EU and U.S. regulations on paediatric research
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Until very recently, decisions about the medical treatment of children with acute or chronic health conditions were based on the results of research conducted almost exclusively in adults. Although differences in treatment effects between young and adult patients are well known (e.g. regarding mechanism of action and metabolism), there were less clinical trials (CTs) than needed to adequately evaluate the effects of new medicines in children. This was mainly due to:
the lack of appropriate rules for the conduct of paediatric CTs, especially with regard to ethical considerations;
the lack of an adequate methodology enabling to provide powered evidences while taking into account the paediatric specificities [1];
the lack of economic interest of the industrial developers due to the limited market offered by children.
Starting from 1994, Food and Drug Administration (FDA) adopts different measures to promote, incentive or oblige to conduct paediatric trials. More recently, for effect of the Paediatric Regulation (EC) No 1901/2006 [2] requiring a sound scientific evidence for treatment benefits in children and adolescents, the conduct of CTs testing medications for their use in children and adolescents becomes mandatory in the European Union (EU).
Despite the high number,,(more than 1000) of Paediatric Investigation Plans (PIPs) applied to receive an opinion by the Paediatric Committee (PDCO) at the European Medicines Agency (EMA) since the Regulation entry into force very few advancements have been done in terms of new studies, new trials and new paediatric approved medicines on the market. [3]. At the same time, looking at the American side, we can observe that the implementation of the existing rules has been and are still strongly problematic and under debate, allowing to recent modifications of rules and guidelines.
The aim of this chapter is to describe the requisites for implementing paediatric CTs in compliance with the principles of good clinical practice (Good Clinical Practice, GCP), and with the regulatory standards in order to be part of an agreed PIP in EU or of a Pediatric Study Plan (PSP) in the United States (U.S.).
It will include the following topics:
Paediatric trial regulatory aspects
Paediatric Plans and paediatric trials methodology
Paediatric trial incentives and main results of the existing legislation
To overcome the lack of paediatric trials, many initiatives have been promoted both in U.S. and in Europe.
The first rule came from FDA in 1994 [1]. It was an attempt to use existing data (may be extrapolated from adults) and additional pharmacokinetic (PK), pharmacodynamic (PD), and safety studies, if the course of the disease and the response to the drug are similar in children and adults. The 1994 law did not impose a general requirement to the manufacturers to carry out studies when existing information was not sufficient and was not successful to obtain its aim.
In 1997, for the first time, the FDA Modernisation Act [6] introduced incentives for conducting paediatric studies on drugs for which exclusivity or patent protection exists, while off-patent drugs were excluded. At that time it was not accepted that FDA would mandate timing and other paediatric studies provisions to the manufacturers.
Today, the current U.S. regulatory framework includes:
The Best Pharmaceuticals for Children Act
The Paediatric Research Equity Act ( More details at: Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm
Noticeably, BPCA provided mechanisms for studying on- and off-patent drugs and to test off-patent drugs by:
Identifying and prioritising drugs which need to be studied;
Developing study requests in collaboration with experts at National Institutes of Health (NIH), FDA and other organisations;
Conducting studies on priority drugs after manufacturers decline to do so.
On the other hand, under the
A similar intervention in the EU arrived almost 10 years later. In fact, the EU Paediatric Regulation [2] entered into force in January 2007. After the Paediatric Regulation approval, relevant changes have been implemented not only in Europe but also in the U.S.
The main pillars of the EU Paediatric Regulation are:
to set up a new Committee at EMA named the Paediatric Committee (PDCO);
to rule a new type of Marketing Authorisation, the Paediatric Use Marketing Authorisation (PUMA) only accessible to off-patent drugs;
to introduce the obligation for the manufacturers to apply for a PIP early in the drug developmental process;
the obligation to conduct the paediatric studies in compliance with an approved PIP that can also include waiver (exemption to conduct any paediatric studies) or deferral (the right for the manufacturer to delay the paediatric study respect to the adults MA);
to state that dedicated incentives should be provided under the European Research Framework to develop off-patent drugs if included in a ‘Priority List’ published by the PDCO-EMA
The introduction of specific rules devoted to implement the paediatric research in the paediatric population allowed an increased attention to the CT approval and conduct.
For many years, the traditional approach to diagnosis and treatment has been based on symptoms and signs, which reflect, in the majority of the cases, the patient phenotype. Accordingly, trials have been conducted by grouping patients into broad groups with similar symptoms. Pharmaceutical and biotechnology companies have developed medicines for these broad populations, and the regulatory assessment of risk and benefit has been based on the average clinical response across these groups. This model has been strongly regulated with the aim of performing ethically and methodologically well-conducted CTs.
In Europe several guidelines, directives and regulations have been released, including Directives 2005/28/EC [9] and 2001/20/EC [4], GCP Guidelines (CPMP/ICH/135/95) [10], Reg. (EC) No 726/2004 [11]. In particular, Directive 2001/20/EC has established specific provisions regarding the conduct of CTs on human subjects involving medicinal products and recognises GCP principles. As internationally agreed and in accordance with GCP [10], a CT may not commence in EU if an Ethics Committee has not approved the study. The Directive 2001/20/EC also introduced the concept of “Competent Authority”, adding the legal obligation to obtain an “authorisation” in addition to the positive opinion of the Ethic Committee.
However, the above mentioned provisions in Europe have never considered the paediatric specificity until the approval of the CT Directive. In fact, the main novelty of the Directive has been represented by the introduction of a dedicated article (art. 4) that refers to differences in the ethical and methodological approaches between paediatric and adult trials and provides the basis for including paediatric trials in the developmental process of adult drugs. Moreover, following the approval of the Paediatric Regulation, destined to increase the number of paediatric trials, the art. 4 of Directive 2001/20/EC was considered insufficient to protect children involved in a trial [12]. The ‘
In U.S. the ethics framework for approval of CTs is quite similar. Every CT must be approved and monitored by an
In the U.S. legislation, details on how to conduct trials in the paediatric population are included into Subpart D (401-409) of the ‘
In addition, research that presents a reasonable opportunity to advance the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children can be also approved under special conditions.
A great relevance is given to the procedures to obtain the children assent. The permission to include a child in the trial is given by both parents in case of researches involving greater than minimal risk, and by only one parent if only a minimal risk is concerned.
After its entry into force, the EU Directive 2001/20/EC has been the object of many concerns and debates leading to a new legislative process aimed to change and consolidate a EU framework by the means of a
In contrast with the U.S. where only one Federal rule applies, in Europe Directive 2001/20/EC, given its ‘non-binding’ nature, needed to be implemented by all the different Member States (MSs). Therefore, the harmonisation of ethical issues and the authorisation procedures in different countries were faced but not solved in the context of Directive 2001/20/EC, and this holds true in the case of paediatric trials [16]. In addition, Directive 2001/20/EC does not provide information on how competent authorities and Ethics Committees of each MS should act in case of multi-centre and multi-national studies, while these studies prevail among the trials aimed to a MA approval.
The main cause for the decreasing number of trials conducted in Europe and for the increasing of costs is due to the double obligation to obtain an “authorisation” from the Ethic Committees and the Concerned Authorities to be repeated in all the concerned member states. As reported in the EC Explanatory Memorandum preparing a new Regulation [15]:
From 2016, with the application of the new EU Regulation on CTs (Regulation 536/2014) [5], a unique central procedure will be applied to be carried out through a single EU CT portal, where an homogeneous submission package (valid for all MSs) will be submitted in order to obtain the CT authorisation. The centralised submission will include also the ethical assessment, both for adults and paediatric trials.
Noticeable, the principal duty of the centralised assessment will consist in confirming or not the nature of trial that could be ‘interventional’ ‘low-risk interventional’ or ‘non-interventional’.
The category of ‘non-interventional trial is a novelty in the EU context and is based on a recognised ‘minimal risk’ of the trial (e.g. only limited procedures added to the current therapy) to which a lower level of requirements (including insurance coverage) is needed.
A “Reporting Member State”, in charge to draw up an “assessment report” and the release of the authorisation, will be proposed by the sponsor corresponding to the country where it intends to carry out the Clinical Trial Application (CTA) at first. In case of multi-national trials, the other involved MSs follow a simplified procedure of assessment focused on national and ethical aspects (e.g. informed consent, recruitment of subjects, data protection, suitability of investigators and trial sites, mechanisms of insurance compensation collection of biological samples, submission fees, arrangements for rewarding/compensating investigators and subjects) for their own territory compliance.
In case of paediatric trials, for effect of a large consultation process and after relevant amendments provided by different stakeholders, in particular by the Paediatric Research Networks (such as EnPREMA EnPREMA is the Network of the existing Paediatric Network, stated in the Paediatric Regulation and set up at EMA TEDDY is a European Network of Excellence for Paediatric Clinical Research. For more information, http://www.teddyoung.net/ GRiP amendments are available here http://www.grip-network.org/index.php/sfPropelFileStorage/download/name/GRiP+on+CT+regulation.pdf
In more details, the Regulation states that:
The application should refer to the PDCO opinions and related approved PIPs: The Reporting MS shall assess the application with regard to the relevance of the CT, including PDCO\' opinions on PIPs.
As stated in the Paediatric Regulation [2], all paediatric studies should be registered in the EU register of CTs, including studies that are part of an agreed PIP and carried out in third countries.
With regards to the preparation of submission documents, besides the rules applying for every type of trials, issues specifically dealing with paediatrics have been established as follow:
the cover letter shall indicate the reference to trial population (minors), and a statement that the trial is part of an agreed PIP.
the link to the Decision of the Agency on its website must be indicated in order to demonstrate that at the time of the Ethic Committee application, the Agency will have already issued the Decision about the PIP;
the protocol shall include a justification for including minors and detail the procedures for inclusion of single subjects;
the summary of the results of the CT shall include paediatric regulatory details (information whether the CT is a part of a PIP).
Finally, some important requirements, already stated in previous non-mandatory documents, such as the need for paediatric expertise or advice in Ethics Committees, become mandatory, such as the involvement of minors in the informed consent procedure according to their age and mental maturity. The table below shows the comparison between EU and U.S. rules on specific key topics of paediatric trials.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tThe Reporting Member State and other MSs involved authorise the trial. The assessment includes the Ethics Committees review. The reporting Member State shall assess the application with regard to the relevance of the clinical trial, including PDCO\' opinions on PIPs. | \n\t\t\tAn Institutional Review Board (IRB) approves and monitors the trial. | \n\t\t
\n\t\t\t\t | \n\t\t\tExperts in paediatric research are members of Ethics Committees reviewing the protocol. Alternatively the Ethics Committees take advice from external experts on clinical, ethical and psychosocial issues in the field of paediatrics. | \n\t\t\tIRBs are also allowed to invite individuals with special expertise or knowledge to provide consultation and information on individual protocols, where needed. | \n\t\t
\n\t\t\t\t | \n\t\t\tNo specific rules. All rules intended to paediatric research apply. Research on non viable or of uncertain viability neonates are not cited. | \n\t\t\tSpecific rules apply to neonates: a) non viable, b) of uncertain viability, c) viable (general rules apply). | \n\t\t
\n\t\t\t\t | \n\t\t\tNo specific rules for paediatric population. | \n\t\t\tEach IRB shall approve only Paediatric Research not involving greater than minimal risk or involving greater than minimal risk if: - presenting the prospect of direct benefit to the individual subjects - likely to yield general knowledge about the subject\'s disorder or condition (if minimal risk increase) - research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (under special conditions). | \n\t\t
\n\t\t\t\t | \n\t\t\tMinimal risk could be defined as the probability of harm or discomfort not greater than that ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests,\n\t\t\t | \n\t\t\tMinimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests (this rule is not a specific paediatric rule). | \n\t\t
\n\t\t\t\t | \n\t\t\tInformed consent of the parents or legal representative. Assent of the children, that are entitled to receive information according their age and maturity. No minimum age is defined for providing assent. Need to obtain the consent if the subject reaches the age of legal competence during the trial | \n\t\t\tParents (both or only one, according the level of risk) or guardians provide permission before children can be enrolled in research. Researchers must seek a child’s assent unless the IRB determines that the children to be involved are not capable of providing assent, given their age, maturity, and psychological state. The regulations do not describe the information that must be provided to children but rely on IRBs to use their discretion in judging assent provisions. | \n\t\t
No specific rules for children issued in Reg. 536/2014 (as well as in the Privacy Directive 95/46/EC) The only reference is present in the EC Ethical Recommendation,2008\n\t\t\t | \n\t\t\tChildren confidentiality and privacy is not mentioned in FDA code. FDA regulation (50.25(a)(5)) states that in seeking parents’ informed consent, (5) a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained (including the possibility of FDA inspection) must be provided. However, this point is not cited with reference to children’s assent. | \n\t\t
EU and U.S. regulations on paediatric research
As detailed before, both EU and U.S. legislation currently require that a developmental plan (i.e. the PIP in EU and the PSP in U.S.) is approved by the responsible Official Bodies before the paediatric studies will start.
