Operation parameters for CS systems [8].
\r\n\t
",isbn:"978-1-83968-076-2",printIsbn:"978-1-83968-075-5",pdfIsbn:"978-1-83968-080-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"456f82c97eafad5734cd36c48e167781",bookSignature:"Dr. Redmond Ramin Shamshiri",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10499.jpg",keywords:"Microclimate Control, Prediction Models, Environment Monitoring, Computer Models, Cloud Computing, IoT Monitoring, Simulink, Solar Greenhouses, Exergy, Urban Greenhouses, Virtual Crop Production, Artificial Lighting",numberOfDownloads:67,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 1st 2020",dateEndSecondStepPublish:"July 22nd 2020",dateEndThirdStepPublish:"September 20th 2020",dateEndFourthStepPublish:"December 9th 2020",dateEndFifthStepPublish:"February 7th 2021",remainingDaysToSecondStep:"7 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Shamshiri is the Member of the International Society of Precision Agriculture and Member of the American Society of Agricultural and Biological Engineering. 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Dr. Shamshiri's research focus is on digital agriculture for food security, involving high-tech control methods, embedded systems, LPWAN sensors, prediction models, and robust data acquisitions for smart farming. He has widely consulted with the industry and academics. 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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"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"54548",title:"Chromosome Abnormalities and Hematopoietic Stem Cell Transplantation in Acute Leukemias",doi:"10.5772/67802",slug:"chromosome-abnormalities-and-hematopoietic-stem-cell-transplantation-in-acute-leukemias",body:'Acute leukemias represent a mixed group of malignant diseases with heterogeneous morphology, cytogenetics, and prognosis. From a genetic point of view, acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL) consist of patients with favorable‐, intermediate‐, and poor‐risk cytogenetic variants. A group of AML patients with favorable cytogenetics traits include those with translocations t(15;17), inv(16)/t(16;16), and t(8;21), whereas t(12;21) and high hyperdiploid karyotypes are associated with better prognosis in ALL patients. Currently, the group of AML patients with poor‐risk cytogenetics includes cases with ‐7/7q‐, ‐5/5q‐, ‐17/17p‐, t(3;3), t(6;9), t(v;11)(v;q23), monosomal, and complex karyotypes, whereas those with ALL exhibit mainly t(4;11) and t(9;22). Since a great part of AML and ALL patients are not cured by single chemotherapy, they need allogeneic hematopoietic stem cell transplantation (allo‐HSCT). So far, the results of allo‐HSCT in patients with poor‐risk and favorable‐risk leukemias were analyzed in common cohorts [1, 2]. The aim of our work is to compare clinical outcomes of allo‐HSCT for the patients with distinct cytogenetic variants.
One of the poor‐risk chromosome abnormalities in AML patients is monosomal karyotype (MK), which is defined by the presence of one single autosomal monosomy in association with, at least, one additional autosomal monosomy or one structural chromosomal abnormality except for marker and ring chromosomes (Figure 1). MK is associated with a dismal prognosis and seems to be prognostically important even in complex karyotype AML. Breems et al. [3] were the first who have noted clinical significance of this finding. More recently, a strong association with TP53 mutations was shown to be an important feature of this malignancy. Although TP53 is only rarely affected in AML, it is the most frequently altered gene in complex and monosomal AML karyotypes. Hence, a conclusion was drawn that the loss‐of‐function of TP53 might cause cytogenetic instability with subsequent development of complex karyotype alterations, but not vice versa [4]. Meanwhile, 5‐year survival of the patients with this pathology did not exceed 5% [5], though 3‐year survival in this group of AML patients may be increased from 5 to 19% following allo‐HSCT [6]. A more favorable 4‐year survival was achieved in a quarter of treated AML patients, if HSCT was performed at the first remission [7–9]. Additional analysis showed that the 5‐year overall survival (OS) in transplanted patients was longer, as compared to those treated with single chemotherapy or by autologous transplantation (19% vs. 9%, respectively; P = 0.02). A similar trend seems to exist with respect to 5‐year disease‐free survival (DFS) or EFS (17% vs. 7%, P = 0.003). Multivariate analysis of these data revealed a strong correlation between lower relapse rates and prolonged EFS (P < 0.001). On the other hand, there was an only minimal difference in results of multivariate and intergroup analyses of posttransplant relapses and EFS between the groups with monosomal karyotypes and with other poor‐risk cytogenetic aberrations. We have observed only eight patients with MK+, including 5q‐ and ‐7/7q‐, in whom a 3‐year disease‐free survival was significantly lower than in MK− patients (13% vs. 27%, P = 0.009) [10]. Impact of MK upon the outcomes allo‐HSCT performed at first remission was evaluated in 263 patients with AML [5]. First, there was a highly significant difference in 5‐year OS ranging between 67%, for the most favorable, and 32%, for the poorest risk group (P = 0.001). Second, patients with non‐MK abnormalities (MK−) and cytogenetically normal cases showed identical incidence of 5‐year relapse (24%). Third, multivariate analysis revealed MK to be an independent prognostic factor, which was able to successfully predict OS (hazard ratios (HR) 3.74, P = 0.01) and relapse incidence (HR 3.74, P = 0.005), as compared to some other criteria, including those of SWOG/ECOG. Finally, subgroup analysis revealed prognostic ability of MK‐based classification to be highly efficient in the patients treated with standard myeloablative conditioning prior to allo‐HSCT (P = 0.0011 for OS, P = 0.0007 for relapse). However, the MK‐based grouping failed to predict OS or incidence of relapse in HSCT patients treated with reduced intensity conditioning (RIC).
GTG‐banded (A) and multicolor FISH (B) karyograms of bone marrow cells with complex and monosomal karyotype in acute myeloid leukemia patient. Karyotype: 45,XX,t(1;13)(q23;q14), der(1)t(1;9)(q21;?), der(3)t(3;5)(q?;?), inv(3)(q21q26),t(4;15)(p12;q22), der(5)t(5;16)(p?;q?)ins(5;3)(?;??),−7,t(8;17)(q22;q25), der(9)t(9;12)(q22;q13),der(12)t(1;12)(q21;q22) ins(12;9)(?;??),del(13)(q14),del(16)(q22).
