# Tissue Engineering Strategies for Retina Regeneration
## 4 Biomaterials and Scaffolds Used for Tissue Engineering
### Synthetic Biomaterials Used as Scaffolds
[98] showed that RPCs seeded on PLLA-PLGA copolymers, down-regulated immature \"stemness\" cell markers (Hes5, nestin, Hes1, and Pax6), and upregulated mature retinal markers such as glial fibrillary acidic protein (GFAP), nevertheless, there was no photoreceptor-specific expression [98]. Parylene-C is a class VI biocompatible polymer having several biomedical applications including the fabrication of Argus(r) II Retinal Prosthesis System [99]. Our preclinical and translational studies showed that composite implant of RPE and parylene is a feasible option to rescue visual function [9; 13; 100; 101]. The parylene material used was semipermeable to molecules of a certain molecular weight when its thickness was reduced to a sub-micron range. [PERSON] et al. [102] designed a mesh-supported sub-micron parylene-C membrane (MSPM). To get better cell adherence, both sides of the membrane were treated with low-power oxygen plasma and coated with matrigel. RPE cells demonstrated good adherence and showed epithelial-like morphology. They developed microvilli, right polarization, and tight intracellular junctions [102]. Survival of the transplanted RPE cells in the subretinal space of Royal College of Surgeons (RCS) rats up to 21 weeks post-implantation was demonstrated by [PERSON] et al. [100]. The implanted hESC-RPE cells remained as a monolayer on the surface of the parylene substrate and performed photoreceptor outer segment phagocytosis (Figure 1). A partially blinded randomized study was conducted on Yucatan minipigs before human clinical trials. Results showed structural preservation of the implant; the RPE cells remained intact and survived in the form of a monolayer [103]. Following this, an RPE+ parylene implant named California Project to Cure Blindness-Retinal Pigment Epithelium 1 (PCCB-RPE1) was developed for use in clinical studies which are currently being conducted in patients with dry AMD. In another in vitro study, specifically designed porous honeycomb PLA films coated with collagen IV were seeded with pigmented hESC, showed cell survival and proliferation during the 6 weeks of the study period [104]. A biomimetic scaffold sheet of plasma modified polydimethylsiloxane (PDMS) coated with laminin was found to facilitate the functional maturation and survival of RPE cells [105]. PCL-gelatin scaffold, poly(lactic-co-glycolic acid) (PLGA)- collagen type I, poly(ethylene glycol) diacrylate (PEGDA)- RGDS peptide motif (arginine-glycine-aspartic acid-serine) are the other polymer types shown to support RPE survival and maturation [106; 107; 108]. Human retinal progenitor cells (hRPCs), isolated from the fetal retina, need extracellular matrix proteins such as fibronectin or laminin for attachment and survival. A synthetic, xeno-free vitronectin-mimicking surface (Synthemax) was fabricated by [PERSON] et al. to grow RPCs; RPCs survived and self-renewed in the in vitro condition [109]. In another study, the authors used xeno-free synthetic RGD peptides to coat the PCL scaffold. The coating promoted the differentiation of rods in vitro but not the differentiation of cones or other retinal cell types. The expression of stem cell markers KLF4 and N-MYC remained high due to which this construct is considered undesirable for human applications [110].