Table shows disorders characterized in AA and the mechanism of action of MSCs in AA pathology.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"2617",leadTitle:null,fullTitle:"Molecular Regulation of Endocytosis",title:"Molecular Regulation of Endocytosis",subtitle:null,reviewType:"peer-reviewed",abstract:'Molecular Regulation of Endocytosis is a compilation of scientific "short stories" about the entry of external substances into cells. As one can see from the chapters, endocytosis regulates diverse processes such as homeostasis of the cell, signal transduction, entry of pathogens and viruses. In addition to the experimental techniques embedded in each chapter, entire chapters are dedicated to experimental approaches that will be useful to all scientists and their model systems. For those more clinically oriented, the final chapters look to the future and ways of utilizing endocytic pathways for therapeutic purposes.',isbn:null,printIsbn:"978-953-51-0662-3",pdfIsbn:"978-953-51-4291-1",doi:"10.5772/2989",price:139,priceEur:155,priceUsd:179,slug:"molecular-regulation-of-endocytosis",numberOfPages:468,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"dfd1b4de49c737272c722b73a0d7facb",bookSignature:"Brian Ceresa",publishedDate:"July 6th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/2617.jpg",numberOfDownloads:54123,numberOfWosCitations:208,numberOfCrossrefCitations:99,numberOfCrossrefCitationsByBook:3,numberOfDimensionsCitations:239,numberOfDimensionsCitationsByBook:4,hasAltmetrics:1,numberOfTotalCitations:546,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 23rd 2011",dateEndSecondStepPublish:"December 21st 2011",dateEndThirdStepPublish:"March 29th 2012",dateEndFourthStepPublish:"June 17th 2012",dateEndFifthStepPublish:"July 17th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8,9,10",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"48114",title:"Dr.",name:"Brian",middleName:null,surname:"Ceresa",slug:"brian-ceresa",fullName:"Brian Ceresa",profilePictureURL:"https://mts.intechopen.com/storage/users/48114/images/system/48114.jpg",biography:"Dr. Brian Ceresa graduated from Vanderbilt University in Nashville, Tennessee in 1995. Following post-doctoral training at the University of Iowa and The Scripps Research Institute, he joined the Department of Cell Biology at the University of Oklahoma Health Sciences Center in Oklahoma City in 2000. As an independent investigator, his National Institute of Health funded research has focused on understanding the molecular mechanisms that regulate the endocytic trafficking of the epidermal growth factor receptor and how endocytic trafficking affects signaling by the receptor. In addition to authoring numerous scientific and review articles, he has served as a lecturer to medical, dental, and graduate students. 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The autoimmunity process in AA occurs due to the activation of the oligoclonal cytotoxic T cells that will lead the hematopoietic cells to apoptosis. Its triggering occurs by the imbalance between CD8 +, CD4 +, T-Helper (Th), Th type 1 (Th1), Th type 2 (Th2), Th17 type (Th17), Natural Killer (NK) and T-regulatory cells (Treg). Besides, there is also an abnormal production of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and transformed growth factor (TGF) [3, 4, 5, 6, 7].
\nBenefits of MSCs paracrine effect (immunomodulatory) on immune cells imbalance. MSCs secrete many soluble mediators, including anti-inflammatory cytokines stimulation that regulates APCs functions capable to decrease proliferation of DCs and regulate macrophage activity by polarizing proinflammatory phenotype (M1) to anti-inflammatory phenotype (M2). Therefore, they are responsible for humoral response regulation by the decrease of B cells proliferation and antibodies production. The APCs are also capable to regulate the T cell activities as well as inhibit cytotoxic T cell proliferation and upregulation and increase of Treg cells. MSCs may also promote the decrease of proinflammatory cytokines secretion. And act on the homing regulation of HSCs mechanism on stages of adhesion, expansion, and migration through chemokine and other factors secretion.
AA disorders x MSC benefits | \n|
---|---|
Aberrant secretion of pro-inflammatory cytokines ↑IFN-γ ↑TNF-α ↑IL-17 ↑IL-2; | \nImmunomodulatory effect: Decreased secretion of proinflammatory cytokines, ↓IFN-γ ↓TNF-α ↓IL-17 ↓IL-2; | \n
Imbalance between CD8+ and CD4+ T cells; ↑ Cytotoxic T cell ↓Treg | \nRegulation of T cell activity and Treg cell proliferation ↓ Cytotoxic T cell ↑Treg | \n
Apoptosis of HSC and progenitor cells ↑ Apoptosis | \nProtect BM by antiapoptotic properties ↓ Apoptosis | \n
BM hypoplasia | \nRecovery of BM ↑ Hematopoiesis improvements ↑ CXCL12 ↑FLT3LG ↑TPO ↑IL-6 | \n
Abnormal APC activation ↑ DCs ↑ Macrophage | \nRegulate APCs functions ↓ DCs maturation and proliferation and ↓ Macrophages M1 activation ↑ Macrophages M2 activation | \n
Abnormal humoral response ↑ B cells ↑ Antibodies production | \nRegulate humoral response ↓ B cells ↓ Antibodies production | \n
Irregular activity of NK cells ↑ Cytotoxicity of NK cells | \n↓ Cytotoxicity of NK cells | \n
Table shows disorders characterized in AA and the mechanism of action of MSCs in AA pathology.
MSC can decrease secretion of pro-inflammatory cytokines such as TGF, IFN-γ TNF-α, IL-17, regulate T cell activity, inhibit proliferation of cytotoxic T cells and stimulate Treg activity. MSC has anti-apoptotic properties, protects BM environment and recovery BM through cytoprotective effect and stimulates macrophages M2 activation and hematopoiesis improvements. MSCs may also regulate APCs functions, humoral response, and cytotoxicity of NK cells.
For severe cases, immunosuppressive therapy is accepted as the first-line treatment option and the allogeneic transplantation of BM and hematopoietic stem cells (HSCs). However, 30–40% of patients with severe aplastic anemia (SAA) remain pancytopenia following the treatment. The transplant option still has a restricted number of compatibility between suitable donors. Additionally, patients aged >50 years are not eligible for transplant [8].
\nA new viable alternative for the treatment of AA has been sought and the use of mesenchymal stem (MSCs) therapy may be a promising therapeutic candidate mainly because of their hypoimmunogenicity and the lack of rejection after transplants and immunomodulatory effects, which may promote decreasing the symptoms of the disease [9, 10]. These benefits are attributed to the paracrine effects, above all by its ability to regulate the immune system [11].
\nActually, is known that MSCs have wide therapeutically potential attributed by paracrine effects and the past decades have seen explosion research directed to understand better these MSCs mechanism and function [12]. One of the main and most important features of MSCs is the low expression of human leukocyte antigen (HLA) class I, with no expression of HLA class II. This feature allows the cell to be characterized as hypoimmunogenic, since it does not stimulate the patient’s immune system and can be used safely in transplants [13]. More recently, the studies showed that the main cause of AA is autoimmunity. Through the secretion of bioactive molecules, MSCs have the capacity of regulating immune responses. The mechanism of MSCs may decrease secretion of proinflammatory cytokines such as transforming growth factor (TGF), IFN-γ TNF-α, interleukin (IL)-17 and increase secretion of many soluble mediators, including anti-inflammatory cytokines stimulation that inhibit antigen-presenting cells (APCs) functions, which are capable to decrease proliferation of dendritic cells (DCs) and regulate macrophage activity by polarizing proinflammatory phenotype (M1) to anti-inflammatory phenotype (M2) [14, 15]. Therefore, the decrease of B cells proliferation and antibodies production and adjustment of T cells activities as well as inhibit the proliferation of cytotoxic T cells and stimulate Treg activity [16].
\nMSCs therapy has gained space due to its vast therapeutic potentials such as immunomodulation mechanisms and main safety as bioproduct. Thus, this chapter will discuss the challenges of allogeneic MSCs as an alternative for an efficient therapeutic in AA immune-mediated treatment.
\nAA is a disorder characterized by BM hypocellularity, and peripheral blood pancytopenia due to a deficit of HSCs. It affects mostly children, young adults, and adults, over 60 years of age [17]. This condition can be similar to other hematologic disorders, however, in most cases, the AA is caused by reduced HSCs function, an increase in HSCs apoptosis level, consequently, the decreased of HSCs and hematopoietic progenitors and lastly, microenvironment fat replacement [18, 19].
\nFollowing the patient diagnosis, AA can be considered as moderate or severe. The patients with pancytopenia may present symptoms of anemia purpura or skin hemorrhage, and in most of the cases there is an infection association, that may worsen the symptoms [20]. Three main criteria are used for the diagnostic: neutrophil count lower than 0.5 × 109 cells/L, reticulocyte count lower than 1% and platelet count lower than 20 × 109 cells/L [21]. To confirm acquired AA, the clinical case must be differentiated from other hematological diseases, as well as from the signs of malignant cell transformation or myelodysplasia [22].
