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Neurite growth on the EVA scaffold. The OV was placed on a 2D scaffold for 5 days and the nerve bundles were found to grow and had a regular arrangement ((a) bottom panel) but were not arranged without a scaffold ((a) up panel). Observe the position of the nerve bundle, near the position of the sphere is the proximal ((b) left panel) and far away from the sphere of the location that is distal ((b) right panel); (c) immunofluorescence was used to validate the RGC-specific markers, the expression of Math5, and the markers of the neural cytoskeleton Tuj1. Nerve bundles of Tuj1 and Math5 can be observed at a lower magnification ((c) up panel, 40×). The neuronal growth pattern was observed with a bright field and the markers of nerve bundles (Tuj1 and Math5) were observed ((c) bottom panel, 100×).
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Optic neuropathies, such as glaucoma and Leber’s hereditary optic neuropathy (LHON) lead to retinal ganglion cell (RGC) loss and therefore motivate the application of transplantation technique into disease therapy. However, it is a challenge to direct the transplanted optic nerve axons to the correct location of the retina. The use of appropriate s...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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... OVs were placed on the scaffold and RGC neurite growth was observed as compared to the control grown on a regular plate. After 5 days of culturing, we found that RGCs grown on the scaffold exhibited long and prominent neurites in contrast to the control RGCs, which had shorter and unorganized axons. (Figure 4a). The average diameter of RGC nerve bundles on the scaffold was measured to be 6.67 µm, indicating the viability of plated RGCs. It is clearly observed that the growth of the nerve bundle on the scaffold showed a relatively straight pattern at both proximal and distal sections (Figure 4b). Furthermore, the proximal section of the nerve bundle showed higher axial density, indicating that the scaffold was able to support the extension of the RGC axons (Figure 4b; left panel). We investigate the OV capability of differentiation into RGCs on an EVA scaffold and follow the expression of RGC markers during neuronal induction. Tuj1 present in neurons for microtubule stability and axonal transport. Math5 plays an important role in the RGC on retinal progenitors and are required in determining RGC fate. Immunofluorescence staining demonstrated that the neurons on the scaffold expressed RGC marker Math5 and the neuron marker Tuj1, thus confirming that RGC identity was not affected when grown on the scaffold (Figure 4c). ...
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Purpose:
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Methods:
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Purpose:
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Citations
... Biodegradable polymer scaffolds may increase survival cell rate, and it also appears that the adhesion and orientation of transplanted retinal cells are promoted by the scaffold porosity (dimensional conformation). In addition, cell orientation can be affected by scaffold topography because of its positive influence on cell morphology, proliferation, migration and adhesion [52]. Good results on biomaterials and RPE cells have been obtained from both, in vitro and in vivo studies; however, how long the transplanted cells could survive has still to be determined [53]. ...
... Both natural biological and synthetic polymeric materials are used to construct scaffolds for photoreceptor implants. Such biological materials that mimic natural architectures include alginate, collagen, etc. Synthetic polymers, such as poly-caprolactone (PCL), poly (lactic-co-glycolic) acid (PLGA), etc., express higher mechanical strength and controlled degradation rates [52]. We would not recommend the use of scaffolds with the capacity to facilitate the differentiation of photoreceptor progenitors (PRPs). ...
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... This allows for better cell viability and electrophysiology while guiding neurite pathfinding, a key aspect in the eye-brain connection [101]. This creation of long, well-aligned, and organized axons in RGCs has also been observed in an EVA scaffold with parallel grooves created by thermal nano-imprinted lithography [8]. These RGCs demonstrated higher functionality than a control without any topographical cue. ...
Hereditary optic neuropathies (HONs) such as dominant optic atrophy (DOA) and Leber Hereditary Optic Neuropathy (LHON) are mitochondrial diseases characterized by a degenerative loss of retinal ganglion cells (RGCs) and are a cause of blindness worldwide. To date, there are only limited disease-modifying treatments for these disorders. The discovery of induced pluripotent stem cell (iPSC) technology has opened several promising opportunities in the field of HON research and the search for therapeutic approaches. This systematic review is focused on the two most frequent HONs (LHON and DOA) and on the recent studies related to the application of human iPSC technology in combination with biomaterials technology for their potential use in the development of RGC replacement therapies with the final aim of the improvement or even the restoration of the vision of HON patients. To this purpose, the combination of natural and synthetic biomaterials modified with peptides, neurotrophic factors, and other low- to medium-molecular weight compounds, mimicking the ocular extracellular matrices, with human iPSC or iPSC-derived cell retinal progenitors holds enormous potential to be exploited in the near future for the generation of transplantable RGC populations.
