These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"7534",leadTitle:null,fullTitle:"Role of Microbes in Human Health and Diseases",title:"Role of Microbes in Human Health and Diseases",subtitle:null,reviewType:"peer-reviewed",abstract:"Microbes are ubiquitous and have ecological interactions with almost all life forms. Likewise, humans invariably engage in host-microbial interactions that could induce short-term or long-term effects. Some of these long-term crossover interactions have allowed successful colonization of microbes within or on the human body, collectively known as the human microbiome or human microbiota. The human microbiome is identified as playing a key role in various physiological processes like digestion, immunity, defense, growth, and development. Any dysbiosis in the human microbiome structure could induce the onset of various metabolic or physiological disorders. Cumulatively, the human microbiome is considered as a virtual human organ that is essential for host survival. Additionally, short-term biological interactions of the host and microbes have exposed microbes to the human cellular system. This exposure could have allowed the microbes to invade human cells for their growth and reproduction-induced onset of various infectious diseases. This book incorporates a number of studies highlighting the role of microbes in human health and diseases.",isbn:"978-1-83880-234-9",printIsbn:"978-1-83880-233-2",pdfIsbn:"978-1-83880-718-4",doi:"10.5772/intechopen.76595",price:100,priceEur:109,priceUsd:129,slug:"role-of-microbes-in-human-health-and-diseases",numberOfPages:82,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ad71073664357a1e5e73eb81f08be582",bookSignature:"Nar Singh Chauhan",publishedDate:"June 5th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7534.jpg",numberOfDownloads:4847,numberOfWosCitations:5,numberOfCrossrefCitations:8,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:11,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:24,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 9th 2018",dateEndSecondStepPublish:"June 1st 2018",dateEndThirdStepPublish:"July 31st 2018",dateEndFourthStepPublish:"October 19th 2018",dateEndFifthStepPublish:"December 18th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"216883",title:"Prof.",name:"Nar Singh",middleName:null,surname:"Chauhan",slug:"nar-singh-chauhan",fullName:"Nar Singh Chauhan",profilePictureURL:"https://mts.intechopen.com/storage/users/216883/images/system/216883.jpeg",biography:"Dr. Nar Singh Chauhan is currently a teaching faculty in the Department of Biochemistry, Maharishi Dayanand University, Rohtak, India. His doctor of philosophy degree, with thesis research on \\'Arsenic detoxification mechanisms in unculturable bacteria using function metagenomics\\' at the CSIR-Institute of Genomics and Integrative Biology, was granted by Savitribai Phule Pune University, Pune, India. His current research focus is on the metagenomic characterization of diverse microbiome for their native community structure, physiological functions, survival strategies under abiotic stress, colonization factors, and host-microbial interactions. In this direction, he has established an association of the human microbiome with the onset of celiac disease and chronic obstructive pulmonary disease. Dr. Chauhan is the author of a number of peer-reviewed research publications in reputed international journals (Genome Biology & Evolution, Scientific Reports, Frontiers in Microbiology, etc.) and has also been awarded many research patents.",institutionString:"Maharishi Dayanand University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Maharshi Dayanand University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"895",title:"Medical Microbiology",slug:"medical-microbiology"}],chapters:[{id:"66113",title:"Introductory Chapter: Human and Microbes in Health and Diseases",doi:"10.5772/intechopen.85217",slug:"introductory-chapter-human-and-microbes-in-health-and-diseases",totalDownloads:951,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Nar Singh Chauhan",downloadPdfUrl:"/chapter/pdf-download/66113",previewPdfUrl:"/chapter/pdf-preview/66113",authors:[{id:"216883",title:"Prof.",name:"Nar Singh",surname:"Chauhan",slug:"nar-singh-chauhan",fullName:"Nar Singh Chauhan"}],corrections:null},{id:"64638",title:"The Therapeutic Potential of the “Yin-Yang” Garden in Our Gut",doi:"10.5772/intechopen.80881",slug:"the-therapeutic-potential-of-the-yin-yang-garden-in-our-gut",totalDownloads:973,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The gut microbiota is made up of trillion microorganisms comprising bacteria, archaea, and eukaryota living in an intimate relationship with the host. This is a highly diverse microbial community and is essentially an open ecosystem despite being deeply embedded in the human body. The gut microbiome is continually exposed to allochthonous bacteria that primarily originates from food intake. Comprising more than 1000 bacterial species, the gut microbiota endows so many different functions—so many that can be considered as an endocrine organ of its own. In this book chapter, we summarize the importance of gut microbiota in the development and maintenance of a healthy human body. We first describe how the gut microbiota is formed during the birth of a human baby and how a healthy microflora is established overtime. We also discuss how important it is to maintain the microbiota in its homeostatic condition. A discussion is also given on how alterations in the microbiota are characteristic of many diseased conditions. Recent investigations report that reestablishing a healthy microbiota in a diseased individual using fecal microbial transplant can be used as a therapeutic approach in curing many diseases. We conclude this chapter with a detailed discussion on fecal microbial transplants.",signatures:"Shabarinath Srikumar and Séamus Fanning",downloadPdfUrl:"/chapter/pdf-download/64638",previewPdfUrl:"/chapter/pdf-preview/64638",authors:[null],corrections:null},{id:"63743",title:"The Role of Leather Microbes in Human Health",doi:"10.5772/intechopen.81125",slug:"the-role-of-leather-microbes-in-human-health",totalDownloads:1350,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Leather tanned from raw hides and skins have been used to cover and protect the human body since early man. The skin of an animal carries thousands of microbes. Some are beneficial and protect the animal while others are pathogenic and cause diseases. Some microbes have no defined roles in animals. These microbes end up in the human body through contact with the animal skin. In recent years, the human body has been studied as an ecosystem where trillions of microorganisms live as a community called microbiome. Humans need beneficial microbes like Bacillus subtilis on the skin surface to stay healthy. Many microbes need the human body to survive. Not many studies have looked into the close link between animal leather and the human microbiome. The assumption is that conventional leather processes inhibit the pathogens on skins from carrying any risk of microbial hazard to the human body. This chapter identifies endemic microbes of “animal skin microbiome” that withstand extreme acidity and alkalinity of leather manufacture and their transmission to humans. Some cause allergic reactions, skin lesion, infections or death to tannery employees with weakened immune systems. This promotes the need to look at leather product microbiome impact on human health.",signatures:"Richard O. 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Despite extensive research, screening, education, and continuous efforts to try to eradicate and control the infection, tuberculosis is still one of the most prevalent infections throughout the world. Even the cases of extra pulmonary dissemination are seen to have increased. Extra pulmonary tuberculous dissemination has a very variable presentation that depends on the organ involved. The diagnosis is difficult and many times a long time passes between diagnosis and initial presentation. In this chapter, we will review how tuberculosis infection presents when the bacilli invades any tissue outside the pulmonary parenchyma, what the literature recommends for the proper work up and diagnosis, and general treatment for major organ system infection.",signatures:"Onix J. 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1. Introduction
Glaucoma remains one of the leading causes of blindness worldwide. In England and Wales glaucoma is a major or contributory factor for 12-14% of all registrations for blindness and partial sight, second only to macular degeneration (Bunce et al., 2010). The worldwide burden is more significant, with glaucoma being the second leading cause of global blindness after cataract (Resnikoff et al., 2004). It has been estimated that 60.5 million people worldwide would be affected by glaucoma by 2010, with the figure expected to rise to 80 million by 2020 (Quigley and Broman, 2006).
Current treatments for glaucoma comprise the lowering of intraocular pressure by eye drops, laser procedures or drainage surgery. However, as implied by the statistics above, many patients experience significant visual loss due to degeneration of retinal ganglion cells (RGCs) despite the advances in the treatments currently available. The need for novel therapies exists for such patients, in particular those with end stage glaucoma, where the maintenance of a small number of surviving RGCs may yet permit a reasonable quality of life (Much et al., 2008). Stem cell therapies developed in the laboratory and translated to clinical practice provide an exciting and realistic hope for those affected by degenerative retinal diseases including glaucoma. This chapter will discuss three mechanisms by which stem cell therapies may potentially offer hope to patients with end stage glaucoma, namely local RGC replacement, optic nerve regeneration and stem cell mediated neuroprotection.
2. Sources of stem cells
Stem cells are characterised by their capacity for unlimited self-renewal and ability to differentiate into different cell types. The term progenitor cell is often applied to multipotent cells with a capacity for self-renewal, however this chapter will use the term stem cell to encompass all progenitor and precursor cell types.
An ideal candidate for developing stem cell based therapies would be readily available, easy to expand in culture, possess an acceptable long term safety profile and be autologous in nature, in order to avoid the need to modulate the host immune response and prevent rejection. Unfortunately a cell type that fulfils all these criteria remains elusive, however current research is directed towards a limited number of cell types which themselves exhibit certain advantages or disadvantages. Such cell populations may be sourced from three broad categories – embryonic or foetal tissue, adult tissue and reprogrammed cells (Figure 1).
Figure 1.
Summary of the sources of cells that may be potentially used for cell based therapies in glaucoma. (Figure composed using Motifolio Inc. diagrams)
2.1. Embryonic stem cells
Embryonic stem cells (ESCs) arise from the inner cell mass of the blastocyst, which is formed at about five days after fertilisation in humans. Such cells are often sourced from excess tissue obtained from embryo donations and fertility treatments and have been associated with ethical objections due to controversies regarding the use of such tissue for research. However they possess an unlimited capacity for self-renewal with an ability to differentiate into any of the cell types within the human body (Evans and Kaufman, 1981). ESCs have been proposed as ideal candidates for cell based therapies to treat human retinal diseases, due their capacity to migrate and differentiate into different cell types. ESCs have been differentiated in vitro into neurons (Bibel et al., 2004) as well as retinal pigmented epithelium (RPE) (Hirano et al., 2003), but controlling their differentiation has proved challenging. In the absence of appropriate intracellular signals, ESCs appear to differentiate towards a neuronal fate by default (Hemmati-Brivanlou and Melton, 1997), although differentiation into retina specific precursors often involves complex laboratory protocols (Osakada et al., 2009). A drawback of a pluripotent cell type is the risk of teratoma formation by uncontrolled growth of transplanted ESCs (Hentze et al., 2007) which remains a major concern. In addition, safety concerns derived from the observed chromosomal instability of cultured ESCs (Moon et al., 2011) require further investigation.
2.2. Adult tissue-derived stem cells
Adult tissue-derived stem cells offer an alternative for the development of cell based therapies which circumvents the ethical controversies surrounding foetal and embryonic tissue. Up to date, various sources of adult stem cells have been investigated for their potential ability to regenerate or replace retinal neurons which are described below.
2.2.1. Müller stem cells
The concept of central nervous system (CNS) regeneration from glial cells has become more accepted in recent years. Radial glia within the brain have been shown to act as neural stem cells within the developing mammalian nervous system, with the ability to generate both new neurons and glia (Merkle et al., 2004). Müller glia are the radial glia of the retina and have been shown to share a common lineage with retinal neurons and to derive from a common multipotent progenitor (Turner and Cepko, 1987). Studies in zebrafish have demonstrated that the ability of this species to regenerate retina is due to the presence of Müller glia with stem cell characteristics (Bernardos et al., 2007). Pharmacological depletion of the ganglion cell layer has been shown to induce a regenerative response in this species, which is characterised by Müller glial cells re-entering the cell cycle and producing neuronal progenitor cells that repopulate the ganglion cell layer (Fimbel et al., 2007).