\nNormally the first AA etiology is uncertain and for this reason, the disorder is considered heterogeneous in origin and characterized as idiopathic [23]. AA is associated with exposures to chemical agents (pesticides and benzene), cytotoxic drugs (antineoplastics, antibiotics, non-steroidal anti-inflammatory drugs), active viral infections exposure (Epstein Barr, hepatitis virus, human immunodeficiency virus parvovirus) and radiation exposure [18, 24, 25]. However, these causes considered secondary etiologies, since the studies are directed to the primary etiology of AA to autoimmunity [26, 27]. AA pathogenesis involves an immunity dysfunction, initially provoked by the activated T cells [23], which leads to an abnormal hematopoietic microenvironment, destruction of hematopoietic stem/progenitor cell and differentiation deficiency. These findings suggest that the immune system plays an important role in the pathogenesis of AA.
\nCurrently, the studies of AA etiology are focused on the immune mechanism of hematopoietic cells destruction. Many researchers [28, 29, 30, 31] have demonstrated that the dysfunction of T cells might be a key factor in recent characterization as an autoimmune disease [28]. Most of the acquired AA is the result of an immune-mediated process as an imbalance between CD8+ and CD4+ T cells, including Th1, Th2, Treg and Th17 cells, NK, and natural killer T cells (NK T) that leads to apoptosis of BM cells triggered by cytotoxic T cells activation [6, 17].
\nThe abnormal immunoregulatory cell functions observed in AA can be attributable to abnormal antigen stimulation and some inappropriate T cells activation [28]. Studies demonstrated that patients with AA have a significantly increased proportion of Th1 cells, and showed a reduced fraction of natural killer T cells and regulatory T cells, together with an increased level of TNF-α, a consequent elevation of IL-6, IL-8, and IL17 productions [18]. Additionally, there is also an abnormal production of proinflammatory cytokines including IFN-γ and TGF [4, 5, 28, 32]. The new T cells subset was characterized as Th17 and currently is known that both Th17 cells and the cytokine IL-17, which is secreted by Th17 cells, also is in an association with AA pathogenesis [31]. Studies showed that AA patients who presented an increase in the frequency of Th17 cells had a positive correlation with an increase in the IFN- γ and IL-17 expression. Autoimmunity promotes inflammatory Th17 immune responses that contributed to disease pathophysiology [29].
\nOtherwise, AA is attributed to inappropriate antigen stimulation and abnormal APCs activation [28], resulting in the priming of T cells specific for hematopoietic cells [33, 34]. APCs exhibit a significant increase in the expression of major histocompatibility class 2 (MHCII), increasing the recognition of CD4+ T cells. In AA, T cells are also stimulated by unknown antigens or abnormal APC activation as DCs and macrophages, which trigger a series of immune responses. Studies have shown that immunoregulatory cell dysfunction leads to a corresponding immune tolerance disorder and renders the body unable to recognize autologous hematopoietic cells [28].
\nAlthough the definitive mechanism has not been identified, some genetic factors are the targets of ongoing research, such as the molecular basis of the aberrant immune response and hematopoietic cell deficiency, telomere repair gene mutations in the target cells and unregulated T cell activation pathways and cytokine genes polymorphisms [9, 26, 28]. These changes in the nucleotide sequence and gene regulation are associated with an increased immune response and suggest a genetic basis for aberrant T cells activation in BM failure [35].
\nThe treatment depends on the severity of the disease, once for moderate cases are based on red blood cell (RBC) transfusions, on platelet transfusions to prevent bleeding, and on supportive care in association with antibiotic aiming to reestablish blood cell volume and prevent secondary infections [17]. However, the pancytopenia of many moderate cases may progress to severe [21]. For severe cases, immunosuppressive therapy is accepted as a first-line treatment option. However, 30–40% of patients with SAA remain pancytopenia following the treatment. Patients with SAA, which are refractory or have a relapse after immunosuppressive treatment, may undergo allogeneic hematopoietic stem cells transplantation (HSCT). However, about one-third of patients do not have a suitable donor for HSCT. Additionally, patients aged >50 years are not eligible for transplant [8].
\nFurthermore, the immunosuppressive drug treatment has several side effects on patients. On the other hand, the patients often do not respond adequately to the therapies and are not suitable for life treatment (refractory patients) [24]. Therefore, immunosuppressive drugs are considered supporting AA treatment, once it does not promote the cure [20].
\nGenerally, patients are treated with allogeneic HSCs or whole BM transplantations, which replace since HSCs, hematopoietic precursors, until differentiated bloodstream cells and immune system cells. However, in all types of transplants, the treatment involves a combination of immunosuppressive agents or radiation therapy to prevent and to eliminate residual host BM [24]. The transplantation success varies according to risk factors, such as age and mainly histocompatibility allogeneic HLA-matched sibling donors, which are rare for the majority of patients. Despite being well established for many years, the transplanted patients can trigger late complications, such as the development of graft versus host disease (GVHD) and infections, especially in patients who have received hematopoietic grafts from HLA antigen matched donor [36, 37]. Studies show that the incidence of GVHD after unrelated donor transplantation can achieve ∼14%, and overall survival index was 57% for all 8 HLA-loci matched transplants and 39% for 1-loci mismatched transplant [38]. Thus, for BM and HSCT, the immediate challenge is the extension of stem cell therapies to all patients, regardless of age, with a histocompatible sibling [24].
\nSince then a new viable alternative for the treatment of AA has been sought and the use of MSCs transplantation becomes of choice. The MSCs therapy may be a promising therapeutic candidate mainly because of their hypoimmunogenicity, the lack of rejection after transplants and immunomodulatory effects, which may promote decreasing the symptoms of the disease [39]. These benefits are attributed to MSCs paracrine effects, above all to their ability to regulate the immune system. MSCs may help for AA treatment, especially for autoimmune type [11].
\nMSCs are multipotent progenitors, which were first isolated from an adult organism by Friedenstein and colleagues in 1968, and described years later by Caplan and colleagues [40, 41]. These cells include firstly an inherent autocrine effect, as self-renewal and differentiation potential for a variety of cell types, as main adipocytes, osteoclasts, and chondrocytes [42], depending on the surrounding microenvironment conditions [43]. Currently, such cells have shown to be isolated from many postnatal and adult tissues, such as adipose tissue, umbilical cord, placenta, dental pulp, and others [44, 45].
\nInitially, the mechanism therapeutic potential of the MSCs was based only on the potential for regeneration through cellular self-renewal and its plasticity. Further studies have shown low engraft of MSCs in injured areas that questioned the hypothesis that MSCs repair tissue damage by replacing cell loss with newly differentiated cells [46, 47].
\nIt is known that MSCs have wide therapeutically potential attributed to paracrine effects and the past decades explosion research was directed to understand better these MSCs mechanism and function [12]. Although the therapeutic mechanisms of MSCs are not yet well characterized, it is possible to say that their paracrine effects consist in the secretion of bioactive molecules such as a variety of cytokines and growth factors as like anti-inflammatory, anti-apoptotic and angiogenic [46, 47, 48, 49, 50, 51].
\nMSCs can to migrate to the lesion site through signals from specific chemokines. This process called homing consists of the steps of activating adhesion molecules, rolling to the endothelium, adhesion, and migration to the tissue that is the source of chemokine inflammation production [52, 53]. The current hypothesis is that paracrine factors secreted by MSCs promote protective microenvironment and repair by local tissue-resident progenitor populations, favoring the hypothesis of detecting favorable effects even in the absence of the cells at lesion sites [54].
\nOne of the main and most important features of MSC is the low expression of HLA class I, with no expression of HLA class II. Also, MSCs do not appear to express the co-stimulatory molecules CD80 or CD86 required for effector T cell induction [55]. The absence of co-stimulatory molecules implies that any residual engagement of the T cell receptor on Th cells would result in absence of the normal immune response to a particular antigen and contribute to tolerance rather than allogeneic responses. This feature allows the cell to be characterized as hypoimmunogenic, since it does not stimulate the patient’s immune system and can be used safely in transplants [113]. As well, MSCs have properties attributed to immune functions, indicating their ability to immunomodulatory activity. Studies indicated that MSCs can regulate immune responses during chronic inflammation through the innate and adaptive immune system, regulating the recruitment and their function [56, 57].
