Therapeutic agents or vaccine candidates targeting virus or immunity with promisor potential to use during ZIKV infection in pregnant women.
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Zika virus (ZIKV) is an arthropod-borne flavivirus, considered a reemerging infectious disease as well as a neglected tropical disease [1]. Moreover, ZIKV was also classified as sexually transmitted disease (STD), since viral RNA and infectious particles were detectable in reproductive organs and others described some cases related to sexual transmission [2, 3]. Although the major concern about ZIKV infection is the intrauterine transmission [4, 5, 6].
Innate immunity during pregnancy still needs attention when some infection compromises pregnancy success. Recently, the world testified a huge public health problem during Zika virus (ZIKV) outbreak in Latin American countries [7, 8, 9], in which poor outcomes were observed firstly in Brazilian newborns from mothers infected on early pregnancy phase (1st -2nd trimester) [7, 8]. Consequences of viral infections on newborns are irreversible and public health and social costs are immensurable [10], making World Health Organization consider Zika infection a public health emergency in 2016 February [11].
Due to its neurotropic features, the infection caused by ZIKV has been evidenced [12, 13, 14], which show a correlation between clinical manifestations based on its tropism by brain neuronal cells of fetuses and neonates born from infected pregnant women, with a strong association to neurological damage, including microcephaly and other fetal neurological disorders, collectively named as Congenital Zika Syndrome (CZS) or Zika Associated with Birth Defect (ZABD) [15, 16, 17, 18].
The immune system is composed of a set of flexible mechanisms that are fundamental to maintain homeostasis, allowing many interactions and coexistence between different populations of microorganisms and the host. The imbalance of homeostasis can be caused by a microorganism because of its pathogenic behavior. With the establishment of an active infection and consequent immune response, inflammatory mediators, produced initially, collaborate to activate cellular populations of the innate immunity, promoting antiviral and cytotoxic responses, for example. At first, these effector responses would influence the viremia resolution with the re-establishment of homeostasis. However, the loss or dysfunction of this immune response can generate a harmful environment that triggers an uncontrolled damage inflammation and consequent cell death due to a direct cytopathic effect caused by the microorganism [19].
Some studies were conducted to understand the mechanisms involved in vertical transmission. During pregnancy, the transfer of ZIKV to the placenta occurs after an infection of decidua, the placenta maternal region, since studies have shown that decidua cells are permissive to ZIKV infection and remain permissive throughout pregnancy [20, 21]. From the infection of the decidua, there are two routes by which ZIKV reaches the fetus: infection of syncytiotrophoblasts (SBTs) through capillaries containing maternal blood or infection of Extravilous Trophoblast (EVTs) by cell-to-cell propagation [4]. In vitro studies have shown that ZIKV can infect first-trimester cytotrophoblasts CTBs and EVTs [4, 20, 21]. On the other hand, STBs are high producers of type III interferon and remain relatively resistant to viral infection throughout pregnancy, therefore, the main route hypothesis for transplacental transmission of ZIKV is that of the spread of decidua to EVTs [21, 22]. Additionally, infection of placental macrophages, the Hofbauer cells by ZIKV may contribute to both intrauterine transmission and immunomodulation [23, 24]. Further, transplacental transfer of ZIKV is more likely to occur in the pro-inflammatory environment and tolerant to placental immunity in the first trimester.
Histopathological and immunological studies in placentas have shown that infections by ZIKV lead to an increase in important inflammation markers such as TNF, CCL5, and altered vascular permeability such as metalloproteinases [25]. In addition, in vitro experiments demonstrate that trophoblastic cells become progressively more resistant to infection by ZIKV during pregnancy, partly through the secretion of IFNs [26]. In this context, a lot of efforts were raised to provide funds to deeply investigate how to avoid another spread of Zika virus infection, as well as drugs tests and vaccine development based on viral proteins, DNA vaccines, Virus Like Particles (VLP), chimeric viruses, among other strategies [27, 28, 29, 30]. Therefore, there are few studies to investigate the pregnancy immunity and how the immune interface mother-to-child could contribute to infection spread with drastic consequences to fetus [21, 31, 32, 33, 34]. To our knowledge, the imbalance of normal pregnancy immunity is already cause of metabolic disorders and the poor outcome is related to abortion [35, 36, 37]. Then, a viral infection can make this picture worst and tragic [8, 13, 15, 38, 39].
Like other Flaviviruses, ZIKV life cycle modulates machinery and functions of target immune host cells, making essential virus-cells interactions for pathogenesis development. Moreover, while several human and animal models’ studies have argued and proved ZIKV neurotropism, there are still many answers regarding viral pathogenesis in mother and its influence the fetal neural system and persistence, and clinical outcome. In this chapter we will put together the information about innate immunity during gestation, highlighting three parts probably involved with clinical outcome: 1) interferon type III; 2) innate regulatory cells; and 3) cell death pathways modulation. Additionally, we will focus on discussing how the dynamic responses of innate immune system during pregnancy and its effects in newborns, could be modulated by ZIKV, as well as how efforts on development of new/old drugs and vaccines could be effective to help pregnancy success.
The success of pregnancy is dependent on a coordinated balance between the “invading” fetal trophoblast and a receptive maternal decidua in the placenta, maintaining a dynamic and responsive immune system. The longest period of the pregnancy, fetal growth, demands a symbiotic and tolerogenic environment, but congenital viral infections can disrupt this equilibrium. In order to avoid infection severity placenta actively modulates the immunologic profile of the maternal-fetal interface [40, 41]. In this context, recent studies demonstrated that placenta responds to ZIKV infection by production of the newest interferon group type III interferons [21, 42, 43].
Type III interferon (IFN-λ 1–4) comprising a group of cytokines with action pathways under strengthen discovery [44, 45, 46], basically acting with shared inflammatory regulation and antiviral properties [47]. IFN-λs receptor was identified as a complex composed of two subunits: IFN-λR1 and IL-10R2, which is also a receptor subunit of the regulatory cytokines IL10, IL22, and IL26 [48]. In contrast with the classical pro-inflammatory type I interferons which receptors are expressed in almost all cell types, the IFNLR1/IL10RB complex is expressed primarily in cells of epithelial origin and few immune cells conferring selective IFN-λ responsiveness to them: neutrophils [49], myeloid dendritic cells (DCs) [50, 51] and plasmacytoid dendritic cells (pDC) [52]. Because of the restricted cell types producing IFN-λs, this cytokine acts locally as an immunologic barrier in organs with suppressing innate pro-inflammatory responses and limiting host damaging effects associated with inflammation [53]. Moreover, IFN-λs utilize mechanisms to suppress viral infections which induce a strong antiviral state following receptor binding with non-translational and translational processes [49, 54].
Between the different inflammatory regulation actions already described for IFN-λs, the suppression of neutrophil gains prominence because they are the immune cells that present higher expression.
of IFN-λR1 at the steady-state [55, 56, 57]. Neutrophils contribute to various stages of the reproductive process since conception and implantation, ensuring fetal wellbeing during pregnancy and finally contributing to parturition and postpartum maternal health. On the other hand, aberrant neutrophil activity is associated with severe pregnancy-related disorders such as pre-eclampsia, recurrent fetal loss or gestational diabetes mellitus [58, 59, 60]. In murine models, it was demonstrated that neutrophil exposed to IFN-λ can induce antiviral interferon-stimulated genes (ISGs); and IFN-λ (but not IFN-β) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils, which might permit a controlled development of the inflammatory process [49].
Studies utilizing a cellular model of collagen-induced arthritis demonstrated that IFN-λ2 was protective and could stop the progression of the disease, diminishing infiltration of neutrophils to the inflamed joints as well as the production of IL-1β upon treatment with pegylated recombinant IFN-λ2 [57].
