Jeffrey Hartgerink, Professor of Chemistry and Bioengineering at Rice University and Darren Woodside, PhD, Vice President for Research at the Texas Heart Institute, talk about how hydrogel can help with cardiac, cancer and nerve regeneration treatments.
Can you give a very basic explanation of a hydrogel?
Professor Hartgerink: The simplest definition of a hydrogel is a material that can trap a large amount of water and keep it in a fixed place. The example that everybody knows is Jello brand gelatin, right? So that is a hydrogel. And effectively what we do is we make fancy and expensive versions of Jello. And Jello, like most gels have a very small amount of non-water. In our case it’s only 1 percent of peptide and it’s ninety 99 percent water and yet it doesn’t flow. It stays in a fixed place and so it’s kind of in a nutshell what a hydrogel is.
So, it holds it long enough to get the liquid into the body?
Professor Hartgerink: In our case our hydrogel is made from a nanofibrous material. And those nanofibers make a network that might look like a spider web or effectively hold the water in place. So not only do they hold the water in place but anything that happens to be in the water is held in place also. For example if we wanted to deliver cells or proteins or drugs you put them in the water and you mix it with our nanofiber-forming peptide, it collectively makes a hydrogel and all that’s held in place so that the water is held in place. The peptides make this nanofiber and your cells, drugs or proteins are all kind of held in one spot and then are slowly delivered into whatever location you might be interested in.
We talked about cardiac but also cancer and you said nerve regeneration?
Professor Hartgerink: So, we have two other projects that utilize the same kind of fundamental ideas of controlled delivery in a hydrogel. One of them is cancer. And so right now we’re very interested in an immunotherapy project. If you think about cancer and ways that you might treat cancer, chemotherapy is kind of the older more traditional way to treat cancer. Basically, you take something super toxic and it just kills cancer cells. The problem of course are side effects. The flip side of that is immunotherapy which is a pretty new idea. It just recently won a Nobel Prize. And the idea behind immunotherapy is that instead of delivering a toxic drug to the body, you manipulate the body’s own immune system and make it more effective at fighting cancer cells. So, if you can change the way your immune system recognizes cancer cells you can just kill off the cancer without having to deliver toxic drugs. In fact, everybody who doesn’t have cancer right now doesn’t have cancer because your immune system is successfully fighting off cancer and because people get cancer all the time and your immune system kills it. So, the difference is if you have cancer, somehow or another that cancer got the upper hand on your immune system. In fact, cancer is ingenious and kind of scary. It basically puts your immune system to sleep. So, the immune cells come up to the cancer and they’re going to destroy it. The cancer says nope you’re going to bed, so your immune system goes to sleep. If you look at a tumor frequently there’ll be just a mix of cancer cells and immune cells all mixed through there. The immune cells are all just sleeping. If you can go into the cancer and wake up the immune cells, they immediately kill off that cancer. So that sounds fantastic and science fiction like, and it is kind of but there’s an even better benefit. If you have chemotherapy, the biggest problem even if you have a successful treatment is that you have recurrence. In immunotherapy if you successfully treat a cancer, your body now knows how to fight that cancer and you’re immune to that cancer. And there’s not reoccurrence. This sounds magical and it sounds like cancer should be cured now. The difficulty is that of all the cancers maybe at best 20 percent of cancers will be successfully treated by immunotherapy. So, then there’s the other 80 percent where immunotherapy just doesn’t have any effect. So, where do we come in? We didn’t do any of that. What we’re interested in doing is now taking these same hydrogels, loading them up with materials that are going to activate or manipulate the immune system so that we put a hydrogel say around a tumor and the hydrogel is containing these different types of drugs and biologics that can modify the cellular behavior of the immune system and turns the immune system back on. It wakes up and the cancer is killed off that way.
Let’s just say you have a syringe that’s got the hydrogel in it. And it goes into the body and this time it’s going to nerve regeneration. Take us through that whole process.
