Different clinical presentations of sepsis-induced immunological alterations.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"217",leadTitle:null,fullTitle:"Recent Trends in Processing and Degradation of Aluminium Alloys",title:"Recent Trends in Processing and Degradation of Aluminium Alloys",subtitle:null,reviewType:"peer-reviewed",abstract:"In the recent decade a quantum leap has been made in production of aluminum alloys and new techniques of casting, forming, welding and surface modification have been evolved to improve the structural integrity of aluminum alloys. \nThis book covers the essential need for the industrial and academic communities for update information. It would also be useful for entrepreneurs technocrats and all those interested in the production and the application of aluminum alloys and strategic structures. It would also help the instructors at senior and graduate level to support their text.",isbn:null,printIsbn:"978-953-307-734-5",pdfIsbn:"978-953-51-6077-9",doi:"10.5772/741",price:159,priceEur:175,priceUsd:205,slug:"recent-trends-in-processing-and-degradation-of-aluminium-alloys",numberOfPages:530,isOpenForSubmission:!1,isInWos:1,hash:"6b334709c43320a6e92eb9c574a8d44d",bookSignature:"Zaki Ahmad",publishedDate:"November 21st 2011",coverURL:"https://cdn.intechopen.com/books/images_new/217.jpg",numberOfDownloads:114699,numberOfWosCitations:106,numberOfCrossrefCitations:32,numberOfDimensionsCitations:109,hasAltmetrics:0,numberOfTotalCitations:247,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 20th 2010",dateEndSecondStepPublish:"November 17th 2010",dateEndThirdStepPublish:"March 24th 2011",dateEndFourthStepPublish:"April 23rd 2011",dateEndFifthStepPublish:"June 22nd 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"52898",title:"Prof.",name:"Zaki",middleName:null,surname:"Ahmad",slug:"zaki-ahmad",fullName:"Zaki Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/52898/images/1942_n.jpg",biography:"Professor Dr. Zaki Ahmad worked at King Fahd University of Petroleum and Minerals for thirty years in rendered distinguished services in teaching and research. He obtained his PhD from LEEDS University, UK. He was a chartered metallurgical engineer (C.Eng) from engineering council UK. He was a fellow of the institute of Materials, Minerals and Mining(FIMMM). He was a member of the European federation of corrosion and a fellow of institute of Metal Finishing. He substantially contributed to the founding activities in material science, corrosion engineering and nanotechnology at KFUPM and in Iran. He worked on international projects on aluminum with Aluminum, Ranshofen, Austria and Forschungzentrum, Geethscht, Germany and with Metallgesselscheft, Germany. He worked on international projects with Ministry of Technology, Germany. He was a founder contributor of center of excellence in corrosion at KFUPM, Dhahran, Saudi Arabia. He worked on the foundation and development of nanotechnology in Saudi Arabia in 2004. He was the author of “Principles of Corrosion Engineering and Corrosion Control” published by Elsevier in 2006. He has written over 95 research papers and international journals and over forty papers in international research conferences. His research activities included development of Al/SC alloys, Nanostructured superhydrophrobic surfaces, Nanocoatings and self-healing techniques. He was nominated for best researcher award in the Middle East by Energy Exchange in 2011. He was a consultant of several research organizations.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"COMSATS University Islamabad",institutionURL:null,country:{name:"Pakistan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"944",title:"Metallurgy",slug:"metals-and-nonmetals-metallurgy"}],chapters:[{id:"24031",title:"Aluminium Countergravity Casting – Potentials and Challenges",doi:"10.5772/17690",slug:"aluminium-countergravity-casting-potentials-and-challenges",totalDownloads:6625,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Bolaji Aremo and Mosobalaje O. 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This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. 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Overall, it appears that both the description and the therapies apply to acutely ill patients suffering from an infection-induced overwhelming reaction determined by a huge number of pro-inflammatory mediators produced and released by the innate immunity system. However, more than 20 years ago, Bone [3] hypothesized that this early hyperinflammatory phase could be accompanied by a compensatory anti-inflammatory response (CARS) aiming to limit the tissue damage. In the last decade, the concept of CARS has changed from a time-limited and somehow beneficial mechanism to a harmful reaction, potentially leading to a condition of marked reduction of the immune capabilities known as immunoparalysis [4, 5, 6]. Clinically, this condition is marked by recurrent and/or unresolving infections caused by germs with relatively low virulence; the reactivation of silent virus such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpesvirus (HV); a persisting low-grade inflammation; nutrition-resistant hypercatabolism; and muscle wasting [7, 8] (Table 1). The immunoparalysis characterizes also the clinical course of the chronic critically ill patients, namely, subjects who survived the initial insult (i.e., septic shock due to pneumonia, peritonitis, etc.) but fails to recover enough to be weaned from the mechanical ventilation and discharged from the intensive care unit (ICU) [9]. Moreover it should be noted that factors other than pathophysiological mechanisms can reduce the immune response, including the administration of steroids and norepinephrine [1, 10]. The aims of this chapter are (1) to review the main mechanism determining a SS, (2) to describe the transition from an easily recognizable hyperinflammatory condition to a less straightforward diagnosable one featured by a downregulation of the immune capabilities, (3) to provide some monitoring tools of the immune function, and, finally, (4) to identify some possible therapeutic approaches.
\nVariable | \nUncontrolled inflammatory response | \nImmunoparalysis | \n
---|---|---|
Clinical phenotype | \nFever, arterial hypotension, elevated cardiac output, rapidly evolving MODS, community or surgical infections | \nAltered mental status, normo-/hypothermia, slow-evolving MODS, health care- or hospital-acquired infections | \n
Patients population | \nYoung, middle-aged | \nElderly, fragile | \n
Comorbidities | \nOften absent Low Charlson’s index | \nOften present High Charlson’s index | \n
Germs characteristics | \nVirulent, toxin releasing | \nLow virulence, opportunistic Latent virus reactivation | \n
Laboratory findings | \n↑↑ or ↓ neutrophil count, ↑ blood lactate levels | \n↓ lymphocyte | \n
Nutritional status | \nNormal | \nSarcopenia/cachexia Muscle wasting | \n
Clinical course | \nResolution of sepsis Immunorestoration Early deaths | \nProtracted ICU LOS Chronic critical disease Late deaths | \n
Different clinical presentations of sepsis-induced immunological alterations.
LOS, length of stay.
