Modulation of stem cells or dopaminergic (DA) cells with combined cellular transplantation in PD (adopted from “Potential of Neural Stem Cell-Based Therapy for Parkinson’s Disease” [68]).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"}]},book:{item:{type:"book",id:"3839",leadTitle:null,fullTitle:"Trends in Helicobacter pylori Infection",title:"Trends in Helicobacter pylori Infection",subtitle:null,reviewType:"peer-reviewed",abstract:"Helicobacter pylori is a universally distributed bacterium which affects more than half of the world population. The infection is associated with the development of various diseases of the upper gastrointestinal tract, besides extradigestive diseases. This book is a comprehensive overview of contributors on H. pylori infection in several areas. Its chapters were divided into sections concerning general aspects of H. pylori infection, immunopathology and genetic diversity, questions regarding possible routes of bacterium transmission, the importance of the strains characteristics in the development of gastric cancer and the possibilities of prevention, H. pylori infection in children, the possible association between its infection and extradigestive diseases, and the principal therapeutic regimens of bacterium eradication, considering the antimicrobial resistance.",isbn:null,printIsbn:"978-953-51-1239-6",pdfIsbn:"978-953-51-7200-0",doi:"10.5772/57053",price:139,priceEur:155,priceUsd:179,slug:"trends-in-helicobacter-pylori-infection",numberOfPages:392,isOpenForSubmission:!1,isInWos:1,hash:"3dc63cbee177c36f568ff67aa6ec1413",bookSignature:"Bruna Maria Roesler",publishedDate:"April 3rd 2014",coverURL:"https://cdn.intechopen.com/books/images_new/3839.jpg",numberOfDownloads:22734,numberOfWosCitations:8,numberOfCrossrefCitations:70,numberOfDimensionsCitations:168,hasAltmetrics:0,numberOfTotalCitations:246,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 15th 2013",dateEndSecondStepPublish:"May 6th 2013",dateEndThirdStepPublish:"August 10th 2013",dateEndFourthStepPublish:"November 8th 2013",dateEndFifthStepPublish:"February 12th 2014",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"54995",title:"Dr.",name:"Bruna Maria",middleName:null,surname:"Roesler",slug:"bruna-maria-roesler",fullName:"Bruna Maria Roesler",profilePictureURL:"https://mts.intechopen.com/storage/users/54995/images/system/54995.jpg",biography:"Dr. Bruna Maria Roesler is a pharmacist biochemist and holds\r\na Master’s degree in Pharmacology and a Doctoral degree in\r\nBasic Sciences—Internal Medicine from the State University of\r\nCampinas (Campinas, SP, Brazil) where she has identified the\r\nprincipal genotypes of Helicobacter pylori strains in patients with\r\nchronic gastritis, peptic ulcer disease, and gastric cancer (early\r\nand advanced stages) through molecular biology techniques. She\r\nhas published her work in several peer-reviewed journals and given oral and poster\r\npresentations at various congresses. Her research also includes the etiology, epidemiology, and physiopathology of gastrointestinal diseases. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"59296",title:"Development of Neural Stem Cell-Based Therapies for Parkinson’s Disease",doi:"10.5772/intechopen.73870",slug:"development-of-neural-stem-cell-based-therapies-for-parkinson-s-disease",body:'\nParkinson’s disease (PD) is the most common neurodegenerative movement disorder, and its prevalence reaches 0.3% of the entire population in industrialized countries [1]. PD prevalence is increasing with age, affecting 1% of the population above 60 years and 4% in those aged over 80 [2]. Since the clinical trial of neural stem cell (NSC) transplantation therapy has shown promising results for stroke patients [3], the NSC-based therapy could be a potential treatment for restoring neuronal function for PD patients. A better understanding of pathophysiology of PD, establishment of valid and effective NSC lines, and successful clinical trials will point to a novel neuroregeneration strategy to complement current medical treatment and deep brain stimulation.
\nAdvances in the pathophysiology of PD have expanded our traditional knowledge that it is characterized by a profound and selective loss of nigrostriatal dopaminergic (DA) neurons. PD could be considered a developmental disorder with evidence beyond neurodegeneration, regarding relationships among deregulated neurogenesis, disease onset, and its progression. The numbers of proliferating NSCs, for instance, have been found decreased in the PD-affected postmortem brain [4, 5], but evidence of a link between altered proliferation of NSCs, functional DA neurons, and neurological deficits remains insufficient. Besides typical motor symptoms, including asymmetrical bradykinesia, rigidity, postural instability, and resting tremors, patients may have nonmotor symptoms, such as dementia, sleep disturbance, and autonomic dysfunction. Hence, public health education and routine physical examinations are substantial for early diagnosis and intervention.
\nNSCs preserve the ability to self-renew and differentiate into all neural lineage cells, and they are regarded as a potential graft for cellular transplantation. Reducing the possibility of tumorigenesis has to be considered during immortalization of NSC lines which provide a consistency of cell grafting. Furthermore, preclinical studies, such as transcranial injection of NSCs into animal brains with adequate follow-ups, will prove the validity of its clinical application.
\nIndependent ethical and regulatory approval, full financial support from the foundation, and long-term follow-up of systematically collected rigorous measures are the requirements for conducting clinical trials for NSC-based therapies in PD. Appropriately transparent processing with governmental approval could encourage patient cooperation according to experience from cell transplantation therapy in other diseases. In this chapter, we will provide a comprehensive literature review as well as the perspectives on NSC applications in PD.
\nThe pathological diagnosis of PD has been possibly made since Frederic Lewy described microscopic particles in affected brains as early as 1912, later named “Lewy bodies” [6]. The characteristic pathophysiology of PD includes death of DA neurons in the substantia nigra pars compacta (SNpc), degeneration of DA neurotransmission, and the presence of alpha-synuclein and protein inclusions in neuronal cells that are known as Lewy bodies [7]. In general, more than 50% of DA neurons have been lost before typical symptoms of PD develop [8]. It has been found that a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls [9]. Additionally, nigral neuronal loss could be observed before the appearance of alpha-synuclein aggregates [9]. A negative correlation between neuronal density and local alpha-synuclein burden in the substantia nigra was therefore evident in PD patients. Most importantly, stage-dependent nigral neuronal loss and local burden of alpha-synuclein pathological conditions are closely coupled during disease progression of PD.
