Candidate drugs for combiunation with TMZ. STAT3 indicates signal transducer and activator of transcription-3; PARP, poly(ADP-ribose) polymerase; BER, base excision repair.
\r\n\tGoverning equations of the flows and heat transfer with EHD consist of the Navier–Stokes equations, thermal effects, and additional EHD forces. Due to the complex nature of EHD, only a limited number of publications concerning modeling of the effects of EHD on laminar flows, without numerical solutions, can be identified.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"a555a6ba490d37aed450e899a08b13ab",bookSignature:"Dr. Mohsen Sheikholeslami Kandelousi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8914.jpg",keywords:"Electric Field, Nanofluid, Electrode Arrangements, Ferrofluid, Transportation ,Heat Transfer, Joule Heating, Lorentz Forces, Kelvin Forces, Porous Media, Coulomb Forces, Natural Convection, Forced Convection, Mixed Convection, Scaling Analysis,Enhanced Heat Transfer, Semi Analytical Methods, Numerical Simulation",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 8th 2019",dateEndSecondStepPublish:"March 29th 2019",dateEndThirdStepPublish:"May 28th 2019",dateEndFourthStepPublish:"August 16th 2019",dateEndFifthStepPublish:"October 15th 2019",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"185811",title:"Dr.",name:"Mohsen",middleName:null,surname:"Sheikholeslami Kandelousi",slug:"mohsen-sheikholeslami-kandelousi",fullName:"Mohsen Sheikholeslami Kandelousi",profilePictureURL:"https://mts.intechopen.com/storage/users/185811/images/system/185811.jpeg",biography:"Dr. Mohsen Sheikholeslami works at the Babol Noshirvani University of Technology’s Department of Mechanical Engineering in\nIran. He is Head of the Renewable energy systems and nanofluid\napplications in heat transfer Laboratory at Babol Noshirvani University of Technology. His research interests are nanofluid, CFD,\nsimulation, mesoscopic modeling, nonlinear science, magnetohydrodynamic, ferrohydrodynamic, electrohydrodynamic, and heat\nexchangers. He has written several papers and books in various fields of mechanical\nengineering. He is the first scientist to develop a new numerical method (CVFEM)\nand he published the reference book with title: “Application of Control Volume\nBased Finite Element Method (CVFEM) for Nanofluid Flow and Heat Transfer”. He\nis also the first author of the following books: “Applications of Nanofluid for Heat\nTransfer Enhancement”, “Application of semi analytical methods for nanofluid flow\nand heat transfer”, “Hydrothermal Analysis in Engineering Using Control Volume\nFinite Element Method”, and “External Magnetic Field Effects on Hydrothermal\nTreatment of Nanofluid”, which are published in ELSEVIER. According to the\nreports of Thomson Reuters (Clarivate Analytics), he has been selected as a Web of\nScience Highly Cited Researcher (Top 0.01%) in 2016, 2017, and 2018.",institutionString:"Babol Noshirvani University of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"Babol Noshirvani University of Technology",institutionURL:null,country:{name:"Iran"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"288104",firstName:"Ivana",lastName:"Spajic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/288104/images/8497_n.jpg",email:"ivana.s@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6514",title:"Microfluidics and Nanofluidics",subtitle:null,isOpenForSubmission:!1,hash:"4ec06fd827f4dc0d3d7653eda88662de",slug:"microfluidics-and-nanofluidics",bookSignature:"Mohsen Sheikholeslami Kandelousi",coverURL:"https://cdn.intechopen.com/books/images_new/6514.jpg",editedByType:"Edited by",editors:[{id:"185811",title:"Dr.",name:"Mohsen",surname:"Sheikholeslami Kandelousi",slug:"mohsen-sheikholeslami-kandelousi",fullName:"Mohsen Sheikholeslami Kandelousi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5406",title:"Nanofluid Heat and Mass Transfer in Engineering Problems",subtitle:null,isOpenForSubmission:!1,hash:"d47e243d462589591986c11b07212df8",slug:"nanofluid-heat-and-mass-transfer-in-engineering-problems",bookSignature:"Mohsen Sheikholeslami Kandelousi",coverURL:"https://cdn.intechopen.com/books/images_new/5406.jpg",editedByType:"Edited by",editors:[{id:"185811",title:"Dr.",name:"Mohsen",surname:"Sheikholeslami Kandelousi",slug:"mohsen-sheikholeslami-kandelousi",fullName:"Mohsen Sheikholeslami Kandelousi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6807",title:"HVAC System",subtitle:null,isOpenForSubmission:!1,hash:"4805829f41fa799b707e4d442eac16da",slug:"hvac-system",bookSignature:"Mohsen Sheikholeslami Kandelousi",coverURL:"https://cdn.intechopen.com/books/images_new/6807.jpg",editedByType:"Edited by",editors:[{id:"185811",title:"Dr.",name:"Mohsen",surname:"Sheikholeslami Kandelousi",slug:"mohsen-sheikholeslami-kandelousi",fullName:"Mohsen Sheikholeslami Kandelousi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6362",title:"Electric Field",subtitle:null,isOpenForSubmission:!1,hash:"70b535bf877d17b46ddd1678574792a0",slug:"electric-field",bookSignature:"Mohsen Sheikholeslami Kandelousi",coverURL:"https://cdn.intechopen.com/books/images_new/6362.jpg",editedByType:"Edited by",editors:[{id:"185811",title:"Dr.",name:"Mohsen",surname:"Sheikholeslami Kandelousi",slug:"mohsen-sheikholeslami-kandelousi",fullName:"Mohsen Sheikholeslami Kandelousi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7487",title:"Thermal Energy Battery with Nano-enhanced PCM",subtitle:null,isOpenForSubmission:!1,hash:"a917c6664886ab78f757aeb59f45635d",slug:"thermal-energy-battery-with-nano-enhanced-pcm",bookSignature:"Mohsen Sheikholeslami Kandelousi",coverURL:"https://cdn.intechopen.com/books/images_new/7487.jpg",editedByType:"Edited by",editors:[{id:"185811",title:"Dr.",name:"Mohsen",surname:"Sheikholeslami Kandelousi",slug:"mohsen-sheikholeslami-kandelousi",fullName:"Mohsen Sheikholeslami Kandelousi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7774",title:"Nanofluid Flow in Porous Media",subtitle:null,isOpenForSubmission:!1,hash:"694361f15eb61a1b21ff01c6cd96f59a",slug:"nanofluid-flow-in-porous-media",bookSignature:"Mohsen Sheikholeslami Kandelousi, Sadia Ameen, M. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"43963",title:"Chemotherapeutic Agent for Glioma",doi:"10.5772/54353",slug:"chemotherapeutic-agent-for-glioma",body:'Glioma is the most common primary tumors of the central nervous system, accounting approximately for 30% of entire CNS tumors, and classified into four clinical grades as I to IV. The most aggressive and lethal tumors is glioblastoma multiforme (GBM) with median survival of only 14.6 months, mainly because of limited effects of conventional post-surgical chemotherapeutic agents and irradiation [1]. In this chapter, we summarize chemotherapeutic agents for glioma focusing on their mechanism of anti-tumor action and the acquisition of resistance to the agents.