Since the late 1970s, it has become clear that the clinical and biochemical manifestations of sepsis and its related complications are not caused directly by invading germ(s) but rather by the host’s response to the infection. The innate immune response largely accounts for the above described signs and symptoms. The presence of microorganism-derived substances collectively known as pathogen-associated molecular pattern (PAMP) which include endotoxin, capsular antigens, elements derived from the cell wall, flagellins, and other substances derived from the bacterial lysis determines the rapid activation of genes encoding for an extremely elevated (and still partially unknown) mediators able to trigger a strong inflammatory reaction, including the tumor necrosis factor-α (TNF), a number of interleukins (IL), the platelet-activating factor (PAF), etc. (Table 2). It is worthwhile to recall that (a) the list of mediators is incomplete because new elements are added on a weekly or at maximum monthly basis, (b) the rise of blood levels of inflammatory mediators is a matter of minutes since it represents the first line of defense to contrast the deleterious effects of PAMP and DAMPS, and (c) for this reason, the innate response is highly similar among all species of mammalians [6].
\nCytokine | \nSource | \nEffects | \nInteractions | \nAntagonists | \n
---|---|---|---|---|
TNF | \nInnate and adaptive immune system | \nActivation of immune cells Fever cachexia, apoptosis | \nActivation of downstream inflammatory mediators | \nSoluble TNF receptors Anti-TNF ab | \n
IL-1 | \n“ | \nFever, pro-coagulation Hematopoiesis | \n“ | \nIL-1 receptor antagonists | \n
IL-6 | \n“ | \nActivation of T and B lymphocytes Fever | \nInhibits the release of TNF and IL-1 Promotes anti-inflammatory response | \nIL-6 receptor antagonists | \n
IL-12 | \nMonocyte, macrophages, neutrophils, dendritic cells | \nActivation of adaptive response | \nPromotes IFN-γ production | \nUnknown | \n
IFN-γ | \nNKT cells CD 8 T cell | \nAntiviral action Potentially reverse immunoparalysis | \nReleased in response to TNF, IL-12, and IL-18 | \nUnknown | \n
Some relevant pro-inflammatory mediators.
TNF, tumor necrosis factor; IL, interleukin; IFN, interferon.
Independently from their biochemical structure, the term inflammasome lumps together all these heterogeneous mediators that are characterized by (a) the presence of many positive and negative feedback loops, determining an array that can be better conceived as a network and not a cascade, thus making understandable the therapeutic failure demonstrated in many trials in which septic patients were treated with substances aimed to the block a single mediator via monoclonal or chimeric specific antibodies (Ab) such as anti-TNFαAb or with the administration of circulating antagonists (ra) (i.e., soluble IL1-ra and TNF TNFα-ra) directed to block the receptors present on the cell surface; (b) the pleiotropic and paracrine effects, accounting for the multiple effects exerted in different organs; (c) the interference with the mitochondria causing a disturbance of the O2 uptake and consumption by the tissues; and (d) the interaction with other biological systems including the complement system and the coagulative cascade. Notably, the very same mediators are produced in noninfectious conditions, including trauma, low-flow states, surgery, burns, etc.; in these circumstances the trigger is represented by an intracellular substance derived from the injured tissues (DAMP, damage-associated molecular patterns). The endothelium is massively involved in this reaction causing a microvascular plugging and the abnormal production of nitric oxide (NO) which exert a profound vasodilation [11, 12].
\nFrom an evolutionary perspective, it is likely that these mediators have been developed and maintained, aiming to contain the initial inoculum and to destroy the responsible organisms. This explains why in most cases an infection does not cause a SS: actually, the latter occurs only when the pro-inflammatory mediators exert their effects at a systemic level, thus determining the clinical phenotype of SS and the almost unavoidable presence of the simultaneous dysfunction of different organs and systems even not directly involved by the infection (MODS).
\nThe secretion of inflammasome is accompanied by the production of other substances aimed to limit their action at a local level and, at the same time, to prevent their systemic spread (Table 3). As stated above for the inflammatory mediators, their list is incomplete for the very same reasons. Actually, it was hypothesized that during the initial phase (almost), only pro-inflammatory mediators were produced and that these conditions subsided due to the action of the CARS-associated mediators. Despite its popularity, it became clear that this scheme represents an oversimplification as (a) both classes of substances are produced since the initial phase of sepsis albeit in different rates; (b) the action of anti-inflammatory mediators is responsible for the late-onset immunoparalysis; and finally (c) a low-level production of pro-inflammatory substances can be maintained even during the advanced stages of sepsis leading to malnutrition, protein waste, and reduced adaptive immunity. Overall, the sepsis-associated immunoparalysis resembles the normal aging process of the immune system (immunosenescence) that is characterized by the overall downregulation of both the innate and adaptive immunity functions. This appears particularly relevant as the ever-increasing age of septic patients exposes them to both conditions.
\nCytokine | \nSource | \nEffects | \nInteractions | \n
---|---|---|---|
IL-10 | \nInnate and adaptive immune system | \nImmunosuppression Inhibition of antigen presentation and phagocytosis | \nSuppression of the production of inflammatory mediators | \n
TGF-β | \nMacrophages Smooth muscle cells | \nImmunosuppression | \n” | \n
IL-4 | \nMast cells Th2 T cells Basophils Eosinophils | \nPromotes Th2 T-cell differentiation | \nInduces the production of IL-10 | \n
Some relevant anti-inflammatory mediators.
TGF, transforming growth factor.
Put shortly, it appears that the mediators implicated in the CARS can represent a double-edged sword, as they both can exert (a) a beneficial role when they determine the restoration of the immune condition existing prior to the sepsis (immune restoration) and (b) can trigger a life-threatening condition when their excess production and/or duration of action causes the shutdown of the immune response [13, 14].
\nIn conclusion, (at least) three clinical trajectories can be hypothesized (Figure 1): the first includes patients with an intense hyperinflammatory reaction that subsides once the CARS is well established and the immune function is restored; in the second the initial phase is shorter and weaker, and the CARS determines a short-lived immunoparalysis preceding the return toward the baseline immune function; and in the third one, the CARS prevails and causes the loss of the immune capabilities.
\nPossible clinical trajectories of patients with sepsis shock. Line 1, intense hyperinflammatory reaction followed by CARS and the return to the baseline immune state. Line 2, weak hyperinflammatory reaction followed by immunoparalysis and immune restoration. Line 3, immunoparalysis not preceded by a hyperinflammatory reaction.
