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1. Introduction
The cerebellum plays an important role in coordinated movement, motor learning and vestibular function. Cerebellar damage results in impaired body balance and disturbance in gait and posture. The cerebellum is impaired by various genetic diseases, such as spinocerebellar ataxia and mucopolysaccharidosis, and these diseases could be good candidates for gene therapy. There are at least two challenges that should be overcome before the clinical application of gene therapy is used to treat cerebellar disorders. The first challenge results from its large size, as the cerebellum is the second largest component of the central nervous system. The cerebellum can be subdivided into three main parts: the cerebrocerebellum, the vestibulocerebellum and the spinocerebellum (see Section 2 for details). Each subdivision in the cerebellum plays a distinct role and, to attain a satisfactory rescue of the cerebellar function by gene therapy, a therapeutic gene should be delivered efficiently and extensively into the large cerebellum.
The second challenge is to deliver a gene into specific target cell populations in the cerebellum. In Parkinson\'s disease, which is caused by degeneration of nigra-striatal dopaminergic neurons, cell type-specific delivery of a therapeutic gene is a secondary matter, as the supply of sufficient amounts of dopamine, irrespective of neurons or glia, in the striatum is most critical for the functional recovery of the basal ganglia. By contrast, specific cell populations within the cerebellum, such as cerebellar Purkinje cells, Bergman glia or neurons in the deep cerebellar nuclei, are selectively impaired in most cerebellar diseases, such as spinocerebellar ataxia. Thus, affected cell types differ depending on the disease type, and the selective delivery of a therapeutic gene to a subset of affected cell types could be a key advance for rescuing cells that are degenerating from progressive damage, restoring cerebellar function and, ultimately, helping patients to recover from cerebellar ataxia.
To this end, we have developed methods that allow for Purkinje cell-specific and Bergmann glia-specific gene expression in mice by modifying the culture conditions of lentiviral vector-producing human embryonic kidney (HEK) 293FT cells in combination with cell-type-specific promoters in lentiviral vectors. Moreover, a new injection technique for efficient and widespread gene delivery into the cerebellar cortex has been devised, which takes advantage of the anatomical location of the cerebellum. Using the newly developed gene transfer method for the cerebellum, we aimed to restore the abnormal phenotypes of two types of ataxic mice, both of which are affected in Purkinje cells by different pathologies. The results showed that the efficient and widespread delivery of therapeutic genes into Purkinje cells significantly restored ataxia and morphological and functional abnormalities of these cells in mutant mice. In this chapter, we describe our method that efficiently permits the selective gene delivery to cerebellar Purkinje cells or Bergmann glia and the rescue of two examples of ataxic mice. We also describe existing problems that should be resolved for the future clinical application of lentiviral vectors to cerebellar disorders.
2. Cerebellar organization and neural circuits in the cerebellum
The cerebellum can be subdivided into three main parts based on differences in their sources of input. The largest subdivision in humans is the cerebrocerebellum, which occupies most of the lateral hemisphere and is involved in the regulation of highly skilled movements, including speech. The vestibulocerebellum is the phylogenetically oldest part of the cerebellum; it comprises the caudal lobes of the cerebellum, including the flocculus and the nodulus, and is primarily engaged in the regulation of movements underlying posture and equilibrium. The last of the major subdivisions is the spinocerebellum, which occupies the median and paramedian zone of the cerebellar hemispheres. The spinocerebellum is the only part that receives input directly from the spinal cord. The lateral part and central part (vermis) of the spinocerebellum are involved in the movements of distal and proximal muscles, respectively. The vermis also regulates eye movements in response to vestibular inputs.
The cerebellar cortex contains 5 neurons, the granule cell, the Purkinje cell and three inhibitory interneurons (stellate cell, basket cell and Golgi cell) and is divided into three morphologically distinct parts: the granule cell layer, the Purkinje cell layer, and the molecular layer (Fig. 1a and b). The granule cell layer contains numerous granule cells, in which Golgi cells are scattered. The Purkinje cell layer is a monolayer that consists of the soma of Purkinje cells and Bergmann glia; the Purkinje cells extend their well-differentiated dendrites into the molecular layer (Fig. 1c), where stellate cells and basket cells are located. The Bergmann glia also extend their processes into the molecular layer (Fig. 1b).
A major input to the cerebellar cortex are the mossy fibers, axon bundles projecting from neurons in the thalamus, the brain stem and the spinal cord (Fig. 1b). The excitation of granule cells triggered by mossy fibers is transferred through the axons called parallel fiber to Purkinje cells. One Purkinje cell has more than one hundred thousand dendritic spines (Fig. 1d, arrows), on which parallel fiber terminals make excitatory synapses. Parallel fiber - Purkinje cell synapses are tightly wrapped by processes of Bergmann glia, so as to quickly take up the glutamate released from parallel fiber terminals. In this context, the Bergmann glia prevent the prolonged excitation of Purkinje cells and the spillover of glutamate that would activate the adjacent synapses.
Another excitatory input to the cerebellar cortex is the climbing fiber that originates from neurons in the inferior olivary nucleus of the medulla oblongata. The climbing fiber makes excitatory synapses directly on proximal dendrites of Purkinje cells and neurons in the deep cerebellar nuclei. Excitatory activity of granule cells and Purkinje cells is modulated by 3 types of inhibitory interneurons: Golgi cells, stellate cells, and basket cells. The Purkinje cells eventually integrate the information entered into the cerebellar cortex and send an inhibitory signal as the sole source of output from the cerebellar cortex to neurons in the deep cerebellar nuclei.
Figure 1.
Projections to and neural circuits in the cerebellar cortex. (a) A sagittal section of the vermis of a mouse cerebellum. (b) A schematic diagram of the cerebellar cortex that enlarges the square region in (a). ML, molecular layer; PCL, Purkinje cell layer; GCL, granule cell layer. A Purkinje cell (PC) receives excitatory inputs via parallel fibers (PF) and climbing fibers (CF) and sends inhibitory signals to neurons of the deep cerebellar nuclei (DCN). GC, granule cell, MF, Mossy fiber. (c) Well-differentiated dendrites of Purkinje cells are visualized by GFP expression. (d) Dendritic spines of Purkinje cells (arrows).
3. Disorders of the cerebellum
As cerebellar defects can be easily detected from overt ataxia, such as widespread gait and motor coordination deficits, numerous types of mutant mice with cerebellar degeneration have been isolated over the past 50 years. These mutant mice have contributed significantly to the elucidation of cerebellar physiology. At present, in parallel with advances in the development of viral vectors, we may be able to restore cerebellar defects of ataxic mice by a potential therapeutic gene delivery. Such rescue experiments have significant implications in terms of the future clinical application of gene therapy for patients suffering from cerebellar diseases. The following subsections summarize the cerebellar abnormalities and genetic defects identified in ataxic mice and humans.
3.1. Spontaneously occurring ataxic mice
Table 1 summarizes well-known murine mutants that cause cerebellar impairment. Recently, the genes responsible for those mutants have been identified and include missense mutations, nonsense mutations or frameshift mutations in the causative genes. The hotfoot mice are spontaneously occurring recessive mutants (Guastavino et al., 1990) that carry mutations in Grid2, which encodes the 2 glutamate receptor (GluR2) (Wang et al., 2003). To date, more than 10 mutant alleles have been identified; among these, hotfoot5J mice have been shown to carry a point mutation in exon 12 of Grid2, which creates a stop codon in the region encoding transmembrane 3 of GluR2 protein (Wang et al., 2003). The aberrant GluR2 protein is easily degraded and is not detected in Purkinje cells of hotfoot5J mice; therefore, hotfoot5J mice are mutants lacking GluR2 function.
Table 1.
Genetic abnormalities and affected cell types in spontaneously occurring ataxic mice.
Other loss-of-function mutants are Staggerer and Purkinje cell degeneration (pcd) mice. The staggerer mutation causes a functional impairment in a transcription factor, retinoid-related orphan receptor ( (ROR(), which belongs to the nuclear receptor superfamily (Boukhtouche et al., 2006; Gold et al., 2007). Staggerer mice have a 122-base pair deletion within the ligand binding domain (LBD) of the ROR( gene (Hamilton et al., 1996). For PCD mice, 8 independent alleles have been identified, which carry genetic mutations in the Nna1 gene, encoding a putative nuclear protein (Fernandez-Gonzalez et al., 2002; Wang & Morgan, 2007). Most of the pcd alleles represent complete loss-of-function mutations. Because it is reasonable to postulate that aberrant phenotypes in loss-of-function mutants may be restored by introducing the intact gene, and, as Purkinje cells are the main cell type impaired in the loss-of-function mutants discussed here (hotfoot, staggerer and pcd), the efficient delivery of the intact gene into the specific subset of cells (Purkinje) may be a promising therapy for the recovery of those mutant mice from cerebellar degeneration and, ultimately, ataxia.
There are two important points that should be addressed. First, gene delivery should be performed before Purkinje cells are substantially lost or irreversibly damaged. Purkinje cells of pcd mice die gradually from approximately 18 days of age and are virtually lost by 4 months of age. Similarly, the Purkinje cell number in staggerer mice begins to decrease in the first week after birth, and at least 75-90% of Purkinje cells are lost in adult mutants (Vogel et al., 2000). The degeneration of Purkinje cells causes secondary defects of granule cells and neurons in the inferior olivary nucleus. Therefore, later gene delivery results in less or no functional recovery in staggerer and pcd mutants.
Another important point is that gene delivery should be carried out before the Purkinje cell loses its plasticity. The compensation of a missing gene during an inappropriate time may result in the insufficient restoration of Purkinje cell abnormalities. By the second to third postnatal week, Purkinje cells extend dendrites and make a hundred thousand synapses with different counterparts. A series of developmental processes requires the strictly regulated expression of numerous genes, suggesting that the exogenous delivery of an intact gene after termination of this period may have little therapeutic impact. This period, in which the brain displays a heightened sensitivity to exogenous stimuli (and still maintains capacity to respond to gene therapy), is referred to as the “critical period”. The critical period differs depending on the defects of the mutant animals; thus, a careful examination using animal models can provide clues to deduce the critical period for the human cerebellum.
The Lurcher (Lc) mouse is an autosomal semidominant mutant that displays the degeneration of virtually all of the cerebellar Purkinje cells (Vogel et al., 2007). In heterozygous mice (Lc/+), cerebellar Purkinje cells specifically start to degenerate in a cell-autonomous manner by postnatal day 8 (P8), and most die during the second postnatal week.; other cell types are eventually affected by secondary mechanisms (Wetts & Herrup, 1982). Lc/+ mice exhibit severe ataxia during the third postnatal week, when approximately 90% of the Purkinje cells have disappeared. Lc is caused by an alanine to threonine mutation in the highly conserved third hydrophobic segment of GluR2 (Zuo et al., 1997). As this region works as the gate of a cation channel (Kohda et al., 2000), the mutation converts the receptor into a constitutively leaky cation channel. Thus, lurcher is a gain-of-function mutation, suggesting that a simple delivery of the wild-type GluR(2 would not have a significant therapeutic impact on Lc Purkinje cells. A suppression of the mutant protein expression via, for example, RNA interference would be a promising gene therapy against disorders caused by a toxic-gain-of-function mutation.
3.2. Human cerebellar diseases potentially treatable with gene therapy
3.2.1. Spinocerebellar ataxia
The cerebellum is impaired by various diseases, including neurodegenerative and enzyme-deficient disorders. Spinocerebellar ataxia (SCA) is one of the representative diseases that affect the cerebellum. Approximately one third of the SCA in patients is hereditary. So far, at least 29 types of SCA result from chromosomal loci of the causal genes (Carlson et al., 2009), in which the major lesion of SCA type 1 (SCA1), SCA2, SCA6, SCA14, SCA17 and SCA31 affects Purkinje cells. Neurons in the deep cerebellar nuclei are impaired in SCA3, and cortical Bergmann glia are primarily degenerated in SCA7. The well-known cause of hereditary SCAs is the abnormal expansion of trinucleotide (CAG) repeats in the coding region of genes responsible for the diseases. This expansion produces mutant proteins having an abnormally expanded polyglutamine stretch, leading to the formation of nuclear aggregates with other proteins that are critical for cellular functions. This type of hereditary SCAs is called polyglutamine disease and includes SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. As these diseases are caused by the production of toxic polyglutamine proteins (polyQ), a potential therapeutic approach would be to reduce the mutant polyQ by, for example, RNA interference (Xia et al., 2004) or the facilitation of their degradation. The latter may include the enhancement of the ubiquitin-proteasome pathway (Al-Ramahi et al., 2006; Matsumoto et al., 2004; Torashima et al., 2008; Wang & Monteiro, 2007) and autophagy (Menzies et al., 2010; Menzies & Rubinsztein, 2010; Williams et al., 2006).
Autosomal dominant SCA14, characterized by severe cerebellar atrophy and ataxia, is caused by a missense mutation of the PRKCG gene, which encodes the protein kinase C (PKC) γ gene. γPKC-deficient mice show only mild ataxia and no gross morphological abnormalities in the cerebellum (Chen et al., 1995; Kano et al., 1995), suggesting that the gain-of-toxic function, rather than loss-of-function, of γPKC underlies the pathology of SCA14. Therefore, a decrease in the amount of mutant γPKC protein is thought to be an effective therapy for SCA14. Indeed, recent studies have shown the allele-specific inhibition of mutant gene expression (Alves et al., 2008; Hu et al., 2009), and such mutant allele-targeted RNA interference may result in better therapeutic efficacy.
3.2.2. Mucopolysaccharidosis
Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of undigested macromolecules in the lysosomes due to a significant decrease or a complete absence in the activity of soluble lysosomal enzymes (Neufeld, 1991). As most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme affects peripheral organs, as well as various regions of the brain, including the cerebellum. There are approximately 50 forms of inherited LSDs in humans with incidences of 1 in 7,000 live births (Haskins, 2009). LSDs are usually grouped biochemically by the accumulated metabolite into 3 subgroups: mucopolysaccharidoses (MPS), sphingolipidoses, and mucolipidoses.
The potential treatments for LSDs include bone marrow or cord blood transplantation, enzyme replacement and gene therapy. Among the LSDs, those due to soluble lysosomal enzyme deficiencies are generally considered good candidates for gene therapy. These include MPS I, MPS IIIB and Niemann-Pick AB diseases (Sands & Davidson, 2006). To overcome the blood-brain barrier (BBB), viral vectors should be applied intrathecally (Watson et al., 2006) or directly into the brain parenchyma (Dodge et al., 2005), except in neonates having an incomplete BBB (Hartung et al., 2004; Kobayashi et al., 2005). Recent studies using knockout mouse models of MPS I and Niemann-Pick type A disease have shown a significant rescue of the phenotypic manifestations of the diseases upon intravenous and intrathecal application of adeno-associated virus (AAV) or lentiviral vectors expressing a deficient enzyme (Dodge et al., 2005; Hartung et al., 2004; Kobayashi et al., 2005; Watson et al., 2006). In addition, the injection of AAV vectors expressing the deficient gene, acid sphingomyelinase, into the deep cerebellar nuclei alleviated storage accumulation and corrected behavior deficits in the mouse model of Niemann-Pick type A disease (Dodge et al., 2005). These results suggest that viral vector-based gene transfer is promising for clinical gene therapy of patients with LSDs.