IFN-λ is strongly associated with DCs activity inducing an effector adaptive immunity response [63, 64]. Studies with a mice model of influenza A virus infection demonstrated that IFN-λ directed acts in the migration and function of CD103(+) dendritic cells, also regulating DC IL-10 network [65]. Migratory CD103(+) DCs derived from skin, lung, and intestine, efficiently present exogenous antigens in their corresponding draining lymph nodes to specific CD8(+) T cells through a mechanism known as cross-presentation, demonstrating the IFN-λ importance for the development of specific CD8+ T cell responses [65, 66]. Moreover, IFN-λ contributes to the formation of tolerogenic DCs cell, contributing to control inflammatory responses and homeostasis by fostering the conversion of naive T cells into induced Foxp3(+) regulatory T cells [66]. In vitro studies demonstrated that IFN- λ directs DCs to a regulatory phenotype with diminished capacity to stimulate T cell proliferation in a PD-1/PD-L1 dependent manner with contribution from the imbalanced cytokine milieu, such as low IL-12 and IL-2 and/or high IL-10 production [50]. Another study using mixed lymphocyte cultures demonstrated that IFN- λ -treated DCs specifically induced IL-2-dependent proliferation of a CD4(+) CD25(+) Foxp3(+) T-cell subset with contact-dependent suppressive activity on T-cell proliferation initiated by fully mature DCs [51].
Plasmacytoid dendritic cells (pDC) are rare cells found in peripheral blood and lymphoid tissues, considered to be “professional” type I IFN-producing cells and produce 10- to 100-fold more IFN-α than other cell types in response to enveloped viruses. However, in vitro IFN-λ treatment of pDC resulted in increased virus-induced expression of both IFN-α and IFN-λ, indicating that pDC are high producers of IFN-λ1 and -λ2 in response to viral stimulation and the consequences of this high IFN-λ production by pDC should be further explored [52].
In human congenital ZIKV infections, it was demonstrated that ZIKV infection leads to a typical inflammatory response in the placenta, including the expression of anti-viral Type I interferon genes (
Summary of Interferon lambda (IFN-λ) function during normal pregnancy (A), Healthy Congenital Zika infection (B), and Zika-Associated Birth Defects (C). (A) In normal pregnancy, trophoblasts exhibit a constitutive IFN-λ production, contributing to the general tolerogenic environment demanded by pregnancy (A1); Considering the peripheral blood tissue IFN-λ Interact with: (A2) neutrophils leading to a decrease in ROS and IL1β, and (A3) migratory CD103+Dendritic cells (DC) that present low levels of PD1, IL2 and IL12 together with high IL10. These CD103+DC foster the conversion of naive T cells into induced Foxp3(+) regulatory T cells (Treg) (A4). In the placenta, the constitutive IFN-λ is accompanied by decreased type I IFN pathway: low expression of IFIT5, IFNA, and IFNB, and high expression of type I IFN the negative regulator ISG15 (A5). In the lack of viral infection, the interferon regulatory factors IRF7 and IRF9 present low expression levels (A7). (B) In healthy congenital Zika infections, the placenta expresses high levels of IFN-λ to protect the fetus from congenital defects (B1). In this low damage antiviral response, high levels of IFN-λ elicits the production of ISGs and the decrease of ROS and IL1β by circulating neutrophils (B2), meanwhile the CD103+ DC presents an accented regulatory profile (B3), with induction of high specific anti-ZIKV response by Treg (B4) and TCD8+ cells (B5). In the placental level type, I interferon pathway shows a slight increase, together with the enhance of IRF7 and IRF9, forming a balanced antiviral response. (C) In Congenital Zika Syndrome (CZS) the lack of IFN-λ contributes to a damaging outcome (C1). Diminished levels of IFN-λ could not control the neutrophil activity, culminating in augmented ROS and IL1β (C2), and presence of aberrant activation forms as well as degranulation, migration, and NETosis (C3). Without IFN-λ the Dendritic Cells (DC) present a prό-inflammatory profile, with augmented PD1, IL2, and IL12 and diminished IL10 (C4). The placenta shows an exacerbated type I interferon response, which together with low IFN-λ levels (C5), leads to an imbalanced damaging antiviral response. Grey arrows represent the production or expression levels (up = high, down = low). Double arrows represent a high magnitude of production or expression. Red dashed arrows represent the direction of function/induction events that have been known and those suggested. Figure created using Biorender software (
Immunity during pregnancy is very important to be explored since successful pregnancy requires that immunoregulatory mechanisms are triggered to suppress activated fetal-specific T cells lymphocytes [36, 37]. Maternal immune cells can recognize paternal antigens on fetus. Thus, it has been very well described that dysfunction of immune cells during pregnancy can lead to immunologic fetal rejection by mother, in which the consequences are related to abortion, preterm delivery, or other severe complications [35, 36, 37].
Then, maternal-fetal tolerance involves the regulation of mother’s immune system to tolerate the semi allogeneic fetus expressing paternal antigens without immune rejection. Even though, some studies showed that regulatory T cells are the main cells which plays an important role in suppressing activated T cells during gestation; since then innate immunity system is poorly investigated [69, 70, 71].
Considering infections during pregnancy, it is also important to know that changes on maternal immune responses are required to induce limited immunosuppression without loss of host defense, in which a balance between activated and immunosuppressed cells needs to be regular [35].
Myeloid-derived suppressor cells (MDSC) are a heterogeneous mixture of immature myeloid cells, been part of innate immune cells, having a crucial role in immunomodulatory mechanisms during pregnancy [36, 72, 73]. There are two subtypes of MDSC, a monocytic and granulocytic. Phenotype is characterized by expression of CD33 and CD11b in humans, CD14 by monocytic MDSC and CD15 by granulocytic MDSC cells but lacks the maturation marker HLA-DR. But both subtypes share the characteristic of immune-suppressive function inhibiting activated NK and T cell expansion [73, 74].
Normally, immature myeloid cells as MDSC are scarcely found in peripheral blood, and their maturation includes macrophages, dendritic cells, and granulocytes formation. Nevertheless, the MDSC are also recognized by their role in some pathological conditions, like cancer, sepsis, stress, autoimmune disorders and infectious diseases [38, 75, 76].
Several studies have been reported that a decrease of MDSC during pregnancy may lead to poor outcomes, as miscarriage [77]. Also, it has been shown that progesterone levels increase MDSC during pregnancy in mice, as well as high levels of TNF and IL-1β, pro-inflammatory cytokines [38, 78].
In murine models, it was demonstrated that MDSC can produce TGF-β and IL-10, as immunosuppressive cytokines, similarly to regulatory T cells. Adding to that, MDSC can suppress T cell activation and function by arginase-1 (Arg-1) secretion, as well as nitric oxide synthase and indoleamine 2,3 dioxygenase aimed to deplete nutrients for T cell proliferation, as I-arginine (I-Arg). According to Ismail 2018, arginine is also involved in replication, and virulence of several agents, as viruses and bacteria. Then, it is suggested that an accumulation of MDSC in placenta could influence an increase of arginase activity, and it would serve for a dual purpose, inhibiting the adaptive immune system whilst also providing potential protection against infection by arginine auxotrophic pathogens [79].
Nitric oxide (NO) has been related to embryo successful implantation during early pregnancy, but excessive NO production by decidual macrophages seems to be harmful and was linked with early pregnancy loss [37, 80, 81]. Another study suggests that in early pregnancy in decidua CD33+ cells express nitric oxide synthase, playing an important role to maintained pregnancy during this phase, while in later pregnancy CD33+ cells lose the expression of this enzyme [35, 37].
