There’s currently no way to repair an injured spinal cord. The best we can do is manage the after-effects and prevent further damage: surgery to relieve pressure on the spinal cord, medication to reduce pain and inflammation, rehabilitation strategies.
But getting the injured tissue to regenerate? For a long time, it was considered impossible. Spinal cord injury destroys cells and nerve fibres involved in transmitting information to the brain – and brings on secondary damage, like scars forming at the injury site, that can prevent the tissue from healing. To get the tissue to repair itself, you need to figure out how to stimulate growth within that complex biological environment.
Researchers are investigating how biomaterials could be used to help here. Not only are these materials biocompatible, but they can be engineered to provide cues that could promote repair. Plus, their properties can be tailored depending on how the material is to be used – for instance, if it needs to be injected via a syringe – or what it needs to facilitate, such as passing electric signals across injured tissue to stimulate regrowth of nerve fibres (axons).
“What we’re trying to do is focus on how we can make the body regenerate itself,” says Aleksandra Serafin, postdoctoral fellow at the University of Limerick, who worked on developing a new biomaterial for spinal cord repair for her PhD research. “Can we promote axons to keep on regrowing, to have these connections established again? And getting around the glial scar and all the inflammation. It’s actually incredibly difficult.”
Yet labs around the world are rising to the challenge. “There are so many materials that are being tried and tested,” Serafin says. “The field right now is booming.”
Conductive scaffolds
One approach is using electroconductive scaffolds to induce repair. The spinal cord is naturally conductive and passes on messages – i.e. electrical signals, between the body and the brain. If the tissue is injured, this ability is impaired or completely blocked.
Here, scaffolds can be thought of as a kind of bridge: they’re materials that provide a framework for tissue growth. In this case, they facilitate transmission of signals over the ‘gap’ created by the injury, to help re-establish those damaged pathways. It’s a strategy that shows promise.
Electroconductive hydrogel scaffolds have been found to promote regeneration of axons both in the lab and animal models, for instance. In 2021 research published in the journal Neural Regeneration Research, describe how their scaffold fabricated with graphene oxide and chitosan, a sugar found naturally in the outer skeleton of shellfish, promoted growth of nerve cells, the formation of new blood vessels, neuron migration and neural tissue regeneration in rats.
To increase the conductivity of their biomaterials, people often add components like carbon nanofibres or conductive polymers, Serafin explains. But during her PhD research, she found that a lot of these commonly used polymers didn’t degrade well within the body – which could potentially bring on toxicity. “Sometimes the carbon nanofibres can end up in the liver or kidneys, because the body doesn’t really know how to get rid of them,” she says.
The researchers then set out to create a new biomaterial that retained its conductive properties while being biodegradable. They started with the PEDOT:PSS, a commercially available polymer that’s used in tissue engineering. The PSS component is what makes the polymer soluble, but it also shows poor biocompatibility once implanted – meaning it could potentially bring on a toxic response in alreadydamaged tissue.
Via a miniemulsion technique using a surfactant, the team was able to create novel PEDOT nanoparticles without the PSS component. These nanoparticles were then incorporated with gelatin and hyaluronic acid to create a scaffold.
So far, the material has been tested in stem cells and rats that had undergone a complete spinal cord injury at the T3 level. Due to time constraints, the rats could only be observed for a month – but the researchers did see some progress.
“Can we promote axons to keep on regrowing, to have these connections established again?”
Aleksandra Serafi n, University of Limerick
The protein GFAP is used as a biomarker for the severity and extent of recovery following spinal cord injury. In rats treated with the material, there was diminished GFAP activity and less scarring present, Serafin shares. “The second thing we’ve seen is that we had more axons growing into the lesion site in our group rather than the control group… and the third thing was that there were less inflammatory responses happening in the scaffold group.”