Temozolomide (TMZ) is an alkylating agent which is applied to the treatment of malignant glioma including GBM. TMZ induces DNA methylation of guanine at O6 position (O6-MG; 6% of adducts formed), as well as 7-methylguanine (N7-MG; 70% of adducts formed), and 3-methyladenine (N3-MA; 9% of adducts formed) [2]. O6-MG incorrectly pairs with thymine and triggers the mismatch repair (MMR) system leading to double strand break of the genome that result in the arrest of cell cycle and induction of apoptosis. N7-MG and N3-MA are removed by the methylpurine glycosylase followed by AP endonuclease which are the first two enzymes in the base excision repair (BER) pathway. Efficient BER system functions and repairs DNA lesions in normal and tumor cells. 573 patients with newly diagnosed as GBM were randomly assigned to be treated by radiotherapy alone or by radiotherapy plus continuous daily medication of temozolomide [3]. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone.
MGMT specifically removes the methyl/alkyl group from the O6-position of guanine and restore the guanine to its normal form escaping from DNA strand breaks (Fig. 1). Thus, the expression of MGMT in tumors has a protective effect against alkylating agents-dependent cell death correlating between MGMT activity and TMZ resistance. MGMT expressing tumor cells exhibit 4- to 10-folds increase of resistance to TMZ, BCNU, and their related compounds [4]. MGMT-mediated repair is unique compared with other DNA repair pathways because : (a) it acts alone without relying on any other proteins or cofactors; (b) it transfers the alkyl group to an internal cysteine residue in the protein, acting as both a transferase and an acceptor of the alkyl-group; (c) it inactivates itself after receiving the alkyl-group from guanine, and thus, it is a suicidal protein; (d) it repairs in a stoichiometric fashion. As one molecule of MGMT removes one alkyl molecule, an excess of DNA adducts at the O6-position could completely deplete MGMT. MGMT is ubiquitously expressed in normal human tissues [5] but is overexpressed in all types of human tumors, including colon cancer, glioma, lung cancer, breast cancer, leukemia, lymphomas, and myeloma. These properties make MGMT as an important drug resistance factor and an ideal target for suppression of drug resistance [2].
It is well known that MGMT expression levels vary widely in tumor cells [6; 7]. Hypermethylation of CpG islands within the promoter region is associated with epigenetic inactivation of the MGMT. In the EORTC trial with 206 GBM patients, MGMT promoter methylation was observed in 45% cases [8]. In cases with methylated MGMT promoter which means negative of MGMT expression, TMZ was effective as median survival was 21.7 months treated with TMZ and RT compared with 15.3 months with only RT (P = 0.007). A study of German Glioma Network (GGN) also showed that MGMT promoter methylation was associated with prolonged progression-free survival (PFS) and OS in patients receiving TMZ [9]. Several other studies have also shown predictive and prognostic significance of MGMT promoter methylation in GBM [10].
In the MGMT promoter region, there are several specific sequences for the binding of transcription factors including SP1, GRE, AP-1, and NF-κB, thus MGMT can be induced by glucocorticoids, cyclic AMP, protein kinase C activators, and NF-κB [11; 12; 13; 14]. p53 is also reported to suppress MGMT expression by directly binding to the MGMT or by suppressing the transcription factor of SP1 [15; 16]. In addition, MGMT expression can be induced by radiation or other forms of DNA damages [17]. However, physiological roles and regulation of MGMT induction is not elucidated.
MGMT protein was reported to be degraded
Strategies to potentiate the effecacy of TMZ by suppressing MGMT or BER pathway have been examined. Pseudosubstrates of MGMT such as O6-benzylguanine were expected to suppress drug resistance by depleting MGMT [20; 21; 22]. However, clinical trials did not show significant restoration of TMZ sensitivity in patients with TMZ-resistant GBM [23]. IFN-β down-regulates the expression of MGMT and sensitizes resistant glioma to TMZ and phase II study has been started [15; 24].
We discovered post-transcriptional regulation of MGMT by signal transducer and activator of transcription-3 (STAT3) and demonstrated that STAT3 inhibitor or STAT3 knockdown potentiated TMZ efficacy in TMZ-resistant GBM cell lines [25] (Fig 2). Furthermore, immunohistochemical analysis of 44 malignant glioma specimens demonstrated significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (pSTAT3) (p<0.001, r=0.58) (Fig 2). Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with TMZ for TMZ-resistant GBM patients.
In spite of the correlation between promoter methylation of MGMT and temozolomide sensitivity, survival time of the patients who have methylated promoters of MGMT is still short and this suggests the involvement of other mechanism in TMZ resistance. Especially, key molecules of MMR, BER, and Fanconi anemia repair pathway such as MSH6 [26; 27], N-methyl purine DNA glycosylase (MPG) [28], DNA polymerase β (Polβ) [28], alkylpurine-DNA-N-glycosylase (APNG) [29] and FANCD1/BRCA2 [30] have been reported to affect to TMZ resistance. The unfolded protein response regulator GRP78/BiP was shown to act as a novel target for increased chemosensitivity in malignant gliomas [31]. Inhibition of Y-box binding protein-1 (YB-1) slows the increased growth of GBM and sensitizes to temozolomide independent of MGMT [32]. High levels of HOXA9/HOXA10 gene expression were associated with a shorter survival in pediatric high-grade glioma patient samples. [33]. Phosphatase and tensin homologue (PTEN) deficiency in GBM confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir [34].
\n\t\t\t\t | \n\t\t
Candidate drugs for combiunation with TMZ. STAT3 indicates signal transducer and activator of transcription-3; PARP, poly(ADP-ribose) polymerase; BER, base excision repair.
