Table of Contents Author Guidelines Submit a Manuscript
Journal of Ophthalmology
Volume 2014, Article ID 510285, 13 pages
http://dx.doi.org/10.1155/2014/510285
Review Article

Current Treatment Limitations in Age-Related Macular Degeneration and Future Approaches Based on Cell Therapy and Tissue Engineering

1Ophthalmology Experimental Laboratory, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain
2Tissue Engineering and Biomaterials Unit, CEIT and TECNUN (University of Navarra), Paseo de Manuel Lardizabal 15, 20018 San Sebastian, Spain
3Department of Ophthalmology, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany
4Department of Ophthalmology, Geneva University Hospitals, Faculty of Medicine, University of Geneva, Rue Alcide-Jentzer 22, 1211 Geneve 14, Switzerland
5Department of Functional Materials in Medicine and Dentistry, University of Würzburg, Pleicherwall 2, 97070 Würzburg, Germany
6Department of Ophthalmology, School of Medicine, Clinica Universidad de Navarra, Avenida Pio XII 36, 31008 Pamplona, Spain

Received 26 July 2013; Accepted 10 December 2013; Published 14 January 2014

Academic Editor: Edward Manche

Copyright © 2014 P. Fernández-Robredo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. With an ageing population, it is anticipated that the number of AMD cases will increase dramatically, making a solution to this debilitating disease an urgent requirement for the socioeconomic future of the European Union and worldwide. The present paper reviews the limitations of the current therapies as well as the socioeconomic impact of the AMD. There is currently no cure available for AMD, and even palliative treatments are rare. Treatment options show several side effects, are of high cost, and only treat the consequence, not the cause of the pathology. For that reason, many options involving cell therapy mainly based on retinal and iris pigment epithelium cells as well as stem cells are being tested. Moreover, tissue engineering strategies to design and manufacture scaffolds to mimic Bruch’s membrane are very diverse and under investigation. Both alternative therapies are aimed to prevent and/or cure AMD and are reviewed herein.

1. Age-Related Macular Degeneration: Socioeconomic Burden and Limitations of Current Therapies

1.1. General Introduction

Age-related macular degeneration (AMD) is one of the leading causes of vision loss and the most common cause (almost epidemic) of blindness in industrialized countries. It is the first source of legal blindness (visual acuity < 20/200) in Europe and mainly affects people over the age of 50 affecting about 30 million people worldwide. The dramatic loss of autonomy and life quality associated with AMD [1, 2] leads to increased costs for healthcare and long-term care. AMD is multifactorial but clearly age-related pathology. The number of affected people is expected to double by the year 2020 as a result of ageing of the world’s population. Even, in developed countries, AMD is gaining attention due to increased life expectancy and improved visual care facilities [3].

AMD is an inflammatory chronic progressive eye disease with damage to retinal pigment epithelium (RPE) cells in its early stage, while late stage has two distinct forms: the slowly progressing “nonvascular” and the rapidly progressing “neovascular” AMD [4]. However, both forms eventually lead to blindness [5] through degeneration of retinal pigment epithelium (RPE) and posterior photoreceptor (PR) cells.

Moreover, with age, the metabolic activities of RPE cells decrease leading to deposition of debris on and in BM and decreased turnover and degradation of the extracellular matrix (ECM) resulting in altered filtration of nutrients and metabolic wastes which affects attachment of RPE cells to the BM. The resulting altered metabolism and death of the RPE cells cause the hypopigmentation observed in early AMD [6]. Probably, the presence of debris triggers a local inflammatory response that activates the immune system, causing a chronic and excessive immune response with further damage to the retina [7]. Moreover, patient and in vitro studies reveal that cells do not attach to old or damaged BM and do not form a monolayer over the area of degenerated RPE cells [8]. In AMD patients, BM no longer supports the normal functions of RPE cells, and the RPE cells are no longer able to maintain a normal BM [8, 9].

1.2. Limitations of Current Therapies in Clinical Use

Traditional therapeutic products targeting degenerative diseases have largely focused on palliative forms of treatment that mainly ameliorate or control the symptoms of a disease without addressing the underlying biological cause. There is currently no cure available for AMD, and even palliative treatments are rare. Treatment options span a broad range of therapeutic approaches, including thermal laser photocoagulation, surgical approaches (excision, displacement, or transplantation), and new treatments targeting the choroidal neovascularization (CNV) component and its pathogenic cascade, such as verteporfin with photodynamic therapy (vPDT) and more recently antivascular endothelial growth factor (VEGF) therapies [10].

1.2.1. Intermediate and Advanced AMD Prevention

In addition to the intake of vitamin and minerals supplements described by the two AREDS studies, stopping smoking and a healthy diet are strongly recommended.

1.2.2. Wet/Vascular AMD Treatments

Laser Photocoagulation and Photodynamic Therapy. Treatment strategies for the neovascular form of AMD had been focused several years ago on the prevention of further progress of the CNV either with laser photocoagulation for extrafoveal CNV [1113] or with photodynamic therapy (PDT) [14]. Although PDT has become increasingly prevalent, its effect on the patients’ vision is limited; there is a large number of CNV recurrences reported after PDT and the unpredictable repetition of treatments in 3-month intervals in PDT treatment [1416]. Thermal laser successfully prevented the proliferation of CNV; however, visual loss and recurrences impaired the treatment benefit. Using nonthermal laser energy through vPDT appeared as a healthy alternative, but again, it was unsatisfying given the inability to improve vision in a majority of patients [10].

Anti-VEGF Therapy. Vascular endothelial growth factor (VEGF-A) is the most potent promoter of angiogenesis and its role in the pathogenesis of neovascular AMD is well recognized [17, 18]. The advent of intravitreous VEGF inhibitors has revolutionized the management of neovascular AMD. A portion of patients with neovascular AMD can be symptomatically treated with VEGF inhibitors that are effective in preventing the progression of vascular AMD with some vision recovery in only 30% of patients. Monthly injections of Ranibizumab or Bevacizumab (off label) are the current, gold standard therapy in the management of neovascular AMD. Individualized treatment regimens, including traditional PRN (pro-re-nata) and “treat and extend,” may yield visual outcomes comparable with monthly dosing, although close followup and frequent treatments are still needed. However, inhibition of vascularization only maintains temporarily the status quo in the majority of patients indicating that neovascularization is a late event in the development of AMD and certainly not the causative event. In addition, as VEGF is an essential factor for cell survival, it has been demonstrated that the sustained blocking of VEGF can lead to undesirable adverse effects, such as chorioretinal atrophy [19, 20]. Recent preclinical studies in monkeys clearly show that anti-VEGF therapy has a strong reducing effect on the diameter of the choriocapillaris [21]. These findings offer an explanation why RPE cells and retinal atrophy may develop.

In minimally classic/occult trial of the anti-VEGF antibody ranibizumab in the treatment of neovascular age-related macular degeneration (MARINA) study, patients receiving the 0.5 mg dose of ranibizumab experienced a 21.4 letter improvement compared with sham injections, and in ANCHOR, they demonstrated a 20.5 letter improvement compared with those receiving photodynamic therapy [22]. Data from the CATT study showed that patients who were scrutinized monthly experienced similar outcomes at years 1 and 2 whether treated monthly or PRN with ranibizumab or Bevacizumab. These results suggest that either a PRN or a treat-and-extend regimen provides a reasonable approach to the monthly injection protocol, although the two have not been compared directly with each other in prospective trials [23].

Although anti-VEGF injections have largely improve the visual outcomes of late neovascular AMD, the risk of visual decline and disease activity persists, and the need for anti-VEGF treatment continues in a substantial portion of patients. The long-time results observed after seven years in the SEVEN-UP cohort may reflect the inexorable nature of this chronic disease even in the face of treatment. In this study, 98% of the study eyes were detected to have macular atrophy which mainly involved the fovea, as indicated by definite decreased autofluorescence. Decreased visual acuity in late neovascular AMD may be associated with macular atrophy and the presence of intraretinal or subretinal fluid [20].

Anti-VEGF agents with a higher affinity for VEGF molecule, such as aflibercept (Eylea), offer another option [22]. Aflibercept is a promising new agent recently approved by FDA that may lessen the treatment burden, given the encouraging 1-year (after three initial monthly injections) results from the 2 mg bimonthly maintenance dosing arm of the phase 3 VIEW studies compared to the monthly regimen [19]. Preapproval clinical trials showed benefits and side effects that were similar to those of Ranibizumab. Similar to Ranibizumab, aflibercept binds to all VEGF isoforms (A, B, and C) with a 10-fold higher affinity than Ranibizumab for VEGF [24, 25].

Combined Therapy. PDT in combination with anti-VEGF and steroids is currently used as a second-line therapy in patients not responding to monotherapy with anti-VEGF agents or in whom the treatment burden of monthly injections is too great.

Combination therapy with anti-VEGF therapy and ionizing radiation offers another option to reduce treatment frequency. Radiation was never widely adopted because it did not provide a significant, reproducible effect on visual acuity, while difficulty delivering targeted doses led to complications in some patients [2629]. New options, however, such as epimacular brachytherapy and robotic stereotactic radiotherapy, enable safer, targeted delivery of the most appropriate dosage, minimizing damage to surrounding structures and improving outcomes [3033].

Results of the phase 3 choroidal neovascularization secondary to AMD treated with beta radiation epiretinal therapy trial, which compared epiretinal brachytherapy plus ranibizumab with ranibizumab alone, found that the combination was not noninferior to monotherapy with ranibizumab [34].

Ranibizumab efficacy as sole therapy and in combination with PDT has been evaluated in several trials and 6-month results indicate visual acuity improved by 12.8 letters with few drug-related side effects like transient inflammation ([35], Genentech press release: phase III study shows that Lucentis improved vision compared to Visudyne in patients with wet age-related macular degeneration).