The interest to AML with CK as a distinct biological entity has appeared recently [7–11]. This anomaly is defined as three and more structural and numerical chromosome aberrations per metaphase (Figure 1), when excluding such recurring abnormalities, as t(8;21), inv(16)/t(16;16), t(15;17), or 11q23/MLL rearrangements [11–14]. Nowadays, it accounts for 10–20% of AML cases and increases sharply with age [15]. Despite intensive treatment, including allo‐HSCT, median OS for these patients was <6 months and less than 10% patients achieved long‐term survival [16]. It has been also established that incidence of CK+ cases in AML may increase after chemotherapy [17] and HSCT [18–20]. However, some recent data [21] suggested that a 90% CR rate was achieved for these poor‐risk patients, if allo‐HSCT was performed within 80–100 days after diagnosis even in active phase of the disease. A hypothetic explanation is that poor prognosis of AML patients with CK may be associated with a chromosomal instability which, in turn, is directly related to clonal evolution, selection, and adaptation of leukemic cells [3].
Patients with hyperdiploid karyotypes (HDK) are not so rare in AML too, revealing many in common with aforementioned CK (Figure 2). For instance, in cases of sole chromosomes 8, 21, and 13 trisomies, these cases are classified as intermediate risk group. On the other hand, a new heterogeneous group with high hyperdiploidy and modal chromosome numbers from 49 to 65 has been recently described in about 2% of poor‐risk AML patients [22], which was prognostically poor. Finally, cases with near triploid/tetraploid karyotype, especially associated with structural chromosome anomalies are encountered not so often [23, 24]. Since there are no available publications concerning of allo‐HSCT results in AML patients with HDK, we presented here our data on the topic in details [25]. Study group enrolled 47 AML patients (21 females, 26 males, aged 1–58 years; median age 23.9 years), in whom allo‐HSCT was performed at our university during 2008–2015 years. Cytogenetic evaluation included standard GTG differential staining of chromosomes as well as Multicolor FISH (M‐FISH), which were carried out according to standard manufacturer recommendations. Criteria for defining aberrations and nomenclature for description of the cytogenetic findings were in accordance to the international system for human cytogenetic nomenclature (ISCN) [26]. Allo‐HSCT was performed in 13/47 (28%) patients in the first complete remission (CR), in 7/47 (15%) patients in the second CR, whereas 27/47 (57%) patients were transplanted in active disease. Sources of stem cells for the patients were as follows: bone marrow (n = 23; 49%) or peripheral blood stem cells (n = 21; 45%), while both were used in three (6%) patients. Reduced‐intensity conditioning (RIC) regimen, including fludarabine, busulfan, and/or cyclophosphamide, as well as myeloablative regimen was used in 31 (66%) and 16 (34%) patients, respectively. HLA‐related and nonrelated donors were used for nine (19%) and 32 (68%) patients, respectively. At the same time, related haploidentical allo‐HSCT was performed for six (13%) patients. Thirty‐one of 47 (66%) patients with HDK contained karyotypes with modal chromosome numbers of 47–48. A phenomenon of hyperdiploidy (49–65 chromosomes per metaphase) was revealed in 13/47 (28%) patients. At the same time in 3/47 (6%) patients, the modal numbers were near triploid and near tetraploid. Structural chromosome aberrations were revealed in 23/47 (49%) patients. Complex karyotypes with three or more chromosome anomalies were found in 19/47 (40%) patients, whereas the adverse chromosome abnormalities were registered in nine cases (19%). Numerical chromosomal anomalies were nonrandom. Trisomy 8 was the most common, being revealed in 22 patients (50%) patients excluding those with triploid and tetraploid karyotypes. It was as a single finding in seven (32%) patients while being combined with other structural and numerical chromosome anomalies in 15 (68%) patients. In some patients, trisomy 8 was associated with t(6;9), monosomy 7, and abn(3q26), thus allowing to include them into the poor‐risk cytogenetic group. The second position in the rate of trisomy incidence takes chromosome 21, which was revealed in 14 (32%) patients. It was observed as a single abnormality in seven (50%) patients, whereas in seven other cases (50%), the combination with additional chromosome abnormalities was noted. Of note, one patient exhibited a tetraploid set of chromosome 21. This is followed by chromosome 13 and 22 trisomies, which were revealed in seven patients each (16%). Trisomy 22 was found as single finding in two (29%) patients, in combination with the other chromosome abnormalities in five (71%) patients. Moreover, combination of trisomy 21 and del(11p) was noticed in one patient. Trisomy 13 was not presented alone, having been combined with other chromosome aberrations, with trisomy 19 and additional X chromosome in six (14%) and five (11%) patients, respectively. Numerical aberrations of chromosome 4 were less common, being revealed in four patients (9%), with a tetrasomic set in one case. Moreover, trisomy 7 and trisomy 6 were revealed in three (7%) and two (5%) patients, respectively. Finally, single findings of trisomy 3, 5, 9, 11, 12, 15, and 18 chromosomes as well as double Y were also documented. Chromosomal monosomy in AML patients with HDK was rare. Meanwhile, monosomy 18 was revealed in three (7%) patients from this subgroup. Three other patients had monosomies 2, 7, and 21. According to common classification the karyotypes of 19/47 (40%) may be designated as CK. They exhibited three or more chromosomal abnormalities coupled with, at least, one structural aberration. Poor‐risk cytogenetic aberrations, e.g., ‐7/7q‐, 5q‐, anomalies 3q26, and 17p were revealed in 9/47 (19%) patients. This may be exemplified by a patient with tetraploid chromosome set associated with structural rearrangements including 5q‐ and other anomalies. Univariate analysis showed that OS and DFS after allo‐HSCT significantly depend on clinical status of the patients’ status at allo‐HSCT (P = 0.003 and P = 0.002, respectively) as well as on the presence of adverse chromosome aberrations (P = 0.002 and P = 0.01, respectively). A significant difference in OS and DFS were revealed also in patients who were transplanted in the first or second remissions (P = 0.04 and P = 0.04, respectively). At the same time, the results of allo‐HSCT did not depend on AML variant, patients’ gender, donor’s type, conditioning regime, source of HSC, as well as on modal number of chromosomes and presence or absence of structural rearrangements and complex aberrations in HDK. Using multivariate analysis, we have shown independent predictors for improved OS and DFS in AML patients with HDK, as following: (a) remission at allo‐HSCT (P = 0.003 and P = 0.021, respectively); and (b) the absence of adverse chromosome aberrations (P = 0.002 and P = 0.005, respectively).