Kostlin-Gille
Regarding Zika virus, there are few studies showing the presence of MDSC on women blood and during pregnancy, and considering the facts, it will be very important to know any relationship of their presence with congenital syndrome, as observed in 2016, Brazil [82, 83]. A study with 10 non-pregnant women with Zika infection showed that frequencies of circulating MDSC did not change over time [84]. Another study with pregnant monkeys infected with Zika virus showed that an imbalance on blood frequencies of MDSC and activated CD8 T cells in the acute phase may lead to poor outcome to the fetus. Adding to that, the high frequency of MDSC on placenta from pregnant monkeys showed a positive effect on pregnancy outcome, even more if a drug antiviral treatment was used [85].
Furthermore, it is worth to note that immune signature, sometimes is the key factor to explain some diseases progressions. Despite Dengue viruses is more related to signals and symptoms with Zika virus infection [86, 87], some similarities with hepatitis C virus (HCV) were also noted, and mechanisms of immune evasion have been described, as inhibition of interferon pathway, allowing virus life cycle for a long-term period, up to 100 days [88, 89]. To note, ZIKV infection is also classified as an immune-mediated viral disease, like Dengue and other viruses [86, 87, 90]. Disease progression in HCV patients to chronic infection has been associated to an increase of MDSC phenotype in peripheral blood mediated by viral proteins [38]. Wang et al., 2017 examined Japanese encephalitis virus (JEV) infection leading acute encephalopathy depending on suppression of adaptive immune response, especially T follicular helper cells, mediated by enhanced MDSC populations, such as an involvement of MDSC on splenic B cells reduction, and in lower levels of total IgM JEV-specific neutralizing antibodies in mice models [39]. Burrack et al., also suggests that MDSC has an important suppressive T cells activity and may contribute to reduce the immune-mediated disease during Chikungunya infection [90].
Otherwise, the immunosuppressive activity triggered by RNA viruses, MDSC has been associated with metabolic regulation of immunopathology induced by DNA viruses, like hepatitis B virus (HBV) [91]. Pallett et al., 2015 showed that frequencies of MDSC on liver from HBV patients without liver damage, monitored by levels of liver transaminase enzymes, were higher in comparison with patients with liver damage, showing a protective effect for patients with immune-mediated viral disease, as hepatitis B [91].
In the new coronavirus pandemic (COVID-19), the MDSC have been reported to play an important role in the early phase of symptoms, increasing their frequency on blood in the first days of signals and symptoms, and it was related to poor outcome in severe acute respiratory syndrome in hospitalized patients. Pregnancy is a risk factor for COVID-19 severity, given the Brazilian high mortality rate of 12.7% in June 2020 withing pregnant, which may be associated with the change of the immunity [92, 93, 94].
Although few studies involving MDSC frequencies on blood during Zika infection were published yet, those cell type needs to be investigated, even though in animal models for medical science breakthroughs. The technique to characterize this cell phenotype is simpler than to characterize regulatory T cells, once the procedure does not require intracellular staining [95].
If those MDSC are crucial to maintaining a healthy pregnancy, any adverse effects, as Zika virus infection could trigger an imbalance between MDSC and T cells. This dysfunction may induce a deactivation of functional MDSC on blood and placenta with failure to attempt to eliminate viral infection. In addition, T cell function during ZIKV infection is known to be delayed throughout interferences on interferon pathway, as described above. Then, this scenario may contribute to immune evasion of ZIKV, in which viral replication on maternal-fetal environment is unavoidable, inducing poor outcomes during pregnancy: fetal death, congenital syndrome, abortion, neurological disorders, etc. (Figure 2).
Myeloid-derived suppressor cell (MDSC) activation and regulation triggered by normal pregnancy and by Zika virus infection. Summary of MDSC functionality during normal pregnancy (A) and during acute phase of Zika virus infection (B) as suggested by others into an innate immunity dysregulation observed in abnormal pregnancies on monkeys [
It has been described that a protective response by innate immune cells to viruses is triggered by several distinct mechanisms including apoptosis, necrosis, paraptosis, pyroptosis, autophagy cell death, and others. Each one is depending on several aspects of infection, including where the microorganism was detected, susceptible target-cells, through signaling systems discharging the death signal, and its intensity. During the innate immune response to infections, programmed cell death may occur as a direct pathogenic mechanism of viral spread and escape from the immune system or represents an appropriate host response to limit pathogen replication. Apoptosis of lymphocytes and monocytes also plays an important role in the control of inflammatory responses, as well as in the development of maternal-fetal tolerance [96, 97, 98, 99].
Type 1 programmed cell death, also known as apoptosis, is defined by internucleosomal DNA fragmentation, marked irreversible apoptotic characteristic indicating chromatin condensation, degradation of cytoskeleton and nuclear proteins, protein crosslinking, apoptotic bodies’ formation baring ligands for receptors of phagocytic cells and, finally, the uptake by these phagocytes [97, 98, 99]. Type 2, or autophagic cell death, presents unique characteristics organelles formation including autophagosomes and autophagolysosomes in the dying cell, sources of self-degradation, and recycling [100].
Two pathways can regulate the apoptosis program in different aspects: extrinsic and intrinsic. Extrinsic pathway is activated by a transduction signal through death receptors, in which TNF, Fas ligand, or TRAIL bind to their respective receptors, such as TNF receptor family: TNFR1, Fas (CD95/APO-1) and TRAIL-R1/2. A complex signal mediated by this binding leads to an enzymatic cascade of cell degradation, and at this point caspase-3 is activated promoting DNA damage [101]. Intrinsic pathway involves intracellular mitochondria, which its membrane is the local for many Bcl-2 family members and their activity in inducing / inhibiting the mitochondrial apoptosis program implies in those proteins lead to membrane collapse as well as a transition from mitochondrial permeability promoting apoptosis process [96, 101, 102, 103, 104, 105].
Taking together, type 2, or autophagic cell death, consists of a conserved catabolic process that contributes to degradation and recycling of many intracellular substances, through lysosome activity. In this sense, many studies have shown its importance in immune responses, including degradation of microbes, direct viral peptides MHC class I presentation [106] and even altering T-cell signaling and tolerance [107, 108]. At first, autophagy is necessary to keep the cell alive under stress conditions that precede their demise. Such kind of cell death could be achieved by several mechanisms, including prolonged hypoxia or digestion of vital factors, regulatory molecules or essential organelles. In a stress situation, caused by virus, an infected cell can induce intracellular signals of autophagy, inhibiting cell proliferation, arresting cell cycle and eventually leading to cell death [106, 107, 108, 109, 110, 111].
In the acute ZIKV infection during pregnancy, macrophages and dendritic cells are involved in inflammatory cytokines production, in which CARD9 expression, an important regulator of caspase activity playing an important role in cell apoptosis regulation, is elevated allowing that pattern recognition receptors (PRR) induce pro-inflammatory cytokines cascade, as the first step on CZS, as suggested [67]. According to Quicke et al., Hofbauer cells infected with ZIKV in placenta induces IFN type I activation, reactive oxygen species production, as well as pro-inflammatory cytokines, but with minimal cell death, showing a scape of innate immune response [23]. Recently, Cao et al., showed that ZIKV could activate and increase an autophagic process in pregnant mice, suggesting an imbalance of trophoblastic cells in placenta, and relation with fetal loss [112]. Corroborating, Ribeiro et al. using a human model of placenta explants for in vitro infection demonstrated tissue injury as consequence of the association between fetal pro-inflammatory responses mediated by IL-1β, IL-6 and TNF and extrinsic caspase 3 dependent apoptosis (TNF-TNFR pathway). Together data suggest that ZIKV infection corroborates to placenta innate immune and hormonal dysfunction, increasing loss barrier integrity [42]Thus, this inflammatory status could trigger cell death and barrier loss, allowing ZIKV cross placenta and infect fetuses’ neural stem cells (Figure 3) [23, 113, 114, 115]. Interesting, autophagosomes are present in neural stem cells and it could facilitate ZIKV replication [116], although inflammation generated as well as the cytopathic effect itself culminate in extensive caspase-dependent neuronal cell death.