\nThe paracrine effects of MSCs may have great importance in the treatment of autoimmune diseases. Through the secretion of bioactive molecules, MSCs have the capacity of regulating immune responses. These cells can regulate adaptive immune responses through multiple redundant pathways, interacting with various immune cells and secreting soluble mediators such as IL-6, IL-10, prostaglandin E2 (PGE2), nitric oxide (NO), transforming growth factor-β1 (TGF-β1), and hepatocyte growth factor (HGF), indoleamine-pyrrole 2, 3-dioxygenase (IDO) [58, 59]. They can regulate APCs activity, decreasing maturation and proliferation of DCs [14]. MSC also may regulate macrophage activity by polarizing its pro-inflammatory phenotype (M1) to its anti-inflammatory phenotype (M2) [15]. Therefore, suppress T cell proliferation and activation and regulate the differentiation of Th cells and act on the humoral response by inhibiting of B cell activation and antibody production [60]. MSCs may also reduce pro-inflammatory cytokines proliferation, such TNF-α, which has an important role of the pathogenesis of autoimmune diseases and chronic inflammation (Figure 1) [14, 16, 61].
\nThe first paracrine effect, showed for MSCs, was the capacity to support HSCs growth
At BM microenvironment, MSCs niche supports hematopoietic cells and produce factors recruiting HSCs and supporting hematopoiesis [64]. This mechanism occurs through chemokine secretion of C-X-C motif chemokine ligand 12 (CXCL12), which acts on the homing regulation of HSCs, regulating the stages of adhesion, expansion and migration [65, 66]. The secretion of other factors is also important in the proliferation of HSCs mechanisms such as Flt-3 ligand (FLT3LG) [67], thrombopoietin (TPO) [68] and IL-6 [17]. That despite being a proinflammatory cytokine in general, when IL-6 is secreted in BM microenvironment, is capable to stimulate hematopoiesis [69, 70].
\nMore recently, the studies showed that the main cause of AA is autoimmunity. This process occurs in the result of an imbalance between CD8 + and CD4 + T cells, including Th1, Th2, Th17, NK, leading to the death of hematopoietic cells and their precursors [28]. Many studies have hypothesized that the onset of the immune imbalance in AA begins by stimulating APCs through an unknown antigen resulting in the T cells activation [71]. Another important mechanism of MSCs is the immunomodulation mechanism. MSCs can act directly on AA imbalance by T cells suppression, inhibiting activation and proliferation of T cells [72]. MSCs also inhibit the secretion of two important cytokines present in the pathology of AA, the INF-γ and TNF-α and stimulate the proliferation of Treg, promoting the production of the anti-inflammatory cytokine IL-10 Table 1 [73, 74]. In addition, some studies also show that MSCs also acts through its anti-apoptotic effects [75].
\nIn the last years, several studies have been exploring intravenous administrations (IV) due to being safe and do not present morbidity risk for patients. However, still lack the data about the biodistribution mechanism of MSCs and about how these cells engraftment on the target organ, which is essential for the success of clinical studies. It is known that the biodistribution is influenced in vivo and in vitro conditions. Stromal cell-derived factor 1 (SDF-1) (also known as CXCL12) is upregulated at sites of injury and acts as a chemoattractant to recruit circulating or residing MSCs expressing its cognate receptor CXC chemokine receptor 4 (CXCR4). It has been demonstrated that the CXCR4-SDF-1 axis is critical for BM homing [76]. Diverse studies demonstrate that some in vitro conditions may influence the expression of adhesion molecules [77, 78]. For instance, long expansion periods [79] and cells culturing at high density may reduce CXCR4 cell expression; the cells cultured at higher confluence secrete more metalloproteinase inhibitor 3, which decreases migration of MSCs when compared to those cultured at the low confluence [80]. Hypoxia condition may increase CXCR4 expression; on the other hand, hypoxia may decrease matrix metalloproteinase-2 secretion and an increase in membrane-type 1 matrix metalloproteinase [81].
\nIn vivo engraftment is influenced by interactions of MSCs with different types of immune cells that depend on their ability to respond to signals from the immune system. On the other hands, the MSCs biodistribution and homing depend on the host niche. Interesting the MSCs migration and homing to target tissue can be influenced positively by irradiation. It has been demonstrated an increased absolute number of human MSCs in the brain, heart, bone marrow, and muscles after total body irradiation and MSCs IV administrations in mice, when compared to the untreated control [82].
\nSome animal studies evidence that MSCs can engraftment in BM after systemic administration [83]. Studies in patients showed MSCs engraftment into BM 30 days after the second MSCs IV administration. Although, after MSCs infusion was observed no recovery of hematopoietic tissue, interstitial hemorrhage, edema, and all adipocytic necrosis disappeared in BM [84]. Other studies indicate the engraftment due to myeloid and plated recovery after HSCs and MSCs transplantation [85, 86].
\nMSCs have been implicated in immunomodulatory therapy, in particular, in GVHD treatment and as an adjunct to hematopoietic stem cell transplantation (HSCT) to help enhance engraftment [87, 88]. The first major clinical trial of MSCs (Prochymal) was for the treatment of steroid-refractory of GVHD (NCT00366145) [89, 90]. The primary endpoint of the study was complete remission at day 28 after allogeneic BM-MSCs infusion but was not significantly increased compared to placebo [89, 91]. In 2012, MSCs have bens conditional approval to treat children GVHD in Canada, based on subset analysis that suggested children with GVHD were responsive to MSCs [89, 92, 93]. Many new studies have been developed in recent years; however, a few of them have attempted to look at biological correlates of response to therapy. Isolated studies reported serum biomarkers of GVHD severity including IL-2,
Cotransplantation of HSCs with (umbilical cord) UC-MSCs has been performed to study whether the last will be able to support hematopoiesis, enhance the engraftment of HSCs, and reduce the incidence of GVHD following HSCT [98, 99, 100]. These studies include adult and children in AA patients [101, 102]. Stem cells application was mainly intravenous. In some of the studies multiple (five) infusions were used. All clinical protocols have been developed in the presence of traditional immunosuppressive protocol to prevent GVHD manifestation [98, 99, 100, 101, 102].
\nOne pioneer study, where the conditioning of patients was myeloablative or reduced, followed BM-MSCs treatment together with allogeneic HSCT. This study showed that co-transplantation of MSCs resulted in fast engraftment of absolute neutrophil count and platelets and 100% donor chimerism [87]. In turn, Yamei and co-workers (2014) demonstrate prolonged survival (follow up of 78 months) in 80.9% patients after cotransplantation of the culture-expanded third party donor-derived UC-MSCs in 21 young people with SAA undergoing haplo-HSCT [103]. Even so, the patients did not show infusion toxicity. This study showed that MSCs support
Nowadays there a few clinical studies using only MSCs single to treat AA. All studies used MSCs isolated from BM s and adult patients with severe or non-severe AA and refractory. The via of MSCs administration used was IV and the number of administrations was 2 until 5 depending on study in combination with conventional immunosuppressive therapy.
\nThe study development by Pang et al. showed, six of 18 patients (33.3%) achieved a complete response or a partial response to MSCs treatment [107]. In six patients, two achieved a complete response including recovery of three hematopoietic cell lines after MSCs therapy. Similar results was achieved by Cle et al. 2015 using MSCs being 22% of all patients (18 patients) presents hematologic response at 6 months after MSCs transplantation [108]. One clinical trial phase II conducted in China evaluated the MSC overall response rate and safety using a significant number of refractory AA younger patients (n = 72). The study performed full quality control of BM-MSCs production, which includes counts, viability, morphology, endotoxin, aseptic culture, immunophenotype. It was the first clinical study that showed significant results in BM functional recovery. The rate response of patients was 28.4% being that 6.8% complete response and 21.6% partial response after MSCs transplantation. Among patients with hematologic response, ten patients had normalization of cellularity BM followed for more than 1 year MSCs transplantation. Seven patients got adverse events such as fever and headaches. No other adverse events were observed in the study. At the follow-up endpoint, nine patients died. One patient with RAEB-II died of disease progression, two patients died of intracranial hemorrhages, and six patients died of serious infection [107]. In other two studies were reported adverse events such as, fever, hypoxemia, mild dyspnea and diarrhea during MSCs administration or some hours after MSCs injection, this phenomenon occurs in 2 of 16 patients [107] and 7 of the 18 patients [108]. None major adverse effects were reported in all studies during months of follow-up of each respective study. Fuillard et al., 2003 reported one death due to fungal infection and Cle et al. 2015 four patients died in consequence result of heart failure and bacterial or invasive fungal infections and none of the deaths in both studies were directly attributable to MSCs infusions [84, 108].
\nThese preliminary studies support the concept that MSCs replacement can improve BM stroma and may alleviate symptoms severe and non-severe AA patients. However, larger studies with a significant number of patients are needed to evaluate the utility of MSCs further.