Although a capacity for regeneration similar to that seen in the zebrafish has not been observed in higher species, a population of Müller glia with stem cell characteristics has been identified in the adult human retina (Lawrence et al., 2007). These cells express markers of neural progenitors in vitro and a proportion of them are able to express markers of mature retinal neurons in response to various culture conditions (Lawrence et al., 2007). Data from our laboratory exploring transplantation of these cells in a rodent model of ganglion cell depletion shows that pre-differentiated cells are able to integrate within the host RGC layer and cause partial restoration of the scotopic threshold response, which is a marker of RGC function in the rat electroretinogram (Singhal et al., 2009).
Such cell lines are easily obtained from cadaveric donor retinae (Limb et al., 2002) and further studies may reveal whether it is possible to obtain patient specific cell lines from peripheral retinal biopsies, leading to the possibility of developing an autologous grafting strategy.
2.2.2. Mesenchymal stem cells
Mesenchymal stem cells are most commonly obtained from bone marrow biopsies and umbilical cord blood and have been considered as candidates for autologous cell transplantation. Pharmacological methods have been used to mobilise haematopoetic stem cells from the bone marrow into the bloodstream to facilitate their harvesting for transplantation (Uy et al., 2008) rather than employing more invasive bone marrow trephine techniques. The mobilisation of mesenchymal stem cells is more difficult than that of haematopoietic stem cells, with several strategies showing promise in animal models (Pitchford et al., 2009). During development mesenchymal stem cells differentiate into bone, cartilage and muscle. However they have been reported to de-differentiate in vitro into other cell types including neurons and glia, although at present there is much controversy surrounding this ability (Krabbe et al., 2005). As will be discussed later, this cell type is likely to have a more significant role in neuroprotective strategies rather than neuronal replacement, due to their ability to secrete cytokines.
2.2.3. Oligodendrocyte precursor cells
Oligodendrocyte precursor cells (OPCs) are a type of neural stem cells responsible for the generation of oligodendrocytes during normal development, and for re-myelination of the white matter in the adult CNS (Watanabe et al., 2002). They are the commonest proliferative cell type in the adult CNS (Dawson et al., 2003). OPCs have been reported to exhibit some stem cell characteristics (Nunes et al., 2003) and neuroprotective potential in vitro (Wilkins et al., 2001), which have led to investigations into their potential use for stem cell based therapies to treat neurodegenerative conditions including glaucoma.
2.2.4. Olfactory ensheathing cells
Olfactory tissue is unique within the CNS, in that continuous removal and regeneration of tissue occurs throughout life. The sensory axons that project to the olfactory bulb are closely associated with specialised cells known as olfactory ensheathing cells (OECs). OECs are glial cells which lie within the nasal mucosa and olfactory bulb and characteristically ensheathe axons of the olfactory nerve. Transplantation of these cells has been used to support regenerating axons in animal models of spinal cord injury and to restore function (Li et al., 2008). Due to the relative ease by which nasal mucosal biopsies may be obtained, these cells may potentially constitute a source of cells through which autologous transplantation strategies may be developed in the future. There is considerable molecular heterogeneity and functional diversity of OECs with much work still taking place in animal models (Su and He, 2010). Further investigation into the gene expression and cell fate determination of these cells will facilitate the development of more robust protocols to isolate and expand the OEC progenitor/stem cell population within this complex tissue.
2.3. Induced pluripotent stem cells
The characterisation of induced pluripotent stem cells (iPS) cells has created an alternative potential cell source for transplantation in regenerative medicine. Takahashi & Yamanaka (Takahashi and Yamanaka, 2006) demonstrated that by retroviral induction of Oct3/4, Sox2, c-Myc and Klf4, pluripotent stem cell lines could be derived from fibroblast cultures. Further study of these “reprogrammed” iPS cells showed that their biological behaviour was indistinguishable from that of ESCs (Wernig et al., 2007). Subsequent modifications to the original protocol have enabled iPS cell lines to be created without the use of viral vectors (Okita et al., 2008) and without induction of the oncogene c-Myc (Nakagawa et al., 2008) which may be associated with an increase in tumorigenesis. However before such cells can be used in human therapies, safety concerns regarding the effect of the reactivation of pluripotency, alterations in target cells and characterisation of these cells need to be addressed (Jalving and Shepers, 2009).
3. Potential of stem cells for retinal ganglion cell replacement
One of the strategies to restore vision in glaucoma patients after RGCs have been lost or irreversibly damaged is their functional replacement by autologous or heterologous transplantation.
It is generally accepted that damage to the neural retina during glaucoma is restricted to the impairment of function and subsequently degeneration of RGCs (Kerrigan-Baumrind et al., 2000; Quigley and Green, 1979), making these cells ideal candidates for early cell replacement strategies. Recent evidence indicates, however, that in addition to damage to the optic nerve, prolonged elevation of intraocular pressure may also induce degeneration or loss of function of other retinal neural cell types, most notably of amacrine cells (Hernandez et al., 2009). Similar observations have been made in other retinal degenerative diseases such as retinitis pigmentosa, which is characterized not only by the loss of rod, but also of cone photoreceptors and by major morphological changes of other surviving retinal neurons (Fariss et al., 2000). Therefore early intervention may be preferable, if cell replacement strategies are to succeed, in order to restrict the number of cells types which need to be transplanted. In addition, the correct establishment of synaptic connections between transplanted RGC and native cells may be facilitated, providing that the stratified structure of the retina with its circuitry and at least some of the connections of the RGCs through the optic nerve and the optic chiasm to the lateral geniculate nucleus are preserved.
At present, research has mostly focused on the identification of suitable cells, which can be differentiated towards RGCs and their precursors, as well as the experimental conditions required for the optimal expression of their molecular markers. Furthermore, a small number of studies have investigated the electrophysiological properties of the RGC precursors generated in vitro and their transplantation into in vivo models. Although research has been conducted into the functional replacement of RGCs, and potential candidate stem cells have been identified, there are currently no cell-based therapeutic options that are either available to patients or tested in clinical trials. Establishment of cell based therapies to replace or regenerate RGCs, as with any other cell based therapy, would require validation protocols for safety, efficacy and long term survival of the transplanted cells. In the following sections we will review the potential of human ES cells, iPS cells and adult human Müller stem cells for the generation and transplantation of RGCs and their precursors.
3.1. Human embryonic stem cells as a prospective source of RGCs
Most evidence for the differentiation of ESCs into retinal progenitors and their potential for retinal transplantation has been provided by animal studies. Murine ESCs have been shown to generate RGC-like cells in vitro by differentiation protocols using various growth and differentiating factors. This has resulted in the expression of markers such as Ath5, Brn3b, RPF-1, Thy-1 and Isl-1 (Jagatha et al., 2009), which are characteristically expressed by RGCs. Rx/rax-expressing murine ESCs, which were treated with retinoic acid to induce neural commitment, expressed markers of RGCs and horizontal cells, displayed electrophysiological properties consistent with RGCs and were able to integrate ex vivo into mouse retinae (Tabata et al., 2004). Importantly, when mouse ESCs, which had been differentiated into eye-like structures, were co-cultured with retinal explants following damage to the inner retinal cells, migration into the RGC layer as well as expression of the RGC markers HuD and Brn3b were observed (Aoki et al., 2007).
Proof of concept that human ESCs can successfully differentiate into retinal neurons has been provided by xenologous transplantation. Following intravitreal injection into the adult mouse eye, human ESCs formed structures reminiscent of the developing optic cup and expressed markers of a wide range of retinal progenitors and neurons (Aoki et al., 2009).
In addition transplanted murine ESCs have been shown to integrate into the inner and outer nuclear as well as the inner plexiform layers of the retinae of host mice with retinal degeneration. Transplanted cells adopted a morphology consistent with and displayed molecular markers of a wide range of retinal neurons, such as βIII-tubulin and NeuN, calretinin, PKC-α and rhodopsin (Meyer et al., 2006).
In addition, Lamba et al. have recently provided evidence that human ESCs can generate retinal progenitors with high efficiency, expressing a number of molecular markers usually observed in the developing retina. These cells have shown exceptional correlation between their levels of expression of genes specific for differentiating neurons and the developmental stage of the retina, including markers of RGC and amacrine cells, which constitute the inner retina, i.e. HuD/C, Pax6, neurofilament-M and Tuj1 (Lamba et al., 2006).
Transplantation of human ESC-derived neural and retinal progenitors into animal models of retinal degeneration has been extensively studied by several groups. Neural precursors derived from human ESCs have been transplanted subretinally and intravitreally into mice, where they have been shown to be able to integrate into the retina and survive for long periods of time after grafting. Although these cells mostly displayed photoreceptors markers (Banin et al., 2006), such findings have provided evidence that human ESCs have the potential to form retinal neurons following engraftment. These results have been further supported by additional evidence that human ESCs can adopt a neural morphology and express neural retinal markers following transplantation and differentiating treatment in an in vivo murine model of RGC depletion, without giving rise to teratomas (Hara et al., 2010).
Although human ESCs have shown potential for use in RGC replacement therapies for glaucoma, major disadvantages associated with the use of human ESCs still remain. Ethical constraints relating to the use of these cells, their limited availability and safety issues regarding teratoma formation are likely to curtail the translation of ESCs for human RGC replacement to the clinical setting. Further work should therefore be aimed towards identifying alternative sources of cells that may safely and efficiently replace these cells in the glaucomatous eye without these ethical and practical constraints.
3.2. RGC differentiation of induced pluripotent stem cells
Some of the disadvantages of human ESCs have been addressed by the development of iPS cells, which have been proposed as a viable source of cells for autologous transplantation. The generation of iPS cells does not require the destruction of embryonic tissue and therefore does not have the same ethical implications as work with ESCs, which have been a limitation in a large number of developed countries. In addition, iPS cells can be derived from and tailored to the patient, making cells more widely available and rendering immunosuppressive therapy following transplantation redundant. To date, few studies have investigated the potential for iPS cells in stem cell treatment of retinal degenerative diseases, although recently some progress has been made to generate iPS cell-derived RGC-like cells.
Parameswaran et al. have recently provided evidence that iPS cells, which originated from reprogrammed mouse embryonic fibroblasts by transfection with Oct3/4, Sox2, Klf4 and c-Myc, can give rise to both RGCs and photoreceptors in vitro. They reported that neural induction and exposure to conditioned media from E14 rat retinal cells augmented the expression of Ath1, Brn3b, RPF1 and Irx2, which regulate RGC differentiation, while the retinal progenitor markers Sox2, Rx and Chx10 were reduced. Importantly, the same study reported that the generated RGC-like cells displayed tetrodotoxin-sensitive voltage-dependent sodium currents, which is a hallmark of functional neurons (Parameswaran et al., 2010).
