Making It All Gel
By Tyler Irving
McMaster University’s Todd Hoare creates polymer-based hydrogels that, unlike previous generations of biomaterials, are designed to change their properties in response to the dynamic environment inside the human body. The work encompasses aspects of nanotechnology, polymer science and pharmaceuticals. Last fall, Hoare was recognized with a Polanyi Prize, an award given by the Ontario government to outstanding young researchers in the early stages of their careers. ACCN spoke with Todd Hoare to find out more about the ground he’s breaking.
ACCN: With your recent prize, your research is getting some attention, including your work on gel-based particles. What is your definition of a gel?
T.H.: We work on hydrogels and particle based gels called microgels. They’re basically hydrogels on a micron or nanotype scale. We view a gel as a material that is composed of polymers that are themselves water soluble, but are cross-linked together in some way so they can’t dissolve. We create the hydrogel, swell it with water and then change the conditions of that water; we heat it up, we change the pH, change the solvent conditions, and that way we can contain more or less of the water inside. So we get some dynamics in terms of swelling, de-swelling, average pore sizes, and so on.
ACCN: And some of these gels can biodegrade?
T.H.: That’s true. And that’s what we’re working on now. One of the traditional problems with most conventional hydrogels is that they’re based on carbon-carbon bond backbones. They’re synthetic polymers so once you put them in the body, essentially, they’re there until you die. There’s no obvious mechanism [by which they degrade], or if there is a way in which they degrade, you could actually create unsafe products with depolymerization since some of the monomers are not particularly safe themselves even though the polymers have excellent biological safety. So there has been a lot of concerns about using some of these materials biologically on that basis, because we don’t really know what happens to them long term. So what we’re doing in my lab is we’re making very short chains of these synthetic polymers; things that are less than the molecular weight that your kidneys can clear, so your body can filter them out, and we’re connecting those short chains with biodegradable linkages. We’re trying to capture all the properties and behaviours of synthetic polymers that are favourable — that we can tune them however we want, we can put in different functional groups very easily — we want to capture all that richness of chemistry, but also to do that in a form that can degrade and be cleared, that is not going to accumulate in your body.
Todd Hoare in his lab at McMaster University, next to a high performance
liquid chromatograph which his team uses to accurately measure low
concentrations of drugs in order to study how hydrogels release medicine.
ACCN: What are the potential applications for these hydrogels?
T.H.: There’s a few applications. The one we’re most interested in by far is drug delivery. The hydrogels have a very high free volume inside of them because there’s a lot of solvent in them, so we can load a lot of drugs inside. And by changing how they swell in different environments — so whether we heat them up in a specific environment or whether we go from an area that’s acidic to basic, for example — we can cause these things to swell and deswell and thus change the rate of drug release from the materials. So that’s our main interest, but there’s also a lot of interest for tissue engineering applications. Particularly, the hydrogels we’re making now are injectable. You basically start with liquid-like precursors outside the body and when you inject them into the body, they gel very quickly. So we can entrap cells inside that material at the same time and that should enable us to aid in tissue engineering depending on what the hydrogel is.
ACCN: So the gel acts as a scaffold for tissue engineering?
T.H.: Exactly. And we can change how quickly it degrades depending how quickly the cells grow and form the tissue.
ACCN: Let’s go back to drug delivery application for a second. You mentioned there’s a lot of space in between the pores of these gels. Why doesn’t the drug wash right out? What holds it in there?
T.H.:That’s the advantage of having these synthetic networks that we can control really tightly. We can put functional groups or chemistries inside those networks that can either actually react with the drug, so we can actually get a degradable bond between the polymer and the drug so it will release slowly, or it can just interact. We’ve seen that if you put even opposite charges — so a positive charge on the drug and a negative charge on the polymer chain — these can interact and significantly slow the release. In some hydrogels that we’ve been working on, we’ve achieved up to almost two months of release of small molecules just by changing the chemistry of the hydrogel and how that hydrogel interacts with the chemistry of the drug we’re trying to deliver.
ACCN: Are there any technologies that release drugs slowly right now?
T.H.: There are, yes, but most of them are hard, insoluble type polymers and most of them have degradation products that are fairly acidic. As they break down, you often get acidic products which can cause problems in the body. Also, because they’re very hard, they’re basically insoluble polymer blocks. The body doesn’t respond to them in the same way. Proteins stick to them more, they don’t have the same sort of mechanical and chemical structure that the matrix of cells are used to, which hydrogels do. So typically, you get more severe inflammatory or immune responses from these when placed inside the body than you do with a hydrogel based system. That’s why we’re trying to engineer these hydrogel systems to achieve these long periods of release, because we have some biological advantages.
