Taiwan Journal of Ophthalmology

: 2021  |  Volume : 11  |  Issue : 4  |  Page : 336--347

Retinal cell transplantation in retinitis pigmentosa

Tongalp H Tezel, Adam Ruff 
 Department of Ophthalmology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

Correspondence Address:
Dr. Tongalp H Tezel
Department of Ophthalmology, Harkness Eye Institute, Columbia University Vagelos College of Physicians and Surgeons, 63 West 165th Street, New York, NY 10032


Retinitis pigmentosa is the most common hereditary retinal disease. Dietary supplements, neuroprotective agents, cytokines, and lately, prosthetic devices, gene therapy, and optogenetics have been employed to slow down the retinal degeneration or improve light perception. Completing retinal circuitry by transplanting photoreceptors has always been an appealing idea in retinitis pigmentosa. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to accomplish this goal. The eye is an ideal organ for cell transplantation due to a low number of cells required to restore vision, availability of safe surgical and imaging techniques to transplant and track the cells in vivo, and partial immune privilege provided by the subretinal space. Human embryonic stem cells, induced pluripotential stem cells, and especially retinal organoids provide an adequate number of cells at a desired developmental stage which may maximize integration of the graft to host retina. However, stem cells must be manufactured under strict good manufacturing practice protocols due to known tumorigenicity as well as possible genetic and epigenetic stabilities that may pose a danger to the recipient. Immune compatibility of stem cells still stands as a problem for their widespread use for retinitis pigmentosa. Transplantation of stem cells from different sources revealed that some of the transplanted cells may not integrate the host retina but slow down the retinal degeneration through paracrine mechanisms. Discovery of a similar paracrine mechanism has recently opened a new therapeutic path for reversing the cone dormancy and restoring the sight in retinitis pigmentosa.

How to cite this article:
Tezel TH, Ruff A. Retinal cell transplantation in retinitis pigmentosa.Taiwan J Ophthalmol 2021;11:336-347

How to cite this URL:
Tezel TH, Ruff A. Retinal cell transplantation in retinitis pigmentosa. Taiwan J Ophthalmol [serial online] 2021 [cited 2022 Jan 25 ];11:336-347
Available from: https://www.e-tjo.org/text.asp?2021/11/4/336/331545

Full Text


Retinitis pigmentosa is a diverse group of inherited degenerations caused by more than 3000 mutations in 80 genes which finally lead to progressive degeneration of the rod and cone photoreceptors. It affects 1 in 4000 people worldwide and is accepted as the most common hereditary retinal disease.[1] Causative mutations can disrupt phototransduction, rhodopsin cycling, and cell trafficking pathways and lead to the classical clinical appearance of bone spicule formation, attenuated retinal vasculature, and optic nerve head pallor. In the early stages of the disease, degeneration of rods manifests itself with nyctalopia and peripheral visual field loss, but, later on, loss of cones results in severe visual loss and loss of color discrimination.[2] Depending on the inheritance pattern, retinitis pigmentosa group of retinal degenerations can be classified as autosomal-dominant, autosomal recessive, X-linked, and mitochondrial retinitis pigmentosa. 5%–15% of the cases display X-linked inheritance pattern which has a worse prognosis compared to patients with autosomal recessive (50%–60%) and autosomal-dominant (30%–40%) forms of the disease.[2] Several systemic disorders may also accompany ocular findings in 20%–30% of the cases due to the expression of the mutant protein in other organs. Thirty such clinical syndromes have been described which are termed as the syndromic form of retinitis pigmentosa.[3]

Several treatments have been employed to alter the course of retinal degeneration. Attempts to slow down the retinal degeneration using dietary supplements, such as Vitamin A,[4] docosahexaenoic acid,[5] or lutein,[6] did not reveal a clear benefit except in a subgroup of patients with high cone amplitude at baseline.[7] Several neuroprotective agents, such as human ciliary neurotrophic factor,[8] valproic acid,[9] topical unoprostone isopropyl,[10] and transcorneal electrical stimulation[11] have also been tried to slow the retinal degeneration but yield no substantial success. Oral or topical carbonic anhydrase inhibitors,[12] steroids,[13] and anti-vascular endothelial growth factor agents[14] have been used to treat cystoid macular edema which develops in 20% of the patients.[15] Epiretinal, subretinal, and suprachoroidal retinal prosthetic devices have been developed providing visual perception to patients with light perception or no light perception vision due to advanced retinitis pigmentosa. Two of these prosthetic devices such as Alpha IMS, developed by Germany-based Retina Implant AG and Argus II developed by U. S.-based Second Sight Medical Products, CA, USA, have received approval from regulatory agencies. Although these devices are associated with serious perioperative complications,[16] the visual improvement they provide improves the quality of life in this subset of patients with advanced retinitis pigmentosa.[17]

Identification of rhodopsin mutation as a cause of autosomal-dominant retinitis pigmentosa 1990[18] paved the path for the development of gene therapy to modify or manipulate the expression of mutated genes with several gene treatment techniques. These efforts recently led to the approval of an AAV vector-based RPE-65 gene delivery treatment (Voretigene neparvovec-rzyl; Luxturna™, Spark Therapeutics, PA, USA) aimed to correct the biallelic mutations of the RPE65 gene causing Leber's congenital amaurosis and some forms of retinitis pigmentosa.[19] A number of studies are in the pipeline for delivering the correct copy of the mutant genes or to perform gene editing using the CRISPR/Cas system to inactivate mutant genes.[20] Unfortunately, heterogeneity of the causative genes stands as a major obstacle for the development of an universal gene treatment that may be used for all forms of retinitis pigmentosa. Treatments that can be applied to all forms of retinitis pigmentosa are also underway, such as rewiring of the retinal circuity using optogenetics[21] or reactivation of the dormant cones by restoring glucose transport.[22]

 The Rationale for Retinal Cell Transplantation

The idea of retinal cell transplantation for retinitis pigmentosa stems from the early histopathology reports which revealed relative preservation of the inner retina even in late stages of retinitis pigmentosa.[23] Lack of synaptic input and trophic factors inevitably causes transneuronal degeneration of the inner retinal neurons as photoreceptors die; however even in severe retinitis pigmentosa, 30% of the ganglion cells and approximately 80% of the inner nuclear layer neurons remain intact.[23] This fact gave rise to the idea to complete the retinal circuitry by transplanting photoreceptors into the subretinal space with the hope that grafted photoreceptor cells will integrate into the host retina by establishing synapses with the host's bipolar cells. The eye is considered an ideal organ for cell transplantation due to the low number of cells required to restore visual function.[24] Similar to the anterior chamber,[25] it also provides a partial immune privilege which may limit the rejection of the graft by downregulating delayed-type hypersensitivity response observed after transplantation of tissues to conventional sites.[26],[27] Availability of established safe surgical and imaging techniques facilitates the transplantation and in vivo tracking of the cells.