\nThe progress in dissecting the underlying and complex pathophysiology of AA has been gain space over the past years in the hematology research community [26]. In addition to that, the need for an optimal alternative of a targeted treatment for this disorder. It is too soon to place the conventional AA treatment methods, but MSCs have gained space for demonstrating positive results in several AA clinical studies and other hematological diseases. The hypoimmunogenicity advantages, ensuring the absence of rejection in patients due to no expression of MHC class II, prevention and treatment of GVHD traditional transplants, and mainly immunomodulatory action presented [109]. Essential in the environment imbalance provoked by own immune system in people committed by the AA disorder. The MSCs are able in a modulating way to relieve the BM self-attack [110].
\nContemporary, personalized therapies are famous in the whole scientific world. The MSCs may fit into this class due to their paracrine effects. These cells can assist in diverse situations such as: migration, injury recovery, stimulates cells renewal, death cell prevention, anti-inflammatory and modulation of the immune system to control the autoimmune environment [111]. Thus, MSCs have the heterogeneous capacity in varied therapies field. And the patient may have alternative use according to their needs.
\nIn that event, the current way is providing the MSCs safety and acceptance by regulatory agencies as new biological product [112], which has already been proven to be more efficient than synthetic industries products [113]. And finally, implement the MSCs as ideal allogeneic transplant model, even for adequacy periods used as support for other established therapies.
\nThanks to everyone on the Cellavita team who helped us so much. Special thanks to the company Cellavita Ltda., for financial and professional supporting. And to Butantan Institute, to providing us space and the research opportunity.
\nThe authors declare no conflict of interest.
In past 20 years, scanning probe microscopes have emerged as an essential technique in various fields. The atomic force microscope (AFM) uses the most common scanning probe technique for materials characterization [1, 2]. Major advantages of AFM involves its high resolution in three dimensions, the sample is not necessary to be conductive and it does not need to be operated within a vacuum. It help in studying a large range of topographies and many types of materials can be imaged under it. AFM is capable of imaging 3D topography information from the angstrom level to the micron scale with extraordinary resolution. In AFM, the
A representation of the AFM.
Evidences such as blood, fibers, hair, soil, finger prints, gunshot residue, pollen etc. are found on the crime scene at nano or even at molecular level. At present, different nanotechnologies such as the application of nanoscale powders, high resolution scanning and transmission electron microscopy and atomic force microscopy are applied for the examination of various evidences for forensic investigations [4, 5]. Nevertheless, forensic trace depiction of forensic evidences at the nanoscale does not yield applicable forensic information as explained by Inman and Rudin [6, 7] with the principle of divisible matter. Examination of such type of evidences require combination of sophisticated instrumentation which can help in proving the facts and can provide a conclusive results which can provide justice to the society. As mentioned earlier AFM technique has showed application for the examination of such type of evidences which is centered with an extremely high resolution scanning probe microscope to sense intermolecular and interatomic forces between a sharp probe and the specimen. AFM is highly applied in forensic field as it has the biggest advantage of examination of evidences in minimal non-destructive manner as well as possess imaging capabilities to examine the sample in various environmental conditions. As it possess highly accurate piezoelectric scanners its lateral resolution is hundreds of times better than the diffraction limit of traditional optical microscope. The sample is scanned by the tip of the cantilever which results into the deflection because of the attractive or repulsive forces between sample and tip molecules. The cantilever’s deflection is measured by the laser beam which is later converted into an electrical signal by photodiodes, thus helping in imaging of the topography surfaces of the sample at the nano-level.
Sample preparation art is in fact a simple procedure of critical-path steps, where every single step makes a large difference. The sample preparation in AFM is easier as compared to the other electron microscope techniques [8]. Further, AFM provides advantage of operating in almost any environment conditions, such as aqueous solutions, in air, vacuum, or other gases. Typically, AFM is operated at three different modes namely contact mode, noncontact mode, and tapping mode. Contact is a static mode, and tapping and noncontact are dynamic modes, as the cantilever oscillates in tapping and noncontact modes. This is achieved by adding an extra piezoelectric element that oscillates up and down between 5 and 400 kHz to the cantilever holder. The contact mode is the mode where the tip of the cantilever scans the sample in close contact with the surface. This mode is used usually for surface force measurements. In noncontact mode, the tip flies about 5–15 nm above the sample surface. Whereas in tapping mode the tip of probe touches the sample, and moves completely away from the sample in each oscillation cycle. The tip usually taps the sample during each oscillation in tapping mode, hence it is often the most stable mode used in air. In noncontact mode the cantilever stays close to the sample all the times and possess much smaller oscillation amplitude. The contact mode imaging is heavily influenced by frictional and adhesive forces which may damage samples and distort image data. The non-contact imaging mostly provides low resolution and can get hindered by the contaminant thus producing interfere with oscillation. On the other side the tapping mode imaging overcome the disadvantages of the other two modes. It eradicates the frictional forces by spasmodically contacting the surface and oscillating with appropriate amplitude to avoid the tip from being trapped by adhesive meniscus forces from the contaminant layer.
In general, for particle analysis in AFM the smaller the size of the particles the flatter/smoother the substrate should be that is the size of the particles should be greater than the topographical features of the substrate. Commonly used substrates are glass cover slips, highly ordered pyrolytic graphite, silicon oxide wafers, mica and atomically flat gold. For biological samples like imaging DNA12 and proteins, atomically flat substrates are used while for fine-size features examination like bio-cells, colloids, quantum dots and carbon nanotubes, glass, mica and silicon substrate are used. If a sample comes in the form of a bulk material such as wood or epoxy-resin, metal discs are used as a substrate. The adhesive used in this case is typically carbon tape or thermal wax [3].
In case of biological samples, in order to observe biological structures in their native state, they are supposed to be attached to a smooth solid substrate to resist the lateral forces exerted by the scanning tip, in that reverence, mica, glass and silicon oxide have proved to be excellent substrates for the examination. Muscovite mica, is a non-conducting layered mineral composed of multiple 1 nm thick layers [9]. It can be cleaved simply with the help of adhesive tape to yield clean, atomically flat surfaces which are negatively charged. Mica is most normally used substrate for imaging double-stranded DNA, DNA-protein complexes, protein arrays, densely packed proteins, supported lipid films and animal cells. Also, the mica surface can be modified with silanes which helps in both to promote adsorption or to allow covalent binding of the biomolecules [10]. Glass represents another suitable substrate for imaging biological samples. For imaging cells and other large structures glass cover slips are flat enough for imaging adsorbed molecules while in some cases, silicon oxide wafer scan also be used instead of glass. Though they are more expensive and difficult to handle, they offer much smoother surface than glass. Hydrophobic substrates, highly orientated pyrolytic graphite, which is atomically flat over large areas [11] are also preferred for biological sample preparation. Hydrophobic surface can be obtained by coating the mica surface with carbon for immobilizing DNA [12, 13].
For imaging document, adhesives and fibers sample under AFM, the frequently used substrate is microscope slide. Usually the samples are cut as per the required area to be imagined under the AFM and then double-sided adhesives are applied to affixed the sample at its fixed position as when the AFM tip is scanning it does not get deviated from the position. For soil sample analysis usually the grains are pressed into pressure-sensitive adhesive putty to provide suitable support during the scanning process thus this allows for retrieval of the grains afterwards or realignment if necessary during analysis [14, 15, 16].
The hair samples are priory washed before been examined under microscope using solvent namely sodium dodecyl sulfate solution or doubled distilled water. The substrate like metal discs or glass slide can be used as they are stable and shown eligible drift or creep. Adhesives such as conductive sticky carbon pads or double-sided tape are used to fix the sample at its position. If conductive sticky carbon pads are used as an adhesive then the hair sample are lowered onto the pads and pressed into place using tweezers, so that the fibers did not roll on the pad and hence pick up any contamination from the adhesive [14, 17, 18]. Researchers have also used epoxy as an adhesives at the sample ends to ensure that no interference with the top surface occurs and the adhesion between the hair sample and AFM disc keeps the middle of the sample fixed to the disc during AFM measurements [19].
This section recapitulates a number of AFM studies that illustrates applicability of AFM in relation forensic traces evidence analysis and its potential for crime investigations or reconstruction.
Blood stains are the most common type of forensic evidence found on the crime scene. The blood stains play very important role in the time determination of the actual criminal activity, hence determination of the age of bloodstains can prove to be highly effective in solving the crimes in shorter time duration. This information can provide a good perceptions regarding the victim time of death or to create a link between the suspects to the crime scene at the time when crime was committed. These area has attracted much attention worldwide over the years of various researchers since very few techniques such as electron paramagnetic resonance, high-performance liquid chromatography, quantification of RNA degradation and hyperspectral imaging [20, 21, 22]. In the review published by Bremmer et al. [23] they mention about the invasive techniques such as HPLC method, RNA analysis and EPR. Hyperspectral imaging are applied for the same problem. Even though HSI is a promising technology it has high error rate of about 2.7 days as per Edelman et al. [22].