Only recently it became clear that the CARS does not represent only a physiologic counterbalance to the inflammatory response to PAMP and DAMP but that it can determine a critical condition in and by itself [13, 15].
\nActually, different experimental and clinical studies indicate that the advanced stage of sepsis and SS is characterized by a reduction of both the innate and adaptive immune responses (Table 4). Extensive evidence supports this model, even if large inter-patient differences exist. First, monocytes present a reduced expression of membrane HLA-DR in association to either a decreased secretion of inflammatory mediators when stimulated or a diminished antigen presentation. Second, different membrane-bound receptors able to potentiate the immune response, including IL-2α, IL-7R α, CD86, etc., are reduced. Third, the production of immunosuppressant substances, such and programmed death 1 (PD1) and its ligand (PD-L1), is increased in antigen-presenting cells, thus inhibiting the activation of T lymphocytes. Fourth, there is an increased appearance of immunosuppressive T-cell subpopulations, such as myeloid-derived suppressor cell and CD4+ and CD25+ T-regulatory cells (Treg), which suppress adaptive immunity. These appear to be particularly relevant, as Treg (a) actively produce anti-inflammatory cytokines including TGF-β and IL-10, (b) downregulate the secretion of pro-inflammatory mediators, (c) neutralize cytotoxic T cells, and (d) deactivate the monocytes. Fourth, immune cells present an increased apoptosis, and their loss is not replaced enough by the production of new ones. Finally, the phagocytosis of apoptotic cells by fixed and circulating macrophages leads to a switch of the latter to the M2 phenotype, whose feature is an increased production of the anti-inflammatory substances IL-10 and IL-1ra. Put briefly, all these mechanisms exert their action via relatively few common pathways, which include the increased apoptosis determining the reduction of immune cells, the loss of antigen presentation, the blunted response to PAMP, and the reduction of energy production caused by the impairment of the glucose metabolism (Table 5) [16, 17]. All these reactions are driven by epigenetic changes causing in different time frames the activation or deactivation of genes involved in the immune response, and the resulting phenotype is an intense inflammatory response or, conversely, an immunoparalysis.
\nFactors involved | \nMarker | \n
---|---|
Monocyte deactivation | \n↓ mHLA-DR expression ↓ TNF-α production | \n
Tissue macrophage dysfunction | \nPresently none | \n
Negative regulatory mediators | \n↑ PD-(L)1 expression ↑ CTL-4, BTLA expression ↑ LAG-3 and TIM-3 expression | \n
Receptors downregulation | \n↓ IL-7 receptor | \n
Apoptosis | \n↑ FAS ↓ lymphocytes | \n
Suppression of immune cells | \n↑ CD-4, CD-25 ↑ myeloid-derived suppressor cells | \n
Anti-inflammatory cytokines | \n↑ IL-10, IL-13, IL-4, IL1 receptor antagonists, TGF-β ↑ IL-10/TNF-α | \n
Factors of immunosuppression.
mHLA-DR, human leukocyte antigen on the monocyte surface; PD-(L1), programmed death ligand; CTLA-4, cytotoxic lymphocyte antigen 4; BTLA, B and T lymphocyte attenuator; LAG-3, lymphocyte activation gene 3; TIM-3, T lymphocyte immunoglobulin protein 3; sFAS, soluble FAS ligand; TGF-β, transforming growth factor-β.
Mechanisms | \nEffect | \n
---|---|
Endotoxin tolerance | \n↑ Anti-inflammatory mediators, ↓ pro-inflammatory mediators ↓ Antigen presentation | \n
Apoptosis | \n↓ Immune cell number Immune cell number anergy | \n
Energy failure | \nImmune cell anergy Apoptosis | \n
Epigenetic regulation | \n↓ Pro-inflammatory mediators | \n
Mechanisms of immunoparalysis.
The recognition of sepsis-induced immunoparalysis is not straightforward because the clinical manifestations associated with the switch from the hyperinflammatory state to CARS and the full-blown depression of the immune capabilities are not so protean as the symptoms of SS [18]. Moreover, the SSC guidelines focus almost exclusively on the former and pay much less attention, if any, to the latter. From a practical and clinical point view, some issues appear particularly relevant.
\nThe transition from the hyperinflammatory phase to immunoparalysis can be challenging to identify and to monitor at the bedside and represents a kind of no man’s land in the clinical course of patients which survived from the initial phase of SS.
\nThe onset is highly variable. Actually, although the secretion of immunomodulatory substances can occur relatively early, their clinical consequences present wide variations. Some authors [19] observed a substantial difference of mHLA-DR starting from 3 to 7 days in a small group of surgical septic patients, and other authors demonstrated that significant decrease of the CD14/HLA-DR and of heat-shock proteins (HSP) 70 and 90 was present already within 24 hours from the onset of sepsis [5]; in both studies, these alterations were more marked in patients who developed SS later on. More recently, Morris et al. [20] in association with raised percentage of regulatory T cells (Treg) were predictive for infections occurring between 3 and 9 days after ICU admission, and a similar timing has been demonstrated also in another study in which the mortally rate of secondary infection was ~14% [17]. On the basis of these findings, it is reasonable to hypothesize that (a) a combination of cellular and soluble factors able to blunt the immune response is present since the very initial phase of sepsis; (b) their effects on the clinical course, namely, the appearance of secondary infections and/or viral reactivation, can occur within the initial 10 days from the admission; and (c) these are associated with a substantial mortality of patients surviving the initial insult.
\nIn ICU patients, every organ system is monitored to allow a change in the treatment tailored on the variation observed. An ideal monitoring system should be accurate, cheap, and not labor-intensive, and the information gathered should be readily if not continuously available. Since it has become clear that the immune system in sepsis undergoes modifications not reflected by the commonly measured biological variables such as the arterial pressure, the heart rate, the urinary output, etc., different investigations aimed to identify one or more markers of changes of its functions whose follow-up could be valuable to modify the therapy according to its changes: as an example, the occurrence of immunoparalysis contraindicates the administration of steroids whose use is recommended by the SSC guidelines.