PSP is required for each drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration (including a biosimilar product that has not been determined to be interchangeable with the reference product).
FDA strongly regulates the timing to which the
In EU the Paediatric Regulation [2] requires
include a description of the studies and of the measures to adapt the medicineformulation to make its use more acceptable in children, such as use of a liquid formulation rather than large tablets;
cover the needs of all age groups of children, from birth to adolescence;
define the timing of studies in children compared to adults EMA website: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000293.jsp&mid=WC0b01ac0580025b91
The table below describes the main measures included in the EMA-PDCO and FDA guidance.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tThe sponsor of a ‘product not yet authorised’ (that NOT includes variations) (art.7). The sponsor of a marketed patented drug willing to introduce variations (art. 8). The sponsor (even different from the MAH) willing to develop a paediatric study on an old off-patent drug (art. 30. This is voluntary and lead to a PUMA). | \n\t\t\tThe sponsor of a ‘new active ingredient’ (that includes variations) (this is an obligation under PREA). | \n\t\t
\n\t\t\t\t | \n\t\t\tEarly, wherever possible (in time for studies to be conducted in the paediatric population, where appropriate, before MAAs are submitted). PDCO requires: “not later than upon completion of the human PK studies and initial tolerability studies, or the initiation of the adult phase-II studies (proof-of-concept studies), but before pivotal trials or confirmatory (phase-III) trials are initiated. Applications during confirmatory or phase-III trials in adults, or after starting CTs in children, are likely to be considered unjustified. | \n\t\t\tNot later than 60 calendar days after the date of the end-of-phase 2 meeting (special rules apply according with the FDA meetings timing). For products for life-threatening diseases, at the end-of-phase 1 meetings. | \n\t\t
\n\t\t\t\t | \n\t\t\tAll the paediatric population’s groups (birth to 18 years). | \n\t\t\tAll relevant paediatric populations (birth to 16 years). | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t - A.5: Regulatory information on CTs related to the condition (EAA). A.6: Marketing authorisation status of the medicinal product. A.7: Advice from any regulatory authorities. A.8: Orphan drug status in the EEA. | \n\t\t\tn.a. | \n\t\t
Overview of the - pathophysiology of the disease, - diagnosis, - currently available treatments and/or prevention - incidence and prevalence of the disease. | \n\t\t\tOverview of the - pathophysiology of the disease, - diagnosis, -currently available treatments and/or prevention - incidence and prevalence of the disease. | \n\t\t|
Overview of the - mechanism of action - potential therapeutic benefits - Other possible therapeutic uses of the drug | \n\t\t\tOverview of the - mechanism of action - potential therapeutic benefits - Other possible therapeutic uses of the drug | \n\t\t|
\n\t\t\t\t - efficacy from adults to children or from older to younger children, - safety information from adults to children can also be included, - modelling of PK and/or PD if used for decision-making. | \n\t\t\tOverview of Planned - any plans to extrapolate efficacy from adult or from one paediatric age group to another including neonates, - extrapolation for other drugs in the same class, can be considered as supportive information,\n\t\t\t | \n\t\t|
\n\t\t\t\t The requirement to submit a PIP shall be waived for specific medicinal products or classes of medicinal products that: are likely to be ineffective or unsafe in part or all of the paediatric population; are intended for conditions that occur only in adult populations; do not represent a significant therapeutic benefit over existing treatments for paediatric patients. | \n\t\t\t\n\t\t\t\t (a) Necessary studies are impossible or highly impracticable (because, for example, the number of patients is so small or the patients are geographically dispersed). (b) There is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in all paediatric age groups. (c) The drug or biological product (1) does not represent a meaningful therapeutic benefit and (2) is not likely to be used in a substantial number of paediatric patients\n\t\t\t\t Partial waiver provision also apply: -if attempts to produce a paediatric formulation failed - for a specific age group. | \n\t\t|
Planned | \n\t\t\t\n\t\t\t\t | \n\t\t|
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Main provision to apply for PIP and PSP
Considering the two described systems, we noted some interesting differences. In particular, while the EU Paediatric Regulation covers all the paediatric medicines (in-patent, off-patent, under development) and deserves incentives only to the off-patent drugs, in U.S. two different regimens apply for: a) medicines to be granted a paediatric exclusivity after a solicited request (Written Request) as stated in BPCA, and b) medicines for which a PSP is mandatory under PREA. Noticeably, the medicines that are under PREA can also be granted a Written Request, allowing to receive a paediatric exclusivity (see also Fig.1).
Paediatric drug regulatory process in EU and U.S. (source: FDA and EMA Paediatric Regulatory Process: J Temek, MD, FDA website)
Moreover, the paediatric developmental plan procedures of the two Agencies are not completely aligned mainly due to the different regulatory status provided by the different regulations and the different approaches of the two Committees. In particular:
In EU, unlike in the U.S., a MAA (Marketing Authorisation Application) (equivalent to NDA in U.S.) must contain the results of the paediatric studies conducted in compliance with the agreed PIP (or waiver or deferral). In lack of this, the MA cannot be granted.
In EU, the paediatric product development is requested earlier in the regulatory process than in U.S.
In EU, the PDCO, the counter part to the PeRC in the U.S, unlike the PeRC, makes binding decisions.
FDA “feasibility ” criteria for waivers do not exist in the EU legislation. Thus, a study may be required in EU but waived in the U.S. under PREA.
FDA may request or grant paediatric studies under BPCA, using the voluntary financial incentive, even during the PSP process, while in Europe patented drugs do not have access to financial incentives.
Finally, unlike the U.S., the EU does not have a public process whereby paediatric focused post-marketing safety reviews are presented to an Advisory Committee.
These differences still represent an obstacle to a prompt development of paediatric drugs in a global context. An intensive work aimed at merging the paediatric efforts at the two levels is highly required and desirable. To this aim, currently a process of ‘Information Exchange’ is in place to discuss product-specific paediatric development issues and general scientific/regulatory/safety issues. The Japan Pharmaceuticals and Medical Devices Act (PMDA) has recently joined this initiative as observer.
Before specific paediatric legislations were in place, regulators, companies and clinicians were well aware that the current methodological approach, based on well-designed RCTs, could result difficult to apply in selected cases such as the paediatric population.
In particular, in paediatrics the following issues are challenging large population available for RCTs, randomisation procedure, placebo use, availability of validate paediatric endpoints, appropriate outcomes, long-term effects evaluations, etc.
The ICH-E11 Guideline, issued in 2000 at international level [19], has represented the main international reference for paediatric CTs and the methodological standard to perform paediatric CTs scientifically correct, and ethical in the same time. It still represents the only standard acceptable by the Regulatory Authorities.
The guideline milestones are:
Paediatric patients should be given medicines that are properly evaluated for their use in the intended population.
Product development programs should include paediatric studies when paediatric use is anticipated.
Development of appropriated products in paediatric patients should be timely and, often requires the development of paediatric formulations.
The rights of paediatric participants should be protected and they should be shielded from undue risks.
Responsibility should be shared among companies, regulatory authorities, health professionals and society as a whole.
Marketing Authorisation Holders (MAHs), and competent authorities/medicine regulatory agencies are the two major stakeholders responsible for medicine safety at the time of authorisation.
The approach to the clinical programme needs to be clearly addressed with the regulatory authorities at an early stage and then periodically during the development process. To this aim, the guideline has provided specific indications on trial characteristics, including:
when initiating a paediatric program for a medicinal product (need of a medicinal products, therapeutic benefits, lack of alternatives);
timing of initiation of paediatric studies during medicinal product development (need that preliminary safety/tolerability data are known in adults);
types of studies (PK, PK/PD, efficacy, safety); according to the principle to avoid unnecessary studies in all paediatric age groups, large efficacy studies should be considered only when extrapolation of results from adults (or from older children to younger) is not feasible; on the contrary, PK studies and short and long term safety evaluations are always required.
age categories: five paediatric ages have been identified from neonates to adolescents and each paediatric group should be given medicines that have been appropriately evaluated for their use;
special rules for ethic approval of paediatric clinical investigation (including children right to be informed and privacy).
Currently, a revision of the ICH-E11 guideline is ongoing. It derives by the relevant changes occurred in the last years, both at scientific and regulatory levels.
use of innovative PK/PD methodologies for dosing and efficacy extrapolation exercises [20];
use of population PK PD (pop PKPD) models to assess different clinical scenarios without exposing children to any risk to explore new drug [21];
use of alternative statistical approaches to reduce the size of the experimental population and the number of the trials needed in the clinical phase [22].
The updated E11 Guideline as proposed in August 2014, aims to include the new scientific and technical knowledge advances in paediatric drug development in a new regulatory guidance. To this aim, an addendum to the ICH Topic E11 guideline will be finalised by November 2015 with the following revised topics:
Timing of paediatric development: need for more harmonisation and clarity to guide the developers of paediatric medicines; it is proposed to focus on the multi-national/multi-regional status of many paediatric trials for which the requirements of multiple regulatory authorities should be satisfied.
Age classification and paediatric subsets including neonates: there is the need for better understanding the developmental process in paediatric subsets, especially neonates and infants.
Ethical considerations in paediatric studies: there is the need for enhance the ethical considerations in paediatric studies.
Types of studies and methodology of CTs: the advances in paediatric CTs design and conduct should be incorporated in the ICH-E11 guidance including: innovative study designs, development of clinical outcome assessments, development of validated age-appropriate clinical endpoints and surrogate markers (biomarkers), specific scales for measuring outcomes particularly in case of younger age groups,
Common rules to apply appropriate principles for extrapolation of data (from adult to paediatric populations or older children or different indication). This last point could possibly lead both the Agencies to agree a Paediatric Algorithm firstly proposed at FDA level and still now not regularly adopted at EMA level.
Formulation challenges in paediatric drug development: need for developing specific comprehensive guidance on formulation development for children.
Paediatric Study decision tree for bridging efficacy data in an adult population to a paediatric population (source: FDA)
As stated before, important changes both in U.S. and EU legislations both imposed the pharmaceutical industry to study medicines in children, with the aim to increase the number of paediatric trials to be conducted, to reduce the existing gap. A comparison between the two regulations in terms of impact on paediatric trials is difficult, because of the existing differences on requirements and incentives provided in the two contexts, as well as the very limited amount of published data on the regulations results. As a general finding, it seems that public funding provisions and active strategies both in Europe and US have a strong relevance in improving the current situation through the conduction of studies in children and adolescent in the world.
In Europe, the most recent available document summarising the main results of the Paediatric Regulation has been released by the EC covering the period 2007-2012. It provides relevant information on PIPs and paediatric trials approved in Europe. It states that:
By the end of 2012, the Agency had agreed 600 PIPs (more than 1.000 presented). Of these, 453 were for medicines that were not yet authorised in the EU (Article 7), while the remaining ones are related to new indications for patent-protected products (Article 8) or PUMA (Article 30).These plans cover a broad range of therapeutic areas, as shown in the figure below and all the paediatric ages including neonates.
Therapeutic areas addressed by the PIPs (2007-2011). Progress Report on the Paediatric Regulation COM (2013) 443 Final
Regarding the number of paediatric trials, the reference derived by the official source EudraCT EUDRACT is the EU register of all (ongoing, completed, prematurely terminated) trials with medicinal products taking place in the European Union and those studying medicines for paediatric use contained in an agreed PIP carried out in third countries.
