2Si2O8). The grain size was controlled in the range 0.01 to 1 μm by varying the heating rate and the final heat treatment temperature. When the volume content of BaTiO3 in the glass-ceramic increased from 30 to 60% and the grain size was about 1 μm, the dielectric constant increased from 100 to 1200. For grain sizes less than or equal to 0.2 μm, the relative permittivity was further decreased and found to be independent of temperature; this was attributed to the presence of surface defects in the fine grains. The highest relative permittivity of 1300 at room temperature was achieved at average grain sizes of about 1 μm, as can be observed in Figure 14; the breakdown strength and electrical resistivity of this ceramic were also reported to be high.
Variation of dielectric constant and loss tangent with the temperature at 1 kHz [
Nano-sized BaTiO3 (20–80 nm) was produced by McCauley et al. [80] following the same approach as Herczog [79] and using different heat treatments and compositions. They observed intrinsic size effects at crystal sizes lower than 80 nm and predicted a critical size of 17 nm, at which BaTiO3 cannot support a ferroelectric transition. Takahashi et al. [81] reported the glass-ceramic of 0.65(Ba1-xSrx)TiO3–0.27SiO2–0.08Al2O3 (BSTS). The heating temperature of glass-ceramics was 1000°C with a small amount of Sn or Zr; also the relative permittivity also decreased with the addition of both of the Sn and Zr. The εr–T relationship showed a broadening and shift of the Curie point towards room temperature, as shown in Figure 15.
The εr–T relationship for BSTS bulk glass-ceramic derived from SnO2-containing glasses [
The use of solid state reaction for the preparation of BaTiO3 ceramics has advantages where the products have good crystallinity and low cost, as well as a high level of accuracy of stoichiometric control [82]. However, many ferroelectric materials have high sintering temperatures (>1200°C), making them unsuitable for certain applications, such as LTCC. In this case, it is necessary to include some additives to reduce the sintering temperature. There have been many studies aimed at lowering the sintering temperature of BaTiO3. The typical additives used include ZnO, CuO, LiF, and CdO. Amongst these additives, LiF proved to be a very effective sintering aid. The effect of LiF in BaTiO3 was investigated and the results indicate that the sintering point is reduced to approximately 900°C [83, 84].
The use of glass additives in BaTiO3 was also shown to improve densification behaviour and reduce the required sintering temperature. Jeon et al. [85] studied the effects of BaO-B2O3-SiO2 (BBS) glass in BaTiO3 ceramics. It was found that the sintering temperature required to reach a high density (≈ 93%) could be reduced to ≈1000°C. The influence of glasses on the sintering behavior and properties of ceramics is dependent upon the glass additive content as well as the chemical reaction between the glass and ceramic phases. Three different glass additives for BaTiO3 were studied by Hsianga; these were BaO-B2O3-SiO2 (BBS), PbO-B2O3-SiO2 (PBS), and ZnO-B2O3-SiO2 (ZBS). It was reported that the glasses containing PbO and BaO led to degradation of the dielectric properties and densification of the ceramic. In addition, adding both BBS and PBS caused the formation of a large number of secondary phases [3].
Lin et al. [86] added a manganese oxide-silica glass to pure BaTiO3 and reported the effect of the liquid phase on the dielectric and ferroelectric properties of the material. The addition of the Mn-Si-O glass enabled densification of the nanocrystalline powder at temperatures in the range 1175–1300°C. At high glass concentrations, they observed the formation of Ba2TiSi2O8 and a Mn solid solution in BaTiO3 grains growing at the grain boundaries and inhibiting grain growth. Figure 16 shows the influence of glass content on the structural and dielectric parameters [86]. It can be observed, that the ceramics with grain sizes in the range of 0.7–1 μm have the higher relative permittivity. Meanwhile, for the glass doped samples, the higher tetragonality of BaTiO3 induced through the liquid phase sintering led to larger dielectric permittivity. However, the dielectric loss was also affected by the Mn solid solution in BaTiO3 and the Ba2TiSi2O8 phases.
