Article by Richard Z. Zhuang & Roberta Lock

Engineering a Blinking Eye On-a-Chip

 Source Publication: 

Multiscale reverse engineering of the human ocular surface, Nature Medicine, 2019

Jeongyun Seo et al., Dongeun Huh Lab 

Blinking probably isn’t something you think about often- it lasts for a fraction of a second and is semi-automatic. However, it plays a vital function in protecting your eyes by releasing a tear film (a mixture of water, oil, and mucus) to keep the surface of the eye smooth and prevent it from drying out. This process is surprisingly complex, and engineering a model of a blinking eye in vitro will help us better understand how blinking impacts the ocular (eye) tissue in both health and disease. 

What did these researchers do?

In this study, the researchers created a model system of a blinking human eye. Traditional tissue culture methods submerge the entire tissue in culture media. However, in the body, one side of the ocular surface is exposed to air. Using a microfluidic device, the researchers engineered an ocular surface tissue cultured at an air-liquid interface. This culture method allowed the researcher to produce ocular surface tissue that more closely resembled a human eye on both a tissue and cellular level compared to traditional models. Upon adding the blinking component to the model, the mechanical stress on the ocular surface and hydrodynamic changes to the thin film of tears exerted by the “eyelid” could be investigated. Interestingly, the mechanical stimulation of the blinking motion also had biological effects, and caused epithelial cells within the engineered tissue to further differentiate (specialize) into corneal cells.


Blinking Eye-on-a-chip platform by D. Huh Lab

This eye model was further tested by decreasing the frequency of “blinking” to simulate dry eye disease, and showed that the differences between the diseased and healthy eye tissues of their model correlated with the differences seen in patients. From there, the researchers tested a drug aimed to treat dry eye disease in patients on their model, and found that drug-treated disease tissues recovered to a point where they once again resembled the healthy tissues, showing the extent of biomimicry their blinking eye model achieves.

Why is this important?

The mechanobiology of blinking is a vital component to human eye health. However, studying this process is rather difficult. Doing so requires the ability to finely control the microenvironments surrounding the eye (ie the air-liquid interface), the blinking motion (frequency, speed, amount of pressure the eyelid exerts on the eyeball, quantity of “tears” released per blink, etc) and examine important aspects of biology on cellular and tissue levels, which current experimental systems lack. In animal models, we run into issues of species differences in biology. A model like this one allows researchers to study the underlying biology with fine control over every parameter of the blinking motion and on human cells too.

How did the researchers do this?

The researchers engineered three components that together replicate the essential features of a blinking eye. First is the ocular surface. In a dome-shaped scaffold, researchers seeded stromal (supporting) cells of the ocular tissue. On the outside, researchers then seeded corneal epithelial cells (cells that regulate hydration for tissue transparency) in the center and conjunctival epithelial cells (cells that produce mucin–a protein essential to maintaining the tears film on the eye surface) as an outer ring. Second is the microfluidic device. The researchers created a device to house the ocular tissue which allows for culture media flow behind the tissue while the outside is exposed to air, and includes a tear channel that deposits liquid onto the tissue surface. Finally is the biomimetic eyelid. Gelatin-based hydrogel flaps were attached to a mechanical arm programmed to mimic blinking by sliding the flap over the ocular tissue.

What comes next?

This novel approach is a significant improvement over traditional methods of studying the blinking process, but only captures a few of the many biological aspects involved. There are many other biological processes involved that can be considered for future models that we think about below:

  • Can we control blinking using nerve cells? In the human eye, corneal nerve cells sense touch, pain, and temperature, and play an important role in tear secretion and blinking. Using nerve cells to control blinking and tear secretion responses would create a much more representative model of the human eye.

  • Do we need an immune component? The immune cell components in the conjunctiva are vital to the body’s response to ocular diseases. Inclusion of an immune component will allow us to better model these complex disease process.