4. Viral vector-mediated gene delivery to the cerebellum
Vectors derived from retrovirus, Sindbis virus, adenovirus, lentivirus and AAV are widely used for gene transfer to mammalian cells; the properties of these vectors are summarized in Table 2. Retroviral vectors can express a foreign gene only in proliferating cells because they cannot pass through the nuclear membrane of host cells: the viral genome that enters into the cytoplasm of an infected cell can access the host chromosome only when the nuclear membrane disappears during mitosis. Exploiting this unique feature of retroviral vectors, they have been used to label neural stem cells (Kageyama et al., 2003; Levison et al., 2003; Namba et al., 2007).
Table 2.
Properties of different viral vectors.
Vectors based on Sindbis virus, a member of the Togaviridae family in the alphavirus subfamily, can infect non-dividing cells, including neurons, and replication occurs entirely in the cytoplasm of the infected cell as an RNA molecule (Griffin, 1998). Therefore, a high level of gene expression starts quickly after infection. One drawback of the Sindbis virus vector is high toxicity, as infected cells deteriorate within a couple of days.
Adenoviral vectors are widely used as gene transfer vectors. They can accommodate a large gene of ~30 kb and infect both neurons and glia, with a higher tropism for glia. Therefore, adenoviral vectors have been used to modify the function of Bergmann glia (Iino et al., 2001). Adenoviral vectors can exert toxicity to infected cells by triggering immune responses, and gene expression generally lasts only for ~2 months (Terashima et al., 1997). The features of adenoviral vectors, including their high infectivity in glial cells and immunogenicity, in combination with the introduction of an apoptosis-triggering gene are often applied to the gene therapy of malignant glioma (Horowitz, 1999; Jiang et al., 2009; Parker et al., 2009; Shinoura & Hamada, 2003).
Vectors derived from lentiviruses, a genus of slow viruses of the Retroviridae family, can replicate in non-dividing neurons with little toxicity to the infected cells (Escors & Breckpot). Moreover, stable gene expression lasts for more than several years. In the cerebellum, lentiviral vectors pseudotyped with vesicular stomatitis virus glycoprotein (VSVG) can infect various types of cortical cells that include Purkinje cells, stellate cells, basket cells, Golgi cells, Bergmann glia and astrocytes (Croci et al., 2006; Torashima et al., 2006a). The properties of lentiviral vectors are described in more detail in the next section (Subsection 4.1).
AAV is a non-pathogenic, small (20 nm), icosahedral and non-enveloped virus that belongs to the genus Dependovirus of the Parvoviridae family. Similar to lentiviral vectors, it infects both dividing and non-dividing cells with very little toxicity and a minimal immune response in the infected cells. To date, a number of AAV serotypes and over one hundred AAV variants have been isolated from adenovirus stocks or from human and non-human primate tissues (Gao et al., 2005; Wu et al., 2006). For gene transfer to cerebellar cells, AAV serotype 1, serotype 2 and serotype 5 (AAV1, AAV2 and AAV5) vectors have been used for the successful transduction of Purkinje cells (Alisky et al., 2000; Hirai, 2008; Kaemmerer et al., 2000; Xia et al., 2004). Thus, lentiviral vectors and AAV vectors, which have the potential to transduce Purkinje cells with almost no substantial toxicity, are promising as gene therapy vectors for cerebellar disorders that affect Purkinje cells. Because of the lack of pathogenicity, AAV vectors are increasingly becoming the vectors of choice for a wide range of gene therapy approaches. One major limitation of AAV vectors is the insert capacity, which is less than 4.7 kb, whereas lentiviral vectors have a higher capacity, up to 8 kb, for transgene accommodation (Table 2) (Hirai, 2008).
4.1. Factors that control the tropism of lentiviral vectors for cerebellar neurons and glia
As the VSVG binds to the phospholipids that constitute cellular membranes, VSVG-pseudotyped lentiviral vectors are thought to infect mammalian cells without cell-type preference. In the cerebellar cortex, lentiviral vectors have successfully transduced Purkinje cells, three types of interneurons, Bergmann glia and astrocytes, but not granule cells. The efficient transduction of Golgi cells and astrocytes present in the granule cell layer suggest that the injected viral solution is accessible to granule cells: however, no or few transduced granule cells, if any, were detected upon injection of lentiviral vectors to the adult cerebellum in vivo (Croci et al., 2006; Torashima et al., 2006a).
The observed lentiviral tropism for Purkinje cells is affected by the serum-lot quality and cultivation period of the HEK293FT cells used for lentiviral production (Torashima et al., 2006b). A three-day culture that causes the degeneration and death of HEK293FT cells results in the production of glia-tropic lentiviral vectors. Although the mechanism underlying this phenomenon has not been clarified, increases in the protease activity in the culture medium seems to be involved because the addition of a protease inhibitor in medium reversed the shift of lentiviral tropism from Purkinje cells to Bergmann glia (our unpublished observation). These results suggest that VSVG is modulated by a protease released from dead HEK293FT cells, leading to the alteration of lentiviral tropism.
The L7/PCP2 promoter is a Purkinje cell-specific promoter, and the Gfa2 promoter works as an astrocyte-specific promoter. Therefore, the combination of the cultivation period of HEK293 FT cells for lentiviral production and the accommodation of the L7 or Gfa2 promoter into lentiviral vectors permits us to specifically transduce Purkinje cells or Bergmann glia, respectively. However, these cell-type specific promoters generally have weak promoter strength. Therefore, the modification of these promoters, by the addition of an enhancer sequence and/or a significant increase in the viral titer by ultracentrifugation, is needed to attain sufficient levels of transgene expression.
4.2. A method that enables efficient and widespread gene delivery to the cerebellum
The cerebellum is a second largest organ in the mammalian CNS. Neurodegenerative diseases and congenital enzyme deficiency usually affect the entire cerebellar cortex, ranging from the vermis to the hemisphere, lobule 1 to lobule 10.
For effective gene therapy, a wide range of therapeutic gene delivery methods is indispensable. Figure 2a is a photo of our viral injection system for the rodent brain.
The injection of viral solutions to the brain parenchyma mechanically damages the tissue around an injection site, and ~1 l is usually the limit for mouse brain regions, such as the striatum and hippocampus. However, we found that when injected at a speed of 0.2 – 0.3 l/minute, it was possible to apply 10 l of viral solution to the subarachnoidal space over lobule 6 of the cerebellar cortex (Fig. 2b) without substantial damage to the cortical tissue. Injected viral particles spread through subarachnoidal spaces and infect Purkinje cells via their well-differentiated dendrites, leading to markedly efficient transduction of the Purkinje cells (Fig. 3). We have also verified that this injection method is applicable to neonatal pups and mature mice (Fig. 2c) (Sawada et al., 2010; Torashima et al., 2006a; Torashima et al., 2006b).
5. Lentiviral vector-based rescue of mice with cerebellar ataxia
5.1. Hotfoot5J mice
Hotfoot mice are spontaneously occurring recessive mutants (Guastavino et al., 1990), and mice homozygous for the mutation showed severe ataxia with jerky tapping of the hindlimbs, which can be noted by two weeks after birth. The Hotfoot5J allele possesses a point mutation in exon 12 of the GluRδ2 gene, which creates a stop codon in the region encoding transmembrane 3 (Wang et al., 2003). Aberrant GluRδ2 protein is easily degraded and not detected in the Purkinje cells of hotfoot5J mice. Therefore, hotfoot5J mice are thought to exhibit a similar phenotype to that of GluRδ2 knock-out mice (Kashiwabuchi et al., 1995). Accordingly, we determined whether the ataxia of hotfoot5J mice could be reliably rescued by lentiviral-vector-based expression of the recombinant wild-type GluRδ2 gene (Iizuka et al., 2009).
Figure 2.
Injection of viral vectors into the mouse cerebellum. (a) A viral vector injection setup. Viral vectors are injected very slowly with a speed of 0.2-0.3 l/minute using an ultramicropump. (b) A schematic of the sagittal view of a mouse cerebellum depicting a viral injection site. (c) A schematic showing the availability of this injection method from a neonatal pup to a mature mouse.
Figure 3.
Highly efficient transduction of Purkinje cells. Lentiviral vectors expressing GFP was injected as shown in Fig. 2. (a and b) Stereoscopic images of GFP fluorescence (a) and the superimposition with the whole brain (b) 7 days after the viral injection. (c) A GFP fluorescent image of Purkinje cells in the sagittal section.
Lentiviral vectors expressing GluRδ2 plus GFP or GFP alone were injected into lobule 6 of the hotfoot5J cerebella at P6, and the motor control ability was assessed at P30 by footprints and a rotarod test. The footprint pattern of mutant mice was markedly ameliorated by the expression of GluRδ2 plus GFP (Fig. 4).
Figure 4.
Footprints of wild-type and hotfoot5J mice at P30. Ink was placed on the hindpaws of a non-injected wild-type mouse, a non-injected hotfoot5J mouse and hotfoot5J mice treated with GluRδ2 plus GFP (+ GluRδ2 & GFP); their footprints are shown. N.I., non-injected.
Figure 5.
Rescue of rotarod performance of hotfoot5J mice treated with GluRδ2 plus GFP. (a and b) Mice were assessed by two different tasks, an accelerating rod that reached 40 rpm from 0 rpm in 3 min (a) and a stably rotating rod with a speed of 10 rpm (b). The results of non-injected wild-type mice, non-injected hotfoot5J mice and hotfoot5J mice injected with lentiviral vectors expressing GluRδ2 plus GFP or GFP alone are presented. Asterisks indicate statistically significant differences compared with non-injected hotfoot5J mice: *p < 0.05, ***p < 0.001 (One-way ANOVA).
In the rotarod analysis, mice treated with GluRδ2 plus GFP showed significantly better performance at both acceleration and fixed-rod-speed tasks than non-injected mutant mice (Fig. 5), whereas neither the footprint pattern (not presented) nor the rotarod performance (Fig. 5) of hotfoot5J mice was altered by the injection of lentiviral vectors expressing only GFP. However, the rescue of ataxia by GluRδ2 expression was obviously incomplete; GluRδ2-treated hotfoot5J mice showed far poorer rotarod performance, particularly in the accelerating rod task (Fig. 5a), than wild-type mice. This was due partly to the expression of recombinant GluRδ2 in restricted lobules of hotfoot5J cerebellum.
Following the immunohistochemical examination, the GluRδ2 immunoreactivity was absent in the Purkinje cells from the non-injected hotfoot5J mice, whereas efficient GluRδ2 expression was detected in the dendritic spines of Purkinje cells from hotfoot5J mice treated with lentiviral vectors expressing GluRδ2 plus GFP.
Figure 6.
Rescue from the persistent multiple CF innervation of hotfoot5J Purkinje cells by GluRδ2 expression. (a) Representative CF-EPSCs recorded from Purkinje cells clamped at −10 mV in non-injected wild-type, non-injected hotfoot5J, GluRδ2/GFP-treated hotfoot5J, and GFP-expressing hotfoot5J mice are shown. Scale bar, 500 pA, 10 ms. (B) Frequency histograms of Purkinje cells in terms of the number of discrete CF-EPSC steps in Purkinje cells from non-injected wild-type (42 cells, 3 animals), non-injected hotfoot5J (48 cells, 4 animals), GluRδ2/GFP-treated hotfoot5J (35 cells, 3 animals), and GFP-expressing hotfoot5J (40 cells, 3 animals) mice. N.I., non-injected.
Previous electrophysiological studies indicated that the multiple climbing fiber innervation of Purkinje cells continued even after maturation in the GluRδ2 knockout mice. GluRδ2-/- Purkinje cells were innervated persistently by multiple climbing fibers (Hashimoto et al., 2001; Ichikawa et al., 2002; Kashiwabuchi et al., 1995), and we examined whether the multiple innervations of hotfoot5J Purkinje cells were restored by the expression of recombinant GluRδ2 using a patch-clamp technique. Only 18% of the Purkinje cells in P31-P35 wild-type mice, and more than 60% of the Purkinje cells from age-matched GluRδ2-null mice, were innervated by multiple climbing fibers (Fig. 6). The failure of the developmental removal of surplus climbing fibers was completely rescued by the lentiviral vector-mediated expression of GluRδ2 plus GFP. However, no significant rescue was observed in hotfoot5J cerebella expressing GFP alone. These results suggest a therapeutic potential of lentiviral vector-based gene therapy for cerebellar disorders that result from a loss-of-function gene mutation.
5.2. The SCA model mice
Polyglutamine diseases, including several autosomal dominant types of SCA, are inherited neurodegenerative diseases caused by expanded polyQ accumulation in neurons (Koshy & Zoghbi, 1997). Recent studies have identified proteins that facilitate the degradation of polyQ aggregates through a ubiquitin-proteasome pathway in cultured cells. Previously, Yanagi and colleagues have identified a novel guanosine triphosphatase (GTPase), CRAG, as one of those proteins. Furthermore, these authors have shown that CRAG triggers the nuclear translocation of a CRAG-polyQ complex, leading to the degradation of polyQ in HeLa cells (Qin et al., 2006). Because the expression of CRAG decreases in the adult brain, it is plausible that a reduced level of CRAG could underlie the onset of polyglutamine diseases. Therefore, we examined the potential of CRAG expression for treating polyglutamine disease and tested our hypothesis by lentivirally introducing CRAG into the cerebellar neurons of mice overexpressing polyQ in the cerebellum.
Figure 7.
Severe cerebellar atrophy in the PolyQ mouse at P21 and P80. (a) A schematic depicting the transgene that drives the mutant ataxin-3(Q69) under the control of the L7 promoter; an HA-tag was fused at the N-terminus of the truncated ataxin-3. Wild-type (b d, and f) and SCA3 model (c, e, and g) mice were fixed at P21 (b and c) or P80 (d-g). (b-e) A dorsal view of the whole brain; cerebella are indicated by arrows. Cb; cerebrum, IC; inferior colliculus, SC; superior colliculus, Sp; spinal cord. (f and g) Klüver–Barrera staining of sagittal sections of the cerebellum from a P80 SCA3 model mouse (g) and a wild-type littermate (f). Scale bars, 500 µm.