GTG‐banded (A) and multicolor FISH (B) karyograms of bone marrow cells with hyperdiploid karyotype and adverse chromosome abnormality 5q– in acute myeloid leukemia patient relapsing after allo‐HSCT. Karyotype: 75,<3n>,XY,–X,–1,der(1)del(1)(p32)ins(1;1)(q21;p32p36)x2,+3,+4,+5,del(5)(q13q33)x2,+6,–7,+8,del(8)(q11q23),–9,+13, der(13)t(1;13)(q21;q34)x2,+15,–17,+19,+20,+21,+22.
AML with 11q23/KMT2A rearrangement is rare, and about 85 genes may be involved as partners for fusion with KTM2A. Most of these cytogenetic subtypes, except translocation of t(9;11)(p22;q23) [27], are classified into poor‐risk cytogenetic group [28]. Predictive ability of this marker in HSCT setting was recently discussed [29, 30]. One of such recent studies [28] enrolled 138 patients with 11q23/KMT2A-rearranged AML, who were allografted in first or second CR. The cohort consisted of patients with t(9;11), t(11;19), t(6;9), and t(10;11) translocations. Two‐year OS, leukemia‐free survival, relapse incidence, and nonrelapse mortality were 56 ± 4%, 51 ± 4%, 31 ± 3%, and 17 ± 4%, respectively. The 11q23.3 rearrangements causing KMT2A (MLL) exchanges of gene are revealed in about 3–7% of adult AML patients. Higher efficiency of allo‐HSCT over chemotherapy alone in the treatment of AML patients with KMT2A (MLL) rearrangements seems to be evident [31].
AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct subtype of AML with recurrent genetic abnormalities. It is commonly refractory to conventional chemotherapy due to EVI1 gene overexpression, thus being associated with poor prognosis [32–36]. Isolated inv(3)/t(3;3) were revealed in 43.7% of such patients [33]. The most frequently observed additional cytogenetic abnormalities were: −7/del(7q) (37.3%), complex chromosome abnormality, and sometimes Ph+ chromosome [33]. Monosomy 7 is reported in approximately 40–60% of inv(3)/t(3;3) AML patients and associated with dismal prognosis [33–35]. Of interest is that AML and MDS patients with inv(3)/t(3;3) regardless of blast number have both similar clinical and pathological characteristics and short OS. Complex and monosomal karyotypes were also considered independent negative prognostic factors in AML patients with inv(3)/t(3;3) [36]. Due to low incidence of this poor‐risk AML subtype, efficacy of HSCT is still subject to small clinical studies [34–36], mainly, with poor results. As an example of treatment failure in such cases, we presented a clinical case of a young female with inv(3)(q21q26.2), −7. The patient underwent a quantitative monitoring with serial expressions of WT1 and EVI gene levels, as reported earlier [35]. The last large investigation in the field has been published recently [36]. It enrolled 32 transplanted patients in the first remission with overexpression of EVI1 gene, induced by aberrations of 3q26 and 11q23 loci, and 119 control patients with low EVI1 expression. The study showed much higher EVI1+ frequency in adverse‐risk group, as compared with intermediate‐risk group (53% vs. 19%, P = 0.005). The results of DFS and OS in 24 months of the EVI1+ cohort were shorter (52.6% vs. 71.0%, P = 0.02 and 52.8% vs. 72.4%, P = 0.01, respectively), whereas cumulative incidence of relapse was higher (39.5% vs. 22.5%, P = 0.01). Multivariate analysis revealed that low EVI1 expression as an independent prognostic factor favoring DFS (HR = 0.47, 95% CI 0.26–0.86, P = 0.01) but not OS. These results indicated that high EVI1 expression might predict high risk of relapse in AML patients undergoing myeloablative allo‐HSCT in CR1.
In view of the data concerning poor‐risk AML groups, it would be interesting to discuss clinical outcomes after allo‐HSCT in cohorts with favorable‐risk cytogenetics. Several such studies should be mentioned [37–39]. The data revealed by Yoon et al. [40] consist of 264 adult patients with CBF‐positive AML, where 206 of whom were in CR. Allo‐HSCT was performed in 115 patients, whereas other patients were treated either by auto‐HSCT (n = 72) or chemotherapy alone (n = 19). There was no difference in OS in groups of patients with CBFβ/MYH11 (n = 62) and RUNX1/RUNX1T1 (n = 144). Meanwhile, it was noted that OS was better in the patients treated by auto‐HSCT, compared to those treated by either allo‐HSCT or chemotherapy alone (P = 0.001). According to cytogenetic data, OS seems to be longer in patients with inv(16), which is not accompanied by trisomy. On the other hand, OS terms were shorter in patients with t(8;21) accompanied by additional chromosome aberrations. It should be mentioned that these findings were not supported by multivariate analysis. Molecular monitoring showed that OS was lower but incidence of posttransplant relapses proved to be higher in those patients with detectable minimal residual disease (MRD). Some other groups have recently reported on high number of additional chromosome and genetic abnormalities in patients with t(8;21), thus suggesting an impact on clinical outcome [41, 42]. We have recently yielded similar results in allo‐HSCT patients with t(8;21) [43]. The study enrolled 25 RUNX1‐RUNX1T1‐positive AML patients (10 females and 15 males, age 2–58 years, a median of 20.2 years). The additional cytogenetic abnormalities were detected in 13 (52%) patients before the transplantation (Figure 3). CK with three or more chromosomal abnormalities were noticed in nine (69%) patients. The median follow‐up was 566 (8–2127) days. Overall survival (OS) was 33% (95% CI 14–53) and relapse‐free survival (RFS) was 26% (95% CI 9–45) at 4 years estimated with Kaplan‐Meier method. The following factors predictive in univariate analysis for increased OS and RFS were: patients’ age (>18 vs. <18 years; P = 0.03 and P = 0.0006, respectively), donor type (matched related/matched unrelated vs. haploidentical; P = 0.0003, P = 0.02, respectively), the disease status at transplant (complete remission vs. active disease; P = 0.0002 and P = 0.005, respectively), time interval from diagnosis to transplant (<360 vs. >360 days; P = 0.008, only for OS), ACA (ACA− vs. ACA+; P = 0.02 and P = 0.009, respectively), complex karyotype (CK− vs. CK+ ; P = 0.004 and P = 0.0003, respectively). In multivariate analysis, the ACA (HR 13.5; P = 0.04), the donor type (HR 6.86; P = 0.01), and time interval from diagnosis to HSCT (HR 6.80; P = 0.02) remained statistically significant for OS. Moreover, age (HR 0.11; P = 0.004) and the donor type (HR 4.16; P = 0.04) were independent predictors for RFS. On the basis of these findings, a conclusion may be drawn that AML with t(8;21)(q22;q22)/RUNX1/RUNX1T1 translocation is a heterogeneous disease. The prognosis in patients with the additional cytogenetic abnormalities, especially in those with the CK, is worse both after the standard chemotherapy (i.e., before allo‐HSCT) and after allo‐HSCT as well.
