A new hydrogel can be directly injected into muscle to help it regenerate

Nick Petrić Howe

Welcome back to the Nature Podcast. This time a gel to replace and regenerate muscles...

Shamini Bundell

...and why starfishes have such strange body plans. I'm Shamini Bundell

Nick Petrić Howe

...and I'm Nick Petrić Howe.

Nick Petrić Howe

What if you could replace a damaged muscle with a stand-in that can help you move whilst also helping the tissues repair? Well, that's something that researchers publishing this week in Nature are trying to make a reality. With an injectable hydrogel solution.

Mikyung Shin

We developed a new type of the hydrogen for recovering the muscle and nervous tissues.

Nick Petrić Howe

That's Mikyung Shin, part of the team behind this new paper. We're going to hear more from her in a moment. But first, a little background. Muscles, like any other tissue, can get injured and severe injuries can leave the muscle and you unable to move. And yet muscles which are not used can waste away and that can make healing very challenging. There are a range of options to deal with this, but all have their drawbacks. For example, mechanical exoskeletons can be used to help people move, but they don't actually help the muscle heal. Alternatively, there are a range of devices that electrically stimulate muscles to help them move or even seek to replace damaged tissue. But often these devices are stiff and cannot be applied to small awkward to reach places. Ideally, the solution would be flexible, able to stimulate the muscles to help their recovery and promote tissue repair. And that's where hydrogels come in. These are soft materials that can be theoretically applied directly into the damaged tissue in tight crevices which are tricky for other materials where they can help aid in healing. Heres Mikyung again.

Mikyung Shin

Hydrogels are very similar to our biological tissues. Our tissue have a lot of water in them and hydrogel have also a lot of water in them, so they can mimic our biological tissue environment. And can trigger the cellular behaviour or cellular growth for tissue repair.

Nick Petrić Howe

Effectively Mikyung believes that hydrogels could almost act as a stand-in for muscles and help them repair. They also have the added benefit of being injectable, which means clinicians could avoid surgery which can damage the surrounding tissue. However, hydrogels still have drawbacks of their own. And so Mikyung and her team set about overcoming them. Firstly, hydrogels don't have great conductivity, which makes stimulating them to help muscles move more difficult. Their solution uses some clever chemistry, she was able to link the backbone of the hydrogel to other compounds that hold gold ions.

Mikyung Shin

In that case, the gold ion can generate the gold nanoparticles. That gold nanoparticle can provide the electrical conductivity very stably to our hydrogels.

Nick Petrić Howe

And that allowed the hydrogel she created to be conductive, allowing muscles to be stimulated and thus used which helps promote healing and helps the patient to move. But that wasn't the end of the problems. Next one is strength. Hydrogels tend to be pretty, well, weak, and so don't last well in the body. In fact, in the moving and strained tissue that is muscle, they are at risk of leaking out. This is a particularly sticky problem, as making them too strong would make them inflexible and unable to be injected into the body. Mikyung and the team needed something flexible and strong. So they went back to the chemistry drawing board and look to something called biphenyl bonds.

Mikyung Shin

We hypothesise that the biphenyl bonds can be different from a simple carbon-carbon bonds. So we think the biphenyl rings can be rearranged it during the syringe injections compared to the carbon-carbon bonds.

Nick Petrić Howe

Unlike a standard carbon-carbon bond, which is fixed, Mikyung thought that these biphenyl bonds would be able to break during injection of the hydrogel, but then reform afterwards, making the gel weak enough to be injected, but then strong again once it's in the body, a hypothesis that they demonstrated worked first in simulations, then studies with cells. And finally, in experiments with rats.

Mikyung Shin

We prepare the rat models with a very severe muscle injury and then we fill our hydrogel into that area, the injured area.

Nick Petrić Howe

With the rats, the team wanted to check two things. First, how well the hydrogel would be able to conduct electrical signals to work as a stand-in while their muscles heal. And second, they wanted to see how well it can help the rats muscles actually regenerate. For the stimulation part three days after the hydrogel was injected, they placed the rats on a tiny treadmill where a robot could sense the signals from the rats own bodies as they tried to walk and help stimulate the hydrogel to move their legs.

Mikyung Shin

So finally, the animals can walk well, helped by the robotic arm.

Nick Petrić Howe

So not long after the injury, the rats were up and walking, albeit not quite as good as new, though certainly much better than those without the hydrogel. But then the hydrogel also helped the rats' recovery it was made from hyaluronic acid, a substance which naturally occurs in the body and is known to aid tissue recovery. And after four weeks, the muscle had regenerated.