Programmed cell death activation during normal pregnancy and abnormal pregnancy induced by Zika virus. Normal pregnancy equilibrium is driven by regulation of number of innate immune cells in placenta leading by programmed cell death. In this situation, caspase activity starts on CARD9 expression with cytokines production by Hofbauer cells (1.A), which oxide nitric (NO) regulates trophoblasts autophagy (2.A, 3.A). Products of Hofbauer cells activity in the surveillance in placental parenchyma contributing to extrinsic (Fas/Fas-L) and intrinsic pathway (BCL2/BAX) activation in fetus brain with low expression of pro-inflammatory cytokines, regulating number of neural stem cells and microglia by apoptosis (4.A), maintaining the healthy pregnancy. Acute ZIKV infection during pregnancy suggests that macrophages and DCs are involved in pro-inflammatory cytokines production, in which CARD9 is upregulated, increasing caspase activity, allowing pro-inflammatory cytokines and reactive species cascade (1.B, 2.B), exacerbating autophagy in placenta (3.B). Taking together this innate immune dysfunction, fetus brain is affected by high activation of apoptosis pathway (4.B), provoking a cascade of cell death with an abrupt reduction of neural cells, causing severe damage [
Corroborating, Lum et al. has shown that ZIKV mainly infects fetal microglia and induces high levels of pro-inflammatory cytokines that could be harmful to the fetus [117]. In addition, the analysis of in vitro culture, fetal brain histology and
Thus, once in fetus central nervous system, ZIKV may contribute to extrinsic (Fas/Fas-L) and intrinsic (Bcl-2) pathways activation for programmed cell death, reducing number of neuronal cells. Thus, the risk of congenital syndrome is eminent, mainly in the first trimester, as well documented (Figure 3) [67, 118, 119, 120, 121, 122, 123]. Some studies with fetuses’ autopsies and infants with microcephaly have been demonstrated a broad spectrum of microscopic neuropathological abnormalities and brain damage, with direct virus cytopathic effects in neural glial cells. In this way, these data support the strong association with apoptotic cell death and microcalcifications [13, 23, 124].
In general, pregnancy is a challenge for prevention and control infectious diseases regard to a safe drug or vaccine development to do not disturb the innate/adaptive immunity homeostasis, however, there were no drugs approved for ZIKV infection treatment [28, 29, 30]. Here, drugs and vaccines candidates tested in animal models or in newborns will be described with details (Table 1).
Therapy | classification | Mechanism of action | Immune effect | Pregnancy safety | References |
---|---|---|---|---|---|
Peg Interferon-λ2 | Not approved | Antiviral immunobiological | Enhance IFNL-λ pathway activity | Yes/Mice models | Jagger et al., 2017 [26] |
Sofosbuvir | Category B/Approved for hepatitis C treatment | Direct-acting antiviral drugs | Not explored | Yes/Mice models | Mesci et al., 2018 [136] |
NITD008 | Not approved | Direct-acting antiviral drugs | Not explored | Yes/Mice models | Watanabe et al., 2019 [27] |
Hydroxycloroquine | Category C/Approved for malaria and autoimmune diseases therapy | Cell membrane interaction to induce cell death | Reduction of autophagy activity | Yes/Pregnant women | Cao et al., 2017 [112] |
rVSV vaccine | Not approved | Recombinant viral vector vaccine | Increases in CD8+/CD44high/IFN-γ + T cell populations on spleen | Yes/Mice models | Betancourt et al., 2017 [147] |
VRC5283 | Clinical trial phase II (VRC-ZKADNA090–00-VP) | DNA plasmid vaccine | Induce antigen-specific antibody production/ induce of CD8+ T cells response | Yes/Mice models | Richner et al.,2017 [155] |
mRNA-LNP vaccine | Clinical trial phase I (NCT03014089) | mRNA vaccine | Induce antigen-specific antibody production/ induce of CD8+ T cells response/Minimizes ADE | Yes/Mice models | Richner et al.,2017 [156] |
Therapeutic agents or vaccine candidates targeting virus or immunity with promisor potential to use during ZIKV infection in pregnant women.
Type III interferon has been emerging as an efficient and low damaging therapeutic agent not only directed for the virus but also for fungal and bacterial infections, as well as cancer, autoimmune, and vascular diseases [54]. The more restricted expression of IFNLR1 likely contributes to the improved safety profile of IFN-λl in clinical studies compared to type I IFN. Pegylated IFN-λ1 have already been tested in phase 2b clinical trial to chronic hepatitis C treatment and hepatitis B, associated with improved rates of virologic response with fewer extrahepatic adverse events compared to pegylated IFN-α [125]. Even though it was deemed less effective than alternative treatments for these infections, pegylated- IFN- λ can be potential candidate ready for deployment if new indications are identified [126]. There are other viral targets for IFN- λ therapy been tested in murine models: norovirus [127], and influenza virus [128], and west nile virus – last one is another member of Flaviviridae family. It is noteworthy the effect of IFN-λ on infection with west nile virus, an encephalitic flavivirus: Treatment of IFNLR1 knockout mice with pegylated IFN-λ2 resulted in decreased blood–brain barrier permeability, reducing west nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge [129].
The effectiveness and low damage treatments for other correlated viral infections, combined with the protagonist of IFN-λs as immunoregulatory and antiviral agent in ZIKV raise the idea of IFN-λs as ZIKV therapy, and some groups already achieve exciting good results. Concerning ZIKV infections, Jagger, et al., (2017) suggest that IFN-λ2 treatment could be a safe solution to minimize Congenital Zika Syndrome severe outcomes. Using a type III interferon-deficient mouse model, authors showed that these animals had an increase of ZIKV replication in the placenta under ZIKV infection, and treatment of pregnant mice with IFN-λ2 reduced ZIKV viremia [26]. Considering the vaginal epithelium as the first line of defense against sexually transmitted ZIKV, treatment of primary human vaginal and cervical epithelial cells lineages with IFN-λ induces host defense transcriptional signatures with augmented expression of ISGs (IFI44L, OASL, OAS1, and MX1) and inhibition of ZIKV replication. Female mice submitted to treatment with IFN-λ and intravaginal ZIKV transmission showed low levels of virus replication in the female reproductive tract with a hormonal stage-dependent role [130].
Some studies were driving to evaluate effects of independent direct-acting antiviral drugs on Zika virus infection (Table 1), as sofosbuvir, an FDA-approved nucleotide analog inhibitor of the hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) [131, 132]. In vitro and
There are few studies investigating innate immunity during antiviral therapy, especially when its concern to Flaviviridae family [38, 135, 138, 139]. Scarce literature revealed knowledge about antiviral therapy immune effects only during hepatitis C infection [138, 139]. Antiviral drugs, as pegylated interferon (PEG-IFN), ribavirin, and direct-acting antiviral agents (DAA) have been related with a reduction of innate regulatory cells, as MDSC, in peripheral blood from hepatitis C chronic patients, in which T cells were increased and immune function was reestablished [138, 139]. Nevertheless, all those drugs are aimed to interrupt viral replication and any dysregulation of immune cells during pregnancy is not safe, then those drugs are not recommended to be used during gestational period [140]. Besides no immune response evaluation was related to DAA therapy, it has been known that small molecules with specific activity should not induce any immune alterations in maternal-fetal immunity [140].
Safety and effectiveness of sofosbuvir on Zika virus infection should be addressed to immune response evaluation, which is poorly explored, even more in pregnant animal models. More studies and investments are needed for non-clinical and clinical studies, to get safety therapeutic protocols aimed to pregnant women with Zika virus or other flavivirus infection.