\n\t\t\t\t | \n\t\t
Paediatric Clinical Trials by year of authorisation.
Of the total number of trials conducted in the last years after the approval of the Paediatric Regulation, only a few have been included in the Marketing Authorisation documentation, in order to obtain a paediatric indication.
In particular, data from TEDDY-EPMD www.teddyoung.net
Between the 1998 and 2011the FDA issued ~340 Written Requests for new paediatric studies, today 533 labelling changes associated with BPCA and PREA acts have been approved (BPCA only = 161; BPCA + PREA = 73; PREA only = 249; Rule = 49; None = 1), which is significantly higher if compared to the number of labelling changes approved in Europe.
On the basis of these data, according to Lynn Yao it is possible to affirm that: ‘Before BPCA and PREA became law, more than 80% of the drugs approved for adult use were being used in children, even though their safety and effectiveness had not been established in children. Today that number has been reduced to about 50%. (http://blogs.fda.gov/fdavoice/index).
\n\t\t\t\t PK Efficacy Safety | \n\t\t\t\n\t\t\t\t 122 133 281 | \n\t\t
With no New Pediatric Studies | \n\t\t\tN°49 | \n\t\t
TOTAL | \n\t\t\tN°533 | \n\t\t
FDA- New Pediatric Labelling Information Database (1998-2014)
An analysis performed on 174 CTs completed for Pediatric Exclusivity published in May 2010 [23], demonstrated that the U.S. is the most frequent site for conducting CTs, followed by Europe. However, 65% of paediatric trials were conducted in at least 1 country outside the U.S. and 11% did not include any sites in the U.S. Fifty-four countries were represented, and 38% of trials enrolled patients in more than 1 site located in a developing/transition country.
Location of 174 trials included in BPCA act.
Under these programs, ~436 separate studies that enrolled ~56,000 children were performed over a 5-years period. An example of results achieved by public incentives to paediatric research is provided by an extensive study evaluating outcomes of BPCA procedures granted from 2002 to 2007 [24]. This study, analysing 99 Written Request A Written Request may be initiated by FDA or in response to a Proposed Pediatric Study Request (PPSR).
257 paediatric CTs (average 2.6 trials per application) have been conducted, covering approximately 60 indications. The most commonly studied indications were bacterial infections;
the paediatric trials enrolled at least 46,000 subjects in 5,850 clinical centres;
all paediatric ages have been addressed, but most of patients were aged 12-17 years old;
in contrast with the sponsors’ trend to shift the location of adult trials away from the country, the U.S. remains the dominant location for paediatric trials (54%), although most paediatric drug programmes are global;
The trials were distributed across more than 60 countries and the EU contributed 11% of the centres and 7% of patients
Both in EU and in U.S., funding is devoted to better support paediatric drugs development. Initiatives in this direction are justified under many points of view such as:
Relatively few trials specifically studying the younger age groups, (neonates, infants and toddlers) were approved. In fact it has been demonstrated [23] that from 1998 through 2010, only 23 (6 percent) of the 365 labelling changes, after the submission of new paediatric studies, included the addition of information from studies with neonates.
The most commonly studied indications do not necessarily reflect greatest paediatric therapeutic needs but closely matched the distribution of these drugs over the adult market, and not the drug utilization by children [23].
Off-label drugs are poorly studied. Neither the financial benefit for the pharmaceutical companies in USA, neither the new MA, the PUMA, ad hoc created in EU, demonstrated to be attractive for the commercial sponsors.
Strategies have put in place to overcome this limitation mainly based on funding ad hoc studies and promoting non-commercial, research-driven paediatric trial. Positive examples of these strategies in EU and in US are described below.
The EU supports research into paediatric medicinal products through its multi-annual Framework Programme for Research and Technological Development.
According to article 40 of the Regulation, the European Research Framework Programs should reserve funds to support PUMAs in case of off-patent drugs recognised as of high therapeutic interest for children and included in a ‘Priority List’ (PL) adopted, on annual basis, by the EMA (European Medicines Agency) through its Paediatric Committee.
In the last 6 years such EC funds have been delivered through the Seventh Framework Programme for Research (FP7-FRP). In particular, with reference to HEALTH-(2007-2013) Programme area, five calls for proposal have been released with reference to the topic 4.2-1 ‘to develop off-patent medicinal products for the paediatric population’.
From 2007 to 2013, 20 projects were granted with funds. The total amount awarded to these projects is 98.6 million Euros.
The twenty approved projects are investigating a total of 24 active substances, in 10 therapeutic areas (see tab. 5). In particular a total of 71 studies have been funded, involving almost 400 investigational sites in EU and non-EU countries, 246 partners of whom 51 are private companies and around 7000 children (representing 23% of all the paediatric patients included in clinical trials in Europe from 2007 to 2011) were recruited. Eighty percent of the projects include studies to develop new age-appropriate formulations or dosage form and all paediatric subgroups are represented in the clinical trials with particular reference to preterm and/or term newborns.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
TINN | \n\t\t\tCiprofloxacin* | \n\t\t\ttreatment of infections in preterm and term newborns | \n\t\t\tInfections | \n\t\t
Fluconazole | \n\t\t|||
TINN2 | \n\t\t\tAzithromycin | \n\t\t\ttreatment of infections in preterm and term newborns | \n\t\t|
NeoMero | \n\t\t\tMeropenem | \n\t\t\ttreatment of late-onset sepsis in neonates and infants aged <3 months treatment of bacterial meningitis in neonates and infants aged <3 months | \n\t\t|
NeoVanc | \n\t\t\tVancomycin | \n\t\t\ttreatment of late onset bacterial sepsis caused by vancomycin susceptible bacteria in neonates and infants aged under three months | \n\t\t|
NeoOpioid | \n\t\t\tMorphine | \n\t\t\ttreatment of acute pain | \n\t\t\tPain | \n\t\t
Fentanyl | \n\t\t|||
GAPP | \n\t\t\tGabapentin | \n\t\t\ttreatment of chronic pain | \n\t\t|
Loulla & Philla | \n\t\t\tMethotrexate* | \n\t\t\ttreatment of Acute Lymphoblastic Leukemia | \n\t\t\tMalignant neoplasms | \n\t\t
6-Mercaptopurine* | \n\t\t|||
03K | \n\t\t\tCyclophosphamide | \n\t\t\ttreatment of paediatric malignancies | \n\t\t|
Temozolomide | \n\t\t|||
EPOC | \n\t\t\tDoxorubicin* | \n\t\t\ttreatment of childhood cancer | \n\t\t|
HIP trial | \n\t\t\tDopamine | \n\t\t\tmanagement of hypotension in preterm newborns | \n\t\t\tCardiology | \n\t\t
NeoCirc | \n\t\t\tDobutamine | \n\t\t\ttreatment of systemic hypotension in infants | \n\t\t|
LENA | \n\t\t\tEnalapril | \n\t\t\tcardiac failure in children | \n\t\t|
NEMO | \n\t\t\tBumetanide | \n\t\t\ttreatment of neonatal seizures in babies with hypoxic ischemic encephalopathy | \n\t\t\tNeurology | \n\t\t
KIEKIDS | \n\t\t\tEthosuximide | \n\t\t\ttreatment of absence and myoclonic epilepsy | \n\t\t|
TAIN | \n\t\t\tHydrocortisone* | \n\t\t\ttreatment of adrenal insufficiency in neonates and infants | \n\t\t\tEndocrinology | \n\t\t
METFIZZ | \n\t\t\tMetformin | \n\t\t\ttreatment of polycystic ovary syndrome | \n\t\t|
CloSed | \n\t\t\tClonidine* | \n\t\t\tSedation in intensive care | \n\t\t\tIntensive care/anaesthesiology | \n\t\t
DEEP | \n\t\t\tDeferiprone* | \n\t\t\ttreatment of chronic iron overload | \n\t\t\tHaematology | \n\t\t
PERS | \n\t\t\tRisperidone | \n\t\t\ttreatment of conduct disorder treatment of schizophrenia | \n\t\t\tChild & adolescent psychiatry | \n\t\t
NEuroSIS | \n\t\t\tBudesonide* | \n\t\t\tprevention of bronchopulmonary dysplasia | \n\t\t\tRespiratory and cardiovascular disorders | \n\t\t
FP7 approved projects in Europe ([25]
* received an Orphan Drug designation (four in the same indication addressed by the project)
These data demonstrated that paediatric studies receiving support from the EU institutions are attractive even outside Europe and also for the private companies engaged in view of the final PUMA approval.
Furthermore, to date, 22% of the planned enrolment for these trials is completed, that is in contrast with the reported low recruitment capacity and difficulties with the conduct of paediatric trials in Europe.
Sponsored by the Eunice Kennedy Shriver National Institute of Child Health and by the Human Development (NICHD), the Pediatric Trials Network (PTN) is an alliance of clinical research sites located around the United States that are cooperating in the design and conduct of paediatric CTs. PTN relates to BPCA since funds are devoted to develop research driven studies in the area where the investments of private companies are very limited and the FDA incentives resulted insufficient.
As European Consortia, the PTN is studying the formulation, dosing, efficacy, and safety of drugs used in paediatric patients. In keeping with the goals of the Best Pharmaceuticals for Children Act, data collected from PTN trials will help regulators to revise drug labels for safer and more effective use in infants and children.
Currently 20 PTN trials are in progress, the results of 4 of them have been published. Noticeably, 3 active substances funded within PTN are also funded under EU FP7 projects. The list of the projects is available on the FDA website and results are continuously updated.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Metronidazole | \n\t\t\tEnrolment and analysis completed, clinical study report submitted to FDA, results published | \n\t\t
TAPE | \n\t\t\tEnrolment completed in less than 2 months, results published | \n\t\t
Acyclovir | \n\t\t\tEnrolment complete, analysis in progress, results published | \n\t\t
Hydroxyurea | \n\t\t\tEnrolment completed | \n\t\t
POPS | \n\t\t\tEnrolment ongoing | \n\t\t
Lisinopril PK | \n\t\t\tDatabase locked; analyses in progress | \n\t\t
Midazolam | \n\t\t\tData analysis in progress | \n\t\t
Ampicillin | \n\t\t\tResults published | \n\t\t
Obesity informatics | \n\t\t\tAnalysis in progress | \n\t\t
Anti-staph trio | \n\t\t\tEnrolment ongoing | \n\t\t
Sildenafil | \n\t\t\tEnrolment ongoing, interim PK analysis | \n\t\t
Clindamycin obesity | \n\t\t\tEnrolment ongoing | \n\t\t
Fluconazole safety | \n\t\t\tMeta-analysis ongoing | \n\t\t
Midazolam obesity | \n\t\t\tProtocol in development | \n\t\t
Acyclovir phase II | \n\t\t\tProtocol complete, opening sites | \n\t\t
Pantoprazole | \n\t\t\tEnrolment ongoing | \n\t\t
Pediatrix meta-analysis | \n\t\t\tProtocol complete, analysis ongoing | \n\t\t
Antibiotic safety (SCAMP) | \n\t\t\tProtocol complete, selecting sites | \n\t\t
Diuretic safety | \n\t\t\tProtocol complete, opening sites | \n\t\t
Methadone pharmacokinetics | \n\t\t\tEnrolment ongoing | \n\t\t
PTN trials
Taking into account these results, we consider that the problems issued by paediatric drug development are only partially solved. Regulations are now quite similar both with reference to the requirements and the incentives provided but profound differences still exist in the practical application.
The U.S. remains the dominant location for paediatric trials but the balance may change in the future. EU results in increasing the numbers of paediatric approved drugs are still disappointing but in EU the number of studies in specific categories (neonates) and of projects responding to real therapeutic need (off-label) is higher than in US. However the approved drugs in this category still remain very few (on a total of 533 labelling changes in U.S. only 19 off-patent drugs have been the object of a FDA Written Request while in EU only 2 PUMA have been granted till now).
Despite many regulatory provisions have globally focused, in EU and in US, the attention on the paediatric themes, some significant issues have to be further improved in order to fill in the existing gaps. Some of the most relevant criticisms are summarised below.
Especially in EU, it has been recognised that paediatric development strategy is still often perceived as a regulatory obligation, more than an integral part of the whole medicinal development process [26].