 Initial Attempts

Initial attempts of full-thickness retinal transplantation date to 1946 when differentiation of grafted embryonic retina was observed in the brain of the rats.[28] This was followed by transplantation and survival of the fetal rat retina in the anterior chamber.[29],[30] First, transplantation of neonatal rat retina into the subretinal space was done in 1986 through a transscleral incision. Graft survival seemed to be better by younger donors. These promising results led to initial human full retina transplantation attempts.[31] Two patients with autosomal retinitis pigmentosa received whole sheets of fetal human retina into the subretinal space. Although no immune rejection was observed, only a transient multifocal electroretinography response was obtained in one patient. Subsequent attempts included transplantation of intact fetal human neuroretinal sheets into the subretinal space of 5 patients with retinitis pigmentosa in a Phase I study[32] followed by a Phase II study with 6 patients with retinitis pigmentosa.[33] None of the five patients enrolled in Phase I study show any visual benefit. Three patients who received the fetal retinal grafts in the Phase II trial gained mediocre visual improvements, but two patients experienced worsening of their vision after surgery. A detailed histopathology of fetal full-thickness grafts transplanted into the subretinal space of transgenic pig carrying the mutation Pro347 Leu demonstrated that the grafted cells do not form connections with the host neurons.[34] This makes it difficult to interpret the results which may also be attributed to trophic effects of the graft or simply to the impact of transplantation surgery on the remaining retinal neurons.[35]

Transplantation of photoreceptors into the subretinal space was first done in 1991.[36] A suspension of newborn rat photoreceptors labeled with tritiated thymidine was injected into the subretinal space of RCS rats. Some of the transplanted photoreceptor cell bodies were found in clusters in the outer nuclear layer region for as long as 3 months after transplantation. However, transplanted photoreceptors slowly degenerated over time and failed to develop outer segments. Subsequent studies indicated higher rates of grafted photoreceptor survival and relatively better development of outer segments if aggregates of neonatal photoreceptors were used rather than dissociated neonatal photoreceptors.[37] One major limitation for the use of retinal aggregates was identified as photoreceptor rosette formation in the host's subretinal space.[38],[39] In parallel with this in vitro work, injection of human fetal retinal cell suspension into the subretinal space of 14 patients did not yield any functional benefit.[40]

Limitations of photoreceptor transplantation as cell suspensions or aggregates led to the techniques of transplanting intact photoreceptor sheets. Initial isolation of photoreceptor sheets with a vibratome proved to be highly traumatic to the retina and results in abnormal morphology.[41],[42] Vibratome was replaced with excimer laser for atraumatic harvest of photoreceptor sheets[41] [Figure 1]. Pure adult human photoreceptor sheets harvested with excimer laser were shown to preserve >86.5% viability for 72 h in vitro. These cells interacted with the host retinal pigment epithelium after transplantation into rhesus monkeys as evidenced by phagocytosis of shed photoreceptor outer segments by the retinal pigment epithelium [Figure 2]. Adult human photoreceptor sheets harvested with excimer laser were then used in the first human photoreceptor sheet transplantation study.[43],[44] Eight patients with advanced retinitis pigmentosa received 3.0 mm × 1.0 mm trapezoidal adult human photoreceptor sheets and followed for 12 months. No functional improvement was observed. Although patients were not put on any immunosuppressive regimen, no homograft reaction was observed.[44]{Figure 1}{Figure 2}

 Requirements for Successful Transplantation

In animal models of retinitis pigmentosa, only a few transplanted cells establish synapses with the host bipolar cells. These cells produce outer segments and bear a resemblance to rods morphologically.[45] The main reason for the lack of functional success in photoreceptor transplantation in retinitis pigmentosa is the failure of the grafted cells to integrate the host retina and establish functional synaptic circuitry. Histopathology of the eyes with retinitis pigmentosa provides clues why grafted photoreceptors do not integrate to host retina. In eyes with advanced retinitis pigmentosa, extensive remodeling of the retina occurs with dramatic rod neurite sprouting, especially at or near the areas of photoreceptor death.[46] Rather than establishing synapses with bipolar cells, rods extend these neurites along activated Muller cells as far as to the inner limiting membrane. Neurite sprouting is also observed in amacrine and horizontal cells.[47] Rod sprouting and Muller cell activation is the result of the altered retinal homeostasis due to degenerating retina in retinitis pigmentosa. This microenvironmental shift can also affect the behavior of the grafted cells resulting in a similar neurite sprouting and bypassing the targeted bipolar cells. Rod spouting does not occur in rodent models of retinitis pigmentosa which may be the reason for the discrepancy between the relatively successful results of retinal cell transplantation in rodents compared to human trials.[46] However, experiments with animal models of outer retinal degeneration have given us some important clues about the prerequisites of synapse formation with the host retina:

Use of immature nonretinal neurons or other neural progenitor cells may not yield high numbers of differentiation of these cells into photoreceptors and integration to the host retina. Results indicate that most of these cells do not differentiate into mature retinal neurons[48],[49]Survival and integration of the transplanted photoreceptor cells is dependent on the developmental stage of the transplanted photoreceptor cells. Eloquent experiments conducted by transplanting Green Fluorescent Protein (GFP)-expressing photoreceptors under the control of the rod-specific postmitotic transcription factor Nrl, into Gnat1−/− murine model of stationary night blindness, indicate that highest integration could be obtained with transplantation of immature postmitotic photoreceptor precursor cells destined to differentiate into rod photoreceptors. Integration of the cells to host retina is poorer if progenitor cells or mature photoreceptors are used.[50] Decreased synapse formation and poorer viability of the mature photoreceptors[51] have caused a shift toward using cells at earlier development stagesThe stage of the outer retinal degeneration is a key factor in determining the integration of the transplanted cells to host retina. Experiments conducted with six murine models of inherited photoreceptor degeneration indicated that integration to host retina is mainly determined on the stage of glial scarring and the integrity of the outer limiting membrane during disease progression.[52] A good example can be given by looking at the results from three different models of retinal degeneration. Integration gradually decreases in Gnat1−/−; Rho−/− model of where the outer limiting membrane remains intact and gliosis becomes more prominent as the disease progress. In contrast, an increase in host integration with progression of the outer retinal degeneration was observed in Prph 2+/Δ307 model where gliosis decreases in time and outer limiting membrane integrity is not preserved. Integration rate does not change with disease progression in PDE6βrd1/rd1 mutation where the outer limiting membrane is disrupted, but gliosis progresses with disease progressionOuter retinal degeneration creates an environment that prevents the ability of the cells to migrate and form synapses with the recipient's cells. Like central nervous system injury or degenerations, outer retinal cell death in retinitis pigmentosa evokes a gliotic scar formation. During this process, chondroitin sulfate proteoglycans production is dramatically upregulated by glial cells which form a glial scar. Chondroitin sulfate proteoglycans are known to limit cell migration, axonal plasticity, and regeneration.[53] Inhibition of the retinal gliosis,[54] targeted disruption of the outer limiting membrane,[55] or enzymatic digestion of the chondroitin sulfate proteoglycans[56] are shown to increase the integration of the transplanted photoreceptor cells into the host retinaFluorescent markers used to identify the grafted cells may be misleading due to cytoplasmic material transfer between the grafted cells and host retina. Thus, previous reports relying on reporter expression to conclude about integration of the grafted cells to the host retina and even functional benefits after photoreceptor transplantation must be reinterpreted cautiously since both findings might simply be the result of reporter material or functional proteins transfer from donor cells to remaining host photoreceptors.[57]

Animal experiments indicated that highest synapse formation can be obtained using postmitotic rod precursor cells.[50] In human development, a comparable stage occurs during the early phases of the second trimester. Limited availability of fetal tissue and several ethical as well as legislature considerations have aroused interest in the potential to generate new photoreceptor precursors from various stem cell sources. A good source for generating photoreceptors has been the pluripotent embryonic stem cells. These cells are derived from the inner cell mass of the blastocysts and can be directed to retinal fate under conditioned media.[58],[59] Human embryonic stem cells have been transplanted into the subretinal space of rodent[60] and primate[61] models of retinal degeneration. Grafted cells can differentiate into a range of retinal cell types, including rod and cone photoreceptors. Embryonic stem cell-derived photoreceptor transplantation studies confirmed the previous observations that photoreceptor precursors at earlier developmental stages integrate with the host better.[62] Transplantation of the retinal cultures earlier than 20 days of culture produced large tumors and prolonged retinal culture resulted in mature photoreceptors but no integration to the host retina.[63] The use of embryonic stem cells to generate photoreceptors also suffers from ethical and legal restrictions. Furthermore, immune-mediated rejection of embryonic stem cell-derived grafts is a concern since these cells are allogeneic to the recipient patients.[64] These difficulties were thwarted with the discovery that forced expression of four transcription factors (Oct4, Sox 2, c-Myc, and Klf4) the nuclei of differentiated somatic cells can be reprogrammed toward a pluripotent state.[65] Pluripotential stem cells generated with this method bear multipotentiality and self-renewal characteristics such as embryonic stem cells. They are not subject to immune rejection and can be expanded in vitro and differentiate to all retinal cells,[66] including photoreceptors.[67] Moreover, these cells can form three-dimensional retinal organoids that can allow production of vast number of photoreceptors for transplantation and genetic engineering.[68],[69] This vast source of photoreceptors can allow selection and transplantation of cones that are essential for visual acuity, color, and foveal vision. Pluripotential stem cell-derived photoreceptor cells have been purified from the rest of the cells using fluorescence-activated cell sorting and transplanted into the subretinal space of rodents. Integration of these cells to host retina has been reported[69] along with several studies revealing improved visual function after transplantation in various rodent models of retinitis pigmentosa;[63],[70] however, these observations should be reinterpreted considering the possibility of cytoplasmic material transfer between the grafted photoreceptors and to recipient's retinal cells. The ability of human photoreceptor progenitors derived from both human embryonic and induced pluripotent stem cells in integrating the retina and improving the visual function was also tested in PDEβrd[1]/rd[1] mouse which exhibits end-stage retinal degeneration.[71] This model allows a better understanding of the fate of the grafted cells in patients with retinitis pigmentosa due to the resemblance of the stage of outer retinal degeneration. Human photoreceptor progenitors transplanted into PDEβrd[1]/rd[1] mouse differentiated into mature photoreceptors and established connections with host retinal neurons. Behavioral tests showed improved visual function after transplantation.

 Trophic Effects of the Transplanted Cells

Cell transplanted into the subretinal space may exert a positive effect on the survival of the remaining retinal neurons regardless of their types and independent of their ability to synapse with the host retina. This paracrine effect was eloquently demonstrated in an outer retinal degeneration model of RhoP[23] H/+ mice.[72] An intriguing hypothesis was put forward using the pig model of autosomal-dominant retinitis pigmentosa to explain this paracrine effect.[22] Cone photoreceptors which last longer than rods along the course of retinitis pigmentosa depend on glucose delivery from the retinal pigment epithelial cells to maintain their high metabolism and regeneration of their outer segments. In the setting of retinitis pigmentosa, glucose is not delivered to the subretinal space by retinal pigment epithelial cells resulting in starvation of the cones and subsequent loss of their outer segment and mitochondria-rich inner segments. Transplantation of rod precursors or even subretinal injection of glucose restores cone metabolism and outer segment synthesis.