... However, the success of retinal transplantation by injecting cell suspensions has limited cell survival and lacks cellular integration [92]. Nanostructured scaffolds such as nanofibers, nanoporous gels, nanotopography, and 3D printing can support cell adhesion, survival, proliferation, migration, differentiation, and integration, and improve visual function [92][93][94][95][96]. ...
... Topography plays a vital role in neurite growth and orientation. Electrospinning and 3D printing are suitable methods for generating nanotopograhy [42,44,95]. In a previous study, RGCs were seeded on randomly arranged polypyrrole-graphenemodified PLGA nanofibers to obtain neurite growth of 80-100 µm. ...
... These nanowires also support synapse formation significantly better than a flat surface, suggesting the importance of topography in retinal tissue engineering [44]. In another study, poly(ethylene-co-vinyl acetate) was designed with parallel straight grooves using 3D imprinting lithography [95]. Human-induced pluripotent stem cell (iPSC)-derived RGCs grown on this scaffolding displayed organized axons, which projected axially. ...
Retinal diseases are one of the leading causes of blindness globally. The mainstay treatments for these blinding diseases are laser photocoagulation, vitrectomy, and repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) or steroids. Unfortunately, these therapies are associated with ocular complications like inflammation, elevated intraocular pressure, retinal detachment, endophthalmitis, and vitreous hemorrhage. Recent advances in nanomedicine seek to curtail these limitations, overcoming ocular barriers by developing non-invasive or minimally invasive delivery modalities. These modalities include delivering therapeutics to specific cellular targets in the retina, providing sustained delivery of drugs to avoid repeated intravitreal injections, and acting as a scaffold for neural tissue regeneration. These next-generation nanomedicine approaches could potentially revolutionize the treatment landscape of retinal diseases. This review describes the availability and limitations of current treatment strategies and highlights insights into the advancement of future approaches using next-generation nanomedicines to manage retinal diseases.
... The absence of physical support possibly limits the survival and differentiation of the injected cells. Some recent studies demonstrated that engineered scaffolds or biomaterials can stimulate RGC axon outgrowth in vitro (Kador et al., 2014;Sluch et al., 2015;Li et al., 2017;Yang et al., 2017). Introducing a RGC-scaffold biomaterial into the eye would be a real progress compared to an injection of cell suspension as reported recently in rabbits and monkeys (Li et al., 2017). ...
Inherited visual disorders, major cause of visual impairment, can be subdivided into inherited retinal dystrophies (iRD), due to the progressive loss of photoreceptors and retinal pigment epithelium, or inherited optic neuropathies (iON), due to the loss of retinal ganglion cells whose axons form the optic nerve. IRDs and IONs represent two genetically and clinically heterogeneous groups for which cell replacement is one of the most encouraging therapeutic strategies. For stem cell-based therapy, using human induced pluripotent stem cellsHuman induced pluripotent stem cells (hiPSCs)(iPSCs)Induced pluripotent stem cells (iPSCs) is crucial to obtain a relatively homogenous cell population to be transplanted. We will present effective strategies based on magnetic-activated cell sorting to select transplantable retinal ganglion cells or photoreceptors by targeting a cell surface antigen specifically expressed in each of the two retinal cell types from human iPSC-derived retinal organoidsRetinal organoids.
... With advancement in stem cell biology, retinal equivalent construct can be bioprinted by using stem cells responsible for retinal tissue engineering such as embryonic stem cells (ES) and induced pluripotent stem cells (iPSC). Reconstruction of destroyed retina can be done by using the differentiation capability of induced pluripotent stem cells into different types of retinal cells (retinal pigment epithelial cells, retina ganglion cells etc.) (Yang et al. 2017). ...