\nThe diagnosis of PD can be made through the detection of mutations in specific genes responsible for familial PD in the era of molecular biology. But only about 10% of diagnosed patients are found carrying identifiable pathological mutations, and the majority of PD cases are sporadic [2]. Several of the PD-associated genes are related to mitochondrial dysfunction although most are of unknown or poorly understood function. Three of the genes associated with a recessive, early-onset form of the disease (DJ-1, PINK1, Parkin) are directly linked to mitochondrial function, providing a potential connection with changes associated with aging [10]. DJ-1 is a mitochondrially enriched, redox-sensitive protein, and it is able to signal oxidative challenges and potentially coordinate a variety of mitochondrial oxidative defense mechanisms [11, 12]. Parkin and PTEN-induced putative kinase 1 or PINK1 also have mitochondrial roles [13, 14].
\nThe strongest risk factor in PD is age, beyond the other three best-documented pan-cellular factors, including genetic mutations, environmental toxins, and inflammation [2, 15]. It is widely speculated that declining mitochondrial function is a key factor why age is such a strong risk factor [10, 16]. However, the pattern of neuronal pathology and cell loss in PD is difficult to explain without cell-specific factors. It has been proposed that the opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of SNc DA neurons and accordingly the increase in mitochondrial oxidant stress and susceptibility to toxins [15]. This cell-specific stress could increase the negative consequences of pan-cellular factors. Therefore, antagonists for L-type calcium channels have been proposed to complement current attempts to boost mitochondrial function in the early stages of PD [17], but there is still lack of strong evidence in its therapeutic effects.
\nIn the adult mammalian brain, NSCs are largely restricted to two regions: the subependymal zone (SEZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampal formation [18, 19]. The NSC niche can be regarded as a specialized neurovascular unit (NVU) because the vasculature plays an indispensable role for maintaining the stem cell niche [20]. The NSC niche in the adult SEZ contains an extensive planar vascular plexus with specialized properties. Within such a unique NVU, endothelial cells (ECs) exert their influence over NSCs to regulate fate specification, differentiation, quiescence, and proliferation, through direct contact and paracrine signaling [20]. For example, a U-shaped gradient of the soluble factor, stromal cell-derived factor 1 (SDF-1), established by both ependymal and endothelial cells, helps guide SEZ quiescent NSCs moving from the ependymal niche to the endothelial niche, where they are activated [21]. Endothelial factors, including SDF-1, therefore have differential effects on neural progenitor populations. The vessels also produce a laminin-rich extravascular basal lamina, which is organized into branched structures known as fractones, regulating NSC behaviors via direct contact [22]. Interestingly, vascular pericytes in the central nervous system (CNS) have been found to possess the ability of differentiating into vascular and neural lineage cells [23], in addition to the originally defined functions of pericytes, such as controlling cerebral blood flow and limiting blood flow by constricting capillaries [24, 25].
\nAt the interface of neural and vascular compartments in the CNS is the blood brain barrier (BBB), which is the first barrier leading to transport limitations for both cellular and acellular elements. Paul Ehrlich demonstrated the integrity of this barrier first in 1885 when he injected vital dyes into the circulatory system and observed that all organs except the brain and the spinal cord were stained [26]. The integrity of this barrier was attributed to ECs and could be examined with an electron microscope demonstrating the tight junctions [27]. The barrier function of endothelium is considered a hallmark feature when validating models of the BBB. It is also important to assess the barrier function while culturing ECs with other types of cells comprising the NVU in order to investigate adult neurogenesis [28].
\nThe CNS endothelium is not only the inner lining of the blood vessel, but also an active participant in many signaling pathways. Brain-derived neurotrophic factor (BDNF), for instance, is one of the endothelium-secreted factors affecting the behaviors of NSCs [29, 30]. Blood capillaries may regulate NSCs through interactions via collagen IV and laminin in the basal lamina [31]. Blood vessels also provide an access to circulate systemic factors, including glucocorticoids, sex hormones, and prolactins. The barrier properties of the BBB allow only certain molecules to cross the endothelium. The BBB is maintained when endothelium has a prevalence of tight junctions and specific transport proteins. The BBB is characterized by an organ-specific high transendothelial electrical resistance (TEER, up to 5000 ohm·cm2; in contrast with placental TEER 20–50 ohm·cm2) [32, 33]. The BBB is the major site for the exchange of molecules between the blood and the CNS, given the small diffusion distance to neurons. Proximity of the finest branches of brain capillaries to individual neurons is typically 8–25 μm [34].
\nIn the neurogenic niche of the mouse brain, the basal processes of NSCs contact the vasculature, and at these sites of contact, a modified BBB exists that lacks astrocytic endfeet and pericytic coverage [20]. Direct physical contact between the brain capillary ECs and the NSCs reflects their intimate relationships. Juxtacrine signaling is therefore essential for devising a NVU model using ECs and NSCs. A NVU with direct contact between NSCs and ECs provides a neurovascular network, where the concentration of soluble factors recently released from nearby cells can remain high locally, and this cannot be observed using the transwell co-culture system. Furthermore, extracellular matrix (ECM) molecules produced by ECs and NSCs, which mediate cell differentiation and tissue morphogenesis, are involved in contact-dependent signaling between NSCs and ECs. The firm adhesion of cells to an ECM is indispensable to a cell culture model of three-dimensional cytoarchitecture for investigating NSCs and adult neurogenesis within a specific NVU.
\nTo devise an advanced NVU model and to promote NSC-based therapies may benefit from studies on the neurovascular development. Accumulating evidence shows that shared molecules and coordinated cellular mechanisms regulate the development of vascular and neuronal systems [35, 36]. Neurogenesis and angiogenesis are also found co-regulated in both embryonic and adult brains, as well as damaged brains. To date, most of this evidence has been obtained from in vivo experiments [37, 38]. Transgenic animal models were commonly used for these studies because relevant human material was still limited. A major technical difficulty in using these primary tissues is that numerous types of cells interact with each other in a very thin compartment. The ECs, for example, are not easily isolated for both qualitative and quantitative biochemical analysis.
\nAlternatively, ex vivo organotypic NVU model systems consisting of the slice of brain and brain ECs have been applied to experiments studying crucial BBB parameters such as TEER and transport mechanisms [39]. Researchers using cortical organotypic slice cultures or SEZ whole mounts [40] are able to observe the cellular interactions within a relatively complete but complicated system. In contrast, experiments using in vitro cell culture models of the NVU provide a useful tool in order to disentangle intercellular paracrine, autocrine, and juxtacrine signaling.
\nParacrine signaling is a form of cell-to-cell communication in which the target cell is close to the signaling cell and the secreted and diffusible signal molecule affects only nearby target cells. During CNS development, common signaling molecules guide vascular and axonal outgrowth via paracrine mechanisms, and these factors may have to be considered in NSC-based therapies in PD. For example, growth cones of axons project numerous filopodia that actively extend and retract in response to four families of extracellular guidance cues: ephrins, semaphorins, netrins, and slits [41]. Guidance cues can be divided into attractive or repulsive signals. These cues are cell-membrane-bound acting on nearby axons or secreted forming gradients that influence the trajectories of extending axons [41].