Another stem cell type that can exert trophic effects is the umbilical stem cells. Umbilical stem cells can be a mixed population of hematopoietic and mesenchymal stem cells that can be harvested from the cord blood or cord tissue. Cells generated from umbilical stem cells exert a protective effect in animal models of retinal degeneration[73],[74] and laser injury.[75] This trophic effect was found to be related to restoration of retinal pigment epithelium phagocytosis in Royal College of Surgeons (RCS) rats by secreting several humoral factors and bridge molecules that enhance the binding of photoreceptor outer segments to retinal pigment epithelium.[74]

Bone marrow stem cells have the potential to differentiate into various lineage cells including neural cells. Although there have been reports indicating that these cells may incorporate into host retina and express some retinal cell markers,[76],[77] it is believed that most of their beneficial effect occur through paracrine mechanisms.[78],[79] Another stem cell that can be harvested from the bone marrow is the CD34+ hematopoietic stem cell which is shown to exert a neuroprotective effect in eyes with retinal degeneration.[80] After intravitreal injection, these cells gather around retinal vasculature rather than the degenerating retina suggesting a paracrine effect.[78]

Intravitreal injection of bone marrow-derived mesenchymal stem cells has also been used in 14 patients with retinitis pigmentosa.[81] A short-term improvement of visual acuity returned to preoperative levels. Several adverse effects were reported, including posterior synechia, choroidal detachment, intraocular ossification, tractional retinal detachment, vitreous hemorrhage, and intraocular lens subluxation. Bone marrow-derived mesenchymal stem cells exert their effect mainly through the paracrine route. Previous studies revealed that mesenchymal stem cell secretomes possess neuroprotective properties and delay photoreceptor cell loss due to their paracrine effects.[82],[83]

Adipose tissue-derived mesenchymal stem cells were also transplanted into the subretinal space of 11 patients with advanced retinitis pigmentosa.[84] Apart from one patient, no major visual benefit was observed. In contrast, one patient developed choroidal neovascularization and five patients required repeat vitrectomy and silicone oil tamponade due to epiretinal membrane formation.

Another cell type that exerts its effect through paracrine mechanisms is the neural stem cell. Once transplanted into the subretinal space of the rd1 mice, these cells delay retinal degeneration by suppressing microglia activation.[85]

 Human Trials

Human trials of retinal cell transplantation for retinitis pigmentosa are listed in [Table 1]. Currently, 8 of these 19 trials are still active and 6 of them are recruiting patients. Cells planned to be transplanted into patients with retinitis pigmentosa include autologous CD34+ stem cells harvested from bone marrow, human umbilical cord-derived mesenchymal stem cells, human embryonic stem cell-derived retinal pigment epithelial cells, bone marrow-derived stem cells, and human retinal progenitor cells.{Table 1}

 Safety Issues

Generation of human embryonic or pluripotential stem cells requires strict control during the manufacturing process to ensure cellular stability, production consistency, eliminate the possibility of tumorigenicity, toxicity, and immunogenicity. For this purpose, “good manufacturing practice protocols have been put forward by Food and Drug Administration. These guidelines describe the required technological and manufacturing standards for creating and maintaining human stem cell lines for regenerative medicine use. Sight-threatening complications seen after the uncontrolled use of stem cell therapy in ophthalmology[86],[87],[88] have proved the importance of such regulatory legislature.[89],[90]

Unlimited self-renewal and high differentiation potential of both human embryonic stem cells and induced pluripotential stem cells pose a danger to develop teratomas.[91] Embryonic stem cell-derived neural precursor transplants into the subretinal space of rhodopsin-knockout mice yielded teratomas in half of the donor animals 8 weeks after engraftment.[92] This necessitates the employment of screening tests to detect malignant transformation and complex morphogenesis or even organogenesis that may not occur in vitro. Another major safety concern is the integration of the viral gene fragments and the use of genetic transcription factors during the production of induced pluripotential stem cells. These may induce endogenous genetic and epigenetic alterations, such as insertional mutagenic lesions leading to tumor formation after transplantation.[93] Several alternative reprogramming techniques have been developed to overcome this possibility, such as nongenetic transcription factors, and nonintegrating delivery systems, such as Sendai virus.[94] Genetic and epigenetic stability should also be strictly controlled during the propagation of human stem cells since reprogramming of somatic cells can alter the integrity of the parental cell genome or conceal chromosomal instabilities.[95] Several reports revealed chromosomal aberrations and mitochondrial genome mutations after the reprogramming process.[96],[97] Such alterations occasionally can result in rapid telomere shortening, increased apoptosis, severely limited growth and expansion capability, and early senescence.[98] Deletion of three genes and mutations in another three, including an oncogene, in a cell line halted a human trial of induced pluripotential stem cell-derived retinal pigment epithelium transplantation recently.

Although immune response may not be a problem with the use of induced pluripotent stem cell, a vast number of studies indicate that human embryonic stem cells can still evoke an immune response.[64] Several strategies have been developed to avoid an immune-mediated rejection of the human embryonic stem cell derived cells, including encapsulation of the cells,[99] application of somatic cell nuclear transfer to reprogram patient's somatic cells into pluripotent embryonic stem cells,[100] gene editing to abrogate the HLA surface expression,[101] and bone marrow or hematopoietic stem-cell transplantation to create hematopoietic chimerism.[102] Currently, HLA-matchmaker algorithms are employed to predict the most compatible immunogenic donor HLA types to decrease the host's immune response and increase graft survival.[103] Studies with solid organ transplantation have shown that matching in HLA-A, HLA-B, and HLA-DR groups is still required for long-term graft survival despite the employment of an immunosuppressive regimen.[104] HLA matching also shortens the duration of the immunosuppressive regimen.[105] Unfortunately, this method requires the development of large HLA-matched embryonic stem cell banks.[106] Apart from ethical and legal obstacles, establishing haplobank of human embryonic stem cells will create a challenge itself considering that HLA system is the most polymorphic locus consisting of nearly 10,000 HLA-I and-II alleles.[107] This challenge will be enormous in countries with diverse ethnic backgrounds, such as Brazil,[108] compared to ethnically more homogenous countries such as Japan[109],[110] and the United Kingdom.[111]

