HealthTech Nexus with University of Twente

A new way of looking at the retina retina-on-a-chip

The retina is a complex structure within the eye and consists of different segments. To better understand what happens in the eye in patients with eye disease, scientists at HealthTech Nexus, a partnership between the University of Twente and Radboud university medical center, are developing a more advanced model of a ‘retina on a chip’. This model incorporates the three distinct layers of the retina. These three layers have never been successfully combined before. If feasible, this model can be used to learn more about the retinal defects underlying eye disease and about how new therapies could treat them. This could be a promising development for patients.

In the Retina-on-Chip project, researchers are developing a model that mimics the retina. 'It’s a complex process, because the retina is made up of different cell types that each have their own function, but also work together,' says Alex Garanto from Radboudumc. 'What we develop in the lab has all the components of the human retina that are relevant to the functioning of the eye. We want to know how the model responds to age-related or hereditary eye diseases. This hasn’t always been successful in animal testing, which is why we’ve chosen this approach.'

The microchips incorporated in this model are not the same as those used in cars, smartphones and many other products. 'We use microfluidic chips,' says Andries van der Meer of the University of Twente. 'Liquid-filled compartments about one millimetre in size. This size has been chosen because the retina has a similar thickness. The tissues and cells produced by Alex are only partially organised and lack some of the connections between the different cell types that exist in the intact retina. We try to recreate the structure of the intact retina in the Retina-on-Chip project. If we succeed in mimicking the function of the human retina, we will have a state-of-the-art assay for testing therapies that could reverse or slow down the progression of eye diseases.'

Exceptional research

Scientists have previously tried to combine cells in an experimental research setting. However, what is new here is the controlled combination of all three layers of the retina – the choroid, the pigment epithelium layer and the nerve layer – in a way that allows this combination to be used for research.

'With regard to the complexity of this work, we are definitely one of the leading groups,' says Van der Meer. 'And, because it is a chip that we use to try to recreate the retina, it is also very meticulous work. In the eye, a continuous interaction between light, blood, pressure and mechanical stimuli takes place. The chip allows us to closely monitor these interactions. The chip also enables us to make controlled adjustments to each parameter - such as increasing the light or pressure slightly - to determine their consequences. We can replicate the techniques that are used daily in the clinic.'

Collaboration

This project requires collaboration. 'We make good use of the iPS (induced pluripotent stem cells) facility at Radboudumc, where the cells we need for our chips are generated,' says Van der Meer. 'And at the TechMed Centre, we have the bioengineering expertise to manufacture the chips and to analyse whether these chips function properly.' Garanto adds: 'We have the know-how of the clinical and cellular aspects, while the University of Twente understands the technical aspects. By working together, we can develop assays that can be used in clinical practice.'

There are a number of reasons why this project is important for multiple stakeholders, including the search for therapeutic solutions to prevent vision loss.

Challenges

Currently, the researchers are facing two major challenges. 'The first is the variability between the models we produce,' Garanto explains. 'We’re making progress in reducing this variability, but we’re not quite there yet.' Van der Meer: 'But more importantly, it is essential that we can demonstrate to potential stakeholders that we can significantly increase our throughput. In other words, we can produce not just one, but a hundred retinas on a chip in one week, without significant interchip variation. The issue is that it takes approximately 250 days to reprogram stem cells into cells that are suitable for our application. This is an internationally recognised problem in our field. We are trying to speed up the process. To save time, we are working in parallel whenever possible.'

We now have a prototype of the first two layers of the retina. 'Incorporating the third layer, the nerve layer, is still a challenge,' says Garanto. 'It must be of consistent quality, and we need to be able to determine its functioning before we can start working on the connection with the brain.' Van der Meer: 'With the models we already have, we always check to see if there are any effects that can be linked to eye diseases.'

Future prospects

When asked what this development could mean for patients, Garanto and Van der Meer remain cautious. 'It depends on whether the patient expects a treatment or simply better understanding of what’s happening in the eye with a particular disease,' says Garanto. Van der Meer adds: 'Even if we had the perfect model available tomorrow, it would still take the pharmaceutical industry an average of five to ten years to develop a new medicine and to obtain approval for clinical use. The time to develop a new medicine may be shorter for very rare genetic diseases. The pharmaceutical industry is less interested in such diseases because they affect only a small number of people. Fortunately, Radboudumc has strong expertise in developing treatments for rare genetic diseases.'

Garanto and Van der Meer are patient and find their work fascinating. 'My dream is to recreate the complexity of the human body in the laboratory,' says Van der Meer, 'so that we can see the cells retain their function when brought together in this controlled setting. This automatically raises the question: "If we can do this, what else would we be able to do?" That’s what makes it so interesting to me.' Garanto’s dream is slightly different: 'My dream is to get this to patients faster. That’s why I find it so meaningful that we’re taking this step together, from fundamental research to research that truly makes its way into real-world application.'

About HealthTech Nexus

This research is part of HealthTech Nexus, the strategic collaboration between Radboudumc and the University of Twente. Together, they focus on addressing unmet healthcare needs: urgent challenges for which no viable solutions currently exist. This Retina-on-Chip project involves scientists from the University of Twente (Andries van der Meer, scientific lead in the Organ-on-Chip Centre Twente) and Radboud university medical center (Alex Garanto Iglesias, associate professor and research group leader at the Department of Pediatrics and the Department of Human Genetics).