\nSeveral monitoring systems exploring both legs of the immune response have been developed so far, based on the repeated assessments of the cells involved, their response to different challenges, and the measurement of the blood concentrations of soluble mediators involved in the different clinical frames [14, 15, 21, 22]. It could be useful to describe separately those currently available and those which will be used likely in the next future. Most of the former (Table 6) can be obtained cheaply and on a daily basis; among all, the neutrophil-to-lymphocyte ratio has been indicated as the less costly and more rapidly available monitoring tool [23, 24]. Other advanced, expensive, and not yet widely available monitoring tools take advantage of more sophisticated lab techniques (Table 7) requiring lab expertise and financial resources putting them at risk of not being used outside the research center. Another dynamic approach, which shares the very same limitations of the previously described advanced techniques, consists in challenging the immune cells with substances able to trigger their activation, including LPS, other PAMP, and phytohemoagglutinin; actually, a number of investigators demonstrated that a blunted response to the stimulation is associated with an increased rate of severe infectious complications in different patient populations [25, 26, 27].
\nFunction | \nCell | \nMarker | \nOutcome | \nLab technique | \nRunaround (h) | \n
---|---|---|---|---|---|
Innate immunity | \nNeutrophils | \n↑ Immature forms | \nDeath Secondary infections | \nFC. Hematology analyzer | \n1.5 | \n
Monocytes | \n↓ HLA-DR | \nDeath Secondary infections | \nFC, IHC, PCR | \n1.5 | \n|
Adaptive immunity | \nAll lymphocytes | \nLymphopenia | \nDeath Secondary infections | \nFC. Hematology analyzer | \n0.5 | \n
White blood cells | \nNTL | \nDeath Secondary infections | \nFC. Hematology analyzer | \n0.5 | \n|
Both | \nLymphocytes | \nViral reactivation | \nDeath | \nPCR | \n12 | \n
Some currently available indicators of immune function.
FC, flow cytometry; IHC, immunohistochemistry; PCR, polymerase chain reaction; NTL, neutrophil/lymphocyte ratio.
Function | \nCell | \nMarker | \nOutcome | \nLab technique | \nRunaround (h) | \n
---|---|---|---|---|---|
Innate immunity | \nMonocytes | \n↓ sCD127 | \nDeath, secondary infections | \nFC, PCR, IHC, ELISA | \n5 | \n
Endotoxin tolerance | \nNot clear | \nCell culture, ELISA, FC, IHC | \n72 | \n||
↑ PD-L1 | \nSecondary infections | \nFC, IHC | \n1.5 | \n||
IL10/TNF ratio | \nDeath | \nELISA | \n5 | \n||
Dendritic cells | \n↓ Count | \nDeath, secondary infections | \nFC | \n1.5 | \n|
Adaptive immunity | \nAll lymphocytes | \n↑ CTLA 4, BTLA | \nNot clear | \nFC, IHC | \n1.5 | \n
↑ PD | \nDeath | \nFC, IHC | \n1.5 | \n||
CD 127 | \nDeath, secondary infections | \nFC, IHC | \n1.5 | \n||
T cells | \nProliferation | \nDeath, secondary infections MODS | \nCell culture + FC | \n72 | \n|
Treg\n | \n↑ Treg\n | \nDeath | \nFC | \n1.5 | \n|
Both | \nTranscriptomic | \nCD 74, CX3CR1 | \nNot clear | \nPCR, microarray | \n72 | \n
Some promising, yet not currently available, markers of immunoparalysis.
FC, flow cytometry; IHC, immunohistochemistry; PCR, polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay.
Independently from the systems used, it should be clear that the monitoring of the immune response in septic as well in other clinical conditions (a) is based on the time variations of a panel of indicators and not on a single one and (b) due to their direct and indirect costs, it should be limited to the subjects at risk; as an example, it is worthwhile to monitor the immune function in patients undergoing multiple abdominal surgical procedures for suture dehiscence but not in another one safely recovering after peritonitis.
\nEven with the exclusion of clinical conditions and/or treatments known to cause an immunoparalysis (i.e., solid and hematologic cancers, autoimmune disorders), etc., this circumstance can occur in virtually all ICU patients; however, different studies identified some predisposing factors that should be considered particularly relevant, including septic shock, advanced age, health care-associated infections, elevated Charlson’s score indicating a substantial underlying fragility, comorbidities, prolonged hospital and ICU length of stay, and multiple surgical procedures [17, 28, 29]. The latter, which are associated with the repeated activation of the inflammatory and anti-inflammatory responses, according to the multiple hits model, ultimately lead to the exhaustion of the immune response [30] (Figure 2).
\nThe multiple hits phenomenon ultimately leading to the exhaustion of the immune response.
In the last decade, a number of drugs have been developed to restore a normal immune function in patients with solid or hematologic tumors on the basis of many investigations demonstrating the tumor cells are able to suppress in many different ways the host’s immune response against themselves. Independently from the substance use and the molecular target, these innovative treatments have been demonstrated to be effective but somehow difficult to handle, as they are associated with a number of side effects ranging from mild to life-threatening [31]. As several similarities exist between tumor- and sepsis-induced blunting of the immune response [32], it is likely that in the next future the immune-boosting treatments will be developed to treat the latter, aiming to develop a precision medicine also in ICU patients [33] (Table 8).
\nCells/factors involved | \nAlterations | \nPossible therapies | \n
---|---|---|
Myeloid cells | \n↑ Immature neutrophils ↑ Tolerant dendritic cells ↑ Myeloid-derived suppressor cells ↓ Monocyte HLA-DR expression | \nGM-CSF Toll-like receptor antagonists FTL3L TNF | \n
Lymphocytes | \n↓ Cytokine production Altered metabolism ↓ Proliferation ↑ Immune checkpoint inhibitors Malfunction of NKT cells ↑ Treg and Breg cells ↑ CD 155 expression | \nAnti-PD1 ab Anti-PDL 1 ab Anti CTLA4, TIM3, LAG3 ab | \n
↑ Systemic cytokine release | \n↑ IL-10 ↑ PGE 2 ↑ TGFβ | \nGM-CSF TLR agonists FT3L TNF | \n
Immunosuppressive pathways shared by cancer and sepsis.
GMC-SF, granulocyte-macrophage colony-stimulating factor; FTL3L, FMS-related tyrosine kinase 3 ligand; PD, programmed death; PDL1, programmed cell death ligand 1; CTL4, cytotoxic T-cell protein 4; TIM3, T-cell immunoglobulin mucin receptor 3; Treg Breg, regulatory T and B cells; TGFβ, transforming growth factor-β; PGE, prostaglandin E2.