Research has been done where the application of AFM is explored to study morphological changes of red blood cells (RBCs) to determine the relation with the time of death of individual. Wu et al. [24] has studied, the time-dependent, morphological changes of RBC in three different conditions such as room-temperature condition (controlled), outdoor environmental condition (uncontrolled) and low-temperature condition (controlled) using AFM on clean glass or newly peeled mica. They found that the substrate types have different effects on cellular morphology of RBC. Further, the RBC showed typical biconcave shape on mica and biconcave shape or flattened shape on glass, also the mean volume of RBCs on mica was significantly larger than that of cells on glass. In relation to the time, the changes in cell volume and adhesive force of RBC under the controlled room-temperature condition were similar to those under the uncontrolled outdoor-environmental condition as the time lapse. However, under the controlled low-temperature condition, the changes in cell volume happened mainly due to the RBCs collapse and the adhesive force curves exhibited the high alternations in RBC viscoelasticity. They concluded that AFM has significant application in forensic medicine or investigations, in relation to the estimation of age of bloodstain. Figure 2 shows the morphological comparison of RBCs on mica (a) and glass.
Morphological comparison of RBCs on mica (a) and glass (c) and (d). (a) and (d) RBCs in typical biconcave shape. (c) A flattened RBC. (a1) presents a height profile extracted from the cross section indicated by the dashed line in (a). The AFM-measured concave depth (CD) and width (CW) (FWHM) of RBC are 368.2 nm and 3.125 mm, respectively. (c1) and (d1) present the height profiles from the dashed lines in (c) and (d), respectively. The CD and CWin (d) are 219.6 nm and 2.561 mm, respectively. (b) and (e) present histograms of CD (b) and CW (e) of RBCs on various substrates. (f) and (g) indicate the differences of cell volume (f) and adhesive force (g) between RBCs on mica and on glass.
Chen and Cai did study on the morphological changes in a whole erythrocyte and of the erythrocyte membrane surface ultrastructure using tapping mode atomic force microscopy (TM-AFM) on mica substrate exposed in air over a 5-day period. They observed that the erythrocyte showed deformation of whole cell and membrane surface of unfixed erythrocytes as the time lapse. After 0.5 days of exposure, the fissures and cell shrinkage was observed and at 2.5 days of exposure, the development of nanometer-scale protuberances was observed, also the protuberances number increases with increasing time. Hence the present study presented the application that the changes of cell shape and cell membrane surface ultrastructure can prove to be helpful to estimate the time of death [25].
Lamzin and Khayrullin in their work studied the changes of RBC membranes stiffness in sRBC and the form and size of RBC probed using AFM by storing samples for 35 days at standard temperature conditions as shown in Figure 3. Their research revealed that statistically significant increase of YM values of RBC were observed as well as alteration of their form to echinocytes and spheroechinocytes of sRBC within 35 days at +4°C was noticed. They mentioned that this work can prove to be useful as an immediate criteria for applicability of sRBC for blood transfusion [26]. Marco Girasole et al. has exploited the full potential of atomic force microscopy (AFM) to investigate various characteristic of the erythrocytes’ life, death and interaction with the environment. As per Marco Girasole et al. [27] AFM is still a continuously growing technique which can be applied for studying more variant information in relation to the RBCs biochemical or biophysical status at different environmental conditions.
The AFM image of the dry specimen prepared from sRBC after 1 day (a) and 35 days (b) of storage.
Threes Smijs et al. applied atomic force microscopy to investigate the elasticity of RBCs from the peripheral zone of 4–8 day old bloodstains. They observed that the elasticity of six RBCs from a 5 day old bloodstain seemed homogenous with a mean Young’s modulus of 1.6 ± 0.4 GPa. As the time lapse, a significant age effect was observed in RBC elasticity that is on 4 days: 0.8 ± 0.1 GPa; 5 days: 1.7 ± 0.9 GPa; 6 days: 2.3 ± 0.6 Gpa; 7 days: 4.5 ± 0.6 GPa; 8 days: 6.0 ± 1.8 GPa; probe spring constants 25.16–67.48 N/m. They found that a bloodstain age determination with a 24 h precision only for 6–7 day old stains can be done. The silicon tip condition was regularly checked using scanning electron microscopy as an increase in bluntness was noticed after four to six cell indentations [28].
Cavalcanti and Silva studied biophysical properties that is morphology and elasticity of RBCs using atomic force microscopy. They aimed to investigate the time since death (TSD) from blood smears by analyzing changes occurring in the RBCs of a group of voluntary. Further, they also investigated that whether any difference in TSD analysis occurs on three different surfaces such as glass, metal, or ceramic after blood smears deposition occurs on these surfaces. They calculated force × distance curves obtained from RBCs membrane surface deformation as a function of time. They observed that there is no appreciable difference in the structure of RBCs over 28 days but significant differences were noticed on glass, metal, or ceramic surfaces. They concluded that the use of AFM in crime scenes still requires the development for accurate estimation of the TSD for blood spots [29]. Strasser et al. also explored erythrocytes in a blood sample to study elasticity changes in a fresh blood spot on a glass slide. At first they found presence of several RBCs in “doughnut-like” structure, which could easily be detected due to their typical “doughnut-like” appearance further the elasticity pattern showed a decrease over time which may be due to alteration of the blood spot during the drying and coagulation process. They concluded that these preliminary data can demonstrates the capacity for development of calibration curves, which have potential in estimation of bloodstain ages during forensic investigations [30]. Different body fluids are also been utilized for the extraction of DNA because of its use as a forensic tool during investigation. AFM can add in the characterization of the “trace DNA” deposited on various surface during any mutual contact. The stiffness of DNA’s double strand can be discriminated from its single strand and counting of the copied DNA can be done by using AFM [31].
Document examination involves techniques which causes less or no damage to the documents and allows maximum retrieval of data from it. The determination of the sequence of strokes is still a big problem in the field of forensic document examination. Till today the optical microscope are used with different illumination methods and magnifications in determination of sequence of strokes. But the use of same does not provide a reliable results in every cases because of the interaction of the light with crossing ink lines, the depth of focus, low resolving power as well as low magnification range of the optical microscopes. Kasas et al. [32] studied line crossing problem on paper printed form dot matrix printers and different ball-point pens on plain paper. They found that AFM produces qualitatively similar results and overcomes some of the scanning electron microscope limitations, i.e., vacuum and specimen’s conductive coating. Figure 4 shows the cut-outs of crossings of ball-point pen strokes on dot matrix printed letters in newer printer ribbon and worn printer ribbon. They concluded that AFM is a powerful alternative to the SEM for line crossing problem. Brandao et al. in their work has focused on the problem of counterfeiting which involves making an imitation or copy manufactured without the legal sanction of the government. They explored AFM and Raman techniques for the examination of both authentic and counterfeit Brazilian driver licenses, and national and international banknotes. The AFM results showed that the parameters, such as roughness and topographic profiles of the chalcographic region of banknotes and Brazilian driver licenses, can be successfully visually discriminate between authentic and counterfeit documents. They also showed the application of statistical analysis using the Student\'s t-test which showed that the asymmetry values obtained from series numbers and micro-letter regions can help in identifying the counterfeiting. They also indicated that the paper used to counterfeit the Brazilian driver license and the real banknote was an “office” type with inkjet printing by the use of the AFM technique [33]. Further the combination can also help to recognize the crossing lines between ballpoint pens, and ballpoint pens and printers, to discriminate between genuine and counterfeit medicines, to identify counterfeit documents produced from washing methods, to determine the microstructural information on textile fibers (discriminate between carpets, clothes, cars, etc.) in a crime scene investigation. The combination provides fast, very reliable, and reproducible analysis.
Cut-outs of crossings of ball-point pen strokes on dot matrix printed letters. (a) Newer printer ribbon; (b) worn printer ribbon.
Chen et al. in their work highlighted the quality of AFM compared to SEM for forensic forgery investigations in relation to crossing lines. They examined topographic features of four papers namely duplicator, copper printing, glassine and kraft paper on which crossing lines were done with three different types of oil-based pens as shown in Figure 5. For all pens they establish similar differences in height profiles analogous to the inks accumulations at the places where the first pen stroke overlay with the edge of second pen stroke. The work do showed the usefulness of AFM imaging to detect crossing lines under the selected test conditions [15]. As per Ellen, AFM imaging technique can provide high potential in forensic document examination especially in cases to study crossing lines and document forgery cases which can further be explored [34]. Although the many research is been done to prove the usefulness of AFM imaging to detect crossing lines but the overall paper surface roughness hampers the detection of erased, partially erased lines or slightly printed ink patterns on the pages. The height profiles of ink streaks on documents differs on the different types of the paper as the absorption differs. These hinder the correct interpretation of the height images. Though if AFM imaging is applied in these types of investigations the confirmation can only be achieved by usage of other instruments such as Raman spectroscopy to convey the final crucial decisive information.
