Clinical trials for neurofibromatosis type 1-associated plexiform neurofibromas.
\r\n\t
",isbn:"978-1-83969-558-2",printIsbn:"978-1-83969-557-5",pdfIsbn:"978-1-83969-559-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"97b6de623f15598880112f6bafedc3e1",bookSignature:"Dr. Robert M.X. Wu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11916.jpg",keywords:"Business Models, E-commerce Marketing Strategy, E-commerce Business Models, Digital Transformation, Business Intelligence, E-business Applications, Research, Information System Management, Marketing Management, Electronic Commerce, Internet Marketing, Information Systems",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 26th 2022",dateEndSecondStepPublish:"June 30th 2022",dateEndThirdStepPublish:"August 29th 2022",dateEndFourthStepPublish:"November 17th 2022",dateEndFifthStepPublish:"January 16th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"7 hours",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:'Dr. Wu holds a Ph.D. in e-Commerce, lectures at the School of Engineering and Technology in Australia, and is a Distinguished Professor at Shanxi Normal University, China. In 2011, Dr. Wu was recognized as a ‘Top 100 Outstanding Academic Leader for China’s Informatics’ by the China Informatics Society. He was awarded "Outstanding Contribution in Reviewing" by Q1 Journals such as Electronic Commerce Research and Applications (Elsevier).',coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"190913",title:"Dr.",name:"Robert M.X.",middleName:null,surname:"Wu",slug:"robert-m.x.-wu",fullName:"Robert M.X. Wu",profilePictureURL:"https://mts.intechopen.com/storage/users/190913/images/system/190913.jpg",biography:"Robert M.X. Wu has a diploma in Computer Science, a bachelor’s degree in Economics, and master’s and doctorate degrees in e-Commerce. He is currently lecturing e-commerce / Information Systems at Central Queensland University Australia (CQU). He has led more than ten industry-based research projects since 2012 and contributes to reviewing five A-level Australian Business Deans Council (ABDC) journals and Q1 journals.\r\nIn July 2011, Dr. Wu was recognized as a ‘Top 100 Outstanding Academic Leader for China’s Informatics’ by the China Informatics Society. In 2017 he was appointed Distinguished Professor at Shanxi Normal University, China. He was also awarded ‘Outstanding Contribution in Reviewing’ in 2016 and 2018 by the Electronic Commerce Research and Applications journal (Elsevier) and ‘Student Voice Commendation – EDUCATORS of THE YEAR 2020’ for Emerging Technologies in E-Business, CQU.",institutionString:"Central Queensland University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Central Queensland University",institutionURL:null,country:{name:"Australia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440204",firstName:"Ana",lastName:"Cink",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440204/images/20006_n.jpg",email:"ana.c@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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This dysregulation eventually leads to tumors of the central and peripheral nervous systems as well as multiorgan involvement. The incidence of Neurofibromatosis type 1 (NF1) is approximately 1 in every 2500–3500 births [1], while the incidence of neurofibromatosis type 2 (NF2) is approximately 1 in every 25,000–33,000 births [2]. Schwannomatosis (SWN) has been identified as a distinct entity with different genetic etiology and clinical phenotype from NF2, but it is difficult to assess the precise incidence of this condition. Although the tumors that develop most frequently in NF1, NF2 and SWN are histologically benign, they can cause significant neurologic disabilities and even mortality due to the involvement of the central and peripheral nervous systems. These tumors represent a unique therapeutic challenge due to the heterogeneity in severity and rate of progression among patients and hence novel therapeutic approaches are needed. In this chapter, we will review the recent studies in the field of neurofibromatosis therapeutics along with the collaborative efforts for innovative clinical trial designs.
\nThe establishment of the NFCTC in 2006 by the Department of Defense was a landmark in the field of NF therapeutics development [3]. The consortium has been in continuous operation since inception. It provides infrastructure, and shared resources across multiple institutions to generate resource-efficient clinical trials. The REiNS working groups are another clear example of the influence of collaboration among NF experts to advance the NF drug development efforts. The Children’s Tumor Foundation (CTF) has provided support to the NF community, including efforts to advance research as well as public education and patient support. In 2007, the CTF invested $4 million to launch the Neurofibromatosis Preclinical Consortium (NFPC) to test candidate drug therapies in NF1 and NF2 models. The Neurofibromatosis Therapeutic Acceleration (NTAP) was established as a private philanthropy to accelerate the development of effective therapeutics for pNFs and cNFs. NTAP has partnered with CTF in the evaluation of potential therapeutic agents in animal models of pNFs.
\nThe collaborative efforts among academic, federal regulatory, and private foundations have resulted in early successes in the NF therapeutic development. In February 2018, selumetinib, a MEK1/2 inhibitor co-developed by AstraZenca and Merck&Co, received breakthrough status from the FDA. Selumetinib was granted Orphan Drug Designation based on data from the phase II trial that tested selumetinib in pediatric patients with inoperable pNFs (NCT01362803) [4] and hence, selumetinib may become the first approved drug for NF. This success highlights the power of collaboration, which moved Selumetinib from a repurposed oncology drug to its current clinical success in NF patients. The funders involved for in this “MEK story” are the CTF, the National Institute of Health (NIH), the Congressionally Directed Medical Research Program (CDMRP) through NFCTC, and the NTAP at Johns Hopkins University [5].
\nUnderstanding of the pathogenesis and molecular landscape of the NF1-associated tumors has advanced dramatically in recent years. This advancement, along with the continued collaborative approaches across the research community, has fueled therapeutic development efforts against many of the NF1 manifestations. Therapeutic development in NF1 has been tumor-specific, due to the substantial heterogeneity of the development and behavior of NF1-associated tumors across and within patients. Plexiform neurofibromas (pNFs), the source of major morbidity in NF1, has been an area of major focus for therapeutic development, followed by other NF1-associated tumors including cutaneous neurofibromas (cNF), optic pathway gliomas (OPG), and malignant peripheral nerve sheath tumors (MPNST).
\nPlexiform neurofibromas (pNFs) affect up to 50% of NF1 patients and can involve any peripheral nerve [6, 7]. They occur most commonly in the trunk, followed by the extremities [6]. pNFs tend to grow most rapidly in early childhood and may increase by ≥20% per volume per year in young children [8]. Though surgery remains the mainstay for treatment of pNF, complete resection is virtually impossible due to the frequent involvement of adjacent normal tissue, and occasionally critical structures. Moreover, surgical resection is frequently challenging since pNF can cross tissue planes and involve multiple body regions. The most common morbidities leading to surgery are neurologic, disfigurement, and airway involvement [9]. A substantial risk of pNF regrowth after surgical resection has motivated the ongoing research to find non-invasive therapies for pNF.
\nThere are multiple ongoing clinical trials (Table 1) targeting pNF which represent a rapid expansion in the pNF therapeutic landscape. Though some of the tested drugs have failed to achieve the primary endpoint, they helped establish the natural history of the growth rates of pNF [10, 11]. The therapeutic development efforts in pNFs had shifted from testing “empirically,” usually cytotoxic, agents to agents being supported by well-established transitional studies. The first agent that showed radiographic response was imatinib, with a response rate of 17% [12]. Ras-pathway targeted therapy has been of particular interest, as it provides an opportunity for treating multiple manifestations of NF1 with one drug. For example, Selumetinib, which is a MEK (mitogen-activated protein kinase) inhibitor, has shown activity in pNF and low-grade gliomas (including OPG) associated with NF1 [13].
\nDrug | \nTarget | \nPhase | \nAge (y) | \nEndpoints | \nResults | \n
---|---|---|---|---|---|
Thalidomide [14] | \nAngiogenesis | \nI | \n>5 | \nORR | \nCompleted/unclear benefit | \n
Sirolimus [15] NCT00634270 | \nmTOR | \nII | \n>3 | \n3D ORR, TTP | \nModest increase in TTP, no objective response | \n
Sorafenib [16] NCT00727233 | \nRaf kinase, c-kit, PDGF, VEGFR2,3 | \nI | \n3–18 | \n3D ORR | \nIntolerable, decrease in QOL due to pain, no objective response | \n
Pirfenidone [17, 18] NCT00076102 | \nFibroblast proliferation | \nI, II | \n3–21 | \n3D ORR | \nCompleted, no objective response | \n
Cediranib NCT00326872 | \nVEGFR-1, -2, -3 | \nII | \n≥18 | \n3D ORR | \nTerminated due to slow accrual | \n
Tipifarnib [19] NCT00021541 | \nFarnesyl transferase | \nI, II | \n3–25 | \nTTP, 3D ORR | \nCompleted, No difference in TTP | \n
PEG-Interferon alpha 2b [20, 21] NCT00396019 | \nImmune, angiogenesis | \nI, II | \n18 months–21 years in phase II | \nTTP, 3D ORR | \nDoubled TTP, 3D ORR less than 20% | \n
Vinblastine/Methotrexate NCT00030264 | \nCytotoxic | \nII | \n≤25 | \nTTP | \nCompleted, pending results | \n
Celecoxib; PEG-Interferon alpha 2b NCT00846430 | \nImmune, angiogenesis | \nII | \n2–30 | \nSymptoms improvement, ORR | \nActive, not recruiting | \n
Nilotinib NCT01275586 | \nBCR-ABL, PDGFR, c-kit | \nPilot | \n≥18 | \nRECIST,3D ORR | \nCompleted | \n
Everolimus [22] NCT01412892 | \nmTOR | \nII | \n18–60 | \n3D ORR | \nCompleted, no objective response | \n
Everolimus NCT01365468 | \nmTOR | \nII | \n>10 | \n3D ORR, TTP | \nTerminated due to slow accrual | \n
Imatinib [23] NCT01673009 | \nc-kit, PDGFR | \nII | \n3–65 | \nRECIST, 3D ORR | \n17% 3D ORR | \n
Sunitinib NCT01402817 | \nPDGFR, VEGFR, c-kit | \nII | \n3–65 | \n3D ORR | \nTerminated (1 patient died) | \n
Pexidartinib [24] NCT02390752 | \nc-kit, FLT3, CSF1R | \nI, II | \n3–31 | \nORR | \nRecruiting | \n
Cabozantinib NCT02101736 | \nRET, c-MET, VEGFR | \nII | \n≥3 | \n3D ORR | \nRecruiting | \n
Trametinib NCT02124772 | \nMEK | \nI | \n1 month–17 years | \nPK, PD, toxicity | \nRecruiting | \n
PD-0325901 [25] NCT02096471 | \nMEK | \nII | \n≥16 | \n3D ORR | \nCompleted, 42% 3D ORR | \n
Selumetinib [26] NCT01362803 | \nMEK | \nI, II | \n2–18 | \n3D ORR | \nActive, not recruiting, 71% 3D ORR | \n
Selumetinib NCT02407405 | \nMEK | \nII | \n≥18 | \n3D ORR | \nRecruiting | \n
Binimetinib NCT03231306 | \nMEK | \nII | \n≥1 | \n3D ORR | \nRecruiting | \n
Selumetinib (intermittent dosing) NCT03326388 | \nMEK | \nI, II | \n3–18 | \nToxicity, 3D ORR | \nActive, not recruiting | \n
Trametinib NCT03363217 | \nMEK | \nII | \n1 month–25 years | \n3D ORR, TTP RECIST | \nRecruiting | \n
Imatinib (in pNF with airway involvement) NCT03688568 | \nc-kit, PDGFR | \nII | \n6 months–12 years | \nSleep study/PFT, 3D ORR | \nRecruiting | \n
Clinical trials for neurofibromatosis type 1-associated plexiform neurofibromas.