\nThe brain vascular system develops from the cephalic mesenchyme through the sprouting of capillaries into the brain parenchyma. This process is regarded primarily as angiogenesis which refers to the de novo formation of blood vessels by the sprouting and splitting of vessels already established by vasculogenesis [42]. Vascular endothelial growth factor (VEGF) has been implicated in the control of CNS angiogenesis. The temporal and spatial expression of VEGF is consistent with the hypothesis that VEGF is synthesized and released by the ventricular neuroectoderm and may induce the ingrowth of capillaries from the perineural vascular plexus [43]. Upon entering the CNS parenchyma, blood vessels migrate along a preformed latticework of neuroepithelia and radial glia, which are NSCs and neural progenitors that give rise to differentiated neurons and astrocytes [44].
\nVEGF is strongly expressed by NSCs in the ventricular zone. VEGF is a key signal orchestrating vascularization of the neuroectoderm [45]. At the tips of vascular sprouts, the leading endothelial tip cells extend filopodia toward hypoxic regions where higher VEGF is produced [46]. Tip cells react to VEGF via VEGF receptor 2 (VEGFR2) expressed on filopodia. Tip cells produce high levels of the Notch ligand delta-like 4 (Dll4) that activates Notch signaling on adjacent ECs. These ECs then differentiate into stalk cells, which form the stalk of the sprouting vessel with a lumen that allows for blood flow and tissue oxygenation [47]. Stalk cells down-regulate expression of VEGFR2 and VEGFR3 and increase levels of the decoy receptor VEGFR1, thus becoming less sensitive to VEGF [48]. These studies suggest that VEGF/VEGFR2 is one of the signaling pathways involved in angiogenesis and is also important for neurogenesis during CNS development.
\nVascular-derived neurotrophic factors, such as BDNF, are key factors in the co-ordination of vascular and neural development [49]. In a co-culture experiment using transwell inserts, mouse ECs released soluble factors that stimulated the self-renewal of mouse NSCs and inhibited their differentiation [50]. Depending on the culture condition, mouse ECs may favor maintenance of the progenitor phenotype of mouse NSCs through the production of soluble factors or to promote neuronal differentiation through direct contact [51].
\nAutocrine signaling is a form of cell signaling in which a cell secretes a substance that binds to its own surface receptors, leading to changes within the cell. Initially discovered for their role in axon guidance during vessel formation, VEGFs and their high-affinity tyrosine kinase VEGF receptors are now implicated in the development of the CNS [52]. In embryonic mouse forebrain and embryonic cortical neurons grown in vitro, VEGF acts as an autocrine survival factor for VEGFR2-expressing postmitotic neurons [53]. In the adult rat brain, VEGFR2 is expressed by neuronal progenitors in the SEZ, and intracerebral administration of VEGF-A stimulates both neurogenesis and angiogenesis in the SEZ and hippocampus [54].
\nJuxtacrine is a type of cell-to-cell or cell-to-ECM signaling that requires close contact. This stands in contrast to autocrine or paracrine signaling, where a signaling molecule is released and diffused into extracellular space [55]. Cell-to-cell communication between blood vessels and glia cells in the NVU occurs primarily via intervening vascular basement membranes that contain a variety of growth factors and ECM proteins [56].
\nJuxtacrine signaling is indispensable for neuroblasts migrating along blood vessels as neuroblasts primarily interact with the ECM surrounding astrocyte endfeet in a vasophilic migration model in the mouse brain [57]. In the SEZ neurogenic niche, NSCs differentiate into neural progenitors (NPCs) which have a limited proliferative ability and does not exhibit self-renewal. The relatively quiescent NPCs give rise to rapidly dividing transit-amplifying cells which further differentiate into neuroblasts. These neuroblasts sense microenvironmental cues and migrate tangentially from the SEZ to the olfactory bulb along rostral migratory stream (RMS).
\nTissue regeneration or cell replacement for loss of DA neurons is a potential approach for PD. Since the late 1980s, over 300–400 PD patients worldwide have received transplants of human fetal ventral mesencephalic (VM) tissue, which is rich in postmitotic DA neurons [58]. Two double-blind, placebo-controlled trials of VM transplants for PD patients, however, showed variable efficacy and occurrence of side effects, such as “off-medication” and “graft-induced dyskinesias” (GIDs) [59, 60]. It was observed that the PD pathologic process might propagate from host to grafted cells, and the presence of Lewy bodies in grafted neurons suggests host-to-graft disease propagation [61]. Implanted neurons could be affected by the disease process and did not function normally. Parkinson’s pathogenesis or GIDs therefore could propagate from host to grafted cells although recipients had experienced long-term symptomatic relief with the majority of grafted cells functioning unimpaired. On the other hand, CNS involvement of graft versus host disease (GvHD) has been found as a cause of CNS disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT) which is administered systemically [62]. Although transplantation of fetal tissue or stem cells was conducted transcranially instead for PD patients, the rare heterogeneous chronic CNS GvHD symptoms might happen with cerebrovascular manifestations, demyelinating disease, or immune-mediated encephalitis. GvHD could be prevented or treated with immunosuppressant such as corticosteroids, but CNS-related GvHD after allo-HSCT is associated with a poor prognosis.
\nGIDs could be serious side effects after transplantation of fetal VM tissue for PD patients. Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in PD have been investigated [63]. On-medication dyskinesias are typically generalized and choreiform. In contrast, off-medication dyskinesias are usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off-medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias which are associated with partial or incomplete dopaminergic reinnervation of the striatum [63]. The pathophysiological mechanism underlying GIDs can be partially attributed to excessive serotonergic innervation in the grafted striatum of patients who developed off-medication dyskinesias later following the initial improvement of motor symptoms after transplantation. It has been realized that the dyskinesias can be markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT1A) agonist [64]. A recent study demonstrated a mechanistic link between serotonin 5-HT6 receptor or a cyclic adenosine monophosphate (cAMP)-linked designer receptors exclusively activated by designer drugs (DREADD), intracellular cAMP, and GIDs since exclusive activation of serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs [65]. GIDs resulting from cell therapies for PD with fetal tissue or stem cells are therefore possibly avoided and treated with serotonin receptor agonists.