Duplicator paper (1), copper printing paper (2), glassine paper (3) and kraft paper (4); (a) topographic image, (b) amplitude image.
Hair can prove to be a useful evidence in crimes in relation to determine the history of drug intake and abuse as well as exposure to toxins as the chemical composition of hair does not change by the external environment. Hair is the most encountered evidence in a forensic investigation and can act as a good source of DNA. The mitochondrial DNA present in the hair shaft and nuclear DNA is mostly within the root sheath paly important role in DNA examination [35]. AFM offers unique advantages for analysis of hair surface, primarily due to the high image resolution as well as an ease of sample preparation. Durkan and Wang employed atomic force microscopy in a forensic approach to distinguish between different hair care products on the basis of the deposits left behind. They studied AFM techniques on hair samples that which were washed/treated with a number of different shampoos/conditioners and 2-in-1 products as shown in Figure 6. They found that the exocuticle carries a negative charge and gets deposits on unwashed hair with a mean roughness of up to 50 nm. Further they found that washing hair with shampoos reduces the roughness of hair + deposits to typically below 10 nm also the 2-in-1 products, conditioners or shampoos shows deposits that cover the entire surface, with roughness up to 30 nm. They concluded that the measurement of surface roughness combined with images of the resulting surface deposits can prove effective to distinguish between the effects of different hair care products [17].
(a) AFM image of unwashed human hair. Scale bar is 5 lm. (b) The same image after flattening, where the debris on the hair is now more prominent. (c) Side-lit 3D representation of an area of hair revealing that particulates and deposits are relatively uniformly distributed across the hair surface. Scale bar is 3 lm. (d) Smaller scale image showing deposits on hair, away from particulates and cuticle edges. Scale bar is 200 nm. (e) Cross-section through topography of a 35 lm long section of hair with four cuticle edges in the range 200–500 nm thick with a lateral spacing approximately 7 lm, and where the deposits can be seen as ripples/bumps. (f) AFM topography image revealing woodgrain striations, characteristic of the exocuticle. (g) Cross-section through a clean hair devoid of deposits, for comparison to
The surface topography of human hair is defined by the cuticles which helps in cosmetic properties determination of the hair. The cuticles condition has the potential to aid in the medical diagnosis and forensic sciences. AFM offer unique advantages in hair surface analysis as it provides high resolution image and the simplicity of sample preparation. Gurden used an algorithm for the automatic examination of AFM images of human hair. By using a series of descriptors such as tilt angle, step height and cuticle density, the cuticular structure of hair was characterized and quantitatively investigated. They studied 38 AFM images consisting of hair samples untreated and bleached hair samples along with examination of the root and distal ends of the hair fiber. The multivariate classification technique partial least squares discriminant analysis was used to test the capability of the algorithm for further characterization of the images according to the hair properties. They were able to classify 86% hair images correctly. They study the classification of hair properties based on several cuticular descriptors by calculating it form the height images of various hair parts. The cuticular descriptors provided information on hair surface properties which can be correlate between the hair structure characteristics and environmental conditions the hairs are exposed to. Though the direct forensic relevance of this work was not established but the study do created extensive database of hair image along its mechanical properties [36].
Jeong et al. [18] have given an interesting contribution by studying the effects of aging on normal Korean hair diameter and surface features using AFM. They examine 60 Korean volunteers of various ages who had no hair diseases and studied hair diameter, hair surface, cuticular descriptors and micro-scale mechanical properties to determine their associations with aging. They found that hair diameter increases for the first 20–30 years of life and later showed decrease. AFM images of most of the younger subjects showed clear scale edges of hair while of older subjects revealed dilapidated structures, poorly defined scale edges and undulated surfaces. The cuticular descriptors, surface roughness showed increase significantly with age. Also the force to distance analysis confirmed its dependence on age. They concluded that aging causes changes in hair diameter and surface structure. These work done by Jeong et al. do contribute in estimating the age from forensic trace evidences like hair. The hair surface area studies were done by Tomes et al. using both SEM and AFM which showed little difference in quality of surface profiles obtained. For forensic hair imaging, the minimally invasive AFM technique can be preferred over SEM [37].
AFM is also used to investigate the effects of ethnicity, fatigue and water absorption on the tensile strength of hair and found in different ethnic hair types namely Caucasian, Asian and African and the results indicated that they have different mechanical properties [38]. Seshadri did the similar study on the tensile strength of hair by imaging the cuticular structure of hair. They found that hair shows stress-strain curve for keratinous fiber. Also the chemical, mechanical damage and conditioner treatment does not have any effect on the stress-strain curve or its tensile properties [39]. DelRio and Cook [19] provided interesting data of hair samples untreated virgin hairs and conditioned and bleached hairs. They stated an indentation modulus of 2.4 ± 1.1 GPa and 1.8 ± 0.9 GPa respectively for virgin and the bleached hairs samples while for the conditioned hairs, the indentation modulus varied between 0.05 and 0.5 GPa. They performed all the measurements on a 5 by 5 μm area.
Diatoms are a group of algae found in oceans and fresh waters possessing tough silica wall (SiO2) which is resistant to decay. Diatoms plays very crucial role in cases of drowning to determine whether it is antimortem or postmortem drowning, hence proving useful in forensic investigation. The recovery of diatoms from different organs, their quantitative and qualitative composition examination prove to be very trustworthy proof to determine the place and time of drowning in many cases [40]. They are studied in forensic geoscience in relation to transfer from different environments to clothing to obtain information of the crime scene and the perpetrator [41]. Newer techniques namely nuclear magnetic resonance, AFM, inductively coupled plasma (ICP) hyphenated technologies, fluorimetry and automatic diatom identification and classification are also been used for diatom study. AFM is used to study the diatoms morphological characteristics which can act as an indicator of its location, its growth cycle henceforward demonstrating its usefulness in forensic application. AFM has the potential to differentiate diatoms on the basis of its feature and can individualized atoms by scanning the objects that are 8″ long and having a diameter of 0.5″. Even the largest diatoms can be scanned in this range also the technique has the additional advantage of scanning the object in vertical and horizontal axis [42].
Almqvist et al. explored the possibilities of AFM to study diatoms in relation to its biomineralization and micromechanical properties. They studied the silica shell of the diatom Naviculapelliculosa (Bréb.) Hilse. The structure was imaged and the shell’s micromechanical properties were studied in semi-quantitatively manner. The results indicated that the diatom’s overall hardness and elasticity are same as that of silicas. Figure 7 shows the separated epitheca and hypotheca of one cell. They also showed that certain areas of the shell were significantly harder or more elastic which can be detect in different crystalline phases [43].
The separated epitheca and hypotheca of one cell [
In most the crime, fingerprints are the most common type of evidence found on to the crime scene. A fingerprints are impression of friction ridges on human finger. The discovery, visualization of latent fingerprints constitutes an important part of any crime investigation. Finger prints consist of exogenous and endogenous compounds. The endogenous part mainly includes the skin remnants, sweat gland and sebaceous secretions along with many different inorganic and organic substances. The finger prints remains unchanged throughout the life of an individual hence they play very important role in person identification. Usually visible and latent fingerprints are found at the crime scene. The visible prints do not require any aid to be visualized while the latent prints are invisible thus require physical, chemical and instrumental techniques to be visualized [44]. Very few researchers have tried to explore the use of AFM in fingerprint investigation.
Atomic force microscopy technique highlight its use to study the deposition characteristics and detection efficiency of fingerprint details. Direct application of the AFM is not soon in the examination of comparison of the fingerprint but the use of AFM is shown in the fingerprint cases by some researchers. Jones et al. used AFM to characterize the various substrates erstwhile of fingermark deposition in relation to the surface roughness, maximum height variation, skew and kurtosis. The finger prints were developed using iron oxide powder on formica, polyethylene and unplasticised polyvinylchloride surfaces [45]. As per Goddard et al. the limitation of the AFM height imaging to study the fingerprint ridge is the surface roughness when it is in the same order of magnitude as the height of the ridges as shown in Figure 8 [46]. The same problem avail with lifted finger prints as well as the prints present on the metal surfaces. The roughness of the surface on which the finger prints are present is main obstacle for routine applications of AFM in fingerprint analyses. In case were the surface roughness can be reduced atomic force microscopy can be useful in recovering the missing details that are essential to reconstruct a fingerprint. This problem was overcome by using scanning Kelvin probe force microscopy performed by Williams and McMurray. They studied the fingerprints deposited on metallic surfaces. They were able to retrieve sufficient ridge detail of fingerprint which were physically removed. Furthermore they demonstrated the use of Volta potential mapping to examine the fingerprint present on planar brass substrates [47].