 Bioengineering Semi-Organic Constructs

Thermosensitive gelatin encasing was used in early adult human photoreceptor sheet transplantation which eased the handling and delivery of the graft into the subretinal space.[41] Use of artificial matrices to improve cell growth and synapse formation was first introduced in 2004.[112] The suggested construct was made up of Mylar membranes with an array of perforations of 3–40 μm in diameter. Retinal cells seeded in the microperforations were first cultured and then transplanted into the subretinal space of adult RCS rats. Histopathology revealed retinal tissue growth through these perforations. These early studies were followed by the development of microcylinder scaffolds which allow the vertical growth of the cells and protect them from shear forces that may occur during the transplantation procedure.[113] Since then, several hydrogel polymer scaffolds for culture and transplantation of retinal progenitor cells have been described.[114],[115] Poly (L-lactic acid)/poly (lactic-co-glycolide acid) (PLLA/PLGA), poly (methyl methacrylate) (PMMA) and poly(ε-caprolactone) (PCL) has been tried as a polymer scaffold for retinal progenitor transplantations. Ten-fold improved cell survival was observed with PLLA/PLGA, but associated fibrosis and inflammation have limited its use.[116] Nondegradable characteristics and surface modification requirements are PMMA's disadvantages.[117] PCL also carries disadvantages such as inhibition of retinal progenitor cell proliferation and differentiation toward photoreceptors.[118] Surface coating of PCL membranes with vitronectin-mimicking oligopeptides was reported to increase cell adhesion and differentiation.[118] Bioengineering methods were also employed to correctly apposition photoreceptor cells with host retina using ultrathin and biocompatible elastomer films composed of nonbiodegradable polydimethylsiloxane and biodegradable poly (glycerol-sebacate). These “wine glass” scaffold design serves to position the photoreceptors cells in a correctly polarized configuration.[119]


Retinal cell transplantation has covered a long way since its first introduction in 1946. This fact can be exemplified by looking at the fact that 44% (1,673/3,815/) of the scientific publications in this field have been produced within the last 10 years. Recent developments in stem cell technology, ophthalmic imaging systems, tissue engineering methods as well as our understanding of synapse formation and pathophysiology of retinitis pigmentosa provide a unique opportunity to restore the vision of patients with retinitis pigmentosa.