For this project, we generated transgenic mice (SCA model mice) expressing an expanded polyQ in cerebellar Purkinje cells using a truncated form of human ataxin-3, the gene responsible for Machado-Joseph disease (SCA3) with 69 CAG triplet repeats (ataxin-3[Q69]) (Kawaguchi et al., 1994; Yoshizawa et al., 2000) (Fig. 7a). The transgene expression was driven by a Purkinje cell-specific L7 promoter (Hirai et al., 2005). The SCA model mice started to show ataxic gait at approximately P10, which became more obvious as they developed further.
The cerebella of SCA model mice at P21 and P80 were substantially smaller than that of wild-type littermates (Fig. 7b-g). A low magnification of the sagittal sections of the SCA model mouse cerebellum showed that the overall structure of the cortex was not grossly affected (Fig. 7g). However, examination at a higher magnification revealed that the Purkinje cells were markedly disarranged, concomitant with a substantial impairment of dendritic differentiation (Fig. 8).
Figure 8.
Drastic morphological alteration in Purkinje cells of the SCA3 model mouse. Cerebellar sections from a P21 SCA3 model mouse (a) and a wild-type littermate (b) immunolabeled for calbindin. Note the markedly decreased thickness of the molecular layer and disarrangement of the Purkinje cell soma in the SCA3 model mouse cerebellum. Scale bar, 50 m.
Immunostaining of the cerebellar sections for the hemagglutinin (HA)-tag at the N-terminus of polyQ revealed a weak and diffuse accumulation of polyQ mainly in the nucleus of Purkinje cells at P21. The polyQ was markedly increased and formed numerous inclusion bodies in or around the Purkinje cell bodies by P80. In addition to the immunoreactivity in the Purkinje cell layer, small inclusion bodies with strong immunoreactivity for polyglutamine and ubiquitin were detected in the axon terminals of the Purkinje cells in the deep cerebellar nuclei.
Lentiviral vectors expressing CRAG GTPase were injected into the midline cerebellar lobules of P21-P25 mice. The effect of CRAG or GFP expression was assessed by a rotarod test, in which mice were challenged with an accelerating rod paradigm just before or 4 or 8 weeks after the viral injection (Fig. 9a). The rotarod performance of the non-injected SCA3 model mice and the model mice expressing GFP alone deteriorated slightly at 8 weeks. In contrast, the performance of mice treated with CRAG was significantly improved at both 4 and 8 weeks after the injection, as compared with the results of non-injected mice. To examine the effect of CRAG expression on motor learning, mice were evaluated again by a rotarod test with a different paradigm, in which the rod speed was fixed at 5 rpm, and the trial was repeated 6 times. Non-injected SCA3 model mice and those treated with GFP showed almost no improvement in the performance even at the 6th trial (Fig. 9b). In contrast, mice treated with CRAG learned quickly how to stay on the rod, indicating the rescue of motor learning ability.
Figure 9.
Rescue of the ataxic phenotype in polyQ mice upon the lentivector-mediated expression of CRAG. (a and b) Results of the rotarod test. The rod was accelerated from 0 rpm and reached the maximum speed (40 rpm) in 3 min, as depicted above the graph (a). Mice treated with wild-type CRAG, but not those treated with GFP, exhibited significant improvement (a) (n = number of individual mice in each cohort). In the stable rod speed paradigm (5 rpm) administered 8 weeks after the injection, mice treated with CRAG learned quickly how to walk on the rod and showed a drastically better performance, compared with the non-injected and GFP-expressing mice (b). *p<0.05, **p<0.01, ***p<0.001, compared with results of non-injected mice.
We next examined the cerebellar sections from untreated mice or mice treated with the lentiviral vectors by immunohistochemistry. Whereas strong labeling with numerous polyQ inclusions was observed in the cerebellar slices from non-injected polyQ mice and those injected with virus expressing GFP, the overall labeling with an anti-HA antibody for polyQ was faint and diffusely distributed in the cytoplasm and nuclei of the Purkinje cells in CRAG-expressing slices (Fig. 10a-d). Notably, the arrangement and dendritic differentiation of the Purkinje cells was altered upon the expression of CRAG. Double immunolabeling for calbindin and Flag-tag fused with CRAG showed that only the CRAG-expressing Purkinje cells extended dendrites. Consistently, the molecular layer was significantly wider in the cerebella of polyQ mice treated with CRAG than in those of non-injected animals (p<0.01, Fig. 10e). These in vivo data substantiated previous cell-culture-based results and further extended the usefulness of the targeted delivery of genes facilitating the ubiquitin-proteasome pathway as a gene therapy against polyglutamine diseases and other neurodegenerative disorders.
Figure 10.
Degradation of polyQ aggregates in Purkinje cells by lentiviral-vector-mediated expression of CRAG. (a-d) Cerebellar sections from mice receiving no injection (a and b) or treated with CRAG (c and d). Upper panels are fluorescent images of polyQ immunolabeled for HA (green), which were merged with those of Purkinje cells immunolabeled for calbindin (magenta, lower panels). ML; molecular layer, PL; Purkinje cell layer. (e) A graph of the thickness of the molecular layer. The thickness of the molecular layer in the cerebellum from SCA3 model mice (Tg) treated without (Non-injected) or with CRAG and their wild-type littermates (WT) was measured, and the data were plotted on the graph. The average ± SD is presented beside the each plot. Three animals in each experimental group and virus vectors obtained from at least two independent cultures were used for quantitative analysis. Asterisks indicate significant differences compared with results of non-injected mice, **p<0.01.
6. Underlying problems for the clinical application of lentiviral vectors to cerebellar diseases
6.1. The significantly larger size of human cerebellum compared with the mouse cerebellum
Figure 11 is a comparison of the mouse cerebellum with that of the cynomolgus monkey. Although our injection method allowed us to deliver a transgene very efficiently to mouse cerebellar cells, the human cerebellum is much larger than that of the cynomolgus monkey. Therefore, it is a tremendous challenge to attain the efficient transduction of Purkinje cells in the human cerebellum. To overcome this volume problem, we are exploring ways to increase the amount of the viral solution from 10 l to 1,000 l and the number of injection sites from one to, for example, three points.
Figure 11.
Comparison of the mouse cerebellum (right) with that of the cynomolgus monkey (left).
6.2. Side effects that might be caused by the use of lentiviral vectors
6.2.1. Toxicity of lentiviral vector infection on Purkinje cells
Infection with Borna disease virus, an RNA virus tropic for cerebellar neurons, has been shown to cause developmental, neuroanatomical and behavioral abnormalities (Rubin et al., 1999). HIV infection has also been shown to cause a decreased expression of mRNA and protein of AMPA-type glutamate receptors in cerebellar Purkinje cells (Everall et al., 1995). Compared with adenoviral vectors that have immunogenicity, lentiviral vectors cause almost no immune responses to infected cells and are thought to exert little toxicity on host cells. However, it has not been fully clarified whether the infection of high-titer lentiviral vectors lacks an adverse influence on neurons in vivo. To clarify the influence of high-titer lentiviral vector infection and the subsequent expression of the transgene, we injected lentiviral vectors having a titer of 1.0 x 1010 transduction units (TUs) into the neonatal rat cerebellum. Neonates were used for examining lentiviral toxicity because the brain is extremely vulnerable to developmental damage following perinatal insult.
Lentiviral vectors expressing GFP under the control of the murine stem cell virus (MSCV) promoter were injected into the cerebellar cortex of neonatal rat pups. Three weeks after treatment, the GFP-expressing Purkinje cells were compared with control Purkinje cells from phosphate-buffered, saline-injected mice. An analysis of the dendritic tree showed that the total dendrite length in the GFP-expressing Purkinje cells was almost 80% of that in the control Purkinje cells. Furthermore, an electrophysiological examination showed that the short-term synaptic plasticity at the parallel fiber–Purkinje cell synapses and climbing fiber–Purkinje cell synapses was significantly altered in the GFP-expressing Purkinje cells. In contrast, the morphological and functional maldevelopment of infected Purkinje cells was attenuated substantially when lentiviral vectors with much weaker promoter activity were used. These results suggest that the maldevelopment of the Purkinje cells was caused mainly by the subsequent expression of a high amount of GFP driven by the strong MSCV promoter and that the toxic influence of lentiviral vector infection itself was minimal.
6.2.2. Insertional mutagenesis
Upon infection of a retrovirus into a cell, the viral RNA is inserted into the cytoplasm, where the RNA is reverse-transcribed into DNA by reverse transcriptase, which is then inserted into the host genome by an integrase. The viral genome sequence integrated into the host chromosome is called a “provirus”. The provirus insertion may disrupt regions of the host genome that are critical for cellular functions, such as the control of the cell cycle or apoptosis; this process is called “insertional mutagenesis”. In fact, ex vivo gene therapy using a murine leukemia virus (MLV) vector caused leukemia in 3 of the 11 children that were being treated for X-linked SCID (Hacein-Bey-Abina et al., 2003). However, lentiviral vectors are considered to be less likely to disturb the regulation and expression of host genes because of a difference of integration sites between the MLV vectors and lentiviral vectors: MLV vectors integrate primarily in promoter regions and CpG islands, whereas lentiviral vectors integrate into transcriptionally active genes (Mitchell et al., 2004; Schroder et al., 2002). Although it is not clear whether insertional mutagenesis can lead to the transformation of postmitotic neurons, lentiviral vectors do infect and cause insertional mutagenesis in glial cells with proliferative properties. Therefore, the risk of insertional mutagenesis should be considered when lentiviral vectors are used clinically to treat neurological diseases (Jakobsson & Lundberg, 2006).
7. Conclusion
The cerebellum develops significantly after birth (Goldowitz & Hamre, 1998), and, therefore, the expression of various genes is strictly regulated. Cerebellar granule cell precursors that proliferate vigorously in the external granule cell layer migrate along the processes of Bergmann glia to form the internal granule cell layer during the first postnatal two weeks in rodents. The migrating granule cells supply trophic factors, such as brain-derived neurotrophic factor (BDNF), which stimulates the Purkinje cells to form differentiated dendrites (Schwartz et al., 1997). During the migration process, parallel fibers, granule cell axons, (Granule cell axons are called “parallel fibers”) make synapses with extending dendrites of Purkinje cells. Synaptic clefts between the parallel fibers and dendritic spines of a Purkinje cell are wrapped by processes of Bergmann glia that reuptake released glutamate, thereby modulate the synaptic transmission. Thus, 5 neurons and Bergmann glia in the cerebellar cortex concertedly elaborate the functional cerebellar neuronal circuit. One attractive therapy against diseases that impair Purkinje cells is the transplantation of Purkinje cells or their precursors engineered from stem cells into the damaged cerebellum. However, unless other cells surrounding Purkinje cells, such as the granule cells and interneurons, have sufficient plasticity, the transplanted Purkinje cells are not properly integrated to form a functional network, resulting in little therapeutic impact.
In contrast, gene therapy aims to salvage degenerating Purkinje cells by delivering a therapeutic gene. Accordingly, when Purkinje cells are not lost, this approach is theoretically more effective than stem cell-based cell replacement therapy for diseases that impair Purkinje cells; this is despite the fact that the surrounding cells have only limited plasticity. To attain sufficient therapeutic efficacy in gene therapy, the broad and efficient gene delivery to cerebellar neuronal or glial cells is indispensable, and this has been a significant challenge for decades. However, the problem is being solved by recent marked progress in both lentiviral and AAV vectors. The further accumulation of knowledge, including therapeutic genes and the critical period corresponding to distinct cerebellar defects, along with the development of animal models, would facilitate the clinical application of viral vector-based gene therapy for patients with various cerebellar disorders.
Acknowledgments
This work was supported by KAKENHI (19670003) and the Funding Program for Next Generation World-Leading Researchers (LS021).
