The Template for Transplantation

I’ll start with a horrific statistic: one in 70 patients globally who would benefit from a corneal transplant will actually receive one – and the lack of available tissue is a major reason why. Even in locations around the world that have good eye bank management, the supply is only just keeping up with demand. Trying to solve this significant problem and unmet need has been a major driving force and inspiration for me and my colleagues in our work on tissue engineering. 

To make progress, we’ve had to really understand the cornea to its core – how does it actually work? And that’s meant increasing our fundamental understanding of corneal biology. For example, uncovering how cells interact with their surrounding resident extracellular matrix (ECM) to inform our tissue engineering approaches. We’ve also needed to consider the tissue as a whole – what is the spatial orientation of cells, what is their specific phenotype?

Bioinspiration not perspiration

What we now work on is a bioinspired approach to growing cornea, using the concept of tissue templating. Although bioinspired is a fashionable word, it basically means that you’re taking the tissue and building from the bottom up. As opposed to the more conventional approach, where you generate a scaffold, often a biopolymer or synthetic polymer, with specific stiffness and porosity, and then add the cells to it. The common flaw in this latter approach is that you’ve already decided on the properties of the scaffold. But we don’t know how to make the scaffold as well as the cells do and, right now, we definitely can’t make it with all the same attributes – it’s extremely complex with different growth factors, it responds physically to different tensile loads, and so on. This should come as no surprise, as the cornea has developed over many millennia. 

The importance of the scaffold in which transplanted cells are being introduced to humans is something that can be underestimated to drastic effects – you only have to look at the tracheal implants’ disaster, where patient stem cells were seeded to plastic trachea…

Inside the body, cells know what to do, they’re given instructions, and they can create a cornea during development. And the corneal tissue that the cells are able to generate has all the different features that it requires – from types of ECM to the specific arrangement within the ECM and the cells that reside there.

In tissue templating, we need to identify the right instructions – the specific biochemical and biomechanical signals that direct cells to grow and produce ECM with the correct alignment, the correct structure and the correct composition. If we get it right, we can ultimately create the tissue outside the body. Using tissue templating, we can grow cornea, skin, and even muscle into hierarchical structures – something that is beyond the traditional engineering capabilities that exist today. Creating a cornea with collagen fibers of a certain diameter, density, alignment that form collagen bundles that stack in the appropriate manner (an extremely important property of functioning cornea) is beyond the limitations of a top-down approach with scaffolds. 

Put even more simply, you can imagine the cells acting like mini 3D bioprinters, producing the tissue and extruding the scaffold themselves. We basically say to the cells, “You know what you’re doing, so we’re just going to let you get on with it – with some guidance.”

Speaking of 3D bioprinting… 

Initially, we did look at 3D bioprinting to create the necessary spatial deposition of cells for the growth of a cornea. We were one of the early adopters of this technology in the UK back in 2018, and purchased a CellInk 3D bioprinter. After getting the bioink right – my major focus – we managed to print the corneal tissue with corneal stroma cells (see Figure 1).

We had the aforementioned advantages of knowing how to handle corneal cells and extensive knowledge of the ECM, which allowed us to publish a nice paper detailing 3D bioprinted corneal tissue – a good first step in our journey.

On paper at least, 3D bioprinting seems like the ideal solution to corneal tissue generation – with precise deposition of cells in the correct surrounding ECM (a bioink) you could form a fully functional tissue. However, a major issue is the resolution of the structures being printed whilst maintaining cell viability and avoiding viscosity issues. Today’s printers can hit a resolution of maybe 20–50 µm – but that’s a long way off the intricacy of real corneal tissue. And that’s why it’s not a big part of our plans moving forward. Presumably, the technology will one day reach a point where it can be used for this purpose, and it will no doubt continue to develop as a useful tool for cell-free devices like contact lenses…

Running a lab – and a company

Serendipitously, the publicity gained from our 3D bioprinting paper generated international interest in our lab and the work that we do. It also waved a flag at investors, who wanted to know how real it is and what we can actually do with it – ultimately, this helped me and co-founder Ricardo Gouveia acquire the initial investment for 3D Bio-Tissues – a spinout from Newcastle University, UK.

The corneal tissue engineering lab is still running at the university, with PhD students exploring different aspects – some are even sponsored by 3D Bio-Tissues Ltd. 

One of the major differences going from academia into the industrial space is the need to scale up – if we truly want to meet our goal of addressing corneal tissue availability, we’ll need to create high numbers of corneas in the same predictable fashion with all the same attributes.

I’ve had to separate my University and commercial work, partly for intellectual property (IP) reasons and partly to avoid any blurred lines between ownership and my role at the University. This separation is more challenging than you might expect – you have to be regimented, strict, and fair with IP (what is created in service of the University is the University’s IP, and vice versa). Thankfully, I find the interplay and movement between academia and industry to be both rewarding and exciting. After all, getting technology and discoveries out into the real world is why I started doing research in the first place.

Given my industry experience – I lived through the process, the pitfalls, the opportunities, the good and the bad – I’ve been able to take on the role of director of business development for the faculty of Medical Sciences at Newcastle University. I get to oversee the IP opportunity committee and deal with spin outs, but I’m also there to encourage academics (young and old – whatever their career stage) to think about opportunities to commercialize their work – offering my oversight whilst they work with companies or deal with IP.

The cornea transplant of tomorrow

Looking further ahead, a professor of microelectronics and I also share a PhD student who is developing a bionic cornea. Put simply, we want to embed a microchip within the tissue. First, we have to determine how to power the microchip and how to send and receive signals. Typically, a major problem when integrating microchips into tissue is rejection or integration,  but as the cornea is an immune privileged site, partly due to the absence of blood vessels – pre-implantation of an electronic device into a tissue that will be immune-tolerated, side steps current issues with bio-electronic integration. Once our lab-grown cornea is indiscernible from the real thing – and we are 90 percent there – then including other structures - like a microchip – doesn’t seem so much like science fiction. 

If we can reach our goal, the big question becomes: What do we want the electronics to do? For example, it would be relatively easy to monitor intraocular pressure (IOP). But what about including an internally facing camera to measure blood flow – or an external camera enables vision on different wavelengths… Now we are back in the realm of science fiction, but the technology is almost within grasp. 

But before we start enhancing vision, we need to save it. We are focused on replacing human corneal donor tissue with our approach – and we are getting much closer to that bold goal.