1.2.3. Nonvascular AMD

Currently, there are no treatments available for nonvascular AMD [3638]. Transplantation of RPE cells alone has failed to supply a sustainably functional monolayer RPE cells, and delivery of autologous RPE cells into the subretinal space results in insufficient cell survival [39, 40]. Although there is evidence that the combination of specific vitamins might slow progression of nonexudative AMD, this involves a rather small risk group of patients. In addition, the long-term tolerability and side effects of high dose vitamin treatments must be carefully evaluated [41]. Other treatment options currently evaluated in studies are rheopheresis for extracorporeal blood filtration, which has been undertaken in patients with early stages of AMD, namely, drusen and small RPE atrophies [4244]. Grid and focal laser application and also subthreshold laser application in patients with drusen have shown no vision recovery and an increase in the number of neovascularizations in the treated groups [15, 45, 46].

Surgery. Proof-of-principle for the replacement of RPE cells has been provided by several experimental surgical procedures for treating AMD [15, 47]. Macular translocation surgery is achieved by the detachment and rotation of the neural retina of the patient, to reposition the macula from the diseased macular RPE to an area of healthy RPE cells [4850]. However, it yields only temporary recovery of vision; the large retinotomies associated with this procedure have high complication rates [51] and require further surgery to reposition extraocular muscles. Yet the procedure demonstrates two important points: (1) replacing the degenerated RPE cells does restore vision and (2) BM at the macular region is defective and cannot support normal RPE functions since, with time, the translocated RPE cells degenerate again. As translocated cells survive in their original position, RPE cells do not degenerate because of an “endogenous” defect; rather, it appears that the substratum (BM) is not appropriate for survival. The alternative was “autologous RPE transplantation,” which is accomplished by removing a small area of healthy peripheral RPE and transplanting it beneath the macula to replace the diseased RPE [5257]. This technique carries less risk than macular translocation, but the surgical procedure is longer and showed postsurgery complications, such as retinal detachment. Retinal rotation techniques may be an alternative in a very large CNV in nonresponders to new therapies or when it is associated with large hematomas [58].

1.3. Socioeconomic Burden

The emotional and economic burden of AMD is often underrecognized. The prevalence of neovascular AMD (NV-AMD), which accounts for 90% of AMD-related severe visual impairment, increases exponentially with age [59, 60]. Patients with visual impairment such as AMD are more likely to have falls and fall-related injuries, lose driving privileges, experience depression, and anxiety, use special vision aids, and need assistance with day-to-day functioning [6163], all of which are associated with higher resource utilization than the general population [64]. Moreover, the aging population will create a drain on our available healthcare resources—a burden that will continue to grow in magnitude over the next decades.

In contrast to other age-related eye diseases like cataracts that are largely solved by current therapies, the visual prognosis for most patients with AMD is poor and the late stages of both wet and dry AMD are usually associated with severe visual loss, which has profound effects on overall quality of life. The shortages in executing ordinary tasks are also extended to their psychological functioning, as evidenced by patients with AMD reporting greater emotional distress than visually intact peers [65].

Without treatment, the neovascular form of AMD often leads not only to severe loss of vision but also to considerable associated economic burden [6668]. Despite their benefits, frequent, indefinite injections of VEGF blocking agents introduce a significant treatment burden for patients with neovascular AMD. Sequential intraocular injections of anti-VEGF agents are very expensive (1,200 euros per injection, in addition to monthly medical visits) and require its application over long periods of time (12–20 months in most cases and subsequent retreatments). This means a high cost to the National System of Health. Improvement obtained in MARINA was sustained over 2 years, remarkably, but relied on monthly injections to achieve this. This regimen is difficult for patients to maintain, particularly older patients who may not drive, and spurs investigation of other treatment options [69]. Some studies have been aimed to investigate the cost effectiveness of Ranibizumab versus Bevacizumab, given the low cost of the last one. The average 1 year cost of Bevacizumab was 50 times reduced versus Ranibizumab: US$595 in the Bevacizumab versus US$23 400 in the Ranibizumab monthly group and US$385 in the Bevacizumab versus US$13 800 in the Ranibizumab as-needed dosing group. The results of the CATT study support the use of Bevacizumab in the treatment of neovascular AMD and highlight the significant economic benefit of Bevacizumab over Ranibizumab. A recent large, multicenter, randomized prospective study (ABC Trial) which demonstrated MARINA/ANCHOR-like results lends further support for Bevacizumab use in neovascular AMD [70]. Although bimonthly injections certainly are less burdensome on patients than monthly injections, development of new pharmacologic agents and treatment modalities such as regenerative medicine are ongoing in an attempt to mitigate this burden. Interventions that improve the morbidity caused by AMD have the potential to greatly benefit the quality of life of individual patients, as well as the overall economic well-being.

The economic impact of AMD on society is expected to increase in the near future as population age and the prevalence of AMD increase. With new AMD therapies, healthcare decision makers will require reliable quantitative data on AMD-related resource utilization to evaluate alternatives, as the ones suggested in the present review.

The mean annual direct vision-related medical cost was reviewed by Cruess et al. and estimated to range from 2153€ per patient in the UK to 4390€ per patient in Canada. The mean direct nonvision related medical cost was estimated to range from 597€ (11% of the total cost) in the UK to 1657€ (21% of the total cost) in Canada. The annual societal costs estimated in 2004 for bilateral NV-AMD were €1.3 billion in Germany, €624 million in France, €511 million in the UK, €311 million in Canada, and €268 million in Spain. The mean annual cost per bilateral NV-AMD patient ranged from €5300 to 12 445, of which direct vision-related medical costs accounted for 23–63% of the total cost. These estimates are higher than those of two previous prospective studies [64]. Sharma and Oliver-Fernandez estimated the NV-AMD patient annual cost to be $Can3865 (year 2004 values, equivalent to €2715) in North America, with 90% attributable to direct medical costs (photodynamic therapy, 77%) and the remainder to nonmedical costs (home support, 6%) [71]. Similarly, a study involving two French referral centres [72] estimated a €3660 (year 2000 value) mean annual per NV-AMD patient cost, with medical costs accounting for 51% of the total.

There are extensive data that emphasize the need for new treatments for AMD that will prevent vision loss and progression to blindness in order to lessen the ensuing economic burden [73]. Overall, on the basis of current policies, age-related public expenditure is projected to increase in average by about 4.75 percentage points of GDP by 2060 in the EU and by more than 5 percentage points in the euro area—especially through pension, healthcare, and long-term care spending; all of the above concepts succeed in this pathology, and it is necessary to solve these problems in order to avoid negative effects on general European economy. Inactive people in active period of life generate an increase in pensions. Many AMD sufferers are below 65 years old and they are in active life period and they are obligated to ask for pensions. AMD is a disease related to ageing and is associated with decreased functional abilities and quality of life, which result in an increase in healthcare resource utilization.

2. Cell Therapy in AMD: Perspectives and Limitations

It has now been almost 40 years since Gouras and colleagues [74] showed that, using a pars plana approach, rabbit RPE cells transplanted subretinally in rabbits survived and phagocytized photoreceptor outer segments. Since Gouras’ work, a number of investigators have transplanted RPE cells, iris pigment epithelial (IPE) cells, human stem cells, and genetically modified cells in a number of animal models; cell transplantation did prevent photoreceptor degradation and improved vision [39, 7582]. The positive results of cell transplantation in animals, especially the results in the Royal College of Surgeon (RCS) rats in which RPE degeneration is followed by photoreceptor degeneration similar to AMD, led to the transplantation of cell to the subretinal space of AMD patients.

In 1997, Algvere and colleagues transplanted patches of human fetal RPE into patient with neovascular AMD as well as in patients with nonexudative AMD and concluded that “it is technically feasible to transplant human RPE into the submacular space without adversely affecting visual function in nonexudative AMD over relatively long periods of time” [83]. Since 1997, a number of investigators have transplanted RPE cells, choroid-Bruch’s-RPE explants [9, 52, 53, 56, 84], and IPE cells [8587], and recently human embryonic stem cells have been transplanted in one patient with geographic atrophy [88] and a phase I/II, open-label study to determine safety of subretinal transplantation of human embryonic stem cell [NCT01344993] in geographic atrophy (GA) patients is planned. Janssen Research and Development, LLC, plans a clinical trial (NCT01226628) that will transplant human umbilical tissue-derived cells to the subretinal space of patients with visual impairment resulting from GA.

Since the harvesting of autologous RPE cells for transplantation requires an elaborate surgical procedure, a number of investigators have transplanted IPE cells as a substitute for RPE cells since autologous IPE cells can be easily harvested [89]; in vitro studies have shown that RPE and IPE share many morphologic and functional similarities [85, 90, 91], and transplantation of IPE cells to the subretinal space of RCS rats prevented photoreceptor degeneration [39, 81, 92, 93]. The results of these studies have not fulfilled the promise that cell transplantation would be the solution to the treatment of AMD; cell transplantation has failed to show significant improvement in vision in AMD patients.