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Introduction",level:"1"},{id:"sec_2",title:"2. Cerebellar organization and neural circuits in the cerebellum",level:"1"},{id:"sec_3",title:"3. Disorders of the cerebellum",level:"1"},{id:"sec_3_2",title:"3.1. Spontaneously occurring ataxic mice",level:"2"},{id:"sec_4_2",title:"3.2. Human cerebellar diseases potentially treatable with gene therapy",level:"2"},{id:"sec_4_3",title:"3.2.1. Spinocerebellar ataxia",level:"3"},{id:"sec_5_3",title:"3.2.2. Mucopolysaccharidosis",level:"3"},{id:"sec_8",title:"4. Viral vector-mediated gene delivery to the cerebellum",level:"1"},{id:"sec_8_2",title:"4.1. Factors that control the tropism of lentiviral vectors for cerebellar neurons and glia",level:"2"},{id:"sec_9_2",title:"4.2. A method that enables efficient and widespread gene delivery to the cerebellum",level:"2"},{id:"sec_11",title:"5. Lentiviral vector-based rescue of mice with cerebellar ataxia",level:"1"},{id:"sec_11_2",title:"5.1. Hotfoot5J mice",level:"2"},{id:"sec_12_2",title:"5.2. The SCA model mice",level:"2"},{id:"sec_14",title:"6. Underlying problems for the clinical application of lentiviral vectors to cerebellar diseases",level:"1"},{id:"sec_14_2",title:"6.1. The significantly larger size of human cerebellum compared with the mouse cerebellum",level:"2"},{id:"sec_15_2",title:"6.2. Side effects that might be caused by the use of lentiviral vectors",level:"2"},{id:"sec_15_3",title:"6.2.1. Toxicity of lentiviral vector infection on Purkinje cells",level:"3"},{id:"sec_16_3",title:"6.2.2. Insertional mutagenesis",level:"3"},{id:"sec_19",title:"7. Conclusion",level:"1"},{id:"sec_20",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Al-RamahiI.LamY. C.ChenH. K.de GouyonB.ZhangM.PerezA. M.et al.2006CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem,\n\t\t\t\t\t281362671426724'},{id:"B2",body:'AliskyJ. M.HughesS. M.SauterS. L.JollyD.DubenskyT. W.Jr StaberP. 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Gunma University Graduate School of Medicine, Japan
Gunma University Graduate School of Medicine, Japan
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Greene and Noel G. McElvaney",authors:[{id:"39463",title:"Dr.",name:"Catherine",middleName:"M.",surname:"Greene",fullName:"Catherine Greene",slug:"catherine-greene"},{id:"42784",title:"Prof.",name:"Noel G.",middleName:null,surname:"McElvaney",fullName:"Noel G. McElvaney",slug:"noel-g.-mcelvaney"}]},{id:"17781",title:"Critical Stages in the Development of the First Targeted, Injectable Molecular-Genetic Medicine for Cancer",slug:"critical-stages-in-the-development-of-the-first-targeted-injectable-molecular-genetic-medicine-for-c",totalDownloads:1694,totalCrossrefCites:0,signatures:"Erlinda M. Gordon and Frederick L. Hall",authors:[{id:"41830",title:"Prof.",name:"Erlinda",middleName:"Maria",surname:"Gordon",fullName:"Erlinda Gordon",slug:"erlinda-gordon"},{id:"52254",title:"Dr.",name:"Frederick",middleName:null,surname:"Hall",fullName:"Frederick Hall",slug:"frederick-hall"}]}]},relatedBooks:[{type:"book",id:"224",title:"Gene Therapy",subtitle:"Developments and Future Perspectives",isOpenForSubmission:!1,hash:"2ac914d87083789b03d84f122a49daca",slug:"gene-therapy-developments-and-future-perspectives",bookSignature:"Chunsheng Kang",coverURL:"https://cdn.intechopen.com/books/images_new/224.jpg",editedByType:"Edited by",editors:[{id:"32217",title:"Prof.",name:"Chunsheng",surname:"Kang",slug:"chunsheng-kang",fullName:"Chunsheng Kang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"17705",title:"New Vectors for Stable and Safe Gene Modification",slug:"new-vectors-for-stable-and-safe-gene-modification",signatures:"Francisco Martín, Karim Benabdellah, Marién Cobo, Pilar Muñoz, Per Anderson and Miguel G. Toscano",authors:[null]},{id:"17706",title:"Gene Therapy Using RNAi",slug:"gene-therapy-using-rnai",signatures:"Yu-Lin Yang , Wen- Teng Chang and Yuan-Wei Shih",authors:[{id:"33451",title:"Prof.",name:"Yu-Lin",middleName:null,surname:"Yang",fullName:"Yu-Lin Yang",slug:"yu-lin-yang"},{id:"73493",title:"Dr.",name:"Wen- Teng",middleName:null,surname:"Chang",fullName:"Wen- Teng Chang",slug:"wen-teng-chang"},{id:"73494",title:"Dr.",name:"Yuan-Wei",middleName:null,surname:"Shih",fullName:"Yuan-Wei Shih",slug:"yuan-wei-shih"}]},{id:"17707",title:"Scalable Technology to Produce Pharmaceutical Grade Plasmid DNA for Gene Therapy",slug:"scalable-technology-to-produce-pharmaceutical-grade-plasmid-dna-for-gene-therapy",signatures:"Odalys Ruiz, Miladys Limonta, Jorge Valdés, Martha Pupo and Eduardo Martnez",authors:[{id:"33539",title:"Dr.",name:"Odalys",middleName:"Hernández",surname:"Ruiz",fullName:"Odalys Ruiz",slug:"odalys-ruiz"},{id:"37053",title:"MSc.",name:"Miladys",middleName:null,surname:"Limonta",fullName:"Miladys Limonta",slug:"miladys-limonta"},{id:"37054",title:"MSc.",name:"Jorge",middleName:null,surname:"Valdés",fullName:"Jorge Valdés",slug:"jorge-valdes"},{id:"37055",title:"MSc.",name:"Martha",middleName:null,surname:"Pupo",fullName:"Martha Pupo",slug:"martha-pupo"},{id:"37056",title:"Dr.",name:"Eduardo",middleName:null,surname:"Martnez",fullName:"Eduardo Martnez",slug:"eduardo-martnez"}]},{id:"17708",title:"Small interfering RNAs: heralding a new era in gene therapy",slug:"small-interfering-rnas-heralding-a-new-era-in-gene-therapy",signatures:"Maro Bujak, Ivana Ratkaj, Mirela Baus Lončar, Radan Spaventi and Sandra Kraljevic Pavelic",authors:[{id:"39895",title:"Dr.",name:"Sandra",middleName:null,surname:"Kraljevic Pavelic",fullName:"Sandra Kraljevic Pavelic",slug:"sandra-kraljevic-pavelic"},{id:"91862",title:"BSc.",name:"Maro",middleName:null,surname:"Bujak",fullName:"Maro Bujak",slug:"maro-bujak"},{id:"91864",title:"Dr.",name:"Ivana",middleName:null,surname:"Ratkaj",fullName:"Ivana Ratkaj",slug:"ivana-ratkaj"},{id:"91865",title:"Dr.",name:"Mirela",middleName:null,surname:"Baus Lončar",fullName:"Mirela Baus Lončar",slug:"mirela-baus-loncar"},{id:"91868",title:"Prof.",name:"Radan",middleName:null,surname:"Spaventi",fullName:"Radan Spaventi",slug:"radan-spaventi"}]},{id:"17709",title:"MiRNAs-based Gene Therapy on the Horizon: Novel and Effective Therapeutic Advancement",slug:"mirnas-based-gene-therapy-on-the-horizon-novel-and-effective-therapeutic-advancement",signatures:"Mohammad Reza Noori-Daloii and Azim Nejatizadeh",authors:[{id:"42950",title:"Prof.",name:"Mohammad Reza",middleName:null,surname:"Noori-Daloii",fullName:"Mohammad Reza Noori-Daloii",slug:"mohammad-reza-noori-daloii"},{id:"94601",title:"Dr",name:"Azim",middleName:null,surname:"Nejatizadeh",fullName:"Azim Nejatizadeh",slug:"azim-nejatizadeh"}]},{id:"17710",title:"Gene Therapy Strategies Incorporating Large Transgenes",slug:"gene-therapy-strategies-incorporating-large-transgenes",signatures:"Jennifer Johnston, Christopher B. Doering and H. Trent Spencer",authors:[{id:"45593",title:"Dr.",name:"H. Trent",middleName:null,surname:"Spencer",fullName:"H. Trent Spencer",slug:"h.-trent-spencer"}]},{id:"17711",title:"Recent Advances and Improvements in the Biosafety of Gene Therapy",slug:"recent-advances-and-improvements-in-the-biosafety-of-gene-therapy",signatures:"Jaichandran Sivalingam and Oi Lian Kon",authors:[{id:"44534",title:"Dr.",name:"Oi Lian",middleName:null,surname:"Kon",fullName:"Oi Lian Kon",slug:"oi-lian-kon"},{id:"44855",title:"Mr.",name:"Jaichandran",middleName:null,surname:"Sivalingam",fullName:"Jaichandran Sivalingam",slug:"jaichandran-sivalingam"}]},{id:"17712",title:"Impacts of DNA Microarray Technology in Gene Therapy",slug:"impacts-of-dna-microarray-technology-in-gene-therapy",signatures:"Jaleh Barar, Amir Ata Saei and Yadollah Omidi",authors:[{id:"33200",title:"Dr.",name:"Yadollah",middleName:null,surname:"Omidi",fullName:"Yadollah Omidi",slug:"yadollah-omidi"},{id:"33354",title:"Dr.",name:"Jaleh",middleName:null,surname:"Barar",fullName:"Jaleh Barar",slug:"jaleh-barar"},{id:"33355",title:"Dr.",name:"Amir Ata",middleName:null,surname:"Saei",fullName:"Amir Ata Saei",slug:"amir-ata-saei"}]},{id:"17713",title:"Hopes and Disillusions in Therapeutic Targeting of Intercellular Communication in Cancer.",slug:"hopes-and-disillusions-in-therapeutic-targeting-of-intercellular-communication-in-cancer-",signatures:"Mustapha Kandouz",authors:[{id:"35004",title:"Dr.",name:"Mustapha",middleName:null,surname:"Kandouz",fullName:"Mustapha Kandouz",slug:"mustapha-kandouz"}]},{id:"17714",title:"Promising Role of Engineered Gene Circuits in Gene Therapy",slug:"promising-role-of-engineered-gene-circuits-in-gene-therapy",signatures:"Wei-Dong Wang and Jinyi Lang",authors:[{id:"28244",title:"Dr.",name:"Wei-Dong",middleName:null,surname:"Wang",fullName:"Wei-Dong Wang",slug:"wei-dong-wang"},{id:"45231",title:"Dr.",name:"Jinyi",middleName:null,surname:"Lang",fullName:"Jinyi Lang",slug:"jinyi-lang"}]},{id:"17715",title:"Comparison of DNA Delivery and Expression Using Frequently Used Delivery Methods",slug:"comparison-of-dna-delivery-and-expression-using-frequently-used-delivery-methods",signatures:"Sara Collins, David Morrissey, Simon Rajendran, Garrett Casey, Martina Scallan, Patrick Harrison, Gerald O’Sullivan and Mark Tangney",authors:[{id:"32919",title:"Dr.",name:"Mark",middleName:null,surname:"Tangney",fullName:"Mark Tangney",slug:"mark-tangney"},{id:"46562",title:"Prof.",name:"Sara",middleName:null,surname:"Collins",fullName:"Sara Collins",slug:"sara-collins"},{id:"46563",title:"Dr.",name:"David",middleName:null,surname:"Morrissey",fullName:"David Morrissey",slug:"david-morrissey"},{id:"46564",title:"Prof.",name:"Simon",middleName:null,surname:"Rajendran",fullName:"Simon Rajendran",slug:"simon-rajendran"},{id:"46565",title:"Prof.",name:"Garrett",middleName:null,surname:"Casey",fullName:"Garrett Casey",slug:"garrett-casey"},{id:"46566",title:"Dr.",name:"Martina",middleName:null,surname:"Scallan",fullName:"Martina Scallan",slug:"martina-scallan"},{id:"46567",title:"Dr.",name:"Patrick",middleName:null,surname:"Harrison",fullName:"Patrick Harrison",slug:"patrick-harrison"},{id:"46568",title:"Prof.",name:"Gerald",middleName:null,surname:"O’Sullivan",fullName:"Gerald O’Sullivan",slug:"gerald-o'sullivan"}]},{id:"17716",title:"Preclinical and Clinical Prospects of Gene Therapy in Myocardial Infarction",slug:"preclinical-and-clinical-prospects-of-gene-therapy-in-myocardial-infarction",signatures:"Saurabh Bharti, Ashok Kumar Sharma, Bhaskar Krishnamurthy and Dharamvir Singh Arya",authors:[{id:"41294",title:"Prof.",name:"Dharamvir",middleName:"S",surname:"Arya",fullName:"Dharamvir Arya",slug:"dharamvir-arya"},{id:"106805",title:"Dr.",name:"Saurabh",middleName:null,surname:"Bharti",fullName:"Saurabh Bharti",slug:"saurabh-bharti"}]},{id:"17717",title:"Gene Therapy for Therapeutic Angiogenesis",slug:"gene-therapy-for-therapeutic-angiogenesis",signatures:"Rudolf Kirchmair",authors:[{id:"41854",title:"Prof.",name:"Rudolf",middleName:null,surname:"Kirchmair",fullName:"Rudolf Kirchmair",slug:"rudolf-kirchmair"}]},{id:"17718",title:"Cancer Gene Therapy- Developments and Future Perspectives",slug:"cancer-gene-therapy-developments-and-future-perspectives",signatures:"David Good, Wei Duan, Jozef Anné and Ming Wei",authors:[{id:"28459",title:"Prof.",name:"Ming",middleName:null,surname:"Wei",fullName:"Ming Wei",slug:"ming-wei"},{id:"118655",title:"Dr.",name:"David",middleName:null,surname:"Good",fullName:"David Good",slug:"david-good"},{id:"118996",title:"Prof.",name:"Jozef",middleName:null,surname:"Anné",fullName:"Jozef Anné",slug:"jozef-anne"},{id:"118997",title:"Prof.",name:"Wei",middleName:null,surname:"Duan",fullName:"Wei Duan",slug:"wei-duan"}]},{id:"17719",title:"Differential Gene Expression and Its Possible Therapeutic Implications",slug:"differential-gene-expression-and-its-possible-therapeutic-implications",signatures:"Safdar Ali and Sher Ali",authors:[{id:"33032",title:"Dr.",name:"Sher",middleName:null,surname:"Ali",fullName:"Sher Ali",slug:"sher-ali"},{id:"39116",title:"Dr.",name:"Safdar",middleName:null,surname:"Ali",fullName:"Safdar Ali",slug:"safdar-ali"}]},{id:"17720",title:"Engineered Drug Resistant Cell-Mediated Immunotherapy",slug:"engineered-drug-resistant-cell-mediated-immunotherapy",signatures:"H.Trent Spencer and Anindya Dasgupta",authors:[{id:"45593",title:"Dr.",name:"H. Trent",middleName:null,surname:"Spencer",fullName:"H. Trent Spencer",slug:"h.-trent-spencer"},{id:"45598",title:"Dr.",name:"Anindya",middleName:null,surname:"Dasgupta",fullName:"Anindya Dasgupta",slug:"anindya-dasgupta"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"64063",title:"Fiber Bragg Gratings as e-Health Enablers: An Overview for Gait Analysis Applications",doi:"10.5772/intechopen.81136",slug:"fiber-bragg-gratings-as-e-health-enablers-an-overview-for-gait-analysis-applications",body:'\n
\n
1. Fiber Bragg gratings: an introduction
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Fiber Bragg gratings (FBGs) are sensing elements based on the longitudinal modulation of the refractive index of the optical fiber core. This type of device has all the advantages associated with optical fiber sensors, with the added feature of easily multiplexing several sensing points along one single fiber.
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The production methodology of FBGs has evolved significantly since its initial approach. In the late 1970s, it was shown that optical fibers can be photosensitive, opening the door for FBGs production and its applications, both as sensing devices and in optical communications [1]. In 1981, Lam and Garside suggested that the formation of the FBGs was related to the interaction between UV light with defects in the doped silica core. Such findings lead to the later confirmation that the refractive index changes could be induced by doping the optical fibers core with germanium, given a new insight on the FBGs production [2, 3].
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One decade has passed since new breakthroughs emerged regarding the FBGs production methodology. In 1989, Meltz et al. reported an FBG external inscription technique. The authors used a split 244 nm beam, which was later recombined in order to produce an interference pattern in the optical fiber core [4, 5]. With this technique, the authors were able to create a periodic and permanent change in the optical fiber core refractive index [5]. The reflected Bragg wavelength can be adjusted by changing the angle between the two split beams. In that way, the period of the interference pattern and the refractive index will change accordingly.
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Alternatively, FBGs can be inscribed using phase masks, which are periodic patterns usually etched onto fused silica. In this technique, when the radiation from a UV laser is incident in the phase mask, the diffracted orders +1 and −1 are maximized, while the remaining ones are suppressed, creating an interferometric reflective pattern along the optical fiber core [6]. In Figure 1, the FBG inscription based on the phase mask technique as well as a representation of the FBG sensing mechanism is shown.
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Figure 1.
(a) Schematic representation of the setup typically used to inscribe FBG sensors in photosensitive optical fiber using the phase mask methodology; and (b) working principle of an FBG sensor.