\n | Treatment | \nEffect | \nPro | \nAgainst | \n
---|---|---|---|---|
Available | \nIvIg | \nAntibacterial action ↓ TNF and other pro-inflammatory mediators | \nMany small RCT demonstrated their efficacy | \nNo EBM-validated Heterogeneity of patients treated High costs | \n
Blood purification techniques | \nRemoval of mediators | \nMany small RCT demonstrated their efficacy | \nNot selective Heterogeneity of techniques (i.e., HVHV vs. plasma adsorption) Heterogeneity of patients treated Need of anticoagulation Not selective | \n|
Not yet available | \nInterferon-γ | \nEnhanced production of pro-inflammatory mediators | \nSome small RCT and case reports demonstrated its efficacy | \nPossible septic shock-like Systemic inflammatory reactions | \n
GMC-SF | \nEnhanced production of immune cells | \n” | \nPossible septic shock-like Systemic inflammatory reactions | \n|
IL-7 | \nEnhanced production of pro-inflammatory mediators | \n” | \nPossible septic shock-like Systemic inflammatory reactions | \n|
Immune checkpoint inhibitors | \nReduced apoptosis | \n” | \nPotentially severe and life-threatening side effects High costs No RCT available | \n
Possible immunomodulating treatments in septic shock.
Presently, according to the SSC guidelines [2], the immune-targeted approaches are limited to the administration of steroids in not fluid and catecholamine-responding SS, whereas the use of intravenous immunoglobulins (IvIg) is discouraged. Actually, this latter position is questionable as a number of trials performed in several thousands of patients demonstrated that (a) the administration of IvIg is associated with the reduction of mortality in different subsets of SS patients; (b) among the different preparations available, the only ones containing supranormal concentrations of IgM and IgA appears more effective, and (c) the improvement of survival is time-dependent, as a ~6% increase of mortality has been observed for every day of delay in the administration [34].
\nBesides steroids and IvIg, other treatments aimed to modulate the immune response include blood purification (BPT) techniques and a number of substances able to boost it.
\nSince the 1980s, a number of extracorporeal techniques have been developed aiming to remove the “toxic” mediators responsible for the clinical manifestations of SS.
\nIndependently from their principle of functioning (see later), the BPT consists in an extracorporeal circuit where the patient’s blood flows till enters in the depurative device; once the latter is passed, the blood returns to the patient. According to the principle used, the BPT can be subdivided into (a) blood processing or (b) plasma processing techniques. In the former, the whole blood is depurated via a number techniques, which differ in terms of type and surface of the membranes used, their permeability to the high molecular weight of the septic mediators, etc., whereas in the latter the plasma is separated from the blood, processed in a cartridge, and reinfused downstream. The mediators can be eliminated through the membranes or adsorbed over it. In both cases, the neutralizing capabilities are time-limited. A detailed description of the BPT is beyond the aim of this chapter, but some considerations are necessary. First, there are no studies clearly demonstrating the superiority of one of them, even if some meta-analysis indicates that the those using the adsorption are more effective; (b) they can remove also antibiotics, nutrients, vitamins, hormones, etc.; (c) they require anticoagulation; and, most importantly; and (d) they are not selective and thus remove pro- as well as anti-inflammatory mediators [35].
\nDifferent substances have been used or likely will be used in the next future (Table 9) to enhance the depressed immune function in septic and non-septic critically ill patients, including [36, 37]:
Interferon-γ (IFN-γ) is a cytokine produced by helper T cell and an activator of monocytes. Different case series and case report performed in a limited number of patients demonstrated that its administration was associated with an increased HLA-DR expression; however, presently there are no RCT fulfilling the EBM criteria demonstrating a beneficial effect on the outcome of patients with SS.
Granulocyte-macrophage colony-stimulating factor (GMC-SF) stimulates the production of neutrophils from the bone marrow. Even if prophylactic use in neutropenic patients did not demonstrate any beneficial effect, a number of investigations demonstrated that its administration was associated with an improved outcome especially in patients with a decreased HLA-DR expression.
Interleukin-7 (IL-7) is a cytokine released by bone marrow and thymus cells that prompts the growth and the differentiation of T cells. This substance is considered an immune-boosting agent in patients with cancer and multifocal leukoencephalopathy and in septic patients suffering from immunoparalysis.
Programmed death inhibitors (PD1i) are proteins whose effect is to block the programmed death of immune cells, which appears to be a critical factor for the progression of cancer. This approach is new as it is aims to increase the immune response to the cancer cells without interfering with their metabolism. Due to their mechanism of action, their administration could determine a potentially life-threatening inflammatory reaction caused by the sudden release of mediators determining a “cytokine storm”; although their use is not codified yet in critically ill septic patients, in a recent RCT, the restoration of the immune response in the absence of a hyperinflammatory reaction was demonstrated in some SS patients given a novel PD1i at different doses [38].
Independently from its source, septic shock can be considered a double-step process: the initial phase is characterized by an intense inflammatory response that is counterbalanced by the production of several anti-inflammatory substances aiming to restore the immunity pre-sepsis steady state. However, in many cases this compensatory mechanism prevails and not only extinguishes the initial response but determines a condition of immunoparalysis that dominates the clinical course and influences the outcome. Unfortunately, the current approach is mainly directed against the initial inflammatory phase although some techniques of monitoring of the immune function are currently developed and others are being studied. The same concepts apply to treatments directed to potentiate the immune capabilities, but in this case the goal appears to be still far.
\nTitanium (Ti) is a lustrous metal with a silver color. This metal exists in two different physical crystalline state called body centered cubic (bcc) and hexagonal closed packing (hcp), shown in Figure 1 (a) and (b), respectively. Titanium has five natural isotopes, and these are 46Ti, 47Ti, 48Ti, 49Ti, 50Ti. The 48Ti is the most abundant (73.8%).
\n\nCrystalline state of titanium: (a) bcc, and (b) hcp [8].
Titanium has high strength of 430 MPa and low density of 4.5 g/cm3, compared to iron with strength of 200 MPa and density of 7.9 g/cm3. Accordingly, titanium has the highest strength-to-density ratio than all other metals. However, titanium is quite ductile especially in an oxygen-free environment. In addition, titanium has relatively high melting point (more than 1650°C or 3000°F), and is paramagnetic with fairly low electrical and thermal conductivity. Further, titanium has very low bio-toxicity and is therefore bio-compatible. Furthermore, titanium readily reacts with oxygen at 1200°C (2190°F) in air, and at 610°C (1130°F) in pure oxygen, forming titanium dioxide. At ambient temperature, titanium slowly reacts with water and air to form a passive oxide coating that protects the bulk metal from further oxidation, hence, it has excellent resistance to corrosion and attack by dilute sulfuric and hydrochloric acids, chloride solutions, and most organic acids. However, titanium reacts with pure nitrogen gas at 800°C (1470°F) to form titanium nitride [1, 2].