Even though cell transplantation has failed in the past, the successful transplantation in animal models suggests that theoretically cell transplantation has the potential to be a significant treatment for AMD. The failure of cell transplantation to improve vision in AMD patients is part of the result of the lack of knowledge of the factors that underlay development and progression of AMD. However, there is enough knowledge about AMD to be able to construct a theoretical framework necessary to eventually achieve restoration of vision by cell transplantation. In general, the approach has been to transplant autologous or homologous cell suspensions or autologous peripheral retina choroid-BM-RPE explants without taking into account the status of the patient’s retina. In considering the status of the retina, two characteristics of the disease must be taken into account, namely, the severity and the factors underlying the disease. For this discussion, we will assume that the severity of the disease and loss of vision does not follow a gradient but instead is segregated into three independent phases. Specifically, initially, phase 1: RPE cells in the macular region are intact or reversibly damaged and vision loss is the result of the reversible loss of some function(s) by RPE cells and/or loss of communication between RPE cells and photoreceptors. Later, phase 2: RPE cells in the macular region are degenerated or irreversibly damaged but the photoreceptors are intact or reversibly damaged and loss of vision is the result of nonfunctional RPE cells in the macular region. Finally, phase 3: both RPE cells in the macular region and photoreceptors are degenerated or irreversibly damaged and loss of vision is due to lack of both RPE cells and photoreceptors. As for the factors underlying the disease, numerous studies have indicated that the CNV associated with neovascular AMD results from the lack of the proper balance between angiogenic (VEGF) and antiangiogenic factors (pigment epithelial derived factor, PEDF) [94, 95]. The demonstration that the overexpression of VEGF in the retina is the driving force for pathological neovascularization [96, 97] and overexpression of VEGF in the retina is responsible for neovascular AMD [98, 99] led to the development of antiangiogenic therapies for neovascular AMD. Factors underlying geographic atrophy are unknown; however, from studies on the viability and rescue of photoreceptors, it appears that factors produced by RPE cells, including basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF), are responsible for normal functioning of the retina and photoreceptors’ viability [100102]. In fact, the intravitreal injection of CNTF in a feline model of hereditary retinal degeneration leads to the long-term survival of photoreceptors [103].

In the eye, RPE cells are the principal source of PEDF, a neuroprotective and cytoprotective factor and a potent inhibitor of VEGF [104, 105] that is essential in maintaining the macula avascular [106, 107]. In neovascular AMD, there is an overexpression of VEGF [18] and decreased levels of antiangiogenic factors [108112]. Here it is interesting to note that smoking, a risk factor for neovascular AMD, is associated with poor visual improvement after anti-VEGF treatment and that nicotine increases the VEGF/PEDF ratio in RPE [113, 114] indicating that VEGF is the driving force for neovascular AMD development.

Based on the overexpression of VEGF, intravitreal administration of anti-VEGF monoclonal antibodies (Avastin or Lucentis) has become standard therapy for neovascular AMD with approximately 30% of patients gaining 3 or more lines of visual acuity and stabilization in 90% of patients [37, 115, 116]. However, the short half life of the antibodies in vivo requires repetitive, mostly monthly injections to maintain the therapeutic effect. In addition to the difficulty and cost of monthly treatment for elderly patients, the repetitive intravitreal injections carry substantial risks for the patient, for example, endophthalmitis, ocular hypertension, submacular haemorrhage, and retinal detachment [117, 118]. The difficulties associated with anti-VEGFs necessitate better and more lasting treatments for neovascular AMD.

It was thought that transplantation of RPE cells to the subretinal space would be a better and more permanent treatment for AMD. However, transplantation of RPE or IPE cell suspensions could not be an effective treatment for AMD since normal RPE cells would not supply the increased levels of PEDF necessary to inhibit the augmented VEGF and possibly necessary levels of growth factors required to protect photoreceptors from degenerations. An appropriate treatment for phase 1 neovascular AMD, in which RPE cells and photoreceptors are intact or reversibly damaged, would be the transplantation of genetically modified, autologous pigment epithelial (RPE or IPE) cells that would produce increased levels of VEGF inhibitor, such as PEDF and/or endostatin. In addition, the gene for the inhibitor of VEGF should be integrated into the host cell genome, such that the synthesis and secretion of the augmented PEDF would be for the life of the patient.

Cell transplantation for the treatment of phase 2 neovascular AMD, in which RPE cells are degenerated but the photoreceptors are functional, will require genetically modified, autologous, PEDF and/or endostatin-transfected pigment epithelial cells transplanted as a monolayer on a biocompatible substratum that supports RPE cell functions. A biocompatible substratum is necessary since cell suspensions transplanted to the subretinal space of AMD patients do not attach and form a monolayer [87] because the aged BM, especially neovascular AMD BM, is altered and does not appear to support good attachment and survival of pigment cells [119123]. A number of biocompatible substrates have been investigated and have been found to support attachment, growth, and functionality of RPE cells [40, 124126]; however, these have not been transplanted in patients. The transplanted cell monolayer would replace the degenerated cells and rejuvenate BM by synthesizing a new basal lamina.

Phase 3 of the disease, in which both RPE cells and photoreceptors are degenerated or nonfunctional, will require the manufacture and transplantation of a complex structure that encompasses a biocompatible substratum upon which autologous, PEDF, and/or endostatin transfected pigment epithelial cells are allowed to form a monolayer; the monolayer is then overlaid with photoreceptor precursor cells. In animal models of retinal degeneration, transplanted photoreceptors integrate into the host retina and improve function [127129].

Photoreceptor precursor can be selected from iPS cells derived from the patient’s fibroblasts. A number of methods have been devised to reprogram fibroblasts and induce iPS cells [130, 131]. In the case in which both RPE cells and photoreceptors are degenerated or nonfunctional, it may be necessary to transplant stem cells or iPS-derived RPE cells that may have a wider complement of factors that may be essential to reconstruct a BM-RPE photoreceptor complex [58, 132135]. iPS derived RPE cells have been shown to form pigmented patches of typical cobble-stone cells that express the tight junction protein ZO-1, RPE65, and bestrophin and showed phagocytic activity by the uptake of fluorescent latex beads [136]. Photoreceptors have been generated from iPS cells, have been transplanted in animal models, and have been shown to integrate into the host retina and express photoreceptor markers [137, 138].

The essential goal of cell transplantation in neovascular AMD, when the RPE and photoreceptors are intact or reversibly damaged, is the effective inhibition of blood vessel invasion of the subretinal space and restoration of RPE and photoreceptor functions. For such purpose, the addition of the PEDF gene to the transplanted cells should affect blood vessel inhibition and restore RPE and photoreceptor functionality. It will be critical that the PEDF gene be integrated into the host genome so that its activity will last for the life of the patient. For such purpose, the Sleeping Beauty (SB100X) transposon system is ideal as the gene delivery system since it is highly efficient, similar to retroviral vectors, but without the associated side effects. The SB100X system delivers genetic material into a target cell genome resulting in robust and stable expression of the transgene [139142].

For later stages of neovascular AMD and GA, it may be necessary to introduce into the cells to be transplanted not only the PEDF gene, but also other neuroprotective genes, such as CNTF and IGF1 to engender a neurogenic supportive environment. Before cell transplantation can become a routine procedure, it will be necessary to develop methodologies to identify the stage of degeneration of RPE cells and photoreceptors in AMD patients and transplant cell in an appropriate genetically modified and proper architecture.

3. Tissue Engineering in AMD: Materials, Scaffolds, and Material-Cell Interactions

Another challenge of cell therapy is the lack of cell engraftment and survival in the host tissue after implantation. Therefore, the need arises where this is assisted by artificial supports, known as scaffolds, which are structured biocompatible materials that mimic the host tissue. As described above, different cell types have been tested for treating AMD, including RPE, IPE, retinal progenitor cells (RPC), photoreceptor, and stem cells [143]. Previous works highlight the crucial role of cell adhesion onto BM, the despaired engraftment derived from the deterioration of this membrane, and they show that the best adhesion occurs on the RPE basal lamina [144]. Therefore, tissue engineering approaches for AMD treatment are mainly focused on the transplantation of artificial constructs that ensure cell engraftment and activity, overcoming the limitations of classical cell therapy and empowering the promises of gene therapy.

3.1. Material and Fabrication

The approaches from tissue engineering for the design and manufacturing of scaffolds are very diverse. Decellularized matrices are the most natural scaffolding form. The strategy consists in removing every cell from an organ or tissue and reusing it for in vitro recellularization and subsequent in vivo implantation. In the particular case of retina regeneration, different natural tissues have been tested to be used as recellularized scaffolds. In early experiments, RPE and IPE cells have been transplanted in vitro onto human BM from cadaveric origin [145], Descemet’s membranes [146], lens capsules [147], and amniotic membranes (AM) [148, 149]. Furthermore, cell growth has been modulated by performing microcontact printing on the surface of lens capsules [150]. More recently, trabecular meshwork mesenchymal stem cells and AM have been combined, showing that differentiation towards photoreceptor-like cells is induced [151]. Despite these advances, the access to natural scaffolds is limited to donors; thus, artificial scaffolds are also being developed to elude this restriction. In soft tissues, polymeric materials are preferred for scaffold manufacture due to their tunable capacity and similarity with the host tissue in terms of mechanical properties. In the case of retina, the most used polymeric material from natural origin is collagen. Recently, in vitro and in vivo studies have been performed where RPE cells were cultured on ultrathin collagen membranes. They have proven to form cell monolayers amenable in a way that permits transplantation into subretinal space [40]. Nevertheless, the tunable capacity of the natural polymers is limited and, in some cases, they cannot provide the scaffold with the required properties; therefore, synthetic polymeric materials are chosen as a highly adjustable alternative. Some of the materials already tested for retinal regeneration are Poly(Lactic-co-Glycolic) Acid (PLGA), [152, 153], Poly(glycerol Sebacate) (PGS), [154], Polycaprolactone (PCL) [155], and Poly(methyl methacrylate) (PMMA) [156]. A detailed review of the materials investigated for retinal regeneration has been published by Hynes and Lavik [124].

Among the vast variety of techniques for the fabrication of polymeric scaffolds [157], particle leaching, phase separation, and freeze-drying are the preferred ones for porous structures. However, pointing towards mimicry of the natural ECM assembly, fibrous structures reproduce in a greater extent the microscopic morphology of the native ECM. Consequently, electrospinning has become a remarkably advantageous technique for fibrous scaffolds. With this technique, randomly oriented polymeric fibers in the range of 1 μm in diameter can be deposited; yet, up to date, no precise deposition of the single fibers is possible and only the final macroscopic arrangement can be customized [158, 159]. A new technique for direct writing known as melt electrospinning has recently entered the field of polymeric scaffolds, which allows a precise control of the localization and orientation of every single electrospun fiber [160]. Nonetheless, the dimensions are still too large for a subretinal implantation and further scaling down of the features is necessary [161]. This technique, although still under development, offers new alternatives for tunable structure of polymeric scaffolds in the micrometric range. Additionally, traditional microfabrication techniques, which were originally employed in the silicon industry, are lately being explored and applied in the field of tissue engineering for the fabrication of scaffolds. Photolithography, thin film deposition, and polymer casting etcetera allow the production of well-defined microscopic topographical features on the scaffolds and enhanced cell activity [162, 163].

