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1. Introduction
Glaucoma remains one of the leading causes of blindness worldwide. In England and Wales glaucoma is a major or contributory factor for 12-14% of all registrations for blindness and partial sight, second only to macular degeneration (Bunce et al., 2010). The worldwide burden is more significant, with glaucoma being the second leading cause of global blindness after cataract (Resnikoff et al., 2004). It has been estimated that 60.5 million people worldwide would be affected by glaucoma by 2010, with the figure expected to rise to 80 million by 2020 (Quigley and Broman, 2006).
Current treatments for glaucoma comprise the lowering of intraocular pressure by eye drops, laser procedures or drainage surgery. However, as implied by the statistics above, many patients experience significant visual loss due to degeneration of retinal ganglion cells (RGCs) despite the advances in the treatments currently available. The need for novel therapies exists for such patients, in particular those with end stage glaucoma, where the maintenance of a small number of surviving RGCs may yet permit a reasonable quality of life (Much et al., 2008). Stem cell therapies developed in the laboratory and translated to clinical practice provide an exciting and realistic hope for those affected by degenerative retinal diseases including glaucoma. This chapter will discuss three mechanisms by which stem cell therapies may potentially offer hope to patients with end stage glaucoma, namely local RGC replacement, optic nerve regeneration and stem cell mediated neuroprotection.
2. Sources of stem cells
Stem cells are characterised by their capacity for unlimited self-renewal and ability to differentiate into different cell types. The term progenitor cell is often applied to multipotent cells with a capacity for self-renewal, however this chapter will use the term stem cell to encompass all progenitor and precursor cell types.
An ideal candidate for developing stem cell based therapies would be readily available, easy to expand in culture, possess an acceptable long term safety profile and be autologous in nature, in order to avoid the need to modulate the host immune response and prevent rejection. Unfortunately a cell type that fulfils all these criteria remains elusive, however current research is directed towards a limited number of cell types which themselves exhibit certain advantages or disadvantages. Such cell populations may be sourced from three broad categories – embryonic or foetal tissue, adult tissue and reprogrammed cells (Figure 1).
Figure 1.
Summary of the sources of cells that may be potentially used for cell based therapies in glaucoma. (Figure composed using Motifolio Inc. diagrams)
2.1. Embryonic stem cells
Embryonic stem cells (ESCs) arise from the inner cell mass of the blastocyst, which is formed at about five days after fertilisation in humans. Such cells are often sourced from excess tissue obtained from embryo donations and fertility treatments and have been associated with ethical objections due to controversies regarding the use of such tissue for research. However they possess an unlimited capacity for self-renewal with an ability to differentiate into any of the cell types within the human body (Evans and Kaufman, 1981). ESCs have been proposed as ideal candidates for cell based therapies to treat human retinal diseases, due their capacity to migrate and differentiate into different cell types. ESCs have been differentiated in vitro into neurons (Bibel et al., 2004) as well as retinal pigmented epithelium (RPE) (Hirano et al., 2003), but controlling their differentiation has proved challenging. In the absence of appropriate intracellular signals, ESCs appear to differentiate towards a neuronal fate by default (Hemmati-Brivanlou and Melton, 1997), although differentiation into retina specific precursors often involves complex laboratory protocols (Osakada et al., 2009). A drawback of a pluripotent cell type is the risk of teratoma formation by uncontrolled growth of transplanted ESCs (Hentze et al., 2007) which remains a major concern. In addition, safety concerns derived from the observed chromosomal instability of cultured ESCs (Moon et al., 2011) require further investigation.
2.2. Adult tissue-derived stem cells
Adult tissue-derived stem cells offer an alternative for the development of cell based therapies which circumvents the ethical controversies surrounding foetal and embryonic tissue. Up to date, various sources of adult stem cells have been investigated for their potential ability to regenerate or replace retinal neurons which are described below.
2.2.1. Müller stem cells
The concept of central nervous system (CNS) regeneration from glial cells has become more accepted in recent years. Radial glia within the brain have been shown to act as neural stem cells within the developing mammalian nervous system, with the ability to generate both new neurons and glia (Merkle et al., 2004). Müller glia are the radial glia of the retina and have been shown to share a common lineage with retinal neurons and to derive from a common multipotent progenitor (Turner and Cepko, 1987). Studies in zebrafish have demonstrated that the ability of this species to regenerate retina is due to the presence of Müller glia with stem cell characteristics (Bernardos et al., 2007). Pharmacological depletion of the ganglion cell layer has been shown to induce a regenerative response in this species, which is characterised by Müller glial cells re-entering the cell cycle and producing neuronal progenitor cells that repopulate the ganglion cell layer (Fimbel et al., 2007).
Although a capacity for regeneration similar to that seen in the zebrafish has not been observed in higher species, a population of Müller glia with stem cell characteristics has been identified in the adult human retina (Lawrence et al., 2007). These cells express markers of neural progenitors in vitro and a proportion of them are able to express markers of mature retinal neurons in response to various culture conditions (Lawrence et al., 2007). Data from our laboratory exploring transplantation of these cells in a rodent model of ganglion cell depletion shows that pre-differentiated cells are able to integrate within the host RGC layer and cause partial restoration of the scotopic threshold response, which is a marker of RGC function in the rat electroretinogram (Singhal et al., 2009).
Such cell lines are easily obtained from cadaveric donor retinae (Limb et al., 2002) and further studies may reveal whether it is possible to obtain patient specific cell lines from peripheral retinal biopsies, leading to the possibility of developing an autologous grafting strategy.
2.2.2. Mesenchymal stem cells
Mesenchymal stem cells are most commonly obtained from bone marrow biopsies and umbilical cord blood and have been considered as candidates for autologous cell transplantation. Pharmacological methods have been used to mobilise haematopoetic stem cells from the bone marrow into the bloodstream to facilitate their harvesting for transplantation (Uy et al., 2008) rather than employing more invasive bone marrow trephine techniques. The mobilisation of mesenchymal stem cells is more difficult than that of haematopoietic stem cells, with several strategies showing promise in animal models (Pitchford et al., 2009). During development mesenchymal stem cells differentiate into bone, cartilage and muscle. However they have been reported to de-differentiate in vitro into other cell types including neurons and glia, although at present there is much controversy surrounding this ability (Krabbe et al., 2005). As will be discussed later, this cell type is likely to have a more significant role in neuroprotective strategies rather than neuronal replacement, due to their ability to secrete cytokines.
2.2.3. Oligodendrocyte precursor cells
Oligodendrocyte precursor cells (OPCs) are a type of neural stem cells responsible for the generation of oligodendrocytes during normal development, and for re-myelination of the white matter in the adult CNS (Watanabe et al., 2002). They are the commonest proliferative cell type in the adult CNS (Dawson et al., 2003). OPCs have been reported to exhibit some stem cell characteristics (Nunes et al., 2003) and neuroprotective potential in vitro (Wilkins et al., 2001), which have led to investigations into their potential use for stem cell based therapies to treat neurodegenerative conditions including glaucoma.
2.2.4. Olfactory ensheathing cells
Olfactory tissue is unique within the CNS, in that continuous removal and regeneration of tissue occurs throughout life. The sensory axons that project to the olfactory bulb are closely associated with specialised cells known as olfactory ensheathing cells (OECs). OECs are glial cells which lie within the nasal mucosa and olfactory bulb and characteristically ensheathe axons of the olfactory nerve. Transplantation of these cells has been used to support regenerating axons in animal models of spinal cord injury and to restore function (Li et al., 2008). Due to the relative ease by which nasal mucosal biopsies may be obtained, these cells may potentially constitute a source of cells through which autologous transplantation strategies may be developed in the future. There is considerable molecular heterogeneity and functional diversity of OECs with much work still taking place in animal models (Su and He, 2010). Further investigation into the gene expression and cell fate determination of these cells will facilitate the development of more robust protocols to isolate and expand the OEC progenitor/stem cell population within this complex tissue.
2.3. Induced pluripotent stem cells
The characterisation of induced pluripotent stem cells (iPS) cells has created an alternative potential cell source for transplantation in regenerative medicine. Takahashi & Yamanaka (Takahashi and Yamanaka, 2006) demonstrated that by retroviral induction of Oct3/4, Sox2, c-Myc and Klf4, pluripotent stem cell lines could be derived from fibroblast cultures. Further study of these “reprogrammed” iPS cells showed that their biological behaviour was indistinguishable from that of ESCs (Wernig et al., 2007). Subsequent modifications to the original protocol have enabled iPS cell lines to be created without the use of viral vectors (Okita et al., 2008) and without induction of the oncogene c-Myc (Nakagawa et al., 2008) which may be associated with an increase in tumorigenesis. However before such cells can be used in human therapies, safety concerns regarding the effect of the reactivation of pluripotency, alterations in target cells and characterisation of these cells need to be addressed (Jalving and Shepers, 2009).
3. Potential of stem cells for retinal ganglion cell replacement
One of the strategies to restore vision in glaucoma patients after RGCs have been lost or irreversibly damaged is their functional replacement by autologous or heterologous transplantation.
It is generally accepted that damage to the neural retina during glaucoma is restricted to the impairment of function and subsequently degeneration of RGCs (Kerrigan-Baumrind et al., 2000; Quigley and Green, 1979), making these cells ideal candidates for early cell replacement strategies. Recent evidence indicates, however, that in addition to damage to the optic nerve, prolonged elevation of intraocular pressure may also induce degeneration or loss of function of other retinal neural cell types, most notably of amacrine cells (Hernandez et al., 2009). Similar observations have been made in other retinal degenerative diseases such as retinitis pigmentosa, which is characterized not only by the loss of rod, but also of cone photoreceptors and by major morphological changes of other surviving retinal neurons (Fariss et al., 2000). Therefore early intervention may be preferable, if cell replacement strategies are to succeed, in order to restrict the number of cells types which need to be transplanted. In addition, the correct establishment of synaptic connections between transplanted RGC and native cells may be facilitated, providing that the stratified structure of the retina with its circuitry and at least some of the connections of the RGCs through the optic nerve and the optic chiasm to the lateral geniculate nucleus are preserved.
At present, research has mostly focused on the identification of suitable cells, which can be differentiated towards RGCs and their precursors, as well as the experimental conditions required for the optimal expression of their molecular markers. Furthermore, a small number of studies have investigated the electrophysiological properties of the RGC precursors generated in vitro and their transplantation into in vivo models. Although research has been conducted into the functional replacement of RGCs, and potential candidate stem cells have been identified, there are currently no cell-based therapeutic options that are either available to patients or tested in clinical trials. Establishment of cell based therapies to replace or regenerate RGCs, as with any other cell based therapy, would require validation protocols for safety, efficacy and long term survival of the transplanted cells. In the following sections we will review the potential of human ES cells, iPS cells and adult human Müller stem cells for the generation and transplantation of RGCs and their precursors.