Genetic manipulation has been proven to be a promising tool for vaccine and therapy development. Considering the type 2 of programmed death, autophagy is activated by ZIKV in placental parenchyma and is involved in poor outcome during pregnancy, this cell death pathway has been a target for therapies [112, 141, 142, 143].
Recently, a study showed the role of an autophagy gene (Atg16I1) during ZIKV infection in pregnant mice model, in which inducing a deficiency in this gene limited ZIKV vertical transmission, as well fetal damage, improving placental and fetal outcomes [112]. In addition, an antiviral compound approved to be used by pregnant women for malaria and autoimmune diseases [141], hydroxychloroquine (HCQ), has been used to dampen autophagic activity
Based on the knowledge of ZIKV infection that can trigger a caspase-3 activation contributing to cell death of neural progenitor cells during pregnancy, it is an extremely relevant approaches targeting cell death pathways for antiviral treatments even though for therapeutic vaccines.
Recombinant viral vectors have been highlighted as therapeutic alternatives to prevent and treat infectious disease [144, 145], considering its specificity and the adverse effects of antiviral drugs and some vaccines [140, 146]. Betancourt et al., 2017 showed that a recombinant viral vector from vesicular stomatitis virus (rVSV) anti-ZIKV vaccine increased IFN-γ production by splenic CD8+ T cells as well as high neutralizing anti-ZIKV antibody titers from pregnant mice. This study also demonstrates that neonatal mouse from vaccinated dams was partially protected against neurological manifestations of ZIKV infection following wild-type virus challenge [147]. This rVSV using pre membrane and envelope region together obtained from a ZIKV strain as reference had the potential to protect from ZIKV infection during prenatal and neonatal development, likely through the transmission of maternal IgG. Despite rVSV vaccine induces IFN-γ production in pregnant mice, this vaccine needs to be evaluated for other types of interferon, mainly its effects on placental tissues .
mRNA vaccines as well as DNA-based vaccines represent a versatile vaccine platform and an alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration [148]. Recent technological advances have allowed mRNA vaccines to demonstrate encouraging results in both animal and human models. Regarding prophylactic mRNA vaccines, a number of reports have demonstrated the potency and versatility of mRNA to elicited protective immunity against a variety of infectious agents in animal models against, including influenza virus, Ebola virus, Zika virus, Human Immunodeficiency virus 1 (HIV-1), herpes simplex virus, cytomegalovirus, hepatitis C and respiratory syncytial virus [149, 150, 151]. It has been noted that approximately ten mRNA vaccines programs have entered clinical trials [152].
The importance of mRNA-based vaccines and therapies is emphasized when mRNA-based biopharmaceuticals are entering the market with guidance of new biopharmaceutical companies. Modern Therapeutics, an mRNA therapy company evaluated various mRNA vaccine technologies to identify immunogenic and scalable candidates. The pipeline of this company shows different investigative stages mRNA vaccines of the following vaccines Respiratory Syncytial virus (RSV), Cytomegalovirus (CMV), human metapneumovirus (hMPV) + Parainfluenza virus Type 3 (PIV3), Influenza A subtypes H10N8, and H7N9, Zika, and Chikungunya. Curevac is the first biopharmaceutical company that developed the first prophylactic mRNA vaccine in the clinics, recently they showed that RNActive® vaccines induced long-lived and protective immunity to influenza A virus infections in various animal models [153].
Thus, big pharmaceutic companies, such as Merck & Co., have been invested in Modern Therapeutics aiming to expand the field of mRNA vaccine (https://www.modernatx.com/). Indeed, nucleic acid vaccine platform has been presented to combat the emergence of acute viral diseases, mainly to rapidly contain emerging outbreaks before they spread out of control. In this context, two vaccines were developed to combat the ZIKV outbreak (1) DNA plasmid vaccine encoding the prM-E genes of ZIKV and (VRC5283) (2) mRNA vaccine (mRNA-LNP), both vaccines mediate protection from ZIKV infection in mouse models. The DNA plasmid vaccine is in phase 2 human clinical trials (VRC-ZKADNA090–00-VP) and vaccine mRNA-LNP is in phase 1 clinical trial (NCT03014089) [154, 155, 156].
Considering that vaccine trials might not be performed in pregnant women and have not yet tested vaccines against ZIKV vertical transmission, there is a need for establishing the efficacy of ZIKV vaccines against mother-to-child transmission in animal models. In order to address those questions, it has been shown that vaccination with DNA plasmid encoding Zika virus prM-E and a lipid-encapsulated mRNA vaccine-elicited antigen-specific antibody and CD8+ T cell responses in mice, being able to generate a high level of protection against vertical transmission. Moreover, the mRNA-LNP vaccine not only inhibited vertical transmission but also ensured that fetuses are protected therefore, reinforcing its potential as promising vaccine for pregnant women [155]. Since there are few studies in the field of ZIKV vaccine candidates that evaluated vertical transmission, intrinsic maternal factors as well as fetal health, nucleic acid vaccines are pointed as a great opportunity to contain ZIKV infection.
Considering the normal pregnancy, the innate immunity balance is conduct by downregulation of effector T cells and NK cells leading by innate regulatory cells (MDSC) and upregulation of pro-inflammatory cytokines. This innate immune modulation that occurs mainly at the placenta, includes interferon pathway and cell death modulation as shown in Figure 4A. Gestation has its own difficulties to successful outcomes regarding maternal immune tolerance. Zika virus infection becomes classified as disease-causing birth defects, developing an abnormal pregnancy, as consequence of immune dysregulation (Figure 4B). Thus, antiviral therapy is the key to control this immune imbalance showing positive effects in innate immunity on pregnant mice models. It has been known that efforts through vaccines development targeting pregnant women will be the solution for ZIKV prevention, as well as for other arboviral infections, to maintain immune homeostasis and generate healthy babies. Finally, this chapter brings some new thoughts that help for targeted improvements in medical science considering Zika infection on pregnancy, and innate immune system linked to therapies previewing the prevention and control.
Summary of innate immunity functionality during normal pregnancy and in Zika virus infection focus on interferon III, myeloid-derived suppressor cells, and programmed cell death activities. During pregnancy, initial signal is dependent on nidation process and placenta formation leading by trophoblasts expansion and activation. Following this process, innate cells, such as neutrophils, DCs, and cytokines are activated (1.A, 2.A) with IL10 and TGF-beta production in periphery, allowing immunosuppressive functionality triggered by regulatory cells (MDSC and Treg) (3.A). This condition facilitates suppression of effector cells (NK and lymphocytes) in peripheral blood and in placenta triggered by MDSC (4.A), whereas Hofbauer cells maintain reactive species (NO) balanced (5.A) as well as the IFN-λ downregulation, IFN type I upregulation, and trophoblast autophagy (6.A), contributing to the cross-linking in the fetus-maternal interface. Adding to that, programmed cell death contributes to control the accelerated growth of neural cells in fetus brain (7.A), corroborating with a successful pregnancy. Zika virus has been related to abnormal pregnancy, leading to massive innate immune alteration, causing severe brain damage to fetus. Given that, when the virus is in the blood, there is a gross activation of innate cells, elevation of cytokines and chemokines (1.B, 2.B), and suppressive activity by regulatory cells is compromised (3.B), generating early activation of NK and T cells in blood (4.B) and macrophages in placenta (5.B). Virus invasion in placenta through Hofbauer and trophoblast cells results in high autophagy activity with interferon type I gene highly expressed combined with super downregulation of interferon type III (6.B). This imbalance also contributes to fetal brain damage, orchestra by high activation of apoptosis pathway, avoiding neural cells growing progress. Thus, Zika provides severe damage to fetus, in which drugs, vaccines and immunotherapies have been designed suggesting a modulation of three important keys of innate immunity to control virus replication and spread into fetus-maternal interface: interferon type III expression, MDSC frequency, and autophagy process (highlighted with red rectangles) to avoid severe fetus brain damage, allowing a healthy pregnancy. This figure was made based on the information from
The authors would like to thank Directory of Technological Development from Immunobiological Technology Institute, Biomanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil for founding support.