3.2. Improved Biomaterial Surfaces

Control over surface chemistry is essential to regulate the interaction between cells and scaffolds. A traditional strategy to improve cell adhesion on biomaterials has been the immobilization of proteins on the surface via incubation. Thus, collagen, fibronectin, vitronectin, laminin, and other ECM proteins were directly bound to the surface, allowing cells to anchor onto them [164]. An alternative to protein immobilization is peptide immobilization, which avoids wettability and orientation effects, and allows a tailored design of the aminoacid sequence and precise control towards cell-scaffold interaction. Peptides consist of cell recognition motifs that are found in the proteins, which integrins bind to. The best known motif is the RGD (arginine, glycine, and aspartic acid) sequence, which is prevalently present in fibronectin, although other proteins do contain varied forms of the sequence as well, such as RGDV in vitronectin or RGDT in collagen. It has been shown that cyclic RGDfK-type peptides with different conformations show enhanced integrin binding affinity and especially selectivity [165]. One of the most recent works of scaffolding as substitutes for BM is presented by Treharne et al. where they develop methacrylate-based copolymers. The copolymers are chemically modified by succinimidyl carbonate groups; thus, the hydrophilicity altered favoring peptide adhesion [166]. Results show enhanced peptide and RPE cell adhesion on succinimidyl carbonate functionalized scaffolds. Although initially surface modification was performed in synthetic scaffolds, in the last years, same strategies have started to be translated into natural origin scaffolds. An example of that is provided by Sistiabudi and colleagues where they modify the inner collagenous layer of Bruch’s membrane with a collagen binding motif, where bioactive molecules are anchored [167].

Recent strategies in biomaterials development aim at the combination of increased hydrophilicity and minimized unspecific protein adsorption and cell adhesion, with the ability to permit selective cell binding by the incorporation of cell adhesion motifs. Such techniques have been developed for flat model substrates but remain challenging for biomaterials and three-dimensional structures. One promising one-step technique for the generation of nonwoven textile sheets with basal-membrane like structure and functionalization, with large potential as artificial BM, has recently been introduced [168]. The method relies on the use of an amphiphilic macromolecular additive based on star-shaped PEO to clinically used biodegradable polyesters during fibre generation by electrospinning. This way, hydrophilic fibres are obtained, on which protein adsorption and cell adhesion are minimized. However, cell adhesion peptides can be immobilized on the surface of these fibres, so that specific adhesion of cells onto the fibrous sheets results. With this method, scaffolds could be produced that influence the reaction of immune cells [169] and that mimic the basal membrane in skin [170]. Hence, such strategies bear great potential for TE approaches in AMD, where materials that mimic the BM are one key factor for success.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