3.1. Human embryonic stem cells as a prospective source of RGCs
Most evidence for the differentiation of ESCs into retinal progenitors and their potential for retinal transplantation has been provided by animal studies. Murine ESCs have been shown to generate RGC-like cells in vitro by differentiation protocols using various growth and differentiating factors. This has resulted in the expression of markers such as Ath5, Brn3b, RPF-1, Thy-1 and Isl-1 (Jagatha et al., 2009), which are characteristically expressed by RGCs. Rx/rax-expressing murine ESCs, which were treated with retinoic acid to induce neural commitment, expressed markers of RGCs and horizontal cells, displayed electrophysiological properties consistent with RGCs and were able to integrate ex vivo into mouse retinae (Tabata et al., 2004). Importantly, when mouse ESCs, which had been differentiated into eye-like structures, were co-cultured with retinal explants following damage to the inner retinal cells, migration into the RGC layer as well as expression of the RGC markers HuD and Brn3b were observed (Aoki et al., 2007).
Proof of concept that human ESCs can successfully differentiate into retinal neurons has been provided by xenologous transplantation. Following intravitreal injection into the adult mouse eye, human ESCs formed structures reminiscent of the developing optic cup and expressed markers of a wide range of retinal progenitors and neurons (Aoki et al., 2009).
In addition transplanted murine ESCs have been shown to integrate into the inner and outer nuclear as well as the inner plexiform layers of the retinae of host mice with retinal degeneration. Transplanted cells adopted a morphology consistent with and displayed molecular markers of a wide range of retinal neurons, such as βIII-tubulin and NeuN, calretinin, PKC-α and rhodopsin (Meyer et al., 2006).
In addition, Lamba et al. have recently provided evidence that human ESCs can generate retinal progenitors with high efficiency, expressing a number of molecular markers usually observed in the developing retina. These cells have shown exceptional correlation between their levels of expression of genes specific for differentiating neurons and the developmental stage of the retina, including markers of RGC and amacrine cells, which constitute the inner retina, i.e. HuD/C, Pax6, neurofilament-M and Tuj1 (Lamba et al., 2006).
Transplantation of human ESC-derived neural and retinal progenitors into animal models of retinal degeneration has been extensively studied by several groups. Neural precursors derived from human ESCs have been transplanted subretinally and intravitreally into mice, where they have been shown to be able to integrate into the retina and survive for long periods of time after grafting. Although these cells mostly displayed photoreceptors markers (Banin et al., 2006), such findings have provided evidence that human ESCs have the potential to form retinal neurons following engraftment. These results have been further supported by additional evidence that human ESCs can adopt a neural morphology and express neural retinal markers following transplantation and differentiating treatment in an in vivo murine model of RGC depletion, without giving rise to teratomas (Hara et al., 2010).
Although human ESCs have shown potential for use in RGC replacement therapies for glaucoma, major disadvantages associated with the use of human ESCs still remain. Ethical constraints relating to the use of these cells, their limited availability and safety issues regarding teratoma formation are likely to curtail the translation of ESCs for human RGC replacement to the clinical setting. Further work should therefore be aimed towards identifying alternative sources of cells that may safely and efficiently replace these cells in the glaucomatous eye without these ethical and practical constraints.
3.2. RGC differentiation of induced pluripotent stem cells
Some of the disadvantages of human ESCs have been addressed by the development of iPS cells, which have been proposed as a viable source of cells for autologous transplantation. The generation of iPS cells does not require the destruction of embryonic tissue and therefore does not have the same ethical implications as work with ESCs, which have been a limitation in a large number of developed countries. In addition, iPS cells can be derived from and tailored to the patient, making cells more widely available and rendering immunosuppressive therapy following transplantation redundant. To date, few studies have investigated the potential for iPS cells in stem cell treatment of retinal degenerative diseases, although recently some progress has been made to generate iPS cell-derived RGC-like cells.
Parameswaran et al. have recently provided evidence that iPS cells, which originated from reprogrammed mouse embryonic fibroblasts by transfection with Oct3/4, Sox2, Klf4 and c-Myc, can give rise to both RGCs and photoreceptors in vitro. They reported that neural induction and exposure to conditioned media from E14 rat retinal cells augmented the expression of Ath1, Brn3b, RPF1 and Irx2, which regulate RGC differentiation, while the retinal progenitor markers Sox2, Rx and Chx10 were reduced. Importantly, the same study reported that the generated RGC-like cells displayed tetrodotoxin-sensitive voltage-dependent sodium currents, which is a hallmark of functional neurons (Parameswaran et al., 2010).
Chen et al. have used a similar approach by creating iPS cells from reprogrammed murine fibroblasts, which had been transduced with Oct3/4, Sox2, c-Myc and Klf4, to generate RGC-like cells. These cells expressed markers of retinal progenitor cells, i.e. Pax6, Rx, Otx2, Lhx2 and nestin, the levels of which were attenuated after differentiation towards a RGC fate. Differentiation was accompanied by expression of markers of RGC progenitors such as Brn3b and Isl-1, as well as Thy-1.2, a marker of mature RGCs. However, transplanted cells did not engraft into murine retina following intravitreal injection and they retained their pluripotency as demonstrated by their ability to form intraocular teratomas (Chen et al., 2010).
These studies illustrate major problems associated with the transplantation of cells derived from iPS cells, which need to be addressed. In particular, as described by Chen et al., the ability of iPS to form teratomas and therefore their potential to form cancerous growths may prove problematic. These findings suggest that preparation of iPS cell derived RGC progenitors for individual patients may need to undergo extensive validation for safety and efficacy, making them likely to be impractical and expensive for autologous therapies.
3.3. Müller stem cells as a source of RGCs for glaucoma therapies
The lack of regenerative potential of the human retina in vivo may be due to presently unknown inhibitory factors within the fully developed retina, since human Müller glia cells with stem cell characteristics have been reported to retain the ability to divide indefinitely in vitro (Limb et al., 2002). Until further research can elucidate the nature of these inhibitory factors, it is however unlikely that treatment options involving re-activation of endogenous Müller stem cells in the adult human retina can be developed. Cell replacement by transplantation of Müller stem cell-derived retinal neural progenitors may therefore currently offer a more promising strategy to restore visual function after irreversible damage or substantial loss of RGCs in glaucoma.
Müller glia with stem cell characteristics have been demonstrated to be predominantly located in the peripheral sections of the adult human retina (Bhatia et al., 2009). Human Müller stem cells can be easily isolated from cadaveric donor retina, and these cells can be grown and expanded indefinitely in vitro, and express markers of neural progenitor cells, such as Sox2, Notch1, Pax6, Shh and Chx10, as well as markers of Müller glia cells and retinal neurons e.g. CRALBP, HuD, PKC, and peripherin (Lawrence et al., 2007). When cultured under differentiating conditions in the presence of extracellular matrix and growth factors, enriched populations of cells expressing markers of specific retinal neurons can be obtained (Bhatia et al., 2011; Lawrence et al., 2007; Singhal et al., manuscript submitted).
This is illustrated by the fact that Müller stem cells cultured under various conditions develop a neuronal morphology and upregulate their expression of retinal neural and RGC precursor markers such as βIII-tubulin, Brn3b, Isl-1 and rhodopsin. Simultaneously expression levels of the neural progenitor marker Pax6 and the glial cell marker vimentin are also attenuated (Bhatia et al., 2011), indicating that existing Müller stem cell lines may have the potential to form RGC precursors.
However at present, intraocular transplantation studies using Müller stem cells have been conducted using mostly undifferentiated cells. Initially Lawence et al. reported integration of subretinally transplantated Müller stem cells into neonatal Lister Hooded rats and adult dystrophic RCS rats. Engrafted cells were shown to express the photoreceptor markers recoverin and rhodopsin, the RGC marker HuD as well as calretinin, which identifies RGCs and amacrine cells (Lawrence et al., 2007). Although integration of undifferentiated Müller stem cells has been observed after subretinal transplantation into adult dystrophic RCS rats, these cells were located in all retinal layers and did not selectively locate to the ganglion cell layer or adopt RGC-like morphology (Singhal et al., 2008).
Undifferentiated Müller stem cells have also been used for intravitreal and subretinal transplantation in a rat model of glaucoma. Although only few of the transplanted cells expressed the Müller glia and astrocyte marker GFAP, expression of βIII-tubulin indicates that at least some of the transplanted cells were able to adopt a neural phenotype. Interestingly, many of the grafted cells showed a migratory phenotype and aligned towards the host retina, in particular the optic nerve head, although they did not migrate and disseminate within the retina (Bull et al., 2008).
Recently it has been reported that Müller stem cells can be differentiated into RGC precursors, which integrate into the retina after intravitreal injection and can partly restore function in RGC-depleted retina as measured by electroretinography (Singhal et al., 2009). Although at present understanding of Müller stem cell differentiation towards RGC precursors is limited, previous work with this cell type has shown that they may have the potential for therapeutic regeneration of RGC function in glaucoma. In particular the maturity of Müller stem cells may potentially decrease the risk of teratoma formation. In addition, their ontogenetic proximity to retinal neurons may likely facilitate the development of protocols not only to successfully derive and transplant RGC precursors, but also to induce endogenous retinal regeneration without the need for transplantation.
3.4. Barriers to successful stem cell transplantation
Although some progress has been made regarding the successful production, delivery, integration and survival of RGC progenitors, major obstacles for successful engraftment and functional restoration remain and will be discussed below. These include the host immune response and extracellular matrix, which form a barrier for cell integration into the healthy host retina. During retinal degenerative processes, there is abnormal deposition of extracellular matrix, mainly chondroitin sulphate proteoglycans, which are responsible for the formation of glial scarring (gliosis). In addition, accumulation of microglia occurs, which has been shown to surround transplanted cells, inhibit their migration and induce their death (Singhal et al., 2008). Additionally, effective migration and integration of the transplanted cells has been suggested to be dependent upon their ontogenetic stage (MacLaren et al., 2006). These requirements will be discussed in more detail below.
3.4.1. Modulation of the host extracellular matrix
Various transplantation studies using a wide range of cells derived from ESCs as well as Müller stem cells have concluded that successful engraftment into the healthy adult retina is impeded by extracellular matrix components and the physical barrier of the inner limiting membrane (Chacko et al., 2003; Johnson et al., 2010b). This is unlikely to be influenced by the route of cell delivery, since transplantation by either intravitreal or subretinal injection did not yield integration of transplanted cells into the healthy host retina in the adult rat (Bull et al., 2008). In addition dissemination of the transplanted cells within the retina has been reported to be highly restricted (Banin et al., 2006). Conversely, integration of transplanted cells has been demonstrated in neonates (Chacko et al., 2003) or in the adult retina following injury (Chacko et al., 2003), indicating that these environments may be more permissive for successful engraftment.