Effect of glass addition on the (a) grain size (b) tetragonality and (c) dielectric constant and loss of die-pressed BaTiO3 [
More recently, Chen et al. [87] studied the addition of 50–90% of B2O3–Bi2O3–SiO2–ZnO (BBSZ) glass on the dielectric and ferroelectric properties of BaTiO3. By this means, the sintering temperature was reduced to 400–450°C. The second phase of Bi24Si2O40 was observed when samples were sintered at 450°C and the BBSZ concentration was higher than 60 wt%. Once the solubility limit of BBSZ on BaTiO3 was exceeded (BBSZ>60 wt%) and the formation of the Bi24Si2O40 and glass phases took place, some pores of about 1–2 μm appeared due to the capillary pressure, rearranging the particles and affecting the packing; this reduction in density led to a lower relative permittivity for the 60 wt% modified samples. When the amount of liquid increased (up to 70 wt%), the porosity decreased and relative permittivity values of 132 and 207 were achieved at 100 kHz and 100 MHz, respectively. The dielectric loss remained at the same level as that of the pure glass at 100 kHz (0.006). At higher BBSZ concentration (80 and 90 wt%), the overall dielectric properties of the samples decreased due to the lower relative permittivity of the glass phase.
Choi et al. [88] reported that the addition of 1 to 7 wt% of BBS into BaTiO3 (prepared using flame spray pyrolysis) reduced the sintering temperature at 1000°C, yielding an improvement in relative permittivity in comparison with pure BaTiO3 sintered at 1300°C. It was also found that the glass additives improved the density of the material with an increase in the grain size by several microns. Wang et al. [26] found that the sintering temperature of BaTiO3 ceramics could be reduced to about 1100°C using a glass with the composition 27.68BaCO3–6.92SrCO3-29TiO2–22SiO2-12Al2O2–2.4BaF2 (mol %). The effect of this additive was a reduction in the average grain size. It was also found that the energy storage density of the ceramics increased gradually with increasing glass concentration; the highest energy density value of 0.32 J cm−3 was obtained for the sample with 7 mol% of the glass. The influence of glass additives on modified barium titanate ceramics was reported by Puli et al. [35], who studied the dielectric and ferroelectric properties of glass-modified BCZT, specifically the composition 0.85(BaZr0.2Ti0.8O3)-0.15(Ba0.7ZCa0.3TiO3). The addition of 15 wt% (0.1BaO + 0.4B2O3 + 0.5ZnO) and (0.3BaO + 0.6B2O3 + 0.1ZnO) glass powders yielded dielectric breakdown field strengths of 260 and 280 kV cm−1, with recoverable energy density values of about 1.12 and 0.50 J cm−3, respectively. The resulting samples were composites comprising a mixture of two phases, BCZT and the glass phase. They attributed the high breakdown strength to the presence of alkali free glass composition, and the low loss dielectric to the low dielectric loss of BZT–BCT ceramic composition.
The effect of up to 9 wt% of CaO–B2O3–SiO2 (CBS) glass additions on the microstructure and electrical properties of Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) was studied by Lai et al. [89]. Samples were sintered at 1300°C for 4 hours in air; in the CBS-free sample, they observed the coexistence of orthorhombic and tetragonal BCZT phases with a small amount of CaTiO3 secondary phase by means of XRD. The addition of the CBS glass induced a phase transformation to pseudo-cubic, a shift of the reflections towards lower 2θ values and the coexistence of the orthorhombic and tetragonal phases disappeared. These phase transformations were accompanied by the appearance of another secondary phase, reported to be Ba2TiSi2O8. The density of the BCZT samples increased with CBS content, reaching a maximum when the addition of CBS was 2 wt%, and then slowly decreasing at higher CBS concentrations. Regarding the electrical properties, the sample with 2 wt% CBS exhibited the best ferroelectric properties, a dielectric constant of 8874 (at 106 Hz), a Curie temperature of 116°C, Pr of about 3.18 μC cm−2, and d33 of 159 pC N−1 due to the improved density achieved by the addition of CBS.
KNN is one of the most promising candidates for energy storage properties, yet at present much research has focused on the development of, for example, (BaO,SrO)-TiO2 [90, 91], (BaO,SrO)-Nb2O5 [50] and (BaO,Na2O)-Nb2O5 [92] glass-ceramics. Therefore, the study of KNN glass-ceramics still needs more exploration and in-depth research [93]. Many studies have been conducted on sintering of KNN, but there are currently few reports of true glass-ceramics.
Some previous studies have reported the formation of KNN in a glass-ceramic form [56]. Vernacolota et al. [94] reported that glass-ceramics containing KN and KNN phases can be obtained using silicate glasses prepared with alkali metal and niobium additions. The effects of substituting K by Na on thermal and crystallisation behaviour of KNN-SiO2 glass-ceramics were reported by Aronne et al. [95]. Kioka et al. [96] and Kongputhon et al. [97] studied the control of the crystallisation behaviour in KNN-SiO2, by varying the K:Na ratio, as a means of modifying the dielectric properties. Alumina-silicate glasses have also been used to fabricate glass-ceramics containing ferroelectric KNN and their dielectric properties reported by Yongsiri et al. [54]. The influence of CeO2 as a nucleation agent in borosilicate glasses containing KNN have been reported for energy storage capacitor application by Hanyu et al. [93]. On the basis of their results, Yongsiri et al. [54] suggested that KNN glass-ceramics could be favourable for use in electro-optical applications. The microstructure, crystallite sizes, and crystal quantity of the KNN glass-ceramics were studied as a function of the heat treatment conditions. The heat treated glass-ceramics were found to contain a KAlSiO2 phase at heat treatment temperatures between 600 and 675°C, while the perovskite KNN phase was observed at a higher temperature of 700°C, Figure 17. The glass-ceramic containing 23.75 mol% of SiO2 exhibited a relative permittivity value of ≈ 260 and loss tangent ≈ 0.02 at 10 kHz.