\nThe TRNSEURO (NCT01898390), a multicenter European initiative on PD transplantation using fetal VM tissue, has been conducted since 2012, in an attempt to overcome obstacles such as inconsistent methods between the previous trials [66]. The issues on administration of immunosuppressant and anticonvulsant, the method of graft preparation, and the precise site of graft placement will be further resolved. However, heterogeneous compositions of the graft, difficulties in standardization of cellular material, and ethical concerns are limitations in these trials using fetal VM tissue. In addition, complications associated with procedures of transplantation, such as subdural hematoma, have to be prevented [59].
\nNSCs preserve the ability to self-renew and differentiate into all neural lineage cells, including neurons, astrocytes, and oligodendrocytes, and they are therefore a source of potential graft for cellular transplantation in neurological disorders. Together with ECs and pericytes, NSC can constitute the functional NVU for tissue restoration in PD. Since neurons are integrated into the neurovascular network with other cellular and acellular compositions in the NVU, combined transplantation of NSCs with other types of cells or biomaterials may be more efficacious for tissue replacement. Local factors within the microenvironment of transplanted NSCs affect the fate of the cells, as measured by survival, proliferation, differentiation, and neurogenesis [67]. Several groups have studied modulation of stem cells or DA cells with combined cellular transplantation in animal models of PD (Table 1) [68]. Besides the attempt to replace damaged tissues, it was shown that grafted cells may promote endogenous vasculogenesis and neurogenesis in the neighboring tissues [69].
\nType of transplanted cells | \nAnimal model | \nSignificance | \nRef. | \n|
---|---|---|---|---|
Mouse fetal DA neurons | \nMouse mesencephalic NSCs overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs) | \n6-OHDA rat | \nApomorphine-induced rotation was reduced by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress GDNF, which supports differentiation into DA cells and their survival. | \n[72] | \n
Human embryonic NSC | \nMacaque autologous Schwann cells (SCs) | \n6-OHDA macaque | \nGomez-Mancilla dyskinesia score in the group of co-transplantation with SCs and NSCs was significantly lower than the control group. SCs harvested from the autologous peripheral nerves can avoid rejection. | \n[89] | \n
Human umbilical cord-derived MSCs | \nHuman dermal fibroblasts | \nMPTP rat | \nFibroblasts may be common cell contaminants affecting purity of MSC preparations and clinical outcome in stem cell therapy protocols. | \n[90] | \n
Rat embryonic DA neurons | \nRat Schwann cells (SCs) overexpressing basic fibroblast growth factor (FGF-2) | \n6-OHDA rat | \nCo-transplantation of DA neurons and FGF-2 overexpressing SCs differentially affects survival and reinnervation. Behavioral recovery underlines the necessity of direct contact between FGF-2 and DA neurons. | \n[91] | \n
Modulation of stem cells or dopaminergic (DA) cells with combined cellular transplantation in PD (adopted from “Potential of Neural Stem Cell-Based Therapy for Parkinson’s Disease” [68]).
To administer cell transplantation therapies, NSCs can be delivered transcranially through the needle into deep targets, such as putamen for PD. This approach minimizes the problem that BBB could be a barrier preventing intravascularly transplanted cells from crossing the vessel wall into brain tissue [70]. It has been proposed that 100,000 surviving DA neurons per putamen is the minimum required for a successful outcome following intracranial transplantation [71]. Bilateral injection targeting putamen is favored more than unilateral transplantation although there seems to be no consensus yet.
\nIt is reasonable to optimize the microenvironment surrounding the transplanted NSCs or DA neurons in order to support differentiation into DA cells and their survival in vivo. A recent study demonstrates that co-transplantation of fetal DA neurons with mouse NSCs, genetically modified to overexpress human glial-derived neurotrophic factor (GDNF), mitigates motor symptoms in a rat model of PD [72]. To optimize survival and guide appropriate differentiation of grafted NSCs, ECs have been combined with NSCs for transplantation into animal brains with stroke but not yet in brains with PD [73].
\nTechnically DA neurons could be derived from embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), umbilical cord blood hematopoietic stem cells (HSCs), and induced-pluripotent stem cells (iPSCs) generated from adult somatic cells, as well as directly from NSCs [74]. Several factors including the long-term survival and phenotype stability of stem cell-derived neurons or glial cells in the graft following transplantation, the purity of populations of cells derived from NSCs, and safety issues related to the risk of tumorigenesis have to be evaluated in greater depth [75]. An appropriate cell culture model for investigating, paracrine, autocrine, and juxtacrine signaling pathways within the neurovascular environment can provide a platform for characterizing cells with various origins and for selecting the optimal cells for transplantation [76].
\nNSCs derived from the whole ganglionic eminence and the ventral mesencephalon region of human fetuses have been immortalized using the technique of c-mycER transduction, and these NSC lines have been induced and differentiated to neurons potentially producing tyrosine hydroxylase (TH), a critical enzyme involved in dopamine synthesis [77, 78]. A recently devised cell culture model combined human adult brain ECs with fetal-derived NSCs which retain the ability of differentiating and further integrate together with ECs into the neurovascular tissue [79]. In this system, a distinctive neurovascular cytoarchitecture comprised of NSCs and ECs was observed. It simulates several features of the neurovascular niche, such as diffusible proteins, an extensive matrix, and expression of receptors, and genes unique to each cell type [76]. Moreover, complex multi-stage angiogenic processes can be studied by modulating the contact and soluble factor-mediated signaling pathways [76]. Studies using this NVU model will promote the best regimen for NSC-based therapies in PD [80].
\nAppropriate cell-to-matrix interactions are required for neurovascular tissue regeneration by NSCs and ECs. It is therefore important to investigate contact-dependent factors, including ECM components which are involved in NSC-mediated endothelial morphogenesis and vasculature shaping. ECM molecules are differentially expressed within the NVU [76] and they may have inhibitory and excitatory bioactivities. Astrocyte-derived thrombospondins, for example, have been shown to induce presynaptic differentiation in the CNS [81], but conversely, thrombospondin-1 functions as a negative regulator of angiogenesis [82]. The functions of these ECM molecules are associated with expression of their respective receptors, such as integrins. Most integrins recognize several ECM molecules, and most matrix molecules bind to more than one integrin. Consequently, various ECM molecules compete to bind specific integrins [83]. When studying neurovascular regeneration for NSC-based therapies in PD, an ideal in vitro NVU model should provide a system for investigating not only intercellular, but also cell-to-matrix interactions [76, 79].
\nResearches on pathophysiology of PD and establishment of valid and effective NSC lines will benefit from development of advanced cell culture models of the NVU. Patients with PD will have the opportunity to be treated with the cells if DA neuronal differentiation can be guided appropriately. Preclinical studies on image-guided injection and noninvasive monitoring of tissue regeneration in animal models of PD will provide the optimal therapeutic window, cell dose, and delivery route for cell transplantation [80]. Finally, appropriate patient selection and clinical follow-ups are required as a precondition for successful clinical translation of NSC-based therapies.