Glaucomatous changes of the retina are generally accompanied by reactive gliosis as well as remodelling and deposition of extracellular matrix components (Guo et al., 2005). Increased production of chondroitin sulphate proteoglycans (CSPGs), which have been shown to inhibit rat optic nerve regeneration after crush injury (Selles-Navarro et al., 2001) and reduce axonal and dendritic growth (Zuo et al., 1998), has been demonstrated following CNS and spinal cord damage (Bradbury et al., 2002). CSPGs have also been reported to form a barrier to cell migration following transplantation in animal models (Singhal et al., 2008) (Figure 2). Furthermore, degradation of CSPGs has been shown to enhance dendritic and axonal regeneration following brain and spinal cord injury (Bradbury et al., 2002; Zuo et al., 1998).
As a result of these findings, the effects of modulation of extracellular matrix components have recently been explored in conjunction with retinal progenitor transplantation. Evidence has been provided to show that co-administration of chondroitinase ABC or erythropoietin, which has been reported to upregulate MMP-2 (Wang et al., 2006), greatly increases the number of cells, which successfully integrate into the host retina (Singhal et al., 2008; Suzuki et al., 2007). Similarly, the integration of murine neonatal retinal cells into the adult rat host retina by ex vivo transplantation has been shown to be augmented by the induction of MMP-2 (Suzuki et al., 2006).
Figure 2.
Confocal imaging of rodent retina 2 weeks after subretinal transplantation of Müller stem cells. Sections on the left column shows the transplanted cells (green) surrounded by N-terminal CSPG, neurocan and versican (red). The middle column shows the same sections under Nomarski illumination to illustrate the accumulation of CD68 positive microglia (black). The column on the right shows the merged images under Nomarski illumination illustrating co-localization (arrows) of CD68 positive cells and CSPGs (red) surrounding the transplanted cells (green) (from Singhal et al., 2008).
3.4.2. Modulation of the host immune response
A successful transplantation scheme requires long term survival of the grafted cells. Allogeneic grafts induce a host immune response, leading to rejection and failure of the transplant. However cell survival is greatly increased by systemic immunosuppression of the recipient following allogeneic cell transplantation into the eye (West et al., 2010). Triple therapy with oral immunosuppressives has recently been used to increase survival of xenografted Müller stem cells to 2 to 3 weeks, although microglia and macrophage activation was observed and transplants were destroyed after 4 weeks (Bull et al., 2008).
Activation of phagocytic microglia, the resident immune cells of the CNS, which may promote axonal degeneration of RGCs and of the optic nerve, is frequently observed during glaucoma (Ebneter et al., 2010; Yuan and Neufeld, 2001). In transplantation models, microglia prevent the migration of transplanted cells into the retina (Singhal et al., 2008) (Figure 3). Suppression of the intraocular immune response and inhibition of microglial activation by intravitreal injection of triamcinolone acetonide may therefore promote the integration and the survival of RGC precursors into retinae with glaucomatous changes. Intravitreal injection of triamcinolone acetonide in combination with oral immunosuppression and anti-inflammatory medication has previously been shown to greatly reduce microglial activation against the xenograft (Singhal et al., 2008; Singhal et al., 2010).
Figure 3.
A. Müller stem cells (green) accumulate in the subretinal space and do not migrate into the retina. Middle image shows Nomarski illumination identifying CD68 positive cells (black) in the same retinal section. Right figure shows Nomarski illumination identifying co-localization of transplanted cells with microglial cells expressing CD68 (black). B. Transplanted cells can be seen forming a large cluster in the subretinal space 2 weeks after transplantation. Middle image shows localization of microglia (black) around the transplanted cells (green). Right figure shows microglia (black) surrounding the transplanted cells (green) and resembling a granuloma-type structure (From Singhal et al., 2008).
In experimental animal models, immune-tolerization of embryos or neonates by intraperitoneal injection of grafted cells may be used to further reduce the host immune response (Billingham et al., 1953).
3.4.3. Ontogenetic stage of transplanted cells
Currently the role played by the ontogenetic stage of transplanted RGC precursors upon their integration into host retina, as well as on functionality of the engrafted cells, has not been investigated. Previous transplantation studies have demonstrated that stem cells isolated from adult individuals rarely migrated into the healthy adult retina (Johnson et al., 2010a; Lawrence et al., 2007; Singhal et al., 2008), while embryonic and neonatal retinal progenitors and other stem cells have been shown to successfully integrate into the host retina (Warfvinge et al., 2001; Wojciechowski et al., 2004), suggesting that the developmental stage of the transplant may be crucial for successful migration and functional integration.
Several studies have investigated the role of the developmental stage of grafted retinal neurons for successful incorporation into the host retina. Based on this work, it has been concluded at least in the case of photoreceptor transplantation that early postnatal post-mitotic precursors or cells of a similar ontogenetic stage are the most promising candidates for transplantation in terms of their ability to migrate and disseminate into the retina and differentiate towards a functional phenotype (MacLaren et al., 2006).
However, more recent studies have suggested that there may be no need for transplantation of photoreceptor progenitors for these cells to integrate, as fully mature photoreceptors retain the ability to integrate into the mature retina upon transplantation (Gust and Reh, 2011). Moreover, integration of photoreceptors derived from human Müller glia into the degenerated rat retina has shown to be independent from NRL expression by these cells (Jayaram et al., unpublished observations).
In addition the developmental phase of transplanted cells will likely have major implications on treatment safety, with less differentiated cells posing a greater risk of tumorigenesis. In fact, a number of studies using cells derived from embryonic stem or iPS cells have reported the occurrence of teratomas (Arnhold et al., 2004; Chen et al., 2010), whereas no formation of cancerous growths was reported after transplantation of adult-derived stem cells.
In summary, future research will be needed to elucidate the effects of the ontogenetic stage of transplanted RGC precursors on graft integration, function and safety.
3.5. Strategies to measure functional outcome
With the development of methods for the transplantation of RGC in glaucoma, the measurement of functional outcomes will become increasingly important. It can be anticipated, however, that these will encompass techniques currently available for the monitoring of disease progression. Electrophysiological measurements are widely used to assess glaucomatous damage both in patients and in experimental animal models and will likely continue to play a major role in evaluating treatment success. Some of these protocols have been standardized by the International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines (Holder et al., 2007; Marmor et al., 2009), although they may be complemented by other methods established for laboratory use.
The pattern ERG is currently one of the most useful techniques to assess glaucomatous damage in patients. It generally utilizes a black and white checkerboard stimulus with pattern reversal as prescribed by the ISCEV standards (Holder et al., 2007). The pattern ERG has been shown to be reduced in patients with glaucoma and correlates with visual field defects (Wanger and Persson, 1983). In addition the use of variable check sizes may be advisable to assess the extent of glaucomatous change (Bach et al., 1988). Recently multifocal pattern electroretinograms have been demonstrated to be reduced in glaucoma patients (Monteiro et al., 2011; Stiefelmeyer et al., 2004), although other studies have reported that localized reductions of the signal amplitude could not be correlated with visual field defects (Klistorner et al., 2000). Since this method requires good accommodation and fixation (Holder et al., 2007), it is widely used in human subjects, while its applicability to animal models is limited.
Preclinical studies will likely favour methods employing Ganzfeld stimulation, which are relatively easy to apply to a laboratory setting. The most commonly used of these is the scotopic threshold response, a low intensity light response with stimulation below the psychophysical threshold, which has be ascribed to RGC function, although it may species-dependently contain contributions from amacrine cells (Frishman et al., 1996; Korth et al., 1994; Sieving, 1991). More recently the photopic negative response has been established as a measure of RGC function (Viswanathan et al., 1999), although other cellular origins, such as glia and amacrine cells, have been suggested (Machida et al., 2008). However, at present this has not been assimilated into ISCEV guidelines.
Pattern reversal, pattern onset/offset or flash visual evoked potentials can be used to assess RGC and optic nerve function. Although they are usually employed in a clinical setting (Odom et al., 2010), especially the flash, the pattern onset/offset visual evoked potentials may potentially be used for experimental applications in animals (Huang et al., 2011; Ver Hoeve et al., 1999). Recently multifocal mapping of visual evoked potentials has been developed (Hasegawa and Abe, 2001), but has not been widely applied to practice. However, for clinical purposes perimetry will remain important, as gains in the visual field of patients may indicate whether potential RGC cell therapies are successful.
4. Optic nerve regeneration
It has been considered critical for the functional success of RGC replacement therapies in glaucoma that transplanted cells form axons, restore the optic nerve and establish new connections with their physiological targets. The optic nerve has traditionally been thought to be incapable of renewal, with axonal damage invariably leading to the degeneration of RGC somata and resulting in the irreparable loss of vision.
A range of studies has investigated the effects of peripheral nerve transplantation on RGC survival as well as axonal sprouting and re-growth. Extensive evidence has been presented that autologous grafts of peripheral nerves can protect axotomized RGCs from cell death and in addition can promote the regeneration and re-growth of axons. Some studies have even shown that after transplantation of peripheral nerves, RGCs regenerated long axons, which extended into the superior colliculus, where they formed synapses in their physiological target region (Aguayo et al., 1991; Vidal-Sanz et al., 1991).
Other cell types such as OECs and macrophages have been suggested to augment axon formation. The promoting effect of OECs on neurite formation may likely be contact-mediated (Leaver et al., 2006). In addition, macrophages have been reported to promote axonal growth, probable through the release of oncomodulin and activation of the protein kinase Mst3b and Ca2+/calmodulin kinases as downstream effectors (Lorber et al., 2009 ; Yin et al., 2006).
Distinct growth factors have been identified which may affect optic nerve regeneration. A combination of fibroblast growth factor 2 (FGF2), neurotrophin 3 (NT3) and brain derived neurotrophic factor (BDNF) (Logan et al., 2006) has been reported to stimulate axonal outgrowth of RGCs. Furthermore a range of molecules have been identified, which can reduce dendrite formation, e.g. Nogo-A, myelin-associated glycoprotein and components of the extracellular matrix such as proteoglycans (Koprivica et al., 2005; Su et al., 2009; Wong et al., 2003). Many of these inhibitory factors converge on the small G-protein RhoA, inhibition of which has been shown to result in stimulation of axon formation (Bertrand et al., 2005).
Interestingly, the length of new axons grown from cultured RGCs has been reported to be reduced after the developmental age at which synaptic connections in the superior colliculus are formed, although the proportion of cells generating axons was not altered (Goldberg et al., 2002).