This review paper is primarily focused on bioprinting technology for biomedical applications. Bioprinting can be utilized for fabrication of wide range of tissue, based on which this chapter describes in detail its application in tissue regeneration. Further, the difficulties and potential in developing a construct for tissue regeneration are discussed herein. In this review paper, application of 3D bioprinting in tissue regeneration will be discussed in depth.
... Finally, iPSCs can be transplanted in an autologous fashion to avoid immunogenicity and enhance their in vivo survival. Many studies have demonstrated that human iPSCs can differentiate into various lineages, including cardiomyocytes [4], neurons [5], hematopoietic progenitors [6,7], endothelial cells [8], osteoclasts [9], hepatocyte-like cells [10], and retinal cells [11][12][13][14][15][16]. Due to these distinctive advantages, iPSCs are regarded as promising candidates for cell therapy, tissue engineering, and iPSCbased disease modeling. ...
Induced pluripotent stem cells (iPSCs) are essentially produced by the genetic reprogramming of adult cells. Moreover, iPSC technology prevents the genetic manipulation of embryos. Hence, with the ensured element of safety, they rarely cause ethical concerns when utilized in tissue engineering. Several cumulative outcomes have demonstrated the functional superiority and potency of iPSCs in advanced regenerative medicine. Recently, an emerging trend in 3D bioprinting technology has been a more comprehensive approach to iPSC-based tissue engineering. The principal aim of this review is to provide an understanding of the applications of 3D bioprinting in iPSC-based tissue engineering. This review discusses the generation of iPSCs based on their distinct purpose , divided into two categories: (1) undifferentiated iPSCs applied with 3D bioprinting; (2) differentiated iPSCs applied with 3D bioprinting. Their significant potential is analyzed. Lastly, various applications for engineering tissues and organs have been introduced and discussed in detail.
... NTA is a subclone of the human-induced pluripotent stem cell (iPSC) line that was reprogrammed from peripheral blood, were collected following Ethical and Institutional Review Board of Taipei Veterans General Hospital (ID No. 2020-05-004C), using the integration-free Sendai virus carrying the four Yamanaka factors, as described in [43], and their genome integrity and pluripotency were evaluated. NTA was maintained in StemFlexTM Medium (Thermo Scientific, Waltham, MA, USA). ...
The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.
... A recent work by Evans et al. [36] found that the structure, composition and properties of biopolymer scaffolds play an important role in encouraging the cells to develop a functional replacement tissue. Specific to RGC differentiation, Yang et al. [35] examined the impact of a nanoimprinted scaffold made of poly (ethylene-co-vinyl acetate) in human iPSC-derived RGC differentiation and reported on scaffold induced axial elongation of RGCs' axon extension along the underlaying scaffold grooves. Chen et al. [15] showed that polybenzyl glutamate scaffold was capable of reducing the time it takes for the RGC cellular differentiation process complete. ...
The stem cell-based retinal ganglion cells (RGCs) replacement therapy offers a potential to restore vision in progressive optic neuropathies including glaucoma by replacing degenerated RGCs and by simulating axonal regeneration. Injured optic nerve axons do not regenerate owing to the limited intrinsic capacity of the neurons and the inhibitory environment at the injury site. Polymeric tissue scaffolds are able to modulate the physical environment while providing structural support for transplanted cells, however, their application specific to the RGC generation has been far from conclusive. The successful generation of clinically safe and functional RGCs that can appropriately integrate into the hosts’ retinas still remain largely unresolved.
Our study reports on a process that enables generation of RGCs from human embryonic stem cells (hESCs) that is simple, straightforward and repeatable and, investigates the influence of the aligned poly(glycerol sebacate) (PGS)/poly(ε-caprolactone) (PCL) scaffold on this differentiation process. Our findings demonstrate that PGS/PCL scaffold promotes differentiation of hESCs into RGC-like cells possibly by the simulation of cell active environmental signalling and, facilitates the growth of RGCs neurites along their lengths.