\nSome of the major areas where titanium is used include the aerospace industry, orthopedics, dental implants, medical equipment, power generation, nuclear waste storage, automotive components, and food and pharmaceutical manufacturing.
\nTitanium is the ninth-most abundant element in Earth‘s crust (0.63% by mass) and the seventh-most abundant metal. The fact that titanium has most useful properties makes it be preferred material of future engineering application. Moreover, the application of titanium can be extended when alloyed with other elements as described below.
\nAn alloy is a substance composed of two or more elements (metals or nonmetals) that are intimately mixed by fusion or electro-deposition. On this basis, titanium alloys are made by adding elements such as aluminum, vanadium, molybdenum, niobium, zirconium and many others to produce alloys such as Ti-6Al-4V and Ti-24Nb-4Zr-8Sn and several others [2]. These alloys have exceptional properties as illustrated below. Depending on their influence on the heat treating temperature and the alloying elements, the alloys of titanium can be classified into the following three types:
\nThese alloys contain a large amount of α-stabilizing alloying elements such as aluminum, oxygen, nitrogen or carbon. Aluminum is widely used as the alpha stabilizer for most commercial titanium alloys because it is capable strengthening the alloy at ambient and elevated temperatures up to about 550°C. This capability coupled with its low density makes aluminum to have additional advantage over other alloying elements such as copper and molybdenum. However, the amount of aluminum that can be added is limited because of the formation of a brittle titanium-aluminum compound when 8% or more by weight aluminum is added. Occasionally, oxygen is added to pure titanium to produce a range of grades having increasing strength as the oxygen level is raised. The limitation of the α alloys of titanium is non-heat treatable but these are generally very weldable. In addition, these alloys have low to medium strength, good notch toughness, reasonably good ductility and have excellent properties at cryogenic temperatures. These alloys can be strengthened further by the addition of tin or zirconium. These metals have appreciable solubility in both alpha and beta phases and as their addition does not markedly influence the transformation temperature they are normally classified as neutral additions. Just like aluminum, the benefit of hardening at ambient temperature is retained even at elevated temperatures when tin and zirconium are used as alloying elements.
\nThese alloys contain 4–6% of β-phase stabilizer elements such as molybdenum, vanadium, tungsten, tantalum, and silicon. The amount of these elements increases the amount of β-phase is the metal matrix. Consequently, these alloys are heat treatable, and are significantly strengthened by precipitation hardening. Solution treatment of these alloys causes increase of β-phase content mechanical strength while ductility decreases. The most popular example of the α-β titanium alloy is the Ti-6Al-4V with 6 and 4% by weight aluminum and vanadium, respectively. This alloy of titanium is about half of all titanium alloys produced. In these alloys, the aluminum is added as α-phase stabilizer and hardener due to its solution strength-ening effect. The vanadium stabilizes the ductile β-phase, providing hot workability of the alloy.
\nThe α-β titanium alloys have high tensile strength, high fatigue strength, high corrosion resistance, good hot formability and high creep resistance [3].
\nTherefore, these alloys are used for manufacturing steam turbine blades, gas and chemical pumps, airframes and jet engine parts, pressure vessels, blades and discs of aircraft turbines, aircraft hydraulic tubing, rocket motor cases, cryogenic parts, and marine components [4].
\nThese alloys exhibit the body centered cubic crystalline form shown in Figure 1 (a). The β stabilizing elements used in these alloy are one or more of the following: molybdenum, vanadium, niobium, tantalum, zirconium, manganese, iron, chromium, cobalt, nickel, and copper. Besides strengthening the beta phase, these β stabilizers lower the resistance to deformation which tends to improve alloy fabricability during both hot and cold working operations. In addition, this β stabilizer to titanium compositions also confers a heat treatment capability which permits significant strengthening during the heat treatment process [4].
\n\nAs a result, the β titanium alloys have large strength to modulus of elasticity ratios that is almost twice those of 18–8 austenitic stainless steel. In addition, these β titanium alloys contain completely biocompatible elements that impart exceptional biochemical properties such as superior properties such as exceptionally high strength-to-weight ratio, low elastic modulus, super-elasticity low elastic modulus, larger elastic deflections, and low toxicity [1, 3].
\nThe above properties make them to be bio-compatible and are excellent prospective materials for manufacturing of bio-implants. Therefore, nowadays these alloys are largely utilized in the orthodontic field since the 1980s, replacing the stainless steel for certain uses, as stainless steel had dominated orthodontics since the 1960s [2].
\nBecause of alloying the titanium achieve improved properties that make it to be preferred material of choice for application in aerospace, medical, marine and instrumentation. The extent of improvement to the properties of titanium alloys and ultimately the choice of area of application is influenced by the methods of production and processing as discussed in the subsequent sections.
\nThe base metal required for production of titanium alloys is pure titanium. Pure titanium is produced using several methods including the Kroll process. This process produces the majority of titanium primary metals used globally by industry today. In this process, the titanium is extracted from its ore rutile—TiO2 or titanium concentrates. These materials are put in a fluidized-bed reactor along with chlorine gas and carbon and heated to 900°C and the subsequent chemical reaction results in the creation of impure titanium tetrachloride (TiCl4) and carbon monoxide. The resultant titanium tetrachloride is fed into vertical distillation tanks where it is heated to remove the impurities by separation using processes such as fractional distillation and precipitation. These processes remove metal chlorides including those of iron, silicon, zirconium, vanadium and magnesium. Thereafter, the purified liquid titanium tetrachloride is transferred to a reactor vessel in which magnesium is added and the container is heated to slightly above 1000°C. At this stage, the argon is pumped into the container to remove the air and prevent the contamination of the titanium with oxygen or nitrogen. During this process, the magnesium reacts with the chlorine to produce liquid magnesium chloride thereby leaving the pure titanium solid. This process is schematically presented in Figure 2.
\nKroll process for production of titanium: (a) chlorination, (b) fractional distillation [5].
The resultant titanium solid is removed from the reactor by boring and then treated with water and hydrochloric acid to remove excess magnesium and magnesium chloride leaving porous titanium sponge, which is jackhammered, crushed, and pressed, followed by melting in a vacuum electric arc furnace using expendable carbon electrode. The melted ingot is allowed to solidify in a vacuum atmosphere. This solid is often remelted to remove inclusions and to homogenize its constituents. These melting steps add to the cost of producing titanium, and this cost is usually about six times that of stainless steel. Usually the titanium solid undergo further treatment to produce titanium powder required in alloying process. The basic methods used to produce titanium powder are summarized below.