Chen et al. have used a similar approach by creating iPS cells from reprogrammed murine fibroblasts, which had been transduced with Oct3/4, Sox2, c-Myc and Klf4, to generate RGC-like cells. These cells expressed markers of retinal progenitor cells, i.e. Pax6, Rx, Otx2, Lhx2 and nestin, the levels of which were attenuated after differentiation towards a RGC fate. Differentiation was accompanied by expression of markers of RGC progenitors such as Brn3b and Isl-1, as well as Thy-1.2, a marker of mature RGCs. However, transplanted cells did not engraft into murine retina following intravitreal injection and they retained their pluripotency as demonstrated by their ability to form intraocular teratomas (Chen et al., 2010).
These studies illustrate major problems associated with the transplantation of cells derived from iPS cells, which need to be addressed. In particular, as described by Chen et al., the ability of iPS to form teratomas and therefore their potential to form cancerous growths may prove problematic. These findings suggest that preparation of iPS cell derived RGC progenitors for individual patients may need to undergo extensive validation for safety and efficacy, making them likely to be impractical and expensive for autologous therapies.
3.3. Müller stem cells as a source of RGCs for glaucoma therapies
The lack of regenerative potential of the human retina in vivo may be due to presently unknown inhibitory factors within the fully developed retina, since human Müller glia cells with stem cell characteristics have been reported to retain the ability to divide indefinitely in vitro (Limb et al., 2002). Until further research can elucidate the nature of these inhibitory factors, it is however unlikely that treatment options involving re-activation of endogenous Müller stem cells in the adult human retina can be developed. Cell replacement by transplantation of Müller stem cell-derived retinal neural progenitors may therefore currently offer a more promising strategy to restore visual function after irreversible damage or substantial loss of RGCs in glaucoma.
Müller glia with stem cell characteristics have been demonstrated to be predominantly located in the peripheral sections of the adult human retina (Bhatia et al., 2009). Human Müller stem cells can be easily isolated from cadaveric donor retina, and these cells can be grown and expanded indefinitely in vitro, and express markers of neural progenitor cells, such as Sox2, Notch1, Pax6, Shh and Chx10, as well as markers of Müller glia cells and retinal neurons e.g. CRALBP, HuD, PKC, and peripherin (Lawrence et al., 2007). When cultured under differentiating conditions in the presence of extracellular matrix and growth factors, enriched populations of cells expressing markers of specific retinal neurons can be obtained (Bhatia et al., 2011; Lawrence et al., 2007; Singhal et al., manuscript submitted).
This is illustrated by the fact that Müller stem cells cultured under various conditions develop a neuronal morphology and upregulate their expression of retinal neural and RGC precursor markers such as βIII-tubulin, Brn3b, Isl-1 and rhodopsin. Simultaneously expression levels of the neural progenitor marker Pax6 and the glial cell marker vimentin are also attenuated (Bhatia et al., 2011), indicating that existing Müller stem cell lines may have the potential to form RGC precursors.
However at present, intraocular transplantation studies using Müller stem cells have been conducted using mostly undifferentiated cells. Initially Lawence et al. reported integration of subretinally transplantated Müller stem cells into neonatal Lister Hooded rats and adult dystrophic RCS rats. Engrafted cells were shown to express the photoreceptor markers recoverin and rhodopsin, the RGC marker HuD as well as calretinin, which identifies RGCs and amacrine cells (Lawrence et al., 2007). Although integration of undifferentiated Müller stem cells has been observed after subretinal transplantation into adult dystrophic RCS rats, these cells were located in all retinal layers and did not selectively locate to the ganglion cell layer or adopt RGC-like morphology (Singhal et al., 2008).
Undifferentiated Müller stem cells have also been used for intravitreal and subretinal transplantation in a rat model of glaucoma. Although only few of the transplanted cells expressed the Müller glia and astrocyte marker GFAP, expression of βIII-tubulin indicates that at least some of the transplanted cells were able to adopt a neural phenotype. Interestingly, many of the grafted cells showed a migratory phenotype and aligned towards the host retina, in particular the optic nerve head, although they did not migrate and disseminate within the retina (Bull et al., 2008).
Recently it has been reported that Müller stem cells can be differentiated into RGC precursors, which integrate into the retina after intravitreal injection and can partly restore function in RGC-depleted retina as measured by electroretinography (Singhal et al., 2009). Although at present understanding of Müller stem cell differentiation towards RGC precursors is limited, previous work with this cell type has shown that they may have the potential for therapeutic regeneration of RGC function in glaucoma. In particular the maturity of Müller stem cells may potentially decrease the risk of teratoma formation. In addition, their ontogenetic proximity to retinal neurons may likely facilitate the development of protocols not only to successfully derive and transplant RGC precursors, but also to induce endogenous retinal regeneration without the need for transplantation.
3.4. Barriers to successful stem cell transplantation
Although some progress has been made regarding the successful production, delivery, integration and survival of RGC progenitors, major obstacles for successful engraftment and functional restoration remain and will be discussed below. These include the host immune response and extracellular matrix, which form a barrier for cell integration into the healthy host retina. During retinal degenerative processes, there is abnormal deposition of extracellular matrix, mainly chondroitin sulphate proteoglycans, which are responsible for the formation of glial scarring (gliosis). In addition, accumulation of microglia occurs, which has been shown to surround transplanted cells, inhibit their migration and induce their death (Singhal et al., 2008). Additionally, effective migration and integration of the transplanted cells has been suggested to be dependent upon their ontogenetic stage (MacLaren et al., 2006). These requirements will be discussed in more detail below.
3.4.1. Modulation of the host extracellular matrix
Various transplantation studies using a wide range of cells derived from ESCs as well as Müller stem cells have concluded that successful engraftment into the healthy adult retina is impeded by extracellular matrix components and the physical barrier of the inner limiting membrane (Chacko et al., 2003; Johnson et al., 2010b). This is unlikely to be influenced by the route of cell delivery, since transplantation by either intravitreal or subretinal injection did not yield integration of transplanted cells into the healthy host retina in the adult rat (Bull et al., 2008). In addition dissemination of the transplanted cells within the retina has been reported to be highly restricted (Banin et al., 2006). Conversely, integration of transplanted cells has been demonstrated in neonates (Chacko et al., 2003) or in the adult retina following injury (Chacko et al., 2003), indicating that these environments may be more permissive for successful engraftment.
Glaucomatous changes of the retina are generally accompanied by reactive gliosis as well as remodelling and deposition of extracellular matrix components (Guo et al., 2005). Increased production of chondroitin sulphate proteoglycans (CSPGs), which have been shown to inhibit rat optic nerve regeneration after crush injury (Selles-Navarro et al., 2001) and reduce axonal and dendritic growth (Zuo et al., 1998), has been demonstrated following CNS and spinal cord damage (Bradbury et al., 2002). CSPGs have also been reported to form a barrier to cell migration following transplantation in animal models (Singhal et al., 2008) (Figure 2). Furthermore, degradation of CSPGs has been shown to enhance dendritic and axonal regeneration following brain and spinal cord injury (Bradbury et al., 2002; Zuo et al., 1998).
As a result of these findings, the effects of modulation of extracellular matrix components have recently been explored in conjunction with retinal progenitor transplantation. Evidence has been provided to show that co-administration of chondroitinase ABC or erythropoietin, which has been reported to upregulate MMP-2 (Wang et al., 2006), greatly increases the number of cells, which successfully integrate into the host retina (Singhal et al., 2008; Suzuki et al., 2007). Similarly, the integration of murine neonatal retinal cells into the adult rat host retina by ex vivo transplantation has been shown to be augmented by the induction of MMP-2 (Suzuki et al., 2006).
Figure 2.
Confocal imaging of rodent retina 2 weeks after subretinal transplantation of Müller stem cells. Sections on the left column shows the transplanted cells (green) surrounded by N-terminal CSPG, neurocan and versican (red). The middle column shows the same sections under Nomarski illumination to illustrate the accumulation of CD68 positive microglia (black). The column on the right shows the merged images under Nomarski illumination illustrating co-localization (arrows) of CD68 positive cells and CSPGs (red) surrounding the transplanted cells (green) (from Singhal et al., 2008).
3.4.2. Modulation of the host immune response
A successful transplantation scheme requires long term survival of the grafted cells. Allogeneic grafts induce a host immune response, leading to rejection and failure of the transplant. However cell survival is greatly increased by systemic immunosuppression of the recipient following allogeneic cell transplantation into the eye (West et al., 2010). Triple therapy with oral immunosuppressives has recently been used to increase survival of xenografted Müller stem cells to 2 to 3 weeks, although microglia and macrophage activation was observed and transplants were destroyed after 4 weeks (Bull et al., 2008).
Activation of phagocytic microglia, the resident immune cells of the CNS, which may promote axonal degeneration of RGCs and of the optic nerve, is frequently observed during glaucoma (Ebneter et al., 2010; Yuan and Neufeld, 2001). In transplantation models, microglia prevent the migration of transplanted cells into the retina (Singhal et al., 2008) (Figure 3). Suppression of the intraocular immune response and inhibition of microglial activation by intravitreal injection of triamcinolone acetonide may therefore promote the integration and the survival of RGC precursors into retinae with glaucomatous changes. Intravitreal injection of triamcinolone acetonide in combination with oral immunosuppression and anti-inflammatory medication has previously been shown to greatly reduce microglial activation against the xenograft (Singhal et al., 2008; Singhal et al., 2010).
Figure 3.
A. Müller stem cells (green) accumulate in the subretinal space and do not migrate into the retina. Middle image shows Nomarski illumination identifying CD68 positive cells (black) in the same retinal section. Right figure shows Nomarski illumination identifying co-localization of transplanted cells with microglial cells expressing CD68 (black). B. Transplanted cells can be seen forming a large cluster in the subretinal space 2 weeks after transplantation. Middle image shows localization of microglia (black) around the transplanted cells (green). Right figure shows microglia (black) surrounding the transplanted cells (green) and resembling a granuloma-type structure (From Singhal et al., 2008).
In experimental animal models, immune-tolerization of embryos or neonates by intraperitoneal injection of grafted cells may be used to further reduce the host immune response (Billingham et al., 1953).
3.4.3. Ontogenetic stage of transplanted cells
Currently the role played by the ontogenetic stage of transplanted RGC precursors upon their integration into host retina, as well as on functionality of the engrafted cells, has not been investigated. Previous transplantation studies have demonstrated that stem cells isolated from adult individuals rarely migrated into the healthy adult retina (Johnson et al., 2010a; Lawrence et al., 2007; Singhal et al., 2008), while embryonic and neonatal retinal progenitors and other stem cells have been shown to successfully integrate into the host retina (Warfvinge et al., 2001; Wojciechowski et al., 2004), suggesting that the developmental stage of the transplant may be crucial for successful migration and functional integration.
Several studies have investigated the role of the developmental stage of grafted retinal neurons for successful incorporation into the host retina. Based on this work, it has been concluded at least in the case of photoreceptor transplantation that early postnatal post-mitotic precursors or cells of a similar ontogenetic stage are the most promising candidates for transplantation in terms of their ability to migrate and disseminate into the retina and differentiate towards a functional phenotype (MacLaren et al., 2006).