Statement of significance
Glaucoma can lead to the degeneration of retinal ganglion cells (RGCs), with consequential vision loss. RGCs are incapable of self-renewal, replacement of diseased RGCs with healthy cells has been a goal to restore vision in glaucoma patients. In this regard, stem cell RGC replacement therapy has been shown to improve vision in animal models of glaucoma, which could be facilitated by using tissue-engineered polymeric scaffolds. In this study, we generated homogenous stem cell-derived RGCs via a straightforward differentiation protocol and evaluated the effects of PGS/PCL scaffold on RGCs differentiation and growth of RGCs neurites. Our study contributes to the knowledge on how biomaterial scaffolds are able to support the regeneration of RGC neurites (i.e., axons or dendrites) as a part of a possible future clinical therapy for the treatment of glaucoma.
... After that, the OVs were placed on the scaffold, and RGC axons and neurite growth were observed. The scaffold was able to support the extension of long and organized axons that were functional, and they also showed that the generated scaffold enhanced the growth of RGCs derived from a LHON patient [136]. ...
Inherited optic neuropathies share visual impairment due to the degeneration of retinal ganglion cells (RGCs) as the hallmark of the disease. This group of genetic disorders are caused by mutations in nuclear genes or in the mitochondrial DNA (mtDNA). An impaired mitochondrial function is the underlying mechanism of these diseases. Currently, optic neuropathies lack an effective treatment, and the implementation of induced pluripotent stem cell (iPSC) technology would entail a huge step forward. The generation of iPSC-derived RGCs would allow faithfully modeling these disorders, and these RGCs would represent an appealing platform for drug screening as well, paving the way for a proper therapy. Here, we review the ongoing two-dimensional (2D) and three-dimensional (3D) approaches based on iPSCs and their applications, taking into account the more innovative technologies, which include tissue engineering or microfluidics.
... Photoreceptor transplantation with biomaterials. Both synthetic polymers and biological materials can be used in the fabrication of scaffolding structures for photoreceptors implants: natural materials like alginate, collagen, etc., are suitable for imitating natural architectures (Ramakrishna et al., 2001); synthetic polymers, such as poly-caprolactone (PCL) and poly (lacticco-glycolic) acid (PLGA), offer higher mechanical strength and controllable degradation rates although the latter usually cause less biological activity (Yang et al., 2017). Scaffolds for retinal progenitor cells (RPCs) transplants can be cylindrical, mimicking the vertical disposition of cells in the retina, fibrous, mimicking the microstructure of the extracellular matrix or made by hydrogels, to mimic the mechanical properties of the retina (Kador and Goldberg, 2012). ...
... On the other hand, the dimensional conformation or porosity of the scaffold seems to promote the union and subsequent differentiation and orientation of the RPCs (Lee Ventola, 2014). Other studies defend the idea that scaffold topography influences orientation, because of its positive influence on differentiation, morphology, proliferation, migration and adhesion of the cells (Ramakrishna et al., 2001;Kador et al., 2016;Yang et al., 2017). Scaffolds can actively interact with different cellular components. ...
Age-related Macular Degeneration (AMD) is an up-to-date untreatable chronic neurodegenerative eye disease of multifactorial origin, and the main causes of blindness in over 65 y.o. people. It is characterized by a slow progression and the presence of a multitude of factors, highlighting those related to diet, genetic heritage and environmental conditions, present throughout each of the stages of the illness. Current therapeutic approaches, mainly consisting on intraocular drug delivery, are only used for symptoms relief and/or to decelerate the progression of the disease. Furthermore, they are overly simplistic and ignore the complexity of the disease and the enormous differences in the symptomatology between patients. Due to the wide impact of the AMD and the up-to-date absence of clinical solutions, Due to the wide impact of the AMD and the up-to-date absence of clinical solutions, different treatment options have to be considered. Cell therapy is a very promising alternative to drug-based approaches for AMD treatment. Cells delivered to the affected tissue as a suspension have shown poor retention and low survival rate. A solution to these inconveniences has been the encapsulation of these cells on biomaterials, which contrive to their protection, gives them support, and favor their retention of the desired area. We offer a two-papers critical review of the available and under development AMD therapeutic approaches, from a biomaterials and biotechnological point of view. We highlight benefits and limitations and we forecast forthcoming alternatives based on novel biomaterials and biotechnology methods. In this second part we review the preclinical and clinical cell-replacement approaches aiming at the development of efficient AMD-therapies, the employed cell types, as well as the cell-encapsulation and cell-implant systems. We discuss their advantages and disadvantages and how they could improve the survival and integration of the implanted cells.