A. Sancho gratefully acknowledges the Research Mobility Program of the Basque Government for financial support.

References

  1. A. C. Bird, “Retinal photoreceptor dystrophies Ll. Edward Jackson Memorial Lecture,” American Journal of Ophthalmology, vol. 119, no. 5, pp. 543–562, 1995. View at Google Scholar · View at Scopus
  2. R. Klein, B. E. K. Klein, S. C. Jemen, and K. J. Cruichshanks, “The relationship of ocular factors to the incidence and progression of age-related maculopathy,” Archives of Ophthalmology, vol. 116, no. 4, pp. 506–513, 1998. View at Google Scholar · View at Scopus
  3. A. Banerjee, S. Kumar, P. Kulhara, and A. Gupta, “Prevalence of depression and its effect on disability in patients with age-related macular degeneration,” Indian Journal of Ophthalmology, vol. 56, no. 6, pp. 469–474, 2008. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Z. Nowak, “Age-related macular degeneration (AMD): pathogenesis and therapy,” Pharmacological Reports, vol. 58, no. 3, pp. 353–363, 2006. View at Google Scholar · View at Scopus
  5. R. D. Jager, W. F. Mieler, and J. W. Miller, “Age-related macular degeneration,” The New England Journal of Medicine, vol. 358, no. 24, pp. 2544–2617, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. M. A. Zarbin, “Current concepts in the pathogenesis of age-related macular degeneration,” Archives of Ophthalmology, vol. 122, no. 4, pp. 598–614, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. E. Buschini, A. Piras, R. Nuzzi, and A. Vercelli, “Age related macular degeneration and drusen: neuroinflammation in the retina,” Progress in Neurobiology, vol. 95, no. 1, pp. 14–25, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. L. V. del Priore, T. H. Tezel, and H. J. Kaplan, “Maculoplasty for age-related macular degeneration: reengineering Bruch's membrane and the human macula,” Progress in Retinal and Eye Research, vol. 25, no. 6, pp. 539–562, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. T. H. Tezel, L. V. del Priore, A. S. Berger, and H. J. Kaplan, “Adult retinal pigment epithelial transplantation in exudative age-related macular degeneration,” American Journal of Ophthalmology, vol. 143, no. 4, pp. 584–e2, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. J. P. Hubschman, S. Reddy, and S. D. Schwartz, “Age-related macular degeneration: current treatments,” Clinical Ophthalmology, vol. 3, no. 1, pp. 155–166, 2009. View at Google Scholar · View at Scopus
  11. “Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in the macular photocoagulation study. Macular Photocoagulation Study Group,” Archives of Ophthalmology, vol. 109, no. 9, pp. 1242–1257, 1991. View at Scopus
  12. “Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Macular Photocoagulation Study Group,” Archives of Ophthalmology, vol. 111, no. 9, pp. 1200–1209, 1993. View at Scopus
  13. “Persistent and recurrent neovascularization after laser photocoagulation for subfoveal choroidal neovascularization of age-related macular degeneration. Macular Photocoagulation Study Group,” Archives of Ophthalmology, vol. 112, no. 4, pp. 489–499, 1994. View at Scopus
  14. N. M. Bressler, “Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials—TAP report 2,” Archives of Ophthalmology, vol. 119, no. 2, pp. 198–207, 2001. View at Google Scholar · View at Scopus
  15. S. Binder, B. V. Stanzel, I. Krebs, and C. Glittenberg, “Transplantation of the RPE in AMD,” Progress in Retinal and Eye Research, vol. 26, no. 5, pp. 516–554, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. N. M. Bressler, J. C. Silva, S. B. Bressler, S. L. Fine, and W. R. Green, “Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration,” Retina, vol. 14, no. 2, pp. 130–142, 1994. View at Publisher · View at Google Scholar · View at Scopus
  17. N. Ferrara, H.-P. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Kliffen, H. S. Sharma, C. M. Mooy, S. Kerkvliet, and P. T. V. M. de Jong, “Increased expression of angiogenic growth factors in age-related maculopathy,” British Journal of Ophthalmology, vol. 81, no. 2, pp. 154–162, 1997. View at Google Scholar · View at Scopus
  19. D. R. Lally, A. T. Gerstenblith, and C. D. Regillo, “Preferred therapies for neovascular age-related macular degeneration,” Current Opinion in Ophthalmology, vol. 23, no. 3, pp. 182–188, 2012. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Rofagha, R. B. Bhisitkul, D. S. Boyer, S. R. Sadda, and K. Zhang, “Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP),” Ophthalmology, vol. 120, no. 11, pp. 2292–2299, 2013. View at Publisher · View at Google Scholar
  21. U. Schraermeyer and S. Julien, “Effects of bevacizumab in retina and choroid after intravitreal injection into monkey eyes,” Expert Opinion on Biological Therapy, vol. 13, no. 2, pp. 157–167, 2013. View at Google Scholar
  22. T. S. Chang, N. M. Bressler, J. T. Fine, C. M. Dolan, J. Ward, and T. R. Klesert, “Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial,” Archives of Ophthalmology, vol. 125, no. 11, pp. 1460–1469, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. J. A. Haller, “Current anti-vascular endothelial growth factor dosing regimens: benefits and burden,” Ophthalmology, vol. 120, no. 5, supplement, pp. S3–S7, 2013. View at Google Scholar
  24. J. A. Dixon, S. C. N. Oliver, J. L. Olson, and N. Mandava, “VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration,” Expert Opinion on Investigational Drugs, vol. 18, no. 10, pp. 1573–1580, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. P. K. Kaiser, “Emerging therapies for neovascular age-related macular degeneration: drugs in the pipeline,” Ophthalmology, vol. 120, no. 5, supplement, pp. S11–S15, 2013. View at Google Scholar
  26. J. A. Adams, K. L. Paiva, J. E. Munzenrider, J. W. Miller, and E. S. Gragoudas, “Proton beam therapy for age-related macular degeneration: development of a standard plan,” Medical Dosimetry, vol. 24, no. 4, pp. 233–238, 1999. View at Publisher · View at Google Scholar · View at Scopus
  27. P. T. Finger, Y. P. Gelman, A. M. Berson, and A. Szechter, “Palladium-103 plaque radiation therapy for macular degeneration: results of a 7 year study,” British Journal of Ophthalmology, vol. 87, no. 12, pp. 1497–1503, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. V. Sivagnanavel, J. R. Evans, Z. Ockrim, and V. Chong, “Radiotherapy for neovascular age-related macular degeneration,” Cochrane Database of Systematic Reviews, no. 4, Article ID CD004004, 2004. View at Google Scholar · View at Scopus
  29. H. J. Zambarakji, A. M. Lane, E. Ezra et al., “Proton beam irradiation for neovascular age-related macular degeneration,” Ophthalmology, vol. 113, no. 11, pp. 2012–2019, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. M. P. Ávila, M. E. Farah, A. Santos, J. P. Duprat, B. W. Woodward, and J. Nau, “Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration,” British Journal of Ophthalmology, vol. 93, no. 3, pp. 305–309, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. M. P. Ávila, M. E. Farah, A. Santos et al., “Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to amd,” Retina, vol. 29, no. 2, pp. 157–169, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Gertner, E. Chell, K.-H. Pan, S. Hansen, P. K. Kaiser, and D. M. Moshfeghi, “Stereotactic targeting and dose verification for age-related macular degeneration,” Medical Physics, vol. 37, no. 2, pp. 600–606, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. R. A. Silva, A. A. Moshfeghi, P. K. Kaiser, R. P. Singh, and D. M. Moshfeghi, “Radiation treatment for age-related macular degeneration,” Seminars in Ophthalmology, vol. 26, no. 3, pp. 121–130, 2011. View at Publisher · View at Google Scholar
  34. P. U. Dugel, J. D. Bebchuk, J. Nau et al., “Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET),” Ophthalmology, vol. 120, no. 2, pp. 317–327, 2013. View at Google Scholar
  35. J. S. Heier, A. N. Antoszyk, P. R. Pavan et al., “Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study,” Ophthalmology, vol. 113, no. 4, pp. 633.e1–633.e4, 2006. View at Google Scholar
  36. L. J. Hernandez-Pastor, A. Ortega, A. Garcia-Layana, and J. Giraldez, “Ranibizumab for neovascular age-related macular degeneration,” American Journal of Health-System Pharmacy, vol. 65, no. 19, pp. 1805–1814, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. P. J. Rosenfeld, D. M. Brown, J. S. Heier et al., “Ranibizumab for neovascular age-related macular degeneration,” The New England Journal of Medicine, vol. 355, no. 14, pp. 1419–1431, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Schmitz-Valckenberg, M. Fleckenstein, H.-M. Helb, P. C. Issa, H. P. N. Scholl, and F. G. Holz, “In vivo imaging of foveal sparing in geographic atrophy secondary to age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 50, no. 8, pp. 3915–3921, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. G. Thumann, A. K. Salz, P. Walter, and S. Johnen, “Preservation of photoreceptors in dystrophic RCS rats following allo- and xenotransplantation of IPE cells,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 247, no. 3, pp. 363–369, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. G. Thumann, A. Viethen, A. Gaebler et al., “The in vitro and in vivo behaviour of retinal pigment epithelial cells cultured on ultrathin collagen membranes,” Biomaterials, vol. 30, no. 3, pp. 287–294, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. “A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9,” Archives of Ophthalmology, vol. 119, no. 10, pp. 1439–1452, 2001.
  42. R. Klingel, C. Fassbender, I. Fischer et al., “Rheopheresis for age-related macular degeneration: a novel indication for therapeutic apheresis in ophthalmology,” Therapeutic Apheresis, vol. 6, no. 4, pp. 271–281, 2002. View at Google Scholar · View at Scopus
  43. J. S. Pulido, W. B. Anderson Jr., J. T. Flynn, P. R. Lichter, and D. Sanders, “Multicenter prospective, randomized, double-masked, placebo-controlled study of rheopheresis to treat nonexudative age-related macular degeneration: interim analysis,” Transactions of the American Ophthalmological Society, vol. 100, pp. 85–107, 2002. View at Google Scholar · View at Scopus
  44. J. S. Pulido, D. Sanders, and R. Klingel, “Rheopheresis for age-related macular degeneration: clinical results and putative mechanism of action,” Canadian Journal of Ophthalmology, vol. 40, no. 3, pp. 332–340, 2005. View at Google Scholar · View at Scopus
  45. T. R. Friberg, “Laser photocoagulation of eyes with drusen: will it help,” Seminars in Ophthalmology, vol. 14, no. 1, pp. 45–50, 1999. View at Google Scholar · View at Scopus
  46. T. R. Friberg, D. C. Musch, J. I. Lim, L. Morse, W. Freeman, and S. Sinclair, “Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients,” Ophthalmology, vol. 113, no. 4, pp. 612–622, 2006. View at Publisher · View at Google Scholar · View at Scopus