The formation and guidance of axons from RGCs to their targets during development have been intensively investigated. Netrins, semaphorins, laminin, erythropoietin-producing hepatocellular receptor/Eph receptor-interacting protein, Wnt and slits have been shown to act as chemo-attractants and repellants during optic nerve development in the embryo (Erskine and Herrera, 2007; McLaughlin and O\'Leary, 2005). Interestingly, some of these guiding signals have been reported to be retained or restored following injury in the adult brain (Bahr and Wizenmann, 1996), which may help to guide axons formed by transplanted RGCs to the right targets. Additionally it has been shown that following transplantation of embryonic retinal tissue, connections to the superior colliculus are successfully established (Seiler et al., 2010).
5. Stem cell mediated neuroprotection in glaucoma
The pathophysiological mechanisms implicated in RGC loss seen in glaucoma have led to the development of neuroprotective strategies becoming a major focus of current glaucoma research (Danesh-Meyer, 2011). Contemporary research in stem cell mediated neuroprotection for glaucoma has been developed on the backdrop of promising work performed in models of neurodegenerative disease affecting other parts of the CNS.
Glaucomatous RGC loss and neuronal degeneration in other neurodegenerative conditions share mechanisms such as oxidative stress, impairment of axonal transport, excitotoxicity and inflammation (Baltmr et al., 2010) making neuroprotective strategies relevant to patients affected by both conditions.
Stem cell derived strategies for neuroprotection, if successful, offer several theoretical advantages over conventional pharmacological approaches. Should transplanted cells integrate within the host retina, it is possible that a single treatment may provide long term neuroprotection offering support to surviving neurons. The observation that endogenous neural stem cells are able to migrate to the site of injury in ischaemic stroke and differentiate into mature neurons (Felling and Levison, 2003), gives rise to the possibility of a similar phenomenon occurring with transplanted cells in the context of glaucoma, with such cells potentially responsible for the provision of local support.
Stem cells are able to facilitate local neuronal survival by the production of several neurotrophic factors. This multifactorial effect has been demonstrated in animal models of CNS disease (Corti et al., 2007) and work in a rodent model of Parkinson’s Disease showed that neural stem cell transplantation conferred a more significant neuroprotective benefit than both a single injection of neurotrophins or prolonged delivery via local infusion (Yasuhara et al., 2006). Transplantation of neural progenitors in animal models of neurodegenerative disease has been shown to confer neuroprotection via an immunomodulatory mechanism (Pluchino et al., 2005). Alteration of the microenvironment surrounding damaged RGCs, perhaps through immune mediated actions of transplanted cells, may help promote local neuronal survival.
A major beacon of hope in stem cell research is the concept of autologous transplantation. Such a strategy would minimise the risk of graft rejection and prevent a lifetime of potentially toxic immunosuppressive therapy for patients. Neuroprotective strategies involving Müller stem cells, bone marrow derived mesenchymal stem cells and OECs offer realistic potential for autologous transplantation. However, more work is still necessary to design practical approaches to obtain suitable tissue for this purpose, as well as to derive functional cells that can be used for transplantation. Should current concerns regarding the safety of iPS cells for therapeutic use be overcome (Jalving and Shepers, 2009), these reprogrammed adult somatic cells offer an exciting avenue for the development of autologous therapies in the future.
Mesenchymal stem cell mediated neuroprotection has been demonstrated following transplantation in various models of retinal degeneration (Arnhold et al., 2007; Inoue et al., 2007; Lu et al., 2010; Zhang and Wang, 2010). This phenomenon is likely to be secondary to the secretion of neurotrophic factors such as BDNF, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), insulin like growth factor 1 (IGF1) and FGF2 (Cho et al., 2005; Labouyrie et al., 1999) which are known to offer protection to damaged retina. These observations, coupled with promising results showing neuroprotection in models of CNS degenerative disease (Andrews et al., 2008; Karussis et al., 2008; Parr et al., 2007; Torrente and Polli, 2008), have led to this category of stem cells becoming a focus for the development of cell-based neuroprotective strategies to treat glaucoma.
Disruption of the retrograde axonal transport of BDNF has been shown to be involved in the pathophysiology of glaucoma (Pease et al., 2000) and attempts to upregulate expression of BDNF (Martin et al., 2003) and CNTF (Pease et al., 2009) using gene therapy have been shown to attenuate RGC loss in experimental models. A reduction in RGC loss has been observed in rodents with raised intraocular pressure following intravitreal transplantation of mesenchymal stem cells (Johnson et al., 2010a; Yu et al., 2006). The latter reported increased levels of CNTF, BDNF and FGF within the retinae of treated eyes, which were hypothesised to be responsible for this neuroprotective effect. Survival of the cells was observed at up to five weeks, but currently there is a lack of data describing long term graft survival and a prolonged neuroprotective effect, both of which will be essential for such a therapy to be translated to the clinic.
Despite suggestions that mesenchymal stem cells may possess a capacity to migrate from the systemic circulation into diseased tissue, migration into chronically damaged neural tissue is regarded as being limited, and hence strategies for cell delivery would be best served by direct injection into affected tissue. In the context of glaucoma models, cells administered via an intravenous approach were unable to be detected in the eye and had no effect in attenuating RGC loss (Johnson et al., 2010a).
The neuroprotective effect of transplanted cells may be optimised further by enhancing the neurotrophin secreting ability of cells through either cytokine driven protocols or gene therapy techniques. Proof of concept for this idea was demonstrated in a model of cerebral ischaemia where intravenous infusion of mesenchymal stem cells genetically modified to deliver BDNF to the cerebral circulation provided a greater neuroprotective effect than untreated cells (Nomura et al., 2005). This principle has been successfully applied to a rodent model of RGC damage induced by optic nerve transection (Levkovitch-Verbin et al., 2010). Mesenchymal stem cells were induced to secrete high levels of BDNF, VEGF and Glial Derived Neurotrophic Factor by using a cytokine driven protocol in vitro. Intravitreal transplantation of both modified and untreated mesenchymal stem cells produced similar neuroprotective effects when compared to sham injection. One interpretation of these findings would be that even small amounts of trophic factor release, as seen with untreated cells, may confer neuroprotection. However a more realistic argument may be that the severity of optic nerve transection is such that even the higher levels of trophic factors delivered by the modified cells would be unlikely to prevent RGC death. Further research into the role of cell populations that have enhanced neurotrophin secreting capability in models of glaucoma may provide further insight into the therapeutic potential of such an approach.
Inflammation has frequently been associated with neurodegenerative disease. It is commonly observed as a consequence of acute injuries including trauma and stroke, but is also a characteristic feature of demyelinating disease where autoimmune processes are central to the pathophysiology. Mesenchymal stem cells derived from the bone marrow are known to have the ability to modulate the inflammatory response. There is much hope and optimism in the field of multiple sclerosis that these cells may provide in situ immunomodulation and neuroprotection (Payne et al., 2011) with the results of clinical trials eagerly awaited. It is quite feasible that this mechanism may be applicable to glaucomatous RGC loss, however further studies are required to investigate this possibility.
The observation that OPCs exhibit neuroprotective properties in vitro (Wilkins et al., 2001) has led to some interest in their role as a potential candidate for cell-based therapies in a model of glaucoma. Interestingly OPCs were only able to demonstrate a neuroprotective effect following concomitant activation of pro-inflammatory cells using zymozan (Bull et al., 2009). The neuroprotective effect was not contact-mediated and was attributed to the release of diffusible trophic factors from the activated OPCs. A potential risk of transplanting such cells into glaucomatous eyes is the potential of excessive myelination, which carries the theoretical risk of blocking the transmission of light within the eye and reducing the electrical conduction of RGCs. However further studies into the nature of the trophic factors released by these cells may aid the design of further novel neuroprotective strategies to treat glaucoma.
OEC transplantation has been observed to increase axonal regeneration in models of spinal cord injury (Ramon-Cueto and Valverde, 1995). These initial observations led to the development of further studies into the potential of these cells to develop novel treatments for optic nerve disorders and glaucoma. In vitro work has demonstrated that OECs cause ensheathment of RGCs without the process of myelination occurring (Plant et al., 2010). Transplantation of OECs into the distal stump of transected optic nerves provided further evidence of regeneration of several axons (Li et al., 2003; Wu et al., 2010) that were supported by the transplanted cells. Following transretinal delivery into normal rodent eyes, OECs migrate along the RGC layer into the optic nervehead demonstrating ensheathment of RGC axons by the cytoplasm of transplanted cells (Li et al., 2008). It is possible that this process may provide some mechanical support to compromised axons, which may subsequently be able to maintain sufficient functional vision if therapies can be developed for patients with end stage glaucoma.
Evidence from models of spinal cord transection suggests that OEC transplantation is associated with an increased secretion of neurotrophins such as BDNF which appears to correlate with the neuroprotective effect (Sasaki et al., 2006). However it was not clear whether the BDNF was secreted by the transplanted cells or by activation of endogenous cells. Attempts to combine OEC transplantation with concomitant neurotrophin administration have shown promising results to date. Combination therapy in a model of optic nerve crush resulted in restoration of the latency of the visual evoked potential to almost 90% of normal levels with retrograde RGC labelling suggesting of axonal regeneration (Liu et al., 2010).
Future studies using these cells directed towards attenuating glaucomatous RGC loss may focus upon the potential of external support of RGC axons exiting via the lamina cribrosa as well as internal neuroprotection mediated by the provision of trophic factors. In addition further study into the functional characteristics of OECs is required as well as investigation of the effects of OEC in models of experimental glaucoma.
The perfect stem cell-based therapy to treat glaucoma would involve the activation of endogenous stem cells to repair damaged RGCs and thus restore function. The damaged CNS lacks plasticity and neuronal regeneration is notoriously difficult due to a lack of trophic cues (Hou et al., 2008) and the inhibitory nature of the microenvironment (Asher et al., 2001). Nevertheless there is growing evidence that endogenous neural stem cells may proliferate in response to brain injury such as stroke (Felling and Levison, 2003). Although only a proportion of new cells differentiate into new neurons and survive in the long term (Naylor et al., 2005), methods have been established to enhance the proliferation of endogenous neural stem cells following ischaemic injury (Ninomiya et al., 2006).
With respect to damaged neurons within the retina, it may be the Müller glia that hold the key for endogenous reactivation. Their well-documented capacity to regenerate retinal neurons in the teleost retina (Bernardos et al., 2007; Fimbel et al., 2007) and the known presence of similar cells in adult human retina (Lawrence et al., 2007) would make these cells a promising target around which studies of endogenous stem cell repair could be developed.
6. Conclusion
The rapidly evolving field of stem cell research offers exciting potential in the long term for innovative therapies moving from bench to bedside in patients who are affected by advanced glaucoma. Although regeneration of the optic nerve itself may be unrealistic with current scientific knowledge, further studies into local retinal ganglion replacement and neuroprotective mechanisms using transplanted stem cells may offer hope that such treatments may be translated to patients in years to come.
Acknowledgments
Supported by The Medical Research Council (MRC), UK (Grants G0900002 and G0701341). HJ holds a Fellowship from the MRC and the Royal College of Surgeons of Edinburgh.