GTG‐banded (A) and partial multicolor FISH (B) karyograms of bone marrow cells from AML patient demonstrate reciprocal translocation t(8;21)(q22;q22) and additional chromosome abnormalities, including “jumping” translocation 17q21‐17qter followed by the production of derivative chromosomes #1, #2, #14. Karyotype: 45,X,-X,der(2)t(2;17)(q37;q21),t(8;21)(q22;q22)/45,X,-X, t(8;21),der(14)t(14;17)(p13;q21)/45,X,-X,der(1)t(1;17)(p36;q21),t(8;21).
Philadelphia‐positive acute lymphoblastic leukemia (Ph+ ALL) has been regarded for decades as the ALL subgroup with inferior outcome. However, introduction of tyrosine kinase inhibitors (TKI) in the induction treatment provided complete hematologic remissions (CHRs) in nearly all patients [44–51], thus allowing to recommend them as gold for Ph+ ALL patient’s treatment. Together, these findings show that complete response to the therapy, including molecular remission, were achieved earlier in TKI‐treated cohorts of ALL patients, whereas OS and DFS in these patients lasted longer than in a cohort that avoided TKI, regardless of their combinations with auto‐ or allo‐HSCT. It has been also noticed that additional chromosome aberrations may be a poor predictor for the treatment results [51]. Three‐year leukemia‐free survival (79.8% vs. 39.5%, P = 0.01) and 3‐year OS (83% vs. 45.6%, P = 0.02) were superior in the Ph+ only cohort compared with the ACA cohort (n = 12). Our recent data are in a good accordance with the above results, and supported the aforementioned opinion. The study was performed in 65 patients with Ph‐positive ALL (26 female and 39 males aged 5–48 years, a mean of 26.2 years). Thirty‐one (48%) and 20 (31%) patients were transplanted in the first or the second remissions, respectively, whereas 14 (21%) patients received transplant in active disease. The stem cell sources were bone marrow (n = 31; 49%) and peripheral blood cells (n = 32; 49%) or both (n = 2; 3%). Reduced-intensity conditioning regimen (RIC) was used in 36 (55%) patients, whereas myeloablative conditioning was applied in 29 (45%) patients. Cytogenetic evaluation at diagnosis was carried out in 53 (80%) patients. Ph‐chromosome as a sole karyotype anomaly was detected in 33 (62%) patients. Due to high number of additional chromosomal changes (≥3) in a quarter of this group, they are described as “complex karyotypes” (Figure 4). HLA‐related siblings were donors for 18 recipients (38%), whereas stem cells from HLA‐matched nonrelated donors were used in 42 patients (65%). Moreover, five patients (7%) were transplanted with CD34+ cells from haploidentical family members. The number of CD34+ transfused cells ranged from 1.3 to 12.2 (mean 5.03) per kg of weight body. The study showed that additional chromosomal changes in Ph+ ALL were represented by numeric and/or structural abnormalities. Numeric changes were observed in 12 (60%) patients, affecting chromosomes 1, 2, 7, 8, 9, 10, 17, 19, and 22. Trisomy 1, 10, 22, and monosomy 7 were revealed in two patients each, whereas trisomy 2, 17, and 19 were revealed in single cases. The patterns and incidence of structural chromosome changes were as follows: deletions and translocations, involving 9p (n = 4; 20%); reciprocal translocations of 7p (n = 3; 15%), interstitial deletions/translocations of 5q (n = 4; 20%), deletions and translocations of chromosome 1 (n = 3; 15%) and 2 (n = 4; 20%), and structural aberrations of chromosome 17 (n = 2), including i(17q). Moreover, a double derivative of chromosome 22 was an additional chromosome abnormality in two patients. Univariate analysis revealed that 5‐year OS was longer, when allo‐HSCT was performed from HLA-matched related and unrelated donors (P = 0.02), when the patients had neither additional chromosome abnormalities in karyotypes (P = 0.04) nor primarily “complex” karyotypes (P = 0.01). On the other hand, DFS was longer in patients transplanted in the first remission (P = 0.01) with CD34‐positive cells from completely matched donors (P = 0.02).
GTG‐banded (A) and multicolor FISH (B) karyograms of bone marrow cells with translocation t(9;22)(q34;q11) and additional cytogenetic abnormalities in acute lymphoblastic leukemia patient relapsing after autological HSCT. Karyotype: 47,XX,der(6)t(6;13)(q23;q1?)ins(6;12)(q23;q13q24),‐9,der(12) t(6;12)(q23;q13), del(13)(q1?),+22,+der(22)t(9;22)(q34;q11).