Identification of biological mechanisms contributing to GBM oncogenesis contributes to provide appropriate targeted therapies to improve patient outcomes. In a large-scale multidimensional analysis performed by the Cancer Genome Atlas involving, the most frequent gene amplifications were: epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor α (PDGFRα), 2 transmembrane receptors with tyrosine kinase activity; cyclin-dependent kinase 4 (CDK4), and murine double minute (MDM)2 and MDM4 which are suppressors for p53 [35]. The most frequent homozygous gene deletions were CDKN2A, CDKN2B, and CDKN2C, which encode tumor suppressor proteins that suppress CDK4 and CDK6, phosphatase and tensin homolog (PTEN), a tumor suppressor that inhibits phosphatidylinositol-3 kinase (PI3K) signaling such as retinoblastoma (RB1), a cell-cycle inhibitor as PARK2, a regulator of dopaminergic cell death, and neurofibromin 1 (NF1), a negative regulator of the RAS signal transduction pathway. The most frequently mutated genes were p53, PTEN, NF1, EGFR, human epidermal growth factor receptor 2 (HER2), RB1, and PIK3R1 and PIK3CA-2 components/regulators of the PI3K signaling pathway. This study shows that several genes encoding proteins which are involved in signaling pathways of receptor tyrosine kinases/PI3K, and p53 and the cyclin/RB1, are considerably altered in GBM (Fig. 3). Another study has identified characteristic mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of patients with GBM. IDH1 mutations occurred in a high proportion of young patients and in the majority of secondary GBM cases and were associated with increased OS (3.8 years), compared with wild-type IDH1 (1.1 years) [36]. This may be due to increased tumor sensitivity to chemotherapy, although a large controlled series in the German Glioma Network did not find any association between prolonged survival of patients with tumors with IDH1 mutations and administration of a specific therapy [9]. Mutation of the IDH1 active site prevents conversion of isocitrate to α-ketoglutarate but allows the mutated enzyme to catalyze the nicotinamide dinucleotide phosphate-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG) [37]. Accumulated 2HG appears to act as an oncometabolite that contributes to glioma formation and malignant progression. This observation is supported by data from patients with inherited 2-hydroxyglutaric aciduria, in whom deficient 2HG dehydrogenase causes an accumulation of brain 2HG. These patients have an increased risk of developing brain tumors, possibly because of increased production of reactive oxygen species [38].
EGFR is one of the most attractive therapeutic targets in GBM. Approximately 50% of GBM overexpress EGFR and 25% express a constitutively active mutated form of EGFR known as EGFRvIII, which has a large deletion in the extracellular domain and renders the receptor ligand independent for signaling [39]. Overexpression of EGFR is more common in primary tumors than in secondary GBM [40]. The deletion also renders a unique codon, which is not found in the wild-type receptor, thereby creating a tumor-specific epitope that can be exploited for therapeutic targeting. Increased EGFR signaling drives tumor cell proliferation, invasiveness, motility, angiogenesis, and inhibition of apoptosis.
Small-molecules of EGFR inhibitor such as gefitinib and erlotinib are well tolerated in patients with malignant gliomas, phase II trials have so far shown limited clinical benefit of erlotinib in patients with either recurrent or newly diagnosed GBM, either in combination regimens [41; 42; 43; 44] or as monotherapy [45]. Neither the EGFR/HER-2 inhibitor lapatinib [46], nor the monoclonal antibody against EGFR, cetuximab [47], have proven to be effective. Attempts to identify biomarkers to predict response to EGFR inhibitors have yielded conflicting results. There is no convincing evidence of a correlation between the drug efficacy and the expression levels of EGFR in tumor tissue. In a phase I study, patients with gliomas expressing high levels of EGFR and low levels of activated AKT had better responses to erlotinib than did those with low EGFR expression and high levels of activated AKT [48]. Another study have shown significant correlation of therapeutic response of erlotinib and the presence of EGFR deletion mutant variant III [49]. However, not all studies confirmed these initial observations to predict the sensitivity to EGFR inhibitors [45].
PDGFR is a receptor tyrosine kinase with α and β isoforms. Overexpression of PDGFRα has been demonstrated in astrocytoma and GBM, indicating a potential role in tumor development [50]. Several PDGFR-targeting agents have been developed that may have therapeutic potential against tumors with elevated PDGFR expression.
Sorafenib is an orally available antiangiogenic agent that inhibits tumor cell growth and proliferation by blocking the action of intracellular and receptor kinases, including PDGFR, RAF kinase, VEGFR2, and c-KIT [51]. In human GBM cell lines, sorafenib inhibited proliferation synergistically in combination with bortezomib, a proteosome inhibitor [52], and rottlerin, an experimental inhibitor of protein kinase C [53]. A phase II trial found that first-line TMZ and radiotherapy followed by TMZ plus sorafenib was tolerated by patients with GBM, although preliminary efficacy data for this regimen (median PFS duration, 6 months; 12-month PFS rate, 16%) were similar to data for standard therapy.
Imatinib mesylate, a small-molecule inhibitor for PDGFR, ABL, and c-KIT, was reported to have significant antitumor activity both
Tandutinib is an orally active inhibitor of PDGFR, FLT3, and c-KIT tyrosine kinase activity. Although no preclinical data was available for tandutinib in GBM, 2 early-phase trials are assessing tandutinib in recurrent/progressive GBM as monotherapy or combined with bevacizumab. As correlation between increased gene expression levels of PDGFR and preclinical data for therapeutic efficacy was reported, PDGFR may be a promising target for treating GBM. However, the available clinical data suggest otherwise. Trial data of combination regimens involving PDGFR inhibitors are awaited [61].
There are multiple reasons for adapting anti-angiogenic drugs to the treatment of malignant gliomas. Malignant glioma exhibits higher vascularization which is one of the pathological hallmarks of GBM. One of the difficulties of developing effective treatments for gliomas has been poor drug penetration through the blood-brain barrier. The dense network of angiogenic vessels in GBM typically display structural, functional, and biochemical abnormalities, including large endothelial cell fenestrae, deficient basement membrane, decreased pericytes and smooth muscle cells, haphazard interconnections with saccular blind-ended extensions, complex tortuosity, and dysregulated transport pathways [62; 63; 64; 65; 66; 67]. Therefore, by targeting the tumor vasculature, it is possible to bypass this dependence on drugs to pass the blood-brain barrier to reach their targets. Further, there is also both experimental [68] and clinical [69; 70] evidence that anti-angiogenic drugs can decrease vasogenic edema and patients\' requirement for corticosteroids which contributes to morbidity in this population.