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The FBG operational principle consists in monitoring the Bragg wavelength (λBragg) shift reflected by the grating, as a function of the monitored parameter. The Bragg wavelength is dependent on the effective refractive index of the fiber core (neff) and the grating period (Λ) by the relation [4]:
\n
\n\n\nλ\nBragg\n\n=\n2\n\nn\neff\n\nΛ\n\nE1
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Therefore, the Bragg wavelength can be actuated by variations in the grating period or in optical fiber core effective refractive index. So, the Bragg wavelength dependence on strain and temperature can be translated by:
where the first term refers to the strain influence on the λBragg and the second describes the temperature effect. Hence, in Eq. (2), ∆λBragg represents the shift of the Bragg wavelength, while ρ, α, and ξ are the photoelastic, thermal expansion, and thermo-optic coefficients of the fiber, respectively; ∆ε and ∆T corresponds to strain and temperature variations.
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The FBG sensing mechanism comprises of a spectral broadband optical signal launched into the fiber, and an optical spectra analyzer to monitor the Bragg wavelength shifts. At the grating region, the Bragg wavelength component of the spectrum will be reflected, while in the transmitted optical signal that same Bragg wavelength component will be missing, as illustrated in Figure 1b.
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Based in the described mechanisms, FBG sensors have a wide field of applications that range from their use for structural health monitoring, in oil and aeronautic industry and also as biomedical sensors and e-Health enablers, among others. Moreover, as the FBGs are elements with only few millimeters long, several gratings can be inscribed along the same optical fiber, allowing to multiplex a diverse network of sensing elements.
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\n
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2. Gait analysis: relevance and impact in an e-Health scenario
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Gait analysis research was given a pilot role in the nineteenth century, when the study of gait parameters started to be relevant in sports and medicine [7]. Regarding the medical point of view, from gait pattern analysis, a change in its normal parameters can reveal key information on patient’s quality of life and/or in the evolution of different diseases. Gait disorders affect a large number of world population, since they are direct consequence of neurodegenerative diseases, such as spinal amyotrophic, multiple sclerosis, amyotrophic lateral sclerosis, neuromuscular diseases, cerebrovascular and cardiovascular pathologies, or even the physiological aging process [8, 9, 10, 11, 12]. Neurodegenerative diseases can be reflected in gait by showing a poor balance, a slower pace, shorter steps, lower free speed, and higher cadence [8, 9, 10, 11].
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The study of dynamic characteristics of human gait for clinical purposes has been widely reported lately. It aims to enhance the life’s quality of patients suffering from gait disorders, and also, for their early detection, to enable early diagnosis and an adaptable treatment according to the evolution of the diseases or disorders [7, 13, 14, 15, 16].
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2.1. Gait analysis: gait cycle pattern
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Gait analysis can be seen as the comprehensive study of the human locomotion, which as previously mentioned, has a major role in physical rehabilitation assessment, disorder diagnosis, surgical decision, and recovering follow up. Such study comprises the kinematic analysis (joint angles, angular velocities, and accelerations) and the kinetic analysis (ground reaction and joint forces) during the gait cycles [17, 18].
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One gait cycle is the period of time between two consecutive contacts of the heel of the same foot with the floor. Generally, a cycle can be divided in two major phases: the stance phase, corresponding to the period in contact with the ground, which lasts for ~60% of the cycle; and the swing phase, corresponding to the period when there is no contact with the floor, and has a duration of ~40% of the total gait cycle [12, 19]. In Figure 2, the different phases are illustrated, along with events and periods that characterize a gait cycle.
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Figure 2.
Representation of the stance and swing phases of a gait cycle.
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The gait cycle can be further subdivided into six periods and eight functional events, five during the stance phase and three in the swing phase. Considering only one limb, the stance phase encompasses three different support periods. The first consists in a period of a double support, which is followed by single support and ends with the second double support period [18, 19, 20]. The double support period corresponds to the percentage of the cycle when both feet are simultaneously in contact with the floor and it describes the smooth transition between the left and the right single limbs support [18]. During the first double support, the heel strikes the floor (heel strike), marking the beginning of the gait cycle. The cycle evolves then toward the single period support, with the foot moving down toward the floor into a foot-flat position, where a stable support base is created for the rest of the body. Within the single support phase, the body is propelled over the foot, with the hip joint vertically aligned with ankle joint in the event characterized as the mid stance. From that point onward, the second double support phase starts, with the lower limb moving the body center of mass forward during the heel rise event, where the heel loses contact with the floor. The last contact of the foot with the floor is made by the big toe (hallux), at the toe off event, which also marks the end of the stance phase and the beginning of the swing phase [20].
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During the swing phase, there is no contact between the plantar foot and the floor, and the limb continues its movement forward, which can be divided into three different periods: initial swing, mid swing, and terminal swing. In the initial swing, the lower limb vertical length should be reduced, for the foot to clear the floor and to accelerate forward by flexing the hip and knee, together with ankle dorsiflexion. The mid swing is characterized by the alignment of the accelerating limb with the stance limb. In this phase, the ankle and the hip joints are aligned. During the terminal swing, the limb undergoes a deceleration while it prepares for the contact with the floor, in the heel strike of the start of a new cycle [19, 20, 21]. As described, the swing phase is characterized by accelerations and decelerations of the lower limb, which require a more demanding muscular effort at the hip level [18].
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2.2. Gait parameters
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Gait analysis is a systematic procedure that allows the detection of negative deviations from normal gait pattern, as well as their causes. Based on such analysis, it is possible to quantify the parameters involved in the movement of the lower limbs and retrieve the mechanisms that rule the human body movement [22]. Based on the gait cycle pattern described earlier, there are several parameters that can be physically monitored in order to assess the patient’s health: anthropometric, spatio-temporal, kinematic, kinetic, and dynamic electromyography (EMG), as shown in Table 1 [22]. From such parameters, the ones that require a more specialized technology to be monitored outside the clinical environment, and therefore passible of being monitored in a gait e-Health architecture, are [7, 23, 24]:
the stance and the swing phases duration for each foot;
the walking velocity and gait cadence (number of steps per unit of time);
The step length, width (distance between two equivalent points of both feet), and angles (direction of the foot during gait);
the body posture (bending and symmetry) and the existence of tremors;
the shear and the foot plantar pressure during the stance phase; and
the direction and alignment of the limb segments with the ankle, knee, and hip joints.
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Parameters
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Definition
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Evaluation of:
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Anthropometric
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Related to the corporal dimensions of the human body.
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Age, gender, height, weight, limb length, and body mass index.
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Spatio-temporal
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General gait parameters used for a simple objective gait evaluation, considering the time-distance characteristics.
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Step and stride length, step width, cadence, velocity, stance and swing phases, and gait cycle events (for instance, heel strike).
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Kinematic
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Quantification of movements and geometric description of the lower limbs motion, without reference to forces.
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Joint and segments angles, angular motion, acceleration, and segment trajectory.
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Kinetic
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Evaluation of the forces involved in the body locomotion.
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Ground reaction forces, torque, and momentum.
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EMG
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Refers to the analysis of muscular activity, generally performed by using EMG surface electrodes.
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Motor unit action parameters.
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Table 1.
Parameters generally used for gait analysis (adapted from [22]).
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The act of walking implies the movement of the whole body, and specifically, it requires a synchronized movement of each lower limb apart. Therefore, the gait pattern of an individual can be affected by a disorder in any segment of the body, like for instance, problems in the spinal cord or from a reduced knee flexion in patients with an anterior cruciate ligament reconstruction [25]. For that reason, the analysis of the gait cycle is a vital tool for the biomechanical mobility monitoring, as it can give crucial information not only about the lower limbs health condition, but also allows to infer details about other possible pathologies related to the dynamic movement of the body [26]. So, by monitoring the parameters previously listed, it is possible to assess the health conditions for the body parts involved in walking, namely the lower limbs and its joint. These parameters can be analyzed using objective and subjective techniques [7, 27, 28].
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The subjective analysis is based on the observation of the patient while walking, and is generally performed in clinical environment under the supervision of a doctor or a therapist. For this analysis, the patient is asked to vary several gait-related parameters, while walking in a predetermined circuit [7]. This type of analysis is bit limited in the information that can be retrieved, nevertheless, this could be useful for an initial evaluation and posterior decision on which objective techniques should be used. In contrast to the subjective techniques, objective gait analysis is more of a quantitative evaluation of the parameters listed above. This type of analysis requires the use of different types of equipment and procedures to measure the gait parameters. These methodologies can be categorized according to the technology used, varying from the ones based on imaging, instrumented walking platforms or floor sensors, and wearable sensors [7, 24, 29].
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For an e-Health architecture, the most suitable technology would be the one built using wearable sensors, which would be able to acquire the patient gait parameters, everywhere and under any conditions. Among those, FBGs can be considered as an objective technique for gait analysis (allows the quantification of parameters during gait analysis), which could be used in instrumented platforms or as wearable sensors [30]. Recently, the use of FBGs as wearable sensors for remote monitoring of patients has been reported [12, 31, 32].
The Internet of Things (IoT) concept is the fusion between pervasive network connectivity and the computing capability expanded to sensing devices and objects, able to acquire and exchange data autonomously. In recent years, due to the potential gains brought to the citizens’ quality of life, IoT is seen as a whole platform able to bridge people and objects by integrating the smart concept into people’s life, namely, smart cities, homes, wearables, and mobility [33].
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Within the vast field of applications provided by IoT, e-Health stands out as one of the most influential topics on life-quality of humans, as smart and connected healthcare services have been requested more enthusiastically. e-Health is gaining too much attention mainly due to the joint effect of the increase of insufficient and ineffective healthcare services, allied to the change in population demographics and the increasing demand of such change entails. The world’s population aged over 60 years is expected to reach 2 billion by 2050 [34], which implies the rise of chronic diseases that may be translated on different degrees of mobility impairments, requiring a close monitoring and a patient-centered healthcare service, where the healthcare providers and patients are pervasively connected [12, 33]. Also aligned with such demands, the market for home medical devices is set to significantly grow from $27.8 billion in 2015 up to nearly $44.3 billion by 2020 [35]. The increase in available e-Health solutions is a remarkable step toward improving the healthcare services, along with the autonomy of debilitated or impaired citizens. Fundamentally, e-Health can be seen as the solution to help the elders and patients with chronic illness to live an active life, without compromising their mobility or daily routine [32].
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e-Health systems use remote monitoring architectures composed of sensing devices responsible to collect patients’ physiological information, analyze and store such data in the cloud. The information can afterward be wirelessly sent to the healthcare professionals for a decision/action. The continuous flow of information on the patient’s condition improves the provided service at a lower cost, while simultaneously enhancing the life quality of patients, who need continuous attention [33].
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The patients’ physiological information can be collected by networked sensors, integrated in smart wearable systems, or placed within the patients living environment. Considering the specific case of gait analysis, the continuous, automatic, and remote monitoring of gait of impaired or under rehabilitation citizens allows the objective assessment for preventive and proactive supervision of the pathologies, as well as to closely assist the therapies in progress [36]. In this scenario, wearable sensing architecture allows not only the evaluation of the patients in the course of daily life activities, but also provides the feedback on the recovering/rehabilitation therapy to patients and medical staff through ubiquitous connectivity. Based on that feedback, new therapeutic instructions can be given remotely to the patient, maximizing the efficiency of the provided healthcare services [31, 32].
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An e-Health architecture to monitor the gait pattern of a citizen/patient comprises three key elements: the monitoring system composed of a sensors’ network (preferably wearable); a computer/analysis system to collect, analyze, and store the data; and finally, the wireless mobile gateway, responsible for data processing and wireless transmission to medical servers and decision centers [31, 32]. Figure 3 schematizes the typical architecture involved in an e-Health scenario.
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Figure 3.
Possible architecture for a gait e-Health monitoring system.
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The first part of the considered architecture is responsible for the data sensing and consequently, for the information given to action centers. Therefore, it is crucial that the sensing network is as accurate and reliable as possible. The use of FBGs as IoT and e-Health enablers is becoming increasingly common, due to their sensing characteristics, when compared with the ones of their electronic counterparts, namely small size (in the order of micrometers), biocompatibility, multiplexing capability, immunity to electromagnetic interference, in addition to their high accuracy and sensitivity, even for applications in challenging environments [37, 38, 39]. Consequently, FBGs can be used as a reliable solution for the integration in e-Health architectures, as for monitoring sensing systems in biomechanics and physical rehabilitation. Some examples can be mentioned, covering the detection of bone strains, mapping of gait plantar and shear pressures, measuring of pressures in orthopedic joints and angles between the body segments, as have already been successfully reported [12, 30].
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In the following sections, the use of FBGs to monitor different body segments involved in gait will be explored.
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3. Plantar pressure and shear analysis
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The assessment of plantar and shear pressures is of great importance for the gait health evaluation analysis, aiming to understand the effects induced in/by the body and to prevent the ulceration of the foot [40]. The pressure ulcers occur when tissue is compressed during prolonged periods of time, resulting in a wound that can infect and cause amputation, or in more severe cases, the patient’s death [41]. An early identification of individuals at risk of foot ulceration (people with diabetes mellitus and peripheral neuropathy) is one of the primary means to reduce its incidence [40, 41]. Due to the poor load distribution, resulting from the reduced sensitivity of the foot, abnormally high plantar pressures occur in certain areas of the foot, and when that happens, it can lead to the growth of pressure sores in these locations [42]. The most affected areas are those with bony prominences, such as under the metatarsal bones, where the majority of plantar neuropathic ulcers occur [43]. Correct and continuous mapping of plantar pressure can prevent the occurrence of these pathologies, with the adoption of different walking habits or the use of correction equipment. On the other hand, in the case of the existence of ulcers, a redistribution of the forces imposed on the foot during walking aids healing and prevents further ulceration.
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The force applied to the skin surface by a supporting structure has two components: the pressure acting normal to the surface and the shear stress acting in a tangential direction. Many authors have suggested that shear stresses have a pathogenic factor in the development of plantar ulcers [40, 41, 42, 43]. This shear stress exists if there is sliding between two surfaces (foot and shoe), and it is closely related to friction [44]. Despite the importance of shear monitoring in assessing gait patterns, only normal pressure is widely reported. The lack of a validated and commercially available shear stress sensor is one of the main reasons why shear analysis is not as referenced as plantar pressure.
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There are several solutions in the market for measuring plantar pressure, static in the form of fixed platforms, and wearable as shoes insoles. In regards of the importance of gait-related pathologies in the general population, and in the elder generation in particular, several works have been developed to improve the state-of-the-art. The literature reports the use of various technologies of plantar pressure and shear sensors, such as magneto-resistors, strain gauges, piezoelectric materials, capacitive sensors, and micro-strip antennas and coils.
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As an alternative to these electronic devices, optical fiber-based sensors stand out due to their small diameter (hundreds of micrometers) and robustness, biocompatibility, high precision, electromagnetic insensitivity, as well as being electrically free at the point of measurement and owning the property of being able to multiplex several sensors in the same fiber, which allows to simultaneously monitor different parameters [45, 46].