AFM images from the polished and printed brass surface showing 3D image of part of ridge detail.
Gunshot residues (GSR) mainly contains unburned or partially burnt propellant powder, particles from the ammunition primer, grease, smoke, metal residues and lubricants from the fired cartridge while the organic compounds in GSR originate from propellant and firearm lubricants [48, 49]. The analysis of the inorganic GSR can evidence to be useful in forensic reconstruction of shooting incidents. Techniques such as neutron activation analysis, ICP, atomic absorption spectrometry (AAS), and SEM combined to energy dispersion analysis are used for inorganic GSR analysis [50, 51, 52, 53]. Neutron activation analysis are used for analysis of barium and antimony and for lead analysis conventional AAS and ICP are useful. High-resolution ICP-MS are reported to identify lead, barium and bismuth concentrations upto 1 ng/mL [54]. SEM-EDX is considered as golden standard of forensic GSR analysis as it has the ability to characterize GSR both chemically and morphologically. The SEM analysis is a time-consuming process. The organic GSR analysis are done by using gas chromatography, HPLC or GS-MS [55]. For both inorganic and organic GSR characterization time of-flight secondary ion mass spectrometry, Raman micro-spectroscopy and ablation-ICP/MS are reported [56, 57]. Apart from these, AFM technique have shown a great applicability in forensic GSR analysis on the basis of its morphological structure in relation to solving the crime [58].
The estimation of shooting distance plays a vital role in firearm cases also when combined with other evidence it helps in reconstructing shooting events. The bullet entrance hole appearance and the GSR patterns around the wound are usually used to estimate the firing distance [59, 60, 61]. Most commonly used color test Griess test along with series of modified and improved Griess tests are used to determine the presence of nitrites and hence for estimation of muzzle to target distance. Mou et al. reported the application of atomic force microscopy and Fourier transform infrared attenuated total reflectance spectroscopy. They use the techniques for firing distance estimation or muzzle-to-target shooting distance as well as the manufacturers of the cartridge and its powder. In their work, standard procedures contain test firing at various distances along with the evidence pattern comparison. They observed that for the samples the Winchester SuperX and CCI cartridges GSR particle sizes increased as the shooting distance decreased. From the AFM images of GSR they found that particles size distribution is inversely proportional to the shooting distance. AFM can be applied for the investigation of various materials unrelatedly to their conductivity. AFM is a non-destructive technique which helps in measurements in either air, liquid, or controlled atmospheres thus allowing the intact sample to be characterized without any pretreatments of the samples. The AFM images of GSR particles showed with different shapes like spherical, twins-like, irregular, boomerang-like, non-spherical, heart-like, rod-like and cube/rectangular-like as shown in Figure 9. The results indicated that the particles size distribution was inversely proportional to the shooting distance [62]. As per Jones when AFM is used for the GSR particles analysis the powder get stuck on the probe tip, thus drastically changing the shape and size of the powder particles resulting into the newer shape formation hence significantly alters the subsequent analysis [63]. This could be considered as a drawback of AFM for the analysis of fine GSR particles. But these same was overcome by Mou et al. which prove to be useful in firing distances determination.
AFM images of GSR particles showing various particle shapes, twins-like (a), heart-like (b), boomerang-like (c), and rod and cube like (d). The bullet type is CCI and the shooting distance is 10 ft.
D’Uffizi et al. in their work examine the GSR particles deposited on the bullet and on the shooter hands using combination of scanning electron microscopy + energy-dispersive spectroscopy, atomic force microscopy and selected-area X-ray photoelectron spectroscopy. The GSR samples were collected using double-sided tape. They studied the micromechanical and micromorphological features of gunshot residue particles. Of importance in this investigation the use of AFM itself (Nanoscope IIIa Digital Instruments microscope, tapping mode, frequency: 250–390 kHz) was done to examine the height and phase imaging [64]. Some research has shown the applicability of AFM in context to forensic gunshot and explosive investigation with regards to physicochemical characterization that can be detected on hairs and in between the ridges of fingermarks.
The mechanical properties of the organic and inorganic particles present in GSR and explosives, were studied by Xu et al. They showed the application of AFM techniques, including force volume mode, phase imaging as well as Kelvin probe force microscopy with resonance enhancement for dielectric property mapping was used to map the local physical properties of mock explosive materials. These work will allow the identification of sub-micrometer heterogeneities in relation to their electrical and mechanical properties [65].
One of the recent advancements showed the use of AFM as a characterization technique for explosives detection. The surface morphology of explosives such as triamino-trinitro-benzene, plastic-bonded explosives, ammonium perchlorate was analyzed through AFM [66, 67, 68]. The surface morphology of such explosives helps in understanding the different characteristics of explosives which can help in identification [69].
Accumulation of explosives namely 2,4,6-trinitrotoluene (TNT) and triacetone triperoxide (TATP) in chemically treated hair sample was studied by Oxley et al. [70] using AFM and SEM. The interaction of TNT and TATP as a function of chemical pretreatment with acetonitrile, neutral and alkaline hydrogen peroxide, methanolic potassium hydroxide and potassium permanganate was studied and further the morphological changes which resulted from these treatments were studied. Hair examination surface showed different degrees of smoothening. Density functional theory calculations were employed to known the possible nucleation sites of TATP microcrystals on the hair samples. From their calculations study they concluded that the dark hair adsorbs explosives better than light hair. The authors have showed the use of AFM on their previously described applications of AFM in hair structure investigations [17, 36, 71]. Studied reported shows that AFM play a vital role in trace evidence analysis in post-explosion cases. These studies indicate that recently the potential of the AFM technology has been explored in relation to the forensic evidences analysis and the full potential of technology is yet to be discovered. The possibility of mapping a number of physical and chemical material properties prove to be a worthy contribution in distinguishing the different components in complex heterogeneous structure of explosive residues samples. The AFM technology is only a complementary technique its use can be enhanced if combined with other analytical technique which can prove to be of great importance in forensic context for not only examination of GSR or post explosives residues but also for other trace evidences found on to the crime scene.
Valle et al. [72] used AFM to investigate and identify several characteristics of firearms. Replica molding of the head of these cases was done using the fired cartridge cases and the surface morphology of replicated areas at the breech faces were studied. In this framework, the method showed reproducibility of different copies of the similar sample indicating that they are indistinguishable over all the accessible length scales.
Researchers have also shown the utility of AFM in fire investigation cases. In fire cases the determination of source of fires plays very important role in order to validate [73, 74]. In fire cases, molten electric marks are found on the electric arc bead. Examination of these marks can help to determine the source of the fire. Gao et al. used OM and AFM to examine a molten mark on copper wire by artificially creating the molten mark inflicted on the wire under laboratory conditions. The AFM results showed that the technique is an brilliant add-on to examine the copper molten mark and thus provide excellent data to confirm the actual causes of fire [75].
Soils vary among different areas and possess characteristics due to their natural effects and transfers made by human being and other living beings with time. Examination of soil in forensic context can help in determination of crime location. Investigative and interpreting the soil or sediment can help in their origin determination [76]. Konopinski et al. studied the grain surface texture of quartz sand using AFM. AFM analysis provide topographical data from the grain surface that permits statistical analysis, 3D reconstruction and quantitative valuations of the microscopic surface textures. AFM offers numerous statistical methods which can discriminate between grain surface textures and also helps in creating automated database to compile and generate reports. AFM has great potential to be used for forensic analysis where sample preservation is extremely valuable. As per Konopinski et al. using AFM helps in quantifiable measurement of quartz grain surface textures which opens up a number of possibilities for forensic quartz grain surface texture analysis as it provides a corroborative independent verification of quartz type classifications as shown in Figure 10 [14].
Topography (a) and amplitude (b) maps offset from clearly visible is the interface between two different surface textures.
Sullivan et al. in their work investigated the surface characteristics of plastic wrapping materials of forensic interest in soil environments in order to determine the environmental factors that influence the degradation process of such polymers. They buried polyethylene bags and poly (vinyl chloride) sheeting in model environments surrounding different soil types, moisture content, pH and temperature. Atomic force microscopy was used to study the changes which results on the polymer surface at a nanometre level. They found that over a 2-year burial period, the degradation of polyethylene was greater by an increased moisture content and a raised soil pH. The plasticizer content of poly (vinyl chloride) was got affected by burial, thus leaching of the same was observed in all environments continually over the burial period. The surface roughness measurement of plastics using atomic force microscopy was sensitive to the burial environment and demonstrates the potential of technique to measure relatively subtle changes to burial items when exposed to different environments conditions [77].