These results demonstrate early signs of regeneration, but we don’t yet know the extent to which the material could reverse an injury nor whether any motor function would be restored. The same might be said about the approach more broadly – some studies on electroconductive scaffolds have shown signs of tissue repair, but we can’t yet say what outcomes those effects could lead to. “All of it is quite in its infancy,” says Serafin. “There’s still a lot of unknowns in the field at the moment.”
Repair cues
Biomaterials can also be used to provide cues or information that would prompt cells to engage in repair activities. That’s what the lab of Tim O’Shea, assistant professor of biomedical engineering at Boston University, is currently investigating.
“We’re really interested in astrocytes,” he explains. “For us, the astrocyte is the main cell that’s enabling the repair process to take place.” Astrocytes are the predominant type of glial cell – cells that maintain the viability of connections between neurons – in the central nervous system (CNS) and that will mount a wound response when there’s an injury.
When we’re very young, our astrocytes have a natural ability to bring on repair after CNS injury, O’Shea explains. However, this capability drops off as we get older: in adults, they instead form a protective border around the lesion. “Our goal is: how can we mobilise astrocytes to engage in these wound repair responses more broadly, and for longer periods of time, to kind of mimic what happens in these more immature systems?”
His lab’s answer is to engineer materials that provide astrocytes with different types of information: the right kind of growth cues that encourage mounting of the wound response, the metabolic fuel they need to carry out these activities, and information that gives them an idea of where to position themselves within the lesion environment – for instance, by sensing the concentration of molecules around them. These materials can be injected right into the injury site, O’Shea adds.
Research is at preclinical stage and so far, the team have investigated the effects of their materials in mouse studies. “We’ve seen some interesting biological effects in terms of wound repair outcomes by augmenting the astrocyte response,” O’Shea shares. “We’re now at the present stage of seeing how those interventions confer functional outcomes.”
This means that, as it stands, we can say that this strategy has the potential to bring on wound repair – but we don’t yet know what degree of tissue regeneration it could lead to, and to what extent it could restore functionality.
O’Shea’s approach aims to incite the wound response from inside the body, by modulating cell populations around the lesion. However, scaffolds can also incorporate growth-promoting molecules in order to encourage regeneration: here, the cells are transplanted onto the injury site.
Some materials also have innate properties that can support repair by preventing further damage. For instance, chitosan can inhibit the secretion of chemical messengers that bring on inflammation while PEG may help suppress production of free radicals, unstable atoms that can damage cells.
A long road ahead
These advances are certainly exciting – but it’s still very early days. There’s a long way to go before we’ll see regenerative treatments in human trials, let alone in clinics. It’s a journey that Serafin thinks will consist of many little steps over a number of years, until researchers eventually reach their ‘aha’ moment.
At present, the main form of therapy being investigated in clinical trials is rehabilitation strategies, says O’Shea. And in that space, our most advanced option is electrical stimulation – such as peripheral nerve, epidural and deep brain stimulation – to restore locomotor functions, like walking. It aims to recover, or rewire, damaged circuits rather than regenerate injured tissue.
Some electrical stimulation treatments are available in clinics that may restore muscle strength and help with some movements, like a hand-gripping motion. Yet because this requires some viable nerve fibres to work with, it won’t be of much help to people with complete injuries where there are none to stimulate, O’Shea adds. “There is definitely going to be a need to continue to work on these regenerative type strategies, where we’re focused on actually dealing with repairing and regenerating tissue, to be able to augment outcomes in people that have really severe injuries.”
But whatever the approach, materials are set to play a key role. For instance, we could develop scaffolds that have the optimal amount of conductivity for promoting repair – something that Serafin says is currently being looked into. Or design those that interface better with neural tissue so they can stay implanted safely for a long time, adds O’Shea.
Over the next few decades, we’ll hopefully see strategies for spinal cord repair develop and mature. Though in the meantime, there’s plenty for us to still discover about the injury itself. “I think we understand a lot, but we don’t understand everything,” says Serafin. “It’s such a complex tissue… your spinal cord is basically the width of your pinky finger. It’s [amazing to] think that something like that has so much power.”
