Nerve Repair Using Peripheral Nerve-Based Hydrogels—Dr. Young Hye Song—The Schmidt Lab, University of Florida

Richard Jacobs: Hello. This is Richard Jacobs with the future Tech and Future Tech Health podcasts. I have Doctor Dr. Young, Hye Song, a postdoctoral associate, University of Florida biomedical engineering and the Schmidt Lab. So, uh, that’s young. Thanks for coming. How are you doing?

Dr. Young: Hi, how are you?

Richard Jacobs: Yeah, good. Tell me what, what kinds of things happen inside the Schmidt lab, what goes on there?

Dr. Young: So our lab is focused on utilizing naturally dry buy materials to develop in vitro disease models as well as creating scaffolds that can help nerve repair. So natural biomaterials we largely use the hydraulic acid-base, as well as recent focus, has been on using desterilize tissues? That’s what we do.

Richard Jacobs: Okay. I had thought that the nerves don’t really regenerate or repair themselves. Do they? Is it just that they lack a scaffolding or what is the missing components to allow the regeneration in the body.

Dr. Young: So it depends on the destiny for the central nervous system. The nerves don’t regenerate spontaneously and then in case of injury, that’s particularly because of the extracellular matrix proteins that are deposited after the injury specifically inhibit and Gama regeneration therapies that have worked in various literature include enzymes or proteases that particularly the specifically cleaves these inhibitory extracellular matrix proteins so that’s largely for central nervous system or peripheral nervous system up until a certain injury lane the neurons can regenerate by themselves.

Richard Jacobs: Why do you think, um, the central nervous system, what regenerate, why is this extra cellular matrix created? Is that the body’s wages of trying to heal and isolate the damage and, but it doesn’t account for the need for nerve regrowth.

Dr. Young: Yeah! So glial cells such as pasture sites that are present and brain and spinal cord, upon injury, they become reactive and then they deposit glial scar filled with conjointly assault eight proteoglycans, proteoglycans or CSP which are the inhibitory components bottle. So the Myleene teeth and the central nervous system, which is created by oligodendrocytes breakdown and also the breakdown of those Myleene are inhibitory as well. Whereas in the peripheral nervous system the Schwann cells, which also create Myleene teeth these cells produce different types of ECM proteins, and the ECM profuse that are derived by Schwann cells actually promote nerve regeneration. Well, I think it’s a combination of different cellular compositions in central versus peripheral nervous system that’s soliciting different responses.

Richard Jacobs: Yeah! So I guess there’s what cell to cell communication between the existing nerve cells and this newly created matrix and the matrix is telling that don’t grow.

Dr. Young: Yeah! That’s what’s happening in the central nervous system. Like for spinal cord injury, for example.

Richard Jacobs: Okay! So what’s your goal, is to replace or inhibit the current extracellular matrix so that the signaling doesn’t occur or the growth of the Matrix itself?

Dr. Young: So a lot of the initial work on spinal cord injury repair them by the Schmidt labs has focused on delivering, I guess utilizing the biomaterials that chose the hydrogels to drive from the peripheral nerve.

How your doe, because, um, as I said earlier, peripheral nervous system, they can regenerate. The nerves can regenerate because of the differences in components.

So what the Schmidt lab has done is take out the nerves, the peripheral nerve, and then you desterilize them, meaning you simply subject the nerve to have a series of different treatments to remove the cellular components while retaining the extracellular matrix proteins, and then after that you can digest these desterilized nerves to create injectable hydrogels and you can take these three gel formulation and then injected into the spinal cord, um, legion, because what happens, um, after spinal cord injury is that you get this legion cavity that’s basically just the hole in the middle of the spinal cord so you can fill it with these injectable hydrogels created from the decentralize peripheral nervous nerves.

Does that make sense?

Richard Jacobs: Okay. I’m not sure if you can maybe just explain it once more.

Dr. Young: So like earlier I said the peripheral nervous system, the nerves can regenerate spontaneously and that’s because of the different ECM components and the peripheral nervous system versus the spinal central nervous system. So what our lab has recently done is, it’s known for developing a technique to desterilize peripheral nerves, so what the Schmidt lab has done earlier, like over a decade ago, is you take dyadic nerves from a rat and then you treat it with detergent and another buffer to remove the cells while retaining all the extras, there learned nature tricks, proteins, so what we have started doing recently is that you take those decentralized nerves and then you digest it an acid solution containing enzymes or proteases, then you get this then the nerves become like homogeneous solution and the asset and the same cocktail becomes this homogeneous pre-gel solution.