Paediatric provisions demonstrated not to be able to specifically address the paediatric needs. For example, in Europe most of the therapeutic needs periodically identified by expert groups at EMA/PDCO are still uncovered by PIPs and/or PUMAs. In the U.S. there is a discrepancy between the drug prescription pattern in children and the drugs granted paediatric exclusivity. Actually, the majority of drugs granted paediatric exclusivity is rarely used by children and drugs frequently used by children are underrepresented in the paediatric studies aimed to obtain exclusivity [27].
The field of neonatology is quite critical. In Europe, the number of neonates included in clinical trials substantially increasedafter the Paed. Reg. entered into force [3]. However many neonatal therapeutic needs recognised by EMA/PDCO are still unmet [28]. Similarly, in the U.S. only a small percentage (6%) of the labelling changes involving the submission of new paediatric studies included the addition of information from studies with neonates [29].
With reference to the availability of drug formulations suitable for children, a lack of age-appropriate formulations, in terms of safety of excipients, palatability, acceptability, dosing flexibility, accuracy and practical handling still exists [3]. In U.S., a public-funded Pediatric Formulations Platform http://bpca.nichd.nih.gov/collaborativeefforts/initiatives/pages/index.aspx
Deferral measures have been introduced in both regions to avoid delays, provoked by paediatric development, to the availability of drugs for adults. As a negative counterpart, deferrals are deeply impairing paediatric drug development: 63% of new medicines intended for both adults and children have a deferral in the agreed PIP [3]. In the U.S, despite nearly all (98%) of the rationales for deferrals were consistent with the law, the amount of deferred studies delayed and/or pending is relevant (78%). It has been estimated that the number of pending studies grew by 50%, while the number of delayed studied increased by more than 80% [30].
Another example of criticism in paediatric drugs availability deals with rare diseases: both in EU and in the U.S, very few medicinal products for rare diseases affecting children have a paediatric indication data deriving from EuOrphan, a database of EU and U.S. orphan drugs hosted by Gianni Benzi Foundation
Finally, a lack of appropriate measures to incentive paediatric research has been observed especially in EU. As already mentioned, the PUMA has been unsuccessful until now and, despite the positive results achieved by the projects for the development of off-patent drugs, the specific funding programme setup from 2007 to 2013 under the EU Seventh Framework Programme has not been renewed in Horizon 2020.
On the basis of these few considerations, EU and U.S. regulators should continue to discuss coordinated approaches and to share results.
In particular, these efforts should be concentrate to minimize unnecessary paediatric trials and to optimize trial design, so that the limited paediatric populations available are enrolled only in ethically implemented, scientifically important trials.
This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n° 261060 - GRiP (Global Research in Paediatrics).
Composites exist in nature. A piece of wood is a composite, with long cellulose fibres held together by a substance called lignin. Composite materials are formed by combining two or more materials that have quite different properties, and they do not dissolve or blend into each other. The different materials in the composite work together to give the composite unique properties. Humans have been using composite materials for thousands of years in different areas. The first uses of composites date back to the 1500 BC, when early Egyptians and Mesopotamian settlers used a mixture of mud and straw to create strong and durable buildings. The combination of mud and straw in a block of brick provides it a strong property against both squeezing and tearing or bending. The straw continued to provide reinforcement to ancient composite products, including pottery and boats [1]. In 1200 AD, the Mongols invented the first composite bow using a combination of “animal glue”, bone, and wood. The bows were pressed and wrapped with birch bark. These bows were powerful and accurate. Composite Mongolian bows helped to ensure Genghis Khan’s military dominance. Due to their advantages such as being light weight and strong, many of the greatest advancements in composites were the result of wartime needs. During World War II, many composite materials were developed and moved from the laboratory into actual production [1, 2].
\nThe development and need for composite materials also result in the fibre-reinforced polymers (FRP) industry. By 1945, more than 7 million pounds of glass fibres were used for various products, primarily for military applications. Composite materials continued to take off after the war and grew rapidly through the 1950s. The composite innovators were ambitiously trying to introduce composites into other markets such as aerospace, construction, and transportation. Soon the benefits of FRP composites, especially its corrosion resistance, became known to the public sector. Boats were one obvious product that benefited. The first composite commercial boat hull was introduced in 1946. A full automobile body was made from composite and tested in 1947 [1, 2]. This led to the development of the 1953 Chevrolet Corvette. The advent of the automobile age gave rise to several new methods for moulding such as compression moulding of bulk moulding compound (BMC) and sheet moulding compound (SMC). The two techniques emerged as the dominant method of moulding for the automotive industry and other industries. In the early 1950s, manufacturing methods such as large-scale filament winding, pultrusion, and vacuum bag moulding were developed. In the 1960s, the marine market became the largest consumer of composite materials [1, 2]. In 1961, the first carbon fibre was patented and several years later became commercially available. In the 1970s the composites industry began to mature. Many better resins and improved reinforcing fibres were developed during this period for composite applications. In the 1970s, the automotive market surpassed marine as the number one market—a position it retains today. During the late 1970s and early 1980s, composites were first used in infrastructure applications in Asia and Europe. The first all-composites pedestrian bridge was installed in Aberfeldy, Scotland, in the 1990s. In this period, the first FRP-reinforced concrete bridge deck was built in McKinleyville, West Virginia, and the first all-composites vehicular bridge deck was built in Russell, Kansas. Composites continue to find applications today [1, 2, 3]. Nanomaterials are incorporated into improved fibres and resins used in new composites. Nanotechnology began to be used in commercial products in the early 2000s. Bulk carbon nanotubes can be used as composite reinforcement in polymers to improve the mechanical, thermal, and electrical properties of the bulk product [3].
\nNowadays, the composite industry is still evolving, with much of the growth now focused around renewable energy. Wind turbine blades, especially, are constantly pushing the limits on size and require advanced composite materials, for example, the engineers can design to tailor the composite based on the performant requirements, making the composite sheet very strong in one direction by aligning the fibres that way, but weaker in another direction where strength is not so important. The engineers can also select properties such as resistance to heat, chemicals, and weathering by choosing an appropriate matrix material. In recent years, an increasing environmental consciousness and awareness of the need for sustainable development have raised interest in using natural fibres as reinforcements in composites to replace synthetic fibres [4, 5, 6, 7]. This chapter seeks to provide an overview of the science and technology in relation to the composite material, manufacturing process, and utilisation.
\nIn general, a composite consists of three components: (i) the matrix as the continuous phase; (ii) the reinforcements as the discontinuous or dispersed phase, including fibre and particles; and (iii) the fine interphase region, also known as the interface [8, 9]. By carefully choosing the matrix, the reinforcement, and the manufacturing process that brings them together, the engineers can tailor the properties to meet specific requirements [10]. Over the recent decades, many new composites have been developed, some with very valuable properties.
\nAny material can serve as a matrix material for composite. However, matrix materials are generally ceramics, metals, and polymers. In reality, the majority of matrix materials that exist on the composites market are polymer. There are several different polymer matrices which can be utilised in composite materials. Among the polymer matrix composites, thermoset matrix composites are more predominant than thermoplastic composites. Though thermoset and thermoplastics sound similar, they have very different properties and applications. Understanding the performance differences can help to make better sourcing decisions and the product designs as composites [11].
\nThermosets are materials that undergo a chemical reaction or curing and normally transform from a liquid to a solid. In its uncured form, the material has small, unlinked molecules known as monomers. The addition of a second material as a cross-linker, curing agent, catalyst, and/or the presence of heat or some other activating influences will initiate the chemical reaction or curing reaction. During this reaction, the molecules cross-link and form significantly longer molecular chains and cross-link network, causing the material to solidify. The change of the thermoset state is permanent and irreversible. Subsequently, exposure to high heat after solidifying will cause the material to degrade, not melt. This is because these materials typically degrade at a temperature below where it would be able to melt.
\nThermoplastics are melt-process able plastics. The thermoplastic materials are processed with heat. When enough heat is added to bring the temperature of the plastic above its melting point, the plastic melts, liquefies, or softens enough to be processed. When the heat source is removed and the temperature of the plastic drops below its melting point, the plastic solidifies back into a glasslike solid. This process can be repeated, with the plastic melting and solidifying as the temperature climbs above and drops below the melting temperature, respectively. However, the material can be increasingly subject to deterioration in its molten state, so there is a practical limit to the number of times that this reprocessing can take place before the material properties begin to suffer. Many thermoplastic polymers are addition-type, capable of yielding very long molecular chain lengths or very high molecular weights [12].
\nBoth thermoset and thermoplastic materials have its place in the market. In broad generalities, thermosets tend to have been around for a long time and have a well-established place in the market, frequently have lower raw material costs, and often provide easy wetting of reinforcing fibre and easy forming to final part geometries. In other words, thermosets are often easier to process than thermoplastic. Thermoplastics tend to be tougher or less brittle than thermoset. They can have better chemical resistance, do not need refrigeration as uncured thermosets (prepreg materials) frequently do, and can be more easily recycled and repaired. Table 1 presents a comparison between thermoset and thermoplastic. This table is not providing all but rather some information for the researchers and manufacturers when considering the utilisation of these materials.
\n\n | Thermoset | \nThermoplastic | \n
---|---|---|
Processing | \nContain monomers that cross-link together during the curing process to form an irreversible chemical bond. The cross-linking process eliminates the risk of the product remelting when heat is applied, making thermosets ideal for high-heat applications such as electronics and appliances | \nPellets soften when heated and become more fluid as additional heat is applied. This characteristic allows thermoplastics to be remoulded and recycled without negatively affecting the material’s physical properties | \n
Features and benefits | \n\n
| \n\n
| \n
Thermoset vs. thermoplastic.
Thermosets are classified into polyester resins, epoxy resins, vinyl ester resins, phenolic, polyurethane, and other high-temperature resins such as cyanate esters, etc. The rapid industrialisation in developing economies the world over is one of the major boosting factors for the thermoset market. The demand for high-performance and lightweight materials from various end-use industries such as automotive, chemical tanks, and water tanks is expected to expand the global market for thermosets over the next 6 years. The growing demand for thermosets from emerging economies like Brazil, Russia, India, and China (BRIC) is expected to drive the market. BRIC nations are the four fastest-growing economies in the world with their GDP growth rates higher than the global GDP growth rate. However, frequent fluctuation in raw material prices acts as one of the major factors inhibiting the market growth. Asia-Pacific accounts for the biggest market for thermosets owing to the growth of the automobile market, primarily in China and India. Japan is a mature market and is expected to remain stagnant over the next years. China is the biggest automobile market in the world, and India also lists itself in the top five automobile markets in the world. Asia, along with being the largest market, is also the fastest-growing market for thermosets. The North American market for thermosets is primarily driven by the regulatory initiative to reduce automobile weight by 50% by 2020 in the USA in order to cut fuel consumption. Polyester resins and polyurethane account for the two most popular types of thermosets in the global market. The global market for thermosets is dominated by big multinational corporations which are present across the value chain. Some of the major companies operating in the thermosets market include Arkema, BASF, Asahi Kasei Chemical Corp, Bayer AG, Chevron Phillips Chemical Company LLC, Sinopec, Dow Chemical Company, Eastman Chemical Company, and Lyondell Basell Industries, among others [13]. To date, thermosets have been used predominantly in the industry. Thermosets are generally favoured for a variety of reasons, especially on commercial aircraft. Thermoset composites have been used for 30–40 years in aerospace. For example, the fuselage of the Boeing 787 is an epoxy-based polymer [14].