Milica Radisic

The fact that there was regeneration was important.

Nick Petrić Howe

This is Milica Radisic, a biomedical engineer who's written an expert analysis of the new paper in Nature.

Milica Radisic

And the fact that the gel could propagate electrical impulses to help the animal move the leg only three days after injury was really important, because it shows that this approach, the hydrogel, together with electrical stimulation restores the function and for injured humans that's the most important thing, restoring the function: ability to walk, ability to use the limbs after injury, shortly after injury is tremendously important. And the sooner they can regain this walking function improves the quality of life. But also perhaps, it minimises detrimental effects of the injury because it breaks that cycle of use it or lose it, if they don't use their muscles, they will lose the ability to use them in the future.

Nick Petrić Howe

Milica though did point out that there's still quite a bit of work to be done before we see this in humans.

Milica Radisic

Can this be used in humans? I would say not right now. I would think that large animal studies would be needed to prove that in larger defects, this same approach works, right? One of the key differences between rats and humans is that rats are much smaller than humans. And something that's a very large defect in an injured leg of a rat is not that large for human muscle. So we will have to show that this same approach works over large injuries. So there will be additional both safety and efficacy studies that are needed before this approach could be used in humans, but it really opens the door to such approach being implemented in the future.

Nick Petrić Howe

Another aspect that may prove tricky is getting approval for this to be tested in humans, as the hydrogel is quite complicated with many different components. Mikyung does also think that approval will be a challenge but is optimistic that the team will get it because the material is very well accepted by the body. It's very biocompatible.

Mikyung Shin

We already demonstrate biocompatibility of our materials in the cellular study and the animal study. So it can be much… hopefully much easier to have the approval to be implemented into the human body.

Nick Petrić Howe

For now, though, Mikyung and the team are focusing on trying to make their system a bit more simple with fewer cables and leads, so they'll hopefully be better placed to help humans in the near future.

Mikyung Shin

We have a very complex system combined with a robot and some electrical wire. But if we can stimulate our materials, without any lead, that can be much easier to stimulate tissues. And that can cause much better recovery of the patient and their damaged tissue.

Nick Petrić Howe

That was Mikyung Shin from Sungkyunkwan University in South Korea. You also heard from Milica Radisic from the University of Toronto in Canada. For more on this story, check out the show notes for some links.

Shamini Bundell

Coming up, searching for symmetry in a five armed starfish. Right now though, it's time for the Research Highlights with Dan Fox.

Dan Fox

Researchers think they may have resolved the missing link between the first Homo sapiens in Europe, and later arrivals. Homo sapiens first reached Europe 45,000 years ago. But studies have so far suggested that this first arrival may have been a false start. These early pioneers seem to have vanished without a genetic trace. Now though, ancient human genomes from the Crimean Peninsula could resolve this mystery. Researchers studied two skull fragments unearthed from a rock shelter in the Crimean Peninsula. They found that the fragments came from separate male individuals who lived 36 to 37,000 years ago. Both individuals genomes are most similar to those of hunter gatherers who lived in southwest Europe some 7000 years later, but both individuals also carried DNA sequences linking them to Europe's earliest Homo sapiens, hinting that the first arrivals did in fact, leave a genetic legacy by interbreeding with some of the people who followed them. You won't have to wait 45,000 years to find a link to that research, it's in Nature Ecology and Evolution.

Dan Fox

Insect slaying proteins found in some ferns, could provide a tool for engineering new pest resistant crops. Around the world, farmers have planted more than one billion hectares of transgenic Bt crops genetically modified to produce insecticidal proteins that are normally found in the bacterium Bacillus thuringiensis. But insects are increasingly becoming resistant to these proteins. Searching for alternatives, researchers observed the extracts from some ferns, stunted insect growth. They found that the ferns produced a family of proteins similar to those made by Bacillus thuringiensis. Maize and soybeans bioengineered to produce these fern proteins were damaged less by insects than their unaltered counterparts. And these proteins remained effective, even when fed to pests normally resistant to the bacterial produced proteins. Don't resist this story, you can find that paper in full in Proceedings of the National Academy of Sciences of the United States of America.

Shamini Bundell

Finally on the show, it's time for the Briefing Chat where we discuss a couple of articles that have been featured in the Nature Briefing. So Nick, what have you got for us this time?

