Current and Future Cornea Chip Models for Advancing Ophthalmic Research and Therapeutics

Abstract

Corneal blindness remains a significant global health challenge, with limited treatment options due to donor tissue scarcity outside of the United States and inadequate in vitro models. This review analyzes the current state of cornea chip technology, addressing fundamental challenges and exploring future directions. Recent advancements in biomaterials and fabrication techniques are discussed that aim to recapitulate the complex structure and function of the human cornea, including the multilayered epithelium, organized stroma, and functional endothelium. The review highlights the potential of the cornea chips to revolutionize ocular research by offering more predictive and physiologically relevant models for drug screening, disease modeling, and personalized medicine. Current designs, their applications in studying drug permeability, barrier function, and wound healing, and their limitations in replicating native corneal architecture, are examined. Key challenges include integrating corneal curvature, basement membrane formation, and innervation. Applications are explored in modeling diseases like keratitis, dry eye disease, keratoconus, and Fuchs' endothelial dystrophy. Future directions include incorporating corneal curvature using hydraulically controlled systems, using patient-derived cells, and developing comprehensive disease models to accelerate therapy development and reduce reliance on animal testing.

Keywords: biofunctional membranes; cornea chip; cornea disease modeling; corneal curvature; drug screening; extracellular matrix; microfluidics; ophthalmology; organ chip; tissue engineering.

Figure 1

Recapitulation of human cornea anatomy and physiology. A) The structure of the mimicked in‐vitro corneal model. Schematic of the corneal model includes three vertically stacked compartments with three different cell types. B) Exploded view and schematics of cornea chip (B, right) with three microchannel compartments separated by hybrid interfacial membranes.

Figure 2

The representative current cornea chip designs. A) Schematic of a two‐chamber microfluidic device with a polycarbonate membrane, designed to control tear flow. Reproduced with permission.^{[ 32 ]} Copyright 2018, Royal Society of Chemistry. B) The blinking ocular surface model incorporates a dome‐shaped 3D polystyrene scaffold with cells embedded in hydrogel using a compression approach. Reproduced with premission^{[ 9 ]} Copyright 2019, Springer Nature. C) The open‐top design provides an air‐liquid interface for corneal epithelial cells and includes a TEER measurement port. Reproduced with permission.^{[ 33 ]} Copyright 2022, Elsevier. D) Horizontally organized microfluidic chambers on a chip, fabricated using diverse soft‐lithography techniques, enable the co‐culture of three cell types and facilitate cellular investigation. Reproduced under terms of the CC‐BY license.^{[ 36 ]} Copyright 2020, Royal Society of Chemistry.

Figure 3

Adaptable Tissue‐engineered techniques on Cornea chip model. A) Self‐assembled curvature, regulated by stiffness through cell properties and RGD peptide interaction. Reproduced with permission.^{[ 42 ]} Copyright 2019, Wiley. B) The 3D in vitro cornea model, incorporating natural materials like fibrin and collagen, along with innervation systems and stem cells. Reproduced with permission.^{[ 44 ]} Copyright 2017, Elsevier. C) Membrane formation, characterized by laminin and Thrombospondin‐1 expression in the corneal epithelial‐stromal interface layer. Reproduced under terms of the CC‐BY license.^{[ 43 ]} Copyright 2019, MDPI.

Figure 4

Future directions for cornea chip technology, highlighting advancements in structure, function, design, materials, integration with other ocular tissues, and personalized medicine approaches.