\nOn the other hand, the use of thermoplastic polymers (acrylic, polyolefin, acrylonitrile butadiene styrene (ABS), etc.), the more easily moldable and resettable composite material relative to thermoset polymers, is a growing material trend in the fibre-reinforced polymer (FRP) industry. According to the American Composites Manufacturers Association (ACMA), the thermoplastic industry is expected to grow 4.9% over the next years and reach an estimated $8.2 billion by 2017, with even larger opportunities in emerging economies. Thermoplastic polymers also offer an easy solution to recycling composite components, a concern when it comes to adopting composite materials. Thermoplastic composites can repeat the heating and cooling cycle many times, thus giving the product an almost indefinite shelf life and adding more value for industries concerned with composite recyclability. This is especially the case for the growth of natural fibre thermoplastics in the USA and Western Europe. For example, wood-plastic composites, used for decking material and other wood substitutions, have grown by 35–40% in the past 5 years. According to Lucintel (the premier global management consulting and market research firm), countries in Asia and Eastern Europe will lead the growth for thermoplastic adoption because automotive production and thermoplastic automotive component production are quickly growing in those regions. However, the automotive sectors in the USA and Western Europe may not experience the same high rate of growth but are expected to develop steadily in the next 5 years, mainly due to the acceptance of new composite application. The study indicates that although gains will be limited by rising energy costs and competition from lower cost materials, there is significant opportunity in emerging economies such as China, Russia, Brazil, and India [15]. Recently, a major trend in the aerospace industry is a move toward greater use of thermoplastics vs. “traditional” thermoset epoxies. This also opens an opportunity for thermoplastics.
\nThermoplastic are the dominant plastic materials overall, especially in non-reinforced applications. Thermosets are used in non-reinforced applications for a specific purpose where they have an advantage because of some unique property. However, within the reinforced or composites marketplace, thermoset dominant and thermoplastic are used only in applications where their unique advantages are important. Within the composite market, thermoset represents about 80% of the total material used [16]. The global composite resin market size by end-use applications, in terms of value, was USD 9317.4 Million in 2014 and is projected to grow at a CAGR of 5.6% between 2015 and 2020 [17].
\nAs mentioned above, thermoplastics are capable of being repeatedly softened by the application of heat and hardened by cooling and have the potential to be the most easily recycled, which has seen them most favoured in recent commercial uptake, whereas better realisation of the fibre properties is generally achieved using thermosets. There are several types of polymers in the market. The most common polymers are summarized in Table 2 [18, 19, 20, 21, 22, 23].
\n\n | Polymers | \nDensity (g/cm3) | \nElongation (%) | \nTensile strength (MPa) | \nYoung’s modulus (GPa) | \n
---|---|---|---|---|---|
Thermoplastic | \nAcrylonitrile styrene acrylate (ASA) | \n1.0–1.1 | \n30.0 | \n43.5 | \n2.2 | \n
Acrylonitrile butadiene styrene (ABS) | \n1.0–1.1 | \n270.0 | \n47.0 | \n2.1 | \n|
Cross-linked polyethylene (PE) | \n0.9 | \n350.0 | \n18.0 | \n0.5 | \n|
Ethylene vinyl acetate (EVA) | \n0.9–1.0 | \n750.0 | \n17.0 | \n0.02 | \n|
High-density polyethylene (HDPE) | \n0.9–1.0 | \n150.0 | \n32.0–38.2 | \n1.3 | \n|
High-impact polystyrene (HIPS) | \n1.0 | \n2.5 | \n42.0 | \n2.1 | \n|
Low-density polyethylene (LDPE) | \n0.9 | \n400.0 | \n10.0–11.6 | \n0.2–0.3 | \n|
Nylon 6 (PA 6) | \n1.1 | \n60.0 | \n81.4 | \n2.8 | \n|
Nylon 66 (PA 66) | \n1.1 | \n60.0 | \n82.7 | \n2.8 | \n|
Perfluoroalkoxy (vinyl ether) | \n2.15 | \n260.0–300.0 | \n28.0–31.0 | \n0.50–0.60 | \n|
Polybutylene (PB) | \n0.95 | \n220–300 | \n29.0–35.0 | \n0.29–0.30 | \n|
Polylactic acid (PLA) | \n1.2–1.3 | \n2.1–30.7 | \n5.9–72.0 | \n1.1–3.6 | \n|
Polycarbonate (PC) | \n1.2 | \n200.0 | \n69.0 | \n2.3 | \n|
Polycaprolactone (PCL) | \n1.1 | \n700.0 | \n16.0–23.0 | \n0.4 | \n|
Polyethylene cross-linked (PEX) | \n0.92 | \n\n | 20.0 | \n\n | |
Polyethylene terephthalate (PET) | \n1.5–1.6 | \n300.0 | \n55.0–159.0 | \n2.3–9.0 | \n|
Polyether ether ketone (PEEK) | \n1.3–1.5 | \n1.6–50.0 | \n92.0–95.0 | \n3.7–24.0 | \n|
Polyether ketone (PEK) | \n1.2–1.4 | \n20.0 | \n100.0–110.0 | \n3.5 | \n|
Polyhydroxyalkanoates (PHA) | \n1.2–1.3 | \n2.0–1200.0 | \n10.0–39.0 | \n0.3–3.8 | \n|
Polyhydroxybutyrate (PHB) | \n1.2 | \n1.56–6.0 | \n24.0–40.0 | \n3.5–7.7 | \n|
Poly-3-hydroxybutyrate (P-3-HB) | \n1.3 | \n0.4–6.0 | \n40.0 | \n3.5 | \n|
Poly-3-hydroxybutyrate-co-3-hydroxyvalerate (P-3-HB-3 HV) | \n0.2–0.3 | \n1.6–20.0 | \n23.0–40.0 | \n3.5 | \n|
Poly-3-hydroxybutyrate (P-3-HB) | \n1.2 | \n1000.0 | \n104.0 | \n— | \n|
Poly(methyl methacrylate) (PMMA) | \n1.1–1.2 | \n2.5 | \n72.4 | \n3.0 | \n|
Polypropylene (PP) | \n0.9–1.3 | \n80.0 | \n35.8 | \n1.6 | \n|
Polystyrene (PS) | \n1.04 | \n1.6 | \n34.0 | \n3.0 | \n|
Polytetrafluoroethylene (PTFE) | \n2.20 | \n40.0–650.0 | \n0.862–41.4 | \n0.392–2.25 | \n|
Polyvinyl chloride (PVC) | \n1.3–1.5 | \n50.0–80.0 | \n52.0–90.0 | \n3.0–4.0 | \n|
Polyvinylidene fluoride (PVDF) | \n1.8 | \n50.0 | \n43.0 | \n2.0 | \n|
Rigid thermoplastic Polyurethane (RTPU, PUR-RT) | \n1.1 | \n5.0 | \n75.0 | \n4.0 | \n|
Thermoset | \nEpoxy (EP) | \n1.2–1.3 | \n1.3 | \n55.0–130.0 | \n2.7–4.1 | \n
Melamine formaldehyde (MF) | \n1.5–1.6 | \n0.6 | \n65.0 | \n12.0 | \n|
Phenol formaldehyde (PF) | \n1.2 | \n1.2 | \n45.0–60.0 | \n4.0–7.0 | \n|
Rigid thermoset polyurethane (RPU) | \n1.2 | \n90.0 | \n60.0 | \n2.2 | \n|
Unsaturated polyester (UPE) | \n1.1 | \n2.0 | \n34.0–105.0 | \n2.1–3.5 | \n|
Urea formaldehyde (UF) | \n1.5–1.6 | \n0.8 | \n65.0 | \n9.0 | \n|
Polyurethane rubber | \n1.2–1.3 | \n300.0–580.0 | \n39.0 | \n2.0–10.0 | \n|
\n | Vinyl ester (VE) | \n1.23 | \n2.0–12.0 | \n73.0–81.0 | \n3.0–3.5 | \n
Properties of some polymers.
Composite reinforcements can be in various forms such as fibres, flakes, or particles. Each of these has its own properties which can be contributed to the composites, and therefore, each has its own area of applications. Among the forms, fibres are the most commonly used in composite applications, and they have the most influence on the properties of the composite materials. These reasons are that the fibres have the high aspect ratio between length and diameter, which can provide effective shear stress transfer between the matrix and the fibres, and the ability to process and manufacture the composites part in various shapes using different techniques.
\nVarious types of fibres have been utilised to reinforce polymer matrix composites. The most common are carbon fibres (AS4, IM7, etc.), glass fibre (E-glass, S-glass, etc.), aramid fibres (Kevlar® and Twaron®), and boron fibres. Glass fibres have been used as reinforcement for centuries, notably by Renaissance Venetian glass workers. Commercially important continuous-glass fibre filaments were manufactured in 1937 by a joint venture between Owens-Illinois and Corning Glass. A variety of glass fibre compositions are available for different purposes as presented below. Table 3 shows compositions of some commonly used glass fibres for composite materials.
Grade A is high alkali grade glass, originally made from window glass.
Grade C is chemical-resistant grade glass for acid environments or corrosion.
Grade D is low dielectric grade glass, good transparency to radar (quartz glass).
Grade E is electrical insulation grade; this is the most common reinforcement grade.
Grade M is high modulus grade glass.
Grade R is reinforcement grade glass; this is the European equivalent of S-glass.
Grade S is high strength grade glass, a common variant is S2-glass. This fibre has higher Young’s modulus and temperature resistance than E-glass. It is also significantly more expensive.
Oxide | \nE-glass with boron | \nE-glass without boron | \nECR-glass | \nS-2 glass | \nR-glass | \nEffect on fibre properties | \n
---|---|---|---|---|---|---|
SiO2\n | \n52–56 | \n59 | \n54–62 | \n64–66 | \n60–65 | \nVery low thermal expansion | \n
Al2O3\n | \n12–16 | \n12.1–13.2 | \n9–15 | \n24–26 | \n17–24 | \nImproved chemical durability | \n
B2O3\n | \n5–10 | \n— | \n— | \n— | \n— | \nLow thermal expansion | \n
CaO | \n16–25 | \n22–23 | \n17–25 | \n— | \n5–11 | \nResistance to water, acids, and alkalis | \n
MgO | \n0–5 | \n3.1–3.4 | \n0–5 | \n8–12 | \n6–12 | \nResistance to water, acids, and alkalis | \n
ZnO | \n— | \n— | \n2.9 | \n— | \n— | \nChemical durability | \n
Na2O | \n0–1 | \n0.6–0.9 | \n1.0 | \n0–0.1 | \n0–2 | \nHigh thermal expansion, moisture sensitivity | \n
K2O | \nTrace | \n0–0.2 | \n0.2 | \n— | \n0–2 | \nHigh thermal expansion, moisture sensitivity | \n
TiO2\n | \n0.2–0.5 | \n0.5–1.5 | \n2.5 | \n— | \n— | \nImproved chemical durability especially alkali resistance | \n
Zr2O3\n | \n— | \n— | \n— | \n0–1 | \n— | \n— | \n
Li2O | \n— | \n— | \n— | \n— | \n— | \nHigh thermal expansion, moisture sensitivity | \n
Fe2O3\n | \n0.2–0.4 | \n0.2 | \n0.1 | \n0–0.1 | \n— | \nGreen colouration | \n
F2\n | \n0.2–0.7 | \n0–0.1 | \nTrace | \n— | \n— | \n— | \n
\nTable 4 presents the mechanical properties of the main grades of glass fibre for composite materials.
\nFibre | \nDensity (kg/m3) | \nYoung’s modulus (GPa) | \nVirgin filament strength (MPa) | \nRoving strength (MPa) | \nStrain to failure (%) | \n
---|---|---|---|---|---|
A (alkali) | \n2460 | \n73 | \n3100 | \n2760 | \n3.6 | \n
C (chemical) | \n2460 | \n74 | \n3100 | \n2350 | \n∼ | \n
D (dielectric) | \n2140 | \n55 | \n2500 | \n∼ | \n∼ | \n
E (electrical) | \n2550 | \n71 | \n3400 | \n2400 | \n3.37 | \n
R (reinforcement) | \n2550 | \n86 | \n4400 | \n3100 | \n5.2 | \n
S (strength) | \n2500 | \n85 | \n4580 | \n3910 | \n4.6 | \n
S2\n | \n2460 | \n90 | \n3623 | \n∼ | \n∼ | \n
S3\n | \n2830 | \n99 | \n3283 | \n∼ | \n∼ | \n
Mechanical properties of the main grades of glass fibre [24].
Carbon fibre was first invented near Cleveland, Ohio, in 1958. It wasn’t until a new manufacturing process was developed at a British research centre in 1963 that carbon fibre’s strength potential was realised [27]. The principle precursors for carbon fibres are polyacrylonitrile (PAN), pitch, cellulose (Rayon), and some other potential precursors such as lignin and polyethylene. Carbon fibres are manufactured by stretching PAN polymer precursor, melt spinning of molten pitch, and graphitization under tensile stress [28].