Professor Hartgerink: Right now what we’re going after is peripheral nerve regeneration. If you want to kind of divide up all the nerves into two categories you have the ones associated with the brain, the central nervous system. That’s not what we’re talking about. We’re talking about peripheral nerves, nerves that feed your legs and arms and stuff like that. These kinds of nerves are injured in many different ways. It could be from – a soldier has a battle injury or many things that can result in peripheral nerve damage – diabetes patients frequently have peripheral nerve damage. So those are the nerves that we’re going after. And the idea here is that when a nerve is damaged and dies, you have a disconnect between the source of the nerve and whatever its target is – whether that’s a muscle or what not. So, we make conduits that connect from the source of the nerve to wherever the target is and that conduit basically looks like a flexible straw. And it’s loaded with our hydrogel. That hydrogel provides a route or a pathway for the nerves to regrow in a directed fashion towards wherever their target is.
In terms of the placeholder aspect of it, will you walk us through that part of it?
Professor Hartgerink: Let’s talk a little bit about the hydrogel and why it works the way it does. If you back up, you know how we make that in a laboratory like this? The beginning steps of it are chemistry. We make very small molecules, but we design them in a very specific way. A molecule you know is so small you can’t see it. And it can’t really affect anything by itself very easily. But the ones that we make like to get together with their friends in a process called self-assembly. So one of these peptides will find another one which will find another one and they stack on top of one another assembling into thousands and thousands of units that instead of now being on the size of molecules start being something that has a macroscopic size. You make these tiny little threads that grow and grow. And it’s a little bit like cooked spaghetti. Like all these different fibers entangling with one another and that fibrous entanglement then is what traps the water or these proteins and drugs into this hydrogel. You start with a molecule and they expand into nanofibers. They create a material – the hydrogel that can control delivery properties of drugs and proteins and stuff like that. This lab is where we make those small molecules and where we find out how to kind of convince them that assembling into these fibers is the right thing to do. And we test their early properties of what kind of a hydrogel do they make. You can imagine Jello brand gelatin you might eat but maybe you grew up with wigglers which are Jello with more of the Jello in it. You can pick them up and eat them that way. So hydrogels are the same way. Some of them are mushy and soft. Some of them are stiffer and harder. And depending on the biological application we can change that. And whether they’re stiff or soft can impact their overall biomedical properties.
How do you make the molecules here in the lab?
Professor Hartgerink: All the students in my laboratory first have to learn that language. And learning the language of chemistry is not any different than learning French or Italian or Japanese or whatever. It’s difficult and takes a lot of time. But once you can speak the language of chemistry then you can talk to the molecules through chemistry and make them behave in a certain way. You might do that by adjusting P.H. or the acidity of the solution or by changing the amount of salt in solution. So the molecules that we make what kind of the things that they like and what they don’t like. So, if you give them just the right kind of like incentives and disincentives then they’ll do what you want – which in our case is make nanofibers that make hydrogels. But the synthesis starts here. We must purify them and make sure that we’ve made the right thing and do lots of different analytical characterizations of them. Later on after we know that we’ve made the right thing and the material properties are just right, then we would go across the street and talk to Daryn over in Texas Heart Institute and he can look at it and know how the materials that we’ve made really impact a biological system.
Darren Woodside, PhD, Vice President for Research at the Texas Heart Institute.
Can you give us an overall summation of Hydrogels?