However, more recent studies have suggested that there may be no need for transplantation of photoreceptor progenitors for these cells to integrate, as fully mature photoreceptors retain the ability to integrate into the mature retina upon transplantation (Gust and Reh, 2011). Moreover, integration of photoreceptors derived from human Müller glia into the degenerated rat retina has shown to be independent from NRL expression by these cells (Jayaram et al., unpublished observations).
In addition the developmental phase of transplanted cells will likely have major implications on treatment safety, with less differentiated cells posing a greater risk of tumorigenesis. In fact, a number of studies using cells derived from embryonic stem or iPS cells have reported the occurrence of teratomas (Arnhold et al., 2004; Chen et al., 2010), whereas no formation of cancerous growths was reported after transplantation of adult-derived stem cells.
In summary, future research will be needed to elucidate the effects of the ontogenetic stage of transplanted RGC precursors on graft integration, function and safety.
3.5. Strategies to measure functional outcome
With the development of methods for the transplantation of RGC in glaucoma, the measurement of functional outcomes will become increasingly important. It can be anticipated, however, that these will encompass techniques currently available for the monitoring of disease progression. Electrophysiological measurements are widely used to assess glaucomatous damage both in patients and in experimental animal models and will likely continue to play a major role in evaluating treatment success. Some of these protocols have been standardized by the International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines (Holder et al., 2007; Marmor et al., 2009), although they may be complemented by other methods established for laboratory use.
The pattern ERG is currently one of the most useful techniques to assess glaucomatous damage in patients. It generally utilizes a black and white checkerboard stimulus with pattern reversal as prescribed by the ISCEV standards (Holder et al., 2007). The pattern ERG has been shown to be reduced in patients with glaucoma and correlates with visual field defects (Wanger and Persson, 1983). In addition the use of variable check sizes may be advisable to assess the extent of glaucomatous change (Bach et al., 1988). Recently multifocal pattern electroretinograms have been demonstrated to be reduced in glaucoma patients (Monteiro et al., 2011; Stiefelmeyer et al., 2004), although other studies have reported that localized reductions of the signal amplitude could not be correlated with visual field defects (Klistorner et al., 2000). Since this method requires good accommodation and fixation (Holder et al., 2007), it is widely used in human subjects, while its applicability to animal models is limited.
Preclinical studies will likely favour methods employing Ganzfeld stimulation, which are relatively easy to apply to a laboratory setting. The most commonly used of these is the scotopic threshold response, a low intensity light response with stimulation below the psychophysical threshold, which has be ascribed to RGC function, although it may species-dependently contain contributions from amacrine cells (Frishman et al., 1996; Korth et al., 1994; Sieving, 1991). More recently the photopic negative response has been established as a measure of RGC function (Viswanathan et al., 1999), although other cellular origins, such as glia and amacrine cells, have been suggested (Machida et al., 2008). However, at present this has not been assimilated into ISCEV guidelines.
Pattern reversal, pattern onset/offset or flash visual evoked potentials can be used to assess RGC and optic nerve function. Although they are usually employed in a clinical setting (Odom et al., 2010), especially the flash, the pattern onset/offset visual evoked potentials may potentially be used for experimental applications in animals (Huang et al., 2011; Ver Hoeve et al., 1999). Recently multifocal mapping of visual evoked potentials has been developed (Hasegawa and Abe, 2001), but has not been widely applied to practice. However, for clinical purposes perimetry will remain important, as gains in the visual field of patients may indicate whether potential RGC cell therapies are successful.
4. Optic nerve regeneration
It has been considered critical for the functional success of RGC replacement therapies in glaucoma that transplanted cells form axons, restore the optic nerve and establish new connections with their physiological targets. The optic nerve has traditionally been thought to be incapable of renewal, with axonal damage invariably leading to the degeneration of RGC somata and resulting in the irreparable loss of vision.
A range of studies has investigated the effects of peripheral nerve transplantation on RGC survival as well as axonal sprouting and re-growth. Extensive evidence has been presented that autologous grafts of peripheral nerves can protect axotomized RGCs from cell death and in addition can promote the regeneration and re-growth of axons. Some studies have even shown that after transplantation of peripheral nerves, RGCs regenerated long axons, which extended into the superior colliculus, where they formed synapses in their physiological target region (Aguayo et al., 1991; Vidal-Sanz et al., 1991).
Other cell types such as OECs and macrophages have been suggested to augment axon formation. The promoting effect of OECs on neurite formation may likely be contact-mediated (Leaver et al., 2006). In addition, macrophages have been reported to promote axonal growth, probable through the release of oncomodulin and activation of the protein kinase Mst3b and Ca2+/calmodulin kinases as downstream effectors (Lorber et al., 2009 ; Yin et al., 2006).
Distinct growth factors have been identified which may affect optic nerve regeneration. A combination of fibroblast growth factor 2 (FGF2), neurotrophin 3 (NT3) and brain derived neurotrophic factor (BDNF) (Logan et al., 2006) has been reported to stimulate axonal outgrowth of RGCs. Furthermore a range of molecules have been identified, which can reduce dendrite formation, e.g. Nogo-A, myelin-associated glycoprotein and components of the extracellular matrix such as proteoglycans (Koprivica et al., 2005; Su et al., 2009; Wong et al., 2003). Many of these inhibitory factors converge on the small G-protein RhoA, inhibition of which has been shown to result in stimulation of axon formation (Bertrand et al., 2005).
Interestingly, the length of new axons grown from cultured RGCs has been reported to be reduced after the developmental age at which synaptic connections in the superior colliculus are formed, although the proportion of cells generating axons was not altered (Goldberg et al., 2002).
The formation and guidance of axons from RGCs to their targets during development have been intensively investigated. Netrins, semaphorins, laminin, erythropoietin-producing hepatocellular receptor/Eph receptor-interacting protein, Wnt and slits have been shown to act as chemo-attractants and repellants during optic nerve development in the embryo (Erskine and Herrera, 2007; McLaughlin and O\'Leary, 2005). Interestingly, some of these guiding signals have been reported to be retained or restored following injury in the adult brain (Bahr and Wizenmann, 1996), which may help to guide axons formed by transplanted RGCs to the right targets. Additionally it has been shown that following transplantation of embryonic retinal tissue, connections to the superior colliculus are successfully established (Seiler et al., 2010).
5. Stem cell mediated neuroprotection in glaucoma
The pathophysiological mechanisms implicated in RGC loss seen in glaucoma have led to the development of neuroprotective strategies becoming a major focus of current glaucoma research (Danesh-Meyer, 2011). Contemporary research in stem cell mediated neuroprotection for glaucoma has been developed on the backdrop of promising work performed in models of neurodegenerative disease affecting other parts of the CNS.
Glaucomatous RGC loss and neuronal degeneration in other neurodegenerative conditions share mechanisms such as oxidative stress, impairment of axonal transport, excitotoxicity and inflammation (Baltmr et al., 2010) making neuroprotective strategies relevant to patients affected by both conditions.
Stem cell derived strategies for neuroprotection, if successful, offer several theoretical advantages over conventional pharmacological approaches. Should transplanted cells integrate within the host retina, it is possible that a single treatment may provide long term neuroprotection offering support to surviving neurons. The observation that endogenous neural stem cells are able to migrate to the site of injury in ischaemic stroke and differentiate into mature neurons (Felling and Levison, 2003), gives rise to the possibility of a similar phenomenon occurring with transplanted cells in the context of glaucoma, with such cells potentially responsible for the provision of local support.
Stem cells are able to facilitate local neuronal survival by the production of several neurotrophic factors. This multifactorial effect has been demonstrated in animal models of CNS disease (Corti et al., 2007) and work in a rodent model of Parkinson’s Disease showed that neural stem cell transplantation conferred a more significant neuroprotective benefit than both a single injection of neurotrophins or prolonged delivery via local infusion (Yasuhara et al., 2006). Transplantation of neural progenitors in animal models of neurodegenerative disease has been shown to confer neuroprotection via an immunomodulatory mechanism (Pluchino et al., 2005). Alteration of the microenvironment surrounding damaged RGCs, perhaps through immune mediated actions of transplanted cells, may help promote local neuronal survival.
A major beacon of hope in stem cell research is the concept of autologous transplantation. Such a strategy would minimise the risk of graft rejection and prevent a lifetime of potentially toxic immunosuppressive therapy for patients. Neuroprotective strategies involving Müller stem cells, bone marrow derived mesenchymal stem cells and OECs offer realistic potential for autologous transplantation. However, more work is still necessary to design practical approaches to obtain suitable tissue for this purpose, as well as to derive functional cells that can be used for transplantation. Should current concerns regarding the safety of iPS cells for therapeutic use be overcome (Jalving and Shepers, 2009), these reprogrammed adult somatic cells offer an exciting avenue for the development of autologous therapies in the future.
Mesenchymal stem cell mediated neuroprotection has been demonstrated following transplantation in various models of retinal degeneration (Arnhold et al., 2007; Inoue et al., 2007; Lu et al., 2010; Zhang and Wang, 2010). This phenomenon is likely to be secondary to the secretion of neurotrophic factors such as BDNF, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), insulin like growth factor 1 (IGF1) and FGF2 (Cho et al., 2005; Labouyrie et al., 1999) which are known to offer protection to damaged retina. These observations, coupled with promising results showing neuroprotection in models of CNS degenerative disease (Andrews et al., 2008; Karussis et al., 2008; Parr et al., 2007; Torrente and Polli, 2008), have led to this category of stem cells becoming a focus for the development of cell-based neuroprotective strategies to treat glaucoma.
Disruption of the retrograde axonal transport of BDNF has been shown to be involved in the pathophysiology of glaucoma (Pease et al., 2000) and attempts to upregulate expression of BDNF (Martin et al., 2003) and CNTF (Pease et al., 2009) using gene therapy have been shown to attenuate RGC loss in experimental models. A reduction in RGC loss has been observed in rodents with raised intraocular pressure following intravitreal transplantation of mesenchymal stem cells (Johnson et al., 2010a; Yu et al., 2006). The latter reported increased levels of CNTF, BDNF and FGF within the retinae of treated eyes, which were hypothesised to be responsible for this neuroprotective effect. Survival of the cells was observed at up to five weeks, but currently there is a lack of data describing long term graft survival and a prolonged neuroprotective effect, both of which will be essential for such a therapy to be translated to the clinic.
Despite suggestions that mesenchymal stem cells may possess a capacity to migrate from the systemic circulation into diseased tissue, migration into chronically damaged neural tissue is regarded as being limited, and hence strategies for cell delivery would be best served by direct injection into affected tissue. In the context of glaucoma models, cells administered via an intravenous approach were unable to be detected in the eye and had no effect in attenuating RGC loss (Johnson et al., 2010a).