The VEGF family of growth factors and their respective receptors are the best characterized proangiogenic proteins in glioma. The VEGF family includes 6 secreted glycoproteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor [PlGF]). VEGF-A, the best characterized member, typically localizes adjacent to pseudopalisading necrosis in GBM [71], and the levels of VEGF-A is increased in higher grade of glioma [72; 73], and is associated with poor prognosis [74]. The VEGF receptor (VEGFR) family includes VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3, neuropilin-1 (NRP-1), and NRP-2, which exhibit different binding affinities of the VEGF homologs. VEGFR-1 and VEGFR-2 regulate angiogenesis, whereas VEGFR-3 regulates lymphangiogenesis. Vascular endothelial growth factor production and secretion by tumor cells is stimulated mainly by hypoxia, and malignant gliomas are rapidly growing and innately hypoxic tumors. More specifically, VEGF-A binds to VEGFR-2 expressed in blood vessels, which promotes endothelial cell migration and proliferation results in new blood vessel formation in a manner of paracrine signaling loop.
Bevacizumab, a recombinant humanized monoclonal antibody composed of human immunoglobulin G1 (IgG1; 93%) and murine VEGF-binding complementarity-determining regions (7%), binds all isoforms of VEGF with high affinity and specificity [75]. Despite initial reluctance to evaluate bevacizumab in patients with brain tumors owing to concerns of intracranial hemorrhage, a series of 29 patients with recurrent malignant glioma treated with bevacizumab and irinotecan showed no significant hemorrhage with remarkable tumor regression as radiographic response rate of 66% compared with ordinal chemotherapeutic reagents as rates of 9% [76; 77]. These results led rigorous prospective clinical trials of bevacizumab in recurrent malignant gliomas. The combination of bevacizumab and irinotecan was studied in single-arm phase 2 trials for recurrent malignant glioma (n = 33) and GBM (n = 35), showing response rates as 61% and 57%, and progression-free survival (PFS) at 6 months as 55% and 46% [78; 79], respectively. These results were compared with previous rates of PFS at 6 months as 9% to 15% for recurrent GBM and 17% to 31% for recurrent malignant gliomas [80]. A large phase 2 trial randomized 167 patients of recurrent GBM to analyze efficacy of combination of either bevacizumab or bevacizumab with irinotecan. This noncomparative randomized study showed radiographic response rates as 28% and 38%, and a PFS at 6 months of 43% and 50%, respectively [69]. In addition, patients treated with bevacizumab often exhibit less vasogenic edema and decreased corticosteroid dependence secondary to neutralization of VEGF, a known vascular permeability factor. Another phase 2 trial involved bevacizumab monotherapy in 48 heavily pretreated patients with recurrent GBM [70]. The radiographic response rate was 35%, and the PFS6 rate was 29%. Ongoing phase 3 studies are evaluating the combination of bevacizumab with temozolomide and radiotherapy. The results will be of great interest because of the uncertainty regarding the impact of bevacizumab on overall survival. Combinations of bevacizumab and other chemotherapeutics or targeted molecular drugs are also currently in clinical trials.
VEGF Trap (aflibercept) sequesters all isoforms of VEGF-A and PDGF as a soluble, recombinant, decoy receptor, composed of the second Ig domain of VEGFR-1 and the third Ig domain of VEGFR-2 bound to the hinge region of the Fc portion of human IgG1 [81]. Single arm phase II study of aflibercept in recurrent malignant glioma was proceeded [82]. 42 patients with GBM and 16 patients with malignant glioma who had received concurrent radiation and temozolomide therapies, and adjuvant temozolomide were enrolled at first relapse. The 6-month progression-free survival rate was 7.7% for GBM cohort and 25% for patients with malignant glioma. Overall radiographic response rate was 24% (18% for GBM and 44% for malignant glioma). The median PFS was 24 weeks for patients with malignant glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with GBM (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. This study suggested Aflibercept monotherapy had moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.
Several inhibitors for VEGFR tyrosine kinase have shown significant antiangiogenic and antitumor activity in preclinical GBM models [83; 84; 85; 86; 87; 88], which may also enhance cytotoxic therapy [89; 90; 91]. In addition, several these agents are undergoing evaluation in phase I/II clinical trials, but only cediranib has advanced to phase III investigation. In an initial phase II study of single-agent cediranib (45 mg/d), 27% of patients with recurrent malignant glioma exhibited a radiographic response and a 6-month PFS was 26%. In addition, cediranib induced rapid normalization of tumor vasculature, including decreased diameter of microvessels and diminished permeability, which reversed after cediranib interruption. Adverse events including hypertension and fatigue were observed, and nearly half of the patients required a dose reduction or interruption of therapy because of its toxicity [92].
Although antiangiogenic therapies prolong PFS of GBM patients, further progression of disease is inevitable. Progression of tumors under antiangiogenic therapy cannot often be treated successfully thereafter, and most patients die of the disease within a few months. In the cediranib study, serum levels of the proangiogenic factors bFGF, stromal-derived factor 1 (SDF1), and soluble VEGFR2 increased at the time of failure [93]. The alternative proangiogenic pathways depends on these angiogenic factors may drive angiogenesis in the setting of VEGFR inhibition. Furthermore, for many gliomas, particularly malignant gliomas, there is often little evidence for vascular proliferation. As the individual infiltrating tumor cell tends to grow along normal cerebral vasculature, and thus there is no need for tumor-associated angiogenesis. Indeed, there is at least a theoretical concern that inhibition of angiogenesis in malignant glioma may prevent the formation bulky tumor but has little effect on sparsely infiltrative GBM cells results in little impact on OS of patients. Early clinical and radiographic observations of patients treated with bevacizumab suggest that this may be the case [94; 95]. Another concern is recent laboratory evidence that suggests that inhibition of VEGF may actually increase invasiveness of tumor cells [96]. The infiltrative tumor cells are often responsible for relapse leading to the death of patients.
Combination of antiangiogenic and anti-invasion therapy may delay disease progression. Studies of co-administration of cediranib (pan-VEGFR inhibitor) with cilengitide (integrin inhibitor) and bevacizumab (neutralizing VEGF antibody) with dasatinib (PDGFRβ inhibitor) are ongoing. Another potential mechanism of resistance to antiangiogenic therapies involves increased PDGF signaling. PDGF stabilizes neovasculature by recruiting pericytes and facilitating pericyte-endothelial cell interactions [97]. Preclinical data suggest that dual VEGFR/PDGFR inhibition potentiates antiangiogenic efficacy and reduces resistance to therapy [98], and this approach is currently being evaluated in clinical trials.