  47. L. da Cruz, F. K. Chen, A. Ahmado, J. Greenwood, and P. Coffey, “RPE transplantation and its role in retinal disease,” Progress in Retinal and Eye Research, vol. 26, no. 6, pp. 598–635, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. E. de Juan Jr., A. Loewenstein, N. M. Bressler, and J. Alexander, “Translocation of the retina for management of subfoveal choroidal neovascularization II: a preliminary report in humans,” American Journal of Ophthalmology, vol. 125, no. 5, pp. 635–646, 1998. View at Publisher · View at Google Scholar · View at Scopus
  49. J. C. Lai, D. J. Lapolice, S. S. Stinnett et al., “Visual outcomes following macular translocation with 360° peripheral retinectomy,” Archives of Ophthalmology, vol. 120, no. 10, pp. 1317–1324, 2002. View at Google Scholar · View at Scopus
  50. R. Machemer and U. H. Steinhorst, “Retinal separation, retinotomy, and macular relocation: II. A surgical approach for age-related macular degeneration?” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 231, no. 11, pp. 635–641, 1993. View at Publisher · View at Google Scholar · View at Scopus
  51. F. Gelisken, M. Voelker, R. Schwabe et al., “Full macular translocation versus photodynamic therapy with verteporfin in the treatment of neovascular age-related macular degeneration: 1-year results of a prospective, controlled, randomised pilot trial (FMT-PDT),” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 245, no. 8, pp. 1085–1095, 2007. View at Publisher · View at Google Scholar · View at Scopus
  52. S. Binder, I. Krebs, R.-D. Hilgers et al., “Outcome of transplantation of autologous retinal pigment epithelium in age-related macular degeneration: a prospective trial,” Investigative Ophthalmology and Visual Science, vol. 45, no. 11, pp. 4151–4160, 2004. View at Publisher · View at Google Scholar · View at Scopus
  53. C. I. Falkner-Radler, I. Krebs, C. Glittenberg et al., “Human retinal pigment epithelium (RPE) transplantation: outcome after autologous RPE-choroid sheet and RPE cell-suspension in a randomised clinical study,” British Journal of Ophthalmology, vol. 95, no. 3, pp. 370–375, 2011. View at Publisher · View at Google Scholar · View at Scopus
  54. A. M. Joussen, “How complete is successful? “Autologous retinal pigment epithelium and choriod translocation in patients with exsudative age-related macular degeneration: a short-term follow-up” by Jan van Meurs and P.R. van Biesen,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 241, no. 12, pp. 966–967, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. A. M. Joussen, F. M. A. Heussen, S. Joeres et al., “Autologous translocation of the choroid and retinal pigment epithelium in age-related macular degeneration,” American Journal of Ophthalmology, vol. 142, no. 1, pp. 17–30, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. R. E. MacLaren, G. S. Uppal, K. S. Balaggan et al., “Autologous transplantation of the retinal pigment epithelium and choroid in the treatment of neovascular age-related macular degeneration,” Ophthalmology, vol. 114, no. 3, pp. 561–570, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. G. A. Peyman, K. J. Blinder, C. L. Paris, W. Alturki, N. C. Nelson Jr., and U. Desai, “A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring,” Ophthalmic Surgery, vol. 22, no. 2, pp. 102–108, 1991. View at Google Scholar · View at Scopus
  58. A. J. Carr, M. J. Smart, C. M. Ramsden, M. B. Powner, L. da Cruz, and P. J. Coffey, “Development of human embryonic stem cell therapies for age-related macular degeneration,” Trends in Neurosciences, vol. 36, no. 7, pp. 385–395, 2013. View at Publisher · View at Google Scholar
  59. M. Desai, L. A. Pratt, H. Lentzner, and K. N. Robinson, “Trends in vision and hearing among older Americans,” Aging Trends, no. 2, pp. 1–8, 2001. View at Google Scholar · View at Scopus
  60. L. Verma, T. Das, S. Binder et al., “New approaches in the management of choroidal neovascular membrane in age-related macular degeneration,” Indian Journal of Ophthalmology, vol. 48, no. 4, pp. 263–278, 2000. View at Google Scholar · View at Scopus
  61. P. Dargent-Molina, F. Favier, H. Grandjean et al., “Fall-related factors and risk of hip fracture: the EPIDOS prospective study,” The Lancet, vol. 348, no. 9021, pp. 145–149, 1996. View at Publisher · View at Google Scholar · View at Scopus
  62. R. Q. Ivers, R. G. Cumming, P. Mitchell, and K. Attebo, “Visual impairment and falls in older adults: the blue mountains eye study,” Journal of the American Geriatrics Society, vol. 46, no. 1, pp. 58–64, 1998. View at Google Scholar · View at Scopus
  63. H. K. M. Lee and R. J. Scudds, “Comparison of balance in older people with and without visual impairment,” Age and Ageing, vol. 32, no. 6, pp. 643–649, 2003. View at Publisher · View at Google Scholar · View at Scopus
  64. A. F. Cruess, G. Zlateva, X. Xu et al., “Economic burden of bilateral neovascular age-related macular degeneration: multi-country observational study,” PharmacoEconomics, vol. 26, no. 1, pp. 57–73, 2008. View at Google Scholar · View at Scopus
  65. R. A. Williams, B. L. Brody, R. G. Thomas, R. M. Kaplan, and S. I. Brown, “The psychosocial impact of macular degeneration,” Archives of Ophthalmology, vol. 116, no. 4, pp. 514–520, 1998. View at Google Scholar · View at Scopus
  66. “Laser photocoagulation of subfoveal recurrent neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group,” Archives of Ophthalmology, vol. 109, no. 9, pp. 1232–1241, 1991. View at Scopus
  67. G. Brown and M. M. Brown, “Let us wake the nation on the treatment for age-related macular degeneration,” Current Opinion in Ophthalmology, vol. 21, no. 3, pp. 169–171, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. M. M. Brown, G. C. Brown, J. D. Stein, Z. Roth, J. Campanella, and G. R. Beauchamp, “Age-related macular degeneration: economic burden and value-based medicine analysis,” Canadian Journal of Ophthalmology, vol. 40, no. 3, pp. 277–287, 2005. View at Google Scholar · View at Scopus
  69. A. Oishi, M. Mandai, A. Nishida, M. Hata, T. Matsuki, and Y. Kurimoto, “Remission and dropout rate of anti-VEGF therapy for age-related macular degeneration,” European Journal of Ophthalmology, vol. 21, no. 6, pp. 777–782, 2011. View at Publisher · View at Google Scholar
  70. A. Tufail, P. J. Patel, C. Egan et al., “Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study,” British Medical Journal, vol. 340, article c2459, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. S. Sharma and A. Oliver-Fernandez, “Age-related macular degeneration and quality of life: how to interpret a research paper in health-related quality of life,” Current Opinion in Ophthalmology, vol. 15, no. 3, pp. 227–231, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. J. Bonastre, C. le Pen, G. Soubrane, and G. Quentel, “The burden of age-related macular degeneration: results of a cohort study in two french referral centres,” PharmacoEconomics, vol. 21, no. 3, pp. 181–190, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Cruess, G. Zlateva, X. Xu, and S. Rochon, “Burden of illness of neovascular age-related macular degeneration in Canada,” Canadian Journal of Ophthalmology, vol. 42, no. 6, pp. 836–843, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. R. Lopez, P. Gouras, M. Brittis, and H. Kjeldbye, “Transplantation of cultured rabbit retinal epithelium to rabbit retina using a closed-eye method,” Investigative Ophthalmology and Visual Science, vol. 28, no. 7, pp. 1131–1137, 1987. View at Google Scholar · View at Scopus
  75. S. Arnhold, P. Heiduschka, H. Klein et al., “Adenovirally transduced bone marrow stromal cells differentiate into pigment epithelial cells and induce rescue effects in RCS rats,” Investigative Ophthalmology and Visual Science, vol. 47, no. 9, pp. 4121–4129, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. P. J. Coffey, S. Girman, S. M. Wang et al., “Long-term preservation of cortically dependent visual function in RCS rats by transplantation,” Nature Neuroscience, vol. 5, no. 1, pp. 53–56, 2002. View at Publisher · View at Google Scholar · View at Scopus
  77. C. Gias, M. Jones, D. Keegan et al., “Preservation of visual cortical function following retinal pigment epithelium transplantation in the RCS rat using optical imaging techniques,” European Journal of Neuroscience, vol. 25, no. 7, pp. 1940–1948, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. P. Gouras, J. Kong, and S. H. Tsang, “Retinal degeneration and RPE transplantation in RPE65−/− mice,” Investigative Ophthalmology and Visual Science, vol. 43, no. 10, pp. 3307–3311, 2002. View at Google Scholar · View at Scopus
  79. B. Lu, C. Malcuit, S. Wang et al., “Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration,” Stem Cells, vol. 27, no. 9, pp. 2126–2135, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. R. D. Lund, S. Wang, I. Klimanskaya et al., “Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats,” Cloning and Stem Cells, vol. 8, no. 3, pp. 189–199, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. I. Semkova, F. Kreppel, G. Welsandt et al., “Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 20, pp. 13090–13095, 2002. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Wang, B. Lu, S. Girman, T. Holmes, N. Bischoff, and R. D. Lund, “Morphological and functional rescue in RCS rats after RPE cell line transplantation at a later stage of degeneration,” Investigative Ophthalmology and Visual Science, vol. 49, no. 1, pp. 416–421, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. P. V. Algvere, L. Berglin, P. Gouras, Y. Sheng, and E. D. Kopp, “Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 235, no. 3, pp. 149–158, 1997. View at Publisher · View at Google Scholar · View at Scopus
  84. Z. Ma, L. Han, C. Wang et al., “Autologous transplantation of retinal pigment epithelium-Bruch's membrane complex for hemorrhagic age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 50, no. 6, pp. 2975–2981, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. T. Abe, M. Yoshida, H. Tomita et al., “Functional analysis after auto iris pigment epithelial cell transplantation in patients with age-related macular degeneration,” Tohoku Journal of Experimental Medicine, vol. 189, no. 4, pp. 295–305, 1999. View at Google Scholar · View at Scopus
  86. T. Abe, M. Yoshida, Y. Yoshioka et al., “Iris pigment epithelial cell transplantation for degenerative retinal diseases,” Progress in Retinal and Eye Research, vol. 26, no. 3, pp. 302–321, 2007. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Aisenbrey, B. A. Lafaut, P. Szurman et al., “Iris pigment epithelial translocation in the treatment of exudative macular degeneration: a 3-year follow-up,” Archives of Ophthalmology, vol. 124, no. 2, pp. 183–188, 2006. View at Publisher · View at Google Scholar · View at Scopus
  88. S. D. Schwartz, J.-P. Hubschman, G. Heilwell et al., “Embryonic stem cell trials for macular degeneration: a preliminary report,” The Lancet, vol. 379, no. 9817, pp. 713–720, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Arnhold, I. Semkova, C. Andressen et al., “Iris pigment epithelial cells: a possible cell source for the future treatment of neurodegenerative diseases,” Experimental Neurology, vol. 187, no. 2, pp. 410–417, 2004. View at Publisher · View at Google Scholar · View at Scopus