Structural rearrangements of 11q23.3 caused by inducing exchanges of KMT2A (MLL) gene are revealed in about 3–7% ALL patients, with up to 70–80% in newborn patients [28]. The main of these translocations—t(4;11)(q21;q23) KMT2A/AFF1 [52]—occurs in 8–10% of ALL cases with a peak of incidence in infants. Despite generally poor prognosis for ALL with t(4;11) in all pediatric patients, it is the worst for infants [53–55]. Because of absent for this category of patient a targeted drug, allo-HSCT remains a single curative treatment [53]. According to recent findings, 5‐year OS reached 67.4% in newborns with KMT2A+ ALL, subjected to earlier performed allo‐HSCT in first remission [56–58]. Such curative effect did not depend on patient’s age, initial leukocytosis, cytogenetic findings, donor type, and options of conditioning regimen, although myeloablative conditioning with Busulfan seems to be preferable in these cases. Multivariate analysis showed the number of transfused mononuclear donor cells to be a basic predictor for longer OS (P = 0.04). To our knowledge, only one survey concerned results of allo‐HSCT in adult patients with t(4;11) [31]. In general, allo‐HSCT was performed in 56 patients, including 46 patients over 15 years old, and 10 children. Twenty‐nine patients (7–64 years old) were enrolled for autologous HSCT or chemotherapy alone, as a comparison group. Despite it, all tested patients showed myeloid engraftment. Overall, posttransplant relapses were diagnosed in 12 transplanted patients after a median of 208 days, reaching a cumulative incidence of hematological relapse of 25.3% at 3 years. Additional analysis showed that 6/41 (14.6%) transplanted in CR1 and 6/15 (40%) patients with non‐CR1 status at transplantation relapsed after HSCT (P = 0.04). Univariate analysis showed that the 3‐year CIR was 48.1 and 17.9% for the patients transplanted in CR1 and non‐CR1 status, respectively (P = 0.03). In multivariate analysis, CR1 status at transplantation proved to be the only predictor of lower relapse rate (P = 0.018). Noteworthy, 37 patients were alive at the last follow‐up, with a median survival time of 742 (range 172–1866) days after HSCT without recurrence of the disease. The probabilities for OS and DFS were 61.8 and 56.3% at 3 years, respectively, after HSCT. Adults and children had comparable OS and DFS rates. The patients who received nucleated cells above the median level had higher OS than the recipients transplanted at smaller cell doses (72.2% vs. 39.2%, P = 0.02). The predictive value of MNC numbers was mainly attributed to peripheral blood graft. Specifically, since patients receiving more nucleated cells in peripheral blood graft had higher OS than the patients, who received lower MNC quantities (65.8% vs. 42.9%, P = 0.03). In multivariate analysis higher MNC doses were found to be the only predictor for higher OS with hazard ratio (HR) of 0.34 (95% CI, 0.12–0.98, P = 0.04). In our recent study, HSCT was performed at the first or the second remissions in 11 (44%) and three (12%) patients, respectively, whereas 11 (44%) patients were transplanted in relapse state. This group included 21 patients with t(4;11)(q21;q23) KMT2A/AFF1 and four recipients with variant translocations at 11q23 locus. Translocation t(4;11)(q21;q23) was the “sole” finding only in 10 (48%) patients. In 11 patients (52%), it was associated with other structural changes, i.e., del(1), del(3p), i(7q), i(17q), and der(19p). It should be also mentioned that seven patients had each ≥3 chromosome aberrations, thus allowing to place them to the group with “complex” karyotype. Rearrangements of chromosomes 1, 7, and 3 should be mentioned as additional chromosomal aberrations (in 5, 4, and 3 patients, respectively). Stem cells sources were bone marrow (n = 7), peripheral blood (n = 17), or both (n = 1). Reduced‐intensity (n = 13; 52%) or myeloablative (n = 12; 48%) conditioning regimens were used for HSCTs. Donors were HLA‐matched related or matched unrelated (6 and 11 patients, respectively). On the other hand, in eight (32%) patients haploidentical transplantation was performed. Univariate analysis confirmed the existing view that OS and DFS of patients with KMT2A involvement was significantly longer, when HSCT was performed in complete remission regardless of the first or the second remission (P = 0.0001), and if other sources than peripheral blood were used for HSCT (P = 0.01 and P = 0.07 for OS and DFS, respectively). Finally, DFS was shorter in patients with additional chromosome abnormalities in karyotypes (P = 0.05), especially with CK (P = 0.01). Data from multivariate analysis supported conclusions drawn by previous investigators demonstrating a favorable influence of CR status on HSCT outcomes only on outcome of HSCT in adult ALL patients with 11q23 abnormality.
Analysis of the HSCT results in patients with prognostically different cytogenetic variants of acute leukemias showed that this approach may be efficient in all the tested patients and that it can be effective enough in all tested cohorts, including patients with the most poor‐risk leukemias with monosomal and complex karyotypes, as well as those with translocations t(4;11)(q21;q23), t(9;22)(q34;q11.1), t(3;3)(q21;q26.2), etc. The situation can be dramatically changed with the introduction of highly effective targeted drugs, e.g., TKIs, into therapeutic protocols for Ph‐positive leukemias.
The authors would like to acknowledge the assistance of Professor Alexei Chukhlovin in the preparation of this manuscript.
Titanium (Ti) is a lustrous metal with a silver color. This metal exists in two different physical crystalline state called body centered cubic (bcc) and hexagonal closed packing (hcp), shown in Figure 1 (a) and (b), respectively. Titanium has five natural isotopes, and these are 46Ti, 47Ti, 48Ti, 49Ti, 50Ti. The 48Ti is the most abundant (73.8%).
\n\nCrystalline state of titanium: (a) bcc, and (b) hcp [8].
Titanium has high strength of 430 MPa and low density of 4.5 g/cm3, compared to iron with strength of 200 MPa and density of 7.9 g/cm3. Accordingly, titanium has the highest strength-to-density ratio than all other metals. However, titanium is quite ductile especially in an oxygen-free environment. In addition, titanium has relatively high melting point (more than 1650°C or 3000°F), and is paramagnetic with fairly low electrical and thermal conductivity. Further, titanium has very low bio-toxicity and is therefore bio-compatible. Furthermore, titanium readily reacts with oxygen at 1200°C (2190°F) in air, and at 610°C (1130°F) in pure oxygen, forming titanium dioxide. At ambient temperature, titanium slowly reacts with water and air to form a passive oxide coating that protects the bulk metal from further oxidation, hence, it has excellent resistance to corrosion and attack by dilute sulfuric and hydrochloric acids, chloride solutions, and most organic acids. However, titanium reacts with pure nitrogen gas at 800°C (1470°F) to form titanium nitride [1, 2].
\nSome of the major areas where titanium is used include the aerospace industry, orthopedics, dental implants, medical equipment, power generation, nuclear waste storage, automotive components, and food and pharmaceutical manufacturing.
\nTitanium is the ninth-most abundant element in Earth‘s crust (0.63% by mass) and the seventh-most abundant metal. The fact that titanium has most useful properties makes it be preferred material of future engineering application. Moreover, the application of titanium can be extended when alloyed with other elements as described below.