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Following such path, research studies have been carried out with FBG-based sensors used to measure not only plantar pressure but also shear parameters.
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3.1. Plantar pressure sensors
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The plantar pressure monitoring devices can be presented as fixed platforms or as insoles to be used directly in the footwear. Platform systems are typically constructed of several pressure sensors arranged in an array embedded in the floor or in a rigid platform. These systems can be used for static and dynamic studies, but are generally restricted to clinics and laboratories. In the case of the static tests, the patient stands still on the platform. On the other hand, for the dynamic tests, the platform is placed on the floor and the patient walks through it. The application of these types of measuring systems has the advantage of being easy to use, since the platforms are flat and stationary. Nevertheless, these systems also present disadvantages, since they are influential to the patient’s gait, once during the examination, he/she will have to tread specific areas of the platform surface [47].
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Insole sensors can be incorporated into shoes, so that the measurements truly reflect the interface between the foot and the shoe. These systems, as they are flexible and portable, allow a greater accuracy of the acquired data, regarding the natural gait of the patient, and also greater variety of studies with different walking tasks, footwear, and even diverse floors/terrains [47]. However, insoles usually have a reduced number of sensors compared to platforms. The main requirements for the development of wearable/in-shoe sensors are: mobility, reduced number of cables, low power consumption, low cost, high acquisition frequency, proper sensitivity, noninvasiveness, and do not represent any danger to the user. Therefore, fiber optic sensors, due to their characteristics, have proven to be a reliable solution in this type of applications. Also, within the range of fiber optic sensors, the FBGs seem to be the best solution, since their multiplexing capability allows to have multiple sensors into a single fiber, reducing the number of cables needed in the insole. In this section, some recently developed work using optical fibers with Bragg gratings, as plantar pressure sensors in fixed platforms and in-shoe equipment, will be described.
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The first work with FBG sensors incorporated in platforms for the measurement of plantar pressure was published in 2003, when Hao’s team developed an insole shaped device with a silica optical fiber with five FBGs [48]. The insole was constituted of 10 layers of carbo-epoxy, among which the optical fiber was placed. The sensing FBG units were placed strategically at the main pressure points (heel and metatarsal areas). The device was tested in static tests to determine which areas have the greatest and lowest pressure at different user positions. The results showed that the sensors had an average sensitivity of 5.44 pm/N.
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In 2014, Suresh et al. published a work comparing the use of FBGs and piezoelectric (PZT) sensors for gait monitoring at low and high speeds [49]. To manufacture the optical sensing platform, the FBGs were embedded between layers of a carbon composite material (CCM) in the form of an arc. After that, both types of sensors were placed on the underside of a commercial shoe (Figure 4a). For the dynamic test and to verify the behavior of both types of sensors, a healthy male walked on a treadmill wearing those shoes at various speeds. For the FBGs sensors, a mean pressure sensitivity of 1.3 pm/kPa was obtained. The study revealed that the FBG sensors have a better performance in the static moments and at lower speeds, while the piezoelectric sensors had greater performance for higher speeds.
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Figure 4.
(a) Scheme of the shoe with the attached FBG and PZT sensors (adapted from [49]); and (b) schematic representation of an arc shaped FBG pressure sensor (left) and the insole sensing scheme (right) (adapted from [50]).
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Other approach was made by the same team, in which similar FBG cells were incorporated in an insole structure, as can be verified in the Figure 4b. The device was constituted by four arc-shaped cells, strategically placed in the forefoot and heel area. In this study, the plantar pressure was analyzed in both the fixed platform and the in-shoe systems. An average pressure sensitivity of 1.2 pm/kPa was obtained [50].
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In 2016, Liang et al. proposed a sensing system based on six FBGs inscribed into a single fiber, which was embedded in silicone rubber [51]. The data registered by the optical sensors were compared to the ones collected through an i-Step P1000 digital pressure plate with 1024 barometric sensors. For the sensors’ validation, 11 participants were tested, and according to the results, the viability of the optical sensor for this kind of measurement was demonstrated. Additionally, four different foot supporting types were successfully identified.
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In 2017, Domingues et al. reported the development of two noninvasive solutions with FBGs in silica optical fiber incorporated in cork to monitor the body center of mass displacements and vertical ground reaction forces induced in the foot plantar surface during gait [12, 32]. One of the solutions, containing five FBGs, was developed to act as a fixed platform, and the other, with six FBG sensors, to be used as an instrumented insole to be adapted in a shoe as shown in Figure 5. Although the insole is made of five FBGs multiplexed in the same fiber, a clear isolation of each sensing point was also demonstrated, as seen in Figure 6a. Upon the calibration of the sensors located at point 1 (heel area), when the increasing load is applied in that point, only the FBG 1 shows a Bragg wavelength shift, proportional to the load applied (Figure 6b) [12].
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Figure 5.
Schematic representation of the cork insole FBG monitoring system (adapted from [12]).
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Figure 6.
(a) Reflection spectra of the five FBGs multiplexed in the cork insole for three different load values; and (b) Bragg wavelength shift dependence on the load applied for FBG1 (adapted from [12]).
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The obtained results demonstrated the accuracy and reliability of the proposed systems to monitor and map the vertical active forces on the foot’s plantar area during gait, Figure 7, with a sensitivity up to 11.06 pm/N.
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Figure 7.
Representation of two complete gait cycles registered using a cork insole instrumented with five multiplexed FBGs (adapted from [12, 32]).
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The top graphic representation corresponds to the values independently registered by the five FBGs along time during two gait cycles, where the sum of the forces acquired by each FBG corresponds to the typical gait pattern [12]. In more detail, in the bottom graphic representation, it is possible to see which points of the insole are more actively pressed during the stance phase of the gait cycle. The dark blue representations in the foot, corresponds to the foot area that supports a higher load in the different stages of the stance phase [12, 32].
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In the same year, a polymer optical fiber (POF) sensing system based on FBGs to measure foot plantar pressure was also described [52]. The plantar pressure signals were detected by five FBGs recorded in a cyclic transparent optical polymer (CYTOP) fiber, which was embedded in a cork platform in the form of an insole to monitor plantar pressure during gait. Initially, two studies were made with the insole as a fixed platform, one in which the user walked through the sensing structure and another where he stood in the platform just moving the body center of mass. The data obtained from this device in both tests showed good repeatability and a sensitivity twice as high as the solutions based on silica optical fiber. Additionally, a team of researchers from Shanghai presented a sensing platform based on FBGs using the fused deposition modeling (FDM) method for the construction of the structure [53]. This platform was composed of several cylindrical structures in polylactic acid (PLA) with the FBG inside them. This device was designed to be used as a fixed broad platform for plantar pressure monitoring, which demonstrated to have a reliable mechanical performance.
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Finally, a noninvasive and efficient insole FBG-based architecture for monitoring plantar pressure was presented in [32]. This work stands out from the others, because the authors introduced a whole IoT solution with the insole sensors integrated with a wireless transceiver, exhibited high energy efficiency and secured data transmission, to ensure the mobility and privacy of user data. The presented data reflected the precision of the proposed system, with the sensors having sensitivities up to 7.8 pm/kPa.
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3.2. Plantar pressure and shear sensors
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FBGs have also great potential for measuring shear stresses in the shoe. Although there are reports of sensors developed for shear measurement [54, 55], measuring plantar and shear pressure simultaneously is more attractive and provides more insights about the wellbeing of the foot and the overall health of the person. Due to the advantages of fiber optics, and FBGs in particular, several researchers have been working on the design of FBG-based cells able to measure these two forces simultaneously. Although the main objective is the measurement of these parameters during gait, none of the studies refers the introduction of the developed sensing cells in insoles or platforms, presenting only the cells in its isolated form.
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The first work published with simultaneous shear and vertical forces sensing with FBGs goes back to the year of 2000. The team of Koulaxouzidis developed a cell, using three optical fibers with an FBG each, embedded in a block of elastic material, as schemed in Figure 8a [56]. The developed sensor was able to measure the vertical stress, as well as the magnitude and direction of the shear stress on its top surface. The experimental results showed a good repeatability and a resolution near to 5 kPa in the measurement of both forces. Later, in 2013, Zhang et al. developed an identical sensor to the previous one. In this case, two POFs with one FBG each were used, one of them was placed horizontally (hPOF, hFBG), while the other was tilted (tPOF, tFBG). Both fibers were embedded in a soft polydimethylsiloxane (PDMS) matrix, as shown in Figure 8b [57]. The sensor had a 27 mm length and width, and a 22 mm height. In this work, the obtained pressure sensitivity was 0.8 pm/Pa in a full range of 2.4 kPa, and the shear stress sensitivity was 1.3 pm/Pa for a full range of 0.6 kPa.
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Figure 8.
Schematic representation of the FBG-based sensor cell developed in (a) silica (adapted from [56]) and (b) POF (adapted from [57]) fibers.
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In 2015, Chethana et al. developed an optical sensor ground reaction force measurement platform for gait and geriatrics studies [58]. The developed system consisted of eight FBGs to measure the respective soil reaction forces on the three axes (x, y, and z). Four of the FBGs were placed at the vertices of the measuring platform, monitoring the shear motions on the x and y-axes (two for the x-axis and two for the y-axis motions detection). The remaining four FBGs were placed one on each frame supporting leg to measure the plantar pressure exerted on these zones. According to the authors, the optical fiber sensors platform for ground reaction force measurements presented a zero cross-force sensitiveness in all three loading axes [58].
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In 2018, Tavares et al. developed a cell with the same operating principle as previously reported, but using only one silica optical fiber with two FBGs placed individually in two adjacent cavities, one made of cork and another of polylactide acid (PLA), as shown in Figure 9 [59]. For the cells’ calibration, the used method was similar to the one described in Ref. [57], and the obtained values were compared with a 3-axial electronic force sensor. The results demonstrated that the developed device is a reliable solution for simultaneous measurement of shear and vertical forces. This solution has a great advantage over previous ones, since it only requires one optical fiber, which facilitates its incorporation into insoles. Therefore, several points, along the foot plantar surface, can be measured with a single optical fiber [12, 51, 52], with the advantage of being able to simultaneously diferentiate the two diferent forces (shear and pressure).
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Figure 9.
Scheme of the shear and pressure sensing cell with its different components and respective dimensions (adapted from [59]).
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There are also studies using FBGs for vertical and shear forces measurements, but in which shear measurement is indirectly inferred from temperature variations. The authors argue that a rise in temperature in a certain area of the foot presupposes that there was friction between the surface of the foot and the shoe (shear force) [44, 60]. Najafi’s team published a work in 2017 with the validation of a smart-textile based on fiber-optics with FBGs (SmartSox) for simultaneous measurement of temperature, pressure, and joint angles in patients with diabetic peripheral neuropathy (PND), where irregular temperature increase suggested the presence of shear forces [44]. In this study, FBG sensors were placed in socks that were successfully tested in a clinical setting by 33 individuals with PND to evaluate plantar pressure and temperature during normal gait velocity in a clinical setting.
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4. Lower limb joints monitoring
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The knee, hip, and ankle have a key role in gait, as it allows the body locomotion with muscles’ minimum energy consumption and provides stability to walk in different terrain relief. During gait, the lower limb joints act together in order to provide the smoothest locomotion for the body. In Figure 10, the kinematics of the lower limbs in the different phases of gait are represented, namely the stance (a) and the swing phases (b) [14, 28].
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Figure 10.
Schematic representation of the lower limbs kinematics involved in the: (a) stance and (b) swing phases.
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At the beginning of the stance phase, in first double support and at the heel strike, the hip is flexed at 30°, the knee is extended and the ankle is at a neutral position. As the loading response approaches with the foot flat, the hip continues in a flexed mode as the knee starts flexing 5–10°, along with the ankle plantar flexing up to 20°, for the weight acceptance, shock absorption, and to propel the body forward. At the mid stance, the hip is extended, the knee flexed by 5–10° and the ankle is dorsi-flexed, with the purpose to move the body over the stationary foot. As the heel rises, with the ankle dorsi-flexing at 15°, the hip is extended at 15–30° and the knee is extended and then flexing. At the last point of the stance phase, in the toe off moment, the hip is flexing, the knee is also flexing at 30–40° and the ankle has a plantar flexing of 20–30°, in the preparation for the swing phase and the transfer of the load to the other limb [61].
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At the initial swing, the hip continues flexing at 15°, the knee is flexing up to 65°, and the ankle is plantar flexed at 10° to clear the foot from the floor and advance the limb. At the mid swing, the hip is flexed at 30°, while the knee is flexing at 25°, and the ankle is at a neutral position. At the terminal swing, the hip is flexed at 25°, the knee is extended, and the ankle is at a 0° plantar flexion, to prepare the next heel contact at the beginning of the new stance phase [61].
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The use of objective techniques to evaluate the health conditions of the knee can be a powerful tool for researchers and medical staff, providing relevant information about tendon-ligament strains and vibration, pressure, angular range of movements, and even temperature [62, 63].
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There are numerous conventional techniques that can be used to monitor the joint conditions, such as stereo-optic, solid state, and piezo-resistive sensing methods, which employ accelerometers, magneto-resistive sensors, flexible goniometers, electromagnetic tracking systems, among others [24, 62, 64]. However, these techniques usually require complex and expensive electronics, which are susceptible to magnetic interferences and also cannot be used in humid/wet environments. Therefore, they do not represent an ideal solution for wearable sensing configurations, where the human transpiration may influence the sensors performance. So, the increasing research in the field of optical fiber sensors has also been focusing in the introduction of FBG technology in monitoring the lower limb joints during walking. Optical fiber sensors can be easily adapted to curved surfaces and various contours of the human body, especially the knee, a joint with complex anatomy [62, 63, 65, 66, 67].
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The ideal technology to monitor limb joints should be able to measure curvature, being useful not only to monitor the motion of the lower limb segments, as well as to evaluate all the corporal posture [65]. The development of a smart garment, based on FBGs and flex sensing technologies, to monitor the body posture and lower and upper limbs’ movements, was reported. An FBG-based sensing belt was produced by encapsulating FBG sensors inside a synthetic silica gel, as depicted in Figure 11, which was afterward attached to a garment for monitoring joints and body posture. The encapsulation of the FBG was made with an applied pre-stress, so the sensor is able to monitor both extension and compression deformations. The proposed FBG belt, fixed near the limb joints, is influenced by the body posture shifts, and the consequent sensor’s Bragg wavelength shift was correlated with the angles at the limb joint [65]. Although the results presented by Abro et al. are only related to tests made at the upper limbs, the reasonable results obtained within the tests and exercises are a good indication of its potential application for the monitoring of the lower limbs motion.
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Figure 11.
Schematic representation of the FBG belt proposed by Abro et al. (adapted from [65]).