Also supported by Fight for Sight and the NIHR Biomedical Research Centre for Ophthalmology Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, UK
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Astrid Limb",authors:[{id:"44484",title:"Dr.",name:"G Astrid",middleName:null,surname:"Limb",fullName:"G Astrid Limb",slug:"g-astrid-limb",email:"g.limb@ucl.ac.uk",position:null,institution:null},{id:"44487",title:"Mr.",name:"Hari",middleName:null,surname:"Jayaram",fullName:"Hari Jayaram",slug:"hari-jayaram",email:"h.jayaram@ucl.ac.uk",position:null,institution:{name:"University College London",institutionURL:null,country:{name:"United Kingdom"}}},{id:"44488",title:"Dr.",name:"Silke",middleName:null,surname:"Becker",fullName:"Silke Becker",slug:"silke-becker",email:"silke.becker@ucl.ac.uk",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Sources of stem cells",level:"1"},{id:"sec_2_2",title:"2.1. Embryonic stem cells",level:"2"},{id:"sec_3_2",title:"2.2. Adult tissue-derived stem cells",level:"2"},{id:"sec_3_3",title:"2.2.1. Müller stem cells",level:"3"},{id:"sec_4_3",title:"2.2.2. 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Strategies to measure functional outcome",level:"2"},{id:"sec_19",title:"4. Optic nerve regeneration",level:"1"},{id:"sec_20",title:"5. Stem cell mediated neuroprotection in glaucoma",level:"1"},{id:"sec_21",title:"6. Conclusion",level:"1"},{id:"sec_22",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'AguayoA. J.RasminskyM.BrayG. M.CarbonettoS.Mc KerracherL.Villegas-PerezM. P.Vidal-SanzM.CarterD. A.1991Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci 331337343'},{id:"B2",body:'AndrewsE. M.TsaiS. Y.JohnsonS. C.FarrerJ. R.WagnerJ. P.KopenG. C.KartjeG. L.2008Human adult bone marrow-derived somatic cell therapy results in functional recovery and axonal plasticity following stroke in the rat. 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Hare and Larry Wheeler",authors:[{id:"37227",title:"Dr.",name:"William",middleName:"Alan",surname:"Hare",fullName:"William Hare",slug:"william-hare"},{id:"48055",title:"Dr.",name:"Cun-Jian",middleName:null,surname:"Dong",fullName:"Cun-Jian Dong",slug:"cun-jian-dong"},{id:"93652",title:"Dr.",name:"Larry",middleName:null,surname:"Wheeler",fullName:"Larry Wheeler",slug:"larry-wheeler"}]},{id:"23822",title:"Glaucoma Genetics – Regulation of Cell Surviving and Death in the Retina",slug:"glaucoma-genetics-regulation-of-cell-surviving-and-death-in-the-retina",signatures:"Maria D. Pinazo-Durán, Roberto Gallego-Pinazo, Vicente Zanón-Moreno and Manuel Serrano",authors:[{id:"30637",title:"Dr.",name:"Vicente",middleName:null,surname:"Zanon-Moreno",fullName:"Vicente Zanon-Moreno",slug:"vicente-zanon-moreno"},{id:"52533",title:"Prof.",name:"Maria D.",middleName:null,surname:"Pinazo-Duran",fullName:"Maria D. Pinazo-Duran",slug:"maria-d.-pinazo-duran"},{id:"52539",title:"Dr.",name:"Roberto",middleName:null,surname:"Gallego-Pinazo",fullName:"Roberto Gallego-Pinazo",slug:"roberto-gallego-pinazo"},{id:"52540",title:"Prof.",name:"Manuel",middleName:null,surname:"Serrano",fullName:"Manuel Serrano",slug:"manuel-serrano"}]},{id:"23823",title:"A Vascular Approach to Glaucoma",slug:"a-vascular-approach-to-glaucoma",signatures:"Luís Abegão Pinto and Ingeborg Stalmans",authors:[{id:"37316",title:"Prof.",name:"Ingeborg",middleName:null,surname:"Stalmans",fullName:"Ingeborg Stalmans",slug:"ingeborg-stalmans"},{id:"37393",title:"Dr.",name:"Luis",middleName:"Abegão",surname:"Pinto",fullName:"Luis Pinto",slug:"luis-pinto"}]},{id:"23824",title:"Corneal Viscoelastical Properties Related to Glaucoma",slug:"corneal-viscoelastical-properties-related-to-glaucoma",signatures:"Horea Demea, Sorina Demea and Rodica Holonec",authors:[{id:"50784",title:"Mrs",name:"Sorina",middleName:null,surname:"Demea",fullName:"Sorina Demea",slug:"sorina-demea"},{id:"51213",title:"Prof.",name:"Rodica",middleName:null,surname:"Holonec",fullName:"Rodica Holonec",slug:"rodica-holonec"},{id:"52314",title:"Mr",name:"Horea",middleName:null,surname:"Demea",fullName:"Horea Demea",slug:"horea-demea"}]},{id:"23825",title:"Effects of High Altitude Related Oxidative Stress on Intraocular Pressure and Central Corneal Thickness – A Research Model for the Etiology of Glaucoma",slug:"effects-of-high-altitude-related-oxidative-stress-on-intraocular-pressure-and-central-corneal-thickn",signatures:"Sarper Karakucuk",authors:[{id:"36102",title:"Prof.",name:"Sarper",middleName:null,surname:"Karakucuk",fullName:"Sarper Karakucuk",slug:"sarper-karakucuk"}]},{id:"23826",title:"Sleep Apnea and Glaucoma – Greater Risk for Blacks?",slug:"sleep-apnea-and-glaucoma-greater-risk-for-blacks-",signatures:"Ferdinand Zizi, Adnan Mallick, Monika Dweck, Douglas Lazzaro and Girardin Jean-Louis",authors:[{id:"58174",title:"Dr.",name:"Jean-Louis",middleName:null,surname:"Girardin",fullName:"Jean-Louis Girardin",slug:"jean-louis-girardin"},{id:"58175",title:"Dr.",name:"Ferdinand",middleName:null,surname:"Zizi",fullName:"Ferdinand Zizi",slug:"ferdinand-zizi"}]},{id:"23827",title:"Quality of Life (QoL) in Glaucoma Patients",slug:"quality-of-life-qol-in-glaucoma-patients",signatures:"Georgios Labiris, Athanassios Giarmoukakis and Vassilios P. Kozobolis",authors:[{id:"61997",title:"Dr.",name:"Georgios",middleName:null,surname:"Labiris",fullName:"Georgios Labiris",slug:"georgios-labiris"},{id:"94480",title:"Dr.",name:"Athanassios",middleName:null,surname:"Giarmoukakis",fullName:"Athanassios Giarmoukakis",slug:"athanassios-giarmoukakis"},{id:"94481",title:"Prof.",name:"Vassilios",middleName:null,surname:"Kozobolis",fullName:"Vassilios Kozobolis",slug:"vassilios-kozobolis"}]},{id:"23828",title:"Glaucoma Animal Models",slug:"glaucoma-animal-models",signatures:"Elena Vecino and Sansar C. Sharma",authors:[{id:"31685",title:"Prof.",name:"Elena",middleName:null,surname:"Vecino",fullName:"Elena Vecino",slug:"elena-vecino"},{id:"36188",title:"Prof.",name:"Sansar",middleName:null,surname:"Sharma",fullName:"Sansar Sharma",slug:"sansar-sharma"}]},{id:"23829",title:"Management of Glaucoma in the Era of Modern Imaging and Diagnostics",slug:"management-of-glaucoma-in-the-era-of-modern-imaging-and-diagnostics",signatures:"Anurag Shrivastava and Umar Mian",authors:[{id:"37586",title:"Dr.",name:"Umar",middleName:null,surname:"Mian",fullName:"Umar Mian",slug:"umar-mian"},{id:"50939",title:"Dr.",name:"Anurag",middleName:null,surname:"Shrivastava",fullName:"Anurag Shrivastava",slug:"anurag-shrivastava"}]},{id:"23830",title:"Anterior Chamber Angle Assessment Techniques",slug:"anterior-chamber-angle-assessment-techniques",signatures:"Claudio Campa, Luisa Pierro, Paolo Bettin and Francesco Bandello",authors:[{id:"35590",title:"Dr.",name:"Claudio",middleName:null,surname:"Campa",fullName:"Claudio Campa",slug:"claudio-campa"},{id:"140329",title:"Prof.",name:"Luisa",middleName:null,surname:"Pierro",fullName:"Luisa Pierro",slug:"luisa-pierro"},{id:"140330",title:"Prof.",name:"Paolo",middleName:null,surname:"Bettin",fullName:"Paolo Bettin",slug:"paolo-bettin"},{id:"140331",title:"Prof.",name:"Francesco",middleName:null,surname:"Bandello",fullName:"Francesco Bandello",slug:"francesco-bandello"}]},{id:"23831",title:"End Stage Glaucoma",slug:"end-stage-glaucoma",signatures:"Tharwat H. Mokbel",authors:[{id:"35637",title:"Prof.",name:"Tharwat",middleName:null,surname:"Mokbel",fullName:"Tharwat Mokbel",slug:"tharwat-mokbel"}]},{id:"23832",title:"Update on Modulating Wound Healing in Trabeculectomy",slug:"update-on-modulating-wound-healing-in-trabeculectomy",signatures:"Hosam Sheha",authors:[{id:"50400",title:"Dr.",name:"Hosam",middleName:null,surname:"Sheha",fullName:"Hosam Sheha",slug:"hosam-sheha"}]},{id:"23833",title:"Novel Glaucoma Surgical Devices",slug:"novel-glaucoma-surgical-devices",signatures:"Parul Ichhpujani and Marlene R. Moster",authors:[{id:"52529",title:"Dr.",name:"Marlene",middleName:null,surname:"Moster",fullName:"Marlene Moster",slug:"marlene-moster"},{id:"52530",title:"Dr.",name:"Parul",middleName:null,surname:"Ichhpujani",fullName:"Parul Ichhpujani",slug:"parul-ichhpujani"}]},{id:"23834",title:"Cyclodestructive Procedures",slug:"cyclodestructive-procedures",signatures:"Sima Sayyahmelli and Rakhshandeh Alipanahi",authors:[{id:"29623",title:"Dr.",name:"Sima",middleName:null,surname:"Sayyahmelli",fullName:"Sima Sayyahmelli",slug:"sima-sayyahmelli"},{id:"41265",title:"Dr.",name:"Rakhshandeh",middleName:null,surname:"Alipanahi",fullName:"Rakhshandeh Alipanahi",slug:"rakhshandeh-alipanahi"}]},{id:"23835",title:"Another Look on Cyclodestructive Procedures",slug:"another-look-on-cyclodestructive-procedures",signatures:"Antonio Fea, Dario Damato, Umberto Lorenzi and Federico M. Grignolo",authors:[{id:"36351",title:"Dr.",name:"Antonio",middleName:null,surname:"Fea",fullName:"Antonio Fea",slug:"antonio-fea"},{id:"140326",title:"Prof.",name:"Dario",middleName:null,surname:"Damato",fullName:"Dario Damato",slug:"dario-damato"},{id:"140327",title:"Prof.",name:"Umberto",middleName:null,surname:"Lorenzi",fullName:"Umberto Lorenzi",slug:"umberto-lorenzi"},{id:"140328",title:"Dr.",name:"Federico",middleName:null,surname:"Grignolo",fullName:"Federico Grignolo",slug:"federico-grignolo"}]},{id:"23836",title:"Controlled Cyclophotocoagulation",slug:"controlled-cyclophotocoagulation",signatures:"Paul-Rolf Preußner",authors:[{id:"43694",title:"Prof.",name:"Paul Rolf",middleName:null,surname:"Preußner",fullName:"Paul Rolf Preußner",slug:"paul-rolf-preussner"},{id:"43698",title:"Dr.",name:"Jochen",middleName:null,surname:"Wahl",fullName:"Jochen Wahl",slug:"jochen-wahl"}]},{id:"23837",title:"Congenital Glaucoma",slug:"congenital-glaucoma",signatures:"Jair Giampani Junior and Adriana Silva Borges Giampani",authors:[{id:"35331",title:"Prof.",name:"Jair",middleName:null,surname:"Giampani Junior",fullName:"Jair Giampani Junior",slug:"jair-giampani-junior"},{id:"35333",title:"Prof.",name:"Adriana",middleName:null,surname:"Borges-Giampani",fullName:"Adriana Borges-Giampani",slug:"adriana-borges-giampani"}]},{id:"23838",title:"Primary Angle Closure Glaucoma",slug:"primary-angle-closure-glaucoma",signatures:"Michael B. Rumelt",authors:[{id:"62809",title:"Dr.",name:"Michael",middleName:null,surname:"Rumelt",fullName:"Michael Rumelt",slug:"michael-rumelt"},{id:"140318",title:"Dr.",name:"M.D.",middleName:null,surname:"Emeritus",fullName:"M.D. Emeritus",slug:"m.d.