\nThe modulus of carbon fibres depends on the degree of perfection of the alignment. Imperfections in alignment results in complex shaped voids elongated parallel to the fibre axis, which act as stress raisers and points of weakness. The alignment varies considerably with the manufacturing route and conditions. High-modulus fibres are those which have been subjected to heat treatment in excess of 1650°C, possess three-dimensional ordering of the atoms, have carbon contents above 99% (although their graphitic structure is still less than 75%), and have a tensile modulus above 350 GPa. High-modulus, high-strength carbon fibres have diameters of 7–8 μm and consist of small crystallites of “turbostratic” graphite. The layers have no regular stacking sequence, and the average spacing between the planes is 0.34 nm. To obtain high modulus and strength, the layer planes of the graphite must be aligned parallel to the fibre axis [29]. Carbon fibres have several advantages including high stiffness, high tensile strength, low weight, high chemical resistance, and high temperature. The carbon fibres can be utilised in various applications such as aerospace, automotive, sporting goods, and consumer goods. Table 5 shows properties for the different grades of carbon fibre.
\nPrecursor | \nPAN | \nPAN | \nPitch | \nPitch | \nRayon | \nPitch (K13D2U) | \n
---|---|---|---|---|---|---|
Modulus | \nLow | \nHigh | \nLow | \nHigh | \nLow | \nUltrahigh | \n
Tensile modulus (GPa) | \n231 | \n392 | \n161 | \n385 | \n41 | \n931 | \n
Tensile strength (GPa) | \n3.4 | \n2.5 | \n1.4 | \n1.8 | \n1.1 | \n3.7 | \n
Strain to failure (%) | \n1.4 | \n0.6 | \n0.9 | \n0.4 | \n2.5 | \n0.4 | \n
Relative density | \n1.8 | \n1.9 | \n1.9 | \n2.0 | \n1.6 | \n2.2 | \n
Carbon assay (%) | \n94 | \n100 | \n97 | \n99 | \n99 | \n>99 | \n
Indicative properties for the different grades of carbon fibre [27].
Kwolek is a DuPont chemist who in 1965 invented an aramid fibre known as Kevlar, the lightweight, stronger-than-steel fibre used in bulletproof vests and other body armour around the world. The chemical structure of the materials is being alternated aromatic (aryl) benzene rings and the amide (CONH) group. The commercial name of the reinforcement’s fibres is Kevlar from DuPont and Twaron from AkzoNobel, which are believed to be poly-(para-phenylene terephthalamide). The polymer is produced by the elimination of hydrogen chloride from terephthaloyl chloride and para-phenylene diamine. The polymer is washed and dissolved in sulphuric acid to form a partially oriented liquid crystal solution. The solution is spun through small die holes, orientation taking place in the spinnerette, and the solvent is evaporated. Hull suggests that the solution is maintained between −80°C and −50°C before spinning and is extruded into a hot-walled cylinder at 200°C. Kevlar was introduced for commercial products in 1971. There are three principal types of Kevlar fibre as shown in Table 6.
\nFibre type | \n\n | E (GPa) | \nσ’ (GPa) | \nε’ (%) | \n
---|---|---|---|---|
Kevlar 29 | \nHigh-toughness, high-strength, intermediate modulus for tyre cord reinforcements | \n83 | \n3.6 | \n4.0 | \n
Kevlar 49 | \nHigh modulus high-strength for composite reinforcement | \n131 | \n3.6 | \n2.8 | \n
Kevlar 149 | \nUltra-high modulus recently introduced | \n186 | \n3.4 | \n2.0 | \n
Characteristics of the different grades of aramid fibre [27].
Recently, with advantages of reasonable mechanical properties, low density, environmental benefits, renewability, and economic feasibility, natural fibres have been paid more attention to in composite applications. The natural fibres in simple definition are fibres that are not synthetic or man-made and are categorized based on their origin from animals, mineral, or plant sources [30]. Natural fibres are one such proficient material which would be utilised to replace the synthetic materials and their related products for the applications requiring less weight and energy conservation. Natural plant fibres are entirely derived from vegetative sources and are fully biodegradable in nature. Fibre-reinforced polymer matrix got considerable attention in numerous applications because of its good properties. The current indicators are that interest in natural fibre composites by the industry will keep growing quickly around the world. The application of natural fibre-reinforced polymer composites and natural-based resins for replacing existing synthetic polymer or glass fibre-reinforced materials is huge. However, natural fibre quality is influenced significantly by the age of the plant, species, growing environment, harvesting, humidity, quality of soil, temperature, and processing steps, and there is a move to reduce the on-field processing to improve consistency and reduce costs. The properties of several natural fibres and commonly used synthetic fibres are shown in Table 7 [31, 32, 33, 34, 35].
\nFibre | \nDensity (g/cm3) | \nElongation (%) | \nTensile strength (MPa) | \nYoung’s modulus (GPa) | \n
---|---|---|---|---|
Abaca | \n1.5 | \n— | \n511.0–1051.0 | \n13.5–29.8 | \n
Alfa | \n0.89 | \n— | \n350.0 | \n22.0 | \n
Bagasse | \n1.2 | \n1.1 | \n20.0–290.0 | \n19.7–27.1 | \n
Banana | \n1.3–1.4 | \n2.0–7.0 | \n54.0–789.0 | \n3.4–32.0 | \n
Bamboo | \n1.5 | \n— | \n575.0 | \n27.0 | \n
Coconut | \n1.4–3.8 | \n— | \n120.0–200.0 | \n19.0–26.0 | \n
Coir | \n1.2 | \n15.0–30.0 | \n175.0–220.0 | \n4.0–6.0 | \n
Cotton | \n1.5–1.6 | \n3.0–10.0 | \n287.0–597.0 | \n5.5–12.6 | \n
Curaua | \n1.4 | \n— | \n825.0 | \n9.0 | \n
Flax | \n1.4–1.5 | \n1.2–3.2 | \n345.0–1500.0 | \n27.6–80.0 | \n
Hemp | \n1.4–1.5 | \n1.6 | \n550.0–900.0 | \n70.0 | \n
Henequen | \n1.4 | \n3.0–4.7 | \n430.0–580.0 | \n— | \n
Isora | \n1.2 | \n— | \n550.0 | \n— | \n
Jute | \n1.3–1.5 | \n1.5–1.8 | \n393.0–800.0 | \n10.0–30.0 | \n
Kapok | \n0.4 | \n— | \n93.3 | \n41.0 | \n
Kenaf | \n1.2 | \n2.7–6.9 | \n295.0 | \n— | \n
Palf | \n1.4 | \n3.0 | \n170.0–635.0 | \n6.2–24.6 | \n
Piassava | \n1.4 | \n— | \n138.5 | \n2.8 | \n
Pineapple | \n1.5 | \n1.0–3.0 | \n170.0–1672.0 | \n82.0 | \n
Ramie | \n1.5 | \n2.0–3.8 | \n220.0–938.0 | \n44.0–128.0 | \n
Silk | \n1.3–1.4 | \n— | \n650.0–750.0 | \n16.0 | \n
Sisal | \n1.3–1.5 | \n2.0–14.0 | \n400.0–700.0 | \n9.0–38.0 | \n
Softwood Kraft | \n1.5 | \n— | \n1000.0 | \n40.0 | \n
Wool | \n\n | \n | 120.0–174.0 | \n5.0–10.9 | \n
Properties of several natural fibres and commonly used synthetic fibres.
Increasingly, the fibres have replaced parts formerly made of steel. The fibres used in composite materials appear at different forms and scales as shown in Figure 1.
\nVarious fibre forms.
There are several methods for fabricating composite materials. The selection of a method for a part will depend on the materials, the part design, the performance, and the end-use or application.
\nHand lay-up is an open contact moulding technique for fabricating composite materials. Resins are impregnated by the hand into fibres which are in the form of woven, knitted, stitched, or bonded fabrics. In this technique, the mould is first treated with mould release, dry fibres or dry fabrics are laid on a mould, and liquid resin is then poured and spread onto the fibre beds [36]. This is usually accomplished by rollers or brushes, with an increasing use of nip-roller-type impregnators for forcing resin into the fabrics by means of rotating rollers and a bath of resin. A roller or brush is used to wet the fibres and remove air trapped into the lay-ups. A few layers of fibres are wetted, and laminates are left to cure under standard atmospheric conditions. After these layers are cured, more layers are added, as shown in Figure 2.
\nHand lay-up process.
Spray-up is also an open-mould application technique for composite. The spray lay-up technique is considered an extension of the hand lay-up method. In this process, the mould is first treated with mould release. If a gel coat is used, it is sprayed into the mould at a certain thickness after the mould release has been applied. The gel coat then is cured, and the mould is ready for process. The fibre and catalysed resin at a viscosity of 500–1000 cps are sprayed into the mould using a chopper spray gun. The gun chops continuous fibre tow into short-fibre bundle lengths and then blows the short fibres directly into the sprayed resin stream so that both materials are applied simultaneously on the surface of the mould, as shown in Figure 3. In the final steps of the spray-up process, the workers compact the laminate by hand with rollers. The composite part is then cured, cooled, and removed from the mould [37, 38].
\nThe schematic of the spray lay-up process.
Hand lay-up and spray-up methods are often used in tandem to reduce labour cost. This is a common process for making glass fibre composite products such as bathtubs, boat hulls and decks, fenders, RV components, shower stalls, spas, truck cabs, and other relatively large and noncomplex shapes.
\nWith the ever-increasing demand for faster production rates, the industry has used alternative fabrication processes to replace hand lay-up as well as encouraged fabricators to automate those processes wherever possible.
\nResin transfer moulding (RTM), sometimes referred to as liquid moulding, is a fairly simple process. In this technique, the mould is first treated with mould release. The dry reinforcement, typically a preform, is then placed into the mould and the mould is closed. Low viscosity resin and catalyst are metered and mixed and then pumped into the mould under low-to-moderate pressure through injection ports, following predesigned paths through the preform. Low-viscosity resin is used in RTM technique to ensure that the resin permeates through the preform quickly and thoroughly before gel and cure, especially with thick composite parts.
\nReaction injection moulding (RIM) injects a rapid cure resin and a catalyst into the mould in two separate streams. Mixing and chemical reaction occur in the mould instead of in a dispensing head. Automotive industry suppliers have combined structural RIM (SRIM) with rapid preforming methods to fabricate structural parts that do not require a class A finish. Figure 4 describes the schematic of the RTM process [39, 40].
\nThe schematic of the RTM process.
Representing the fastest-growing moulding technology is vacuum-assisted resin transfer moulding (VARTM), as shown in Figure 5. The difference between VARTM and RTM is that in VARTM, resin is drawn into a preform use a vacuum only, rather than pumped in under pressure as RTM. VARTM technique does not require high heat or pressure. VARTM usually operates with low-cost tooling, making it possible to inexpensively produce large, complex parts in one shot [41, 42, 43].
\nThe schematic of the VARTM process.
Resin film infusion (RFI) is a hybrid process in which a dry preform is placed in a mould on top of a layer, or interleaved with multiple layers, of high-viscosity resin film. Under applied heat, vacuum, and pressure, the resin liquefies and is drawn into the preform, resulting in uniform resin distribution, even with high-viscosity, toughened resins, because of the short flow distance. Using the resin infusion techniques, the fibre volumes can be up to 70%, and automated controls ensure low voids and consistent preform reproduction, without the need for trimming. Resin infusion has found significant application in boatbuilding. This method has been employed by The Boeing Co. (Chicago, IL, USA) and NASA, as well as small fabricating firms, to produce aerospace-quality laminates without an autoclave [36, 44]. Figure 6 presents the schematic of the resin film infusion process.
\nThe schematic of the resin film infusion process.
Compression moulding is a precise and potentially rapid process for producing high-quality composite parts in a wide range of volumes. The material is manually or robotically placed in the mould. The mould halves are closed, and pressure is applied using hydraulic presses. Cycle time ranges depending on the part size and thickness. This process produces high-strength, complex parts in a wide variety of sizes. The composites are commonly processed by compression moulding and include thermosetting prepregs, fibre-reinforced thermoplastic, moulding compounds such as sheet moulding compound (SMC), bulk moulding compounds (BMC), and chopped thermoplastic tapes. Figure 7 shows the schematic of the compression moulding process.