And then this becomes hydrogel elevating the temperature as well as the PH of the presale solutions. Yeah. And this presale solution like before you elevate the temperature, you can so neutralize the PH of the fetal solution to make it ready for chelation. Like basically polymerizing to become this like Jello-like structure like water turning into Jello or something like that but what you can do is you’ll take this water like structure with neutralized PH and then you take it into a syringe and then you inject it into a spinal cord lesion, which is actually a cavity or a hole in the middle of the spinal cord. And since it’s in a body temperature, this predella solution from desterilized peripheral nerve when the temperature of this gets elevated to body temperature it’ll turn into a gel and then it’ll start to fill the spinal cord lesion cavity.

And the goal is that we can use this strategy to entice the severed neuron in the spinal cord to regenerate across the lesion site. But also we can engineer these hydrogels to contain cells or other therapeutic molecules to deliver additional therapeutic benefits.

Richard Jacobs: So you are seeding a man-made ECM with the components necessary for the central nervous system to act like the peripheral nervous system and regrow and innovate a damaged area.

Dr. Young: Yeah, in a way, But we’re not developing the material from scratch ourselves. So we would take the peripheral nerves our work has been done with rats, dyadic nerves.

So we will take nerves from the rat and then we processed that to develop our injectable hydrogel.

Richard Jacobs: Does this migrate very much like when you inject a damage site, you know, what’s the radius in which it has effectiveness? Do you need to inject, you know, dozens or hundreds of times in a small radius for this to work and does it migrate outside of the area? And you know, how well does this work so far?

Dr. Young: Oh No, the Dell doesn’t really migrate outside of the cavity. It fills the cavity and it stays in there. And if anything, it’ll be degraded over time and then for the rat injury, rat spinal cord injury model, which we have tested our hydrogels the only, we only need to inject like six microliters of this predella solution. So it’s a very small volume that we’re dealing with here.

Richard Jacobs: So how would you do this and people, would you have to sacrifice part of a nerve, like one of their peripheral nerves that they didn’t care about and then create these gels and seed them and then, you know, inject the spot of real trouble or how would this happen?

Dr. Young: No, ideally you want to take a donor nerve that way you don’t create like additional donor site morbidity in the patient, earlier I said Dr. Schmidt has developed this on desterilized techniques with peripheral nerves. And her technique was actually licensed by a biotech company called an accident, which is actually based near Gainesville, Florida, so there are other ways to obtain the nerves from oxygen and then work with those nerves to create these hydrogels. So I imagine that’s how it should be done for human patients. I don’t think we’re anywhere near testing this platform in humans yet.

Richard Jacobs: Why wouldn’t there be an expedited path yeah. Through the FTA for people that are paralyzed? Yeah. Because of a spinal cord injury, it seems like what harm would come to them by trying this, you know, even if he did cut it, if you cannibalize, let’s say they had like the one problem and they were, a quadriplegic, what harm would come from trying to harvest something from like there, your toe or their ankle or a nerve there and then try to see the area that damaged to try to restore most of their function?

Dr. Young: That’s a good question. I mean, with the spinal cord, that person suffering from spinal cord injury, their immune response is generally weaker. So I’ve imagined trying to perform additional surgery just to take those nerves out of their body. I think that it would be a pretty challenging taste, and then we also don’t know if they’re like I think we would, we would need to make sure the nerves taken from the spinal cord injury patients retain similar ECM proteins and they can be processed similarly.

Richard Jacobs: In the Rad so far what specific proteins or chemicals are causing the regeneration?

Dr. Young: We haven’t tested those specifically, but generally what the field, I think largely agrees upon is Collagen and Laminin are the main ECM components that promote neural regeneration.

Richard Jacobs: Have they tried to just isolate those two?

Dr. Young: Not specifically from the nerves themselves, but I mean there are ways to easily make column hydrogels that are composed of Collagen and laminate, but I am not aware if people have done that specifically for spinal cord injury with pair.

Richard Jacobs: Yeah! I think that’ll be an easier, a good confirmatory path. You don’t have to harvest. You don’t need to harvest anything. You can just culture yourselves and to produce those two substances.