-emeritus"}]},{id:"23839",title:"Plateau Iris",slug:"plateau-iris",signatures:"Yoshiaki Kiuchi, Hideki Mochizuki and Kiyoshi Kusanagi",authors:[{id:"32982",title:"Prof.",name:"Yoshiaki",middleName:null,surname:"Kiuchi",fullName:"Yoshiaki Kiuchi",slug:"yoshiaki-kiuchi"},{id:"48345",title:"Dr.",name:"Hideki",middleName:null,surname:"Mochizuki",fullName:"Hideki Mochizuki",slug:"hideki-mochizuki"},{id:"48346",title:"Dr.",name:"Kiyoshi",middleName:null,surname:"Kusanagi",fullName:"Kiyoshi Kusanagi",slug:"kiyoshi-kusanagi"}]},{id:"23840",title:"Normal-Tension (Low-Tension) Glaucoma",slug:"normal-tension-low-tension-glaucoma",signatures:"Tsvi Sheleg",authors:[{id:"62356",title:"Dr.",name:"Tsvi",middleName:null,surname:"Sheleg",fullName:"Tsvi Sheleg",slug:"tsvi-sheleg"}]},{id:"23841",title:"Drug-Induced Glaucoma (Glaucoma Secondary to Systemic Medications)",slug:"drug-induced-glaucoma-glaucoma-secondary-to-systemic-medications-",signatures:"Eitan Z. Rath",authors:[{id:"59158",title:"Dr.",name:"Eitan Z.",middleName:null,surname:"Rath",fullName:"Eitan Z. Rath",slug:"eitan-z.-rath"}]},{id:"23842",title:"Steroid Induced Glaucoma",slug:"steroid-induced-glaucoma",signatures:"Avraham Cohen",authors:[{id:"61596",title:"Dr.",name:"Avraham",middleName:null,surname:"Cohen",fullName:"Avraham Cohen",slug:"avraham-cohen"}]},{id:"23843",title:"Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis",slug:"glaucoma-in-cases-of-penetrating-keratoplasty-lamellar-procedures-and-keratoprosthesis",signatures:"Shimon Rumelt",authors:[{id:"54335",title:"Dr.",name:"Shimon",middleName:null,surname:"Rumelt",fullName:"Shimon Rumelt",slug:"shimon-rumelt"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"69527",title:"An Intelligent Clinical Decision Support System for Assessing the Needs of a Long-Term Care Plan",doi:"10.5772/intechopen.89663",slug:"an-intelligent-clinical-decision-support-system-for-assessing-the-needs-of-a-long-term-care-plan",body:'
1. Introduction
Facing the unavoidable aging population, the demands for long-term care services are increasing and need to be addressed in modern society [1, 2]. In order to effectively provide long-term care to the elderly in the community, the Taiwan government proposed a 10-year long-term care project, namely Long-term Care Project 1.0 (LTCP 1.0), in 2007. The goal of the project was to establish a comprehensive community-based care system for (i) providing appropriate services to the elderly, (ii) improving the independence of the elderly, (iii) enhancing the quality of life, and (iv) maintaining autonomy and dignity [3]. Difference in gender, level of urbanization, culture, economy and health are also considered in this system. Eight services items are covered in LTCP 1.0: daily care services, transportation services, meal services, home and community-based rehabilitation services, respite care services, home nursing, rental of equipment and long-term care institution services [4]. Subsequently, the government launched a more extensive public framework, i.e., LTCP 2.0, in 2017 to increase the services coverage in the community [5]. Table 1 shows the differences between LTCP 1.0 and LTCP 2.0, in which LTCP 2.0 expands the scope of services to optimize the front-end preventive care and to provide back-end connections to multi-target support services and home hospice services.
LTCP 1.0
LTCP 2.0
Services targets
4
8
Services scopes
8
17
Financial resources
Government funding
Medical development funding
Government funding
Social welfare funding
Long-term service development funding
Innovative service
N/A
ABC community care model
Table 1.
Differences between LTCP 1.0 and LTCP 2.0.
In order to provide high quality and affordable services, the ABC community care model with 3 tiers was established to clearly define the roles and responsibilities of healthcare parties involved in LTCP 2.0, as shown in Figure 1 [6]. Tier A refers to a community integrated care service center for coordinating and allocating the resources of care services based on the care plan formulated by care managers. Moreover, Tier A also provides a localized delivery system that connects to Tier B and Tier C. Based on the assessment results from Tier A, Tier B, i.e. a multiple service center, provides corresponding diverse healthcare services for the public. Information from Tier A and Tier B is then sent to the long-term care station in Tier C for providing various care functions to the elderly. Therefore, the care managers in Tier A play an important role in LTCP 2.0 in evaluating the needs and formulating care plans [7]. However, it is complicated for care managers to perform the tasks of health assessment, reviewing historical health records and resources planning in a short time. In addition, it requires care managers with adequate knowledge and experience to handle these tasks. Due to the fact that in healthcare resources are as shortages in terms of staff and equipment, the implementation of care planning in LTCP 2.0 becomes challenging to achieve the goals of providing accurate and fast-responsive healthcare services.
Figure 1.
ABC community care model.
To address the above problems, the objective of this article is to present an intelligent clinical decision support system (ICDSS) for care planning. The case-based reasoning (CBR) technique is adopted to provide the knowledge support for decision-making in care planning. By extracting the relevant knowledge from similar past cases, the care plans can be formulated in a cost-effective and time-efficient manner so as to maintain the high quality of services. The rest of article is structured as follows. Related studies and background are discussed in Section 2. Section 3 describes the architecture of the proposed system while Section 4 discusses the case study and findings. Section 5 shows the future research directions. Conclusions are drawn in Section 6.
2. Related work
Due to the development of medical technology and increased life expectancy, the number of elderly people in Taiwan is expected to increase continuously annually. According to the statistics [8], the percentage of the elderly population aged 65 or above is 13.2% in 2016. It is estimated that this population in 2026 will reach to 20.6%. Associated with the fast growth of the aging population, the reporting of chronic diseases has also increased significantly. As a consequence, the needs for long-term care services have become more demanding and urgent. In response to the increased demands for long-term care services, the government of Taiwan has considered long-term care services in healthcare industry as one of eight key industries to minimize the threats of chronic diseases [9]. Therefore, the Long-term Care Project 1.0 (LTCP 1.0) was launched in 2007 and was an initiative to integrate the home and residential-based services in Taiwan. Up to the end of 2015, over 160,000 people had received the services offered by LTCP and there are nearly 2800 institutions providing care services following the principles of LTCP. In view of the benefits offered by LTCP 1.0, a revised version of the original LTCP, i.e. LTCP 2.0, was created to further facilitate the integration of preventative care, social care and medical care in the community. In order to facilitate the implementation of LTCP 2.0 and coordinate the operation of long-term services and resources, researchers have been focusing on improving the performance of LTCP. Liu and Yao [10] adopted latent class analysis to examine the interrelationship among health indicators so as to determine the level of needs of the elderly care recipients. Lin et al. [11] studied the performance of LTCP according to the dimensions of the workforce, sources of funding, application of technology, service nature and norms. The aims of their study is to identify problems in LTCP and develop a continuous improvement strategies so as to improve the long-term care services. However, attention is rarely paid to the field of LTCP as well as providing knowledge support for decision-making. In fact, due to the shortage of knowledge manpower, it is time-consuming and tedious for care managers to effectively provide an integrated “one-stop” consultation for applications, health evaluations, care plans formulation and the coordination and delivery of long-term care services. Therefore, it is essential to provide knowledge support for decision-making processes in the care planning of LTCP.
In recent years, decision support systems have become increasingly popular for providing decision support in various industries [12, 13], and are designed to facilitate precise decision-making through the use of accurate and timely data, information and knowledge management. In the healthcare industry, the clinical decision support system is a specific term for the health customized version of decision support system [14]. The emerging clinical decision support system allows healthcare professionals to manage and manipulate the massive amount of data in an effective and efficient manner. In this situation, automatic decision-making can be provided for evaluating the health status of patients and providing corresponding treatment. Case-based reasoning (CBR) is one of the well-known artificial intelligent techniques commonly embedded in the clinical decision support system and adopts previous experience and knowledge for solving new problems [15]. The general CBR model has been formalized for computer reasoning as a four-step process: (i) retrieve the most similar case, (ii) reuse the retrieved case for solving the new problem, (iii) revise the content in the solutions if necessary, and (iv) retain the solutions as the new case stored in the case library [16]. The predictive process in the CBR allows users to takes less effort and time to generate solutions. CBR has been widely adopted in the healthcare industry in disease diagnosis, planning and resources allocations [17, 18]. Chang et al. [19] adopted CBR to develop a continuous care information system for facilitating discharge planning. By the adoption of computer-reasoning in the evaluation process of care planning, accurate continuing care solutions can be formulated in a timely manner. Wang et al. [20] developed a hybrid CBR approach to shorten the time for providing the treatment planning for the people with mental problems. Petrovic et al. [21] applied CBR in radiotherapy treatment planning to reduce the errors in planning and in recommending radiotherapy solutions. The above studies show that CBR is a promising approach in providing knowledge support for generating the solutions in the healthcare industry.