This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., NYC, NY, Foley Research Fund, New York, NY.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Verbakel SK, van Huet RA, Boon CJ, den Hollander AI, Collin RW, Klaver CC, et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 2018;66:157-86.
2Tsang SH, Sharma T. Autosomal dominant retinitis pigmentosa. Adv Exp Med Biol 2018;1085:69-77.
3Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006;368:1795-809.
4Berson EL, Rosner B, Sandberg MA, Hayes KC, Nicholson BW, Weigel-DiFranco C, et al. A randomized trial of Vitamin A and Vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol 1993;111:761-72.
5Berson EL, Rosner B, Sandberg MA, Weigel-DiFranco C, Moser A, Brockhurst RJ, et al. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving Vitamin A treatment: Subgroup analyses. Arch Ophthalmol 2004;122:1306-14.
6Bahrami H, Melia M, Dagnelie G. Lutein supplementation in retinitis pigmentosa: PC-based vision assessment in a randomized double-masked placebo-controlled clinical trial [NCT00029289]. BMC Ophthalmol 2006;6:23.
7Schwartz SG, Wang X, Chavis P, Kuriyan AE, Abariga SA. Vitamin A and fish oils for preventing the progression of retinitis pigmentosa. Cochrane Database Syst Rev 2020;6:CD008428.
8Birch DG, Bennett LD, Duncan JL, Weleber RG, Pennesi ME. Long-term follow-up of patients with retinitis pigmentosa receiving intraocular ciliary neurotrophic factor implants. Am J Ophthalmol 2016;170:10-4.
9Bhalla S, Joshi D, Bhullar S, Kasuga D, Park Y, Kay CN. Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid. Br J Ophthalmol 2013;97:895-9.
10Akiyama M, Ikeda Y, Yoshida N, Notomi S, Murakami Y, Hisatomi T, et al. Therapeutic efficacy of topical unoprostone isopropyl in retinitis pigmentosa. Acta Ophthalmol 2014;92:e229-34.
11Sinim Kahraman N, Oner A. Effect of transcorneal electrical stimulation on patients with retinitis pigmentosa. J Ocul Pharmacol Ther 2020;36:609-17.
12Grover S, Apushkin MA, Fishman GA. Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 2006;141:850-8.
13Schaal Y, Hondur AM, Tezel TH. Subtenon triamcinolone for cystoid macular edema due to retinitis pigmentosa unresponsive to oral acetazolamide. Can J Ophthalmol 2016;51:e113-5.
14Yuzbasioglu E, Artunay O, Rasier R, Sengul A, Bahcecioglu H. Intravitreal bevacizumab (Avastin) injection in retinitis pigmentosa. Curr Eye Res 2009;34:231-7.
15Wang AL, Knight DK, Vu TT, Mehta MC. Retinitis pigmentosa: Review of current treatment. Int Ophthalmol Clin 2019;59:263-80.
16da Cruz L, Dorn JD, Humayun MS, Dagnelie G, Handa J, Barale PO, et al. Five-year safety and performance results from the Argus II retinal prosthesis system clinical trial. Ophthalmology 2016;123:2248-54.
17Health Quality Ontario. Retinal prosthesis system for advanced retinitis pigmentosa: A health technology assessment. Ont Health Technol Assess Ser 2016;16:1-63.
18Dryja TP, McGee TL, Reichel E, Hahn LB, Cowley GS, Yandell DW, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 1990;343:364-6.
19Miraldi Utz V, Coussa RG, Antaki F, Traboulsi EI. Gene therapy for RPE65-related retinal disease. Ophthalmic Genet 2018;39:671-7.
20Ducloyer JB, Le Meur G, Cronin T, Adjali O, Weber M. Gene therapy for retinitis pigmentosa. Med Sci (Paris) 2020;36:607-15.
21Tomita H, Sugano E. Optogenetics-mediated gene therapy for retinal diseases. Adv Exp Med Biol 2021;1293:535-43.
22Wang W, Lee SJ, Scott PA, Lu X, Emery D, Liu Y, et al. Two-step reactivation of dormant cones in retinitis pigmentosa. Cell Rep 2016;15:372-85.
23Santos A, Humayun MS, de Juan E Jr., Greenburg RJ, Marsh MJ, Klock IB, et al. Preservation of the inner retina in retinitis pigmentosa. A morphometric analysis. Arch Ophthalmol 1997;115:511-5.
24Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, et al. Restoration of vision after transplantation of photoreceptors. Nature 2012;485:99-103.
25Kaplan HJ, Streilein JW. Analysis of immunologic privilege within the anterior chamber of the eye. Transplant Proc 1977;9:1193-5.
26Streilein JW. Ocular immune privilege: The eye takes a dim but practical view of immunity and inflammation. J Leukoc Biol 2003;74:179-85.
27Zhang X, Bok D. Transplantation of retinal pigment epithelial cells and immune response in the subretinal space. Invest Ophthalmol Vis Sci 1998;39:1021-7.
28Tansley K. The development of the rat eye in graft. J Exp Biol 1946;22:221-4.
29Royo PE, Quay WB. Retinal transplantation from fetal to maternal mammalian eye. Growth 1959;23:313-36.
30del Cerro M, Gash DM, Rao GN, Notter MF, Wiegand SJ, Gupta M. Intraocular retinal transplants. Invest Ophthalmol Vis Sci 1985;26:1182-5.
31Radtke ND, Aramant RB, Seiler M, Petry HM. Preliminary report: Indications of improved visual function after retinal sheet transplantation in retinitis pigmentosa patients. Am J Ophthalmol 1999;128:384-7.
32Radtke ND, Seiler MJ, Aramant RB, Petry HM, Pidwell DJ. Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients. Am J Ophthalmol 2002;133:544-50.
33Radtke ND, Aramant RB, Petry HM, Green PT, Pidwell DJ, Seiler MJ. Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol 2008;146:172-82.
34Ghosh F, Engelsberg K, English RV, Petters RM. Long-term neuroretinal full-thickness transplants in a large animal model of severe retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol 2007;245:835-46.
35Silverman MS, Hughes SE. Photoreceptor rescue in the RCS rat without pigment epithelium transplantation. Curr Eye Res 1990;9:183-91.
36Gouras P, Du J, Gelanze M, Kwun R, Kjeldbye H, Lopez R. Transplantation of photoreceptors labeled with tritiated thymidine into RCS rats. Invest Ophthalmol Vis Sci 1991;32:1704-7.
37Gouras P, Du J, Kjeldbye H, Yamamoto S, Zack DJ. Reconstruction of degenerate rd mouse retina by transplantation of transgenic photoreceptors. Invest Ophthalmol Vis Sci 1992;33:2579-86.
38Juliusson B, Bergström A, van Veen T, Ehinger B. Cellular organization in retinal transplants using cell suspensions or fragments of embryonic retinal tissue. Cell Transplant 1993;2:411-8.
39Ivert L, Gouras P, Naeser P, Narfstrom K. Photoreceptor allografts in a feline model of retinal degeneration. Graefes Arch Clin Exp Ophthalmol 1998;236:844-52.
40Das T, del Cerro M, Jalali S, Rao VS, Gullapalli VK, Little C, et al. The transplantation of human fetal neuroretinal cells in advanced retinitis pigmentosa patients: Results of a long-term safety study. Exp Neurol 1999;157:58-68.
41Tezel TH, Kaplan HJ. Harvest and storage of adult human photoreceptor cells: The vibratome compared to the excimer laser. Curr Eye Res 1998;17:748-56.
42Ghosh F, Juliusson B, Arnér K, Ehinger B. Partial and full-thickness neuroretinal transplants. Exp Eye Res 1999;68:67-74.