\nThe schematic of compression moulding process.
Injection moulding is a closed process as shown in Figure 8. This is fast, high-volume, low-pressure, and most commonly used for filled thermoplastics, such as nylon with chopped glass fibre. The injection-moulding process has been in use for nearly 150 years. Reciprocating screw injection-moulding machines were introduced in the 1960s and are still used today [45]. Injection speeds are typically one to a few seconds, and many parts can be produced per hour in some multiple cavity moulds.
\nSimplified diagram of moulding process.
Filament winding is a continuous fabrication method that can be highly automated and repeatable, with relatively low material costs as shown in Figure 9. A long, cylindrical tool called a mandrel is suspended horizontally between end supports. Dry fibres are run through a bath of resin to be wetted. The fibre application instrument moves back and forth along the length of a rotating mandrel with the traverse carriage, placing fibre onto the tool in a predetermined configuration. Computer-controlled filament-winding machines are used to arrange the axes of motion [46, 47, 48]. Filament winding is one example of aerospace composite materials.
\nThe schematic of the filament winding process.
Composite pultrusion is a processing method for producing continuous lengths of fibre-reinforced polymer structural shapes with constant cross-sections. This is a continuous fabrication method that can be highly automated. In this process, a continuous bundle of dry fibre is pulled through a heated resin-wetting station. The wetted bundle is pulled into heated dies, and the cross-sectional shape of the pulled fibre is formed by these dies. The resin is cured, and the composites are formed. Parts are then made by slicing the long-cured piece. This process is limited to straight parts with a constant cross-section, such as I-beams, T-beams, or frame sections and ladder rails. Figure 10 shows the schematic of the pultrusion process [49, 50]. Pultrusion is used in the manufacture of linear components such as ladders and mouldings.
\nThe schematic of the pultrusion process.
Automated fibre placement (AFP) is one of the most advanced methods for fabricating and manufacturing of composite materials as presented in Figure 11. This method is used almost exclusively with continuous fibre-reinforced tape. A robot is utilised to place fibre-reinforced tape and build a structure one ply (layer) at a time. A band of material comprised of multiple narrow strips of tape (tows) is placed where these tows are commonly 0.125 and 0.25 inches wide. The use of robotics gives the operator active control over all the processes critical variables, making the process highly controllable and repeatable. This method allows the fabrication of highly customised parts as each ply can be placed at different angles to best carry the required loads [51, 52].
\nThe schematic of the automated fibre placement process.
Advantages of fibre placement are processing speed and reduced material scrap and labour costs. Often, the process is utilised to fabricate large thermoset parts with complex shapes. Similar to ATP process, automated tape laying (ATL) is an even speedier automated process in which prepreg tape, rather than single tows, is laid down continuously to form parts.
\nAdditive manufacturing is also known as 3D printing technique. Additive manufacturing is a step change in the development of rapid prototyping concepts that were introduced more than 20 years ago. This is a process for making a solid object from a three-dimensional digital model, typically by laying down many successive thin layers of a material. Manufacturing a composite structure with a single nozzle uses polymer composite filament and contains polymer and additives such as rubber microspheres, particles of glass or carbon fibre, wood flour, etc. as shown in Figure 12. This more recent form of composite part production grew out of efforts to reduce the costs in the design-to-prototype phase of product development, taking aim particularly at the material-, labour-, and time-intensive area of toolmaking [53, 54, 55, 56].
\nThe schematic of the 3D printing process for polymer composites.
The polymer composite materials are lightweight, which increases the fuel efficiency of vehicles manufactured from composites and gives them structural stability. In addition, they offer a high strength-to-weight ratio and increased heat resistance. Composites have very different properties and applications depending on the type of matrix, reinforcement, ratio between them, formulations, processing etc. The bonding strength between fibre and polymer matrix in the composite is considered one of the major factors in order to obtain superior fibre reinforcement polymer composite properties. Typical properties of several polymer composites are presented in Table 8 [57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71].
\nComposite | \nDensity (g/cm | \nElongation (%) | \nTensile strength (MPa) | \nYoung’s modulus (GPa) | \n
---|---|---|---|---|
ABS + 30% glass fibre | \n— | \n2.0 | \n60.0 | \n9.0 | \n
Acetal copolymer + 30% glass fibre | \n— | \n3.0 | \n110.0 | \n9.5 | \n
Epoxy + 40–60% carbon fibre | \n1.15–2.25 | \n0.4–11.0 | \n4.6–3220.0 | \n2.6–520.0 | \n
Epoxy + 45% flax yarn-aligned | \n— | \n— | \n133.0 | \n28.0 | \n
Epoxy + 40% glass fibre | \n— | \n— | \n— | \n— | \n
Epoxy + 52% jute fibre | \n— | \n— | \n216.0 | \n31.0 | \n
Epoxy + 52% kevlar fibre | \n— | \n— | \n434.0 | \n28.2 | \n
PEEK + 62% carbon fibre | \n1.60 | \n— | \n750.0 | \n50.0 | \n
PEEK + kevlar fibre | \n1.31–1.50 | \n1.0–6.0 | \n75.0–193.0 | \n4.0–20.7 | \n
Nylon 66 + 25–30% carbon fibre | \n1.20–1.57 | \n0.90–4.0 | \n193.0–261.0 | \n16.0–33.1 | \n
Nylon 6 + 40% glass fibre | \n1.45 | \n2.0–3.0 | \n235.0 | \n12.9 | \n
Nylon + kevlar fibre | \n1.16 | \n4.0 | \n110.0 | \n9.0 | \n
PLA + 30% abaca fibre | \n— | \n— | \n74.0 | \n8.0 | \n
PLA + 20% bamboo fibre | \n— | \n— | \n90.0 | \n1.8 | \n
PLA + 30% flax fibre | \n— | \n— | \n53.0–100.0 | \n8.0 | \n
PF + E glass fibre | \n1.5–1.65 | \n— | \n85.0–330.0 | \n5.0–17.0 | \n
Polycarbonate + 5–40% carbon fibre | \n1.15–1.43 | \n0.9–118.0 | \n46.0–186.0 | \n2.1–25.5 | \n
Polycarbonate + 30–40% glass fibre | \n1.44–1.52 | \n4.0 | \n107.0–159.0 | \n10.0–11.6 | \n
Polycarbonate-ABS + 30% glass fibre | \n1.29 | \n— | \n82.7 | \n— | \n
Polyimide + 20–30% carbon fibre | \n1.38–1.68 | \n0.8–5.5 | \n36.5–241.0 | \n4.5–29.0 | \n
Polyimide + glass fibre | \n— | \n2.0 | \n150.0 | \n12.0 | \n
PP + 30% carbon fibre | \n1.07 | \n1.0 | \n117.0 | \n16.2 | \n
PP + 30% cotton fibre | \n— | \n— | \n58.5 | \n4.1 | \n
PP + 20% glass-chopped strand mat | \n— | \n— | \n77.0 | \n5.4 | \n
PP + 20% glass fibre | \n1.03 | \n3.0–4.0 | \n100.0 | \n4.3 | \n
PP + 40% glass fibre | \n1.22 | \n2.0 | \n127.0 | \n7.6 | \n
PP-MAgPP + 40% hemp fibre | \n— | \n— | \n52.0 | \n4.0 | \n
UPE + 35% jute fibre | \n— | \n— | \n50.0 | \n8.0 | \n
UPE + 47% glass fibre | \n— | \n— | \n201.0 | \n13.0 | \n
Vinylester + carbon fibre | \n1.50–1.65 | \n1.4 | \n900.0–1200.0 | \n136.0 | \n
Vinylester + 24% flax fibre | \n— | \n— | \n248.0 | \n24.0 | \n
Vinylester + 59% glass fibre | \n— | \n— | \n483.0 | \n33.0 | \n
Vinylester + kevlar fibre | \n1.35 | \n— | \n500.0 | \n40.0 | \n
Properties of several fibre-reinforced polymer composites.
The growth of the composites market can be attributed to increased uses in the aerospace, defence, and transportation applications. The global composite materials market is expected to reach an estimated $40.2 billion by 2024, and it is forecasted to grow at a CAGR of 3.3% from 2019 to 2024. The global composite product market is expected to reach an estimated $114.7 billion by 2024 [72].
\nThe most widely used form of fibre-reinforced polymer is a laminar structure, made by stacking and bonding thin layers of fibre and polymer until the desired thickness is obtained. By changing the fibre orientation among layers in the laminate structures, a specified level of anisotropy in composite properties can be achieved. Composites offer many benefits such as corrosion resistance, light weight, strength, lower material costs, improved productivity, design flexibility, and durability. Therefore, the wide range of industries uses composite materials and some of their common applications [3, 15].
\nThe major original equipment manufacturers (OEMs) such as Airbus and Boeing have shown the potential of using composite materials for large-scale applications in aviation. NASA is continually looking to composite manufacturers for innovative approaches and space solutions for rockets and other spacecrafts. Composites with thermoset are being specified for bulkheads, fuselages, wings, and other applications in commercial, civilian, and military aerospace applications. There are several other applications of composites in the areas such as air-foil surfaces, antenna structures, compressor blades, engine bay doors, fan blades, flywheels, helicopter transmission structures, jet engines, radar, rocket engines, solar reflectors, satellite structures, turbine blades, turbine shafts, rotor shafts in helicopters, wing box structures, etc. [3, 15, 26, 37]
\nComposite materials offer flexibility in design and processing; therefore composite materials can be used as alternatives for metal alloys in appliances. Unlike most other industries, trends within the appliance segment move quite quickly. In addition, design and function are subject to both technology advancements and changing consumer taste. Composite materials are being used in appliance and business equipment such as equipment panels, frames, handles and trims in appliances, power tools, and many other applications. Composites are being utilised for the appliance industry in dishwashers, dryers, freezers, ovens, ranges, refrigerators, and washers. The components in the equipment that were utilised composites include consoles, control panels, handles, kick plates, knobs, motor housings, shelf brackets, side trims, vent trims, and many others [3, 73].
\nWith their aesthetic qualities, functionality, and versatility, the composite materials are becoming the material of choice for architectural applications. Composite materials allow architects to create designs that are impractical or impossible with traditional materials, improve thermal performance and energy efficiency of building materials, and meet building code requirements. Composite materials also offer design flexibility and can be moulded into complex shapes. They can be corrugated, curved, ribbed, or contoured in a variety of ways with varying thickness. Further, a traditional look such as copper, chrome or gold, marble, and stone can be achieved at a fraction of the cost using composite materials. Therefore, the architecture community is experiencing substantial growth in the understanding and use of composites in commercial and residential buildings [15].
\nThe automotive industry is no stranger to composites. This is one of the largest markets for composite materials. Weight reduction is the greatest advantage of composite material usage. A lower-weight vehicle or truck is more fuel-efficient because it requires less fuel to propel itself forward. In addition to enabling ground breaking vehicle designs, composites help make vehicles lighter and more fuel efficient. The composite materials are used in bearing materials, bodies, connecting rod, crankshafts, cylinder, engines, piston, etc. While fibre-reinforced polymers such as CFRP in cars get most of the attention, composites also play a big role in increasing fuel efficiency in trucks and transport systems. A number of US state Departments of Transportation are also using composite to reinforce the bridges those trucks travel on [3, 26, 37].
\nConstruction is one of the largest markets for composites globally. The composites can be made to have a very high strength and ideal construction materials. Thermoset composites are replacing many traditional materials for home and offices’ architectural components including doors, fixtures, moulding, roofing, shower stalls, swimming pools, vanity sinks, wall panels, and window frames. Composites are used all over the world to help construct and repair a wide variety of infrastructure applications, from buildings and bridges to roads, railways, and pilings [3, 74].