\nRecently, a preclinical study using a primate model suggests that human iPSC-derived DA progenitors are clinically applicable for the treatment of patients with PD. It was demonstrated that human iPSC-derived DA progenitor cells survived and functioned as midbrain DA neurons in a primate model of PD (Macacafascicularis) treated with the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [84]. The therapeutic effect was consistent regardless of the origins of the cells either derived from PD patients or healthy individuals, and there was no tumor found in the brains for 2 years.
\nAlternatively, using parthenogenetic stem cells as a source of donor tissue have raised hopes for PD patients [85]. The parthenogenetic cells are derived from unfertilized oocytes through suppression of the second meiotic division, leading to a pluripotent diploid cell line containing exclusively maternal chromosomes [86]. They are therefore different from other pluripotent cell sources such as ESCs or iPSCs and may overcome obstacles such as the possibility of tumorigenesis. However, their lack of paternal imprinting may be associated with unique challenges in their adoption clinically as this could affect their cell cycle and differentiation capacity [87]. Notably, preparation of these cells and the transplantation procedure has to be produced under Good Manufacturing Practice (GMP) conditions, the established guidelines and safety regulations [88].
\nIn conclusion, combined with cutting-edge technologies, including cellular reprogramming, advancement in scaffolds for brain tissue engineering, image-guided injection, and noninvasive monitoring of tissue regeneration, NSC-based therapies will alleviate symptoms of PD patients in upcoming clinical trials of cell replacement therapy once the implanted or regenerated DA neurons are integrated into the existing nigrostriatal DA pathway.
\nPreparation of this article was supported by the Ministry of Science and Technology Taiwan, the Republic of China (104-2314-B-016-017-MY3) and Tri-Service General Hospital, National Defense Medical Center (TSGH-C105-085, TSGH-C107-007-007-S05, MAB-106-041, MAB-106-042, and MAB-106-044). The funder had no role in the decision to publish or in manuscript preparation.
\nA previous work by C.Kato et al. stated that the loss of 20 dB/km in a dielectric waveguide could be minimized if it uses pure dielectric material [1]. This encourages many researchers to discover methods to minimize failure in optical silica fibers. Since its proper mechanical and optical properties, silica was used as the material for the improvement of optical fibers. A low-loss was established in 1970 by merging with a 20 dB/km loss [2].
Besides, with ultra-pure precursors with impurities of ppb-order (parts per billion), the growth of low-loss (0.2 dB/km) single-mode fibers about 1550 μm is demonstrated to be possible [3]. Figure 1 displays the attenuating spectrum of conventional single-mode fiber. The wavelength range of 1260–1625 nm is split into several subwavelength bands. A specific ITU-T wavelength range is allocated to each band, as listed in Table 1.
Attenuation spectra of conventional SMF and all-wave fiber [4].
Bands | O | E | S | C | L |
---|---|---|---|---|---|
Wavelength (nm) | 1260–1360 | 1360–1460 | 1460–1530 | 1530–1565 | 1565–1625 |
ITU-T profile of optical wavelength bands in telecommunications.
After the introduction of low-loss fiber, erbium (Er)-doped (EDFA) technology was introduced in 1987 as an advance to revolutionize optical fiber communication. It allowed transatlantic fiber communication [5]. The progression of fiber development to advance low-loss fiber in conjunction with EDFA technology led to the use of the low-loss range for optical fiber communications from 1530 to 1625 nm (C L band). Throughout the years, several techniques including dense wavelength division multiplexing (DWDM), wavelength multiplexing division (WDM), and coarse wavelength multiplexing division (CWDM) with new modulation formats as quadrature phase-shift keying (QPSK) as 16-QPSK, Quadrature Phase-shift Keying (QPSK) and 64-QPSK used to increase capacities for existing silica optical fibers, in the C + L band. Nonetheless, the stated transmission capacity of Standard Single-Mode Fiber (SMF) achieves the non-linear Shannon limit [6]. Figure 2 shows growth in the global population’s use of the internet every ten years. More than 60% of the world’s population is projected to be connected by 2020. The enhanced internet connectivity and comprehensive Internet-based applications such as cloud computing, social media, e-commerce, and e-learning are the drivers of significant demand for fiber transmission. New approaches to improving the potential for existing optical fiber networks must also be considered economically rather than merely adding more traditional single-mode fibers to meet end-user needs. Many researchers have proposed many approaches. One of these approaches is using a low-loss window (1260–1625 nm) of silica optical fibers by improving useful fiber lasers and amplifiers. The other is the development of new fibers such as multi-mode fibers (MMF), multi-core fibers (MCF), and multi-element fibers (MEF) for space-division multiplexing (SDM) in a C band from 1530 to 1565 nm. A further challenge is looking for a different transmission band in a 2000 nm wavelength region with new fibers [6]. The early stages of fiber optic communication in C-bands of about 1550 nm employed silica fibers with a loss of about 0.2 dB / km and a peak of about 1380 nm as shown in Figure 1. Recently, Lucent technologies and Optical Fiber Solutions (OFS) have delivered low-loss optical fiber in the entire 1260–1625 nm wavelength range. Such ultra-low-loss fibers are known as dry fibers and give a bandwidth of about 53THz for optical fiber. The mitigation for these ultra-low loss fibers in the 1260–1625 nm wavelength range is less than 0.4 dB/km, as shown in Figure 1 [4, 8]. Besides, new optical networks have been developed. For nearly every feature, they provide dramatically improved performance over traditional single-mode fiber, including increased usable bandwidth, superior macro-bend performance, and ultra-low dispersion polarization mode (PMD).
The bar chart shows the increase in internet users per each ten-year gap [7].
10 THz belongs to the Er amplification band between 1530 and 1625 nm with 53THz bandwidth provided by these dry fibers. A bandwidth can, therefore, be increased four times by using dry fibers. All of these dry fiber technologies have provided the ultimate flexibility in network construction and provided economic approaches to optimize data transition capability. However, the industry requires useful fiber amplifiers and lasers to use this utterly low-loss belt for optical communications, which are central to communication between an optical fiber. Regrettably, there are no active rare-earth (RE) doped fiber amplifiers and lasers that support the band of 1260–1530 nm. Given numerous attempts to implement various RE dopers in silica fibers to improve lasers and amplifiers in this wavelength range, potential devices available for use are still lacking. The amplifiers development and lasers in the 1260–1625 nm wavelength band, which uses bismuth (Bi) and Er-doped fibers to use the ultra-low loss window of ultra-low loss optical fiber.