The neuroprotective effect of transplanted cells may be optimised further by enhancing the neurotrophin secreting ability of cells through either cytokine driven protocols or gene therapy techniques. Proof of concept for this idea was demonstrated in a model of cerebral ischaemia where intravenous infusion of mesenchymal stem cells genetically modified to deliver BDNF to the cerebral circulation provided a greater neuroprotective effect than untreated cells (Nomura et al., 2005). This principle has been successfully applied to a rodent model of RGC damage induced by optic nerve transection (Levkovitch-Verbin et al., 2010). Mesenchymal stem cells were induced to secrete high levels of BDNF, VEGF and Glial Derived Neurotrophic Factor by using a cytokine driven protocol in vitro. Intravitreal transplantation of both modified and untreated mesenchymal stem cells produced similar neuroprotective effects when compared to sham injection. One interpretation of these findings would be that even small amounts of trophic factor release, as seen with untreated cells, may confer neuroprotection. However a more realistic argument may be that the severity of optic nerve transection is such that even the higher levels of trophic factors delivered by the modified cells would be unlikely to prevent RGC death. Further research into the role of cell populations that have enhanced neurotrophin secreting capability in models of glaucoma may provide further insight into the therapeutic potential of such an approach.
Inflammation has frequently been associated with neurodegenerative disease. It is commonly observed as a consequence of acute injuries including trauma and stroke, but is also a characteristic feature of demyelinating disease where autoimmune processes are central to the pathophysiology. Mesenchymal stem cells derived from the bone marrow are known to have the ability to modulate the inflammatory response. There is much hope and optimism in the field of multiple sclerosis that these cells may provide in situ immunomodulation and neuroprotection (Payne et al., 2011) with the results of clinical trials eagerly awaited. It is quite feasible that this mechanism may be applicable to glaucomatous RGC loss, however further studies are required to investigate this possibility.
The observation that OPCs exhibit neuroprotective properties in vitro (Wilkins et al., 2001) has led to some interest in their role as a potential candidate for cell-based therapies in a model of glaucoma. Interestingly OPCs were only able to demonstrate a neuroprotective effect following concomitant activation of pro-inflammatory cells using zymozan (Bull et al., 2009). The neuroprotective effect was not contact-mediated and was attributed to the release of diffusible trophic factors from the activated OPCs. A potential risk of transplanting such cells into glaucomatous eyes is the potential of excessive myelination, which carries the theoretical risk of blocking the transmission of light within the eye and reducing the electrical conduction of RGCs. However further studies into the nature of the trophic factors released by these cells may aid the design of further novel neuroprotective strategies to treat glaucoma.
OEC transplantation has been observed to increase axonal regeneration in models of spinal cord injury (Ramon-Cueto and Valverde, 1995). These initial observations led to the development of further studies into the potential of these cells to develop novel treatments for optic nerve disorders and glaucoma. In vitro work has demonstrated that OECs cause ensheathment of RGCs without the process of myelination occurring (Plant et al., 2010). Transplantation of OECs into the distal stump of transected optic nerves provided further evidence of regeneration of several axons (Li et al., 2003; Wu et al., 2010) that were supported by the transplanted cells. Following transretinal delivery into normal rodent eyes, OECs migrate along the RGC layer into the optic nervehead demonstrating ensheathment of RGC axons by the cytoplasm of transplanted cells (Li et al., 2008). It is possible that this process may provide some mechanical support to compromised axons, which may subsequently be able to maintain sufficient functional vision if therapies can be developed for patients with end stage glaucoma.
Evidence from models of spinal cord transection suggests that OEC transplantation is associated with an increased secretion of neurotrophins such as BDNF which appears to correlate with the neuroprotective effect (Sasaki et al., 2006). However it was not clear whether the BDNF was secreted by the transplanted cells or by activation of endogenous cells. Attempts to combine OEC transplantation with concomitant neurotrophin administration have shown promising results to date. Combination therapy in a model of optic nerve crush resulted in restoration of the latency of the visual evoked potential to almost 90% of normal levels with retrograde RGC labelling suggesting of axonal regeneration (Liu et al., 2010).
Future studies using these cells directed towards attenuating glaucomatous RGC loss may focus upon the potential of external support of RGC axons exiting via the lamina cribrosa as well as internal neuroprotection mediated by the provision of trophic factors. In addition further study into the functional characteristics of OECs is required as well as investigation of the effects of OEC in models of experimental glaucoma.
The perfect stem cell-based therapy to treat glaucoma would involve the activation of endogenous stem cells to repair damaged RGCs and thus restore function. The damaged CNS lacks plasticity and neuronal regeneration is notoriously difficult due to a lack of trophic cues (Hou et al., 2008) and the inhibitory nature of the microenvironment (Asher et al., 2001). Nevertheless there is growing evidence that endogenous neural stem cells may proliferate in response to brain injury such as stroke (Felling and Levison, 2003). Although only a proportion of new cells differentiate into new neurons and survive in the long term (Naylor et al., 2005), methods have been established to enhance the proliferation of endogenous neural stem cells following ischaemic injury (Ninomiya et al., 2006).
With respect to damaged neurons within the retina, it may be the Müller glia that hold the key for endogenous reactivation. Their well-documented capacity to regenerate retinal neurons in the teleost retina (Bernardos et al., 2007; Fimbel et al., 2007) and the known presence of similar cells in adult human retina (Lawrence et al., 2007) would make these cells a promising target around which studies of endogenous stem cell repair could be developed.
6. Conclusion
The rapidly evolving field of stem cell research offers exciting potential in the long term for innovative therapies moving from bench to bedside in patients who are affected by advanced glaucoma. Although regeneration of the optic nerve itself may be unrealistic with current scientific knowledge, further studies into local retinal ganglion replacement and neuroprotective mechanisms using transplanted stem cells may offer hope that such treatments may be translated to patients in years to come.
Acknowledgments
Supported by The Medical Research Council (MRC), UK (Grants G0900002 and G0701341). HJ holds a Fellowship from the MRC and the Royal College of Surgeons of Edinburgh.
Also supported by Fight for Sight and the NIHR Biomedical Research Centre for Ophthalmology Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, UK
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Astrid Limb",authors:[{id:"44484",title:"Dr.",name:"G Astrid",middleName:null,surname:"Limb",fullName:"G Astrid Limb",slug:"g-astrid-limb",email:"g.limb@ucl.ac.uk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University College London",institutionURL:null,country:{name:"United Kingdom"}}},{id:"44487",title:"Mr.",name:"Hari",middleName:null,surname:"Jayaram",fullName:"Hari Jayaram",slug:"hari-jayaram",email:"h.jayaram@ucl.ac.uk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University College London",institutionURL:null,country:{name:"United Kingdom"}}},{id:"44488",title:"Dr.",name:"Silke",middleName:null,surname:"Becker",fullName:"Silke Becker",slug:"silke-becker",email:"silke.becker@ucl.ac.uk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University College London",institutionURL:null,country:{name:"United Kingdom"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Sources of stem cells",level:"1"},{id:"sec_2_2",title:"2.1. Embryonic stem cells",level:"2"},{id:"sec_3_2",title:"2.2. Adult tissue-derived stem cells",level:"2"},{id:"sec_3_3",title:"2.2.1. Müller stem cells",level:"3"},{id:"sec_4_3",title:"2.2.2. Mesenchymal stem cells",level:"3"},{id:"sec_5_3",title:"2.2.3. Oligodendrocyte precursor cells",level:"3"},{id:"sec_6_3",title:"2.2.4. Olfactory ensheathing cells",level:"3"},{id:"sec_8_2",title:"2.3. Induced pluripotent stem cells",level:"2"},{id:"sec_10",title:"3. Potential of stem cells for retinal ganglion cell replacement",level:"1"},{id:"sec_10_2",title:"3.1. Human embryonic stem cells as a prospective source of RGCs ",level:"2"},{id:"sec_11_2",title:"3.2. RGC differentiation of induced pluripotent stem cells",level:"2"},{id:"sec_12_2",title:"3.3. Müller stem cells as a source of RGCs for glaucoma therapies",level:"2"},{id:"sec_13_2",title:"3.4. Barriers to successful stem cell transplantation",level:"2"},{id:"sec_13_3",title:"3.4.1. Modulation of the host extracellular matrix",level:"3"},{id:"sec_14_3",title:"3.4.2. Modulation of the host immune response",level:"3"},{id:"sec_15_3",title:"3.4.3. Ontogenetic stage of transplanted cells",level:"3"},{id:"sec_17_2",title:"3.5. Strategies to measure functional outcome",level:"2"},{id:"sec_19",title:"4. Optic nerve regeneration",level:"1"},{id:"sec_20",title:"5. Stem cell mediated neuroprotection in glaucoma",level:"1"},{id:"sec_21",title:"6. Conclusion",level:"1"},{id:"sec_22",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'AguayoA. J.RasminskyM.BrayG. M.CarbonettoS.Mc KerracherL.Villegas-PerezM. P.Vidal-SanzM.CarterD. A.1991Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci 331337343'},{id:"B2",body:'AndrewsE. M.TsaiS. Y.JohnsonS. C.FarrerJ. R.WagnerJ. P.KopenG. 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UCL Institute of Ophthalmology & Moorfields Eye Hospital, United Kingdom
UCL Institute of Ophthalmology & Moorfields Eye Hospital, United Kingdom
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1. Introduction
Every year, thousands of people come from the lowlands to high altitude such as the Qinghai-Tibetan plateau, the Andes, and the Alps, for sight-seeing and mountaineering. Although identification on high altitude is controversial [1, 2] (see Table 1), altitude illnesses do not generally occur until 2500 m altitude or greater [2]. Currently, there are hundreds of thousands of non-native people working and living in these areas at altitudes ranging from 4000 to 5072 m including mountaineers, search and rescue personnel, and military personnel.
Poor sleep quality is a common experience for new arrivals at high altitude in the days to weeks following acute ascent. They often encounter with increased awakenings, frequent brief arousals, a sense of suffocation relieved by a few deep breaths, and resumption of sleep, which is now known as periodic breathing (PB). Upon arising from sleep, the impression is one of greatly restless sleep. Poor sleep quality at high altitude is one of the serious complaints in people with mountain sickness and influences physical and mental well-being, which can manifest as impaired cognitive abilities [3, 4] and poor daytime performance [5]. Up to now, there are no acceptable diagnostic criteria for sleep disorder at high altitude. It is recognized as a symptom of mountain sickness rather than an altitude disease.
Here we discuss the features of sleep at high altitude with focus on the role and causes of PB in altitude sleep disturbance, subjective changes in sleep quality, objective variations in sleep architecture, and management of sleep disorder at high altitude. We also discuss whether it is appropriate to name it high-altitude sleep disorder (HASD) as one of the altitude-related illness in accordance with the nomenclature of other high-altitude diseases.
2. Breathing disturbance during sleep at high altitude
One of the most important characteristics of sleep disorder at high altitude is PB, which usually occurs at altitudes above 2000 m [6]. PB during sleep was first recorded in 1886 by Mosso [7] and further observed by Douglas and Haldane in 1909 [8]. It is considered that under high altitude hypoxic circumstances, breathing was stimulated by hypoxia, leading to hypocapnia and lessening of hypoxia, which triggers apnea during sleep. Apnea, in turn, restores ventilatory by raising PCO2 and increasing hypoxia, generating the periodic respiratory cycle. This cyclical crescendo-decrescendo pattern periodicity usually consists of 2–4 breaths, separated by an apnea of 5–15 s in duration from the next burst of 2–4 breaths. Therefore, unstable breathing is the main characteristic of PB.