Authors to declare no conflicts of interest.
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Mahruf C. Shohel",coverURL:"https://cdn.intechopen.com/books/images_new/9974.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"680",title:"Mathematical Modeling",slug:"engineering-acoustical-engineering-mathematical-modeling",parent:{id:"110",title:"Acoustical Engineering",slug:"engineering-acoustical-engineering"},numberOfBooks:1,numberOfSeries:0,numberOfAuthorsAndEditors:27,numberOfWosCitations:8,numberOfCrossrefCitations:8,numberOfDimensionsCitations:19,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"680",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"5708",title:"Computational and Experimental Studies of Acoustic Waves",subtitle:null,isOpenForSubmission:!1,hash:"518d2ac3c49f5c4c48d4f3f3b0729232",slug:"computational-and-experimental-studies-of-acoustic-waves",bookSignature:"Mahmut Reyhanoglu",coverURL:"https://cdn.intechopen.com/books/images_new/5708.jpg",editedByType:"Edited by",editors:[{id:"15068",title:"Dr.",name:"Mahmut",middleName:null,surname:"Reyhanoglu",slug:"mahmut-reyhanoglu",fullName:"Mahmut Reyhanoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"57258",doi:"10.5772/intechopen.71203",title:"Sound Waves in Complex (Dusty) Plasmas",slug:"sound-waves-in-complex-dusty-plasmas",totalDownloads:1381,totalCrossrefCites:5,totalDimensionsCites:5,abstract:"Wave properties of strongly coupled complex dusty (SCCD) plasmas evaluated using the equilibrium molecular dynamics (EMD) simulation technique. In this work, the plasma normalized longitudinal current correlation function CL(k,t) and transverse current CT(k,t) are calculated for a large range of plasma parameters of Coulomb coupling parameter (Γ) and screening strength (κ) with varying wave’s number (k). In EMD simulations, we have analysed different modes of wave propagation in SCCD plasmas with increasing and decreasing sequences of different combinations of plasmas parameters (κ, Γ) at varying simulation time step (Δt). Our simulation results show that the fluctuation of waves increases with an increase of Γ and decreases with increasing κ. Additional test shows that the presented results for waves are slightly dependent on number of particles (N). The amplitude and time period of CL(k,t) and CT(k,t) also depend on different influenced parameters of κ, Γ, k and N. The new results obtained through the presented EMD method for complex dusty plasma discussed and compared with earlier simulation results based on different numerical methods. It is demonstrated that the presented model is the best tool for estimating the behaviour of waves in strongly coupled complex system (dusty plasmas) over a suitable range of parameters.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Aamir Shahzad, Muhammad Asif Shakoori, Maogang He and Sajid\nBashir",authors:[{id:"288354",title:"Dr.",name:"Aamir",middleName:null,surname:"Shahzad",slug:"aamir-shahzad",fullName:"Aamir Shahzad"}]},{id:"58101",doi:"10.5772/intechopen.72215",title:"Wave Propagation in Porous Materials",slug:"wave-propagation-in-porous-materials",totalDownloads:1547,totalCrossrefCites:1,totalDimensionsCites:5,abstract:"This chapter provides different models for the acoustic wave propagation in porous materials having a rigid and an elastic frames. The direct problem of reflection and transmission of acoustic waves by a slab of porous material is studied. The inverse problem is solved using experimental reflected and transmitted signals. Both high- and low-frequency domains are studied. Different acoustic methods are proposed for measuring physical parameters describing the acoustic propagation as porosity, tortuosity, viscous and thermal characteristic length, and flow resistivity. Some advantages and perspectives of this method are discussed.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Zine El Abiddine Fellah, Mohamed Fellah, Claude Depollier, Erick\nOgam and Farid G. Mitri",authors:[{id:"143693",title:"Dr.",name:"Zine El Abiddine",middleName:null,surname:"Fellah",slug:"zine-el-abiddine-fellah",fullName:"Zine El Abiddine Fellah"},{id:"144519",title:"Prof.",name:"Claude",middleName:null,surname:"Depollier",slug:"claude-depollier",fullName:"Claude Depollier"},{id:"178778",title:"Prof.",name:"Mohamed",middleName:null,surname:"Fellah",slug:"mohamed-fellah",fullName:"Mohamed Fellah"},{id:"209074",title:"Dr.",name:"Erick",middleName:null,surname:"Ogam",slug:"erick-ogam",fullName:"Erick Ogam"},{id:"227468",title:"Dr.",name:"Farid G",middleName:null,surname:"Mitri",slug:"farid-g-mitri",fullName:"Farid G Mitri"}]},{id:"56872",doi:"10.5772/intechopen.70590",title:"Acoustic Wave Monitoring of Fluid Dynamics in the Rock Massif with Anomaly Density, Stressed and Plastic Hierarchic Inclusions",slug:"acoustic-wave-monitoring-of-fluid-dynamics-in-the-rock-massif-with-anomaly-density-stressed-and-plas",totalDownloads:1094,totalCrossrefCites:1,totalDimensionsCites:5,abstract:"The geological environment is an open system, on which external and internal factors act. They lead it to an unstable state, which, as a rule, manifests itself locally in the form of zones, called dynamically active elements, which are indicators of potential catastrophic sources. These objects differ from the host geological environment by structural forms, which are often forming of a hierarchical type. The process of their activation can be observed using monitoring with wave fields, for mathematical support of which new modeling algorithms have been developed using the method of integral and integral-differential equations. A new approach to the interpretation of wave fields has been developed, to determine contours or surfaces of locally stressed hierarchical objects. An iterative process of solving the theoretical inverse problem for the case of determining configurations of 2D hierarchical inclusions of the k-th rank is developed. When interpreting monitoring results, it is necessary to use data from such monitoring systems that are tuned to study the hierarchical structure of the environment.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Olga Hachay and Andrey Khachay",authors:[{id:"150801",title:"Prof.",name:"Olga",middleName:"Alexandrovna",surname:"Hachay",slug:"olga-hachay",fullName:"Olga Hachay"},{id:"219182",title:"MSc.",name:"Andrey",middleName:null,surname:"Khachay",slug:"andrey-khachay",fullName:"Andrey Khachay"}]},{id:"57674",doi:"10.5772/intechopen.71647",title:"Optimized Finite Difference Methods for Seismic Acoustic Wave Modeling",slug:"optimized-finite-difference-methods-for-seismic-acoustic-wave-modeling",totalDownloads:1500,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The finite difference (FD) methods are widely used for approximating the partial derivatives in the acoustic/elastic wave equation. Grid dispersion is one of the key numerical problems and will directly influence the accuracy of the result because of the discretization of the partial derivatives in the wave equation. Therefore, it is of great importance to suppress the grid dispersion by optimizing the FD coefficient. Various optimized methods are introduced in this chapter to determine the FD coefficient. Usually, the identical staggered grid finite difference operator is used for all of the first-order spatial derivatives in the first-order wave equation. In this chapter, we introduce a new staggered grid FD scheme which can improve the efficiency while still preserving high accuracy for the first-order acoustic/elastic wave equation modeling. It uses different staggered grid FD operators for different spatial derivatives in the first-order wave equation. The staggered grid FD coefficients of the new FD scheme can be obtained with a linear method. At last, numerical experiments were done to demonstrate the effectiveness of the introduced method.