Aberrant signaling by hepatocyte growth factor (HGF) and its receptor MET has been observed in various tumors including GBM, and potential involvement in tumorigenesis and metastasis has been reported [99]. Recently c-MET overexpression was detected in 18 (29%) of 62 GBM with shorter median survival durations than those of little or no expression of c-MET (median durations of survival, 11.7 vs 14.3 months) [100].
Inhibitors of HGF or c-MET have shown preclinical activity against GBM cell lines [99]. The anti-HGF antibody AMG102 enhanced TMZ-induced inhibition of growth of GBM cell line
PI3K plays a role in intracellular signaling pathways regulating in cell survival, growth, and proliferation. Activated PI3K is recruited to the cell membrane where it mediates signaling after activation of receptor tyrosine kinases. Downstream targets include AKT for cell proliferation and survival; glycogen synthase kinase-3 (GSK-3) for regulation of c-MYC; and mammalian target of rapamycin (mTOR) for regulation of protein synthesis and negative regulator of PI3K. In malignant glioma, PI3K/Akt/mTOR signaling is frequently activated because of the stimulation of receptor tyrosine kinases as EGFR, PDGFR, and mesenchymal-epithelial transition factor (MET), mutation of oncogenic PI3K subunits, and/or loss of PTEN tumor suppressor activity. Therefore inhibiting the PI3K pathway may have therapeutic potential.
NVP-BEZ235, an orally available kinase inhibitor for PDK1, mTOR, and PI3K, induced G1 arrest of a GBM cell line
Enzastaurin, a PKC/PI3K/AKT inhibitor, suppressed proliferation and induced apoptosis
SRC and SRC-Family Kinases (SFKs) are frequently activated in GBM [109] frequently due to their overexpression [110]. SRC and SFKs are promiscuous regulators of multiple signaling pathways for cell proliferation, adhesion, migration, and invasion, which are important processes in tumor invasion and metastasis.
Dasatinib is a potent inhibitor of SRC and SFKs and has been approved for the treatment of certain types of leukemia on the basis of inactivation of BCR-ABL [111]. Dasatinib also inhibits c-KIT and PDGFR [112]. In GBM cells, dasatinib inhibited migration and induced autophagy, resulted in cell death which was enhanced by combination with TMZ [111; 113]. Dasatinib inhibited invasion, promoted tumor regression, induced apoptosis in EGFRvIII-expressing GBM, and enhanced the activity of anti-EGFR antibodies [111]. Trials of dasatinib are ongoing in GBM and several solid tumors. A phase I/II trial involving patients with newly diagnosed GBM is assessing dasatinib combined with radiotherapy and concomitant TMZ, followed by adjuvant dasatinib plus TMZ. Trials of dasatinib for treatment of recurrent GBM include a phase II trial of dasatinib monotherapy, a phase I trial of dasatinib in combination with erlotinib, and a randomized phase I/II trial of dasatinib in combination with CCNU that has started its phase I component with patients who have recurrent GBM.
Integrin plays key roles regulating cell adhesion, migration, and invasion. In addition to a role for matrix-cell contact, integrin also activate intracellular signals including SRC-dependent pathway. In various tumors, integrin has an established role in metastasis and angiogenesis [114]. Therefore, targeting integrin function may have potential for treating GBM.
\n\t\t\t\t | \n\t\t
Targeted molecular agents currently in clinical development for high-grade glioma TKI indicates tyrosine kinase inhibitor; SAHA, suberoylanilide hydroxamic acid; RGD, arginine-glycine-aspartate; STKI. serine-threnoine kinase inhibitor; PKC, protein kinase C.
Cilengitide is a specific αV integrin inhibitor in clinical development. In a phase I/IIa trial, cilengitide combined with the current standard of therapy in patients with newly diagnosed GBM was well tolerated, with 6-month PFS as 69%. Methylation of promoter of O6-methylguanine-DNA methyltransferase (MGMT) predicts a higher likelihood of achieving 6-month PFS, as shown by increases in the durations of PFS and OS to 13.4 months and 23.2 months, respectively, compared with 3.4 and 13.1 months for patients without MGMT promoter methylation [115]. On the basis of these findings, a similar regimen is being compared with radiotherapy/TMZ alone in the phase III CENTRIC trial in patients with newly diagnosed GBM with hypermethylated MGMT promoter. In a phase IIa study of recurrent GBM, cilengitide monotherapy was well tolerated but was largely inactive (6-month PFS rate, 15%); long-term disease stabilization was seen in a small subset of patients: 10% were progression free for 12 months, and 5% were progression free for 24 months [116].
Histone deacetylases (HDACs) are involved in multiple processes to lead malignant phenotype of glioma including maintanance of stemness, angiogenesis, and resistance to DNA damage.
Vorinostat is an orally available inhibitor of class I and II HDAC approved for advance cutaneous T cell lymphoma. In a phase II study of recurrent GBM, vorinostat monotherapy was well tolerated and had modest clinical activity (6-month PFS rate, 15.2%; median OS duration, 5.7 months) [117]. Vorinostat is currently being evaluated for use in newly diagnosed and recurrent GBM as a combination therapy.
Although TMZ prolonged the survival of GBM patients, GBM are still immortal disease with extremely poor prognosis because of acquisition of TMZ resistance. Therefore, other therapeutic agents which suppress MGMT expression or attenuate TMZ resistance are highly desired. As the efficacy of single agent of targeted molecular therapy seems to be limited, combination therapy should be evaluated since multi-pathway is involved in the chemoresistance in GBM. An ‘tailor-made’ selection of chemotherapeutic agents for each GBM patients based on molecular analysis is essential to obtain maximum efficacy of chemotherapeutic agents.
Research on magnesium based-composites has seen sustainable growth in last four decades due to their light weight, higher strength to weight ratio, ductility, hardness, wear resistance and biodegradability [1, 2]. Magnesium based materials, in general, are currently targeted for applications in automotive, aerospace, electronics, sports and biomedical engineering. The driving force for intense research into magnesium-based nano-composites is to utilize them to mitigate global warming, energy consumption and land, air and water toxicity. The presence of reinforcement at nano-length scale leads to grain refinement leading to Hall-Petch strengthening and Orowan strengthening due to presence of nano-particles/fibers with diameter less than 100 nm [3].