XRD patterns of the glass-ceramic sample with 5 mol% alumina and 23.75 mol% SiO2 subjected to different heat treatment temperatures [
The use of a two-stage incorporation method, which involved the separate preparation of KNN and glass powders prior to melting, was also studied by Yongsiri et al. [98]. The calcined KNN powder was mixed with 25 mol% of SiO2 then melted at 1300°C using the conventional melt-quenching technique. The glass was heat treated at temperatures from 525 to 575°C for crystallisation. Increasing heat treatment temperatures were found to improve the crystal size and crystallinity, which in turn plays an important role in controlling the properties of the glass ceramics, including physical, optical, and dielectric properties. It is clear from the SEM results, Figure 18 that the crystallisation of the KNN phase occurred at temperatures lower than the observed crystallisation temperature of 648°C from the DTA results. Furthermore, the amorphous XRD patterns were observed in the glass-ceramic samples heat treated at temperatures lower than 550°C. The highest relative permittivity value was 474 at a heat treatment temperature of 550°C, while the transparency decreased with increased temperatures.
SEM micrographs for glass-ceramic samples heated at different temperatures. (a) 525°C, (b) at 550°C, (c) 575°C [
KNN ceramics prepared by solid state reaction usually require reaction temperatures around 800°C or, sometimes, the double calculation in order to obtain a homogenous powder; sintering temperatures are usually in the range 1100–1200°C [99]. The three starting materials used in KNN are Nb2O5, with a high melting point of 1520°C, and two alkali metal carbonates, K2CO3 and Na2CO3, with melting points of 891°C and 851°C, respectively. Therefore, the alkali metal carbonates/oxides become volatile during the calcination, making it difficult to achieve a chemically homogeneous material. Excess alkali carbonate is used in order to compensate the losses during calcination and to obtain a single phase perovskite product [100]. The studies reported in [96, 100] indicated that a 5 mol% excess of K2CO3 and Na2CO3 in the raw materials leads to increased stability during calcination at 800°C. The other effect of this excess an increase in particle size, which is probably due to the liquid phase which forms during the calcination [100]. By adding 3% and 1% excess alkali carbonate the density of KNN has improved and, at the same time, this excess leads to reduce the sintering temperature to 1000°C [101, 102].
Sintering temperatures for KNN ceramics are usually >1000°C. This needs to be lowered in order to decrease the alkali evaporation during the periods of high temperature, as well as to make it suitable for many desired applications [103]. If lithium additives are added to KNN, the sintering temperature reduces to lower than 1000°C, there is a shift in TC to a higher temperature, and there is an increase in the dielectric constant [104]. Barium borosilicate-based frit (BaO-B2O3-SiO2-Na2O-K2O-CuO-CaO) (abbreviated as BBS) was one glassy additive used previously as a sintering aid to KNN. It has been shown to reduce the sintering temperature to 1000°C. In addition, the additive led to an increase in the mechanical properties and a decrease in the dielectric loss, whilst the TC remained high at 400°C; samples with 1.5 wt% glass frit showed optimal properties as follows: εr = 410, tanδ = 0.57 and d33 = 108 pC N−1, Figure 19 [105].
(a) εr and tanδ (b) d33, kp and Qm of KNN + x wt% BBS ceramics as a function of the x value [
Several different ferroelectric glass-ceramics systems were discussed in this chapter. All glasses types were mixed with ceramics, resulting in much improved densification behaviour at reduced sintering temperatures. In addition, nanocrystalline glass-ceramics containing perovskite-structured ferroelectric phases have been researched. These studies indicate that the materials exhibit promising dielectric properties and good stability of relative permittivity values at low heat treatment temperatures comparison with conventional preparation methods, although relatively high dielectric losses were evident. This review suggests that ferroelectric glass-ceramics exhibit promising dielectric properties with good potential for use as energy storage dielectrics at high electric field levels as a result of their nanocrystalline microstructures.
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