\n
Optic pathway glioma (OPG) is the most common form of glioma seen in individuals with NF1. While 15–20% of children with NF1 will develop OPG [27, 28] only 30–50% will be symptomatic and one-third will require therapeutic intervention [29]. In those with confirmed decline in visual acuity (VA) or involvement in the hypothalamus, chemotherapy is the mainstay of treatment. First-line chemotherapeutic agents include vincristine and carboplatin [30], while second-line agents include vinblastine [31], vinorelbine [32], and temozolomide [33]. There is a report of four cases of refractory OPG (two sporadic and two NF1-associated OPG) that showed marked improvement in VA following treatment with bevacizumab [34]. These agents rarely restore the premorbid visual acuity and the aim of treatment is usually to stabilize disease and prevent further worsening [35, 36]. Radiotherapy is usually avoided in NF1-associated OPG for concern of secondary tumors [37] and moya moya syndrome [38] Surgical excision of OPG is not feasible due to the tumor location and is usually reserved for instances of complete loss of vision, severe proptosis, or hydrocephalus.
\nRecently, small molecule inhibitors have been used for refractory OPG in clinical trials (Table 2). Among these agents, selumetinib has shown promising results in phase II studies and was proven to be active in recurrent, refractory or progressive NF1-associated pediatric low-grade glioma [39].
\nDrug | \nTarget | \nPhase | \nAge | \nEndpoints | \nStatus | \n
---|---|---|---|---|---|
Vinblastine +/− Bevacizumab NCT02840409 | \nCytotoxic/VEGF | \nII | \n6 months–18 years | \nResponse rate, OS, PFS, visual outcome measures, OCT | \nRecruiting | \n
Pegylated interferon NCT02343224 | \nTumor microenvironment | \nII | \n3–18 years | \nResponse rate | \nRecruiting | \n
Pomalidomide NCT02415153 | \nAngiogenesis/immunomodulation | \nI | \n3–20 years | \nToxicity, MTD | \nActive, not recruiting | \n
Lenalidomide NCT01553149 | \nAngiogenesis/immunomodulation | \nII | \n0–21 years | \nResponse rate | \nActive, not recruiting | \n
Everolimus (RAD0001) NCT01158651 | \nmTOR | \nII | \n1–21 years | \nResponse rate | \nActive, not recruiting | \n
Binimetinib (MEK162) NCT02285439 | \nMEK | \nI/II | \n1–18 years | \nMTD, response rate | \nRecruiting | \n
Binimetinib (MEK162) NCT01885195 | \nMEK | \nII | \nOlder than 18 years | \nResponse rate | \nCompleted (pending results) | \n
Selumetinib NCT01089101 | \nMEK | \nI/II | \n3–21 years | \nSafety, MTD, Response rate | \nRecruiting | \n
Clinical trials for optic pathway gliomas (OPG) and other gliomas associated with neurofibromatosis type 1.
\n
Unnecessary cytotoxic therapies for OPG should be avoided, as many OPGs remain asymptomatic and some even regress over time [28]. One of the efforts to standardize the VA assessment in clinical trials for NF1-associated OPG is through using optic coherence tomography (OCT) [40, 41]. OCT provides an objective assessment of the retinal nerve fiber layer thickness. OCT is a noninvasive tool to monitor children with OPG in whom, especially the youngest ones, traditional methods of VA assessment is challenging [42]. Another objective noninvasive tool to asses VA in NF1-associated OPG is automated tractography of the optic radiation that was validated in a recent study [43].
\nA retrospective study that analyzed the clinical and pathological features of gliomas in 100 individuals with NF1 emphasized the wide histologic spectrum of gliomas in those with NF1 [44]. Indeed, individuals with NF1 have an increased risk of malignant gliomas compared with the general population [45], but there are confounding reports on glioblastoma prognosis in those with NF1 vs. cases without NF1 [46, 47]. A recent study analyzed the molecular landscape of gliomas in NF1 and showed that 50% of low-grade gliomas displayed an immune signature, T-lymphocytic infiltrate, and increased neoantigen load [48], findings that may influence future clinical trials in NF1-associated gliomas.
\nMalignant peripheral nerve sheath tumors (MPNSTs) are rare high-grade sarcomas with poor prognosis [49]. MPNSTs occur more frequently in those with NF1 compared with the general population, with a lifetime risk of 8–13% [50]. Several studies have not shown a significant difference in the molecular landscape between sporadic and NF1-associated MPNSTs [51, 52]. FDG-PET remains the gold standard noninvasive diagnostic tool for MPNSTs, with 89–100% sensitivity and 72–95 specificity [53, 54]. Surgical resection with negative margins is the mainstay of treatment [55], though that is not usually feasible. Use of adjuvant radiotherapy to induce local control in MPSNTs failed to show improvement in overall survival in NF1-associated MPNSTs [56].
\nThere are limited chemotherapeutic options, including agents like doxorubicin, and ifosfamide [57, 58]. A phase II study of bevacizumab and everolimus that enrolled 25 individuals (17 had NF1-associated MPNST) did not show a clinical benefit (defined as complete response, partial response or stable disease for ≥4 months) [59]. Although preclinical studies showed EGFR amplification in MPSNT [60], EGFR inhibitors did not show clinical activity against MPNST in clinical trials. A few studies have been conducted in sarcomas using targeted therapy, and these have not shown clinical activity; tested drugs included imatinib [61], dasatinib [62], sorafenib [63], and erlotinib [64]. These negative studies emphasize the importance of developing xenografts to explore new therapeutic targets and explore pathways of interest like the NF1/P53-mutant transgenic MPNST model [65, 66, 67].
\nCombined targeted therapy has been used to exploit cellular vulnerabilities of cancer cells, as in RAS-driven tumors which are refractory to conventional therapies. A preclinical study has shown dramatic tumor shrinkage in a transgenic MPNST mouse model in response to combined HSP90 and mTOR inhibition [68]. This promising preclinical work had led to a phase I/II study of gantespib, a novel injectable inhibitor of HSP90 and the mTOR inhibitor, sirolimus. The study enrolled 20 participants (NCT02008877) and results are pending [69]. Another novel approach undergoing phase I study utilizes the oncolytic potential of the genetically engineered injectable measles virus Edmonston vaccine strain (MVEdm) that encodes thyroid sodium iodide symporter [70] (Table 3).
\nDrug | \nTarget | \nPhase | \nAge (years) | \nEndpoints | \nStatus | \n
---|---|---|---|---|---|
EGFR806 CAR-T cell NCT03618381 | \nImmunotherapy | \nI | \n1–26 | \nToxicity | \nRecruiting | \n
Selumetinib and Sirolimus NCT03433183 | \nMEK and mTOR | \nII | \n≥12 | \nCBR, PFS, OS | \nActive, not recruiting | \n
Injectable MVEdm vaccine strain NCT02700230 | \nOncolytic virotherapy | \nI | \n≥18 | \nToxicity, MTD, ORR | \nRecruiting | \n
Pazopanib vs. Sapanisertib NCT02601209 | \nPDGFR, VEGFR, c-kit (Pazopanib), TORC1&2 (Sapanisertib) | \nI (Sapanisertib), II | \n≥18 | \nMTD, PFS, ORR | \nActive, not recruiting | \n
Lorvotuzumab mertansine NCT02452554 | \nCD-56 antibody | \nII | \n1–30 | \nRECIST | \nActive, not recruiting | \n
Pexidartinib and Sirolimus NCT02584647 | \nc-kit, FLT3, CSF1R, mTOR | \nII | \n≥18 | \nPFS, OS | \nRecruiting | \n
Clinical trials for malignant peripheral nerve sheath tumors in neurofibromatosis type 1.
\n
Cutaneous neurofibromas (cNFs) are among the most common manifestations in NF1, affecting about 99% of patients with NF1 [71]. cNFs are unlikely to undergo malignant transformation or to cause fatal complications or severe neurologic disability. Nevertheless, cNFs are considered one of the greatest concerns in patients, especially adults, with NF1. These concerns are mainly due to disfigurement and dysesthesia, causing substantial psychological distress and negative body image perception [72]. There is immense variability in cNF among patients with NF1 with respect to size, location, age at first presentation, associated symptoms, and number. These factors affect the therapeutic approach to cNFs and emphasize the need for reproducible and reliable endpoints to ensure clinical success for tested agents.
\nClinical management for cNF involves surveillance or procedure-based therapy. Conventional surgical resection promotes complete removal of the lesion, but there are obstacles, including limited number of lesions that can be treated in a single session and the scarring that may be induced by surgical resection. Other alternatives include electrodessication, which remove cNFs through dehydration and denaturation [73]. This allows for removal of large numbers (up to thousands) of cNFs in one session, but it requires general anesthesia and may cause scarring and pigmentation changes. A retrospective study of 106 individuals with multiple, small cNFs treated with CO2 laser ablation reported >90% patient satisfaction, yet a local infection rate was reported to be 15% [74]. Other procedure-based therapies reported in cNFs are laser photocoagulation [75] and radiofrequency ablation [76]. Another approach using local drug/device combinations is the photodynamic therapy (PDT), which is being tested in different cancers [77]. PDT in cNFs studies use a photosensitizer, 5-amino-levulinic acid, plus illumination with red light. PDT was evaluated in phase I study (NCT01682811) and a phase II study (NCT02728388) is active in a single US institution.
\nOne of the early efforts for treatment of cNFs and their associated symptoms used ketotifen [78]. Ketotifen is a histamine 1 receptor blocker which facilitates mast cell stabilization and; its use in NF1 is based on the finding of abundant mast cells in neurofibromas. Improvement in pain and pruritis has been reported, but objective tumor shrinkage has not been documented. Three drugs have been tested in cNFs using local therapeutic approaches; the first was ranibizumab, a vascular endothelial growth factor monoclonal antibody, which was injected intralesionally (NCT00657202). The overall effect of the treatment was minimal and the variability in the tumor volume assessment (measured by a caliper) limited the interpretation of the data. The second agent was topical imiquimod, which showed minimal efficacy in tumor shrinkage compared to baseline volume (measured by a caliper) (NCT00865644). The third agent was topical rapamycin, an mTOR inhibitor, which was initially tested in Tuberous Sclerosis Complex (TSC)-associated angiofibromas (NCT01031901) [79]. The study enrolled 52 patients with TSC and NF1 and data are expected.
\nDue to the relatively benign histology of cNFs and the likely need for long term therapy, there are special considerations pertaining to cNF drug development [80]. The safety profile of tested drugs is a major concern to physicians, regulators, patients and their caregiver. Also, the route of administration and cost are important considerations, as individuals with cNF are more likely to require treatment (either medication or intervention) for an extended period of time. The variant phenotype among affected persons, demographic differences, and the goal of treatment are important factor determining the type and timing of treatment.
\nThe above-mentioned considerations, especially the safety profile, make oral systemic therapies preferable for individuals with a heavy tumor burden. Everolimus, an oral mTOR inhibitor, was evaluated in a phase II study of disfiguring cNF associated with NF1 (NCT02334902). The study enrolled 22 patients and used photographic measurement of selected lesion to assess surface volume. While 5/22 patients withdrew due to adverse events, a very modest effect was reported in <20% of the participants [81]. Due to the promising results of using targeted therapied against MEK, selumetinib is being studied in NF1-associated cNFs (NCT02839720). The study is a phase II, multi-institutional, open label study with the primary outcome measure being the change in the size of cNFs assessed by digital photography and caliper measurements.
\nThe Clinical Trial Design and Development REiNS subgroup, involving experts from different settings, has presented the priorities and challenges associated with conducting clinical trials targeting cNF in NF1 [82]. The subgroup members reviewed key topics like natural history, assessment methods, functional endpoints, safety, and development strategies. One of the most important topics, which pose a major challenge in cNF clinical trials, is the measurement of outcomes. Methods of measurement that have been used include calipers, digital and volume photography, ultrasound, and MRI. The subgroup members support considering clinically meaningful measures of effectiveness in interpreting changes in tumor size or number. Tumor size reduction that correlates with improved pain control or discomfort is more clinically meaningful than the crude number or size of the tumors. New approaches, such as high-frequency ultrasound or optical coherence tomography, may be able to address some of the limitations of the conventional methods like MRI, photography or caliper measurement. These new approaches need to be validated through additional studies. The subgroup members recommend several key factors when designing clinical trials on cNF, including timing to initiate intervention, eligibility criteria to ensure diversity, mechanism of the intervention, route of administration, safety monitoring, and regulatory considerations.