  90. G. Thumann, K. U. Bartz-Schmidt, K. Heimann, and U. Schraermeyer, “Phagocytosis of rod outer segments by human iris pigment epithelial cells in vitro,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 236, no. 10, pp. 753–757, 1998. View at Publisher · View at Google Scholar · View at Scopus
  91. G. Thumann, N. Kociok, K. U. Bartz-Schmidt, P. Esser, U. Schraermeyer, and K. Heimann, “Detection of mRNA for proteins involved in retinol metabolism in iris pigment epithelium,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 237, no. 12, pp. 1046–1051, 1999. View at Publisher · View at Google Scholar · View at Scopus
  92. S. Crafoord, L. Geng, S. Seregard, and P. V. Algvere, “Photoreceptor survival in transplantation of autologous iris pigment epithelial cells to the subretinal space,” Acta Ophthalmologica Scandinavica, vol. 80, no. 4, pp. 387–394, 2002. View at Publisher · View at Google Scholar · View at Scopus
  93. G. Thumann, K. U. Bartz-Schmidt, H. El Bakri et al., “Transplantation of autologous iris pigment epithelium to the subretinal space in rabbits,” Transplantation, vol. 68, no. 2, pp. 195–201, 1999. View at Publisher · View at Google Scholar · View at Scopus
  94. I. A. Bhutto, D. S. McLeod, T. Hasegawa et al., “Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration,” Experimental Eye Research, vol. 82, no. 1, pp. 99–110, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. J.-P. Tong, W.-M. Chan, D. T. L. Liu et al., “Aqueous humor levels of vascular endothelial growth factor and pigment epithelium-derived factor in polypoidal choroidal vasculopathy and choroidal neovascularization,” American Journal of Ophthalmology, vol. 141, no. 3, pp. 456–462, 2006. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Ferrara, “Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications,” Seminars in Oncology, vol. 29, no. 6, supplement 16, pp. 10–14, 2002. View at Google Scholar · View at Scopus
  97. J. W. Miller, J. Le Couter, E. C. Strauss, and N. Ferrara, “Vascular endothelial growth factor a in intraocular vascular disease,” Ophthalmology, vol. 120, no. 1, pp. 106–114, 2013. View at Google Scholar
  98. N. Kwak, N. Okamoto, J. M. Wood, and P. A. Campochiaro, “VEGF is major stimulator in model of choroidal neovascularization,” Investigative Ophthalmology and Visual Science, vol. 41, no. 10, pp. 3158–3164, 2000. View at Google Scholar · View at Scopus
  99. K. Ohno-Matsui, “Molecular mechanism for choroidal neovascularization in age-related macular degeneration,” Nippon Ganka Gakkai Zasshi, vol. 107, no. 11, pp. 657–673, 2003. View at Google Scholar · View at Scopus
  100. M. E. Carwile, R. B. Culbert, R. L. Sturdivant, and T. W. Kraft, “Rod outer segment maintenance is enhanced in the presence of BFGF, CNTF and GDNF,” Experimental Eye Research, vol. 66, no. 6, pp. 791–805, 1998. View at Publisher · View at Google Scholar · View at Scopus
  101. M. M. LaVail, K. Unoki, D. Yasumura, M. T. Matthes, G. D. Yancopoulos, and R. H. Steinberg, “Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 23, pp. 11249–11253, 1992. View at Publisher · View at Google Scholar · View at Scopus
  102. K. Unoki and M. M. LaVail, “Protection of the rat retina from ischemic injury by brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor,” Investigative Ophthalmology and Visual Science, vol. 35, no. 3, pp. 907–915, 1994. View at Google Scholar · View at Scopus
  103. N. H. V. Chong, R. A. Alexander, L. Waters, K. C. Barnett, A. C. Bird, and P. J. Luthert, “Repeated injections of a ciliary neurotrophic factor analogue leading to long-term photoreceptor survival in hereditary retinal degeneration,” Investigative Ophthalmology and Visual Science, vol. 40, no. 6, pp. 1298–1305, 1999. View at Google Scholar · View at Scopus
  104. C. J. Barnstable and J. Tombran-Tink, “Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential,” Progress in Retinal and Eye Research, vol. 23, no. 5, pp. 561–577, 2004. View at Publisher · View at Google Scholar · View at Scopus
  105. D. W. Dawson, O. V. Volpert, P. Gillis et al., “Pigment epithelium-derived factor: a potent inhibitor of angiogenesis,” Science, vol. 285, no. 5425, pp. 245–248, 1999. View at Publisher · View at Google Scholar · View at Scopus
  106. N. Kociok and A. M. Joussen, “Varied expression of functionally important genes of RPE and choroid in the macula and in the periphery of normal human eyes,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 245, no. 1, pp. 101–113, 2007. View at Publisher · View at Google Scholar · View at Scopus
  107. P. Kozulin, R. Natoli, K. M. B. O'Brien, M. C. Madigan, and J. M. Provis, “The cellular expression of antiangiogenic factors in fetal primate macula,” Investigative Ophthalmology and Visual Science, vol. 51, no. 8, pp. 4298–4306, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. I. A. Bhutto, S. Y. Kim, D. S. McLeod et al., “Localization of collagen XVIII and the endostatin portion of collagen XVIII in aged human control eyes and eyes with age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 45, no. 5, pp. 1544–1552, 2004. View at Publisher · View at Google Scholar · View at Scopus
  109. I. A. Bhutto, K. Uno, C. Merges, L. Zhang, D. S. McLeod, and G. A. Lutty, “Reduction of endogenous angiogenesis inhibitors in Bruch's membrane of the submacular region in eyes with age-related macular degeneration,” Archives of Ophthalmology, vol. 126, no. 5, pp. 670–678, 2008. View at Publisher · View at Google Scholar · View at Scopus
  110. N. M. Holekamp, N. Bouck, and O. Volpert, “Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration,” American Journal of Ophthalmology, vol. 134, no. 2, pp. 220–227, 2002. View at Publisher · View at Google Scholar · View at Scopus
  111. N. Ogata, M. Wada, T. Otsuji, N. Jo, J. Tombran-Tink, and M. Matsumura, “Expression of pigment epithelium-derived factor in normal adult rat eye and experimental choroidal neovascularization,” Investigative Ophthalmology and Visual Science, vol. 43, no. 4, pp. 1168–1175, 2002. View at Google Scholar · View at Scopus
  112. J. Spranger, M. Osterhoff, M. Reimann et al., “Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease,” Diabetes, vol. 50, no. 12, pp. 2641–2645, 2001. View at Google Scholar · View at Scopus
  113. S. Lee, S. J. Song, and H. G. Yu, “Current smoking is associated with a poor visual acuity improvement after intravitreal ranibizumab therapy in patients with exudative age-related macular degeneration,” Journal of Korean Medical Science, vol. 28, no. 5, pp. 769–774, 2013. View at Google Scholar
  114. M. Pons and M. E. Marin-Castaño, “Nicotine increases the VEGF/PEDF ratio in retinal pigment epithelium: a possible mechanism for CNV in passive smokers with AMD,” Investigative Ophthalmology & Visual Science, vol. 52, no. 6, pp. 3842–3853, 2011. View at Google Scholar · View at Scopus
  115. D. M. Brown, M. Michels, P. K. Kaiser, J. S. Heier, J. P. Sy, and T. Ianchulev, “Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study,” Ophthalmology, vol. 116, no. 1, pp. 57–65, 2009. View at Publisher · View at Google Scholar · View at Scopus
  116. D. F. Martin, M. G. Maguire, G.-S. Ying, J. E. Grunwald, S. L. Fine, and G. J. Jaffe, “Ranibizumab and bevacizumab for neovascular age-related macular degeneration,” The New England Journal of Medicine, vol. 364, no. 20, pp. 1897–1908, 2011. View at Publisher · View at Google Scholar · View at Scopus
  117. R. A. Adelman, Q. Zheng, and H. R. Mayer, “Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections,” Journal of Ocular Pharmacology and Therapeutics, vol. 26, no. 1, pp. 105–110, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. R. Krishnan, S. Goverdhan, and J. Lochhead, “Submacular haemorrhage after intravitreal bevacizumab compared with intravitreal ranibizumab in large occult choroidal neovascularization,” Clinical and Experimental Ophthalmology, vol. 37, no. 4, pp. 384–388, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. V. K. Gullapalli, I. K. Sugino, Y. van Patten, S. Shah, and M. A. Zarbin, “Impaired RPE survival on aged submacular human Bruch's membrane,” Experimental Eye Research, vol. 80, no. 2, pp. 235–248, 2005. View at Publisher · View at Google Scholar · View at Scopus
  120. A. A. Hussain, Y. Lee, J.-J. Zhang, and J. Marshall, “Disturbed matrix metalloproteinase activity of Bruch's membrane in age-related macular degeneration,” Investigative Ophthalmology & Visual Science, vol. 52, no. 7, pp. 4459–4466, 2011. View at Google Scholar · View at Scopus
  121. A. A. Hussain, C. Starita, A. Hodgetts, and J. Marshall, “Macromolecular diffusion characteristics of ageing human Bruch's membrane: implications for age-related macular degeneration (AMD),” Experimental Eye Research, vol. 90, no. 6, pp. 703–710, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. I. K. Sugino, Q. Sun, J. Wang et al., “Comparison of FRPE and human embryonic stem cell-derived rpe behavior on aged human Bruch's membrane,” Investigative Ophthalmology and Visual Science, vol. 52, no. 8, pp. 4979–4997, 2011. View at Publisher · View at Google Scholar · View at Scopus
  123. X. Yuan, X. Gu, J. S. Crabb et al., “Quantitative proteomics: comparison of the macular Bruch membrane/choroid complex from age-related macular degeneration and normal eyes,” Molecular and Cellular Proteomics, vol. 9, no. 6, pp. 1031–1046, 2010. View at Publisher · View at Google Scholar · View at Scopus
  124. S. R. Hynes and E. B. Lavik, “A tissue-engineered approach towards retinal repair: scaffolds for cell transplantation to the subretinal space,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 248, no. 6, pp. 763–778, 2010. View at Publisher · View at Google Scholar · View at Scopus
  125. B. V. Stanzel, Z. Liu, R. Brinken, N. Braun, F. G. Holz, and N. Eter, “Subretinal delivery of ultrathin rigid-elastic cell carriers using a metallic shooter instrument and biodegradable hydrogel encapsulation,” Investigative Ophthalmology & Visual Science, vol. 53, no. 1, pp. 490–500, 2012. View at Google Scholar · View at Scopus
  126. H. A. J. Thomson, A. J. Treharne, P. Walker, M. C. Grossel, and A. J. Lotery, “Optimisation of polymer scaffolds for retinal pigment epithelium (RPE) cell transplantation,” British Journal of Ophthalmology, vol. 95, no. 4, pp. 563–568, 2011. View at Publisher · View at Google Scholar · View at Scopus
  127. U. Bartsch, W. Oriyakhel, P. F. Kenna et al., “Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into adult mice,” Experimental Eye Research, vol. 86, no. 4, pp. 691–700, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. M. del Cerro, M. F. D. Notter, C. del Cerro, S. J. Wiegand, D. A. Grover, and E. Lazar, “Intraretinal transplantation for rod-cell replacement in light-damaged retinas,” Journal of Neural Transplantation, vol. 1, no. 1, pp. 1–10, 1989. View at Google Scholar · View at Scopus
  129. A. S. L. Kwan, S. Wang, and R. D. Lund, “Photoreceptor layer reconstruction in a rodent model of retinal degeneration,” Experimental Neurology, vol. 159, no. 1, pp. 21–33, 1999. View at Publisher · View at Google Scholar · View at Scopus