Woodside: Well, the technology that the lab has created here at Rice University is an intriguing approach to address a wide variety of different disease indications. The interesting aspect of the work that they’ve been doing here is that you can take these hydrogels and put them into a syringe, for instance, and as it is pushed through the needle (and there’s a shear stress on the hydrogel), it behave like a liquid, so it flows like water. But when it leaves the syringe, it will actually polymerize into a more of a solid. In this sense, you can directly inject things with a variety of different techniques that we have now (like catheters) and have these gels stay in the body for a more extended period of time. So, our part of the collaboration involved testing the hydrogels to see what type of cells in your body react to them. It is still very early in the research and we want to know if the hydrogels are safe and also gain a better understanding about the diseases that might be targets for future applications. So, what our collaborative work did was identify different types of immune responses to different varieties of the hydrogels once they were put into animals. Basically, what we found is if you play around with some of the different charges on these hydrogels, you can recruit different types of cells from the body into them. Some of them can cause a robust inflammatory response like what you would see, for instance, on your skin if you have a blemish or something, you see prominent redness with a recruitment of cells. That kind of occurs in some of these hydrogels. That’s an inflammatory response that brings in cells from the body into the hydrogel itself. What we’ve seen is that the whole process can lead to a complete remodeling of the hydrogel so that it turns it into something completely different and starts to form what’s called a granulation tissue. The result is basically just an accumulation of all these inflammatory cells into one main focal area. You can imagine that if you’re trying to treat cancer, you might want to cause a massive inflammatory response in a specific spot in your body. If you had melanoma, you could potentially inject one of these hydrogels— that maybe even had some other types of drugs that could help kill the cancer cells— and you could cause an inflammation in that tumor to allow your body to better react to that tumor and not only decrease that specific tumor but help your immune system affect tumors in different parts of the body. It’s not that different in concept to what Jim Allison recently won the Nobel Prize in Medicine for with Checkpoint Blockade, where you can turn off the negative breaks in the immune system and cause immune cell activation to fight your tumors. So, in essence, you could think of injecting these hydrogels within the tumor, causing inflammation in the local tumor itself while ramping up your immune system, and then having your body fight off those tumors even in other parts of your body.
Can you give me a succinct definition of a hydrogel?
Woodside: That’s probably better for Jeff to answer. Texas Heart Institute’s component was defining what the body’s response was to these different formulations of the hydrogels that they’ve been developing here at Rice. From a layman’s perspective, which would be mine, considering we’re more on the biological end of things, they’re essentially small proteins, small peptides, that link up together and form a stable matrix that can preside over some time in the body.
You see a wide variety of usages down the road. Could you give us three or four examples of what it might do?
Woodside: So, one of the things that we were really excited about with the technology they are developing here at Rice was the potential use in myocardial infarction. When you have a heart attack, you lose maybe 25 percent of the cardiomyocytes in your heart. That can be a billion cells. So right now, scientists and clinicians are testing stem cell therapies to repopulate those cells that are dead and dying off in the heart after a heart attack. With stem cell therapies, you can now directly inject into the heart muscle with catheters and define exactly where you want the cell-based therapy to go. The doctors inject the cells right around the tissue that is still living on the perimeter of the dead zone of heart tissue after a heart attack. The problem with these stem cell type therapies is that when you inject cells, very few of them stick around over a long period of time. In fact, 90 to 95 percent of these cells are gone within hours to a day after you inject them. Yet, we’re still seeing some early indications of beneficial responses. And so the concept is simple, right? More is better. The idea is that you can actually take stem cells, mix them with the hydrogels, and because the technology that Jeff’s group has developed allows you to easily inject these things with a catheter-based approach, you can mix the two together to make sure that those cells will stick around longer to do their job.
When you say that it goes in as a liquid and then it solidifies and it stays longer, what makes it solidify?
Woodside: The intrinsic nature of the small peptides that are part of hydrogel itself makes it solidify. Jeff’s group has had a long history in developing many different facets of these types of approaches. Obviously, Jeff can explain it a lot better, but the nature is such that the biophysical properties of these things allow them to be liquid when it’s under pressure and when that pressure and shear stress is removed, the hydrogels solidify. So right now, defining how the body reacts to these hydrogels represents some of the earliest work that you can do in the project, and drug development is a long, resource-intense process. The hydrogels may be considered a drug because you can mix things with it, and this is something foreign to the body that you’d be giving to somebody. The processes of drug development can take anywhere upwards of 10 years to 15 years, and they can cost upwards of a billion to two billion dollars. Right now, we’re defining what the earliest responses are from a safety perspective to these hydrogels. For instance, one specific composition of a hydrogel might be more beneficial to inducing inflammation and treating things where you might want to drive inflammation like cancers. Another specific hydrogel composition seems to be completely inert and you don’t see a big inflammatory response to it. You also could add things to that hydrogel, like for instance, a slow-release drug or even the stem cell therapies that we’re talking about. You can define these hydrogels really, really well .You could include other agents in the hydrogels that would make the cells healthier to ensure that they don’t die off as quickly when you inject them into the heart muscle after a heart attack. So, the point we’re at now is very early in development, which also makes it very exciting because the sky’s the limit with what you think you can apply these to.