\nNF2 is an autosomal dominant disorder that affects the central and peripheral nervous systems. NF2 has an estimated incidence of 1 in 25,000–33,000 births, making it far less common than NF1 [83]. Vestibular schwannomas (VS) are considered the hallmark of NF2, and bilateral VS fulfill the clinical diagnosis of definite NF2 [84]. The average age at diagnosis in NF2-associated VS is about 27 years [85]; diagnosis in childhood predicts a severe phenotype and unfavorable prognosis [86]. Though VS are slowly progressive tumors, they can cause significant neurologic disability, including hearing loss and eventually deafness, balance problems, and brain stem compression [87]. The other common tumor associated with NF2 is meningioma, which is the most common intracranial tumor worldwide. Up to half of individuals with NF2 develop meningiomas [88], and despite benign histology, they may lead to a shortened life expectancy [89].
\nThe loss of the tumor suppressor protein merlin in NF2 leads to activation of prosurvival pathways via RAS modulation. Hence, NF2 shares many of the same targets identified in NF1. Merlin is absent not only in NF2-associated VS, but also in sporadic VS [90]. This observation is important as it may point to a shared therapeutic pathway between NF2-associated VS and sporadic VS [91].
\nThough surgery remains the mainstay of treatment in sporadic VS, or stereotactic radiosurgery (SRS) for tumors <3 cm [92], these approaches have proved to be less efficacious in NF2-associated VS, with high rate of complications, including facial nerve weakness, hearing loss, and headache [93, 94]. Moreover, there are growing concerns about utilizing radiation therapy in NF2 due to risk of late malignant transformation [95]. Some of the challenges that face NF2 clinical trials are the substantial variability in disease severity across individuals with NF2, the lack of clear association between the rate of VS growth and the rate of hearing loss, and the variable growth rates between the right and the left VS in same patient [96]. A prospective study that highlighted the lack of correlation between VS size or growth rate and rate of hearing loss was published in 2014 and included 120 individuals with NF2-associated VS (total of 200 VS) [97]. The investigators used word recognition score (WRS) as an objective measurement for hearing decline and defined radiographic tumor growth as ≥20% increase in tumor volume compared with baseline. The study showed that the mean rate of hearing decline from diagnosis was 5% at 1 year and 16% at 3 years, while the rate of VS tumor graphic progression was 31% at 1 year and 79% at 3 years. The median time to progression (14 months) was significantly shorter than the median time to hearing decline (62 months) [93]. This study, along with prior reports, elucidated the natural history of individuals with NF2 to help to determine the most appropriate timing for intervention [81, 83, 98].
\nClinical trials for NF2 have been focused on vestibular schwannomas, since loss of hearing is often the most pressing concern in individuals with NF2. A group of 36 international researchers, physicians, representatives from the pharmaceutical industry, and patient advocates held a workshop to provide consensus recommendations to accelerate clinical trials progress in NF2 [99]. The group provided recommendations on participant selection, clinically meaningful and feasible endpoints, the clinical trials models most appropriate for NF2, and candidate therapeutic agents for NF2.
\nDifferent cellular pathways have been targeted in clinical trials for NF2-associated tumors (Table 4), with mixed responses. One of the most promising agents used in NF2 is bevacizumab, which was initially given on a compassionate use basis for adults with NF2-associated VS with severe disability [100, 101]. In these reports, 6 of 10 participants had ≥20% reduction in tumor volume and significantly improved hearing. The promising results led to designing two phase II clinical trials using bevacizumab in persons with NF2 who suffered from progressive hearing loss. A preliminary report from one of these 2 trials that enrolled 22 participants showed that the overall hearing and radiographic response rates were 41 and 23% respectively, though pediatric participants appeared to benefit less compared to adults (NCT01767792) [102]. Bevacizumab was used in a dose of 10 mg/kg every 2 weeks for 6 months, followed by 5 mg/kg every 3 weeks for 18 months; this regimen was well tolerated.
\nDrug | \nTarget | \nPhase | \nAge (years) | \nEndpoints | \nStatus | \n
---|---|---|---|---|---|
Everolimus [104] NCT01419639 | \nmTOR | \nII | \n≥3 | \nVS: 15% volume reductions | \nNo RR | \n
Everolimus [105] NCT01490476 | \nmTOR | \nII | \n≥15 | \nVS: volume reduction | \nNo RR | \n
Everolimus NCT01345136 | \nmTOR | \nII | \n16–65 | \nVS: volume reduction | \nActive, not recruiting | \n
Everolimus NCT01880749 | \nmTOR | \nEarly phase I | \n≥18 | \nVS and MEN: tumor PK, molecular analysis | \nActive, not recruiting | \n
Lapatinib [106] NCT00973739 | \nEGFR/ErBb2 | \nII | \n4–80 | \nVS: 15% volume reduction | \n23.5% RR | \n
Lapatinib NCT00863122 | \nEGFR/ErBb2 | \nEarly phase I | \n≥18 | \nVS: tumor PK, molecular analysis | \nCompleted, pending results | \n
Axitinib NCT02129647 | \nVEGF, c-kit, PDGFR | \nII | \n≥18 | \nVS: 20% volume reduction | \nActive, not recruiting | \n
Nilotinib NCT01201538 | \nPDGF, c-kit | \nII | \n≥18 | \nVS: 20% volume reduction | \nTerminated | \n
PTC 299 NCT00911248 | \nVEGF | \nII | \n≥18 | \nVS: Tumor volume or WRS | \nTerminated | \n
Endostatin NCT02104323 | \nAnti-angiogenic | \nII | \n16–30 | \nTumor volume | \nCompleted, pending results | \n
AR-42 NCT02104323 | \nHDAC | \nEarly phase I | \n≥18 | \nVS and MEN: tumor PK, molecular analysis | \nActive, not recruiting | \n
Bevacizumab [107] NCT01207687 | \nVEGF | \nII | \n≥12 | \nVS: hearing response measured by WRS | \nCompleted, hearing response 36% | \n
Bevacizumab[102] \n NCT01767792 | \nVEGF | \nII | \n≥12 | \nVS: hearing response measured by WRS | \nActive, not recruiting, hearing response 41%, RR 23% | \n
Acetylsalicylic acid NCT03079999 | \nAntiplatelet, anti-inflammatory | \nII, randomized, placebo-control | \n≥12 | \nVS: PFS | \nActive | \n
Vistusertib (AZD2014) NCT02831257 | \nmTORC1, mTORC2 | \nII | \n≥18 | \nMEN: RR using volumetric MRI | \nActive, not recruiting | \n
Selumetinib NCT03095248 | \nMEK | \nII | \n3–45 | \nVS, MEN, and ependymoma: hearing response measured by WRS, RR | \nActive | \n
Clinical trials in Neurofibromatosis type 2-associated vestibular schwannomas and meningiomas.
\n
NF2 shares many of the same targets identified in NF1; hence, some of the therapeutic agents tested in NF1 are being tested in NF2, including everolimus (NCT01345136), sorafenib, and selumetinib (NCT03095248). The dual mTROC1 and mTORC2 inhibitor, vistusertib (AZD2014), is used in a phase II study for NF2 patients with progressive or symptomatic meningiomas (NCT02831257). While the primary outcome for this study is the radiographic response rate for meningioma using volumetric MRI scans, the secondary outcomes include response assessment for VS and non-target meningioma using volumetric MRI. The NFCTC has approved using crizotinib, a MET and ALK inhibitor, in a phase II study for children and adults with NF2-associated progressive VS. There are promising preclinical studies identifying crizotinib as a potent inhibitor of NF2-null Schwann cell proliferation in vitro and tumor growth in vivo [103]. The goal for these clinical trials is to assess the hearing response rate as a clinically meaningful endpoint and to assess tolerability and long term effects of the tested agents, as well as identify biomarkers that can predict outcomes.
\nSchwannomatosis (SWN), as the name implies, is characterized by the development of multiple peripheral nerve schwannomas, without concomitant involvement of the vestibular nerve, and, less commonly, meningiomas [108, 109, 110]. Since the schwannoma is the most common tumor in NF2 and SWN, there can be overlap between the two syndromes. SWN is a distinct entity with different clinical phenotype and genetic etiology from NF2. Germline mutations in SMARCB1 and LZTR1, both tumor suppressor genes, have been identified in SWN [111, 112, 113]. Unlike NF1 and NF2, pain is the most common symptom reported by individuals affected with SWN, with 68% reporting chronic pain in SWN in a retrospective study [114].
\nSurgical resection is considered the treatment of choice for symptomatic schwannomas for pain relief, though local recurrence is not uncommon. Patients usually require multiple surgical resections due to pain, focal neurologic deficits, or myelopathy [113]. Radiotherapy is reserved for those with life-threatening or enlarging tumors, and in rare occasions, malignant schwannomas. There are no available safety studies with respect to radiotherapy-induced malignant transformation in SWN, though theoretically it is possible given the available data from NF1, and NF2 studies.
\nUp to date, no clinical trials have been conducted in the setting of SWN and no known effective therapies exist. A case report was published using bevacizumab in one individual with SWN-associated refractory pain with a remarkable response in pain control [115].
\nMost early clinical trials for patients with neurofibromatoses used designs and endpoints similar to oncology trials. However, there are major differences in natural history, disease manifestations, and overall prognosis between patients with NF and those with cancers. Hence, there was an unmet need to establish standardized endpoints in NF clinical trials that will allow precise data interpretation and the ability to assess efficacy across different studies. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established in 2011 at the Children’s Tumor Foundation (CTF) meeting to achieve consensus about the design for future clinical trials with major emphasis on endpoints. The collaboration included 7 working groups; disease biomarkers; whole-body MRI; functional, visual, patient-reported, and neurocognitive outcome; and imaging for tumor response. Later, two more working groups were added; cutaneous neurofibromas, and patient representation [116].
\nThe REiNS Collaboration published the initial recommendations for clinical trials endpoint in 2013 [117]. MRI with volumetric analysis was recommended as the standard imaging metric for pNF and VS in NF1 and NF2 clinical trials [118]. A 20% volume change was chosen to indicate an increase or decrease in the tumor size. MRI analysis requires central review to ensure consistent results. This is a time and resource intensive tool; thus, the development of methods that can be incorporated into routine clinical practice and can be performed more easily is warranted. Whole-body MRI imaging (WB-MRI) may serve as an endpoint in clinical trials that target multiple tumors. The working group concluded that while WB-MRI is feasible for identifying tumors using both 1.5 T and 3.0 T systems, choosing a standardized image acquisition and analysis methods is crucial for applying WB-MRIs as a tool for assessing tumors in NF [119]. For clinical trials targeting NF2-associated VS, the REiNS functional outcomes group endorsed the use of maximum word recognition score as the primary endpoint for hearing. The group recommended using the measurement of improvement in lip excursion (SMILE) system for studies of facial function [120]. For clinical trials targeting NF-associated OPG, the visual outcomes working group recommended the use of visual acuity as the primary endpoint, as opposed to measurement of tumor size [121]. The group also recommended assessing the optic disc for pallor to allow accurate interpretation of the visual acuity. Regarding the neurocognitive outcomes, the working group concluded that The Digit Span (DS) subtest from the Wechsler scales is the most appropriate performance-based outcome measure, as it provides the best psychometrics, feasibility, and utility across a wide age range, and is extensively used in previous research [122]. For similar reasons, the Conners scale achieved the highest ratings of behavioral questionnaires and is considered the most appropriate observe-rated outcome measure.