Pressure sensitive adhesive tapes are utilized for various purposes in criminal activities such as packaging of controlled drugs, the restraint of an individual during robbery and offences against a victim, the enclosure of explosive devices and for concealment. To identify chemical constituents techniques such as Fourier transform infrared spectroscopy and pyrolisis–gas chromatography–mass-spectrometry are applied in forensic science laboratories for the discrimination of PSAs. However, AFM can offer supplementary and useful analytical data on PSAs as it has the capability to map the adhesives surface morphological and mechanical properties also AFM can give nanoscopic information. With respect to forensic application it holds the ability to interpret the physical data obtained from evidence found at a crime scene and linking it to a particular suspect [16]. Figure 11 shows the AFM phase images for transparent cello, brown packaging tape and electrical insulation tape.
AFM phase images for (a) transparent cello, (b) brown packaging tape and (c) electrical insulation tape.
Fibers are an important trace evidence that can provide valued evidence to support an association of individual to a crime scene. Standard forensic examinations of man-made fibers usually involves microscopic techniques such as visible, polarized light and fluorescence microscopy as well as micro-spectrophotometry. Infrared spectroscopy is also used to identify the fiber polymer type present if two fibers are indistinguishable by microscopic techniques. Man-made fibers namely polyamides, polyacrylics and polyesters are analyzed using techniques such as FTIR, circular dicroism, Raman spectroscopy, differential scanning calorimetry, transmission electron microscopy and wide angle X-ray diffraction [78]. Forensic comparison of fibers is mainly focused on morphological analysis and spectral analysis. Shady Farah et al. in their study, analyzed polyethylene terephthalate (PET) fiber on three different materials such as plain fibers of pet, a common textile fiber and plastic material. They studied the morphological feature of the fiber using AFM [79].
The ability of the AFM to reconnoiter the nanoscopic morphological changes in the surfaces of fabrics was studied by Canetta et al. This study was focused on two natural namely cotton and wool and a regenerated cellulose (viscose) textile fibres. All the fiber samples were exposed to different environmental stresses for different lengths of times. The surface texture parameters of the environmentally stressed fabrics was measure quantitatively as a function of the exposure time from the obtained AFM images. In the AFM images the nanoscale the finest details of the surfaces of three weathered fabrics was clearly distinguishable between the detrimental effects of the executed environmental conditions. The heights and roughness’s of the unexposed and exposed fiber surfaces was measured by analyzing the obtained AFM images. Figure 12 shows the AFM height images of cotton fibre exposed to loam and riverside soils, and pond and sea waters for 2 and 6 weeks. This study confirmed that the AFM can prove to be a very powerful tool in forensic examination of textile fibers to provide significant fiber examination as an evidence due to its proficiency of distinguishing between different environmental exposures or forced damages to fibers [80].
AFM height images of cotton fibre exposed to loam and riverside soils, and pond and sea waters for 2 and 6 weeks.
In crimes involving digital evidences the data recovery plays very crucial role. Damaged SIM cards are highly useful evidence in such cases. The data obtained from such SIM cards give insights about the link between criminal and aids in future investigation. Nardi et al. used AFM for the enhancement and characterization of a forensically authenticated technique for sample processing and data extraction from a damaged SIM card. They develop a process to view the underside of the embedded EPROM/flash memory arrays present in smart card microcontrollers [81, 82, 83].
Atomic force microscopy works by running a sharp tip attached to a cantilever and sensor over the sample surface and measures the surface forces between the probe and the sample. As the cantilever runs laterally the sample surface, it moves up and down due to the surface features and the cantilever deflects accordingly. This deflection is computed using an optical sensor, with the laser beam being reflected on the back of the cantilever onto the light detector. AFM provides various advantages over other techniques. AFM can operate in ambient air or under liquid, it does not need to be operated in a vacuum hence it is increasingly being used to image biological samples as well as nanoparticles. AFM has resolution in the order of fractions of a nanometer and provide a 3D imaging technique. The AFM allows the topographic characterization of surfaces at resolutions not attainable by optical microscopy. The lateral resolution of the AFM is limited by the tip size and shape and is typically on the order of a few nanometers. The height (
Undeniably, the AFM power to measure topography, morphology, adhesion forces, elastic modulus, dielectric properties and energy dissipation characteristics via minimal invasion. Furthermore, the 3-Dimentional multi-parameter function provide information add-on in cases of trace fusion imaging. Considering the practicality, sampling and sample logistics are still remains desirable in AFM, though with respect to SEM the tedious work of sample preparation as well as high vacuum settings are not required. AFM has its advantages while studying, optimizing, understanding and validating techniques for examination of trace evidences found at the scene of crime. Also, microtraces evidences physiochemical features imaging can be done which can assist in classification and comparison. Though it has such advantages, roughness of substrate do hamper one or other way while studying the sample height measurements. Certain researchers have answer to this solution by accompanying surface roughness along with larger scan areas in supplementary phase imaging. In practice, AFMs can image rough surfaces as long as the roughness does not surpass the limit of scanner in vertical,
The authors declare no conflict of interest.
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\\n\\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
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\n\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
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\n\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
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This new technology can be used in various wireless power transfer applications with different specifications, necessities, and restrictions such as in electric vehicles and consumer electronics. A typical ICWPT system involves a loosely coupled magnetic coupling structure and power electronics circuitries as an integrated system. In this chapter, the emphasis is placed on the magnetic coupling structure, which is the most important part of the system. Although this technology has motivated considerable research and development in the past two decades, still there are several theoretical studies such as the level of the operating frequency, operating at high secondary circuit quality factor, coupling efficiency, etc., that need further investigation to fully develop the governing mathematical relationships of this technology.",book:{id:"5187",slug:"wireless-power-transfer-fundamentals-and-technologies",title:"Wireless Power Transfer",fullTitle:"Wireless Power Transfer - Fundamentals and Technologies"},signatures:"Ali Abdolkhani",authors:[{id:"179618",title:"Dr.",name:"Ali",middleName:null,surname:"Abdolkhani",slug:"ali-abdolkhani",fullName:"Ali Abdolkhani"}]},{id:"78626",title:"Electricity Storage in Local Energy Systems",slug:"electricity-storage-in-local-energy-systems",totalDownloads:221,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Traditionally, power system operation has relied on supply side flexibility from large fossil-based generation plants to managed swings in supply and/or demand. An increase in variable renewable generation has increased curtailment of renewable electricity and variations in electricity prices. Consumers can take advantage of volatile electricity prices and reduce their bills using electricity storage. With reduced fossil-based power generation, traditional methods for balancing supply and demand must change. Electricity storage offers an alternative to fossil-based flexibility, with an increase expected to support high levels of renewable generation. Electrochemical storage is a promising technology for local energy systems. In particular, lithium-ion batteries due to their high energy density and high efficiency. However, despite their 89% decrease in capital cost over the last 10 years, lithium-ion batteries are still relatively expensive. Local energy systems with battery storage can use their battery for different purposes such as maximising their self-consumption, minimising their operating cost through energy arbitrage which is storing energy when the electricity price is low and releasing the energy when the price increases, and increasing their revenue by providing flexibility services to the utility grid. Power rating and energy capacity are vitally important in the design of an electricity storage system. A case study is given for the purpose of providing a repeatable methodology for optimally sizing of a battery storage system for a local energy system. 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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:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. 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He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:6,paginationItems:[{id:"82526",title:"Deep Multiagent Reinforcement Learning Methods Addressing the Scalability Challenge",doi:"10.5772/intechopen.105627",signatures:"Theocharis Kravaris and George A. 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(Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",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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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:'"Politechnica" University Timişoara',institution:null}]},{type:"book",id:"9963",title:"Advances and Applications in Deep Learning",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9963.jpg",slug:"advances-and-applications-in-deep-learning",publishedDate:"December 9th 2020",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"0d51ba46f22e55cb89140f60d86a071e",volumeInSeries:4,fullTitle:"Advances and Applications in Deep Learning",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. 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Ribeiro-Barros",profilePictureURL:"https://mts.intechopen.com/storage/users/171036/images/system/171036.jpg",institutionString:"University of Lisbon",institution:{name:"University of Lisbon",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Sustainable Economy and Fair Society",value:91,count:1}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:1}],authors:{paginationCount:250,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. 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This will ensure that we discover ways to live in our world that allows us and other beings to flourish. We can no longer rely on medicalized approaches to health that wait for people to become ill before attempting to treat them. We need to live in harmony with nature and rediscover the beauty and balance in our everyday lives and surroundings, which contribute to our well-being and that of all other creatures on the planet. This topic will provide insights and knowledge into how to achieve this change in health care that is based on ecologically sustainable practices.
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