ACCN: So they are closer in their properties to the cell’s own tissues than the materials that have traditionally been used?
T.H.: Absolutely.
ACCN: And that’s the real advantage of them? T.H.: It is. The cells don’t feel the environment is foreign to them; they’re mechanically similar, we can engineer the chemistry to be similar, so that’s certainly a huge advantage for any type of application where the material is inside the body.
ACCN:You’re also working on controlling the size of the nanoparticles. Why is that important?
T.H.: What we found is that, depending on how big you make these particles, the body does very different things with them. So on a micron-type scale, the particles generally stay where you inject them. If you reduce the size to 200 or 100 nanometres, sometimes the cells will take them up into the centre of the cell, so they’re not just outside, they’re actually taken internally into the cell. So we can deliver things like DNA or other genetic materials for gene therapy. We’ve shown that that’s possible. In other cases, depending on the surface chemistry, they don’t get taken into the cells, but they do get moved very quickly. So, even within a day or two, if you inject a lot of these particles at one site, and you look a day or two later, they’re completely gone. They’ve been moved away by the inflammatory cells. Circulation is the third thing we can look at. The smaller the particle, the longer it tends to circulate. So if we want to target a particular tissue, a cancerous tumour, for example, that’s an advantage. We have a lot of control over where they go, how long they stick around wherever we want them, and also whether they stay outside cells or go inside cells, by changing the particle size.
Injectable hydrogels are made by mixing two reactive polymers
— one functionalized with aldehyde groups and another functionalized
with hydrazide groups — to form a degradable, hydrazone-bonded network.
A double-barrelled syringe mixes the polymers by co-extruding them through
a mixer at the end of the syringe, converting a low viscosity polymer
solution to a hydrogel within seconds.
ACCN: The interaction of the particles and biomolecules: can you give me some more examples of how that might work?
T.H.: Our main interest is working on microgels that have temperature sensitive properties. As we heat them up past a particular temperature, they shrink. What we’ve found is that we can use biological triggers — for example, the blood has a different protein concentration than the space around your cells, or a cancerous tumour will have a slightly different temperature and a slightly different pH than the surrounding tissue because they are metabolically active, so they have more acid byproducts, more heat being produced because of metabolism — to cause particles to aggregate together or shrink to release drugs specifically at particular sites that we’re interested in in the body.
ACCN: And they’re sensitive enough to react to that tiny change in temperature?
T.H.: Yes, actually. It’s a very discontinuous response. We can tune the temperature to anywhere between 20 to 50 degrees Celsius with a resolution of one to two degrees Celsius. We’ve made gels that can be swollen at 37 and shrink at 38 or 39 degrees Celsius, which is the typical temperature at an inflammation site, for example, or at a cancerous tumour. We’ve made microgels that over a very narrow range of pH, maybe .1 or .2 pH units, can stick together or not stick together. So again, anything metabolically active will be slightly more acidic, so we can deliver things to that location. That’s of real interest in terms of actually being able to localize drug delivery to a place that’s specific inside the body, using these biomolecular and physical cues.
ACCN: Are these polymers made of particularly exotic materials or are they just clever engineering of the polymers that we already use all the time?
T.H.: The polymer that we use a lot is poly(N-isopropylacrylamide. I think 1968 was the first paper on them, so they have been around for awhile. They have been investigated for use in oil recovery, those types of applications, just because they can basically take up water and release water. I wouldn’t call it exotic, but it’s not something you’d go and buy off the shelf at a tonnes scale either. It’s still a specialty material.
ACCN: One thing that strikes me about your work is how interdisciplinary it is. You started off in chemical engineering, but you’re working with oncologists, physicians, all kinds of people in all sorts of medical fields. How does this affect how you do your research?
T.H.: I think, particularly if you’re in the biomedical space, or you’re interested in looking at biomedical applications, it’s absolutely impossible to do any impactful research without collaborating. There’s just so much that you need to know in order to design something and see how it works. I know a little bit about biology and medicine, but [as an engineer] half the time you’re not even sure what types of treatments are needed, or what types of physical cues are reflective of those conditions. Just talking with people like doctors, oncologists, they give you ideas in that they’ve identified a problem based on their experience, so they may give you some information on how to design a material to address their need as well. I think people who are in biomedical research have a hard time identifying one thing they’re good at, you have to know a little bit about a lot of things in order to be effective.
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