**Background**
The corneal endothelium and retinal pigment epithelium (RPE) are barrier-forming cell monolayers critical for ocular function. In Fuchs endothelial corneal dystrophy (FECD), corneal endothelial cells deposit extracellular matrix, thickening Descemet’s membrane and forming guttae, leading to cell loss and vision loss. In dry age-related macular degeneration (dry AMD), drusen form between the RPE and Bruch’s membrane, causing RPE and photoreceptor death. Current treatments include corneal transplantation (DSAEK/DMEK) for FECD and anti-VEGF injections for wet AMD, but donor tissue shortages (12.7 million patients await transplantation globally, with only 1/70 grafted) and lack of effective therapies for dry AMD drive the need for tissue-engineered alternatives. This review summarizes biomaterials proposed for engineering corneal endothelial and RPE monolayers.
**Methods**
The authors conducted a narrative review of biomaterials for tissue engineering of barrier-forming monolayers in the eye, focusing on the corneal endothelium and RPE. They categorized biomaterials into biomimetic substrates (e.g., collagen, silk fibroin, chitosan), natural membranes (e.g., amniotic membrane, anterior lens capsule, Descemet’s membrane), and synthetic scaffolds (e.g., polycaprolactone, PLGA, parylene C). They also discussed cell sources (primary corneal endothelial cells, stem cells, ARPE-19, hESC-RPE, iPSC-RPE), functionality assessments (in vitro: barrier integrity, pump function, phagocytosis; in vivo: animal models including rabbits, cats, pigs, monkeys), and clinical trials.
**Key Results**
- For corneal endothelium: Descemet’s membrane is 5 µm (age 10) to 13 µm (older adult) thick, with elasticity 20–80 kPa (mean 50 ± 17.8 kPa). Biomimetic substrates like collagen, silk fibroin, and self-assembled stromal substitutes support CEC monolayer formation. Natural membranes (amniotic membrane, anterior lens capsule, tilapia fish scales) and synthetic scaffolds (PMMA, PCL, PLGA, PEG) have been tested. In vivo, rabbit models show restored corneal transparency, but rabbit CECs proliferate in vivo, unlike humans. Cats and monkeys are better models due to lack of CEC proliferation. Functionality is assessed by expression of ZO-1, Na⁺K⁺-ATPase, SLC4A11, and permeability assays.
- For RPE: Bruch’s membrane is 2–4 µm thick with elasticity 7–19 MPa. Biomimetic substrates include collagen, chitosan, silk fibroin, and self-assembled choroidal substitutes. Natural membranes (amniotic membrane, Descemet’s membrane) and synthetic scaffolds (PLGA, parylene C, PCL) have been studied. In vivo, RCS rat models show RPE survival and photoreceptor preservation. A phase I/IIa clinical trial (NCT02590692) using hESC-RPE on an ultrathin parylene substrate (CPCB-RPE1) in 16 advanced dry AMD patients showed 17-letter improvement in visual acuity and anatomic integration.
- Challenges include matching thickness, composition, mechanical properties, and surgical compatibility. Few biomaterials have reached clinical trials.
**Clinical Implications**
Tissue engineering of corneal endothelial and RPE monolayers offers potential alternatives to donor tissue transplantation, addressing global shortages. For FECD, a Descemet’s membrane substitute seeded with healthy CECs could replace diseased endothelium. For dry AMD, an RPE monolayer on a Bruch’s membrane substitute could prevent photoreceptor death. However, further research is needed to optimize biomaterial properties, cell quality, and surgical delivery. The CPCB-RPE1 implant shows promise for dry AMD, but long-term safety and efficacy remain to be established.