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Yanfei Wang and Wenquan Liang",authors:[{id:"218676",title:"Prof.",name:"Yanfei",middleName:null,surname:"Wang",slug:"yanfei-wang",fullName:"Yanfei Wang"}]},{id:"57603",doi:"10.5772/intechopen.71411",title:"In-Fiber Acousto-Optic Interaction Based on Flexural Acoustic Waves and Its Application to Fiber Modulators",slug:"in-fiber-acousto-optic-interaction-based-on-flexural-acoustic-waves-and-its-application-to-fiber-mod",totalDownloads:1305,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"The design and implementation of in-fiber acousto-optic (AO) devices based on acoustic flexural waves are presented. The AO interaction is demonstrated to be an efficient mechanism for the development of AO tunable filters and modulators. The implementation of tapered optical fibers is proposed to shape the spectral response of in-fiber AO devices. Experimental results demonstrate that the geometry of the tapered fiber can be regarded as an extra degree of freedom for the design of AO tunable attenuation filters (AOTAFs). In addition, with the objective of expanding the application of AOTAFs to operate as an amplitude modulator, acoustic reflection was intentionally induced. Hence, a standing acoustic wave is generated which produces an amplitude modulation at twice the acoustic frequency. As a particular case, an in-fiber AO modulator composed of a double-ended tapered fiber was reported. The fiber taper was prepared using a standard fusion and pulling technique, and it was tapered down to a fiber diameter of 70 μm. The device exhibits an amplitude modulation at 2.313 MHz, which is two times the acoustic frequency used (1.1565 MHz); a maximum modulation depth of 60%, 1.3 dB of insertion loss, and 40 nm of modulation bandwidth were obtained. These results are within the best results reported in the framework of in-fiber AO modulators.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Miguel Ángel Bello Jiménez, Gustavo Ramírez-Meléndez, Erika\nHernández-Escobar, Andrés Camarillo-Avilés, Rosa López-Estopier,\nOlivier Pottiez, Cristian Cuadrado-Laborde, Antonio Díez, José L.\nCruz and Miguel V. Andrés",authors:[{id:"46578",title:"Dr.",name:"Miguel V.",middleName:null,surname:"Andrés",slug:"miguel-v.-andres",fullName:"Miguel V. Andrés"},{id:"46579",title:"Dr.",name:"Antonio",middleName:null,surname:"Diez",slug:"antonio-diez",fullName:"Antonio Diez"},{id:"46580",title:"Dr.",name:"José L.",middleName:null,surname:"Cruz",slug:"jose-l.-cruz",fullName:"José L. Cruz"},{id:"160262",title:"Dr.",name:"Olivier Jean Michel",middleName:null,surname:"Pottiez",slug:"olivier-jean-michel-pottiez",fullName:"Olivier Jean Michel Pottiez"},{id:"160283",title:"Dr.",name:"Miguel",middleName:null,surname:"Bello-Jiménez",slug:"miguel-bello-jimenez",fullName:"Miguel Bello-Jiménez"},{id:"182010",title:"Dr.",name:"R.",middleName:null,surname:"López-Estopier",slug:"r.-lopez-estopier",fullName:"R. López-Estopier"},{id:"220895",title:"MSc.",name:"Gustavo",middleName:null,surname:"Ramírez-Meléndez",slug:"gustavo-ramirez-melendez",fullName:"Gustavo Ramírez-Meléndez"},{id:"220896",title:"MSc.",name:"Erika",middleName:null,surname:"Hernández-Escobar",slug:"erika-hernandez-escobar",fullName:"Erika Hernández-Escobar"},{id:"220897",title:"BSc.",name:"Andrés",middleName:null,surname:"Camarillo-Avilés",slug:"andres-camarillo-aviles",fullName:"Andrés Camarillo-Avilés"},{id:"220902",title:"Dr.",name:"Christian",middleName:null,surname:"Cuadrado-Laborde",slug:"christian-cuadrado-laborde",fullName:"Christian Cuadrado-Laborde"}]}],mostDownloadedChaptersLast30Days:[{id:"58101",title:"Wave Propagation in Porous Materials",slug:"wave-propagation-in-porous-materials",totalDownloads:1547,totalCrossrefCites:1,totalDimensionsCites:5,abstract:"This chapter provides different models for the acoustic wave propagation in porous materials having a rigid and an elastic frames. The direct problem of reflection and transmission of acoustic waves by a slab of porous material is studied. The inverse problem is solved using experimental reflected and transmitted signals. Both high- and low-frequency domains are studied. Different acoustic methods are proposed for measuring physical parameters describing the acoustic propagation as porosity, tortuosity, viscous and thermal characteristic length, and flow resistivity. Some advantages and perspectives of this method are discussed.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Zine El Abiddine Fellah, Mohamed Fellah, Claude Depollier, Erick\nOgam and Farid G. Mitri",authors:[{id:"143693",title:"Dr.",name:"Zine El Abiddine",middleName:null,surname:"Fellah",slug:"zine-el-abiddine-fellah",fullName:"Zine El Abiddine Fellah"},{id:"144519",title:"Prof.",name:"Claude",middleName:null,surname:"Depollier",slug:"claude-depollier",fullName:"Claude Depollier"},{id:"178778",title:"Prof.",name:"Mohamed",middleName:null,surname:"Fellah",slug:"mohamed-fellah",fullName:"Mohamed Fellah"},{id:"209074",title:"Dr.",name:"Erick",middleName:null,surname:"Ogam",slug:"erick-ogam",fullName:"Erick Ogam"},{id:"227468",title:"Dr.",name:"Farid G",middleName:null,surname:"Mitri",slug:"farid-g-mitri",fullName:"Farid G Mitri"}]},{id:"57258",title:"Sound Waves in Complex (Dusty) Plasmas",slug:"sound-waves-in-complex-dusty-plasmas",totalDownloads:1381,totalCrossrefCites:5,totalDimensionsCites:5,abstract:"Wave properties of strongly coupled complex dusty (SCCD) plasmas evaluated using the equilibrium molecular dynamics (EMD) simulation technique. In this work, the plasma normalized longitudinal current correlation function CL(k,t) and transverse current CT(k,t) are calculated for a large range of plasma parameters of Coulomb coupling parameter (Γ) and screening strength (κ) with varying wave’s number (k). In EMD simulations, we have analysed different modes of wave propagation in SCCD plasmas with increasing and decreasing sequences of different combinations of plasmas parameters (κ, Γ) at varying simulation time step (Δt). Our simulation results show that the fluctuation of waves increases with an increase of Γ and decreases with increasing κ. Additional test shows that the presented results for waves are slightly dependent on number of particles (N). The amplitude and time period of CL(k,t) and CT(k,t) also depend on different influenced parameters of κ, Γ, k and N. The new results obtained through the presented EMD method for complex dusty plasma discussed and compared with earlier simulation results based on different numerical methods. It is demonstrated that the presented model is the best tool for estimating the behaviour of waves in strongly coupled complex system (dusty plasmas) over a suitable range of parameters.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Aamir Shahzad, Muhammad Asif Shakoori, Maogang He and Sajid\nBashir",authors:[{id:"288354",title:"Dr.",name:"Aamir",middleName:null,surname:"Shahzad",slug:"aamir-shahzad",fullName:"Aamir Shahzad"}]},{id:"56289",title:"Acoustic Analysis of Enclosed Sound Space as well as Its Coupling with Flexible Boundary Structure",slug:"acoustic-analysis-of-enclosed-sound-space-as-well-as-its-coupling-with-flexible-boundary-structure",totalDownloads:1280,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Combustion instability is often encountered in various power systems, a good understanding on the sound field in acoustic cavity as well as its coupling with boundary flexible structure will be of great help for the reliability design of such combustion system. An improved Fourier series method is presented for the acoustic/vibro-acoustic modelling of acoustic cavity as well as the panel-cavity coupling system. The structural-acoustic coupling system is described in a unified pattern using the energy principle. With the aim to construct the admissible functions sufficiently smooth for the enclosed sound space as well as the flexible boundary structure, the boundary-smoothed auxiliary functions are introduced to the standard multi-dimensional Fourier series. All the unknown coefficients and higher order variables are determined in conjunction with Rayleigh-Ritz procedure and differential operation term by term. Numerical examples are then presented to show the correctness and effectiveness of the current model. The model is verified through the comparison with those from analytic solution and other approaches. Based on the model established, the influence of boundary conditions on the acoustic and/or vibro-acoustic characteristics of the structural-acoustic coupling system is addressed and investigated.