The extent of PB increased progressively as the altitude increased [9]. There is a strong positive correlation between PB and severity of acute mountain sickness (AMS) as assessed by Lake Louise (LL) score. With the increasing of altitude, normal values for partial pressure of arterial (PaO2) decreased compared to sea level, pH changing to respiratory alkalosis with concomitant hypocapnia [10]. Above 4000 m altitude, PB exists in most people, but this phenomenon may be beneficial, because with the worsening of PB, a higher arterial oxygen saturation (SaO2) was observed during sleep [10, 11]. After 3 months of acclimatization at 3800 altitude, PB could also be observed in lowlanders. Although acclimatized lowlanders experienced PB more frequently than native Tibetans at 89–85% of SaO2 stage, there is no significant difference in total PB events occurring either in non-rapid eye movement (NREM) or rapid eye movement (REM) stage [12]. See details in Figure 1, periodic breathing during sleep between native Tibetans and acclimatized Han lowlanders at 3800 m altitude. Even for a longer time (13 months) of camp in the Antarctic base Concordia (3800 m), PB prevailed for the major part of sleeping time [13]. These findings from a cross-sectional and a longitudinal study support our current understanding which assumes PB would not be largely relieved after acclimatization.
Figure 1.
Periodic breathing during sleep between native Tibetans and acclimatized Han lowlanders at 3800 altitude. Modified from Kong et al. [12].
The mechanism underlying this respiratory pattern for apnea and PB during sleep in hypoxic environments is believed to be a reduction in the PaO2 and acid-base adjustments. The procedure of PB may be summarized as conflicting dynamics between hypoxic stimulation of ventilation and suppression of respiratory output from ensuing hypocapnia. These changes lead to alterations in chemoreflex control and cerebrovascular responses to changes in arterial O2 which finally result in hyperventilation. For lowlanders, acclimatization to high altitude magnifies these changes. Briefly, an elevated chemosensitivity causes a more vigorous response to the rise in PaCO2 while the apnea outweighs the improvements in the effectiveness of ventilation in changing the arterial O2 caused by the chronic hypocapnia leading to the occurrence of PB [14].
The severity of PB is determined to be aggravated by an increasing neural respiratory drive (NRD), which can be measured by the electromyogram of the diaphragm. A sleep study in four healthy mountaineers performed at 3380, 4370, and 5570 m in the Andes, Argentina, confirmed this hypothesis [15]. A high NRD at altitude leads to a higher ventilation to maintain oxygenation, which results in more significant hypocapnia. This triggers apneas and O2 desaturations, as indicated by the positive correlation between the EMG of the diaphragm and the O2 desaturation index.
PB is considered to contribute to and/or be a result of sleep fragmentation by frequent arousals which may be responsible for poor sleep quality following altitude ascent. Sleep and arousals lead to greater breathing instability. Apnea is in correspondence to an increase in PaCO2 and decrease in PaO2 and consequently unstable ventilation. These changes in blood gases also lead to marked alterations in cerebral blood flow (CBF) which, in turn, may result in a sudden elevation (with reduced CBF) or reduction (with increased CBF) in brain stem pH.
Therefore, the uncomfortable sensation of sleep at high altitude is largely due to respiratory disturbance arising from the physiologic ventilatory dilemma of acute ascent, where stimulation by hypoxia alternates with inhibition by hypocapnic alkalosis.
3. Poor subjective sleep quality at high altitude
3.1 Evaluation and prevalence of poor sleep quality at high altitude
Subjective sleep quality at high altitude is usually evaluated by a questionnaire, e.g., sleep log questions, Pittsburgh Sleep Quality Index (PSQI), and Athens Insomnia Score (AIS). The prevalence of sleep disorder may differ considerably at altitude from observational studies. At a 3500 m hotel, 46% of 100 Iranian ski tourists reported frequent awakenings and other subjective sleep disturbances [16]. At an altitude of 3700 m in Lhasa, Tibet, 36.8% of 180 Chinese stationed soldiers reported poor sleep quality as measured by PSQI [17]. Data analysis from the same sample also indicated that poor sleepers (defined as PSQI > 5) were 1.45 times greater in those with polycythemia than those without polycythemia [95% (confidence interval) CI 1.82–2.56] [4]. Report from early pharmacologic treatment trials in acute mountain sickness (AMS) suggested that 53–71% of participants reported difficulty sleeping [18, 19]. Of note, despite the 3 months of acclimatization, a greater proportion of poor sleepers were still observed in lowlanders stationed at 3800 altitude than the native Tibetans (90.91 vs. 45.45%, P = 0.004) [12].
3.2 Sleep quality and severity of mountain sickness
Poor sleep quality at high altitude was one of the most frequently reported symptoms in mountain sickness as assessed by the Lake Louise Symptom Questionnaire and the Qinghai Chronis Mountain Score [12], which are used to diagnose AMS [20] and evaluate severity of chronic mountain sickness(CMS) [21], respectively. This was confirmed by a study using PSQI and AIS which reports decreased subjective sleep quality at high altitude, especially reduced general sleep quality and prolonged sleep induction [22]. For workers rapidly transported from sea level to high altitude, there are no statistically significant differences in polysomnographic parameters between subjects with AMS and those without AMS [23].
For people with CMS stationed at Tibet, the proportion of poor sleepers (defined as PSQI > 5) with severe CMS was 12.54-fold higher than that of good sleepers. See Figure 2, CMS severity comparison between “good” and “poor” sleepers at 3996 m altitude. Subjects with CMS had higher scores in each sleep component of the PSQI score, except the use of sleep medication. After adjusted for CMS score, age, and education, poor sleep quality was determined to be an independent predictor of impaired intelligence quotient [odds ratio (OR) 1.59, 95% CI 1.30–1.95] and short-term memory (OR 1.18, 95% CI 1.07–1.31). Therefore, for people with CMS, the poorer the sleep quality, the worse was the cognitive function [4].
Figure 2.
Sleep quality comparison among different CMS severity at 3996 altitude. Modified from Kong et al. [4].
4. Variation of sleep architecture at high altitude
Polysomnography (PSG) is the gold standard for investigating sleep architecture. However, the technical complexity and logistic demands had brought restriction on its utilization during altitude studies. Although there are several studies that suggest wrist actigraphy-derived data on total sleep time, sleep efficiency and sleep onset latency were similar to those of PSG [24]; actigraphy is insufficient in detecting sleep stage and breathing events.
Objective assessment of sleep architecture at altitude by electroencephalogram was first reported by Joern et al. in 1970 [25]. They found a near absence of stages 3 and 4 and a 50% reduction in rapid eye movement (REM) sleep and reported PB and arousals in one subject. A later study in 1975 confirmed a decrease in deeper sleep and increase in lighter sleep stages and brief arousals after ascending to an altitude of 4300 m at the Pikes Peak when compared to subjects at low altitude [26]. Subsequent studies have generally confirmed the shift at altitude toward lighter sleep stages, with a variable change in duration of REM sleep and increased awakenings associated with PB [27, 28, 29, 30].
Alterations in objective sleep parameters have also been observed during acclimatization. A recent literature review on high-altitude sleep concludes that during rapid ascent to high altitude, there is a reduction in total sleep time, sleep efficiency, and deep sleep (stages 3 and 4) (in new nomenclature N3) and a significant increase in arousals and PB [31]. These variations are possibly high altitude dependent, and the effects tend to moderate with acclimatization [6]. Hypnograms of a partially acclimatized lowlander sleeping and a native Tibetan sleeping at high altitude are shown in Figures 3 and 4.
Figure 3.
Hypnogram of a 27-year-old young man sleeping acclimatized for 11 months at altitude of 3800 m. Frequent awake, less proportion of stage 4 and REM sleep might be observed.
Figure 4.
Hypnogram of a 25-year-old native Tibetan sleeping at altitude of 3800 m. There is sufficient time in stage 4 sleep and scarce REM sleep.
Although subjective sleep quality is impaired at high altitude, attempts to find a correlation between objective and subjective measures have failed to find a connection [24]. One study investigated 63 participants who completed a 3-hour flight from sea level to the South Pole (3200 m) and discovered no association between self-reported sleep quality and sleep efficiency, nocturnal oxygen saturation, and apnea/hypopnea index (AHI) obtained from PSG [32]. When assessed by LL score, there was no significant correlation of the subjective sleep measurement compared to sleep efficiency derived from PSG and actigraphy [24]. Another study investigated 165 young male soldiers stationed in Tibet Plateau (3800 m) for at least 3 months. In a multiple regression model adjusted for age, service time, body mass index, Epworth Sleepiness Scale, anxiety, and depression, sleep onset latency (b = 0.08, 95% CI: 0.01–0.15) and NREM latency (b = 0.011, 95% CI: 0.001–0.02) obtained from PSG were slightly positively correlated with global PSQI, while mean nocturnal SpO2 (b = −0.79, 95% CI: −1.35 to −0.23) and time in stage 3 + 4 sleep (b = −0.014, 95% CI: −0.001 to −0.028) was slightly negatively associated with global PSQI [12].
5. Differences in sleep architecture between lowlanders and native highlanders at high altitude
5.1 Sleep patterns of high-altitude natives
Tibetans and Andeans are the native populations to the Tibetan and Andean Plateaus descending from colonizers. Both populations have been exposed to the hypoxic environmental stress of lifelong exposure to high altitude. But native Tibetans and Andean highlanders exhibit different ways of adaptation to chronic hypoxia [33]. Andean highlanders have blunted hypoxia ventilatory response compared to Tibetans which is thought to be acquired and developed in adolescence [34]. Native Tibetans were reported to have higher maximal oxygen uptake, greater ventilation, and brisker hypoxic ventilatory responses to adapt to the hypoxic environment at high altitude and, therefore, to have a better-quality sleep than Han lowlanders [35] which may largely be attributed to genetic adaptations [36].
Few studies had compared sleep architecture between high-altitude dwellers and non-native highlanders. An elder study investigated the Sherpa highlanders dwelling above 3500 m. The Sherpas exhibited few PB with apnea due to low ventilatory sensitivity to hypoxia at 5300 m altitude [37]. A later study reported the sleep pattern of Peruvian Andeans situated at 4330 m altitude. Sleep architecture is closely resembling to normal of people at sea level with significant amount of NREM sleep and unimpaired REM sleep [38]. Contrary to the previous reports, a recent study surveyed sleep architecture of Peruvian highlanders living in Puno at 3825 m. The highlanders had a longer time in total sleep time and increased wake-after-sleep onset and arousal index but decreased sleep efficiency, which suggest greater disturbances in sleep in highlanders compared with lowlanders [39].
5.2 Sleep architecture in partially acclimatized lowlanders
As we mentioned above, acclimatization would help lowlanders to relieve sleep disturbance after ascending to high altitude. This could be supported by an earlier study which claimed over 3 days of acclimatization over 4559 m resulted in a partial recovery of sleep structure with increases in slow wave sleep and REM sleep and a reduction in the arousal index [40].