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4.1. Knee flexion-extension monitoring
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From the lower limb three joints (ankle, knee, and hip), the knee is one of the body joints most prone to develop osteoarthritis [68]. Therefore, the supervision and monitoring of the motion of the knee are of crucial importance in the medical and physical rehabilitation field [37, 62, 67, 69, 70].
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Rocha et al. suggest a wearable knee motion sensor, designed with a single FBG, embedded in a stretchable band of polyvinyl chloride (PVC) material and placed in the center of the knee joint, as schematized in Figure 12a [67]. The objective is to measure the knee movements from the straight leg to the maximum knee flexion and to obtain graphically the pattern of human gait, by monitoring flexion and extension, with the joint acting as a rotation axis, as represented in Figure 12b. The PVC band with the FBG was attached to an elastic ribbon (knee brace), by metallic pressure-buttons that ensure the stability of the sensing band while walking or running. In the reported work, the authors tested the proposed solution on a treadmill, under different types of run and speed, accompanied by video recorder [67]. The video was used to define the starting time of the stance and swing phases in order to correlate the data provided by the FBG sensor to the different phases of the walking routine [67, 71, 72].
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Figure 12.
(a) Schematic representation of an FBG-based solution for knee movements monitoring (adapted from [67]); and (b) typical keen angle pattern during gait.
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When the leg is straight, the FBG sensor is in the resting position since there is neither flexion nor extension in the optical fiber. Once the bending movement of the knee starts, during walking, it results in an extension of the optical fiber, inducing a strain in the FBG sensor, positioned at the center of the knee joint. Consequently, a positive shift of the reflected Bragg wavelength is obtained. The reverse bending movement, from the maximum knee flexion point to straight leg, leading to a relaxation of the FBG, return to its initial Bragg wavelength value [67]. By monitoring the wavelength shift during these movements, the gait pattern of the patient could be characterized.
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Although the researchers Rocha et al. show a clear characterization of the movement of the knee joint during the gait cycle, they also point out, as a drawback, the noise induced in the signal by vibration, considering that better results are achieved at lower speed, softening the influence of the elastic factor of the knee band [67].
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Similar results can be achieved using kinetic tape (elastic adhesive tape) with an embedded FBG. The kinetic tape is attached to the lower limb, starting at the quadriceps area and ending at the beginning of the tibia, with the FBG placed just a few centimeters above the knee rotation axis, as shown in Figure 13a. Such configuration is a more stable solution, since the fiber containing the FBG is only actuated by the rotation of the knee, which stretches the kinetic tape inducing a strain and consequent positive wavelength shift in the FBG. During the calibration process, using an angle lock goniometer for angles ranging between 0 and 90°, a direct relation between the knee angle and the Bragg wavelength shift was found as displayed in Figure 13b. In Figure 13c is presented the flexion/extension angles, along time for six gait cycles, obtained with the solution represented in Figure 13a, and which as a similar behavior as reported by the authors in Ref. [67], but with a considerable reduced noise level.
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Figure 13.
(a) Photograph of the kinesio tape with an embedded FBG for keen angle monitoring; (b) Bragg wavelength shift dependence with the keen flexion angle; and (c) knee flexion/extension angle during six gait cycles.
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4.2. Ankle flexion and dorsi-flexion monitoring
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Umesh et al. proposed an FBG goniometer based on the deflection produced in an optical fiber by variation of the angle of the goniometer [73]. The purpose of the sensor is to measure the range of movement (ROM), which for the ankle joint the movement can be classified as ROM plantar-flexion and ROM dorsi-flexion. Plantar flexion is described as the rotation that increments the angle described between foot and the shin, and the dorsi-flexion is the rotation that results in a lower angle. The sensor is an assembly of two discs of 30 mm, overlapped by two discs with smaller diameter (5 mm). The two pairs of discs are circled by a rubber belt, to ensure synchronized rotation between them. The optical fiber with the FBG sensor is placed in a cantilever, connected to the upper belt. The rotation arm is linked to the side of the foot and its movement motivates the rotation of the correspondent disc. This rotation moves the cantilever and creates strain in the FBG, which can be rewritten in angle values, by proper calibration. The characterization of these two rotations has crucial importance in clinical diagnosis, helping the evaluation of the limitations of this joint. Furthermore, it is a noninvasive method of measurement with the advantages that optical fibers offer, and that can counteract to limitations of conventional electro-goniometers and video tracking systems as electromagnetic interference, size, and fragility [73].
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4.3. Tendons and ligaments monitoring
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Beyond their ability to measure the flexion, dorsiflexion, and extension of the joints involved in gait, FBGs can broaden their usage to applications related to the tendons and muscles monitoring. Although it may fall a bit out of the scope of e-Health, it is worth mentioning the application of FBGs to perform pressure mapping, and monitor strain and length of tendons and ligaments, when under load or locomotion. Ren et al. presented an FBG sensor embedded in a micro-shape memory alloy tube which is able to measure the displacement of the tendon [74]. To verify the performance of the sensor, the initial tests were made in the Achilles tendon and the results compared with the ones obtained simultaneously with a two-camera stereovision sensor. The fiber-based sensor was also applied to a cadaver knee tendon, in the medial and lateral collateral ligament, to record the deformation of the ligaments in simulated postures. The results proved that the FBG sensor has high sensitivity and low signal-to-noise ratio, without loss of accuracy. It is also easily implemented and minimally invasive to the biological tissues, projected to be applied in-vivo, after some improvements [74].
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5. Prosthetic and exoskeletons applications
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For severe impaired citizens, it is common to adapt prosthetic lower limbs, in order to offer patients mobility. The interface pressure inside the prosthetic sockets is of major relevance, in order to avoid ulcerations in the patients and evaluate its suitability. Moreover, the application of robotics technology to improve the wellbeing of debilitated patients has been highly investigated in the past few years. In particular, exoskeletons can be wearable devices prone to be used to restore functional movements of amputees and persons with paralysis. Therefore, this section surveys the use of FBG sensors for the development and evaluation of prosthetic limbs, in addition to control and automation of exoskeletons.
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5.1. Prosthetic limbs
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The partial or total limb amputation is one of the oldest treatment options available in medicine. Unfortunately, the frequency of the lower limb amputation is growing worldwide. Traffic accidents, particularly motorcycle accidents, health problems (including diabetes, arterial hypertension, chronic renal failure, and hypercoagulability), and advanced age are the main causes. Additionally, this is a predominant incident in countries affected by landmines and other natural disasters, including, for instance, earthquakes. Due to the socioeconomic impact (with the consequent inability to work and socialize), the interference on the life quality, and other complications, such as hematoma, infections, necrosis, contractures, neuromas, and phantom pain; this is a relevant public health problem.
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The key element of amputee rehabilitation is the engineering of solutions, appropriated for individuals to recover their physical capabilities. A prosthesis or artificial limb is a device, whose function is to substitute the limb that was lost, with cosmetic and functionality for the amputee. A lower limb prosthesis results from the assembly of several components, including socket, shank, ankle, and foot, as schematized in Figure 14.
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Figure 14.
Typical transtibial prosthesis (adapted from [75]).
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The socket is the most relevant component of the artificial limb, since it constitutes the critical interface between the amputee’s stump and the amputee. The design and fitting of the socket are also the most difficult processes, due to the particularity of each amputee’s stump. When wearing the prostheses, the appropriated fit and comfort are critical factors that contribute to its successful use. Nevertheless, many amputees still complain about discomfort or pain, reporting a set of problems, including edema, pressure ulcers, dermatitis, and skin irritation, due to the use of the prostheses [76]. This is particularly related with the changes in the residual limb soft tissues (volume, shape, sensitivity, composition, among others), which vary during the day due to factors such as temperature, activity, and hydration.
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As result, in the last years, several measurement systems have been proposed to assess the interface pressure between the residual limb and the prosthetic socket [77]. This includes electrical strain gauge [78], F-socket transducer arrays [79, 80], and finite element analysis [81, 82, 83]. The output from these systems has been used to improve the socket design. Nevertheless, despite the technological advances in the existing socket design and the measurement systems, available sockets still exhibit many weaknesses. For instance, apart from the high accuracy and sensitivity provided, the use of strain gauges requires modifying the sockets with openings for accommodation of the device. This procedure interferes in the socket shape, and consequently in the accuracy of the pressure measurements.
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In the case of the F-sockets, these systems present flexibility, good sensitivity, and ease of use. Additionally, in contrast to strain gauges, no change in the socket shape is required, since F-sockets are quite thin, which can be placed in-situ between the residual limb and the prosthetic socket. Nevertheless, the nonlinearity, hysteresis, drift, and vulnerability to electromagnetic interferences are the main limitations. Additionally, the shear stresses are not accounted for, when this system is used.
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The finite element analysis is a numerical modeling alternative, which, when applied to the residual limb, predicts the soft tissues load distributions and magnitudes. This information has been assisting the technicians during the socket design. Nonetheless, although some models already considered thresholds for tissue injury and adverse adaptation, and other researchers have included in the models parameters, such as comfort and pain threshold, several complaints are still reported from the use of the prostheses, due to the subjectivity, difficulty to evaluate these factors, and the inter- and intra-individual loading [83].
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Consequently, new sensing methodologies with minimal limitations toward accurate measurements of the interface pressure within prosthetic sockets are essentially required. Thereby, the FBG technology was pointed out as a potential alternative to conventional methodologies [84]. In 2010, Kanellos et al. proposed a 2D optical FBG-based pressure sensor, predicting to be suitable for several biomedical applications, namely biomechanics, rehabilitation, and orthotics, including amputee sockets [85]. The device consists of FBGs embedded into a thin polymer layer of PDMS, with the minimum thickness of the sensing pad set to 2.5 mm. The sensor exhibited a maximum fractional pressure sensitivity of 12 MPa−1, with a spatial resolution of 1× 1 cm2, also revealing no hysteresis and real-time operation possibility. Due to the elasticity and ductility of the polymer, which match human skin behavior, the system becomes a flexible 2D pressure sensing surface. This configuration is appropriate to be attached or anchored to irregular shaped objects/bodies, allowing to translate more accurately all the phenomena that may occur in them. These properties meet the requirements of human machine interfaces, comprising amputee sockets, as initially predicted.
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Apart from the medical requirements imposed on the FBG embedded-based sensor pads, which include real time acquisition, high sensitivity and resolution, and increased dynamic range, these systems also need to comply with a set of demands related to fabrication and packaging processes. These conditions result from the diversity of the patients to be treated, and also from their real life conditions. Thus, the influence of the fiber embedding depth (center and top position of pad cross-section), the thickness of the polymer sheet (2 and 3 mm), and the fiber type (hydrogenated SMF-28 and nonhydrogenated GF1B) were assessed in [86]. The results of this study reveal that the sensor pads rigidity and durability are enhanced, when the Bragg grating, inscribed into nonhydrogenated fiber, is embedded at the polymer center, with a thickness of 3 mm.
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Results of the first investigation of the ability of FBGs to measure interface pressure between the stump of a trans-tibial amputee and a patellar tendon bearing (PTB) prosthetic sockets are presented in [75]. The patellar tendon (PT) bar was the key analyses’ area since this supports the majority of the transtibial amputee’s body weight, when the subject is using the PTB socket. In Ref. [75], the FBGs were first embedded into an epoxy material (NOA 61), aiming to acquire the required protection to withstand the high pressure values up to 230 kPa at the PT bar [78]. After that, this sensing pad was placed between two silicone polymeric sheets forming the pressure sensor, as schematized in Figure 15.
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Figure 15.
Schematic representation of an FBG-based system for monitor the interface pressure between the socket and the amputee (adapted from [75]).
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Since the initial contact of the PT with the sensor surface is mostly pressure concentrated, this behavior was imitated using a ball bearing, and positive wavelength shift of 3.8 nm was observed for a maximum load of 30 N, Figure 16a.
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Figure 16.
(a) Representation of the maximum Bragg wavelength shift for maximum load applied (adapted from [75]); and (b) average Bragg wavelength shift as function of the applied force (adapted from [75]).
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Thereafter, an experimental set up was designed to assess, in-situ, the sensor performance, while attached to the inner socket wall. Although there was no subject involved in these tests, consideration was taken to reproduce a real-life situation, as much as possible. The results obtained for the different load cycles reveal the suitability of the sensor to accomplish pressure measurements on the socket stump interface, especially in the PT region. From the calibration procedure, a proportional wavelength shift dependence with the load applied was found Figure 16b.
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Toward using these sensors in-situ, the performance of these sensing pads was broadly assessed concerning the sensitivity, durability, and hysteresis error [87]. Similar to the work of Kanellos et al., three production parameters were investigated, which are the FBG embedding depth (top, bottom, and neutral layers of the sensing pad), the sensing pad thickness (1, 2, and 3 mm), and the type/hardness of sensing pad materials [PDMS (harder) and silicone rubber (softer)]. The best sensor’s performance (highest sensitivity and accuracy) was obtained for the FBG embedded in the neutral layer of PDMS and with the thicker sensing pads. An FBG array was produced with these conditions and used for interface pressure measurements within prosthetic sockets. Additionally, to further assess the performance of the proposed sensing pad, these were evaluated in-situ, in a traumatic transtibial amputee using a total surface bearing socket, with 6 mm silicone liner. The results were validated comparing the data obtained with the FBG technology to the pressure measurements acquired by the F-socket sensors. Although the data obtained for the 8 sub-regions of the amputees’ residual limb follow the same tendency; higher pressure values were registered by the FBG sensors. The difference was attributed to the sensors’ thickness, which is 3 mm in the case of the FBG sensing pads and 0.2 mm in the F-socket sensing mats.
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Aiming to eliminate the previous limitations and provide a simpler and more practical sensing procedure, Al-Fakih et al. proposed an innovative customized FBG-instrumented silicone liner, which consists of two silicone layers with 12 FBGs embedded between them, with the gratings located in clinical interest points [88]. In this study, a custom gait simulation machine was built to test the performance of the sensing system during an amputee’s simulation gait. The data were validated with the findings obtained using an F-socket. The FBG technology revealed sensitivity and accuracy similar to the ones obtained with the F-socket technology. Nevertheless, this new design can be used repeatedly in clinical and research setting, which is an important benefit compared to the F-socket mats that, due to drift and calibration issues, are usually discarded after each utilization.
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Recently, the technologies used to assess the interface pressure between the residual limb and the prosthetic socket, and the challenges found concerning the development of new solutions of sockets for limb prostheses were reviewed in [89]. In this chapter, FBGs are pointed out as one of these technologies. Additionally, the study observes that due to the high risk of the damaging of fibers, their applications are still limited, with further studies still required to confirm their suitability in this field. Nevertheless, the shown advantages of this technology over other sensing methodologies, especially regarding drift and linearity, and the constant low satisfaction level of the amputees, are enough motivations to continue investing on this technology.