In summary, from the above literature, it is found that care managers play an essential role in the LTCP for generating appropriate and personalized long-term care solutions and in coordinating care services resources. Due to the needs for accurate and fast-responsive healthcare services, the adoption of a clinical decision support system using CBR is a feasible solution to shorten the evaluation time and improve the service quality in LTCP.
3. Methodology
In order to facilitate the decision-making of care managers, an intelligent clinical decision support system (ICDSS) is developed. The ICDSS architecture is shown in Figure 2 and consists of three modules: (i) data collection module, (ii) case-based reasoning module, and (iii) care plan formulation module. With a systematic method to provide knowledge support for care managers, the effectiveness and efficiency in the processes of assessing the health information and formulating care plans can be improved. Consequently, accurate and fast-responsive healthcare services can be delivered to the elderly so as to maintain a high quality of care.
Figure 2.
An architecture of ICDSS.
3.1 Data collection module
In the data collection module, the elderly with chronic diseases or disabilities can apply for the community care service through the online platform. Three types of data, historical data, medical records and personal information, are collected and uploaded to the cloud databases in electronic format. Historical data refers to past health data such as vaccination records, surgery records, and the historical data from the past public system. The medical record is the biometric data for reflecting the psychological and physiological aspects of the elderly. Heart rate, blood sugar index, vision and muscle strength are examples of the medical record. Personal information of the elderly including name, age, gender, family relationships, personality, joint condition, sleeping ability and living environment are also collected. Apart from uploading the three types of data, an interview is conducted to understand the problems of the elderly in daily living. By doing so, care managers can collected both subjective and objective data for further data analysis in the case-based reasoning.
3.2 Case-based reasoning module
Traditionally, care managers have to review the massive amount of health data one by one for evaluating the needs of the elderly. The use of ICDSS allows care managers to effectively formulate appropriate care plans according to the needs. In this module, CBR is adopted to retrieve the most similar care records for generating the care solutions. To begin with the first stage in the CBR, i.e. case retrieval, past care records are firstly stored in the case library. An indexing tree is constructed to cluster past care records according to the key attributes that may affect the types of service provided. Along the searching path of the indexing tree, a small group of past case records are retrieved. In the reuse stage, retrieved case records are ranked descending order according to their similarity value. Eq. (1) is the expression for calculating the total similarity value.
Total similarity value=∑i=1nwisimfiIfiR∑i=1nwiE1
where wi is the weighting of the attribute i, sim is the function for calculating the similarity value of attributes, and, fiI and fiR are the values of attributes fi in the new and past cases. The care record with the highest similarity value is selected and considered as the most significant reference to generate care solutions for solving the new problem. After that, care managers can make modifications to the retrieved care records so as to meet the real-life situations of the elderly. Therefore, a new care plan is formulated for serving the elderly.
Differing to the traditional CBR process, a rating scheme is deployed in the case retention process to assess and monitor the effectiveness of the care plan. Figure 3 shows the rating scheme in the case retention of CBR. As it is a long-term care service, regular meetings between care managers and the elderly or their families is required so as to collect their feedback. In addition, feedback from direct service providers, i.e. social workers and nursing staff, are also collected for the performance evaluation. Only care plans with good quality are retained in the case library for continuously improving the quality of the care records.
Figure 3.
Rating scheme in the case retention of CBR.
3.3 Care plan formulation module
After the case revision process of CBR, a new care plan with specific goals is generated. The care plan consists of several elements: (i) type of care, (ii) meals & nutrition, (iii) transportation and (iv) community center/activity recommend. According to the different nature of healthcare services, i.e. home care services or residential care services, different levels of healthcare services are provided for the elderly. In addition, details of the care plan are shared and transferred to the healthcare parties in Tier B and Tier C in the ABC community care model. Based on the care plan, operational guidelines can be provided to caregivers so as to deliver the corresponding healthcare services. Considering the health deterioration occurred in the elderly, the needs of healthcare services will move from less intensive care towards more intensive care via ABC model. Therefore, the re-evaluation of care plan is required every month to ensure its appropriateness.
4. Case example
In this section, a case example is illustrated to demonstrate the application of the ICDSS for providing knowledge support for decision-making in care planning. The case company is one of integrated community service centers located in Taichung, Taiwan. The main objective of the case company is to bring “Health and Happiness” for the elderly so as to maintain their quality of life, and physical and mental health in the community. The main staff members in the case company are care managers and supervisors such as social workers, nurses, occupational therapists and pharmacists for formulating care plan and coordinating care service resources. Figure 4 shows the existing operation flow in the case company. The current practice of information flow, elderly health evaluation, healthcare service suggestions and follow up services are done manually. Care managers base on their experience to provide suggestions for the elderly. However, it is time-consuming and ineffective for care managers to implement these complicated steps in care planning. In addition, human errors easily occurs in these evaluation processes, resulting in high complaint rates and poor service satisfaction in the case company.
Figure 4.
Existing operation flow in the case company.
4.1 Implementation of ICDSS
In order to tackle the above mentioned problems, the case company decided to implement the proposed system in providing knowledge support in care planning. Instead of the traditional in-person application method, the online platform is developed to collect the information. As mentioned in Section 3.1, data such as historical data, medical record and personal information are inputted by the elderly and then stored in the cloud database of the Data Collection Module. After submitting the application, care managers can note the new application in the ICDSS. An interview can be arranged to understand their current health situation and problems faced in daily living. The interview results are also stored in the database. In order to reduce the errors in the care management processes, care managers have to verify the accuracy of the data provided by the elderly.
Relevant information is then extracted and transfer to the Case-based Reasoning Module for further data analysis. In the case-based reasoning module, care managers have to identify the key attributes for constructing the indexing tree and retrieving the past care records. In this situation, five attributes: (i) kind of mobility, (ii) self-care ability, (iii) type of neuropsychiatric condition, (iv) communication method and (v) age are defined as key attributes that may significantly influence the type of services provided in care planning. Figure 5 shows the user interface for case retrieval. According to the structure of the indexing tree, the small group of past case records which match the specifications are retrieved. After that, the retrieved past case records are ranked using Eq. (1) so as to distinguish the most suitable case record. A total of 17 attributes are used to calculate the total similarity value of care records, as shown in Table 2. Based on the results from the case reuse, the care record with highest similarity value is extracted. An applicant is selected to illustrate the mechanism of CBR in ICDSS and details of the applicant are shown in Table 3. It is found that the elderly needs assistive devices for performing the movement and self-care activities. She does not have any problem of cognitive decline. A comprehensive review is implemented for deciding on the type of services. After the processes of case retrieval and reuse, the past care record (ID: 0082) has the highest similarity value (91.21%) to the new applicant. Therefore, care managers can select the past care record (ID: 0082) as the most significant reference for generating the new long-term care solutions.
Figure 5.
The user interface for case retrieval.
No.
Attributes
Weighting
No.
Attributes
Weighting
1
Living condition
1
9
Percentage of falling
2
2
Height
1
10
Drinking
2
3
Weight
1
11
Smoking
2
4
Glucose
1
12
Arthritis
2
5
Heart rate
1
13
Cancer
2
6
Upper blood pressure
1
14
Dysphagia
2
7
Lower blood pressure
1
15
Liver disease
2
8
Body temperature
1
16
Mental disease
2
17
Urinary
2
Table 2.
Attributes for calculating the similarity value of care records.
Items
Detail
Items
Detail
Name
JL
Gender
Female
Age
69
Weight (kg)
57
Communication method
Oral
Height (cm)
160
Mobility
Move with the aid of assistive devices
Blood pressure (mmHg)
108/46
Self-care ability
Function with the aid of assistive devices
Heart rate (bpm)
80
Neuro-psychiatric
No cognitive decline
Body temperature (°C)
36.4
Living condition
Living with family
Fall (%)
18
Table 3.
Details of the applicant.
To formulate a tailor-made care plan according to the needs of the elderly, modifications are made by care managers to add additional healthcare information and revise the content of the past care record. Therefore, a new care plan with services details can be generated, as shown in Figure 6. In the new care plan, home care services are provided to the new applicant three times per week. Therefore, this information is sent to the caregivers in Tier B and Tier C for allocating the corresponding healthcare resources. In each visit, caregivers are required to measure the biometric data including blood pressure, heart rate, blood glucose level and body temperature. They have to assist the elderly in bathing and filling the drug organizer. In addition, transportation service is provided for pick from their home to the hospital for regular checking. By doing so, community-based long-term care services can be delivered.
Figure 6.
The details of the retrieved past care record.
In order to ensure the quality of care provided, a feedback survey is conducted to measure the performance of the care plan, as shown in Figure 7. In addition, a regular meeting is held for nursing staff participating in serving this elderly so as to discuss and understand the problems faced in delivering the healthcare services. The care plan with good quality is then retained in case library for continuously quality improvement purposes.
Figure 7.
Feedback survey for the elderly.
4.2 Findings
Through the pilot study in the case company, the ICDSS contributes to (i) improve the efficiency in care planning, and (ii) enhance the quality of long-term care services.
With the implementation of the ICDSS, it found that ICDSS offers several benefits to the case company. Firstly, it improves the efficiency in care planning. Instead of the traditional manual approach in care planning processes, ICDSS allows the care managers to formulate personalized long-term care solutions based on past explicit knowledge. Table 4 shows the performance improvements after the use of ICDSS. With the use of ICDSS, care managers can review the health records provided by the elderly in the online platform rather than finding such information from separate data files. Therefore, the time for reviewing health records is significant reduced by 80.77% Moreover, the time for formulating the details of the care plan is also reduced from 156 to 22 min. Since the knowledge in past care records is extracted for solving new cases with similar problems, care managers can effectively generate solutions for providing the appropriate healthcare services and promoting the preventive health.
Performance indicator
Without ICDSS (min)
With ICDSS (min)
Improvement (%)
Time for reviewing health records
52
10
80.77
Time for formulating the details of care plan
156
22
85.90
Table 4.
Performance improvement after the use of ICDSS.