\nThe primary processing of MMNCs can be categorized in two groups i.e. ex situ and in situ routes [4]. In ex situ processing during fabrication of MMNCs the major issue is particle clustering. High surface energy navigates to poor wettability of particles/fibers with the matrix during liquid and semi-solid processing. These clustered particles lead to reinforcement distribution inhomogeneity in the matrix leading to inferior properties in as-cast state. Such non-uniform distribution can only be reduced through judicious secondary processing step.
\nThe common liquid and semi-solid ex situ process are stir casting/melt stirring, ultrasound cavitation, disintegrated melt deposition (DMD) and Rheocasting. The solid-state ex situ syntheses are powder metallurgy (PM), severe plastic deformation (SPD) by accumulative roll bonding (ARB) and plastic deformation by friction stir processing. The in-situ processes eliminate the reinforcement clustering, since the reinforcements are distributed in the matrix by thermodynamic and chemical reaction during the process.
\nThe MMNCs processed by ex situ route commonly exhibit microstructural defects such as dendrites, pores, and micro cracks. These require careful characterization followed by using a secondary processing technique that can target the property enhancement required by end application. The common secondary processes are thermal treatment, hot extrusion, hot rolling, equal channel angular pressing (ECAP) and cyclic extrusion and compression (CEC).
\nThe prime objective of this chapter is to provide an overview of various processing methods used currently for synthesizing MMNCs, their benefits and limitations. Critical observations made by other researchers are also highlighted in this chapter.
\nThe processing methodology for fabricating magnesium based nano-composites (MMNCs) normally includes coupling of primary and secondary processing. In primary processing (solid, liquid or two phase), the matrix (master alloy) and the reinforcements are blended together by the application of thermal or mechanical energy to form a composite. During primary processing some undesirable effects are introduced in the composites such as porosity and non-uniform distribution of reinforcement voids. To minimize these defects, secondary processing is utilized to attain a relatively homogeneous microstructure and enhanced mechanical properties.
\nPrimary processing techniques are grouped into liquid state, semi-solid and solid state processing types. The liquid state processes are stir casting, ultrasonic cavitation (UST), disintegrated melt deposition (DMD), in-situ processing. Rheocasting is a semi-solid composite primary processing. The soil-state fabrication includes powder metallurgy (PM), accumulated roll bonding (ARB) and friction stir processing (FSP). These techniques are briefly introduced in following subsections.
\nStir casting is one of the most common liquid-phase technique utilized for processing MMCs for almost last four decades. The schematic of stir casting setup is shown in the Figure 1.
\nSchematic of stir casting setup.
For processing MMNCs, the Mg ingots are melted in a crucible made of graphite or steel at a temperature between 680 and 750 °C in an electric resistance or induction furnace. The liquid melt is mechanically stirred using a coated impeller. The coating is provided onto the impeller to avoid erosion by abrasion and chemical reaction. Predetermined amount of nano-reinforcement is introduced in molten metal along the side of the vortex. The reinforcements were distributed in the melt due to the difference in pressure from the inner to outer surface of the liquid vortex. The vortex is shielded using inert atmosphere to avoid oxidation /ignition. Alternatively, to overcome agglomeration/clustering, the powders of magnesium and the nano reinforcement are ball milled together prior to addition. The liquid slurry is stirred for ~10 min to homogenize the mixture. After homogenization, the liquid slurry is poured into a permanent mold. MMNCs reinforced with Al2O3, SiC and CNTs are commonly synthesized using stir casting technique [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16].
\nThe benefits of stir casting include: (a) ease of processing, (b) economical, and (c) scalability to ensure large volume production. Disadvantages of stir casting includes: (a) unavoidable agglomeration of reinforcement and (b) porosity.
\nOne of the main drawback of the stir casting technique is its inability to avoid agglomeration of nano-reinforcement due to their larger surface energy. This causes inferior mechanical properties of the end composites. Ultrasonic (UST) cavitation method is a relatively more effective technique to disperse the reinforcement into the matrix material in MMCs [17]. By introducing the ultrasonic waves with power and frequency range of as low as 1.5–4.0 kW and 17.5–20 kHz the agglomerates can be fragmented, and a uniform distribution of reinforcement can be realized in the liquid melt. This method has been adopted so far to produce MMNCs reinforcing with CNTs, AlN, SiC, B4C and Al2O3 [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35]. The schematic of UST setup is shown in the Figure 2.
\nSchematic representation of UST [
In the UST process, the Mg alloy is placed in a graphite crucible and heated to the desired temperature using a resistance/induction furnace. Predetermined amount of reinforcement is than added depending on the size of the particles. During processing, Mg melt is protected using argon gas (flow rate of 20 lpm) to avoid oxidation. High-intensity ultrasound shock waves [16] are supplied to disperse nano-particles thoroughly in the melt at semi-solid temperature. The ultrasonic processing temperature is chosen so as to ensure better flowability of the slurry in the mold.
\nThe selection of material for sonotrode plays a vital role in MMNCs melting due to the erosion of sonotrode surface during melting of liquid metal. For better sonification of MMNCs, niobium (Nb) and titanium (Ti) are recommended by the researchers. Ti-based sonotrodes are widely used for UST treatment due to lesser costs when compared to Nb-based sonotrodes. To note that Nb-based sonotrode exhibit less variation in the Young’s modulus as the function of temperature while Ti-based sonotrodes are very stable in MMNCs melt as Ti is insoluble in Mg. Earlier findings have indicated that the high-intensity UST vibration needs an intensity of 100 W/cm2 [4]. For large scale volume production, the requirement of sonification is likely to be higher. The large-scale production of MMNCs require enormous power and frequencies. The key issue is reducing rate of sonification by decreasing the volume of the melt during UST. This can be achieved in two steps firstly, preparing the melt with reinforcement and secondly, passing the liquid melt into a sonotrode assisted UST chamber for fragmenting particle clusters. Further work is required in this area especially regarding scalability.
\nDMD technique is a hybrid technique that incorporates the concepts of casting, melt stirring and spray forming process [36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In DMD, the processing steps involve:
Heating matrix material and reinforcement in a graphite crucible (ceramic bonded clay graphite) to a desired superheat temperature. Mg and its alloys (in the form of chips or turnings) and reinforcement are placed in alternative layers.
Stirring of reinforcement at ~ 450 rpm for 5–10 min using a Zirtex 25 coated stainless-steel impeller realize uniform distribution.