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5.2. Rehabilitation exoskeletons
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The application of robotics, in particular robotic exoskeleton systems, to improve the wellbeing of debilitated patients is already being adopted. This technology is being used in human power augmentation, and its application has become more prominent, as to provide alternative solutions for physically limited people support in their daily movements [90].
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Exoskeletons are known to be wearable robots (robotic exoskeletal structures), with a strict physical and cognitive interaction with the human user, since, typically, it operates alongside human limbs. Although the scientific and technological research on the development and implementation of exoskeletons began in the early 60s, only recently, its application in rehabilitation and functional substitution of movements have been implemented in patients with motor disorders [91].
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Robotic exoskeletons provide unique methods for rehabilitation, by promoting the patient engagement in its training, and retrieving better quantitative feedback and improved functional outcome for patients. In a future perspective, the development of more effective exoskeletons is insight, with solutions for a real-time biological synergy-based exoskeleton, which will allow disabled patients to regain normal mobility capabilities [92, 93].
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The exoskeleton feedback is based on the information, which is retrieved from the embedded sensors in its structure. The current exoskeleton designs can have up to several dozens of sensors, to monitor variables, such as rotation, torque, tilt, pressure, position, velocity, neurological signals, among others. As the sensing systems integrated in the robot are the key devices for its proper performance, the research field on robotics already has a mature and overspread technology, offering good sensitivity, precise measurements, and competitive price, with sensing systems often based on solid-state sensing [64]. Nevertheless, this technology has also shown some drawbacks, due to its susceptibility to electromagnetic interferences resulting from the electric inertial motors. This interference could be enough to degrade the sensors signal, sending erroneous information to the control devices, leading the exoskeleton to perform erratically, and risking injuring the patient.
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Rehabilitation robotics applications also require the analysis of the body motion, in order to close control loops around defined joints. Commercial optical systems, such as Vicon, are considered the standard in human motion analysis. Although Vicon provides accurate position information, it has some significant limitations, such as high costs and limited measure volume, since it has to be used in laboratories with fixed equipment, which prevents its use in rehabilitation robotics applications [94]. On the other hand, soft exoskeletons require even more imperceptible sensors, typically sensor heads with thicknesses below 0.5 mm, in which electronic devices present some drawbacks, including long term instability, inconsistency, excessive drift, and the restriction to a small sensing area requiring the use of more sensors to monitor larger areas [64]. As an alternative to these electronic and optical sensors, the optical fiber sensors offer a small and robust solution, able to acquire kinematic and kinetic measurements, enhancing the exoskeleton performance by adding further responsiveness, controllability, and flexible motion. Nevertheless, the use of FBG sensors in exoskeletons is not yet widely explored, with only a limited number of studies reported. Recently, Domingues et al. reported the instrumentation of an insole with FBG sensors for plantar pressure monitoring [12, 32]. The reported wearable device is able to be adapted to exoskeletons structures, and dynamically retrieve the gait pattern of the patient.
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Although there is a shortage of studies regarding the adaptation of FBG sensing technologies to exoskeletons, for gait aid there are already some reports focusing on its application in robot fingers and glove-based devices [95, 96, 97]. Park et al. presented an FBG-based solution to monitor the force in exoskeleton fingers [95]. The authors embedded the optical fiber sensors in a finger-like plastic 3D mesh, inspired in the design of arthropod limbs, near the fingers base, for enhanced sensitivity. With the developed structure, it is possible to detect forces down to 0.02 N, with a resolution of ~0.15 N. The robot hand instrumented by Park et al. was able to be operated in a hybrid control scheme, with the fingers being capable to sense small forces, with the advantage of being able to have all the FBG sensors in one single fiber, due to FBGs multiplexing ability [95].
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Jiang et al. also described the design and production of an instrumented robotic hand with three fingers that enable both pinch and power grips. The optical FBG sensors were embedded in both the rigid plastic and soft skin material that constitutes the hand bone structure. In the rigid plastic material, the authors included eight FBGs for force sensing, while in the soft skin, they integrated six FBGs strain sensors for tactile monitoring, providing information on the location of the contact points [96]. Although there are already some studies related to the upper limbs motion aid, some work is still needed concerning the application of FBG technology to exoskeletons for gait rehabilitation of patients, which demands a direct focus on the lower limbs synergy between the patient and the exoskeleton.
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Key topics for further development of exoskeletons in rehabilitation scenarios include the need for robust human-robot multimodal cognitive interaction, safe and dependable physical interaction, true wearability and portability, and user aspects such as acceptance and usability [91]. It should be able to augment the ability and/or to treat skeletal parts, which are weak, ineffective, or injured due to a disease or a neurological condition. Therefore, the exoskeleton should be designed to work in parallel with human body and be actuated either passively and/or actively [98].
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6. Conclusion
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e-Health has been widely investigated in recent years, building on technological advances, especially in fields such as sensing and networking. Building on such gains, more innovations are expected to enhance the life quality of citizens, especially debilitated and elder ones. Gait analysis stands out as one promising solution, which can help in the rehabilitation of locomotive impairments, in addition to early diagnosis of other pathologies, such as ulcers in patients with diabetes. Various solutions have been proposed in the literature for close monitoring and analysis of gait. However, recently, FBGs have been pointed out as a promising alternative for a sensing technology to analyze gait movement, building on advantages such as small size, rigidness, low-cost, low power consumption, and minimally invasive. Due to its recent adoption and promising advantages, this chapter has provided a thorough review of research and design efforts of FBG-based sensors for gait analysis. The chapter initially explains the sensing principle underlying the FBG technology, after that the topic of gait analysis and the different phases of gait cycle are described, and then moves toward required e-Health monitoring solutions. Efforts toward the design of solutions to monitor plantar pressure and shear forces are discussed. Monitoring of plantar pressure, independently, is first presented, then simultaneous monitoring of plantar and shear forces is further elaborated. The chapter then moves toward monitoring of lower limb joints, which also play key roles in the gait analysis, since their wellbeing affects the gait cycle pattern. The use of optical fiber sensing in prosthetic and exoskeletons concludes the topics discussed in the chapter. This chapter represents a thorough review of research efforts in the design of optical fiber-based sensors in gait analysis, covering all related topics of monitoring plantar pressure, shear forces, knee and joints, and integration in prosthetic and exoskeletons.
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\n
Acknowledgments
\n
This work is funded by FCT/MEC through national funds and when applicable co-funded by FEDER – PT2020 partnership agreement under the projects, UID/EEA/50008/2013, UID/CTM/50025/2013 and 5G-AHEAD IF/FCT- IF/01393/2015/CP1310/CT0002. Nélia Alberto acknowledges PREDICT (FCT-IT-LA) scientific action; Cátia Tavares acknowledges her PhD grant PD/BD/142787/2018. The financial support from FCT through the fellowships SFRH/BPD/101372/2014 (M. Fátima Domingues) and SFRH/BPD/109458/2015 (Carlos Marques) is also acknowledged.
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\n',keywords:"fiber Bragg gratings, e-Health enablers, gait analysis, plantar pressure, foot shear pressure, gait joint monitoring, instrumentation of prosthetic limbs",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/64063.pdf",chapterXML:"https://mts.intechopen.com/source/xml/64063.xml",downloadPdfUrl:"/chapter/pdf-download/64063",previewPdfUrl:"/chapter/pdf-preview/64063",totalDownloads:833,totalViews:167,totalCrossrefCites:0,dateSubmitted:"June 7th 2018",dateReviewed:"August 24th 2018",datePrePublished:"November 5th 2018",datePublished:"April 24th 2019",dateFinished:null,readingETA:"0",abstract:"Nowadays, the fast advances in sensing technologies and ubiquitous wireless networking are reflected in medical practice. It provides new healthcare advantages under the scope of e-Health applications, enhancing life quality of citizens. The increase of life expectancy of current population comes with its challenges and growing health risks, which include locomotive problems. Such impairments and its rehabilitation require a close monitoring and continuous evaluation, which add financial burdens on an already overloaded healthcare system. Analysis of body movements and gait pattern can help in the rehabilitation of such problems. These monitoring systems should be noninvasive and comfortable, in order to not jeopardize the mobility and the day-to-day activities of citizens. The use of fiber Bragg gratings (FBGs) as e-Health enablers has presented itself as a new topic to be investigated, exploiting the FBGs’ advantages over its electronic counterparts. Although gait analysis has been widely assessed, the use of FBGs in biomechanics and rehabilitation is recent, with a wide field of applications. This chapter provides a review of the application of FBGs for gait analysis monitoring, namely its use in topics such as the monitoring of plantar pressure, angle, and torsion and its integration in rehabilitation exoskeletons and for prosthetic control.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/64063",risUrl:"/chapter/ris/64063",signatures:"Maria de Fátima Domingues, Cátia Tavares, Tiago Leite, Nélia Alberto,\nCátia Leitão, Carlos Marques, Ayman Radwan, Eduardo Rocon, Paulo Antunes\nand Paulo André",book:{id:"8271",title:"Applications of Optical Fibers for Sensing",subtitle:null,fullTitle:"Applications of Optical Fibers for Sensing",slug:"applications-of-optical-fibers-for-sensing",publishedDate:"April 24th 2019",bookSignature:"Christian Cuadrado-Laborde",coverURL:"https://cdn.intechopen.com/books/images_new/8271.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"220902",title:"Dr.",name:"Christian",middleName:null,surname:"Cuadrado-Laborde",slug:"christian-cuadrado-laborde",fullName:"Christian Cuadrado-Laborde"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"52661",title:"Dr.",name:"Maria",middleName:"Fátima",surname:"Domingues",fullName:"Maria Domingues",slug:"maria-domingues",email:"fatima.domingues@ua.pt",position:null,institution:null},{id:"72988",title:"Dr.",name:"Paulo",middleName:"Fernando Da Costa",surname:"Antunes",fullName:"Paulo Antunes",slug:"paulo-antunes",email:"pantunes@ua.pt",position:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"201517",title:"Dr.",name:"Catia",middleName:null,surname:"Leitao",fullName:"Catia Leitao",slug:"catia-leitao",email:"catia.leitao@ua.pt",position:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"206695",title:"Dr.",name:"Carlos",middleName:null,surname:"Marques",fullName:"Carlos Marques",slug:"carlos-marques",email:"carlos.marques@ua.pt",position:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"269571",title:"MSc.",name:"Cátia",middleName:null,surname:"Tavares",fullName:"Cátia Tavares",slug:"catia-tavares",email:"catia.tavares@ua.pt",position:null,institution:null},{id:"269572",title:"MSc.",name:"Tiago",middleName:null,surname:"Leite",fullName:"Tiago Leite",slug:"tiago-leite",email:"tmpl@ua.pt",position:null,institution:null},{id:"269574",title:"Dr.",name:"Nélia",middleName:null,surname:"Alberto",fullName:"Nélia Alberto",slug:"nelia-alberto",email:"nelia@ua.pt",position:null,institution:null},{id:"269575",title:"Dr.",name:"Ayman",middleName:null,surname:"Radwan",fullName:"Ayman Radwan",slug:"ayman-radwan",email:"aradwan@av.it.pt",position:null,institution:null},{id:"269576",title:"Dr.",name:"Eduardo",middleName:null,surname:"Rocon",fullName:"Eduardo Rocon",slug:"eduardo-rocon",email:"e.rocon@csic.es",position:null,institution:null},{id:"269577",title:"Prof.",name:"Paulo",middleName:null,surname:"André",fullName:"Paulo André",slug:"paulo-andre",email:"paulo.andre@lx.it.pt",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Fiber Bragg gratings: an introduction",level:"1"},{id:"sec_2",title:"2. Gait analysis: relevance and impact in an e-Health scenario",level:"1"},{id:"sec_2_2",title:"2.1. Gait analysis: gait cycle pattern",level:"2"},{id:"sec_3_2",title:"2.2. Gait parameters",level:"2"},{id:"sec_4_2",title:"2.3. Gait pattern monitoring: e-Health architecture",level:"2"},{id:"sec_6",title:"3. Plantar pressure and shear analysis",level:"1"},{id:"sec_6_2",title:"3.1. Plantar pressure sensors",level:"2"},{id:"sec_7_2",title:"3.2. Plantar pressure and shear sensors",level:"2"},{id:"sec_9",title:"4. Lower limb joints monitoring",level:"1"},{id:"sec_9_2",title:"4.1. Knee flexion-extension monitoring",level:"2"},{id:"sec_10_2",title:"4.2. Ankle flexion and dorsi-flexion monitoring",level:"2"},{id:"sec_11_2",title:"4.3. Tendons and ligaments monitoring",level:"2"},{id:"sec_13",title:"5. Prosthetic and exoskeletons applications",level:"1"},{id:"sec_13_2",title:"5.1. Prosthetic limbs",level:"2"},{id:"sec_14_2",title:"5.2. Rehabilitation exoskeletons",level:"2"},{id:"sec_16",title:"6. Conclusion",level:"1"},{id:"sec_17",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Kawasaki B, Hill K, Johnson D, et al. Narrow-band Bragg reflectors in optical fibers. Optics Letters. 1978;3:66-68. DOI: 10.1364/OL.3.000066\n'},{id:"B2",body:'Lam D, Garside B. Characterization of single-mode optical fiber filters. Applied Optics. 1981;20:440-445. DOI: 10.1364/AO.20.000440\n'},{id:"B3",body:'Hill K, Meltz G. Fiber Bragg grating technology fundamentals and overview. Journal of Lightwave Technology. 1997;15:1263-1276. DOI: 10.1109/50.618320\n'},{id:"B4",body:'Kashyap R, editor. Fiber Bragg Gratings. 2nd ed. San Diego: Academic Press; 2009. 632 p. ISBN: 9780080919911\n'},{id:"B5",body:'Meltz G, Morey W, Glenn W. Formation of Bragg gratings in optical fibers by a transverse holographic method. Optics Letters. 1989;14:823-825. 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State of the art. Proceeding Engineering. 2012;41:988-994. DOI: 10.1016/j.proeng.2012.07.273\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Maria de Fátima Domingues",address:"fatima.domingues@ua.pt",affiliation:'
Instituto de Telecomunicações, Campus Universitário de Santiago, Portugal
Department of Electrical and Computer Engineering, Instituto de Telecomunicações, Instituto Superior Técnico, University of Lisbon, Portugal
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The combination of pyrimidine nucleotides UTP and CMP is part of a peripheral neuro-regenerative process. Its pharmacological properties are stimulation of nerve cells proteins synthesis, nerve cell membranes synthesis, myelin sheaths synthesis, and neurite sprouting through P2Y receptors activation. Herein, chapter will be discussed the combination of UTP and CMP, and in some cases, the inclusion of cobalamin (B12 vitamin) that appears to have analgesic effects in neuropathic pain secondary to spine structural disorders assigned to a complex pharmacodynamic. 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The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
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