43Kaplan HJ, Tezel TH, Berger AS, Wolf ML, Del Priore LV. Human photoreceptor transplantation in retinitis pigmentosa. A safety study. Arch Ophthalmol 1997;115:1168-72.
44Berger AS, Tezel TH, Del Priore LV, Kaplan HJ. Photoreceptor transplantation in retinitis pigmentosa: Short-term follow-up. Ophthalmology 2003;110:383-91.
45Eberle D, Kurth T, Santos-Ferreira T, Wilson J, Corbeil D, Ader M. Outer segment formation of transplanted photoreceptor precursor cells. PLoS One 2012;7:e46305.
46Li ZY, Kljavin IJ, Milam AH. Rod photoreceptor neurite sprouting in retinitis pigmentosa. J Neurosci 1995;15:5429-38.
47Fariss RN, Li ZY, Milam AH. Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa. Am J Ophthalmol 2000;129:215-23.
48Klassen H, Schwartz PH, Ziaeian B, Nethercott H, Young MJ, Bragadottir R, et al. Neural precursors isolated from the developing cat brain show retinal integration following transplantation to the retina of the dystrophic cat. Vet Ophthalmol 2007;10:245-53.
49Sakaguchi DS, Van Hoffelen SJ, Theusch E, Parker E, Orasky J, Harper MM, et al. Transplantation of neural progenitor cells into the developing retina of the Brazilian opossum: An in vivo system for studying stem/progenitor cell plasticity. Dev Neurosci 2004;26:336-45.
50MacLaren RE, Pearson RA, MacNeil A, Douglas RH, Salt TE, Akimoto M, et al. Retinal repair by transplantation of photoreceptor precursors. Nature 2006;444:203-7.
51Gust J, Reh TA. Adult donor rod photoreceptors integrate into the mature mouse retina. Invest Ophthalmol Vis Sci 2011;52:5266-72.
52Barber AC, Hippert C, Duran Y, West EL, Bainbridge JW, Warre-Cornish K, et al. Repair of the degenerate retina by photoreceptor transplantation. Proc Natl Acad Sci U S A 2013;110:354-9.
53Dyck SM, Karimi-Abdolrezaee S. Chondroitin sulfate proteoglycans: Key modulators in the developing and pathologic central nervous system. Exp Neurol 2015;269:169-87.
54Kinouchi R, Takeda M, Yang L, Wilhelmsson U, Lundkvist A, Pekny M, et al. Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci 2003;6:863-8.
55Pearson RA, Barber AC, West EL, MacLaren RE, Duran Y, Bainbridge JW, et al. Targeted disruption of outer limiting membrane junctional proteins (Crb1 and ZO-1) increases integration of transplanted photoreceptor precursors into the adult wild-type and degenerating retina. Cell Transplant 2010;19:487-503.
56Ma J, Kabiel M, Tucker BA, Ge J, Young MJ. Combining chondroitinase ABC and growth factors promotes the integration of murine retinal progenitor cells transplanted into Rho(-/-) mice. Mol Vis 2011;17:1759-70.
57Gasparini SJ, Llonch S, Borsch O, Ader M. Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives. Prog Retin Eye Res 2019;69:1-37.
58Ikeda H, Osakada F, Watanabe K, Mizuseki K, Haraguchi T, Miyoshi H, et al. Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells. Proc Natl Acad Sci U S A 2005;102:11331-6.
59Lamba DA, Karl MO, Ware CB, Reh TA. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A 2006;103:12769-74.
60Assawachananont J, Mandai M, Okamoto S, Yamada C, Eiraku M, Yonemura S, et al. Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice. Stem Cell Reports 2014;2:662-74.
61Shirai H, Mandai M, Matsushita K, Kuwahara A, Yonemura S, Nakano T, et al. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc Natl Acad Sci U S A 2016;113:E81-90.
62Gonzalez-Cordero A, West EL, Pearson RA, Duran Y, Carvalho LS, Chu CJ, et al. Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nat Biotechnol 2013;31:741-7.
63West EL, Gonzalez-Cordero A, Hippert C, Osakada F, Martinez-Barbera JP, Pearson RA, et al. Defining the integration capacity of embryonic stem cell-derived photoreceptor precursors. Stem Cells 2012;30:1424-35.
64Boyd AS, Rodrigues NP, Lui KO, Fu X, Xu Y. Concise review: Immune recognition of induced pluripotent stem cells. Stem Cells 2012;30:797-803.
65Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663-76.
66Osakada F, Ikeda H, Sasai Y, Takahashi M. Stepwise differentiation of pluripotent stem cells into retinal cells. Nat Protoc 2009;4:811-24.
67Meyer JS, Shearer RL, Capowski EE, Wright LS, Wallace KA, McMillan EL, et al. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci U S A 2009;106:16698-703.
68Llonch S, Carido M, Ader M. Organoid technology for retinal repair. Dev Biol 2018;433:132-43.
69Lamba DA, McUsic A, Hirata RK, Wang PR, Russell D, Reh TA. Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS One 2010;5:e8763.
70Tucker BA, Park IH, Qi SD, Klassen HJ, Jiang C, Yao J, et al. Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One 2011;6:e18992.
71Barnea-Cramer AO, Wang W, Lu SJ, Singh MS, Luo C, Huo H, et al. Function of human pluripotent stem cell-derived photoreceptor progenitors in blind mice. Sci Rep 2016;6:29784.
72Liu X, Chen F, Chen Y, Lu H, Lu X, Peng X, et al. Paracrine effects of intraocularly implanted cells on degenerating retinas in mice. Stem Cell Res Ther 2020;11:142.
73Lund RD, Wang S, Lu B, Girman S, Holmes T, Sauvé Y, et al. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007;25:602-11.
74Cao J, Murat C, An W, Yao X, Lee J, Santulli-Marotto S, et al. Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration. Stem Cells 2016;34:367-79.
75Bammidi S, Bali P, Kalra J, Anand A. Transplantation efficacy of human ciliary epithelium cells from fetal eye and Lin-ve stem cells from umbilical cord blood in the murine retinal degeneration model of laser injury. Cell Transplant 2020;29:1-12.
76Lee ES, Yu SH, Jang YJ, Hwang DY, Jeon CJ. Transplantation of bone marrow-derived mesenchymal stem cells into the developing mouse eye. Acta Histochem Cytochem 2011;44:213-21.
77Tzameret A, Sher I, Belkin M, Treves AJ, Meir A, Nagler A, et al. Epiretinal transplantation of human bone marrow mesenchymal stem cells rescues retinal and vision function in a rat model of retinal degeneration. Stem Cell Res 2015;15:387-94.
78Park SS, Moisseiev E, Bauer G, Anderson JD, Grant MB, Zam A, et al. Advances in bone marrow stem cell therapy for retinal dysfunction. Prog Retin Eye Res 2017;56:148-65.
79Liu X, Hou M, Zhang S, Zhao Y, Wang Q, Jiang M, et al. Neuroprotective effects of bone marrow Sca-1+ cells against age-related retinal degeneration in OPTN E50K mice. Cell Death Dis 2021;12:613.
80Otani A, Dorrell MI, Kinder K, Moreno SK, Nusinowitz S, Banin E, et al. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells. J Clin Invest 2004;114:765-74.
81Tuekprakhon A, Sangkitporn S, Trinavarat A, Pawestri AR, Vamvanij V, Ruangchainikom M, et al. Intravitreal autologous mesenchymal stem cell transplantation: A non-randomized phase I clinical trial in patients with retinitis pigmentosa. Stem Cell Res Ther 2021;12:52.