Doping of the core zone with RE material is necessary for optical fiber fabricated to improve lasers and amplifiers. Various RE elements and their favorite emission bands in silica host are shown in Figure 3. Conventional RE elements, including ytterbium (Yb), Er, and holmium (Ho) or thulium (Tm), cover the wavelength bands about 1000, 1500, and 2000 nm [10]. However, any RE-doped silica does not cover the band between Er and Yb. The Energy level diagram of Yb, Er, Tm is shown in Figure 4. neodymium (Nd) and Praseodymium (Pr)-doped fibers explored extensively in silica host to improve lasers and amplifiers about 1300 nm. Nevertheless, highly phonon energy in a silica host made the dopants ineffective. They changed to a low phonon energy host, as fluoride glass enabled them reasonably active. Fluoride glasses, though, are not appropriate for splicing with traditional silica fibers as required in many applications for all-fiber compact devices. Despite this, the fabrication of these fibers is complex and not mature sufficient, in contrast to conventional changed chemical vapor deposition (MCVD)-solution doping technique. Furthermore, as shown in Figure 4, in the case of Pr, ground-state absorption (3H4-3F4), excited-state absorption (ESA) (1G4-1D2) at the signal wavelength, and pump ESA (1G4-3P0) are prejudicial to improve effective lasers and Pr-doped fiber amplifiers at 1300 nm.
The Spectrum regions covered via different RE doped elements in silica host [9].
Energy level diagram of (a) Yb3+, (b) Er3+, (c)Tm3+ [10] (d) Pr3+ and (e) Nd3+ [11].
For neodymium (Nd), the ESA at a signal wavelength (4F3/2-4G7/2) with a get competition between 1005 nm (4F3/2-4F11/2) and 1.34 μm (4F3/2-4F13/2) are detrimental to improve 1.3 μm amplifiers and lasers [11]. The last research subjects on BDFs covered the main areas of (i) design of BDFs with new materials and compositions, (ii) studying the fabrication techniques and processes to make BDFs with better properties, (ii) spectral characterization method to assess BDFs for desired applications, (iii) post-fabrication techniques and their impacts on spectral properties, (iv) applications of BDFs into gain media, or sensing device or any other, (v) evaluation of optical devices made with BDFs using various configurations and operational conditions, (vi) studying the nature of BACs responsible for producing the emission in BDFs, (vii) unraveling the energy levels of the active centers, and many other similar topics. Among these subjects, the nature of BACs is essential for understanding the spectral characteristics and their effects on applications; however, the issue has not been resolved yet and required more addressing.
Visible emissions from Bi-doped glasses and crystals were deeply clarified [12, 13, 14, 15, 16, 17]. Recently, broadband emissions in the near-infrared (NIR) region from 1200 nm to 1500 nm have been demonstrated in Bi-doped glasses (BDGs) by Fujimoto et al. [18]. Peng also reported broad NIR emission from Bi glasses. et al. as well [19]. With around 1300 nm of optical amplification shown produced by the BDG.s [20]. The first Bi-doped fiber (BDF) and a laser-based on that BDF were reported by Dianov et al. in 2005 [21]. Different BDFs and BDGs have been improved for potential applications as lasers and amplifiers in the second telecommunication window range at around 1.3 μm. It was found that the bandwidth and intensity of emission produced from the BDFs are influenced mainly by the host type and other co-doping materials. Bi can produce emissions in various wavelengths in the NIR wavelength region over (1200–1500) nm, as reported in BDFs and BDGs. For instance, emissions in several BDFs and BDGs (such as silicate, germanate, alumino-silicate, alumino-phosphate, barium-aluminoborate types) have been reported in earlier work [19, 22, 23, 24, 25, 26, 27]. Typical emissions of Bi in some recent work are presented in Figure 5.
Characteristic Bi XPS reported by Fujimoto [28].
Emissions in BDFs and BDGs are accompanied by active centers or BACs. BACs largely determine the spectroscopic properties, performance, and operations of BDFs. Hence, to design a fiber for a specific application, it is essential to know the BAC details and their relationships to the spectral properties. As an approach to studying the nature of BACs can be broadly categorized into two main groups: (a) spectral analyses to determine the type of BAC and (b) instrumental analyses to identify the chemical bonding and electronic states of Bi, which is responsible for forming a particular type of BAC. The spectral analysis gives information about a specific BAC’s spectral characteristics, determined mainly by the composition types in the fiber or glass. Absorption, emission (luminescence or fluorescence), and emission lifetime are some of the most common and basic spectral properties analyzed to identify the BAC types. Besides, an emission-excitation spectroscopic graph described recently was found to be very important to recognize the particular emission [29]. At the initial phase of Bi fiber research, it was thought that Bi emission could be produced only in the presence of Al [23]. However, later, Bi emission was detected in pure silica-doped fibers without any Al co-doping, and lasing was realized in such BDFs [30]. The concept that BACs are linked with other ions in addition to Bi was subsequently considered through the investigation into several Bi fibers and glasses, which were fabricated with different compositions and their relations. Following this advance, Bi fibers with the most straightforward glass compositions were made and BACs in them were characterized, enabling the identification of certain BAC types, e.g., BAC-Si, BAC-Al, BAC-Ge and BAC-P associated respectively with Si, Al, Ge, and P, along with their respective characteristic spectral properties [29, 30, 31, 32, 33]. Instrumental analyses of the BAC study concentrate on how to reveal possible valence and the electronic configuration of specific BAC. This approach included analyses of the nuclear magnetic resonance (NMR), X-ray photoelectron spectroscopy (XPS), electron spin resonance (ESR), X-ray diffraction, and extended X-ray absorption fine structure (EXAFS), etc. [28]. Previous research gave rise to different hypotheses about BACs, such as Bi+, Bi0, BiO, Bi clusters [31, 34, 35], and Bi3+ or Bi5+ by Fujimoto et al. [28, 32], being responsible for the NIR emissions. Dianov recognized two experimental facts related to BACs: (i) Bi3+ and Bi2+ emit visible emission. However, no NIR emission, and (ii) NIR emissions are observed because of the reduction of Bi3+ and Bi2+ to a lower oxidation state. Therefore, the probable origins of NIR emissions in Bi-doped glass and fiber associated with low valence Bi ions and other dopants that form the BAC-Si, BAC-Al, BAC-Ge, and BAC-P were investigated [25, 31, 34]. Following this, the monovalent BACs formed by Bi+ were of definite interest in understanding the NIR emission origin in BDFs. Bi+ was described as having a ground configuration of 6s26p2 and its energy level split by a spin-orbit coupling interaction into the ground state 3P0 and the excited states 1S0, 1D2 and 3P2,1 corresponding to the energy bands around 500 nm, 700 nm, 800 nm and 1000 nm [25, 36]. Recently, energy levels of BAC-Si and BAC-Ge were described. The origin of NIR emission was reported as likely from Bi··· ≡ Si-Si ≡ and Bi··· ≡ Ge-Ge ≡ complexes formed by the interstitial Bi atoms (Bi0) and intrinsic glass defects and ≡ Si-Si ≡ and ≡ Ge-Ge ≡ oxygen vacancies [29, 37]. The energy levels of BAC-Si and BAC-Ge recommended in previous work are presented in Figure 6 shows the excitation and emission characteristics associated with these particular BACs.