\nThe first method is called the Armstrong process, shown in Figure 3, in which the powder is made as the product of extractive processes that produce primary metal powder. This process is capable of producing commercially pure titanium (Ti) powder by the reduction of titanium tetrachloride (TiCl4) and other metal halides using sodium (Na). This process produces powder particles with a unique properties and low bulk density. To improve powder properties such as the particle size distribution and the tap density, additional post processing activities such as dry and wet ball milling are applied. The narrowed particle size distributions are necessary for typical powder metallurgical processes. In addition, the resultant powder’s morphology produced by the Armstrong process provide for excellent compressibility and compaction properties that result in dense compacts with increased green strength than those produced by the irregular powders. For this reason, the powders can even be consolidated by traditional powder metallurgy techniques such as uniaxial compaction and cold isostatic pressing. Figure 4 illustration the scanning electron microscope images of the titanium powders of the Armstrong process. As seen in the figure, the powder has an irregular morphology made of granular agglomerates of smaller particles.
\nIllustration of the Armstrong process [5].
SEM micrographs of CP-Ti produced by Armstrong process [5].
The hydride-dehydride (HDH) process, illustrated in Figure 5, is used to produce titanium powder using titanium sponge, titanium, mill products, or titanium scrap as the raw material. The hydrogenation process is achieved using a batch furnace that is usually operated in vacuum and/or hydrogen atmospheric conditions. The conditions necessary for hydrogenation of titanium are pressure of one atmospheric and temperatures of utmost 800°C. This process results in forming of titanium hydride and alloy hydrides that are usually brittle in nature. These metal hydrides are milled and screened to produce fine powders. The powder is resized using a variety of powder-crushing and milling techniques may be used including: a jaw crusher, ball milling, or jet milling. After the titanium hydride powders are crushed and classified, they are placed back in the batch furnace to dehydrogenate and remove the interstitial hydrogen under vacuum or argon atmosphere and produce metal powder. These powders are irregular and angular in morphology and can also be magnetically screened and acid washed to remove any ferromagnetic contamination. Finer particle sizes can be obtained, but rarely used because oxygen content increases rapidly when the powder is finer than −325 mesh. Powder finer than −325 mesh also possess more safety challenges [5]. The powder can be passivated upon completion of both the hydrogenating and dehydrogenating cycles to minimize exothermic heat generated when exposed to air.
\nHydride-dehydride process for obtaining of titanium powders [6].
The hydride-dehydride process is relatively inexpensive because the hydrogenation and dehydrogenation processes contribute small amount of cost to that of input material. The additional benefit of this process is the fact that the purity of the powder can be very high, as long as the raw material’s impurities are reduced. The oxygen content of final powder has a strong dependence on the input material, the handling processes and the specific surface area of the powder. Therefore, the main disadvantages of hydride-dehydride powder include: the powder morphology is irregular, and the process is not suitable for making virgin alloyed powders or modification of alloy compositions if the raw material is from scrap alloys (Figure 6) [5].
\nSEM micrographs of CP-Ti produced by HDH [5].
Conventional sintering, shown in Figure 7, is one of the widely applied powder metallurgy (PM) based method for manufacturing titanium alloys. In this method, the feedstock titanium powder is mixed thoroughly with alloying elements mentioned in Section 2 using a suitable powder blender, followed by compaction of the mixture under high pressure, and finally sintered. The sintering operation is carried out at high temperature and pressure treatment process that causes the powder particles to bond to each other with minor change to the particle shape, which also allows porosity formation in the product when the temperature is well regulated. This method can produce high performance and low cost titanium alloy parts. The titanium alloy parts produced by powder metallurgy have several advantages such as comparable mechanical properties, near-net-shape, low cost, full dense material, minimal inner defect, nearly homogenous microstructure, good particle-to-particle bonding, and low internal stress compared with those titanium parts produced by other conventional processes [7].
\nPowder metallurgy process [7].
Self-propagating high temperature synthesis (SHS), shown in Figure 8, is another PM based process used to produce titanium alloys. The steps in this process include: mixing of reagents, cold compaction, and finally ignition to initiate a spontaneous self-sustaining exothermic reaction to create the titanium alloy [7].
\nSHS process [7].
Although the above PM processes are mature technologies for fabrication of bone implants they have difficulties of fabricating porous coatings on surfaces that are delicate or with complex geometries. In addition, these processes tend to produce brittle products because of cracks and oxides formed inside the materials. Further, the high costs and poor workability associated with these PM processes restrict their application in commercial production of bone implants. Consequently, new methods, based on additive manufacturing principles were developed [7].
\nThe definitions of advanced methods of production is the use of technological method to improve the quality of the products and/or processes, with the relevant technology being described as “advanced,” “innovative,“ or “cutting edge.” These technologies evolved from conventional processes some of which have been developed to achieve various components of titanium base alloys and aluminides. Atomisation processes are among the most widely used cutting edge methods for production of titanium alloys [5].
\nAtomisation processes are used to make alloyed titanium powders. In these processes, the feedstock material is generally titanium, and the alloy powders produced are further processed typically to manufacture components using processes such as hot isostatic pressing (hip). As mentioned previously, it is generally believed that alloyed powders are not suitable for cold compaction using conventional uniaxial die pressing methods. Moreover, the inherent strength of the alloyed powders is too high, making it difficult to deform the particles in order to achieve desired green density. The atomisation processes produce relatively spherically shaped titanium alloy powders that are most suitable for additive manufacturing using techniques such as selective laser melting or electron beam melting. These spherical powders are also required for manufacturing titanium components using metal injection molding techniques. Typically, additive manufacturing and metal injection molding processes require particle sizes of powders to be in the range of 100 μm to ensure good flowability of the powder during operations. However, the challenge of the atomisation processes usually is that powders produced tend to have a wide particle size distribution, from a few to hundreds of micrometers. Examples of atomisation processes are gas atomisation and plasma atomisation processes described below [5].