\nProducts made from composite materials provide long-term resistance to severe chemical conditions and temperature environments. Composites are often the material of choice for applications in chemical handling applications, corrosive environments, outdoor exposure, and other severe environments such as chemical processing plants, oil and gas refineries, pulp and paper converting, and water treatment facilities. Common applications include cabinets, ducts, fans, grating, hoods, pumps, and tanks [3, 37, 73]. Fibre-reinforced polymer composite pipes are used for everything from sewer upgrades and wastewater projects to desalination, oil, and gas applications. When corrosion becomes a problem with pipes made with traditional materials, fibre-reinforced polymer is a solution [3, 73].
\nWith the rapid growth of the electronics industry, and with strong dielectric properties including arc and track resistance, the composite materials are finding more and more in electronic applications. With strong dielectric properties including arc and track resistance, thermoset components include. Applications and components include arc chutes, arc shields, bus supports and lighting components, circuit breakers, control system components, metering devices, microwave antennas, motor controls, standoff insulators, standoffs and pole line hardware and printed wiring boards, substation equipment, switchgear, terminal blocks, and terminal boards [3, 75].
\nMaterial technology has grown from the early days of glass fibres as major reinforcements for composite material to carbon fibres which are lighter and stronger. The advancements in composites, particularly those from the US Department of Energy, are redefining the energy industry. Composites help enable the use of wind and solar power and improve the efficiency of traditional energy suppliers. Composite materials offer wind manufacturers strength and flexibility in processing with the added benefit of a lightweight components and products [3, 76]. The wind industry has set installation records over the last couple years. According to the Global Wind Energy Council, the trend for this industry may continue with global wind capacity predicted to double in the next few years. Composites play a vital role in the manufacture of structures such as wind turbine blades [3, 77].
\nJust like in the other engineering areas, the main struggle of naval architecture is to achieve a structure as light as possible. The marine industry uses composites to help make hulls lighter and more damage-resistant. With their corrosion resistance and light-weighting attributes, marine composite applications include boat hulls, bulkheads, deck, mast, propeller, and other components for military, commercial, and recreational boats and ships. Composites can be found in many more areas of a maritime vessel, including interior mouldings and furniture on super yachts [3, 78, 79].
\nThe fibre-reinforced composite materials possess some excellent characteristics, including easy moulding, high elastic modulus, high strength, light in weight, good corrosion resistance, and so on. Therefore, fibre-reinforced composite materials have extensive applications in production the manufacturing of sports equipment. From bicycle frames, bobsleds fishing poles, football helmets, hockey sticks, horizontal bars, jumping board, kayaks, parallel bars, props, tennis rackets, to rowing, carbon fibres, and fibreglass composite materials help athletes reach their highest performance capabilities and provide durable and lightweight equipment [3, 80].
\nComposites have many advantages; a wide range of material combinations can be used in composites, which allows for design flexibility. The composites also can be easily moulded into complicated shapes. The materials can be custom tailored to fit unique specifications. Composites are light in weight compared to most woods and metals and lower density as compared to many metals. They are stronger than some other materials. The materials resist damage from weather and harsh chemicals. Composites have a long service life and require little maintenance. Due to the wide variety of available reinforcement, matrix, and their forms, manufacturing processes, and each resulting in their own characteristic composite products, the design possibilities for composite products are numerous. Therefore, a composite and its manufacturing process can be chosen to best fit the developing rural societies in which the products will be made and applied. Composite materials’ research continues. The areas of interest are nanomaterials—materials with extremely small molecular structures and bio-based polymers. To facilitate the advantages of the composites, several aspects must be considered: (a) concept development, (b) material selection and formulation, (c) material design, (d) product manufacturing, (e) market, and (f) regulations.
\nThe author acknowledges Mrs. Marian Parslow and Mrs. Laura Parslow for helping in editing of the chapter.
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These reactions occur through a regular radical chain causing growth of polymer by three steps, namely, initiation, propagation, and termination. To understand ionizing radiation-induced polymerization, the water radiolysis must be taken into consideration. This chapter explores the mechanism of water molecules radiolysis paying especial attention to the basic regularities of solvent radicals’ interaction with the polymer molecules for forming the crosslinked polymer. Water radiolysis is the main engine of the polymerization processes, especially the “free-radical polymerization.” The mechanisms of the free-radical polymerization and crosslinking will be discussed in detail later. Since different polymers respond differently to radiation, it is useful to quantify the response, namely in terms of crosslinking and chain scission. A parameter called the G-value is frequently used for this purpose. It represents the chemical yield of crosslinks, scissions and double bonds, etc. For the crosslinked polymer, the crosslinking density increases with increasing the radiation dose, this is reflected by the swelling degree of the polymer while being immersed in a compatible solvent. If crosslinking predominates, the crosslinking density increases and the extent of swelling decreases. If chain scission predominates, the opposite occurs. A further detailed discussion of these aspects is presented throughout this chapter.",book:{id:"6149",slug:"ionizing-radiation-effects-and-applications",title:"Ionizing Radiation Effects and Applications",fullTitle:"Ionizing Radiation Effects and Applications"},signatures:"Mohamed Mohamady Ghobashy",authors:[{id:"212371",title:"Dr.",name:"Mohamed",middleName:null,surname:"Mohamady Ghobashy",slug:"mohamed-mohamady-ghobashy",fullName:"Mohamed Mohamady Ghobashy"}]},{id:"53504",doi:"10.5772/66925",title:"Applications of Ionizing Radiation in Mutation Breeding",slug:"applications-of-ionizing-radiation-in-mutation-breeding",totalDownloads:3478,totalCrossrefCites:9,totalDimensionsCites:13,abstract:"As a predicted result of increasing population worldwide, improvements in the breeding strategies in agriculture are valued as mandatory. The natural resources are limited, and due to the natural disasters like sudden and severe abiotic stress factors, excessive floods, etc., the production capacities are changed per year. In contrast, the yield potential should be significantly increased to cope with this problem. Despite rich genetic diversity, manipulation of the cultivars through alternative techniques such as mutation breeding becomes important. Radiation is proven as an effective method as a unique method to increase the genetic variability of the species. Gamma radiation is the most preferred physical mutagen by plant breeders. Several mutant varieties have been successfully introduced into commercial production by this method. Combinational use of in vitro tissue culture and mutation breeding methods makes a significant contribution to improve new crops. Large populations and the target mutations can be easily screened and identified by new methods. Marker assisted selection and advanced techniques such as microarray, next generation sequencing methods to detect a specific mutant in a large population will help to the plant breeders to use ionizing radiation efficiently in breeding programs.",book:{id:"5451",slug:"new-insights-on-gamma-rays",title:"New Insights on Gamma Rays",fullTitle:"New Insights on Gamma Rays"},signatures:"Özge Çelik and Çimen Atak",authors:[{id:"147362",title:"Dr.",name:"Özge",middleName:null,surname:"Çelik",slug:"ozge-celik",fullName:"Özge Çelik"},{id:"147364",title:"Prof.",name:"Çimen",middleName:null,surname:"Atak",slug:"cimen-atak",fullName:"Çimen Atak"}]},{id:"32846",doi:"10.5772/36950",title:"Current Importance and Potential Use of Low Doses of Gamma Radiation in Forest Species",slug:"current-importance-and-potential-use-of-low-doses-of-gamma-radiation-in-forest-species",totalDownloads:5277,totalCrossrefCites:2,totalDimensionsCites:13,abstract:null,book:{id:"1590",slug:"gamma-radiation",title:"Gamma Radiation",fullTitle:"Gamma Radiation"},signatures:"L. G. Iglesias-Andreu, P. Octavio-Aguilar and J. Bello-Bello",authors:[{id:"110581",title:"Dr.",name:"Lourdes",middleName:null,surname:"Iglesias-Andreu",slug:"lourdes-iglesias-andreu",fullName:"Lourdes Iglesias-Andreu"}]},{id:"58410",doi:"10.5772/intechopen.72074",title:"Radiation-Induced Degradation of Organic Compounds and Radiation Technologies for Purification of Aqueous Systems",slug:"radiation-induced-degradation-of-organic-compounds-and-radiation-technologies-for-purification-of-aq",totalDownloads:1415,totalCrossrefCites:8,totalDimensionsCites:12,abstract:"Environmental application of radiation technologies is an important part of radiation processing. Radiation treatment of aqueous systems contaminated with organic compounds is a promising method of water and wastewater purification and corresponding technologies are being developed. In this chapter, the following aspects of radiation treatment process are considered: sources of contamination and major contaminants of water and wastewater; primary processes in aqueous systems initiated by ionizing radiation; principal ways of contaminant conversion as consequences of primary processes (complete mineralization of organic compounds, partial decomposition of organic molecules resulted in detoxification, decolorization, disinfection of polluted water, and improvement in biological degradation of contaminant, polymerization of monomers’ contaminants, oxidation-reduction processes, and coagulation of colloids); sources of ionizing radiation; and main equipment applied in radiation technologies of aqueous system purification.",book:{id:"6149",slug:"ionizing-radiation-effects-and-applications",title:"Ionizing Radiation Effects and Applications",fullTitle:"Ionizing Radiation Effects and Applications"},signatures:"Igor E. Makarov and Alexander V. 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These reactions occur through a regular radical chain causing growth of polymer by three steps, namely, initiation, propagation, and termination. To understand ionizing radiation-induced polymerization, the water radiolysis must be taken into consideration. This chapter explores the mechanism of water molecules radiolysis paying especial attention to the basic regularities of solvent radicals’ interaction with the polymer molecules for forming the crosslinked polymer. Water radiolysis is the main engine of the polymerization processes, especially the “free-radical polymerization.” The mechanisms of the free-radical polymerization and crosslinking will be discussed in detail later. Since different polymers respond differently to radiation, it is useful to quantify the response, namely in terms of crosslinking and chain scission. A parameter called the G-value is frequently used for this purpose. 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A further detailed discussion of these aspects is presented throughout this chapter.",book:{id:"6149",slug:"ionizing-radiation-effects-and-applications",title:"Ionizing Radiation Effects and Applications",fullTitle:"Ionizing Radiation Effects and Applications"},signatures:"Mohamed Mohamady Ghobashy",authors:[{id:"212371",title:"Dr.",name:"Mohamed",middleName:null,surname:"Mohamady Ghobashy",slug:"mohamed-mohamady-ghobashy",fullName:"Mohamed Mohamady Ghobashy"}]},{id:"53780",title:"Gamma-Ray Spectrometry and the Investigation of Environmental and Food Samples",slug:"gamma-ray-spectrometry-and-the-investigation-of-environmental-and-food-samples",totalDownloads:2501,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Gamma radiation consists of high‐energy photons and penetrates matter. This is an advantage for the detection of gamma rays, as gamma spectrometry does not need the elimination of the matrix. The disadvantage is the need of shielding to protect against this radiation. Gamma rays are everywhere: in the atmosphere; gamma nuclides are produced by radiation of the sun; in the Earth, the primordial radioactive nuclides thorium and uranium are sources for gamma and other radiation. The technical enrichment and use of radioisotopes led to the unscrupulously use of radioactive material and to the Cold War, with over 900 bomb tests from 1945 to 1990, combined with global fallout over the northern hemisphere. The friendly use of radiation in medicine and for the production of energy at nuclear power plants (NPPs) has caused further expositions with ionising radiation. This chapter describes in a practical manner the instrumentation for the detection of gamma radiation and some results of the use of these techniques in environmental and food investigations.",book:{id:"5451",slug:"new-insights-on-gamma-rays",title:"New Insights on Gamma Rays",fullTitle:"New Insights on Gamma Rays"},signatures:"Markus R. 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Some candidates of the GeV counterpart of gamma-ray bursts, observed by Tupi telescopes, are also presented.",book:{id:"5451",slug:"new-insights-on-gamma-rays",title:"New Insights on Gamma Rays",fullTitle:"New Insights on Gamma Rays"},signatures:"Carlos Navia and Marcel Nogueira de Oliveira",authors:[{id:"189908",title:"Dr.",name:"Carlos",middleName:null,surname:"Navia",slug:"carlos-navia",fullName:"Carlos Navia"},{id:"243084",title:"MSc.",name:"Marcel",middleName:null,surname:"De Oliveira",slug:"marcel-de-oliveira",fullName:"Marcel De Oliveira"}]}],onlineFirstChaptersFilter:{topicId:"227",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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