Furthermore, ICDSS prevents knowledge loss for formulating care plans. Since care managers with different levels of experience are employed in the case company, there may be some variations in the context of care plans. The adoption of ICDSS allows the valuable knowledge to be stored and shared in the form of past care records. Care managers, especially junior care managers, can make use of this knowledge to facilitate their decision-making. Thus, consistent long-term care solutions can be generated by different care managers. In addition, the number of complaints per week is reduced from 8 to 2. With the decrease in the number of complaints, the service satisfaction is significantly improved. Not only can the integrated community service center in Tier A enhance the service satisfaction, but also the healthcare parties in Tier B and Tier C.
5. Future research directions
5.1 Explore the adoption of the Internet of Things (IoT) in residential care services
According to Zhao et al. [22], there is growing evidence that chronic diseases are the major issue associated with aging population. In the last decade, the Internet of Things (IoT) is a newly emerging technology for the healthcare industry [23]. Under the IoT platform, information can be gathered, processed and analyzed to serve individual and healthcare organizations. IoT has been widely adopted in hospitals and home care services for remote monitoring and disease diagnosis. It is not only to help increase the data accuracy of the clinical decision support system, but also to provide early detection of any abnormalities occurring. In fact, its application can be further explored in residential care services. Current adoption of the IoT in nursing homes are lagging behind the hospitals and home care services providers. As one of the important long-term care service providers in LTCP 2.0, future research effort can be paid in extending the adoption of IoT in nursing homes so as to speed up its daily routine processes. Considering that numerous healthcare parties are involved in the LTCP 2.0, the IoT allows the caregivers to real-time collect and monitor the biometric data of the elderly through the equipment of the sensors. It also facilitates the information exchange among various parties. Once the abnormalities occurred, instant actions can be generated by corresponding healthcare parties to prevent the further health deterioration.
5.2 Explore a big data analytics platform for data management and manipulation
On the other hand, due to the application of smart devices and social media in healthcare services, there is an exponentially increase of health-related big data [24]. It is necessary to develop big data analytics platforms with text mining and machine learning abilities for facilitating data management and manipulation. For example, with the use of IoT, massive health data can be collected and stored in the cloud platform. The data analytic techniques such as artificial intelligence help discover the hidden pattern of available data and generate invaluable knowledge for supporting the proactive healthcare services in the LTCP 2.0. Criteria, including the ability to manipulate, continuity, ease of use, availability, quality assurance, privacy and security, should be considered in designing of this platform [25]. In addition, any data lag between data collection and processing should be avoided in this platform for achieving real-time big data analytics. Therefore, how to integrate the mentioned elements in the big data analytics platforms should be considered in future research so as to improve the effectiveness of LTCP.
6. Conclusions
To cope with the aging population, the needs for healthcare services as well as community care services are demanding. With the purpose of reducing the burden on caregivers, healthcare parties are seeking ways to better utilize the limited resources to improve the service quality. In Taiwan, LTCP 2.0 has been launched to create a comprehensive community-based care and health support system for the elderly. Care managers in Tier A play crucial roles in LTCP 2.0 for deciding on the types of service provided and in coordinating with care service resources. However, the traditional manual approach relying on care manager experience to perform the evaluation tasks and care plan formulation is ineffective. Without a knowledge-based decision support system, it is difficult for care managers, in a timely manner, to generate personalized long-term care solutions as well as coordinating care resources in Tier B and Tier C. Therefore, in this chapter, the ICDSS is designed to provide the knowledge support for decision-making in care planning of LTCP 2.0. The adoption of CBR in ICDSS approach allows care managers to disseminate the experience gained from the past similar care records. By doing so, it enables the successful execution of care planning so that fast-responsive and accurate healthcare services can be delivered. Furthermore, it enables data sharing and communication among healthcare parties in the LTCP 2.0, so that correct caring guidelines and knowledge can be transferred in a timely way to caregivers who provide direct care to the elderly timely. By so doing, the service quality can be greatly enhanced.
Acknowledgments
The authors would like to thank Research Office and Faculty of Engineering of the Hong Kong Polytechnic University through the Engineering Doctorate programme for supporting this project (Project Code: RU8J).
\n',keywords:"long-term care, personalized care services, clinical decision support system, artificial intelligence techniques, care plan",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69527.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69527.xml",downloadPdfUrl:"/chapter/pdf-download/69527",previewPdfUrl:"/chapter/pdf-preview/69527",totalDownloads:149,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 14th 2019",dateReviewed:"September 11th 2019",datePrePublished:"October 16th 2019",datePublished:"February 3rd 2021",dateFinished:"October 11th 2019",readingETA:"0",abstract:"With the global aging population, providing effective long-term care has been promoted and emphasized for reducing the hospitalizations of the elderly and the care burden to hospitals and governments. Under the scheme of Long-term Care Project 2.0 (LTCP 2.0), initiated in Taiwan, two types of long-term care services, i.e., institutional care and home care, are provided for the elderly with chronic diseases and disabilities, according to their personality, living environment and health situation. Due to the increasing emphasis on the quality of life in recent years, the elderly expect long-term care service providers (LCSP) to provide the best quality of care (QoC). Such healthcare must be safe, effective, timely, efficiently, diversified and up-to-date. Instead of supporting basic activities in daily living, LCSPs have changed their goals to formulate elderly-centered care plans in an accurate, time-efficient and cost-effective manner. In order to ensure the quality of the care services, an intelligent clinical decision support system (ICDSS) is proposed for care managers to improve their efficiency and effectiveness in assessing the long-term care needs of the elderly. In the ICDSS, artificial intelligence (AI) techniques are adopted to distinguish and formulate personalized long-term care plans by retrieving relevant knowledge from past similar records.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69527",risUrl:"/chapter/ris/69527",signatures:"Paul Kai Yuet Siu, Valerie Tang, King Lun Choy, Hoi Yan Lam and George To Sum Ho",book:{id:"9134",title:"Recent Advances in Digital System Diagnosis and Management of Healthcare",subtitle:null,fullTitle:"Recent Advances in Digital System Diagnosis and Management of Healthcare",slug:"recent-advances-in-digital-system-diagnosis-and-management-of-healthcare",publishedDate:"February 3rd 2021",bookSignature:"Kamran Sartipi and Thierry Edoh",coverURL:"https://cdn.intechopen.com/books/images_new/9134.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"29601",title:"Dr.",name:"Kamran",middleName:null,surname:"Sartipi",slug:"kamran-sartipi",fullName:"Kamran Sartipi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"296597",title:"Dr.",name:"K.L.",middleName:null,surname:"Choy",fullName:"K.L. Choy",slug:"k.l.-choy",email:"kl.choy@polyu.edu.hk",position:null,institution:{name:"Hong Kong Polytechnic University",institutionURL:null,country:{name:"China"}}},{id:"296613",title:"Dr.",name:"H.Y.",middleName:null,surname:"Lam",fullName:"H.Y. Lam",slug:"h.y.-lam",email:"cathy.lam@connect.polyu.hk",position:null,institution:{name:"Hong Kong Polytechnic University",institutionURL:null,country:{name:"China"}}},{id:"305062",title:"Ms.",name:"Valerie",middleName:null,surname:"Tang",fullName:"Valerie Tang",slug:"valerie-tang",email:"v.tang@connect.polyu.hk",position:null,institution:null},{id:"305098",title:"Dr.",name:"G.T.S.",middleName:null,surname:"Ho",fullName:"G.T.S. Ho",slug:"g.t.s.-ho",email:"georgeho@hsu.edu.hk",position:null,institution:null},{id:"305099",title:"Mr.",name:"Paul K.Y.",middleName:null,surname:"Siu",fullName:"Paul K.Y. Siu",slug:"paul-k.y.-siu",email:"paul.ky.siu@connect.polyu.hk",position:null,institution:{name:"Hong Kong Polytechnic University",institutionURL:null,country:{name:"China"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Related work",level:"1"},{id:"sec_3",title:"3. Methodology",level:"1"},{id:"sec_3_2",title:"3.1 Data collection module",level:"2"},{id:"sec_4_2",title:"3.2 Case-based reasoning module",level:"2"},{id:"sec_5_2",title:"3.3 Care plan formulation module",level:"2"},{id:"sec_7",title:"4. Case example",level:"1"},{id:"sec_7_2",title:"4.1 Implementation of ICDSS",level:"2"},{id:"sec_8_2",title:"4.2 Findings",level:"2"},{id:"sec_10",title:"5. Future research directions",level:"1"},{id:"sec_10_2",title:"5.1 Explore the adoption of the Internet of Things (IoT) in residential care services",level:"2"},{id:"sec_11_2",title:"5.2 Explore a big data analytics platform for data management and manipulation",level:"2"},{id:"sec_13",title:"6. Conclusions",level:"1"},{id:"sec_14",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'He A, Chou K. Long-term care service needs and planning for the future: A study of middle-aged and older adults in Hong Kong. Ageing and Society. 2017;1:1-33. DOI: 10.1017/S0144686X17000824'},{id:"B2",body:'Beard HPJR, Bloom DE. Towards a comprehensive public health response to population ageing. Lancet (London, England). 2015;385(9968):658'},{id:"B3",body:'Executive Yuan. Long-Term Care 2.0 Plan for Greater Peace of Mind. Taipei, Taiwan: Executive Yuan; 2018'},{id:"B4",body:'Wang, H. H., & Tsay, S. F. (2012). Elderly and long-term care trends and policy in Taiwan: Challenges and opportunities for health care professionals. The Kaohsiung Journal of Medical Sciences. 28(9):465-469'},{id:"B5",body:'Ministry of Health and Welfare. Achievements of Ten-Year Long Term Care Program. Ministry of Health and Welfare of Taiwan: Taipei, Taiwan; 2017'},{id:"B6",body:'Government of Taiwan. 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Artificial Intelligence in Medicine. 2016;68:17-28'},{id:"B22",body:'Zhao C, Wong L, Zhu Q , Yang H. Prevalence and correlates of chronic diseases in an elderly population: A community-based survey in Haikou. PLoS One. 2018;13(6):e0199006'},{id:"B23",body:'Yuehong YIN, Zeng Y, Chen X, Fan Y. The internet of things in healthcare: An overview. Journal of Industrial Information Integration. 2016;1:3-13'},{id:"B24",body:'Raghupathi W, Raghupathi V. Big data analytics in healthcare: Promise and potential. Health Information Science and Systems. 2014;2(1):3'},{id:"B25",body:'Ohlhorst F. Big Data Analytics: Turning Big Data into Big Money. Vol. 65. Canada: John Wiley & Sons; 2012'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Paul Kai Yuet Siu",address:null,affiliation:'
Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hong Kong
Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hong Kong
'},{corresp:null,contributorFullName:"Hoi Yan Lam",address:null,affiliation:'
Department of Supply Chain and Information Management, The Hang Seng University of Hong Kong, Hong Kong
'},{corresp:null,contributorFullName:"George To Sum Ho",address:null,affiliation:'
Department of Supply Chain and Information Management, The Hang Seng University of Hong Kong, Hong Kong
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