Encyclopedia
The retina is a complex and fragile photosensitive part of the central nervous system which is prone to degenerative diseases leading to permanent vision loss. Retina regeneration refers to the restoration of vision by replacement of the degenerating cells in the retina.
- retinal degenerative diseases
- age-related macular degeneration
- retinal dystrophies
- retinitis pigmentosa
- ESC-RPE
- iPSC-RPE
1. Introduction
The human retina, which is situated in the posterior part of the eye is a transparent, light-sensitive tissue containing multiple cellular layers. It originates from the anterior neural tube during early embryogenesis as a part of the central nervous system [1]. The retina is composed of the light transducing neural retina, as well as the supportive blood-retinal barrier. In the neural retina, after absorption of photons of light energy by the photoreceptors (PR)—the rods and cones, the visual information is converted into chemical signals and then to neural signals that are transmitted to retinal ganglion cells (RGC). The RGC axons form the optic nerve that transmits this information to the brain visual centers where the image is processed [2]. The blood–retina barrier consists of a polarized monolayer of hexagonal cells—the retinal pigment epithelial cells (RPE) which support and nourish the PR; Bruch’s membrane (BM)—a specialized basement membrane which transports nutrients to the retina, and retinal vascular endothelial cells of the underlying choroid [3].
Although there are variations in the pathologies typical of retinal degenerative diseases (RDs) including age-related macular degeneration (AMD), retinitis pigmentosa (RP), and Stargardt’s disease (SD), it is currently considered that RPE dysfunction and the resultant deterioration of photoreceptors are the most common pathologies. Furthermore, BM may thicken and alter its composition, resulting in compromised nutrient transport to the retina. Degeneration of RPE and photoreceptors result in significant visual disability which eventually leads to irreversible vision loss. The existing therapies can only delay the progression of retinal diseases, except for anti-angiogenic treatments for patients with neovascular age-related macular degeneration [4]. Currently, there are no established treatment strategies to completely halt the degenerative process or reinstate regular retinal function to restore vision. Although electronic retinal interface devices [5] and gene therapies [6] are under clinical trials, the extent of achievable results is likely a long way from permanent visual recovery.
In many instances of retinal degeneration, even after RPE and PR loss, the inner layers of the retina with its intricate neural connectivity maintain their architecture for an extended period. If a population of healthy RPE/PR are delivered to the sub-retinal space, they can survive and integrate with the host retina to restore vision. Based on this, a cell replacement strategy is a promising approach for the treatment of AMD and RP. Reports from initial clinical trials involving transplantation of human embryonic stem cell-derived RPE (hESC-RPE) as suspension [7][8][7,8] are encouraging and found to be safe for the treatment of AMD and SD. Simple bolus injection of stem/progenitor cell suspension into sub-retinal space may result in injection reflex and poor cell localization. The compromised cell survival will lead to ineffective cell integration into the damaged retina. Even though cells appear to be well tolerated in relatively short-term animal studies, non-integrated cells will lead to potential complications such as sub-retinal gliosis [9][10][9,10]. To ensure that the cells are in correct orientation and proper interface with the photoreceptor cells, it is desirable to transplant cells as a preformed monolayer along with a supporting substrate. A recent implantation study used, stem cell-derived RPE grown on a bioengineered scaffold (RPE patch), that helps to maintain the polarity and laminar structure of the transplanted RPE cells [9][10][11][12][9,10,11,12]. Results of the on-going Phase1/2a clinical trials indicate good safety and tolerability for surgical implantation of RPE grown on parylene scaffolds [13].
2. Tissue Engineering of the Retina
The environment in which the cells grow and mature can influence their survival and functionality after transplantation. Tissue engineering of the retina is based on the concept that the transplantation of normal healthy cells derived from various stem cell sources needs to be implanted as an intact layer or sheet rather than injected as a suspension. Previously, sub-retinal delivery of cells through bolus injection has laid the groundwork and provided the "proof of concept" that healthy donor stem and progenitor cells can be transplanted into a diseased retina to contribute to visual functional recovery [14][15][70,71]. These preclinical studies emphasized the requirement of improved cell delivery systems to enhance donor cell survival, integration, and neural connectivity.
Advanced AMD is characterized by complete loss of PRs, dysfunctional RPE, and abnormal BM. BM is a 2–4 μm thick extracellular matrix (ECM) composed of collagen types I and IV, laminin, fibronectin, hyaluronic acid, heparan sulfate chondroitin/dermatan sulfate, and elastin [16][72]. The specialized morphology of BM facilitates the reciprocal exchange of nutrients to and from the retina. In the diseased state, the BM show increased lipid body accumulation and a higher level of collagen cross-linking [17][73]. The degenerating RPE monolayer and its disrupted tight junctions further alter the BM morphology. These age-related changes result in decreased adhesion and survival of transplanted donor cells [12]. Several groups attempted to resurface BM to facilitate RPE attachment. Although coating the BM with a mixture of laminin, fibronectin, and vitronectin improved cell survival and phagocytosis of fluorescein isothiocyanate (FITC)-labeled bovine photoreceptor outer segments in both adult RPE and fetal RPE, the improvement was not comparable to healthy BM [18][74].
Transplantation of healthy RPE/PR seeded in a carefully designed scaffold that can mimic the BM morphology and properties can better rescue the deteriorating visual function [9]. The central fovea has a neural retina thickness of 100 μm whereas the BM is only 5 μm [19][75]. In general, the ideal scaffold should be biocompatible, nonimmunogenic, and mechanically robust enough to resist manipulation during implantation. Scaffolds need to be thin enough to allow the exchange of nutrients and metabolites between the choriocapillaris and the retina [20][76]. After transplantation, it should not lead to physical distortion of the photoreceptor layer. Low elasticity of the material prevents adverse events like retinal detachment, retraction, or visual distortion. Carefully designed, cutting-edge biomaterials with fine-tuned topographical properties and micro/nanopatterned structures with extracellular matrix (ECM) properties can hold stem and progenitor cell populations effectively and help to deliver them as a retinal patch into the sub-retinal space.
Different types of biomaterials have been used to design scaffolds for retinal tissue engineering. This includes natural polymers, synthetic polymers, hybrid polymers, decellularized tissues, and thermo-responsive hydrogel polymers.