Nick Petrić Howe

Well, this week, I've been reading a story in Nature all about a way to sort of get rid of Dengue by releasing Wolbachia-infused mosquitoes.

Shamini Bundell

Right, these are all a lot of very familiar terms. Wolbachia and Dengue, can you explain the sort of basic biology of of this disease for us?

Nick Petrić Howe

So Dengue fever is kind of a really nasty disease, you want to avoid getting it if you possibly can, and it's spread by Aedes aegypti mosquito. So these are mosquitoes that also spread things like Zika, and other diseases as well. And so where the Wolbachia comes in is Wolbachia is a bacteria. And what researchers have found is that if mosquitoes have this Wolbachia bacteria in them, it sort of competes with the viruses in the mosquito, and stops them be able to spread the diseases. So it stops things like Dengue and Zika spreading.

Shamini Bundell

So a mosquito that's been infected with the Wolbachia bacteria, is then much less likely to pass on the Dengue virus to a human and thus infect the human.

Nick Petrić Howe

Exactly. So there's been a few different trials of doing this in practice in the real world. So on the Briefing Chat previously, we talked about a trial in Indonesia, where mosquitoes were infected with Wolbachia, and that massively reduced the spread of Dengue. So this is a new experiment that's been done in Colombia by the World Mosquito Programme. And in three of the most populous cities in Colombia, they basically released a lot of mosquitoes that were infected with Wolbachia. And they found that basically, when the Wolbachia infected mosquitoes are well established — so, more than 60% of the mosquitoes have Wolbachia — the Dengue instant dropped by 94 to 97%.

Shamini Bundell

Oh that's huge. This is also one of those really counterintuitive ones where the scientists like just releasing mosquitoes into the wild, but then they hopefully, their mosquitoes outcompete the local ones.

Nick Petrić Howe

Yeah, I mean, the idea here is that they release just so many mosquitoes it kind of like overwhelms the other mosquitoes and they'll interbreed and stuff and when that into breeding, they'll pass on the Wolbachia. And so over time, most of the mosquitoes will have the Wolbachia. So the one caveat I do have for this, though, is that the incidence of Dengue does vary over time. So whilst the evidence from this does look good, there will have to be more studies that, you know, really show that this is the case. But you know, I mentioned that there was that study in Indonesia, as well, there's been other studies other pilot studies around the world to try and establish how well this works. And it looks pretty promising as a way to sort of fight Dengue.

Shamini Bundell

And does this Wolbachia only prevent Dengue virus being passed on? Or does it apply to some of the other diseases that you mentioned at the start as well?

Nick Petrić Howe

Yeah, so this bacteria just competes with other viruses the mosquitoes may carry. So the other example is Zika. So this could help with Zika, and other viruses that mosquitoes may carry. So the idea now is that this technology is going to be scaled up. So this World Mosquito Programme have announced, sorry I laugh because it just sounds sort of funny. But they have announced plans to build a factory to produce mosquitoes—

Shamini Bundell

—oh god—

Nick Petrić Howe

—in Brazil, and they want to release many more over the urban areas of Brazil in the next 10 years. But the next challenge will be how to sort of get this to the most difficult to reach communities because they need sort of community buy-in and that sort of thing to really get those mosquitoes out there.

Shamini Bundell

Yeah, I must say I might be a little sceptical having been bitten by plenty of mosquitoes in my time, about anyone who wants to come and release more of them into my local area. But obviously a really important goal there and some really promising results. So yeah, thanks, Nick. I've got another sort of animal related story for you, going down into the deep sea and also back into the evolutionary past — one of my favourite topics. And this is a Nature paper, about starfishes, which I've also made a film about that you Nick Petric Howe have been helping me with so you actually have a sneak preview of what this story is. But I shall explain for everyone.

Nick Petrić Howe

Yes, indeed. I actually know this paper quite well. So this is about starfish and their body plans. So starfish have five arms, you know, they look like a star—

Shamini Bundell

—So-called arms, yeah. It's not necessarily the equivalent of our arms. But yeah—

Nick Petrić Howe

—yeah, they have their sort of five arms. So they're not really symmetrical, which is quite unlike a lot of other species, such as ourselves.