Dr. Young: Yeah, a lot of people do like culture. Um, so I was like five of us that deposit a lot of ECM to and then harvest those all deposited ECM to make scaffolds so that’s definitely a possibility. So, yeah, but I don’t think people have done that specifically for spinal cord injury. I think people have used it for other tissue regeneration applications.

This whole material, Hydro Gel based approach to repair, injured spinal cord. I think the whole concept is pretty new in itself.

Richard Jacobs: So what happens right now in a central nervous system lesion? Is it just that extra cellular matrix forms but it has no growth factors that have inhibitory factors in it, but there’s still a scaffold there? Or is it random and it’s there no appearance scaffolding there even if they weren’t growth factors?

Dr. Young: Like in regular spinal cord injury cases?

Richard Jacobs: Yeah.

Dr. Young: So over time you get this on legion cavity formed and it’s surrounded by a glial scar which is filled with those inhibitory ECM components and then the legion cavity is filled with fluids and also the Leo Scott Barrier in and of itself inhibits neurons from crossing the cavity could regenerate a call.

So I mean like there may be growth factors, but the presence of the glial scar in and of itself is preventing the neurons from Travers thing across the lesion site.

There was like a close to it a couple of decades ago, there was a breakout paper where a bacterial drive enzyme called conjoint ABC on was shown to specifically cleave this ECS PGS and allowed the neurons to regenerate across the lesion so there’s been a lot of research on using biomaterials better deliver this enzyme to help remove this barrier to break down this area.

Richard Jacobs: Okay, I was just wondering if the nature of the ECM and the spinal cord, when there’s a lesion, is the nature of the ECM itself could it be a scaffolding? Where does it have to be reconfigured in such a way that it would allow it to be? It would become scaffolding. I know it was devoid of growth factors that actually has inhibitory factors in it, but yeah. Is it still considered a scaffolding?

Dr. Young: Okay, I don’t think you would call that scaffolding now. No

Richard Jacobs: I was just wondering if it somehow has that characteristic of scaffolding. I guess not

Dr. Young: No, at my understanding for scaffolding you have to like inject it or implant that somehow, but at least that’s my right. Structurally it would have to change somehow.

Richard Jacobs: I gotcha, Ok! What stage are you at with the rat experiments? I get you at a point where it’s working and you want to move to the next stage or you know, how much has left you to think to make it a viable process, at least in rats.

Dr. Young: Our lab has recently published a couple of papers showing the feasibility of this hydrogel platform. First as a, it’s a hydrogel on its own and second as a delivery carrier for our Schwann cells so we are in our lab is actually now testing a different, a variety of different strategies to utilize this nerve, Dr hydrogels to deliver growth factors or other therapeutic molecules or other cell types and I say those projects that are currently ongoing are pretty, I’m new at this stage.

Richard Jacobs: You guys are pretty new so you’re able to go to the next level?

Dr. Young: Yeah! I think so.

Richard Jacobs: What do you think are some of the remaining challenges that are important?

Dr. Young: Let’s see! I think, so a major issue with biomaterials base approach is that you can entice the neurons too, regenerate into the scaffold, but it’s harder to make the act bonds grow back into the native tissue because they liked the scaffold so much that one of the major issues with biomaterials space approach for spinal cord injury repair. And I think a way to better design the scaffold in a way that the neurons will not only want to start regenerating into the scaffold bottles, extend out back into the native spinal cord tissue to form correct synopses and actually promote or near complete functional recovery.

Richard Jacobs: So it sounds like the scaffolds are important, but also at the edges of the scaffolding you went to the early healthy tissue is super important to have the right transition so that it actually does it.

Dr. Young: Yeah! So I think a lot of the axons that do regenerate into the scaffold tend to just stay in there. So we need to find ways to make them go beyond.

Richard Jacobs: Okay! Yeah. Gotcha. Good. So what’s the best way for people to find out more about you, what’s going on in the Schmidt lab and ask questions and things like that?

Dr. Young: We have a lot of websites, yes Google Schmidt Lab, University of Florida, you’ll find the link. So there’s one way of staying up to date on what’s going on in all that. And also RPI Professor Schmidt also runs a Twitter account for the labs. So that’s another way of finding more information on our lab, current events in our lab.

Richard Jacobs: Okay! Well very good I appreciate it, Thank you.