Gels to help nerves re-grow

20 December 2018

Interview with

James Phillips, UCL; Rebecca Shipley, UCL

Our nerves are very resilient. They run along limbs where they bend and stretch with our daily movements and conduct the impulses necessary for sensation and movement. But physical trauma is one case in which nerves sometimes simply cannot take the strain. So what can be done to help when nerves get severed? The gold standard currently is a surgery called an autograft, taking healthy nerves from somewhere else on the body, usually the leg and putting them into the damaged site to hopefully regain function. But this means another surgical procedure with all the associated risks, injuring another part of the body, and of course scarring. Nervous system tissue engineer James Phillips and biomechanical engineer Rebecca Shipley together direct the Center for Nerve Engineering at University College London and they've been working on gels which would be implanted at the injury site, encouraging the severed ends of nerves to regrow. They told Katie Haylor about their work...

James -  We're trying to learn from the nerve graft approach and to try recreate that in the lab effectively by trying to make an artificial nerve tissue that could be used instead of a nerve graft.
So this would have the same support cells and the extracellular matrix that you find in a nerve graft, but it would be made in a lab so you wouldn't need to go and harvest a bit of healthy tissue from somewhere else on your patient.

Katie - What goes into growing a nerve naturally, and therefore what do you need to put into your artificial tissue to encourage nerves to regrow?

James - Peripheral nerves do have the capacity to regenerate after injury but only in the right environment. Now the right environment is actually the inside of a damaged nerve, so the neurons have died away. What you're left with is just the support cells and the extracellular matrix that used to be there. Those support cells are called Schwann cells and they change their behaviour. They now are cells that can encourage regeneration. So effectively what we would need to do is to build an artificial construct which had cells in it that could effectively do the same job as those supportive Schwann cells.

And the really important thing is that whilst neurons can regenerate given the right environment, they do it quite slowly which means you really need to organise the cells and the materials in such a way that it really will guide neurons directly from A to B. Of course the challenge as with all living cell therapy in regenerative medicine is where you actually get those Schwann cells from.

Katie - So where do you get them from?

James - Ideally we would just want some of the patients Schwann cells. The trouble is you can only get one cells from a patient's nerve and that would involve damaging the nerve. So what we've done over the last few years is explored other ways of getting cells that are either like Schwann cells or we can turn into Schwann cells.

So a few things that we've tried have been taking stem cells from different places, for example from fat tissue, bone marrow even from dental pulp within teeth and trying to turn those cells into Schwann cells or Schwann cell like cells and that can work reasonably well. But of course there are limitations with that. If you take a patient's cells maybe from their tissue and expand them in culture that takes a few weeks and you've no idea whether they're going to work properly.

The most promising cells that we've found are the idea of using what we call an allergeniac source of cells. So that means it's a source of cells that's from another patient. Effectively you could have them already prepared, build your constructs out of them. So as soon as the patient comes in they can be used off the shelf and implanted immediately into a patient who needs them.

Katie - What do these gels actually look like? And also I am guessing you need something to hold them together. So what are they bound by? Do they look like jelly?

James - The cellular materials we make are hydrogels, made of collagen and which is exactly what nerves are made of. They do look just like a very small jelly. We take a solution of collagen and we mix it with our cells and we put it into a mould and it sets. And then what happens inside there is that the cells will naturally interact with the collagen extracellular matrix and by controlling the tension that the cells produce we can actually then organise the cells to be nice and aligned in three dimensions. Typically the ones we make in the lab for experimental use are about 15 millimeters long and maybe a millimeter or two in diameter.

Katie - Once this has gone in to a patient or a model organism, would the idea be that the nerves will regrow, reconnect and then what happens to that gel?

James - Our approach tends to be to use a natural protein material. Effectively it integrates and then will become part of the body's protein and will be turned over by the body's cells in a natural way. I should add however that the cellular gel part of this is just like the middle of a nerve which is actually relatively weak. The thing that gives nerves their strength and resilience really is the kind of outer sheath part of it. So those need to be a bit stronger and a bit tougher generally so that they can withstand all the bending and stretching that's required. Now that part we probably wouldn't want that to dissolve or disappear too quickly, we'd want it to stay there. And again to integrate and become like natural nerve tissue.

Katie - Do you have any problems with things like rejection which seems to be a really big issue in regenerative medicine?

James - The response of the body is absolutely critical for this to succeed well when we really need to make sure that the materials themselves we put in will not be targeted and rejected quickly by the host immune system. One of the other important things of course is if you’re putting in dense cellular material, those cells if they don’t get oxygen and nutrients fairly soon then they're going to die. So actually what we need to do is to make sure that blood vessels grow into our artificial tissues as soon as possible, so that the cells we have implanted will survive. This is one of the things where we've teamed up with Becky's group because they're real experts in modelling and understanding what makes blood vessels grow into particular areas and how we can then design our artificial tissues to really exploit that.

Katie - So on that note, how do you actually design these gels?

Becky - So there's a lot of open questions really around how you should best design one of these repair constructs to encourage growth of neurons and growth of blood vessels through the repair sites. And those questions really come down to where you position the cells and where you position the materials to maximize the chance of a good repair. So we use computer based models to explore different kind of designs and try and predict which ones have the best chance. And then we use that to inform the experimental work in James's labs.

It's really quite fundamental components like for a start how many Schwann cells should we put in one of these devices in the first place and then where we should put them. So one of the really important components that we need to consider is this concept of gradients, so variations in different factors in space and neurons are very clever in being able to respond to these kind of spatial variations.

Katie - How far along are you with them?

James - We’re at a really exciting stage at the moment. For years the problem for us has been what's a realistic source of cells? Cell therapy technology has moved so fast in recent years and there's so many things available now. Our lead option is an off the shelf cell type that's already been used in the clinic to treat things like stroke and that gives us a really good starting cell because we know that it's got the right kind of safety profile and has been through some regulatory procedures, they've been in clinic in trials.

So what we've done is we've taken those cells and we've manipulated them a little bit and used them to build our artificial tissue and we've been testing that over the last few years in the lab and it's looking really quite promising. We've actually formed a company to take this forward, so joined up with some clinical partners and and commercial sector partners to really try and move this forward through regulatory approval, get some investment in. We've got to take the manufacturing forward.

Katie - Looking ahead how would you summarize the significance I guess of this artificial tissue in terms of a difference it could make to someone who has had a traumatic nerve injury?

James - Autograft sounds like a straightforward thing, you just find a nerve that's not really used much and chop it out and use that. But actually these you know it's a really major operation to strip out a section of nerve. There's always going to be damage of that donor site, scarring, extra time, extra cost for the operation but actually the big benefit would be the impact on the patient. The surgeon would only be repairing a nerve. They wouldn't also be having to damage what was previously a healthy nerve.

Becky -  People who have peripheral nerve injuries have already got you know a very serious debilitating injury. So if we can find a way to try and repair that without having to cause them any further harm or further surgeries or further scarring that has the potential to make a real difference.

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