\nIn the gas atomisation process, shown in Figure 9, the metal is usually melted using gas and the molten metal is atomised using an inert gas jets. The resultant fine metal droplets are then cooled down during their fall in the atomisation tower. The metal powders obtained by gas-atomization offer a perfectly spherical shape combined with a high cleanliness level. However, even though gas atomisation is, generally, a mature technology, its application need to be widened after addressing a few issues worth noting such as considerable interactions between droplets while they cool during flight in the cooling chamber, causing the formation of satellite particles. Also, due to the erosion of atomising nozzle by the liquid metal, the possibility for contamination by ceramic particles is high. Usually, there may also be argon gas entrapment in the powder that creates unwanted voids [5].
\nSchematic diagrams of gas atomisation process [5].
Plasma atomisation, shown in Figure 10, uses a titanium wire alloy as the feed material which is a significant cost contributing factor. The titanium alloy wire, fed via a spool, is melted in a plasma torch, and a high velocity plasma flow breaks up the liquid into droplets which cool rapidly, with a typical cooling rate in the range of 100–1000°C/s. Plasma atomisation produces powders with particle sizes ranging from 25 to 250 μm. In general, the yield of particles under 45 μm using the plasma wire atomisation technique is significantly higher than that of conventional gas atomisation processes [5].
\nSchematic diagrams of plasma atomisation process [5].
The future methods for production of titanium alloys depend on the demand of these products and to what extend nature will be able to provide them. The demand for titanium alloys shall also influence the number and type of technological breakthroughs, the extent of automation, robotics’ application, the number of discoveries for new titanium alloys, their methods of manufacturing, and new areas of application. Automation is an important aspect of the industry’s future and already a large percentage of the manufacturing processes are fully automated. In addition, automation enables a high level of accuracy and productivity beyond human ability—even in hazardous environments. And while automation eliminates some of the most tedious manufacturing jobs, it is also creating new jobs for a re-trained workforce. The new generation of robotics is not only much easier to program, but also easier to use due to extra capabilities such as voice and image recognition during operations, they are capable of doing precisely what you ask them to do. The discovery of new titanium alloys, or innovative uses of existing ones, is essential for making progress in many of the technological challenges we face. This discovery can result in new synthesis methods of new alloy compounds and design of super alloys, theoretical modeling and even the computational prediction of titanium alloys. This discovery requires that new methods of manufacturing are developed. In light of this, “additive manufacturing” is being developed and this is viewed as a groundbreaking development in manufacturing advancement that offers manufacturers powerful solutions for making any number of products cost-effectively and with little waste. Examples of additive manufacturing technologies are cold spray, 3-D printing, electron beam melting, and selective laser melting. To fabricate alloy surfaces using these technologies, alloying elements are mixed thoroughly in the feedstock powder and the fabrication processes proceed as described in the following paragraphs [7, 8].
\nCold spray (CS) process, schematically shown in Figures 11 and 12 can deposit metals or metal alloys or composite powders on a metallic or dielectric substrate using a high velocity (300–1200 m/s) jet of small (5–50 μm) particles injected in a stream of preheated and compressed gas passing through a specially designed nozzle. The main components of a generic CS system include the source of compressed gas, gas heater, powder feeder, spray nozzle assembly, and sensors for gas pressure and temperature. The source of compressed gas acquires the gas from an external reservoir, compresses it to desired pressure and delivers it into the gas heater. Then, the gas heater preheats the compressed gas in order to increase its enthalpy energy. The preheated gas is delivered into the spray nozzle assembly whose convergent/divergent geometry not only converts the enthalpy energy of the gas into kinetic energy but also mixes the metal powders with the gas proportionately. The powder feeder meters and injects the powder in the spray nozzle assembly. The sensors for the gas pressure and temperature are responsible for regulating the preset pressure and temperature of the gas stream. The powder injection point in the spray nozzle assembly, the gas pressure, and gas temperature distinguish the low pressure-CS system (LP-CS) from the high pressure CS (HP-CS). In the LP-CS system, the feedstock powder is injected in the downstream side of the convergent section of the nozzle assembly, while in the HP-CS system; the powder is injected in the upstream side of the convergent/diverging section of the nozzle assembly as illustrated in Figures 11 and 12. Several other parameters which contribute towards the distinguishing of the CS systems are summarized in Table 1 [8].
\nLow pressure CS process configuration [8].
High pressure CS process configuration [8].
Operation parameters for CS systems [8].
3-D printing is an additive manufacturing method that applies the principle of adding material to create structures using computer aided design (CAD), part modeling, and layer-by-layer deposition of feedstock material. This cutting-edge technology is also called stereolithography, and is illustrated in Figure 13 [8].
\n3D-printing process [8].
In this technology, the pattern is transferred from a digital 3D model, stored in the CAD file, to the object using a laser beam scanned through a reactive liquid polymer which hardened to create a thin layer of the solid. In this manner, the structure is fabricated on the desired surface. This method was proved in the laboratory setup is still being integrated in commercial set-up because 3-D printing is the most widely recognized version of additive manufacturing. For this reason, the inventors and engineers for this process have for years used machines costing anywhere from a few thousand dollars to hundreds of thousands for rapid prototyping of new products. It can be noted that all of the additive-manufacturing processes follow this same basic layer-by-layer deposition principle but with slightly different ways such as using powdered or liquid polymers, metals, metal-alloys or other materials to produce a desired product [8].
\nElectron beam melting (EBM), shown in Figure 14, is one of the additive manufacturing processes which fabricated titanium coatings by melting and deposition of metal powders, layer-by-layer, using a magnetically directed electron beam. Though this method was proved to be successful, it has high set-up costs due to the requirement of high vacuum atmosphere [7].
\nElectron beam melting method [1].
Selective laser melting (SLM), shown in Figure 15 is the second additive manufacturing method for titanium alloy coatings which completely melt the powder using a high-power laser beam. Similarly, this method is costly because it requires advanced high rate cooling systems. Moreover, the fluctuations of temperatures during processing negatively affect the quality of the products [1].
\nSelective laser melting method [1].
This chapter described the titanium as a metal that exists naturally with two crystalline forms. The chapter highlighted the properties of titanium metal that influence its application. The fact that titanium has advantageously unique properties that can be improved by alloying with other elements makes it to be preferred engineering material for future application in such areas as biomedical implants, aerospace, marine structures, and many others. The chapter discussed the traditional, current and future methods necessary to produce structures using titanium and titanium alloys. Further, the chapter suggested “additive manufacturing methods” as advanced methods for future manufacturing because they offer powerful solutions for making any type and number of products cost-effectively and with little waste. The examples of these methods are cold spray, 3-D printing, electron beam melting, and selective laser melting. Finally, the various processes used during fabrication of alloys using these methods were also presented.
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