Reported energy levels of (a) ВАС-Si and (b) BAC-Ge [31].
Although BAC-Si and BAC-Ge were described with much information about their kind and spectral characteristics, in-depth knowledge of BAC-Al and BAC-P lags far behind. BAC-Al and BAC-P showed notably different spectral behavior in BDFs than those of BAC-Si and BAC-Ge. One of the essential distinctive features is the Stokes shifts in the emission and excitation produced from these two centers, while for BAC-Si and BAC-Ge, no such Stokes shifts were pronounced [29]. Electron-photon interaction giving increase to the detrimental emission processes joined with these two centers was expected as the reason for the Stokes shifts. Furthermore, BAC-Al was quite different from BAC-Si and BAC-Ge based on their susceptibility to electron irradiation [38]. All of these specifications made it hard to discover the complete energy diagram of these active centers.
The properties of near-infrared (NIR) broadband luminescence of Bi-doped silica fibers are sensitive to the composition of glass in addition to the conditions of fabrication. The partial shielding of the unfilled subshell 4f by filled 5 s and 5p in RE ions prevents significant interaction from the host environment. In comparison to RE elements, Bi has filled internal subshells, and external 6 s and 6p electrons interact significantly with the host, showing host-dependent absorption and emission properties. Co-dopants can also dramatically alter the spectrum of luminescence, as shown in Figure 7.
The Spectrum regions covered via different Bi-doped fibers with various hosts [39].
Herein, Bi-doped fibers with aluminosilicate hosts are described as Bi-doped aluminosilicate fibers (BASEs). They have shown a luminescence peak at 1150 nm. In contrast, Bi-doped fibers with phosphorus silicate and Germane silicate core composition hereafter described as Bi-doped phosphorus silicate fiber and Bi-doped German silicate fibers (BGSFs) are known to transfer the emission band to a longer wavelength side of about 1300 and 1450. Recently, by using high GeO2 concentration (50 mol%) within the fiber core, the Bi emission window is extending to a covered wavelength band of 1600–1800 nm. Luminescence in Bi-doped phosphor germane silicate fibers (BPGSFs) is broad compared to phosphorous (P) and other Bi-doped fibers co-doped with germanium (Ge). This makes it possible by changing the fiber core composition using Bi-doped optical fibers to show lasers and amplifiers for cover the full spectrum region about 1150–1800 nm. In Figure 6, the pump wavelength bands are referred to by the arrow. Wavelength bands of the pump about 1050, 1230, and 1310 nm for BASFs, BPSFs, and BGSFs, respectively, usually are utilized. In the case of BGSFs with a high concentration of GeO2, the pump wavelength band is about 1550 nm [39, 40].
BDFs have many applications in different optical systems because of their wavelength based discriminative transmission losses [41]. A 1651 nm single-frequency laser diode is providing with a Bi-doped fiber power amplifier, and its performance is evaluated experimentally [42]. This amplifier is using to increase the performance of methane detection systems, such as remote stand-off systems or photoacoustic spectroscopy (methane has a molecular absorption line of almost 1651 nm). Two amplifier configurations are shown and output power of larger than 80 mW in both cases. The results obtained provide valuable perspective for compact and straightforward fiber amplifiers in the spectral region of ~1630–1750 nm with a power output of over 100 mW. The experimental set-up schematic diagrams are displayed in Figure 8(a) and (b). Two configurations are investigating, both with signal and pump radiation continues to using a WDM coupler to launch pump light at 1550 nm into the BDF and offer the amplified radiation output at 1651 nm. Standard, commercially available WDM coupler that is proposed to operating at 1625 nm and 1550 nm (from the Opto-Link Corporation). Its transmission is calculated to be ~95% at 1550 nm, but only ~65% at 1651 nm. A polarization-independent optical circulator is using in a second configuration (Figure 8(b)) broadband as an alternative a WDM coupler. The circulator (including from OptoLink Corporation) has been proposed for a wavelength of 1525–1610 nm. Nevertheless, its 1550 nm (port 1 - port 2) and 1651 nm (port 2 - port 3) transmissions were quite the same, almost 80 percent.
Two BDF amplifiers configurations: (a) set-up with a WDM coupler using for pump light launch in BDF and processing of amplified signals at 1651 nm; (b) optical circulator set-up. ISO-optical insulator, LD-diode projector.
The Er-Doped Fiber Amplifier (EDFA) is currently one of the most crucial elements for various fiber optic systems [43]. Nevertheless, driven by a continually growing demand, network traffic, which has grown exponentially for decades, would result in the overloading of these”capacity crunch” systems, since EDFA is limited to 1530–1610 nm in the spectrum. New technology will need to be pursued, and the development of optical amplifiers for new spectral regions can be a promising solution. Some of the fiber-optic amplifiers are made with materials doped with rare-earth. As a result, full bands for the gain band of Er-doped fibers are still available in shorter (1150–1530 nm) and longer wavelength (1600–1750 nm) regions. A novel fiber amplifier is operated at a spectrum region of 1640–1770 nm pumping via commercial laser diodes at 1550 nm. This amplifier is achieved by use Bi-doped high-Germania silicate fibers fabricating by an MCVD technique. The experimental set-up of a typical Bi-doped fiber amplifier is illustrated schematically in Figure 9. The BDFA is built using a scheme with Bi-directional pumping (backward and forward pumping). As a pumping source, commercial laser diodes are using with an ultimate output power of 150 mW each. The active fiber was core-pumped through commercial WDMs based on SMF-28. WDMs Transmission spectra are shown in Figure 8. Optical isolators are spliced to the amplifier of the input and output. The first is using to reduce the effect of amplified spontaneous emission (ASE) of a Bi fiber on the signal source. The second prevented possible lasing. Bold points act as splices, where an optical loss is ~1 dB because of the difference between the active fiber mode field diameter and that of conventional fibers (SMF-28).