Say you’re on the rocket ship and you’ve landed on the moon. What are you seeing now?
Woodside: Well now that we’re on the moon, I see a lot of regulatory red tape. One of the issues with the novelty of the approach is, that when something is new, you really have to make sure that you have all your T’s crossed and your I’s dotted from a safety perspective. So, because these would be for sort of a longer release type of new drug product, you just have to make sure you have all the necessary safety testing done right. But once we’re there, what I can see is a system for, let’s say stem cell therapies in heart attack patients, where you can mix known types of stem cells that can help those patients with these hydrogels so they stick around a little longer and maybe these hydrogels can be tuned so that they can cause these cells to produce more factors that are even more beneficial to patients. They could actually be defined so that they can remodeled in such a way that they can repair the heart. Right now, heart attack patients are being treated and sent home with broken hearts – that is their hearts aren’t functioning at maximal capacity. But as technology is advancing, the therapies we are developing may be able to treat those patients. We may be able to treat heart attack patients now and fix their hearts at a later time with regenerative medicine that these hydrogels could probably be a part of. That would be a major bonus for patients.
That’s where we get into the placeholder with respect to these hydrogels. Can you explain that?
Woodside: There is this question of when you would want to time an approach like this. So, let’s say you have a heart attack. There’s a whole series of events that take place after that. You have cell death because they don’t get the nutrients that they need. You have an initial inflammation that causes a lot of the dead cells to be cleared away, and then you have remodeling that occurs after that. If you have dead cells in your heart, you have a very weak area where there should be a lot of pressure from the volume of blood that’s needing to be pumped. So, the body’s response is to try to compensate for that, and you start developing a lot of what is called scar tissue. If you could time the short window right after a cardiac event just right, you could bring in these stem cells with this hydrogel approach to prevent excessive scar tissue from forming and then remodeling the actual components of the heart in that area so that they look more like a normal healthy heart that participates in contraction, conducts electricity and things like that. Another fascinating component of these hydrogels, that will be really interesting to test, and I know other scientists here at Rice are working on this as well, is electro-conductive hydrogels. These hydrogels would combine stem cell therapies with conductive hydrogels as well. If you could conduct electrical signals, you could put these within the heart so that you could actually cause electrical signals to travel better within the heart and address issues that are electrical in nature combined with stem cell based tissue repair.
How much better would this artificial method be than the body’s own method which is scar tissue?
Woodside: Well, the body’s method works as a physical stopgap. The more you develop scar tissue in the heart, the harder it is the heart to perform its function. So the idea would be that before the scar tissue actually starts to develop in full magnitude, you could provide these types of treatments that would either turn the response into more a reparative or regenerative response rather than a response needed to make a physical barrier. If you could “trick” cells in tissue surrounding hydrogels into thinking they are a younger type of cell then you may be able to coax them into behaving like beating cells in the heart, such as cardiomyocytes. There are many technologies now that are being developed to try to trick cells into thinking that they’re still very early in development and when the cells think they are younger than they really are, they can be pushed into changing into cells that make up different organ types. There’s another type of cell in your heart called a fibroblast. If we could trick those into thinking they a very early cell type, then turn into a cardiomyocyte, and result could be less scar tissue formation and more regeneration of the right types of cells that you actually need for the heart to function better.
Interview conducted by Ivanhoe Broadcast News in March 2020.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Mike Williams, Public Relations
Rice University
(713) 348-6728
Keri Sprung, Public Relations
Texas Heart Institute
214 729-3634
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