Bottom pouring of the slurry and disintegration of slurry through 10-mm annular diameter graphite nozzle.
Disintegration of slurry using two argon gas jets.
Deposition of disintegrated slurry into a steel mold to get 40-mm ingots.
DMD processing is carried out under argon inert atmosphere to minimize oxidation. Experimental setup of DMD process is shown in Figure 3. The advantages of the method include:
Bottom pouring of the liquid slurry to ensure almost 100% yield.
Disintegration of molten slurry using low pressure gas jets to ensure improved particle distribution and microstructural homogeneity.
Use of argon gas rather than SF6 (greenhouse gas) to prevent oxidation.
Schematic drawing of DMD [
In-situ casting of MMNCs is a very versatile and an economical process to synthesize MMNCs. The reinforcements are formed and controlled by metallurgical reactions between principal alloy and the additives [46, 47, 48, 49, 50]. The type and number of additives are chosen based on final formulation of the matrix and volume fraction of the reinforcement. Reaction temperature is a key parameter in process design of in-situ MMNCs to ensure the desired matrix and the reinforcement phase. An example of creating in-situ Mg-Zn/MgO composites includes the use of Mg and ZnO as starting materials and heating them to a predetermined temperature to ensure the feasibility of the following two reactions (Eqs. (1) and (2)):
Chelliah et al. [46] synthesized magnesium-polymeric derived ceramic (PDC) silicon carbonitride (SiCNO) nano composite by liquid pyrolysis using stir casting technique. The liquid poly (urea-methyl-vinyl) silazane (PUVMS) was used to formulate magnesium nano-composite. In this method, magnesium was melted in a steel crucible using a resistance furnace at a temperature of 700 °C and shielded with Ar-5%SF6 gas. The melt was stirred mechanically at 600 rpm to form vortex and the liquid PUVMS was injected to the melt. The melt was stirred for 15 min to ensure thorough pyrolysis. The liquid melt was bottom-poured into a rectangular metal mold preheated at 300 °C. Mg/nano- SiCNO composite was fabricated exhibiting uniform distribution of the reinforcement (Figure 4).
\nExperimental setup of liquid pyrolysis stir casting [
The benefits of in-situ MMNCs include: (a) uniform distribution of the reinforcement, (b) elimination of particle wettability issue, and (c) clean and strong matrix-particle interface. The disadvantages of in-situ techniques, in general, are scalability and the amount of reinforcements that can be created using the in-situ reactions.
\nRheocasting is a semi-solid casting method where the matrix is processed in liquidus-solidus (L-S) zone. In this so called semi-solid zone, the reinforcement particles are added, and the resultant slurry is thoroughly stirred to ensure uniform distribution of the reinforcement. Following stirring, the semi-sold composite melt is tapped into a permanent mold. Often cleaning and degassing of the slurry is carried out to avoid oxidation and formation of inclusions.
\nA MMNC of Mg (AZ91E) with Al2O3n (50 nm) was synthesized using a semi-solid Rheocasting process [51]. The Mg ingots were placed in boron nitride coated mild steel crucible. The melt was formed in the metal crucible at 750 °C using electric resistant furnace. The slurry was degassed using argon to avoid oxidation. The reinforcement (Al2O3n) was then added to the slurry at semi-solid (L-S) temperature (~590 °C). The melt slurry was stirred using a mechanical stirrer. The MMNCs slurry was subsequently poured into a permanent mold for further characterization.
\nThe benefits of this technique include: (a) spheroidal/equiaxed grains and no dendrites, (b) less shrinkage and porosity and (c) lower operating temperature.
\nPowder metallurgy (PM) [52] is one of the most common solid-state synthesis method for magnesium based nano-composites [53, 54, 55, 56, 57, 58, 59, 60]. The steps followed in PM are shown in Figure 5. In the first step metal alloy and ceramic particle in powder form are blended/mixed together to get homogenous mixture. The mixing parameters are decided based on the density difference between metal/alloy and reinforcement powder. The blended powders are subsequently compacted using a cold press or hot press or hot isostatic press. Finally, the green compacts are sintered by heating to a predetermined temperature to regain mechanical properties. Near-net-shaped components with simple geometries can be fabricated by PM technique.
\nStep in PM.
Several magnesium-based alloys, conventional and nanocomposites (e.g. Mg/3wt%Al/0.1wt%GNP) have be synthesized using PM technique. Typical processing steps include blending or mechanical alloying the predetermined amounts of metal and ceramic powder with or without steel balls using a planetary ball mill at a speed of 200 rpm for 1 h. A typical planetary type ball mill setup is shown in Figure 6. The composite powders obtained from blending step are subsequently compacted using a 100 T hydraulic press to attain a billet of ~35 mm diameter and height of 40 mm. Compacted billets can be sintered using a conventional furnace or microwave based sintering. Heating time during microwave sintering is kept with 16 min. Conventional microwave 0.9 kW power and 2.45 GHz operating frequency can be used. The schematic diagram of microwave sintering set-up is shown in Figure 7.
\n(a) Diagram shows the steel vial with steel balls and (b) planetary ball mill [
Hybrid microwave sintering setup [
Accumulative roll bonding (ARB) is a solid-state severe plastic deformation technique used to produce layered composite stacked with either similar or dissimilar alloys sheet and reinforcements [61, 62, 63, 64]. The final output of the ARB process depends on the process variables namely weight percent of the alloys and the reinforcement, number of rolling cycles and the temperature. The benefits of the process are grain refinement from fine to ultra-fine, fragmentation of reinforcement clusters and their subsequent uniform distribution. To realize best possible results, the sheets need to be pretreated by grinding and polishing for descaling oxides and to make friction free surface. Degassing process is also often used. The schematic setup of the ARB is shown in Figure 8.
\nSteps in synthesizing nano-composites using ARB [
Monolithic aluminum (Al) and AZ31 magnesium [61] strips of 1 and 0.5 mm thickness were cut to 150 × 50 mm rectangular strips. The strips were annealed at 400 °C for 2 h and furnace cooled near ambient temperature to soften the strips prior to rolling. The sheets were ground, polished, degassed and cleaned prior to rolling. In a steel vial Al and nano-alumina (<50 nm) powder were purged along with 0.5 and 1 mm in diameter steel balls. Milling of Al-alumina powder was conducted at 300 rpm and ball-to-powder ratio of 20:1 for six cycles, each of 45 min duration with a dwell time of 15 min to eliminate undesirable rise in temperature. The milled Al-alumina particles were uniformly spread between the strips for better wettability. The stacking was done as Al/AZ31/Al with reinforcement powder in between. The stack was fastened by copper wires to avoid slipping. The assembly was preheated in the temperature range of 300–350 °C for 15 min in an air furnace. 50% reduction was maintained at each rolling stage. Rolling was carried out for four times.