Shamini Bundell

Yeah. And I give a load of examples, which was quite fun in the film of all the sort of symmetrical species, if you think about all the animals that you could sort of take a straight line down kind of where the spine is and sort of cut them in half. And they're the same on either side. So this is a standard body plan that we're familiar with, because vertebrates have this is called bilateral symmetry. And there's this whole big group of creatures of animals called bilaterians. So yeah, vertebrates, like us, all the sort of mammals, fish, reptiles, all of those. But then also mollusks, so like thinking about slugs and snails, arthropods, so all insects, crabs, as well as some more sort of obscure creatures, including this little group, which starfish are a part of, they're called echinoderms. Sorry, there's loads of there's loads of terminology here. But the echinoderms they're bilaterian, starfish are echinoderms. Everything's symmetrical in this group, almost everything, except echinoderms and echinoderms are kind of a bit of a weird outlier. So why? What's going on there was the question?

Nick Petrić Howe

Yeah, and another weird part of this is that in part of their lifecycle, the larval stage, they are actually symmetrical. So these researchers were trying to figure out what sort of goes on and how they end up with this, you know, star shaped body plan.

Shamini Bundell

And it's all about genetics, basically. And the questions are, you know, it's not why would it evolve this shape, but it's how, evolutionarily, with the genes that you've got to work with, do you kind of turn something that yeah, starts off with this head tail, two symmetrical sides plan into what sort of starfishes and their relatives look like? And the way they did that was to sort of analyse the the genes or more specifically the gene expression, so where different genes are expressed in the body of starfish. And then you can compare because, broadly, the same kind of genes are conserved, like it's the same ones across all these different creatures. So you can kind of compare, okay, if this kind of group of genes is found in the head of all the rest of the bilaterians, where is it found in the starfish? And they were able to do this in sort of a detail that people hadn't really been able to do before.

Nick Petrić Howe

And when they looked at these genes, they found that essentially, the starfish was mostly just head.

Shamini Bundell

Yes. If you think about sort of head to tail in a line, like think about that axis, there are these different genes that are expressed in different places. So the simplified version is let's say you've got a chunk of genes in the sort of top part of your brain, the forebrain, then you've got a different chunk of genes in the midbrain, just behind that. And then behind that, you've got the sort of spine representing the rest of the body. And you've got a third different set of genes. That's the simple version. And yet that third set, the trunk, the body was absent in the starfish, which was not that, you know, they had all these theories before they started and different people have put forward different theories over the decades of how this could work. But none of them theorised that the body would be just entirely missing. And so yeah, they've sort of come up with this pattern, where they've got the forebrain genes in the middle of the starfish in this sort of starfish shaped sort of reaching out into each of the five legs. And then around that they've got this little section of the midbrain genes that are equivalent to ours. And then yeah, just no body, but just this thin layer of, there are certain genes that are usually expressed at that head body boundary. So they found this sort of like thin layer there, and, and nothing else. So as you said, a starfish is kind of all head. That's sort of what it is from a genetic expression point of view. And that's pretty sort of unique and unusual in bilateria.

Nick Petrić Howe

And you know, when we were making this video, like putting various starfish genes on top of starfish and things like that — listeners go check it out its worth a watch I swear — like, the thing that was quite interesting to me was that this was kind of just a curiosity really like trying to just figure this out for the sake of figuring it out.

Shamini Bundell

It's definitely like one of those puzzles that yeah, developmental biologists are like 'but I need to, I need to understand what is going on here'. And it's been this puzzle for a whole while and now they finally fixed it. But it's also relevant to the sort of broader understanding of this whole group, which includes us as well. And when you're sort of considering how this group evolved, when you're considering how body plans evolved, I think the echinoderms, so starfishes, sea urchins, sea cucumbers, weird, weird sea creatures, they've always been considered this sort of weird derived, like, sort of side group, which isn't super relevant. So being able to bring them in and figure out exactly how they are relevant and are still part of this whole bigger group can be quite important. And also talking about sort of palaeontology kind of going back and looking at fossils of echinoderms, the sort of strange shapes you get in the fossil record, understanding how genetically how they evolved, maybe could help palaeontologists figure out kind of what they're looking at with all these starfish fossils.

Nick Petrić Howe

Well, speaking of looking at listeners, go look out for the video. We'll put a link to that in the show notes. But I think that's all we've got time for this week on the Briefing Chat. For more on those stories and for where you can sign up to the Nature Briefing to get more like them direct to your inbox. Look out for the links in the show notes.

Shamini Bundell

So that's it for us for this episode. But as always, you can keep up with us on X. We're @naturepodcast, or why not send us an email we're podcast@nature.com. I'm Shamini Bundell.

Nick Petrić Howe

And I'm Nick Petrić Howe. See you next time.