\nIt is uncommon for pNF to cause airway compromise or pulmonary dysfunction, yet airway pNFs are clinically important. The REiNS functional outcomes group developed consensus recommendations for sleep and pulmonary outcome endpoints in airway pNFs [123]. The group endorsed using the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) of forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV 0.75) as the primary pulmonary endpoint. The group also identified secondary sleep and pulmonary outcomes. Measures of sleep and pulmonary function may be more clinically meaningful as endpoints than changes in tumor size in clinical trials targeting airway pNFs. Regarding patient-reported outcomes (PRO) of pain and physical function in NF clinical trials, the REiNS working group recommended the numeric rating scale-11 (NRS-11) to assess pain intensity for age 8 years and older [124]. To assess pain interference, the group recommended the Pain Interference Index in pediatric studies and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale in adult studies. PROMIS Physical Function Scale was deemed the most appropriate for NF trials to assess the physical functioning domain. The REiNS disease biomarkers working group reported consensus recommendations to provide clinicians and researches with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for neurofibromatoses [125]. The group described the existing biomarkers in NF and report consensus recommendations for standard operation procedures to standardize sample collection and methodology protocols to promote comparison between studies.
\nDrug discovery is a very costly and lengthy process, which may take up to 10 years from first-in-human dosing to approval [126]. This process is usually preceded by years of extensive preclinical research to identify suitable targets for clinical development. The REiNS International Collaboration continues to work on developing consensus endpoints in NF clinical trials and to promote early engagement with FDA and other industry partners to accelerate the drug development and approval for NF-associated tumors.
\nThe field of NF therapeutics is at inflection point. Several clinical trials have been conducted targeting various manifestations of NF and more studies are ongoing. The alignment of endpoints along with utilizing validated clinical outcomes measures represents a priority for therapeutic development for NF. Fortunately, there is a growing interest in NF, which is drawing the attention of pharmaceutical and biotechnology companies to grow the pipeline for NF targeted therapy. These efforts are combined with several ongoing laboratory and preclinical studies that provide unique opportunities to study the complex biology and natural history of NF-associated tumor. The US breakthrough therapy designation that was granted to Selumetinib in NF1 endorses the critical need for partnership among the major consortia and funders to accelerate the therapeutics development efforts in the NF field.
\nMina Lobbous and Bruce Korf report no disclosures relative to the manuscript.
\nPreparing for life on another planet or a planetary object requires an enormous effort from scientists and engineers [1]. The first steps toward extraterrestrial life are the crewed missions to the Moon, aiming to build the basis for the future long-term presence of humans beyond Earth. A remarkable amount of research and feasibility studies are being done by the European Space Agency (ESA) in Europe [2] and the National Aeronautics and Space Administration (NASA) in the USA [3, 4] on how to construct a “new home in space,” in a manner to eliminate the need for supply materials from Earth.
In this context, the use of space resources is one of the key directions in preparation for future human missions to the Moon. The so-called
In space and on the lunar surface, there are many factors potentially leading to damage in materials, such as exposure to vacuum, extreme thermal conditions, impact collisions with micrometeoroids, and radiation [14]. Among these, radiation is considered particularly harmful for different functional components and instruments of spacecraft and lunar surface missions. Radiation can induce structural defects that evolve from nanoscale to micro- and macro-damage, causing degradation of the mechanical, thermal, and electrical properties of materials or can even lead to direct failure in electronic signals before interacting with the very structural composition of the material. Therefore, improving the radiation resistance of materials to be used in space missions and searching for more radiation-resistant materials is of utmost importance. The research effort is directed toward finding composite materials that can better withstand radiation and other challenges faced by mission components in space and on space bodies and exhibit self-healing capabilities [15].
In this chapter, we first introduce some relevant materials for two of the most critical applications on the Moon, i.e., habitat construction and energy production. Then, we provide an overview of the radiation environment on the lunar surface and different radiation effects that can be induced in materials by such an environment. We then discuss the ways of combining traditional methods commonly used to study radiation effects with recent advanced approaches in materials modeling and provide examples of radiation-effects modeling studies on different materials. Additionally, we discuss the possibilities of using novel promising materials with exceptional properties relevant for space exploration, with an emphasis on their radiation resistance.
NASA has identified the most important components of the lunar mission as (i) design and construction of habitats and (ii) resource and power management [16]. In particular, the emphasis is on lightweight materials that will be critical for mass reduction and thus increase the science return of the mission. Both components mentioned above will strongly rely on ISRU, i.e.,
Constructing a habitat on the Moon can be done in two ways, by delivering materials from Earth and by using local resources. Although the latter option is more sustainable, the first one cannot be completely avoided. An important consideration that needs to be made when choosing materials is the type of habitat. NASA considers several types of habitat for different use, namely rigid (metals, alloys, and concrete) [18], inflatable (e.g., inflatable concrete [19]), or hybrid structures, as well as underground construction [20]. Depending on the type of habitat, different materials will be used [16, 21]. For example, unprocessed lunar regolith may be used for radiation shielding of habitat (e.g., lunar regolith geopolymer) [22, 23, 24, 25], as well as for construction when converted into concrete [26, 27], 3D-printed [28, 29, 30], or processed into other construction material (e.g., bricks and glass) [16, 21]. For materials delivered from Earth, it is crucial to ensure their low weight, as well as resistance to very high and very low temperatures (which change from 127°C in the daytime to −173°C at night on the Moon surface) and radiation, durability, reusability, and structural reliability [16].
Metals and alloys are essential structural materials for construction given their compressive strength and good tensile properties and for other applications, such as energy carrier/storage (wires) [31] or equipment (e.g., excavation tools, molds, and rovers) [32]. Al, Ca, Fe, Ti, and Mg are the most abundant metals in the lunar regolith, which also contains smaller amounts of Ni, Cr, Mn, Zr, and V [5, 20]. These metals—together with Si, also abundant on the Moon—can be used to produce alloys. However, only Fe can be easily separated from regolith (using magnets). Other metals are present in the form of oxides and thus have to be obtained by manufacturing. Metal and alloy manufacturing will be extremely important for the exploration of the Moon as they represent an essential part of the construction and are critical ingredients for most technologies.
One of the crucial steps toward the Moon exploration and settlement is a reliable energy technology for electricity generation and power storage [33, 34] that would withstand the temperature gradients, high levels of radiation, and impact. The primary energy sources considered for future crewed lunar missions are solar power [35, 36], nuclear power [37], and fuel cells [38, 39]. Other ways may include the production of electricity from the excess heat from the sunlight collected by an “evergreen” inflatable dome [40]. In this chapter, we focus on solar cells, a safe and reliable source of electricity in space.
In the past decades, solar cells for space applications have evolved from single-crystalline Si-based cells to multi-junction (MJ) ones based on GaInP, GaAs, and Ge [41, 42, 43]. A promising class of materials for next-generation lightweight and high-power-conversion efficiency [44] solar cells are hybrid organic-inorganic perovskites (HOIPs) [45, 46, 47], which are considered as potential candidates for use on future lunar bases [34].
HOIPs possess a unique combination of properties, such as enhanced charge carrier mobility [48, 49, 50, 51], diffusion length, and lifetime [48, 52, 53], high optical absorption [54, 55], and low production costs [56], representing a paradigm shift in solar cell technology [57] on Earth [58] and for space applications [59, 60, 61, 62]. Given their flexibility [63], low weight, small dimensions (0.5 μm as compared to 200 μm for Si solar cells), the possibility of
The radiation environment on the Moon is constituted, apart from solar electromagnetic radiation, by three radiation “populations”—the constant solar wind, the intense but sporadic Solar Energetic Particles (SEPs), and the constant background of Galactic Cosmic Rays (GCRs). A summary of the radiation environment on the lunar surface is given in Table 1.
Source | Particles | Energy, MeV/nuc | Flux, nuc/cm2/s |
---|---|---|---|
Solar Wind | Protons & electrons | ||
SEPs | Protons | 0 – | |
GCRs | Protons | 2–4 |
The solar wind is a constant flux of plasma from the upper atmosphere of the Sun. It consists mainly of ionized hydrogen (protons and electrons), a small percentage of
SEPs originate from solar transient events, such as coronal mass ejections or flares, and consist in a sudden intense flux of high-energy protons and electrons (and a small amount of
GCRs constitute the slowly varying, low-intensity (few particles/cm2(m2) per second), highly-energetic radiation background in space. They are mainly associated with supernova explosions in the galaxy, but extra-galactic contributions also exist. GCRs are constituted by
The annual exposure caused by GCRs on the lunar surface is
The effects of radiation on materials and devices can be cumulative (long term) and noncumulative (caused even by a single particle). The so-called Single Event Effects (SEEs) can occur when an ionizing particle passing through an electronic device carries a charge large enough to affect the device’s performance. SEEs in aerospace technology can lead to errors, corrupt the data, create noise, reset the device, or even cause fatal part failure [92, 93, 94, 95]. Cumulative radiation damage, on the other hand, occurs through continuous radiation exposure or exposure to intense flux due to SEPs events and can lead to the degradation of optical components and solar cells, eventually causing permanent damage. The total ionizing dose experienced by an electronic device can cause variations in threshold voltage or leakage current.
Cumulative non-ionizing damage in materials due to protons, electrons, and neutrons (originating from the interaction of energetic protons and electrons with the lunar surface) leads to defect formation (displacement damage) [94]. The types and sources of radiation, as well as the effects it can cause in materials, are summarized in Table 2.
Particle type | Energy | Sources | Radiation effects |
---|---|---|---|
Electrons | SEPs | Ionization radiation damage | |
Protons | SEPs | Surface damage to materials | |
Protons | SEPs accelerated in shocks | Displacement damage in solar cells | |
Protons | SEPs and GCRs | Ionization and displacement damage, background counting in sensors | |
Protons | SEPs and GCRs | Single event effects | |
Ions | SEPs and GCRs | Single event effects |
Sources and types of radiation and the effects it causes in materials and devices [96].
Cumulative radiation damage is a multiscale process in terms of time and length. A schematic representation of the so-called displacement damage cascade is shown in Figure 1. At first, an energetic external particle approaches (Figure 1(1)) and enters the target (Figure 1(2)). As the particle passes through the material, it first transfers its kinetic energy to electronic degrees of freedom of the target (electronic stopping) (Figure 1(3)). Electronic excitations happen at a very short time scale (
Schematic representation of different stages of the damage cascade in a crystalline material under irradiation.
Atomic displacements described above lead to defect clustering and eventual amorphization in crystalline materials. Consequently, mechanical, physical, and other properties of the irradiated material can be significantly altered. The scale of the changes depends on the energy of incoming particles and the actual number and spatial distribution of survived defects after eventual self-healing [98].
The radiation-induced effects after atomic displacements strongly depend on the type of material. For metals and metallic alloys, the main effect of radiation is the generation of dislocation loops and point defects which cause significant radiation-induced strengthening or hardening. As a result, the ductility and fracture toughness of the metals (alloys) can be reduced, leading to brittle behavior [99]. Ductile-to-brittle transition is especially pronounced at low temperatures at which the defect mobility, and consequently the annealing of defects, is reduced.
As to other materials, such as semiconductors in solar cells, cumulative exposure to space radiation or high SEPs fluxes can strongly affect the performance of MJ solar cells [100]. Moreover, the impacting radiation can reduce the transmittance of the protective SiO2 cover-glass on top of MJ cells by inducing color centers in the oxide material. The color centers appear when electrons excited by radiation become trapped by impurities in the oxide to form stable defect complexes. On the other hand, the radiation which is not blocked by the cover-glass causes damage in the functional layers of MJ solar cells by displacing atoms. Different energy levels can be created within the bandgap as a consequence of such structural defects. Such electronic defect levels affect the electrical performance of MJ solar cells acting as traps, recombination centers, or carrier removal sites which reduce free carrier concentration [100, 101].
Below, we will present different methods used to describe radiation-induced effects in materials focusing on the description of cumulative effects related to atomic displacements.