\nAccumulative roll bonding has yielded good combination of properties due to enhanced microstructural aspects and is investigated further for scaling up.
\nFriction stir processing is a solid-state plastic-deformation-based synthesis method (Figure 9). It can be used to build nano-composite layer/surface composite as well as bulk composites of limited thickness/dimensions. It often leads to uniform distribution of reinforcement and refined grain size [65, 66, 67, 68, 69, 70]. The FSP process uses a shouldered rotating tool that pass over the matrix containing nano-ceramic particles. During the translational movement of tool, matrix get plastically deformed and reinforcement gets simultaneously incorporated in the matrix. The stirring action enables uniform distribution and refine grained structure of the fabricated composite.
\nFSP fabrication stages from 1 to 3 for Mg nano-composite [
The α-Al2O3 nano-particle reinforced AZ31 composite [65] was fabricated using friction stir processing technique. The Mg rectangular plates of 600 × 100 × 10 mm were cut for preparing the composite. The ceramic particles were spread into a groove of width and depth 1.2 × 5 mm cut in the plates as shown in the Figure 8. Two types of shouldered tools were used to form the composite, one pin less shoulder and the other shoulder with a pin of 5 mm height and diameter of 6 mm. The pin less tool was fed first to prevent the nano-phase getting distorted from the groove. The second tool with pin was then passed to complete the process. The tool rotation (800–1400 rpm) and the traverse speed (45 mm/min) were varied to obtain the desired strength and structure of the composite. Higher hardness was observed due to grain refinement at higher tool rotational speed.
\nSecondary processing is essentially performed on primary processed composites to eliminate/minimize defects and microstructural irregularities to enhance mechanical properties such as strength, hardness etc. Secondary processing methods include bulk deformation process such as extrusion/rolling/friction stir processing and severe plastic deformation processing methods such as equal channel angular pressing (ECAP) and cyclic extrusion and compression (CEC).
\nThe MMNC billet is stressed under high pressure ram inside a die which quantitatively reduces the irregularities like pores, cavity, voids and cracks formed earlier in primary processing methods. Normally carried above recrystallization temperature, the hot extrusion processes can be categorized into;
Forward or direct extrusion
Backward or indirect extrusion
The difference in the two method is the flow of billet direction. The billet extruded on the direction of the ram is direct extrusion while in the backward extrusion, the billet is extruded opposite to the direction of movement of ram. Typical forward extrusion process in shown in Figure 10. The key process parameters are extrusion ratio, temperature during extrusion and the speed of the ram. Extrusion ratio in the ratio between initial to the final cross section of the billet. The working temperature and environment should be optimally decided to eliminate oxidation during extrusion.
\nSchematic representation of direct extrusion process.
Rolling is a plastic deformation process in which the MMNCs are deformed by passing through set of high-pressure rolls. The MMNCs are deformed plastically by compressive stress and squeezing action between the rolls. The process enables the MMNCs to obtain fine grain microstructure and eliminates defects caused in the primary processing. The benefits include fine grain microstructure and enhanced mechanical properties of the material. The process parameters are percentage reduction, temperature and the number of passes to achieve the final thickness on the MMNCs. Rolling is also normally carried out a higher temperature to minimize the load required for plastic deformation.
\nECAP (Figure 11) is used to form ultrafine-grained (UFG) microstructure MMNCs. The MMNC billet is passed through two channeled die with identical cross section that intersect at an angle Φ (channel intersection angle). During the process the billet undergoes severe plastic shear deformation (SPD) without altering the geometrical cross-section. The process is normally repeated for several passes in order to attain UFG structure. Different routes followed namely A, BA, BC and C as discussed elsewhere [71]. Previous researcher [71] reported that when Φ is 90°, enhanced grain refinement is realized due to increase in the shear strain (γ). The shear strain for the individual passes can be obtained by:
Schematic diagram of four ECAP routes [
In an earlier research [16] conducted on Mg-9Al-1Si-1SiCn composite, ECAP was performed at a temperature of 360 °C. Route BC was chosen with ram speed of 2 mm/min. Homogenization heat treatment was carried prior to ECAP. Homogenized ECAP composite billet exhibited superior ductility and tensile strength.
\nCEC is another type of SPD technique in which the MMNC ingot is passed through the annual die to attain a fine-grained microstructure shown in Figure 12. The fine-grained structure in the ingot is realized using optimal temperature and the number of reciprocating passes. A typical setup of the CEC is shown in the figure below.
\nSchematic diagram of CEC setup [
AZ91D/SiCn nano-composite was fabricated with refined grain structure using CEC [72]. Fabrication using the CEC was performed by varying the operating temperature from 300 to 400 °C and up to eight passes were made. Superior hardness with refined grain structure were observed.
\nPresent chapter provides an insight into the magnesium nano-composites that are emerging as potential candidates in many weight-critical engineering applications ranging from aerospace, automotive to sport industries. Not only they are significantly lighter than aluminum and titanium, they can also be processed using both conventional and advanced processing methods. Stir casting is the most traditional high-volume production technique capable of generating a uniform dispersion of nano-particles in the magnesium matrix. An improvement using the ultrasonic cavitation as a mean to disperse the nano-reinforcement is already attempted with promising results. Furthermore, disintegrated melt deposition technique has proved to be the most effective one because of its capability to well disperse the nano-additives and refine the microstructure which results in excellent mechanical properties. DMD is also a scalable technique. A different approach to create magnesium based nano-composites employing the chemical reaction to form nano-intermetallics during the casting period is called as in-situ casting. A semi-solid casting technique called Rheocasting applied slurry characteristics to mix the nano-particles into the matrix. The magnesium nano-composites could also be processed using powder metallurgical methodology where the raw matrix material and reinforcements are pre-mixed in powder forms using ball milling followed by compaction and sintering. Other solid-state processing techniques such as accumulative roll bonding and friction stir processing have shown tremendous promise as well. This chapter also introduces conventional and advanced secondary processing techniques such as extrusion, rolling, equiaxed channel angular pressing, and cyclic extrusion and compression. The utilization of secondary processing techniques along with primary processing techniques can lead to enhanced microstructural properties that are key to improved mechanical performance and reliability.
\n