\nAn alloy is a substance composed of two or more elements (metals or nonmetals) that are intimately mixed by fusion or electro-deposition. On this basis, titanium alloys are made by adding elements such as aluminum, vanadium, molybdenum, niobium, zirconium and many others to produce alloys such as Ti-6Al-4V and Ti-24Nb-4Zr-8Sn and several others [2]. These alloys have exceptional properties as illustrated below. Depending on their influence on the heat treating temperature and the alloying elements, the alloys of titanium can be classified into the following three types:
\nThese alloys contain a large amount of α-stabilizing alloying elements such as aluminum, oxygen, nitrogen or carbon. Aluminum is widely used as the alpha stabilizer for most commercial titanium alloys because it is capable strengthening the alloy at ambient and elevated temperatures up to about 550°C. This capability coupled with its low density makes aluminum to have additional advantage over other alloying elements such as copper and molybdenum. However, the amount of aluminum that can be added is limited because of the formation of a brittle titanium-aluminum compound when 8% or more by weight aluminum is added. Occasionally, oxygen is added to pure titanium to produce a range of grades having increasing strength as the oxygen level is raised. The limitation of the α alloys of titanium is non-heat treatable but these are generally very weldable. In addition, these alloys have low to medium strength, good notch toughness, reasonably good ductility and have excellent properties at cryogenic temperatures. These alloys can be strengthened further by the addition of tin or zirconium. These metals have appreciable solubility in both alpha and beta phases and as their addition does not markedly influence the transformation temperature they are normally classified as neutral additions. Just like aluminum, the benefit of hardening at ambient temperature is retained even at elevated temperatures when tin and zirconium are used as alloying elements.
\nThese alloys contain 4–6% of β-phase stabilizer elements such as molybdenum, vanadium, tungsten, tantalum, and silicon. The amount of these elements increases the amount of β-phase is the metal matrix. Consequently, these alloys are heat treatable, and are significantly strengthened by precipitation hardening. Solution treatment of these alloys causes increase of β-phase content mechanical strength while ductility decreases. The most popular example of the α-β titanium alloy is the Ti-6Al-4V with 6 and 4% by weight aluminum and vanadium, respectively. This alloy of titanium is about half of all titanium alloys produced. In these alloys, the aluminum is added as α-phase stabilizer and hardener due to its solution strength-ening effect. The vanadium stabilizes the ductile β-phase, providing hot workability of the alloy.
\nThe α-β titanium alloys have high tensile strength, high fatigue strength, high corrosion resistance, good hot formability and high creep resistance [3].
\nTherefore, these alloys are used for manufacturing steam turbine blades, gas and chemical pumps, airframes and jet engine parts, pressure vessels, blades and discs of aircraft turbines, aircraft hydraulic tubing, rocket motor cases, cryogenic parts, and marine components [4].
\nThese alloys exhibit the body centered cubic crystalline form shown in Figure 1 (a). The β stabilizing elements used in these alloy are one or more of the following: molybdenum, vanadium, niobium, tantalum, zirconium, manganese, iron, chromium, cobalt, nickel, and copper. Besides strengthening the beta phase, these β stabilizers lower the resistance to deformation which tends to improve alloy fabricability during both hot and cold working operations. In addition, this β stabilizer to titanium compositions also confers a heat treatment capability which permits significant strengthening during the heat treatment process [4].
\n\nAs a result, the β titanium alloys have large strength to modulus of elasticity ratios that is almost twice those of 18–8 austenitic stainless steel. In addition, these β titanium alloys contain completely biocompatible elements that impart exceptional biochemical properties such as superior properties such as exceptionally high strength-to-weight ratio, low elastic modulus, super-elasticity low elastic modulus, larger elastic deflections, and low toxicity [1, 3].
\nThe above properties make them to be bio-compatible and are excellent prospective materials for manufacturing of bio-implants. Therefore, nowadays these alloys are largely utilized in the orthodontic field since the 1980s, replacing the stainless steel for certain uses, as stainless steel had dominated orthodontics since the 1960s [2].
\nBecause of alloying the titanium achieve improved properties that make it to be preferred material of choice for application in aerospace, medical, marine and instrumentation. The extent of improvement to the properties of titanium alloys and ultimately the choice of area of application is influenced by the methods of production and processing as discussed in the subsequent sections.
\nThe base metal required for production of titanium alloys is pure titanium. Pure titanium is produced using several methods including the Kroll process. This process produces the majority of titanium primary metals used globally by industry today. In this process, the titanium is extracted from its ore rutile—TiO2 or titanium concentrates. These materials are put in a fluidized-bed reactor along with chlorine gas and carbon and heated to 900°C and the subsequent chemical reaction results in the creation of impure titanium tetrachloride (TiCl4) and carbon monoxide. The resultant titanium tetrachloride is fed into vertical distillation tanks where it is heated to remove the impurities by separation using processes such as fractional distillation and precipitation. These processes remove metal chlorides including those of iron, silicon, zirconium, vanadium and magnesium. Thereafter, the purified liquid titanium tetrachloride is transferred to a reactor vessel in which magnesium is added and the container is heated to slightly above 1000°C. At this stage, the argon is pumped into the container to remove the air and prevent the contamination of the titanium with oxygen or nitrogen. During this process, the magnesium reacts with the chlorine to produce liquid magnesium chloride thereby leaving the pure titanium solid. This process is schematically presented in Figure 2.
\nKroll process for production of titanium: (a) chlorination, (b) fractional distillation [5].
The resultant titanium solid is removed from the reactor by boring and then treated with water and hydrochloric acid to remove excess magnesium and magnesium chloride leaving porous titanium sponge, which is jackhammered, crushed, and pressed, followed by melting in a vacuum electric arc furnace using expendable carbon electrode. The melted ingot is allowed to solidify in a vacuum atmosphere. This solid is often remelted to remove inclusions and to homogenize its constituents. These melting steps add to the cost of producing titanium, and this cost is usually about six times that of stainless steel. Usually the titanium solid undergo further treatment to produce titanium powder required in alloying process. The basic methods used to produce titanium powder are summarized below.