But little is known whether prolonged hypoxia may help to improve sleep architecture at high altitude. Animal studies showed that there was a 50% reduction in the proportion of slow wave sleep and loss of REM sleep when rats were chronically exposed to hypoxia environment simulating an altitude of 5000 m [41, 42]. A clinical study conducted in Shangri-La, which has an altitude of 3800 m, surveyed the differences in sleep architecture between native Tibetans’ and Han lowlanders’ stations for at least 3 months. After adjusted for the length of stay at altitude, significant differences in lower mean nocturnal SpO2 and shorter time in NREM sleep were determined in acclimatized lowlanders than the native Tibetans [12]. Figure 5 indicates a decreased nocturnal artery oxygen of a 3-month acclimatized lowlander. So, it is reasonable to conclude that the effect of prolonged acclimatization to hypoxia is limited in relieving hypoxemia and improving deep sleep which might be an explanation for the impaired cognition brought about by poor sleep.
Figure 5.
Decreasing in artery oxygen during sleep of a 24-year lowlander acclimatized for 3 months at 3800 altitude. The lowest SaO2 is 83% and the mean SaO2 is 92%.
6. Is sleep disorder an altitude-related illness?
Studies on sleep disorder at high altitude from the above reviewed scientific literature confirm the assumption that altitude-related illness including AMS and HAPE may deteriorate sleep quality either directly or indirectly through complaints of headache, hard breathing, cough, etc. It is widely accepted that HAPE usually develops within 2–4 days after quickly ascending to high altitude, but sleep in the first night at altitude may have been affected. Both susceptible HAPE subjects and healthy mountaineers without HAPE revealed a major reduction in sleep efficiency and in NREM stage 3 and 4 sleep (in new nomenclature N3) in the first night after the ascent to 4559 m within 1 day [43]. The deteriorated ventilation and intermittent hypoxia associated with PB in the first 1–2 nights at high altitude with the associated elevation of pulmonary artery pressure may promote the subsequent development of HAPE in susceptible subjects. Thus, the occurrence of sleep disorder is prior to and/or independent of HAPE but may worsen due to HAPE.
Literature reports also provide empirical evidence that sleep disturbance was discordant from other AMS symptoms and absent in 40% of cases with severe headache, long considered a symptom of AMS. Since sleep disorder correlated poorly with other symptoms of AMS, the sleep component had been removed from the 2018 Lake Louise Acute Mountain Sickness Score [44].
Therefore, it is conceivable that sleep disorder should be viewed as an independent altitude-related illness rather than a symptom of AMS despite the fact that it may overlap other mountain sicknesses. In accordance with the nomenclature of other high-altitude diseases [e.g., high altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE), etc.], high-altitude sleep disorder (HASD) might be an appropriate name.
7. Treatment of HASD
Hypoxemia is the main reason and one of the primary independent contributors to poor sleep quality at high altitudes [12]. In theory, correction of hypoxemia by supplemental oxygen or pharmacological suppression of ventilation may have the potential in treating sleep disorder at high altitude.
7.1 Supplemental oxygen
A case report tested the treatment effect of a nasal demand oxygen delivery device on hypoxemia during sleep at high altitude in a 46-year-old male healthy participant at an altitude of 4600 and 5700 m [45]. The participant received a volume of oxygen delivery dose for 0, 16.7, 33.3, and 50 ml/s at random per pulse for every 2 h during sleep period. Results of the study indicated an increase in arterial blood oxygen saturation and decreases in tidal volume and AHI.
Another controlled trial employed a noninvasive ventilation mode named adaptive servo ventilation (ASV) to stabilize periodic breathing due to hypobaric hypoxemia at an altitude of 3800 m, but it failed to affirm its efficacy in controlling central sleep apnea during sleep. However, in their controlled group, supplemental oxygen improved oxygen desaturation index and oxygen saturation, whereas it reduced the arousal index and NREM stage 1 sleep. But neither ASV nor supplemental oxygen could improve subjective quality as measured by the Stanford Sleep Questionnaire and LL score [46].
In summary, based on current limited studies, supplemental oxygen does improve arterial blood oxygen saturation but could not result to a better sleep quality.
7.2 Diet therapy
Dietary nitrate (NO3−), which is found in beetroot and other vegetables, and inorganic NO3− salts have been shown to have vasodilatory properties [47] and also to reduce oxygen uptake during exercise [48], suggesting NO3− supplementation might play a physiological role during sleep at high altitude. A single-blind placebo-controlled trial examined the effects of dietary NO3− supplementation on the degree of sleep-related hypoxemia in healthy subjects at an altitude from 3700 to 4900 m. Each subject received two 70 ml shots of either beetroot juice (∼5.0 mmol NO3− per shot) or placebo (∼0.003 mmol NO3− per shot) over two consecutive nights at altitude. Results of the study favored dietary nitrate in increasing fluctuations in arterial O2 saturation during sleep at altitude in native lowlanders, but it does not improve AHI or oxygenation [49].
7.3 Pharmacological agents
Previous reports suggested that only a few medications may be helpful at high altitudes [50, 51], including theophylline, acetazolamide, zolpidem, zaleplon, temazepam, and integripetal rhodiola herb, a traditional Chinese herb. However, there are often several limitations on pharmacological selection at high altitudes in clinical practice, as current sleeping medications prescribed for sleep disturbances at sea level are not suggested to be used at altitude. For example, it is widely accepted that benzodiazepines (BZDs) may cause hypoventilation, triggering respiratory abnormalities during sleep [52, 53, 54]. Therefore, an ideal choice for medication use at high altitude should neither deteriorate ventilation and oxygen saturation nor affect sleep architecture.
7.3.1 Acetazolamide
Acetazolamide is considered to increase ventilation and oxygenation, effectively reducing PB by approximately 50% [55]. A meta-analysis of randomized controlled trials determined that acetazolamide improves sleep apnea at high altitude by decreasing AHI and percentage of PB time and increasing nocturnal oxygenation. Results from clinic trials also suggested that a 250 mg daily dose may be as effective as higher daily doses for healthy trekkers [56].
7.3.2 Non-benzodiazepines
The efficacy and safety of zolpidem and zaleplon in treating sleep disturbances at high altitude had been confirmed by several well-designed clinic trials [57, 58, 59, 60]. A recent meta-analysis of randomized placebo-controlled trials revealed that zaleplon and zolpidem improved the total sleep time, sleep efficiency, and stage 4 sleep duration, whereas they decreased the wake-after-sleep onset without impairing ventilation [61] (data are shown in Figure 6).
Figure 6.
Summary of non-benzodiazepines in improving sleep architecture at high altitude. Modified from Kong et al. [61].
There was no significant difference in ventilation as measured by SpO2 and PB between participants administered with zaleplon or zolpidem and placebo [58, 59, 60]. Furthermore, participants who were administered with zaleplon or zolpidem expressed a significant improvement in the subjective sleep quality, which was measured by sleep log question [59, 60] and PSQI (4.15 ± 2.76 in zolpidem group vs. 6.58 ± 3.98 in placebo group, P = 0.047) [60].
7.3.3 Benzodiazepines
Benzodiazepine use in this environment is controversial. Early studies showed that 1 mg of oral loprazolam did not worsen either slow wave sleep depression or apnea and allowed normal sleep reappearance after acclimatization [28, 62]. Later, a randomized, double-blind, placebo-controlled trial conducted at 3000 m altitude validated PaO2 decreasing and PaCO2 increasing significantly 1 hour after 5 mg of oral diazepam [63], which suggests that it may cause hypoventilation.
On the contrary, temazepam, a short-acting benzodiazepine, was recommended to be safely used by the International Climbing and Mountaineering Federation MedCom Consensus Guide [51]. However, the effect of temazepam on the objective sleep parameters was inconsistent. Nicholson et al. [64] reported that temazepam significantly shortened the mean sleep onset latency and increased the amount of the REM sleep, whereas Nickol et al. [65] reported no differences in the actigraphy-derived sleep parameters. Results on oxygen saturation and PB from the aforementioned studies were also inconsistent. When compared to the placebo, temazepam showed no significant effect on mean oxygen saturation, yet PB significantly decreased [66]. Although Nickol et al. [65] reported that temazepam could decrease median oxygen saturation, it did not significantly reduce PB during sleep. Because of the inconsistencies in the reported variables, no confirming conclusions can be drawn from available evidence.
To sum up, the use of benzodiazepines should be discouraged at high altitude due to the nocturnal hypoventilation nature of these agents. The efficacy and safety of temazepam need further confirmation by well-designed placebo-controlled trials.
7.3.4 Others
Additional drugs that may be helpful reported by case series include theophylline and the integripetal rhodiola herb, which is a widely used traditional Chinese herb in Tibetan areas. However, strong clinical evidence from randomized controlled trials supporting the effectiveness and safety of these agents has not been demonstrated.
7.4 Recommendations
Evidence from current available studies support the routing use of supplemental oxygen during sleep to increase arterial blood oxygen saturation. Acute dietary NO3− supplementation reduces flow limitation and induces more pronounced SaO2 desaturations during sleep at high altitude. Acetazolamide at 250 mg daily dose is effective in reducing sleep apnea, decreasing AHI and PB, and increasing nocturnal oxygenation. Both zaleplon and zolpidem improved the objective sleep architecture without impairing ventilation.
8. Conclusions
Our understanding on sleep disorder at high altitude is still limited. Mountain tourists commonly complain about subjective sleep disturbances with difficulty in onset of sleep and frequent awakenings in the first few nights at altitude. But those subjective sensations of poor sleep neither are associated with severity of mountain sickness nor tend to disappear after long exposure to high altitude. And consequently, cognitive function was impaired.
There is no reliable evidence that support the consistency between self-report sleep quality and sleep parameters obtained from PSG. The most frequently reported changes in sleep architecture at high altitude are detected by PSG including a decrease in NREM sleep and occurrence of PB. Different patterns of adoption to hypoxic environment exist among native highlanders. For lowlanders ascending to high altitude, acclimatization would be beneficial in relieving hypoxemia and improving deep sleep; however, PB would not be largely relieved after acclimatization.
The occurrence of HASD is prior to most altitude-related diseases and would last for a longer time. We strongly suggest future study to consider it as an independent high-altitude illness as it had been removed from the diagnosing and managing of AMS by the International Society of Mountain Medicine World Congress Committee.
The treatment principle of HASD should not deteriorate nocturnal ventilation and SaO2 or affect sleep architecture. The following evidence-based choices are recommended. Effective treatments for altitude-related nocturnal hypoxemia include dietary NO3− supplementation before sleep and supplemental oxygen during sleep. Medication for respiratory disturbance is 250 mg daily dose of oral acetazolamide, which is beneficial in relieving sleep apnea, decreasing AHI and PB, and promoting nocturnal oxygenation. Both zaleplon and zolpidem are optional agents in improving the objective sleep architecture and subjective sleep quality without impairing ventilation.