High-energy charged particles undergo a daunting number of interactions with target materials. Such interactions include:
electronic collisions leading to ionization and excitation;
multiple Coulomb scattering at small angles (elastic deflection without energy loss, or minimal inelastic loss);
inelastic nuclear reactions, that is, high-energy reactions in which a nucleus in the target struck by an incident particle (with energy
elastic nuclear interactions (
The most commonly used approach to study radiation-induced effects in materials is the Monte Carlo (MC) particle transport method [102, 103]. In MC particle transport, the interactions of individual primary ions and their secondaries are sampled to build a history of charged particle passage and energy deposition in the target [104], with a large enough statistical sample of trajectories. The energy- and angle-dependent cross sections for different interactions are provided by theoretical models of the elementary interactions and/or experimental data, depending on the energy window. Codes, such as Geant4 [105], MCNP6 [106, 107, 108], FLUKA [109], PHITS [110], and HETC-HEDS [111], have been successfully applied to study the radiation at a hemispherical dome made of lunar regolith used to simulate a lunar habitat [112, 113] and the radiation environment around the Moon [114, 115].
Several relevant radiation-induced effects in materials are due to particles with an energy of a few MeV to a few tenths of MeV, as can be seen in Table 2. In this regime, below hadronic interactions causing fragmentation/spallation, atomic displacements are induced in the target by elastic nuclear interactions. Two concepts describe the slowing down of the impacting particles (and the induced secondaries), (i) the
A displacement cascade in MC particle transport simulations is generally modeled within the Binary Collision Approximation (BCA) [119] which assumes a series of independent two-body collisions. Between collisions, particles travel in a straight line. The BCA is valid when (i) the projectile energy is higher than 1 keV per nucleon, which, for PKAs, could be relevant energy, and (ii) the target material has low density, in which case the collisions between the incoming particle and the target atoms occur rarely. BCA allows reducing the computational complexity of the ion-matter interactions compared to a full many-body simulation (e.g., molecular dynamics, discussed in Section 5) and allows for reaching large dimensions with reduced computational needs. However, this method is valid for linear collisions only and describes only primary damage, that is, it does not account for the dynamic evolution of induced defects at later times (Figure 2).
Time and length scales and corresponding methods can be applied to study different stages of radiation damage.
One of the most popular tools in which the BCA is implemented is the Stopping and Range of Ions in Matter (SRIM) code [120]. Besides containing semiempirical data for the electronic stopping power of a variety of targets, SRIM can be applied to model the linear cascades and estimate the number of defects in any material and any ion energy up to 1 GeV. Nuclear stopping in very low-energy intervals uses the so-called ZBL (Ziegler-Biersack-Littmark) universal potential that combines classical Coulomb potential with a semiempirical screening function [120]. The electronic and nuclear degrees of freedom are completely separated in SRIM as well as in other MC particle transport tools used by the particle physics community and the space radiation effects community. Finally, it is important to remark that materials are static in MC particle transport methods—there is no dynamics induced in them by the impact of primaries and the generation and passage of secondaries. Thus, more accurate methods are needed to get access to the processes missing in MC particle transport calculations. Such methods are described in the next section.
There is a large variety of methods used in condensed matter physics and materials science to study radiation effects in materials, each of them describing a particular aspect of the damage process. Figure 2 shows a schematic representation of the different time and length scales with the corresponding computational methods that can be applied to study different stages of radiation damage [97, 121, 122]. The very first stage, at the smallest time-length scale, is the electronic stopping regime. For decades, the semiempirical SRIM code discussed in the previous section has been the most widely used tool to calculate electronic stopping power. Nowadays, the electronic stopping power (and the induced electronic excitations in the target) can be described by
For a complete and accurate description of every aspect of radiation damage, as well as the interplay between them, one has to adopt a combined approach. In recent years, researchers have realized the importance of a multiscale approach to studying radiation damage, as follows from many publications and reviews [121, 122, 130, 131, 132, 133, 134]. Each of the methods presented in Figure 2, as well the ways of combining them, will be discussed below in the order of increasing complexity. The main focus will be on classical MD, AIMD, and TDDFT, which are fundamental for the description of primary radiation damage at the atomic scale.
The most widely used approach in materials science to study the interaction of ions with matter (collision cascades) is MD [135]. MD offers a picture of the ion–ion interaction beyond the linear cascade of the pure BCA by including many-body effects. In MD, atoms are treated as classical particles, and their motion is described by Newtonian dynamics. No electronic effects are thus included.
Cascade simulations need large samples consisting of up to a million atoms (depending on the PKA’s energy), which prohibits using parameter-free methods (such as DFT, see Section 5.2) to compute the interatomic forces. Instead, in MD, the forces on atoms are calculated from empirical or semiempirical interatomic potentials (also called force fields) [136, 137, 138]. MD with empirical potentials proved to work well for large systems and long time scales [139].
In an MD cascade simulation, the system is usually modeled using periodic boundary conditions, that is, by replicating a small unit cell in all directions. Typically, prior to the cascade simulation itself, a regular MD simulation is done to thermally equilibrate the target system at the desired initial temperature. Then, with the equilibrated configuration, the cascade simulation is initiated by changing the velocity of one of the atoms (the PKA), giving it the desired amount of kinetic energy in the intended direction. The system is then evolved in time as in regular MD, that is, by integrating Newton’s equations along with a series of time-steps, which involves computing the atomic forces, velocities, and positions at each time-step (see Refs. [140, 141] for classical texts on MD). At the end of the cascade simulation, the number of defects is obtained by evaluating the final geometry of the system. Usually, cascade simulations are repeated several times, choosing a different PKA and/or a different direction of the PKA’s movement to obtain a statistical average of the number of final defects.
MD has been successfully applied to simulate radiation cascades in a variety of materials [139], from simple metals [142, 143] and compounds [144, 145, 146] to complex nanostructures [147], 2D materials [148], and novel multicomponent alloys [149, 150]. MD simulations can afford to access the processes taking place on a relatively long time scale up to ps or even ns which is enough to describe the damage cascade until the thermal spike of the collision has dissipated. Most of the MD codes, however, describe only elastic collisions between atoms and disregard the energy loss mechanisms such as electronic excitation and ionization. The possibility of including electronic excitations is discussed in Section 5.3.
After the primary damage has been formed, defects may continue diffusing, thus annihilating or forming defect clusters. Such processes occur on a much longer time scale, reaching at least seconds, not accessible via regular MD. The problem of simulating a process not accessible in a feasible amount of computational time has motivated the development of several enhanced sampling techniques [151], which in the case of MD simulations of materials have allowed to observe otherwise challenging processes, such as phase transitions.
KMC [127] simulations are commonly used to access long-time effects of radiation in materials [152, 153, 154, 155]. KMC is designed to model the time evolution of an atomic system. However, instead of solving the equations of motion, as it is done in MD, the KMC method is based on the assumption that the long-time dynamics of a system consists of diffusive jumps from state to state. Each of the states is treated independently, which makes KMC a very efficient method. The dynamics of the system, that is, the probability of transition from one state to another does not depend on the history of the system. The probability of a state-to-state transition is assigned randomly and the most probable transition is statistically chosen. This allows avoiding the complications related to the choice of interatomic potentials, thus overcoming the time limitations of MD simulations (usually
To further extend the problem into the macro-domain, the DD [128] and FEM [129, 156] methods, based on dividing a geometrical space on a number of finite (non-overlapping) segments, are usually applied. FEM has been used to study the response of a macro-object to external stress in engineering and has also been applied to study the behavior of solids under irradiation by extrapolating the known displacements and evaluating the geometry of a 3D object. DD method allows for calculating the motion of dislocations as well as evaluating the plastic deformation in the material induced by the collective motion of dislocations.
AIMD is one of the most important tools in quantum physics and chemistry [157]. In a typical AIMD simulation, it is assumed that the system consists of
Practical DFT calculations are based on the Kohn-Sham (KS) formalism [126], which replaces the complex problem of interacting electrons in the standard Schrödinger equation by a problem of non-interacting electrons moving in an effective potential
where
AIMD is used to simulate any physicochemical process where the electronic structure of the system changes significantly or when a detailed description of the structure is needed. A typical example would be the simulation of chemical reactions, where chemical bonds are formed or broken, which cannot be described via classical force fields.
Although the adiabatic BO approximation is the usual approximation in the methods described above, its applicability is only justified in near-equilibrium situations. However, under ion impact, the electronic subsystem is rapidly driven out of equilibrium.
A realistic description of the dynamics of the electrons in the target during the passage of fast ions can be obtained in the framework of TDDFT which gives access to the electron dynamics out of the electronic ground state. In particular, real-time TDDFT [160] provides a non-perturbative description of the electronic excitations upon an external perturbation and can be combined with the Ehrenfest MD scheme [161], which allows for coupling between electron and ion motion, contrary to the BO picture.
TDDFT consists in solving the time-dependent KS equations [123]:
where
where
The solution of the time-dependent KS equations in real time can be obtained by applying the so-called time-evolution operator, evolving the KS states in time [123]. The time-step of this propagation must be of the order of attoseconds to describe the fast dynamics of the electrons, in contrast to what occurs in AIMD and MD where the time-step is of the order of femtoseconds. The time-dependent electron density is calculated at each step, from which the total energy of the system is obtained. Knowing the total energy as a function of time, the electronic stopping power can be calculated as
Many examples of accurate first-principles calculations of the electronic stopping power are available in the literature [117, 118, 163, 164, 165, 166, 167, 168]. Recent studies have demonstrated that electronic excitations (induced by both the primary impacting ion and especially by PKAs and further displaced atoms) affect the cascade evolution [118, 169, 170, 171] and thus, they need to be accounted for. The electronic stopping effects can be included in MD cascade simulations through the so-called two-temperature (2T) model [118, 172]. In 2 T-MD, the electrons are included as a thermal bath. Each particle is subject to a friction force representing the electronic stopping and a stochastic force representing the coupling between the vibrational degrees of freedom of the lattice and the electrons. This model considers constant electronic density in the entire system and thus, the electronic stopping power is independent of the crystal direction. Recent studies have extended the 2T model by coupling the electronic and nuclear effects via many-body forces that act in a correlated way. This allowed for the construction of a unified model for ion-electron interactions [170, 171, 173, 174] with a complex energy-exchange process between the ionic and electronic subsystems [174].
The previous section provided an overview of computational methods that can be applied to study radiation damage in materials and discussed the advantages of combining such methods into a multiscale approach. This section mainly focuses on the effects of radiation on materials of practical use on the Moon, including several novel and promising materials. We overview the existing radiation damage studies for these novel materials, emphasizing multiscale modeling when available.
Generally, degradation of solar cells is modeled via the non-ionizing energy loss (NIEL) approach, the NIEL being the portion of energy loss per unit path length of the projectile converted into displacement damage. According to Akkerman et al. [175] (the definition used in most simulation tools), the NIEL is defined as:
where
On the basis of a large set of experimental observations, it is assumed that the degradation of a semiconductor device under irradiation can be linearly correlated with the NIEL [176]. In practice, this means that the number of defects should give a measure of the damage irrespective of their distribution, whether clustered in high density in small regions (as in the case of neutron damage) or homogeneously scattered over a relatively wide volume (as in the case of the low-energy proton or
Generally, the NIEL is calculated via MC particle transport codes, assuming amorphous target materials, a static
NIEL for protons and electrons in GaAs for different values of the threshold displacement energy
Another example of possible improvement in the NIEL model is a more precise calculation of the number of radiation-induced defects and of the “quality” of radiation-induced damage (which type of defects are induced). It has been observed that point-like and clustered defects contribute differently to some degradation parameters [191]. Recent MD studies [192, 193, 194] and experimental works [181, 195, 196] have proposed an effective or
On a parallel research stream, multiscale studies in a number of materials combining MD simulations of collision cascades with the electronic stopping from TDDFT offer a more accurate description of both the number and the nature of defects created under realistic conditions. The electronic degrees of freedom and their coupling to the phonons of the target affect the cascade evolution and morphology [170, 171, 173, 174]. This is of relevance for the NIEL which includes a part of energy dissipated to phonons. This fraction depends on the energy of the impinging particle but also on the properties of the material. Some studies have shown that the direction-dependence of the electronic stopping can influence the collision cascades [118]. Other studies have demonstrated that the formation of thermal spikes and therefore of amorphous pockets is sensitive to the electronic specific heat [199] and others that the choice of the model employed for the inclusion of the electronic effects and in particular the overestimation (or underestimation) of electron-phonon coupling can have a significant influence on the number of defects created [171].