\nThe first method is called the Armstrong process, shown in Figure 3, in which the powder is made as the product of extractive processes that produce primary metal powder. This process is capable of producing commercially pure titanium (Ti) powder by the reduction of titanium tetrachloride (TiCl4) and other metal halides using sodium (Na). This process produces powder particles with a unique properties and low bulk density. To improve powder properties such as the particle size distribution and the tap density, additional post processing activities such as dry and wet ball milling are applied. The narrowed particle size distributions are necessary for typical powder metallurgical processes. In addition, the resultant powder’s morphology produced by the Armstrong process provide for excellent compressibility and compaction properties that result in dense compacts with increased green strength than those produced by the irregular powders. For this reason, the powders can even be consolidated by traditional powder metallurgy techniques such as uniaxial compaction and cold isostatic pressing. Figure 4 illustration the scanning electron microscope images of the titanium powders of the Armstrong process. As seen in the figure, the powder has an irregular morphology made of granular agglomerates of smaller particles.
\nIllustration of the Armstrong process [5].
SEM micrographs of CP-Ti produced by Armstrong process [5].
The hydride-dehydride (HDH) process, illustrated in Figure 5, is used to produce titanium powder using titanium sponge, titanium, mill products, or titanium scrap as the raw material. The hydrogenation process is achieved using a batch furnace that is usually operated in vacuum and/or hydrogen atmospheric conditions. The conditions necessary for hydrogenation of titanium are pressure of one atmospheric and temperatures of utmost 800°C. This process results in forming of titanium hydride and alloy hydrides that are usually brittle in nature. These metal hydrides are milled and screened to produce fine powders. The powder is resized using a variety of powder-crushing and milling techniques may be used including: a jaw crusher, ball milling, or jet milling. After the titanium hydride powders are crushed and classified, they are placed back in the batch furnace to dehydrogenate and remove the interstitial hydrogen under vacuum or argon atmosphere and produce metal powder. These powders are irregular and angular in morphology and can also be magnetically screened and acid washed to remove any ferromagnetic contamination. Finer particle sizes can be obtained, but rarely used because oxygen content increases rapidly when the powder is finer than −325 mesh. Powder finer than −325 mesh also possess more safety challenges [5]. The powder can be passivated upon completion of both the hydrogenating and dehydrogenating cycles to minimize exothermic heat generated when exposed to air.
\nHydride-dehydride process for obtaining of titanium powders [6].
The hydride-dehydride process is relatively inexpensive because the hydrogenation and dehydrogenation processes contribute small amount of cost to that of input material. The additional benefit of this process is the fact that the purity of the powder can be very high, as long as the raw material’s impurities are reduced. The oxygen content of final powder has a strong dependence on the input material, the handling processes and the specific surface area of the powder. Therefore, the main disadvantages of hydride-dehydride powder include: the powder morphology is irregular, and the process is not suitable for making virgin alloyed powders or modification of alloy compositions if the raw material is from scrap alloys (Figure 6) [5].
\nSEM micrographs of CP-Ti produced by HDH [5].
Conventional sintering, shown in Figure 7, is one of the widely applied powder metallurgy (PM) based method for manufacturing titanium alloys. In this method, the feedstock titanium powder is mixed thoroughly with alloying elements mentioned in Section 2 using a suitable powder blender, followed by compaction of the mixture under high pressure, and finally sintered. The sintering operation is carried out at high temperature and pressure treatment process that causes the powder particles to bond to each other with minor change to the particle shape, which also allows porosity formation in the product when the temperature is well regulated. This method can produce high performance and low cost titanium alloy parts. The titanium alloy parts produced by powder metallurgy have several advantages such as comparable mechanical properties, near-net-shape, low cost, full dense material, minimal inner defect, nearly homogenous microstructure, good particle-to-particle bonding, and low internal stress compared with those titanium parts produced by other conventional processes [7].
\nPowder metallurgy process [7].
Self-propagating high temperature synthesis (SHS), shown in Figure 8, is another PM based process used to produce titanium alloys. The steps in this process include: mixing of reagents, cold compaction, and finally ignition to initiate a spontaneous self-sustaining exothermic reaction to create the titanium alloy [7].
\nSHS process [7].
Although the above PM processes are mature technologies for fabrication of bone implants they have difficulties of fabricating porous coatings on surfaces that are delicate or with complex geometries. In addition, these processes tend to produce brittle products because of cracks and oxides formed inside the materials. Further, the high costs and poor workability associated with these PM processes restrict their application in commercial production of bone implants. Consequently, new methods, based on additive manufacturing principles were developed [7].
\nThe definitions of advanced methods of production is the use of technological method to improve the quality of the products and/or processes, with the relevant technology being described as “advanced,” “innovative,“ or “cutting edge.” These technologies evolved from conventional processes some of which have been developed to achieve various components of titanium base alloys and aluminides. Atomisation processes are among the most widely used cutting edge methods for production of titanium alloys [5].
\nAtomisation processes are used to make alloyed titanium powders. In these processes, the feedstock material is generally titanium, and the alloy powders produced are further processed typically to manufacture components using processes such as hot isostatic pressing (hip). As mentioned previously, it is generally believed that alloyed powders are not suitable for cold compaction using conventional uniaxial die pressing methods. Moreover, the inherent strength of the alloyed powders is too high, making it difficult to deform the particles in order to achieve desired green density. The atomisation processes produce relatively spherically shaped titanium alloy powders that are most suitable for additive manufacturing using techniques such as selective laser melting or electron beam melting. These spherical powders are also required for manufacturing titanium components using metal injection molding techniques. Typically, additive manufacturing and metal injection molding processes require particle sizes of powders to be in the range of 100 μm to ensure good flowability of the powder during operations. However, the challenge of the atomisation processes usually is that powders produced tend to have a wide particle size distribution, from a few to hundreds of micrometers. Examples of atomisation processes are gas atomisation and plasma atomisation processes described below [5].
\nIn the gas atomisation process, shown in Figure 9, the metal is usually melted using gas and the molten metal is atomised using an inert gas jets. The resultant fine metal droplets are then cooled down during their fall in the atomisation tower. The metal powders obtained by gas-atomization offer a perfectly spherical shape combined with a high cleanliness level. However, even though gas atomisation is, generally, a mature technology, its application need to be widened after addressing a few issues worth noting such as considerable interactions between droplets while they cool during flight in the cooling chamber, causing the formation of satellite particles. Also, due to the erosion of atomising nozzle by the liquid metal, the possibility for contamination by ceramic particles is high. Usually, there may also be argon gas entrapment in the powder that creates unwanted voids [5].