\n',keywords:"sleep architecture, sleep disorder, sleep quality, periodic breathing, high altitude, treatment",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67469.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67469.xml",downloadPdfUrl:"/chapter/pdf-download/67469",previewPdfUrl:"/chapter/pdf-preview/67469",totalDownloads:837,totalViews:0,totalCrossrefCites:2,dateSubmitted:"November 20th 2018",dateReviewed:"May 7th 2019",datePrePublished:"June 3rd 2019",datePublished:"September 15th 2021",dateFinished:"June 3rd 2019",readingETA:"0",abstract:"In this chapter, we discuss the occurrence, mechanism, clinical manifestations, outcomes, and managements of a commonly encountered sleep disorder of someone traveling in high altitude for working and sight-seeing. Humans ascending to altitudes above 2500 m usually suffer from substantial disturbances in sleep quality as difficulty in sleep onset, frequent awakenings, respiratory disturbance, and a feeling of drowsiness on the next day. Data obtained from polysomnographic studies demonstrated several variations of sleep architecture in those healthy subjects ascending to high altitude during sleep, including periodic breathing and decreased non-rapid eye movement deep sleep stage 3 and 4 (in new nomenclature N3), which were usually accompanied by and the lowered arterial O2 and restricted ventilation. Hypoxia is most severe during sleep and in correspondence to periodic breathing and sleep disturbance at high altitude. Poor sleep quality impairs cognition and executive abilities at high altitude though it may largely be improved after full time of acclimatization. Evidence-based choices for clinicians to treat sleep disorder at high altitude are relatively scarce at present. Supplemental oxygen and dietary nitrate are effective in alleviating nocturnal hypoxia. There is strong evidence supporting the efficacy and safety of acetazolamide and nonbenzodiazepines in minimizing periodic breathing and improving sleep quality at high altitude.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67469",risUrl:"/chapter/ris/67469",signatures:"Fanyi Kong",book:{id:"7076",type:"book",title:"Updates in Sleep Neurology and Obstructive Sleep Apnea",subtitle:null,fullTitle:"Updates in Sleep Neurology and Obstructive Sleep Apnea",slug:"updates-in-sleep-neurology-and-obstructive-sleep-apnea",publishedDate:"September 15th 2021",bookSignature:"Fabian H. Rossi and Nina Tsakadze",coverURL:"https://cdn.intechopen.com/books/images_new/7076.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-030-3",printIsbn:"978-1-83969-029-7",pdfIsbn:"978-1-83969-031-0",isAvailableForWebshopOrdering:!0,editors:[{id:"158927",title:"Dr.",name:"Fabian H.",middleName:null,surname:"Rossi",slug:"fabian-h.-rossi",fullName:"Fabian H. Rossi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"285948",title:"Dr.",name:"Fanyi",middleName:null,surname:"Kong",fullName:"Fanyi Kong",slug:"fanyi-kong",email:"kfy9989@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Breathing disturbance during sleep at high altitude",level:"1"},{id:"sec_3",title:"3. Poor subjective sleep quality at high altitude",level:"1"},{id:"sec_3_2",title:"3.1 Evaluation and prevalence of poor sleep quality at high altitude",level:"2"},{id:"sec_4_2",title:"3.2 Sleep quality and severity of mountain sickness",level:"2"},{id:"sec_6",title:"4. Variation of sleep architecture at high altitude",level:"1"},{id:"sec_7",title:"5. Differences in sleep architecture between lowlanders and native highlanders at high altitude",level:"1"},{id:"sec_7_2",title:"5.1 Sleep patterns of high-altitude natives",level:"2"},{id:"sec_8_2",title:"5.2 Sleep architecture in partially acclimatized lowlanders",level:"2"},{id:"sec_10",title:"6. Is sleep disorder an altitude-related illness?",level:"1"},{id:"sec_11",title:"7. Treatment of HASD",level:"1"},{id:"sec_11_2",title:"7.1 Supplemental oxygen",level:"2"},{id:"sec_12_2",title:"7.2 Diet therapy",level:"2"},{id:"sec_13_2",title:"7.3 Pharmacological agents",level:"2"},{id:"sec_13_3",title:"7.3.1 Acetazolamide",level:"3"},{id:"sec_14_3",title:"7.3.2 Non-benzodiazepines",level:"3"},{id:"sec_15_3",title:"7.3.3 Benzodiazepines",level:"3"},{id:"sec_16_3",title:"7.3.4 Others",level:"3"},{id:"sec_18_2",title:"7.4 Recommendations",level:"2"},{id:"sec_20",title:"8. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Davis PR, Pattinson KT, Mason NP, Richards P, Hillebrandt D. 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Zaleplon and zolpidem objectively alleviate sleep disturbances in mountaineers at a 3,613 meter altitude. Sleep. 2007;30:1527-1533'},{id:"B60",body:'Huang Y, Qin J, Gao X, et al. The effect and mechanism of zolpidem for improving sleep quality at high altitude. Chinese Journal of Clinical Research. 2015;28:624-627'},{id:"B61",body:'Kong F, Liu G, Xu J. Pharmacological agents for improving sleep quality at high altitude: A systematic review and meta-analysis of randomized controlled trials. Sleep Medicine. 2018;51:105-114. DOI: 10.1016/j.sleep.2018.06.017'},{id:"B62",body:'Goldenberg F, Richalet JP, Jouhandin M, Gisquet A, Keromes A, Larmignat P. Periodic respiration during sleep at high altitude. Effects of a hypnotic benzodiazepine, loprazolam. Presse Médicale. 1988;17:471-474'},{id:"B63",body:'Roggla G, Roggla M, Wagner A, Seidler D, Podolsky A. Effect of low dose sedation with diazepam on ventilatory response at moderate altitude. Wiener Klinische Wochenschrift. 1994;106:649-651'},{id:"B64",body:'Nicholson AN, Smith PA, Stone BM, Bradwell AR, Coote JH. Altitude insomnia: Studies during an expedition to the Himalayas. Sleep. 1988;11:354-361'},{id:"B65",body:'Nickol AH, Leverment J, Richards P, et al. Temazepam at high altitude reduces periodic breathing without impairing next-day performance: A randomized cross-over double-blind study. Journal of Sleep Research. 2006;15:445-454. DOI: 10.1111/j.1365-2869.2006.00558.x'},{id:"B66",body:'Dubowitz G. Effect of temazepam on oxygen saturation and sleep quality at high altitude: Rrandomised placebo controlled crossover trial. BMJ. 1998;316:587-589'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Fanyi Kong",address:"kfy9989@hotmail.com",affiliation:'
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Fiber-reinforced composite materials are lightweight, stiff, and strong. They have good fatigue and impact resistance. Their directional and overall properties can be tailored to fulfill specific needs of different end uses by changing constituent material types and fabrication parameters such as fiber volume fraction and fiber architecture. A variety of fiber architectures can be obtained by using two- (2D) and three-dimensional (3D) fabric production techniques such as weaving, knitting, braiding, stitching, and nonwoven methods. Each fiber architecture/textile form results in a specific configuration of mechanical and performance properties of the resulting composites and determines the end-use possibilities and product range. This chapter highlights the constituent materials, fabric formation techniques, production methods, as well as application areas of textile-reinforced composites. Fiber and matrix materials used for the production of composite materials are outlined. Various textile production methods used for the formation of textile preforms are explained. Composite fabrication methods are introduced. Engineering properties of textile composites are reviewed with regard to specific application areas. 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\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n
\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:229,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"2",type:"subseries",title:"Prosthodontics and Implant Dentistry",keywords:"Osseointegration, Hard Tissue, Peri-implant Soft Tissue, Restorative Materials, Prosthesis Design, Prosthesis, Patient Satisfaction, Rehabilitation",scope:"
\r\n\tThe success of dental implant treatment is not solely dependent on the osseointegration around the implant. Aside from the criteria used to describe the hard tissue response at the implant level, the success criteria in implant dentistry include three additional aspects: peri-implant soft tissue, prosthesis, and patient’s satisfaction.
\r\n
\r\n\tThe Prosthodontics and Implant Dentistry topic will provide readers with up-to-date resources on the prosthodontics factors such as aesthetics, restorative materials, the design of prosthesis, case selection, occlusion, oral rehabilitation, among others, all of which play an important role in determining the success of a well osseointegrated implant. With the help of digital dental technology, these can now be accomplished more predictably.
\r\n
\r\n\tThe end goal of prosthesis is always considered when planning successful implant placement. The readers in this field will be able to learn more about taking a holistic approach when treating their dental implant cases.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/2.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11398,editor:{id:"179568",title:"Associate Prof.",name:"Wen Lin",middleName:null,surname:"Chai",slug:"wen-lin-chai",fullName:"Wen Lin Chai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHGAQA4/Profile_Picture_2022-05-23T14:31:12.png",biography:"Professor Dr. Chai Wen Lin is currently a lecturer at the Department of Restorative Dentistry, Faculty of Dentistry of the University of Malaya. She obtained a Master of Dental Science in 2006 and a Ph.D. in 2011. Her Ph.D. research work on the soft tissue-implant interface at the University of Sheffield has yielded several important publications in the key implant journals. She was awarded an Excellent Exchange Award by the University of Sheffield which gave her the opportunity to work at the famous Faculty of Dentistry of the University of Gothenburg, Sweden, under the tutelage of Prof. Peter Thomsen. In 2016, she was appointed as a visiting scholar at UCLA, USA, with attachment in Hospital Dentistry, and involvement in research work related to zirconia implant. In 2016, her contribution to dentistry was recognized by the Royal College of Surgeon of Edinburgh with her being awarded a Fellowship in Dental Surgery. She has authored numerous papers published both in local and international journals. She was the Editor of the Malaysian Dental Journal for several years. Her main research interests are implant-soft tissue interface, zirconia implant, photofunctionalization, 3D-oral mucosal model and pulpal regeneration.",institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},editorTwo:{id:"479686",title:"Dr.",name:"Ghee Seong",middleName:null,surname:"Lim",slug:"ghee-seong-lim",fullName:"Ghee Seong Lim",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003ScjLZQAZ/Profile_Picture_2022-06-08T14:17:06.png",biography:"Assoc. Prof Dr. Lim Ghee Seong graduated with a Bachelor of Dental Surgery from University of Malaya, Kuala Lumpur in 2008. He then pursued his Master in Clinical Dentistry, specializing in Restorative Dentistry at Newcastle University, Newcastle, UK, where he graduated with distinction. He has also been awarded the International Training Fellowship (Restorative Dentistry) from the Royal College of Surgeons. His passion for teaching then led him to join the faculty of dentistry at University Malaya and he has since became a valuable lecturer and clinical specialist in the Department of Restorative Dentistry. He is currently the removable prosthodontic undergraduate year 3 coordinator, head of the undergraduate module on occlusion and a member of the multidisciplinary team for the TMD clinic. He has previous membership in the British Society for Restorative Dentistry, the Malaysian Association of Aesthetic Dentistry and he is currently a lifetime member of the Malaysian Association for Prosthodontics. Currently, he is also the examiner for the Restorative Specialty Membership Examinations, Royal College of Surgeons, England. He has authored and co-authored handful of both local and international journal articles. His main interest is in prosthodontics, dental material, TMD and regenerative dentistry.",institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},editorThree:null,series:{id:"3",title:"Dentistry",doi:"10.5772/intechopen.71199",issn:"2631-6218"},editorialBoard:null},onlineFirstChapters:{paginationCount:25,paginationItems:[{id:"82654",title:"Atraumatic Restorative Treatment: More than a Minimally Invasive Approach?",doi:"10.5772/intechopen.105623",signatures:"Manal A. 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Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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