As discussed in Section 2, HOIPs have a unique combination of properties particularly interesting for lunar exploration. The general chemical formula for perovskites is ABX3, where A and B are two metal ions with different ionic radii and X is an anion that is six coordinated to the B-site [200]. HOIPs, in particular, comprise a negatively charged lead-halide inorganic skeleton where B is a metal cation (Sn2+ or Pb2+), X is a halide anion (I−, Br−, and/or Cl−) and A is a monovalent positively charged organic cation, such as methylammonium (MA+ = CH3NH3X+, where X = I, Br, Cl) or formamidinium (
Structure of a HOIP: methylammonium cation (
Despite many advantages, several external factors, such as air, moisture [202], UV light [47, 203], heat, light soaking [204], and partially also radiation [205, 206], induce considerable structural instabilities in HOIPs. An intrinsic instability is also present, caused by a relatively weak cohesion between the organic cation and the inorganic octahedra and predominantly by the low-energy barriers for the migration of halide anions and organic cations, with halide migration being the most prevalent [201, 207, 208, 209, 210]. Phase segregation can be induced by large-scale ion migration [211]. However, some of the challenges that HOIPs-based solar cells face on Earth, such as degradation caused by moisture, are not relevant for space applications [212]. Thermal and vacuum stability, high power-conversion efficiency, and radiation resistance are the main challenges in the space context. A sensible choice of the chemical composition, of eventual use in tandem devices [212] (which also helps to reach an efficiency of up to 30%) or incorporation of a functionalized 2D metal-organic frameworks (MOFs) [213], can improve the long-term operational stability of HOIPs.
A relevant collection of DFT studies for HOIPs can be found in Ref. [214]. A recent study based on DFT + compressed sensing-symbolic regression has shown that mitigation of the propensity of halogens to migrate could be achieved by selectively strengthening specific bonds [215]. The study also unveiled the reasons for improved stability given by specific halogens, the origin of the higher stability offered by certain organic cations compared to others, and highlighted in a quantitative and first-principles manner how weak interactions have a significant role in binding the halogens more strongly.
The study of the radiation tolerance of perovskite solar cells is an extremely active field of research. Solar cells based on HOIPs as active layers have been recently sent to space via first campaigns [60, 216]. Several ground-testing experiments have been performed mostly using protons, either with an energy of several tenths of MeV [69, 211, 217] or with an energy of 150 keV, 100 keV, and 50 keV [70, 218, 219], of less relevance for realistic space conditions.
Superior radiation resistance of perovskite solar cells in comparison to commercially available crystalline Si-based cells has been demonstrated [69]. Moreover, experiments have shown that perovskite solar cells have remarkable self-healing capabilities (at room temperature) that lower the number of defects caused by proton irradiation [69]. Another experimental study has shown that the proton irradiation effects on the physical properties of HOIPs are strongly dependent on the synthesis method [220] which appeared to affect the strength of specific chemical bonds. In particular, HOIPs, produced by mechano-chemical synthesis, have shown practically no change in their physical properties after irradiation with a high-energy 10 MeV proton beam with doses of up to 1013 protons/cm2.
Recently, multi-junction tandem solar cells (combining HOIPs with previous technologies or technologies investigated in parallel) have also been studied under ion irradiation [217]. Lang et al. [217] carried out SRIM simulations of energy loss of high-energy protons as well as the energy transferred to the recoiling nuclei—a measure of the degradation of PV parameters—in tandem solar cells (Figure 5). The study [217] has shown that HOIP/CIGS tandem solar cells possess a high radiation hardness and retain over 85% of their initial performance even after 68 MeV proton irradiation and a dose of
3D scatter plots of the straggling of 68 MeV protons within the (A) HOIP/CIGS(Cu(In,Ga)Se
First-principles calculations of the atomic knock-on displacement events in HOIPs have shown that such displacements are significant and highly energy-dependent [221]. The work has shown that only certain types of atoms are prone to displacements suggesting that mitigation strategies should be directed toward some chemical species more than others. Overall, further studies are necessary, but existing research proves that HOIPs-based solar cells have a remarkable potential for power generation on missions to low Earth orbit, the Moon, and beyond [62].
Another promising class of novel materials for space applications is multi-principal element alloys (MPEAs) [222, 223], which combine superior mechanical properties and enhanced radiation resistance [224]. Also known as high-entropy alloys (HEAs) or concentrated solid-solution alloys (CSSAs), MPEAs consist of at least five principal elements with the concentration of each element from 5 to 35% [222]. Despite the complex composition, MPEAs often form single-phase solid solutions (Figure 6). The interest of researchers in MPEAs has been growing exponentially in recent years, as they exhibit a paradigm shift in alloy development. MPEAs indeed combine a set of outstanding properties, such as high strength, hardness, fracture toughness, corrosion resistance, strength retention at high temperature [226], good low-temperature performance [227], and recently discovered enhanced radiation resistance, superior to conventional alloys and pure metals [149, 222, 223, 228, 229, 230, 231, 232, 233]. Moreover, MPEAs have great potential as 3D printing materials [235]. MPEAs can be printed from a powder, providing manufacturing freedom for lightweight and customizable products of complex geometries for applications in the aerospace, energy, molding, tooling, and other industries, all of the great relevance for the exploration of the Moon.
Atomic structure of a body-centered cubic (BCC) AlCoCrCuFeNi HEA. The Al, Fe, Co, Cr, Ni, and Cu atoms are shown in red, magenta, green, blue, cyan, and gray colors, respectively [
Recent experiments have shown that MPEAs have a higher resistance to defect formation due to high atomic-level stress and chemical heterogeneity [235]. MPEAs also possess lower void swelling and higher phase stability [236, 237] as compared to conventional alloys. Self-healing capability is another remarkable property of MPEAs [227, 236, 238].
The subclass of lightweight (LW) MPEAs have a great potential for space applications due to their high strength-to-weight ratio [239, 240, 241]. The main components of LWMPEAs are low-density elements, such as Al, Mg, Si, and Ti [240]. The latter is of extreme importance for ISRU since 99% of the lunar soil consists of Si, Al, Ca, Fe, Mg, and Ti oxides [5, 242].
Currently, the main focus of computational studies has been on the single-phase random solid-solution (SS) alloys based on transition metals with high densities (Co, Cr, Fe, Ni) for application in radiation environments, in particular in nuclear reactors [148, 149, 232, 236, 243, 244, 245]. MD simulations of displacement cascades applied to pure metals and multicomponent alloys [150, 244, 245, 246, 247, 248] confirm the experimentally observed reduction of the number of defects and defect clusters in MPEAs compared to pure metals (Figure 7).
The number of defects in Ni, NiFe, and NiCoCr from experiments and MD simulations [
The electronic stopping power for a proton in binary alloys has recently been calculated using real-time TDDFT [249]. The study has shown that the electronic stopping power of binary alloys is higher than that of pure Ni, suggesting that alloys more effectively stop the incoming particles. Moreover, the inclusion of the electronic stopping into MD simulations of defect formation significantly reduces the final number of surviving defects, as shown in Figure 8. The inclusion of both the electron-phonon coupling and the electronic stopping in the 2T-MD model not only reduces the actual number of defects but also notably impacts their final arrangement, namely leading to more isolated point defects and reducing the size of defect clusters in binary and ternary alloys [250, 251, 252, 253, 254].
Average number of surviving defects in the classical MD cascade, MD cascade including electronic stopping force, and the 2 T-MD cascade at the end of the simulation for 50 keV Ni cascade in Ni, Ni80Fe20, and NiFe [
The majority of MD studies focus on binary and ternary MPEAs due to the lack of force fields for alloys with more than three elements. However, some studies exist [233] on defect formation in NiCoFeCr alloy in which fewer defects have been found at the end of the displacement cascade with PKA energies from 10 to 50 keV, as compared with pure Ni. The limitations of the classical MD with force fields and the ways of solving this problem are discussed in the following.
Classical MD with empirical potentials is the method that proved to work well for large systems and long time scales [139] for the modeling of collision cascades. However, classical interatomic potentials cannot accurately reproduce interactions between the atoms in MPEAs due to their complex structure and lattice distortions leading to internal strain [149, 255, 256]. On the other hand,
Recent developments in machine learning (ML) approaches can provide a solution to this problem. ML-enhanced materials discovery is an emerging and extremely rapidly growing field. The combination of a precise model based on quantum mechanics and ML algorithms have the potential for an efficient and accurate description of materials properties [257, 258, 259]. Much progress has been made in recent years in the development of ML-based interatomic potentials with the input from electronic structure calculations. First applications have shown that accurate potentials can be obtained for many relevant systems [260, 261, 262, 263, 264, 265]. ML-assisted calculations have been applied to pure metals, binary, ternary alloys [266, 267], and MPEAs [268, 269, 270].
ML and artificial intelligence (AI) may become powerful tools for more accurate multiscale modeling of materials properties. Artificial Neural Networks (ANN) [271] combined with atomistic KMC have already been used to describe the microstructural changes in metals and alloys induced by irradiation [272]. Machine-learned interatomic potentials have been used to study defect formation in refractory MPEAs [273]. The results confirm experimental findings, showing that the 3D migration and increased mobility of defects in MPEAs promote defect recombination leading to more efficient healing. AI, thus, can provide a bridge between different methods, such as DFT, MD, and KMC, and allow for large-scale atomistic simulations of high accuracy, which will accelerate the discovery of new advanced materials.
Fiber-reinforced polymers (FRPs) are composite materials made of a polymer matrix reinforced with fibers. Typical polymers that are often used include epoxy, vinyl ester, polyester thermosetting plastic, and phenol-formaldehyde resins. Typical fibers include, but are not limited to, glass, carbon, and aramid. In a composite FRP material, the polymer and fiber often have significantly different physical and/or chemical properties, which remain separate and distinct within the finished structure but are complementary for tailored properties [274]. Because of their low density (lightweight), great moldability, specific strength, stiffness [275], excellent mechanical stability, and good thermal properties, FRPs are being increasingly used as structural materials in aerospace, automotive, marine industries, and civil infrastructures. Hence, FRPs are of great interest for many applications for lunar missions as potential structural materials [276]. Glass fibers (also “fiberglass”) can be directly produced from the lunar soil as well as from by-products of metal extraction and can be used to reinforce lunar concrete [277].
The radiation environment on the Moon presents challenges for FRPs with concerns on both the immediate reactions taking place in the materials (short-term effects) and continued post-exposure degradation processes (long-term effects) [277, 279]. In the past decades, many selected FRPs have been ground-tested at different kinds of radiation and particle accelerator facilities for their potential use in space-related radiation environments, including UV-light [276, 280],
Carbon-fiber composites have been widely used in aerospace industries due to their high-temperature stability and low density along with high strength, as well as superior beam-induced shock absorption [285, 286]. A combined modeling and experimental study of the radiation effect on carbon-fiber-reinforced molybdenum-graphite compound (MoGRCF) [285], including MC simulations of the energy deposited into a realistic structure by a 200-MeV proton beam (Figure 9) has show that carbon-fiber-reinforced composites have superior beam-induced shock absorption ability compared to that of graphite.