\nSchematic diagrams of gas atomisation process [5].
Plasma atomisation, shown in Figure 10, uses a titanium wire alloy as the feed material which is a significant cost contributing factor. The titanium alloy wire, fed via a spool, is melted in a plasma torch, and a high velocity plasma flow breaks up the liquid into droplets which cool rapidly, with a typical cooling rate in the range of 100–1000°C/s. Plasma atomisation produces powders with particle sizes ranging from 25 to 250 μm. In general, the yield of particles under 45 μm using the plasma wire atomisation technique is significantly higher than that of conventional gas atomisation processes [5].
\nSchematic diagrams of plasma atomisation process [5].
The future methods for production of titanium alloys depend on the demand of these products and to what extend nature will be able to provide them. The demand for titanium alloys shall also influence the number and type of technological breakthroughs, the extent of automation, robotics’ application, the number of discoveries for new titanium alloys, their methods of manufacturing, and new areas of application. Automation is an important aspect of the industry’s future and already a large percentage of the manufacturing processes are fully automated. In addition, automation enables a high level of accuracy and productivity beyond human ability—even in hazardous environments. And while automation eliminates some of the most tedious manufacturing jobs, it is also creating new jobs for a re-trained workforce. The new generation of robotics is not only much easier to program, but also easier to use due to extra capabilities such as voice and image recognition during operations, they are capable of doing precisely what you ask them to do. The discovery of new titanium alloys, or innovative uses of existing ones, is essential for making progress in many of the technological challenges we face. This discovery can result in new synthesis methods of new alloy compounds and design of super alloys, theoretical modeling and even the computational prediction of titanium alloys. This discovery requires that new methods of manufacturing are developed. In light of this, “additive manufacturing” is being developed and this is viewed as a groundbreaking development in manufacturing advancement that offers manufacturers powerful solutions for making any number of products cost-effectively and with little waste. Examples of additive manufacturing technologies are cold spray, 3-D printing, electron beam melting, and selective laser melting. To fabricate alloy surfaces using these technologies, alloying elements are mixed thoroughly in the feedstock powder and the fabrication processes proceed as described in the following paragraphs [7, 8].
\nCold spray (CS) process, schematically shown in Figures 11 and 12 can deposit metals or metal alloys or composite powders on a metallic or dielectric substrate using a high velocity (300–1200 m/s) jet of small (5–50 μm) particles injected in a stream of preheated and compressed gas passing through a specially designed nozzle. The main components of a generic CS system include the source of compressed gas, gas heater, powder feeder, spray nozzle assembly, and sensors for gas pressure and temperature. The source of compressed gas acquires the gas from an external reservoir, compresses it to desired pressure and delivers it into the gas heater. Then, the gas heater preheats the compressed gas in order to increase its enthalpy energy. The preheated gas is delivered into the spray nozzle assembly whose convergent/divergent geometry not only converts the enthalpy energy of the gas into kinetic energy but also mixes the metal powders with the gas proportionately. The powder feeder meters and injects the powder in the spray nozzle assembly. The sensors for the gas pressure and temperature are responsible for regulating the preset pressure and temperature of the gas stream. The powder injection point in the spray nozzle assembly, the gas pressure, and gas temperature distinguish the low pressure-CS system (LP-CS) from the high pressure CS (HP-CS). In the LP-CS system, the feedstock powder is injected in the downstream side of the convergent section of the nozzle assembly, while in the HP-CS system; the powder is injected in the upstream side of the convergent/diverging section of the nozzle assembly as illustrated in Figures 11 and 12. Several other parameters which contribute towards the distinguishing of the CS systems are summarized in Table 1 [8].
\nLow pressure CS process configuration [8].
High pressure CS process configuration [8].
Operation parameters for CS systems [8].
3-D printing is an additive manufacturing method that applies the principle of adding material to create structures using computer aided design (CAD), part modeling, and layer-by-layer deposition of feedstock material. This cutting-edge technology is also called stereolithography, and is illustrated in Figure 13 [8].
\n3D-printing process [8].
In this technology, the pattern is transferred from a digital 3D model, stored in the CAD file, to the object using a laser beam scanned through a reactive liquid polymer which hardened to create a thin layer of the solid. In this manner, the structure is fabricated on the desired surface. This method was proved in the laboratory setup is still being integrated in commercial set-up because 3-D printing is the most widely recognized version of additive manufacturing. For this reason, the inventors and engineers for this process have for years used machines costing anywhere from a few thousand dollars to hundreds of thousands for rapid prototyping of new products. It can be noted that all of the additive-manufacturing processes follow this same basic layer-by-layer deposition principle but with slightly different ways such as using powdered or liquid polymers, metals, metal-alloys or other materials to produce a desired product [8].
\nElectron beam melting (EBM), shown in Figure 14, is one of the additive manufacturing processes which fabricated titanium coatings by melting and deposition of metal powders, layer-by-layer, using a magnetically directed electron beam. Though this method was proved to be successful, it has high set-up costs due to the requirement of high vacuum atmosphere [7].
\nElectron beam melting method [1].
Selective laser melting (SLM), shown in Figure 15 is the second additive manufacturing method for titanium alloy coatings which completely melt the powder using a high-power laser beam. Similarly, this method is costly because it requires advanced high rate cooling systems. Moreover, the fluctuations of temperatures during processing negatively affect the quality of the products [1].
\nSelective laser melting method [1].
This chapter described the titanium as a metal that exists naturally with two crystalline forms. The chapter highlighted the properties of titanium metal that influence its application. The fact that titanium has advantageously unique properties that can be improved by alloying with other elements makes it to be preferred engineering material for future application in such areas as biomedical implants, aerospace, marine structures, and many others. The chapter discussed the traditional, current and future methods necessary to produce structures using titanium and titanium alloys. Further, the chapter suggested “additive manufacturing methods” as advanced methods for future manufacturing because they offer powerful solutions for making any type and number of products cost-effectively and with little waste. The examples of these methods are cold spray, 3-D printing, electron beam melting, and selective laser melting. Finally, the various processes used during fabrication of alloys using these methods were also presented.
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