Experimental BDFA set-up. The figure left side shows a home-built light source producing a wavelength comb of 1615 nm - 1795 nm, which is uniformly spaced with a phase of 15 nm. The figure right side illustrates the amplifier itself. Notably, ISO: An optical isolator, LD: Laser diode operating at 1550 nm, FBG: Fiber Bragg grating and CIR: Optical circulator.
The proposed dual pumping scheme of 830 and 980 nm aims at broadening and flattening Bi/Er multicomponent fiber (BEDF) spectral performance [44]. The distinct BACs of germanium (BAC-Ge), aluminum (BAC-Al), phosphorus (BAC-P), and silique (BAC-Si) have spectral properties characterized by single pumping, respectively, of 980 nm and 830 nm. Depending on the BAC-Al (∼1100 nm) and BAC-Si (∼1430 nm) emission slope efficiencies under the single pumping of 830 and 980 nm, the dual pumping scheme with an optimizing pump power ratio of 25 (980 nm VS 830 nm) is determined to realize flat, ultra-broadband luminescence spectra covered the wavelength range 950-1600 nm. The dual pumping scheme is more illustrated on the on-off gain BEDF performance. The gain spectrum is flattening and broadening over 300 nm (1300-1600 nm) with an average gain coefficient of ∼1.5 dBm−1, due to the pump power ratio of ∼8 (980 VS 830 nm). The spectral covering is about 1.5 and 3 times more expansive compared to single pumping of 830 and 980 nm pumping, respectively. Due to the optical characteristic of the energy level diagrams of 830 and 980 nm, the advantage of dual pumping is clarified. The proposed dual 830 and 980 nm pump scheme with the BEDF multicomponent shows great promise potential in a range of broadband optic applications, such as NIR-band tunable laser, a standard ASE source, and broadband amplifier. The luminescence measurement set-up is shown in Figure 10. The 980 and 830 nm pigtailed laser diodes (LD) were launched into the input end of 3 dB 808 couplers, and the 810/1310 WDM, the BEDF, was spliced with the output end of 1310 beam with ∼1 dB splice loss. The backward optical spectral analyzer (OSA) was used to record the emission signal to remove the effect of residual pump power. To monitor the unabsorbed pump power, a digital power meter was placed at the end of BEDF, and A short length (∼40 cm) of BEDF was tested.
Dual pumping experimental set-up for backward luminescence measurement.
Doped fiber amplifiers (DFAs) are optical amplifiers that use a doped optical fiber as a gain medium to amplify an optical signal. They are related to fiber lasers. The pump laser and the signal to be amplified are multiplexed into the doped fiber, and the signal is amplified through interaction with the doping ions. As an example is the (BDFA), where the core of a silica fiber is doped with Bi ions and can be efficiently pumped with a laser. 1120 nm diode-pumped Bi-doped fiber amplifier is fabricated by N. K. Thipparapu et al. [45]. Bi-doped aluminosilicate fiber is fabricated using an MCVD solution doping and is distinguished by its gain and unsaturated loss. The amplifier performance was compared with the traditional pumping wavelength region of 1047 nm for a novel pumping wavelength of 1120 nm. Unsaturable losses in 1047 and 1120 nm pump wavelengths were 65% and 35%, respectively. At 1180 nm, the maximum gain of about 8 dB was observed for 100 m fibers with pumping at 1120 nm. The 1120 nm pump produced an enhancement of gain of 70% compared with the 1047 nm pump. An additional 3.5 dB gain was achieved at 1047 and 1120 nm simultaneous pumping. Figure 11 shows the schematic experimental set-up used for the measurement of gain in Bi-doped fiber. The set-up consists of an 1180 nm LD as input signal source and fiber pigtailed 1120 nm LD and/or 1047 nm Nd-YLF laser as the pump source. To abstain from the wavelength division multiplexers (WDMs) and back reflections to combining pump and signal sources, Isolators (ISO) was used. The spectrum of the output and input signal is taking through an OSA. The input signal was obtained little before the fiber under trial. In contrast, the output signal is determined by consideration of the WDM loss using to separating the pump from the signal.
Schematic of the experimental set-up to measure gain in Bi-doped fiber (the 1047 nm pump with the dashed line is used for Bi-directional pumping; otherwise, that port of the WDM is used to monitor the excess pump).
O-band has recently been widely used for low-cost data transmission. The feature of O-band is that the transmitter wavelength(s) are laying close to the zero dispersive fiber wavelength (λ0), and no compensation is therefore needed for either optical or electronic chromatic dispersion. O-band transponder total bit rate is enhanced to 425 Gb/s, for instance, using 8 LAN WDM 26.6 Gbaud/s PAM-4 modulated channels [46]. Using WDM and complex modulation formats minimize the power of both the receiver sensitivity and receiver per channel such that optical amplification is appropriate. O-band signal boosting can be achieved by employing Semiconductor Optical Amplifiers (SOA). However, they create considerable distortions due to the modulation of self- and cross- gain [47]. Although most of dispersion broadened channels are amplified [48], SOAs are not approbated for intensity modulation formats transmission like PAM-4 operating near λ0 with relatively small channel count. Praseodymium doped fiber amplifiers (PDFA) with a bandwidth of 1280–1320 nm [49] were shown, but non-silica host glass was required, which makes PDFA complicated and costly. O-band amplification has been extensively studied in Bismuth-doped silica fibers [50]. A 150 m long BDFA with bandwidths of 1320-1360 nm has been reported using a complex dual-wavelength pumping system with only 6 × 10 Gb/s OOK channels [51]. Simple silica-based BDFA with 80 nm 6-dB gain-bandwidth flexibly centered within 1305-1325 nm, and parameters comparable to EDFAs is developed by V. Mikhailov et al. [52]. The amplifier can extend 400GBASE-LR8 transmission (8 × 26.6 Gbaud/s PAM-4 channels) beyond 50 km of G.652 fiber. The active fiber core consists of phosphosilicate glass doped with Bi (>0.01 mol%) produced using the MCVD process. The preform was cladding by a Heraeus F300 tube while all the core components, including P, Si, and Bi, were deposited from the gas phase. The index difference between the fiber core and the cladding was approx. 6 × 10–3, and the cut-off wavelength was near 1.1 μm. As the core diameter of 7 μm of fiber offered reasonable slice capability with silica-based fibers, the regular automatic splicer was used to splice G.652and Bi- fibers. In order to investigate emission properties, 80 meters of Bi-fiber were subsequently pumped with a 3 dB wideband coupler with lasers of 1155, 1175, 1195, 1215, and 1235 nm (Figure 12).
Bi-fiber characterization set-up.
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\n\nThe first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
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