MC modeling of the energy deposition for a 200-MeV proton beam interacting with an irradiation target array (MoGRCF) in tandem with the isotope production array downstream [
In the 1980s, the degradation behavior of carbon-fiber-reinforced plastic (CFRP) under electron beam irradiation in various conditions simulating experiments in space has been studied by Sonoda et al. [283]. It has been observed that there is no change in mechanical properties of CFRP when irradiated by up to a dose of 50 MGy. MC simulations of radiation effects in FRPs have shown that by adding lead nanoparticles it is possible to increase their radiation resistance [287]. According to the study, the addition of 15 wt% of lead nanoparticles to FRPs led to a mass reduction of
An alternative to glass fiber for polymer reinforcement is basalt fiber which offers advantages, such as high specific mechanical and physicochemical properties, biodegradability, non-abrasive qualities, and cost-effectiveness [288]. Arnhof et al. [289] have recently studied mechanical properties of fiber-reinforced geopolymer (FRG) with basalt fiber (i.e., inorganic alumino-silicate polymer) made from lunar regolith simulant as potential shielding and structural material. As basalt fibers can be produced
The additive-manufacturing (AM) techniques for lunar construction from regolith, including FRP materials, and their suitability for ISRU has recently been reviewed in Refs. [292, 293]. The AM techniques for lunar construction include Cement Contour Crafting (CCC), Binder Jetting (BJ), Selective Solar Light Sintering (SSLS) and Selective Laser Sintering/Melting (SLS/SLM) for 3D printing and metal melting, Stereolithography/Digital Light Processing (SLA/DLP), among others. CCC and BJ technologies could be used for outdoor lunar civil engineering. SSLS could be applied to both direct compacting of lunar regolith to ceramic parts and 3D printing. SLA/DLP-based methods could be used for the indoor manufacturing of ceramic instruments, providing higher precision and printing quality and lower defect rate of the printed parts than other AM methods. In the last decade, studies have clearly shown that the 3D-printing technologies will become one of the cornerstones of lunar exploration, providing future astronauts with all the necessary infrastructure [293].
Lunar concrete consisting of mined regolith with the addition of glass fibers (also made
It is worth mentioning that the 4D printing of a “smart material” with FRPs that responds to radiation-induced damages and aging in a programmable way could be realized in near future [296, 297]. In addition to experiments on the radiation environment in a lab, multiscale computational simulations as mentioned above could be helpful for gaining further insights into the radiation-induced molecular changes occurring in polymers.
In this chapter, we introduced some relevant materials for lunar habitat construction and power generation. We discussed the radiation environment on the Moon and the effects that radiation can cause in such materials. We provided an overview of computational methods used to study different stages of radiation damage in materials, focusing on the methods that allow simulating the behavior of materials with extreme accuracy down to the atomic scale. We emphasized that by coupling different methods, it is possible to account for different time and length scales in the evolution of the radiation-induced effects and to combine the electronic effects with atomic displacements.
Several particular examples of radiation damage studies have been discussed with the focus on novel materials with enhanced radiation resistance and other remarkable properties for use on the Moon that can revolutionize space exploration. Such materials include HOIPs for energy production and MPEAs and FRP composite materials for construction. The primary materials considered for lunar construction are FRGs with basalt or glass fibers, which have excellent mechanical properties, can benefit from ISRU, and provide necessary radiation shielding. We emphasized that researchers’ effort is mainly directed toward the development of additive manufacturing techniques, such as 3D printing for habitat construction from lunar regolith. 3D printing will allow producing complex and customizable products in a shorter time and with a lower cost and material consumption.
Nowadays, the radiation-induced effects in materials for space missions are mainly studied by MC particle transport modeling, inheriting the remarkable modeling and computational efforts by the high-energy physics community. However, with the development of first-principles methods and multiscale simulations, a more accurate understanding of radiation effects in materials can be achieved for the regime below hadronic interactions, with details down to atomic scale. It can be expected that the combination of first-principles methods, MC particle transport, and ML will contribute further to the investigation of materials to unravel their full potential for the application in harsh space radiation environments, in particular for what concerns the resistance and resilience to cumulative displacements effects.
The authors are grateful for the funding provided by the project ESC2RAD within the Horizon 2020 Research and Innovation program (grant agreement ID: 776410) and by the project PROIRICE within the program H2020-MSCA-IF 2016 of the Horizon 2020 program of the European Union (grant agreement ID: 748673).
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Morphological and biochemical changes include changes in root and shoot length, number of leaves, secondary metabolite (glycine betaine, proline, MDA, abscisic acid) accumulation in plant, source and sink ratio. Proposed chapter will concentrate on enhancing plant response to abiotic stress and contemporary breeding application to increasing stress tolerance.",book:{id:"9345",slug:"sustainable-crop-production",title:"Sustainable Crop Production",fullTitle:"Sustainable Crop Production"},signatures:"Summy Yadav, Payal Modi, Akanksha Dave, Akdasbanu Vijapura, Disha Patel and Mohini Patel",authors:[{id:"186963",title:"Dr.",name:"Summy",middleName:null,surname:"Yadav",slug:"summy-yadav",fullName:"Summy Yadav"},{id:"308004",title:"Ms.",name:"Payal",middleName:null,surname:"Modi",slug:"payal-modi",fullName:"Payal Modi"},{id:"308005",title:"Ms.",name:"Akanksha",middleName:null,surname:"Dave",slug:"akanksha-dave",fullName:"Akanksha Dave"},{id:"308006",title:"Ms.",name:"Akdasbanu",middleName:null,surname:"Vijapara",slug:"akdasbanu-vijapara",fullName:"Akdasbanu Vijapara"},{id:"308007",title:"Ms.",name:"Disha",middleName:null,surname:"Patel",slug:"disha-patel",fullName:"Disha Patel"},{id:"308008",title:"Ms.",name:"Mohini",middleName:null,surname:"Patel",slug:"mohini-patel",fullName:"Mohini Patel"}]},{id:"45540",doi:"10.5772/56621",title:"Genes and QTLs for Rice Grain Quality Improvement",slug:"genes-and-qtls-for-rice-grain-quality-improvement",totalDownloads:3737,totalCrossrefCites:21,totalDimensionsCites:46,abstract:null,book:{id:"3554",slug:"rice-germplasm-genetics-and-improvement",title:"Rice",fullTitle:"Rice - Germplasm, Genetics and Improvement"},signatures:"Jinsong Bao",authors:[{id:"52135",title:"Dr.",name:"Jinsong",middleName:null,surname:"Bao",slug:"jinsong-bao",fullName:"Jinsong Bao"}]}],mostDownloadedChaptersLast30Days:[{id:"70658",title:"Factors Affecting Yield of Crops",slug:"factors-affecting-yield-of-crops",totalDownloads:4044,totalCrossrefCites:25,totalDimensionsCites:40,abstract:"A good understanding of dynamics involved in food production is critical for the improvement of food security. It has been demonstrated that an increase in crop yields significantly reduces poverty. Yield, the mass of harvest crop product in a specific area, is influenced by several factors. These factors are grouped in three basic categories known as technological (agricultural practices, managerial decision, etc.), biological (diseases, insects, pests, weeds) and environmental (climatic condition, soil fertility, topography, water quality, etc.). These factors account for yield differences from one region to another worldwide. The current chapter will discuss each of these three basic factors as well as providing some recommendations for overcoming them. In addition, it will provide the importance of climate-smart agriculture in the increase of crop yields while facilitating the achievement of crop production in safe environment. This goes in line with the second goal of 2030 Agenda for Sustainable Development of United Nations in transforming our world formulated as end hunger, achieve food security, improve nutrition and promote sustainable agriculture.",book:{id:"8153",slug:"agronomy-climate-change-food-security",title:"Agronomy",fullTitle:"Agronomy - Climate Change & Food Security"},signatures:"Tandzi Ngoune Liliane and Mutengwa Shelton Charles",authors:[{id:"313819",title:"Dr.",name:"Liliane",middleName:null,surname:"Tandzi",slug:"liliane-tandzi",fullName:"Liliane Tandzi"},{id:"314316",title:"Prof.",name:"Charles Shelton",middleName:null,surname:"Mutengwa",slug:"charles-shelton-mutengwa",fullName:"Charles Shelton Mutengwa"}]},{id:"40178",title:"Molecular Markers and Marker-Assisted Breeding in Plants",slug:"molecular-markers-and-marker-assisted-breeding-in-plants",totalDownloads:23030,totalCrossrefCites:81,totalDimensionsCites:146,abstract:null,book:{id:"3060",slug:"plant-breeding-from-laboratories-to-fields",title:"Plant Breeding from Laboratories to Fields",fullTitle:"Plant Breeding from Laboratories to Fields"},signatures:"Guo-Liang Jiang",authors:[{id:"158810",title:"Dr.",name:"Guo-Liang",middleName:null,surname:"Jiang",slug:"guo-liang-jiang",fullName:"Guo-Liang Jiang"}]},{id:"60074",title:"Pollen Germination in vitro",slug:"pollen-germination-in-vitro",totalDownloads:2759,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Pollen germination in vitro is a reliable method to test the pollen viability. It also addresses many basic questions in sexual reproduction and particularly useful in wide hybridization. Many pollen germination medium ranging from simple sugars to complex one having vitamins, growth regulators, etc. in addition to various minerals have been standardized to germinate pollen artificially. The different media, successful pollen germination methods, procedures from pollen germination studies with wheat, rye, brinjal, pigeonpea and its wild relatives are discussed.",book:{id:"6659",slug:"pollination-in-plants",title:"Pollination in Plants",fullTitle:"Pollination in Plants"},signatures:"Jayaprakash P",authors:[{id:"235465",title:"Dr.",name:"Jayaprakash",middleName:null,surname:"P",slug:"jayaprakash-p",fullName:"Jayaprakash P"}]},{id:"62376",title:"Genotype × Environment Interaction: A Prerequisite for Tomato Variety Development",slug:"genotype-environment-interaction-a-prerequisite-for-tomato-variety-development",totalDownloads:2297,totalCrossrefCites:1,totalDimensionsCites:6,abstract:"Tomato (Solanum lycopersicum L.) is the second most important vegetable crop in the world due to its high level of nutrition particularly in vitamins and antioxidants. It is grown in several ecologies of the world due to its adaptability and ease of cultivation. Besides field conditions, tomatoes are grown in controlled environments which range from hydroponics and simple high tunnel structures to highly automated screen houses in advanced countries. However, the yield and quality of the fruits are highly influenced by the environment. This results in unpredictable performances in different growing environments in terms of quality, a phenomenon known as genotype by environment (G × E) interaction which confounds selection efficiency. Various approaches are employed by plant breeders to evaluate and address the challenges posed by genotype by environment interaction. This chapter discusses various field and controlled environments for growing tomatoes and the effect of these environments on the performance of the crop. The various types of genotype × environment interactions and their effect of the tomato plant are discussed. Finally, efforts are made to suggest ways and methods of mitigating the confounding effects of genotype × environment interaction including statistical approaches.",book:{id:"6422",slug:"recent-advances-in-tomato-breeding-and-production",title:"Recent Advances in Tomato Breeding and Production",fullTitle:"Recent Advances in Tomato Breeding and Production"},signatures:"Michael Kwabena Osei, Benjamin Annor, Joseph Adjebeng-\nDanquah, Agyemang Danquah, Eric Danquah, Essie Blay and Hans\nAdu-Dapaah",authors:[{id:"204223",title:"Dr.",name:"Agyemang",middleName:null,surname:"Danquah",slug:"agyemang-danquah",fullName:"Agyemang Danquah"},{id:"217531",title:"M.Sc.",name:"Michael Kwabena",middleName:null,surname:"Osei",slug:"michael-kwabena-osei",fullName:"Michael Kwabena Osei"},{id:"217760",title:"Dr.",name:"Joseph",middleName:null,surname:"Adjebeng-Danquah",slug:"joseph-adjebeng-danquah",fullName:"Joseph Adjebeng-Danquah"},{id:"217768",title:"MSc.",name:"Benjamin",middleName:null,surname:"Annor",slug:"benjamin-annor",fullName:"Benjamin Annor"},{id:"247378",title:"Dr.",name:"Eric Y.",middleName:null,surname:"Danquah",slug:"eric-y.