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Jingtao Du, Yang Liu and Long Liu",authors:[{id:"203133",title:"Prof.",name:"Jingtao",middleName:null,surname:"Du",slug:"jingtao-du",fullName:"Jingtao Du"},{id:"203657",title:"Dr.",name:"Yang",middleName:null,surname:"Liu",slug:"yang-liu",fullName:"Yang Liu"},{id:"203658",title:"Dr.",name:"Long",middleName:null,surname:"Liu",slug:"long-liu",fullName:"Long Liu"}]},{id:"57214",title:"A Novel Idea of Coherent Acoustic Wave-Induced Atmospheric Refractivity Fluctuation and Its Applications",slug:"a-novel-idea-of-coherent-acoustic-wave-induced-atmospheric-refractivity-fluctuation-and-its-applicat",totalDownloads:1412,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The physical mechanism of generating the lasting tropospheric refractivity fluctuation with a stable array-distributed structure by coherent acoustic waves is investigated. An example of the quantitative calculation of atmospheric refractive index is given and analyzed. Based on the theory of electromagnetic wave propagation and scattering in the troposphere, the feasibility to purposefully affect radio wave propagation is qualitatively demonstrated by the experiment of the coherent acoustic source-induced laser interference fringe change. The potential application aspects of synthetically controlling the radio wave propagation by the artificial refractivity fluctuation structure are preliminarily proposed. This chapter will promote the development of the coherent acoustic wave-induced tropospheric refractivity fluctuation, and it has the important theoretical significance and potential application value to purposely apply the positive or negative effects on radio wave propagation.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Shuhong Gong, Yu Liu, Muyu Hou and Lixin Guo",authors:[{id:"218965",title:"Dr.",name:"Shuhong",middleName:null,surname:"Gong",slug:"shuhong-gong",fullName:"Shuhong Gong"},{id:"220994",title:"BSc.",name:"Yu",middleName:null,surname:"Liu",slug:"yu-liu",fullName:"Yu Liu"},{id:"220995",title:"BSc.",name:"Muyu",middleName:null,surname:"Hou",slug:"muyu-hou",fullName:"Muyu Hou"},{id:"220996",title:"Dr.",name:"Lixin",middleName:null,surname:"Guo",slug:"lixin-guo",fullName:"Lixin Guo"}]},{id:"57603",title:"In-Fiber Acousto-Optic Interaction Based on Flexural Acoustic Waves and Its Application to Fiber Modulators",slug:"in-fiber-acousto-optic-interaction-based-on-flexural-acoustic-waves-and-its-application-to-fiber-mod",totalDownloads:1305,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"The design and implementation of in-fiber acousto-optic (AO) devices based on acoustic flexural waves are presented. The AO interaction is demonstrated to be an efficient mechanism for the development of AO tunable filters and modulators. The implementation of tapered optical fibers is proposed to shape the spectral response of in-fiber AO devices. Experimental results demonstrate that the geometry of the tapered fiber can be regarded as an extra degree of freedom for the design of AO tunable attenuation filters (AOTAFs). In addition, with the objective of expanding the application of AOTAFs to operate as an amplitude modulator, acoustic reflection was intentionally induced. Hence, a standing acoustic wave is generated which produces an amplitude modulation at twice the acoustic frequency. As a particular case, an in-fiber AO modulator composed of a double-ended tapered fiber was reported. The fiber taper was prepared using a standard fusion and pulling technique, and it was tapered down to a fiber diameter of 70 μm. The device exhibits an amplitude modulation at 2.313 MHz, which is two times the acoustic frequency used (1.1565 MHz); a maximum modulation depth of 60%, 1.3 dB of insertion loss, and 40 nm of modulation bandwidth were obtained. These results are within the best results reported in the framework of in-fiber AO modulators.",book:{id:"5708",slug:"computational-and-experimental-studies-of-acoustic-waves",title:"Computational and Experimental Studies of Acoustic Waves",fullTitle:"Computational and Experimental Studies of Acoustic Waves"},signatures:"Miguel Ángel Bello Jiménez, Gustavo Ramírez-Meléndez, Erika\nHernández-Escobar, Andrés Camarillo-Avilés, Rosa López-Estopier,\nOlivier Pottiez, Cristian Cuadrado-Laborde, Antonio Díez, José L.\nCruz and Miguel V. Andrés",authors:[{id:"46578",title:"Dr.",name:"Miguel V.",middleName:null,surname:"Andrés",slug:"miguel-v.-andres",fullName:"Miguel V. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). 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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",institutionURL:null,country:{name:"Canada"}}}]}]},openForSubmissionBooks:{paginationCount:3,paginationItems:[{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",hash:"1806716f60b9be14fc05682c4a912b41",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"March 23rd 2022",isOpenForSubmission:!0,editors:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11579",title:"Animal Welfare - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11579.jpg",hash:"12e4f41264cbe99028655e5463fa941a",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"June 1st 2022",isOpenForSubmission:!0,editors:[{id:"51520",title:"Dr.",name:"Shao-Wen",surname:"Hung",slug:"shao-wen-hung",fullName:"Shao-Wen Hung"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg",hash:"3731c009f474c6ed4293f348ca7b27ac",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"June 3rd 2022",isOpenForSubmission:!0,editors:[{id:"225390",title:"Dr.",name:"Asghar Ali",surname:"Kamboh",slug:"asghar-ali-kamboh",fullName:"Asghar Ali Kamboh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:1,paginationItems:[{id:"81831",title:"Deep Network Model and Regression Analysis using OLS Method for Predicting Lung Vital Capacity",doi:"10.5772/intechopen.104737",signatures:"Harun Sümbül",slug:"deep-network-model-and-regression-analysis-using-ols-method-for-predicting-lung-vital-capacity",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:0,authors:null,book:{title:"Decision Science - Recent Advances and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11604.jpg",subseries:{id:"86",title:"Business and Management"}}}]},subseriesFiltersForOFChapters:[{caption:"Business and Management",value:86,count:1,group:"subseries"}],publishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"11392",title:"Leadership in a Changing World",subtitle:"A Multidimensional Perspective",coverURL:"https://cdn.intechopen.com/books/images_new/11392.jpg",slug:"leadership-in-a-changing-world-a-multidimensional-perspective",publishedDate:"May 11th 2022",editedByType:"Edited by",bookSignature:"Muhammad Mohiuddin, Bilal Khalid, Md. Samim Al Azad and Slimane Ed-dafali",hash:"86a6d33cf601587e591064ce92effc02",volumeInSeries:1,fullTitle:"Leadership in a Changing World - A Multidimensional Perspective",editors:[{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038UqSfQAK/Profile_Picture_2022-05-13T10:39:03.jpg",institutionString:null,institution:{name:"Université Laval",institutionURL:null,country:{name:"Canada"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Business and Management",value:86,count:1}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:1}],authors:{paginationCount:249,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, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for 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:"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:null},{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:"Beijing University of Technology",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:"Lakhno Igor Victorovich 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.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of 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 a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), 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 DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. 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: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{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:"243698",title:"M.D.",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:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{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:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{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:"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:"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:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. 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His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. 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