82Usategui-Martín R, Puertas-Neyra K, García-Gutiérrez MT, Fuentes M, Pastor JC, Fernandez-Bueno I. Human mesenchymal stem cell secretome exhibits a neuroprotective effect over in vitro retinal photoreceptor degeneration. Mol Ther Methods Clin Dev 2020;17:1155-66.
83Joe AW, Gregory-Evans K. Mesenchymal stem cells and potential applications in treating ocular disease. Curr Eye Res 2010;35:941-52.
84Oner A, Gonen ZB, Sinim N, Cetin M, Ozkul Y. Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: A phase I clinical safety study. Stem Cell Res Ther 2016;7:178.
85Li Z, Zeng Y, Chen X, Li Q, Wu W, Xue L, et al. Neural stem cells transplanted to the subretinal space of rd1 mice delay retinal degeneration by suppressing microglia activation. Cytotherapy 2016;18:771-84.
86Khine KT, Albini TA, Lee RK. Chronic retinal detachment and neovascular glaucoma after intravitreal stem cell injection for Usher syndrome. Am J Ophthalmol Case Rep 2020;18:100647.
87Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, et al. Vision loss after intravitreal injection of autologous “Stem Cells” for AMD. N Engl J Med 2017;376:1047-53.
88Boudreault K, Justus S, Lee W, Mahajan VB, Tsang SH. Complication of autologous stem cell transplantation in retinitis pigmentosa. JAMA Ophthalmol 2016;134:711-2.
89Singh MS, Park SS, Albini TA, Canto-Soler MV, Klassen H, MacLaren RE, et al. Retinal stem cell transplantation: Balancing safety and potential. Prog Retin Eye Res 2020;75:100779.
90Nirwan RS, Albini TA, Sridhar J, Flynn HW Jr., Kuriyan AE. Assessing “Cell Therapy” clinics offering treatments of ocular conditions using direct-to-Consumer marketing websites in the United States. Ophthalmology 2019;126:1350-5.
91Damjanov I, Andrews PW. Teratomas produced from human pluripotent stem cells xenografted into immunodeficient mice – A histopathology atlas. Int J Dev Biol 2016;60:337-419.
92Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U. Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 2004;45:4251-5.
93Abbasalizadeh S, Baharvand H. Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies. Biotechnol Adv 2013;31:1600-23.
94Oh SI, Lee CK, Cho KJ, Lee KO, Cho SG, Hong S. Technological progress in generation of induced pluripotent stem cells for clinical applications. ScientificWorldJournal 2012;2012:417809.
95Hamada M, Malureanu LA, Wijshake T, Zhou W, van Deursen JM. Reprogramming to pluripotency can conceal somatic cell chromosomal instability. PLoS Genet 2012;8:e1002913.
96Nguyen HT, Geens M, Spits C. Genetic and epigenetic instability in human pluripotent stem cells. Hum Reprod Update 2013;19:187-205.
97Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010;7:521-31.
98Feng Q, Lu SJ, Klimanskaya I, Gomes I, Kim D, Chung Y, et al. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells 2010;28:704-12.
99Orive G, Hernández RM, Gascón AR, Calafiore R, Chang TM, De Vos P, et al. Cell encapsulation: Promise and progress. Nat Med 2003;9:104-7.
100Tachibana M, Amato P, Sparman M, Gutierrez NM, Tippner-Hedges R, Ma H, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 2013;153:1228-38.
101Lee J, Sheen JH, Lim O, Lee Y, Ryu J, Shin D, et al. Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: A step toward universal T cell therapy. Sci Rep 2020;10:17753.
102Pham SM, Mitruka SN, Youm W, Li S, Kawaharada N, Yousem SA, et al. Mixed hematopoietic chimerism induces donor-specific tolerance for lung allografts in rodents. Am J Respir Crit Care Med 1999;159:199-205.
103Charron D, Suberbielle-Boissel C, Tamouza R, Al-Daccak R. Anti-HLA antibodies in regenerative medicine stem cell therapy. Hum Immunol 2012;73:1287-94.
104Opelz G, Döhler B. Effect of human leukocyte antigen compatibility on kidney graft survival: Comparative analysis of two decades. Transplantation 2007;84:137-43.
105Opelz G, Döhler B. Impact of HLA mismatching on incidence of posttransplant non-Hodgkin lymphoma after kidney transplantation. Transplantation 2010;89:567-72.
106Master Z, Williams-Jones B. The global HLA banking of embryonic stem cells requires further scientific justification. Am J Bioeth 2007;7:45-6.
107de Rham C, Villard J. Potential and limitation of HLA-based banking of human pluripotent stem cells for cell therapy. J Immunol Res 2014;2014:518135.
108Fraga AM, Sukoyan M, Rajan P, Braga DP, Iaconelli A Jr., Franco JG Jr., et al. Establishment of a Brazilian line of human embryonic stem cells in defined medium: Implications for cell therapy in an ethnically diverse population. Cell Transplant 2011;20:431-40.
109Tokunaga K, Ohashi J, Bannai M, Juji T. Genetic link between Asians and native Americans: Evidence from HLA genes and haplotypes. Hum Immunol 2001;62:1001-8.
110Nakajima F, Tokunaga K, Nakatsuji N. Human leukocyte antigen matching estimations in a hypothetical bank of human embryonic stem cell lines in the Japanese population for use in cell transplantation therapy. Stem Cells 2007;25:983-5.
111Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA. Banking on human embryonic stem cells: Estimating the number of donor cell lines needed for HLA matching. Lancet 2005;366:2019-25.
112Palanker D, Huie P, Vankov A, Aramant R, Seiler M, Fishman H, et al. Migration of retinal cells through a perforated membrane: Implications for a high-resolution prosthesis. Invest Ophthalmol Vis Sci 2004;45:3266-70.
113Kador KE, Goldberg JL. Scaffolds and stem cells: Delivery of cell transplants for retinal degenerations. Expert Rev Ophthalmol 2012;7:459-70.
114Redenti S, Tao S, Yang J, Gu P, Klassen H, Saigal S, et al. Retinal tissue engineering using mouse retinal progenitor cells and a novel biodegradable, thin-film poly (e-caprolactone) nanowire scaffold. J Ocul Biol Dis Infor 2008;1:19-29.
115Steedman MR, Tao SL, Klassen H, Desai TA. Enhanced differentiation of retinal progenitor cells using microfabricated topographical cues. Biomed Microdevices 2010;12:363-9.
116Sodha S, Wall K, Redenti S, Klassen H, Young MJ, Tao SL. Microfabrication of a three-dimensional polycaprolactone thin-film scaffold for retinal progenitor cell encapsulation. J Biomater Sci Polym Ed 2011;22:443-56.
117Tomita M, Lavik E, Klassen H, Zahir T, Langer R, Young MJ. Biodegradable polymer composite grafts promote the survival and differentiation of retinal progenitor cells. Stem Cells 2005;23:1579-88.
118Lawley E, Baranov P, Young M. Hybrid vitronectin-mimicking polycaprolactone scaffolds for human retinal progenitor cell differentiation and transplantation. J Biomater Appl 2015;29:894-902.
119Jung YH, Phillips MJ, Lee J, Xie R, Ludwig AL, Chen G, et al. 3D microstructured scaffolds to support photoreceptor polarization and maturation. Adv Mater 2018;30:e1803550.