-danquah",fullName:"Eric Y. Danquah"},{id:"248095",title:"Prof.",name:"Essie",middleName:null,surname:"Blay",slug:"essie-blay",fullName:"Essie Blay"},{id:"248096",title:"Prof.",name:"Hans",middleName:null,surname:"Adu-Dapaah",slug:"hans-adu-dapaah",fullName:"Hans Adu-Dapaah"}]},{id:"45153",title:"Irrigation of Sandy Soils, Basics and Scheduling",slug:"irrigation-of-sandy-soils-basics-and-scheduling",totalDownloads:5600,totalCrossrefCites:4,totalDimensionsCites:10,abstract:null,book:{id:"3357",slug:"crop-production",title:"Crop Production",fullTitle:"Crop Production"},signatures:"Mohamed S. Alhammadi and Ali M. Al-Shrouf",authors:[{id:"78245",title:"Dr.",name:"Mohamed",middleName:"Salman",surname:"Alhammadi",slug:"mohamed-alhammadi",fullName:"Mohamed Alhammadi"},{id:"159904",title:"Mr.",name:"Ali",middleName:null,surname:"Al-Shrouf",slug:"ali-al-shrouf",fullName:"Ali Al-Shrouf"}]}],onlineFirstChaptersFilter:{topicId:"29",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81888",title:"Reducing Soil Compaction from Equipment to Enhance Agricultural Sustainability",slug:"reducing-soil-compaction-from-equipment-to-enhance-agricultural-sustainability",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.104489",abstract:"The compaction of agricultural soils cannot be solved, only managed. As a compressible media, soil travel without causing some collapse of the existing structure is impossible. If left uncorrected, farmers can see up to a 50% reduction in yield from long-term compaction. This chapter will describe the effects of soil compaction on the environment, crop quality, and economic sustainability. The base causes will be examined, along with the engineering designs for vehicles that minimize the problem. The tracks versus tires debate will be thoroughly discussed, and the advantages and disadvantages of each system will be detailed. It will be shown that although tires represent the likely current best economic option for vehicle support, the potential of tracks to reduce compaction has been fully exploited. The advantages of four-wheel drive vehicles in reducing soil compaction will be shown, along with the mitigation potential of independently driven wheels and active soil interaction feedback loops. The design of crop production tillage equipment and tillage tool working points will be explored, along with the concept of critical tillage depth. Equipment for compaction relief will also be discussed, as will the sustainable agricultural protocols of cover crops, crop rotation, and controlled traffic farming.",book:{id:"11357",title:"Sustainable Crop Production - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11357.jpg"},signatures:"Michael M. Boland, Young U. Choi, Daniel G. Foley, Matthew S. Gobel, Nathan C. Sprague, Santiago Guevara-Ocana, Yury A. Kuleshov and Robert M. Stwalley III"},{id:"81378",title:"Sustainability-Based Review of Irrigation Schemes Performance for Sustainable Crop Production in Nigeria",slug:"sustainability-based-review-of-irrigation-schemes-performance-for-sustainable-crop-production-in-nig",totalDownloads:31,totalDimensionsCites:0,doi:"10.5772/intechopen.103980",abstract:"Irrigated agriculture has been identified as an important practice to achieving food security and socio-economic development in the face of rapid population growth and climatic uncertainties. In northern Nigeria, irrigation has long been identified as the key to achieving the much-desired increase in food production to meet the ever-increasing population. However, the existing irrigation schemes encountered several challenges coming from different dimensions including economic, social, environmental, institutional and technological. To attain sustainable crop production, this paper attempts to uncover the underline challenges confronting irrigation schemes in northern Nigeria that cut across sustainability pillars. The findings revealed that irrigation schemes contributed immensely toward achieving food security and improving the wellbeing of rural dwellers. However, the huge investment in large- and medium-scale irrigation schemes have resulted in massive economic losses. This could be attributed to their under-utilization, poor management and abandonment although few ones are performing remarkably well. The study recommends the need to adopt new water allocation and application methods that can improve water use efficiency, users-managers join approach (participatory), effective and competent institutions which include improved monitoring, evaluation and surveillance systems, frequent policy review to suit the situation, law enforcement, and timely sensitization and awareness campaigns.",book:{id:"11357",title:"Sustainable Crop Production - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11357.jpg"},signatures:"Nura Jafar Shanono, Nura Yahaya Usman, Mu’azu Dantala Zakari, Habibu Ismail, Shehu Idris Umar, Sunusi Abubakar Amin and Nuraddeen Mukhtar Nasidi"},{id:"81274",title:"Toward the Recent Advances in Nutrient Use Efficiency (NUE): Strategies to Improve Phosphorus Availability to Plants",slug:"toward-the-recent-advances-in-nutrient-use-efficiency-nue-strategies-to-improve-phosphorus-availabil",totalDownloads:43,totalDimensionsCites:0,doi:"10.5772/intechopen.102595",abstract:"Achieving high nutrient use efficiency (NUE) and high crop productivity has become a challenge with increased global demand for food, depletion of natural resources, and deterioration of environmental conditions. Higher NUE by plants could reduce fertilizer input costs, decrease the rate of nutrient losses, and enhance crop yields. Nitrogen and Phosphorus are the most limiting nutrients for crop production in many of the world’s agricultural areas, and their efficient use is important for the economic sustainability of cropping systems. Furthermore, the dynamic nature of N and P in soil-plant systems creates a unique and challenging environment for its efficient management. Although numerous fertilizer recommendation methods have been proposed to improve NUE, technologies and innovative management practices are still lacking. Therefore, maximizing crop phosphorus (P) use efficiency (PUE) would be helpful in reducing the use of inorganic phosphorus fertilizers and their escape in the environment for sustainable agriculture. Improvement of PUE in cropping systems can be achieved through two main strategies: optimizing agronomic practice and breeding nutrient efficient crop cultivars that improves P-acquisition and -utilization efficiency. These strategies are needed for future food security and sustainable agriculture. The major revised points are the following: concept of NUE, application of nutrient stewardship, cereal-legume intercropping, regulating soil pH, etc., for enhancing phyto-availability of P and breeding P-efficient crop cultivars that can produce more biomass with lesser P costs and that acquire more P in P-stress condition. These approaches consider economic, social, and environmental dimensions essential to sustainable agricultural systems and afford a suitable context for specific NUE indicators.",book:{id:"11357",title:"Sustainable Crop Production - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11357.jpg"},signatures:"Addisu Ebbisa"},{id:"81179",title:"Crop Diversification an Effective Strategy for Sustainable Agriculture Development",slug:"crop-diversification-an-effective-strategy-for-sustainable-agriculture-development",totalDownloads:49,totalDimensionsCites:0,doi:"10.5772/intechopen.102635",abstract:"Sustainable agricultural practices involve a variety of approaches. The most important approached for sustainable agriculture development is crop diversification. It allowing the farmers to employ biological cycles to minimize inputs, conserve the resource base, maximize yields and also reduce the risk due to ecological and environmental factors. It serves as an important opportunity to augment income and employment generation for rural communities. Crop diversification promotes the interaction of beneficial soil bacteria, interrupts the disease cycle, and reduces the quantity of weeds. Crop diversification boosts land-use efficiency and crop output by improving the physical and chemical qualities of soil. Crop diversification shows a lot of scope to alleviating the problems such as resurgence of insects-pests and weeds, soil degradation, environmental pollution, soil salinity, decline farm profit and climate change. Crop diversification through crop intensification system enhanced the net returns, B:C ratio, and overall system productivity of a farm. In order to achieve the benefits of crop diversification farmers are shifting from low value low yielding crops to high value high yielding crops. Thus, crop diversification has the sound capacity for achieving the goal of nutritional security, income growth, food security, employment generation and sustainable agriculture development.",book:{id:"11357",title:"Sustainable Crop Production - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11357.jpg"},signatures:"Anamika Barman, Priyanka Saha, Shashank Patel and Anurag Bera"},{id:"80867",title:"Potential Applications of Rhizobacteria as Eco-Friendly Biological Control, Plant Growth Promotion and Soil Metal Bioremediation",slug:"potential-applications-of-rhizobacteria-as-eco-friendly-biological-control-plant-growth-promotion-an",totalDownloads:66,totalDimensionsCites:0,doi:"10.5772/intechopen.102657",abstract:"Modern agriculture has an immense problem in the depletion of agricultural productivity owing to a variety of biotic and abiotic stresses. Agriculture’s sustainability and safety are dependent on ecologically friendly practices. Plant rhizobia have been proven to have an important role in disease control, as well as promoting plant growth, productivity, and biomass. Rhizobacteria are soil bacteria that live on the root surface and either directly or indirectly contribute to plant development. Rhizobia are used to induce mediated immune resistance through the manufacture of lytic enzymes, antibiotics, phytoalexins, phytohormone, metabolites. It supports the growth of plants through nitrogen fixation, nutrient enrichment, phosphate solubilization and phytohormone synthesis. In addition, it supports plants during different stresses such as temperature, osmotic, heavy metal and oxidative stress. Plant growth-promoting rhizobacteria have the ability to control heavy metal pollution of soils as well as enhancing plant growth in these soils. Efficient bioremediation is possible by using rhizobacterial inoculants, still, the distribution and functioning of microbes in the rhizosphere need to be fully explored. This review focuses on the effectiveness, biomonitoring processes and function in promoting plant development. Rhizobia application can be considered an alternative method for the improvement of biodiversity, agriculture, and the environment.",book:{id:"11357",title:"Sustainable Crop Production - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11357.jpg"},signatures:"Nafeesa Farooq Khan, Aatifa Rasool, Sheikh Mansoor, Sana Saleem, Tawseef Rehman Baba, Sheikh Maurifatul Haq, Sheikh Aafreen Rehman, Charles Oluwaseun Adetunji and Simona Mariana Popescu"},{id:"80653",title:"Heavy Metal Contamination in Vegetables and Their Toxic Effects on Human Health",slug:"heavy-metal-contamination-in-vegetables-and-their-toxic-effects-on-human-health",totalDownloads:119,totalDimensionsCites:1,doi:"10.5772/intechopen.102651",abstract:"Vegetables are a prevalent nutrition for people all over the world because they are high in important nutrients, antioxidants, and metabolites that function as buffers for acidic compounds created during digestion. Vegetables, on the other hand, absorbed both vital and poisonous substances through the soil. Possible human health concerns, including as cancer and renal damage, have been linked to the consumption of heavy metal-contaminated vegetables (HMs). Heavy metals like Cr, Mn, Fe, Ni, Cu, Zn, Cd, Pb, and Hg were found in high concentrations in popular vegetables such as Amaranthus tricolour L., Chenopodium album L., Spinacia oleracea, Coriandrum sativum, Solanum lycopersicum, and Solanum melongena. The toxicity, fortification, health hazard, and heavy metals sources grown in soil are detailed in this review study.",book:{id:"11357",title:"Sustainable Crop Production - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11357.jpg"},signatures:"Seema Manwani, Vanisree C.R., Vibha Jaiman, Kumud Kant Awasthi, Chandra Shekhar Yadav, Mahipal Singh Sankhla, Pritam P. Pandit and Garima Awasthi"}],onlineFirstChaptersTotal:7},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. By addressing hot topics in veterinary sciences, we aim to gather authoritative texts within each issue of this series, providing in-depth overviews and analysis for graduates, academics, and practitioners and foreseeing a deeper understanding of the subject. Forthcoming texts, written and edited by experienced researchers from both industry and academia, will also discuss scientific challenges faced today in Veterinary Medicine and Science. In brief, we hope that books in this series will provide accessible references for those interested or working in this field and encourage learning in a range of different topics.",coverUrl:"https://cdn.intechopen.com/series/covers/13.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"19",title:"Animal Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/19.jpg",isOpenForSubmission:!0,editor:{id:"259298",title:"Dr.",name:"Edward",middleName:null,surname:"Narayan",slug:"edward-narayan",fullName:"Edward Narayan",profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",biography:"Dr. Edward Narayan graduated with Ph.D. degree in Biology from the University of the South Pacific and pioneered non-invasive reproductive and stress endocrinology tools for amphibians - the novel development and validation of non-invasive enzyme immunoassays for the evaluation of reproductive hormonal cycle and stress hormone responses to environmental stressors. \nDr. Narayan leads the Stress Lab (Comparative Physiology and Endocrinology) at the University of Queensland. 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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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