  130. I. Grabundzija, J. Wang, A. Sebe et al., “Sleeping Beauty transposon-based system for cellular reprogramming and targeted gene insertion in induced pluripotent stem cells,” Nucleic Acids Research, vol. 41, no. 3, pp. 1829–1847, 2013. View at Google Scholar
  131. Z. B. Jin, S. Okamoto, P. Xiang, and M. Takahashi, “Integration-free induced pluripotent stem cells derived from retinitis pigmentosa patient for disease modeling,” Stem Cells Translational Medicine, vol. 1, no. 6, pp. 503–509, 2012. View at Google Scholar
  132. D. E. Buchholz, B. O. Pennington, R. H. Croze, C. R. Hinman, P. J. Coffey, and D. O. Clegg, “Rapid and efficient directed differentiation of human pluripotent stem cells into retinal pigmented epithelium,” Stem Cells Translational Medicine, vol. 2, no. 5, pp. 384–393, 2013. View at Publisher · View at Google Scholar
  133. J. Maruotti, K. Wahlin, D. Gorrell, I. Bhutto, G. Lutty, and D. J. Zack, “A simple and scalable process for the differentiation of retinal pigment epithelium from human pluripotent stem cells,” Stem Cells Translational Medicine, vol. 2, no. 5, pp. 341–354, 2013. View at Publisher · View at Google Scholar
  134. H. Melville, M. Carpiniello, K. Hollis, A. Staffaroni, and N. Golestaneh, “Stem cells: a new paradigm for disease modeling and developing therapies for age-related macular degeneration,” Journal of Translational Medicine, vol. 11, article 53, 2013. View at Publisher · View at Google Scholar
  135. G. A. Moviglia, G. A. Moviglia, N. Blasetti, J. O. Zarate, and D. E. Pelayes, “In vitro differentiation of adult adipose mesenchymal stem cells into retinal progenitor cells,” Ophthalmic Research, vol. 48, supplement 1, pp. 1–5, 2012. View at Google Scholar
  136. S. R. Mekala, V. Vauhini, U. Nagarajan, S. Maddileti, S. Gaddipati, and I. Mariappan, “Derivation, characterization and retinal differentiation of induced pluripotent stem cells,” Journal of Biosciences, vol. 38, no. 1, pp. 123–134, 2013. View at Google Scholar
  137. D. A. Lamba, A. McUsic, R. K. Hirata, P.-R. Wang, D. Russell, and T. A. Reh, “Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells,” PLoS ONE, vol. 5, no. 1, Article ID e8763, 2010. View at Publisher · View at Google Scholar · View at Scopus
  138. R. E. MacLaren, R. A. Pearson, A. MacNeil et al., “Retinal repair by transplantation of photoreceptor precursors,” Nature, vol. 444, no. 7116, pp. 203–207, 2006. View at Publisher · View at Google Scholar · View at Scopus
  139. A. M. Geurts, C. S. Hackett, J. B. Bell et al., “Structure-based prediction of insertion-site preferences of transposons into chromosomes,” Nucleic Acids Research, vol. 34, no. 9, pp. 2803–2811, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. Z. Ivics, P. B. Hackett, R. H. Plasterk, and Z. Izsvák, “Molecular reconstruction of sleeping beauty, a Tc1-like transposon from fish, and its transposition in human cells,” Cell, vol. 91, no. 4, pp. 501–510, 1997. View at Google Scholar · View at Scopus
  141. Z. Izsvák, P. B. Hackett, L. J. N. Cooper, and Z. Ivics, “Translating Sleeping Beauty transposition into cellular therapies: victories and challenges,” BioEssays, vol. 32, no. 9, pp. 756–767, 2010. View at Publisher · View at Google Scholar · View at Scopus
  142. L. Mátés, M. K. L. Chuah, E. Belay et al., “Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates,” Nature Genetics, vol. 41, no. 6, pp. 753–761, 2009. View at Publisher · View at Google Scholar · View at Scopus
  143. C. Sheridan, R. Williams, and I. Grierson, “Basement membranes and artificial substrates in cell transplantation,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 242, no. 1, pp. 68–75, 2004. View at Publisher · View at Google Scholar · View at Scopus
  144. T. H. Tezel, H. J. Kaplan, and L. V. del Priore, “Fate of human retinal pigment epithelial cells seeded onto layers of human Bruch's membrane,” Investigative Ophthalmology and Visual Science, vol. 40, no. 2, pp. 467–476, 1999. View at Google Scholar · View at Scopus
  145. A. A. Castellarin, I. K. Sugino, J. A. Vargas, B. Parolini, G. M. Lui, and M. A. Zarbin, “In vitro transplantation of fetal human retinal pigment epithelial cells onto human cadaver Bruch's membrane,” Experimental Eye Research, vol. 66, no. 1, pp. 49–67, 1998. View at Publisher · View at Google Scholar · View at Scopus
  146. G. Thumann, U. Schraermeyer, K. U. Bartz-Schmidt, and K. Heimann, “Descemet's membrane as membranous support in RPE/IPE transplantation,” Current Eye Research, vol. 16, no. 12, pp. 1236–1238, 1997. View at Google Scholar · View at Scopus
  147. J. F. Kiilgaard, A. K. Wiencke, E. Scherfig, J. U. Prause, and M. La Cour, “Transplantation of allogenic anterior lens capsule to the subretinal space in pigs,” Acta Ophthalmologica Scandinavica, vol. 80, no. 1, pp. 76–81, 2002. View at Publisher · View at Google Scholar · View at Scopus
  148. C. Capeéans, A. Piñeiro Ces, M. Pardo et al., “Amniotic membrane as support for human retinal pigment epithelium (RPE) cell growth,” Acta Ophthalmologica Scandinavica, vol. 81, no. 3, pp. 271–277, 2003. View at Publisher · View at Google Scholar · View at Scopus
  149. B. V. Stanzel, E. M. Espana, M. Grueterich et al., “Amniotic membrane maintains the phenotype of rabbit retinal pigment epithelial cells in culture,” Experimental Eye Research, vol. 80, no. 1, pp. 103–112, 2005. View at Publisher · View at Google Scholar · View at Scopus
  150. A. Fung, C. J. Lee, T. Leng et al., “Tissue engineered lens capsule as a substrate for IPE and RPE transplantation,” Investigative Ophthalmology & Visual Science, vol. 43, no. 12, 2002, E-abstract 3452. View at Google Scholar
  151. S. Nadri, S. Yazdani, E. Arefian et al., “Mesenchymal stem cells from trabecular meshwork become photoreceptor-like cells on amniotic membrane,” Neuroscience Letters, vol. 541, pp. 43–48, 2013. View at Google Scholar
  152. E. B. Lavik, H. Klassen, K. Warfvinge, R. Langer, and M. J. Young, “Fabrication of degradable polymer scaffolds to direct the integration and differentiation of retinal progenitors,” Biomaterials, vol. 26, no. 16, pp. 3187–3196, 2005. View at Publisher · View at Google Scholar · View at Scopus
  153. J. Yao, S. L. Tao, and M. J. Young, “Synthetic polymer scaffolds for stem cell transplantation in retinal tissue engineering,” Polymers, vol. 3, no. 2, pp. 899–914, 2011. View at Publisher · View at Google Scholar · View at Scopus
  154. W. L. Neeley, S. Redenti, H. Klassen et al., “A microfabricated scaffold for retinal progenitor cell grafting,” Biomaterials, vol. 29, no. 4, pp. 418–426, 2008. View at Publisher · View at Google Scholar · View at Scopus
  155. S. Redenti, S. Tao, J. Yang et al., “Retinal tissue engineering using mouse retinal progenitor cells and a novel biodegradable, thin-film poly(e-caprolactone) nanowire scaffold,” Journal of Ocular Biology, Diseases, and Informatics, vol. 1, no. 1, pp. 19–29, 2008. View at Publisher · View at Google Scholar · View at Scopus
  156. S. Tao, C. Young, S. Redenti et al., “Survival, migration and differentiation of retinal progenitor cells transplanted on micro-machined poly(methyl methacrylate) scaffolds to the subretinal space,” Lab on a Chip, vol. 7, no. 6, pp. 695–701, 2007. View at Publisher · View at Google Scholar · View at Scopus
  157. J. F. Mano, G. A. Silva, H. S. Azevedo et al., “Natural origin biodegradable systems in tissue engineering and regenerative medicine: present status and some moving trends,” Journal of the Royal Society Interface, vol. 4, no. 17, pp. 999–1030, 2007. View at Publisher · View at Google Scholar · View at Scopus
  158. M. A. Alamein, S. Stephens, Q. Liu, S. Skabo, and P. H. Warnke, “Mass production of nanofibrous extracellular matrix with controlled 3D morphology for large-scale soft tissue regeneration,” Tissue Engineering C, vol. 19, no. 6, pp. 458–472, 2013. View at Google Scholar
  159. C. Vaquette and J. J. Cooper-White, “Increasing electrospun scaffold pore size with tailored collectors for improved cell penetration,” Acta Biomaterialia, vol. 7, no. 6, pp. 2544–2557, 2011. View at Publisher · View at Google Scholar · View at Scopus
  160. T. D. Brown, P. D. Dalton, and D. W. Hutmacher, “Direct writing by way of melt electrospinning,” Advanced Materials, vol. 23, no. 47, pp. 5651–5657, 2011. View at Publisher · View at Google Scholar · View at Scopus
  161. C. Wei and J. Dong, “Direct fabrication of high-resolution three-dimensional polymeric scaffolds using electrohydrodynamic hot jet plotting,” Journal of Micromechanics and Microengineering, vol. 23, no. 2, Article ID 025017, 2013. View at Google Scholar
  162. M. R. Steedman, S. L. Tao, H. Klassen, and T. A. Desai, “Enhanced differentiation of retinal progenitor cells using microfabricated topographical cues,” Biomedical Microdevices, vol. 12, no. 3, pp. 363–369, 2010. View at Publisher · View at Google Scholar · View at Scopus
  163. A. C. McUsic, D. A. Lamba, and T. A. Reh, “Guiding the morphogenesis of dissociated newborn mouse retinal cells and hES cell-derived retinal cells by soft lithography-patterned microchannel PLGA scaffolds,” Biomaterials, vol. 33, no. 5, pp. 1396–1405, 2012. View at Publisher · View at Google Scholar · View at Scopus
  164. T. H. Tezel, L. V. del Priore, and H. J. Kaplan, “Reengineering of aged Bruch's membrane to enhance retinal pigment epithelium repopulation,” Investigative Ophthalmology and Visual Science, vol. 45, no. 9, pp. 3337–3348, 2004. View at Publisher · View at Google Scholar · View at Scopus
  165. U. Hersel, C. Dahmen, and H. Kessler, “RGD modified polymers: biomaterials for stimulated cell adhesion and beyond,” Biomaterials, vol. 24, no. 24, pp. 4385–4415, 2003. View at Publisher · View at Google Scholar · View at Scopus
  166. A. J. Treharne, H. A. Thomson, M. C. Grossel, and A. J. Lotery, “Developing methacrylate-based copolymers as an artificial Bruch's membrane substitute,” Journal of Biomedical Materials Research A, vol. 100, no. 9, pp. 2358–2364, 2012. View at Google Scholar
  167. R. Sistiabudi, J. Paderi, A. Panitch, and A. Ivanisevic, “Modification of native collagen with cell-adhesive peptide to promote RPE cell attachment on Bruch's membrane,” Biotechnology and Bioengineering, vol. 102, no. 6, pp. 1723–1729, 2009. View at Publisher · View at Google Scholar · View at Scopus
  168. D. Grafahrend, K.-H. Heffels, M. V. Beer et al., “Degradable polyester scaffolds with controlled surface chemistry combining minimal protein adsorption with specific bioactivation,” Nature Materials, vol. 10, no. 1, pp. 67–73, 2011. View at Publisher · View at Google Scholar · View at Scopus
  169. M. Bartneck, K.-H. Heffels, Y. Pan, M. Bovi, G. Zwadlo-Klarwasser, and J. Groll, “Inducing healing-like human primary macrophage phenotypes by 3D hydrogel coated nanofibres,” Biomaterials, vol. 33, no. 16, pp. 4136–4146, 2012. View at Publisher · View at Google Scholar · View at Scopus
  170. D. Grafahrend, K.-H. Heffels, M. Möller, D. Klee, and J. Groll, “Electrospun, biofunctionalized fibers as tailored in vitro substrates for keratinocyte cell culture,” Macromolecular Bioscience, vol. 10, no. 9, pp. 1022–1027, 2010. View at Publisher · View at Google Scholar · View at Scopus