Biomedical Engineering Center for Translational Research
2007 Conference and Expo
Friday, May 4, 2007.
University of Wisconsin-Madison, College of Engineering.
Engineering Centers Building.

Morning Agenda: Focus on Translational Research.
Kristyn S. Masters, Assistant Professor of Biomedical Engineering; Roham Moftakhar, Resident, Department of Neurosurgery; and Wendy Crone, Associate Professor of Engineering Physics

Designing an Alternative Aneurysm Occlusion Device 

00:00
Speaker: Prof. Robert Radwin, Chair of the Department of Biomedical
 Engineering.
Our next speaker is Professor Kristyn Masters. 
Professor Masters is an assistant professor in the Department of Biomedical Engineering.
And her fields of interest are synthesis of bioactive materials that direct cell function, characterization of cell material interactions, tissue engineering, and drug delivery.
By combining engineering and biological principles, Dr. Masters' lab investigates fundamental issues in cell material interactions in order to create smarter bioactive materials that are capable of directing cell function.
The projects in her lab entail research in a variety of fields, including material design, drug delivery, and physiological characterization with the end goal of creating unique biomaterial systems with clinical applicability. Professor Masters ...

01:03
Speaker: Kristyn Masters

OK, so today, I'm going to talk about my lab's work on an alternative aneurysm occlusion device, and this has been done in collaboration with Roham Moftakhar, who is a resident in the Department of Neurosurgery here and Wendy Crone in the Department of Engineering Physics. 
So, first, a little bit of background on cerebral aneurysms. 
About 5% of the U.S. population is believed to have a cerebral aneurysm. That does not mean that 5% of the population is going to eventually have trouble with a cerebral aneurysm. 
Many people do have them their entire lives and never actually know about it. They have a wide variety of causes, including it could just be a congenital condition. 
It can occur from trauma to the head, high blood pressure, infection, tumors, atherosclerosis. There are lots of reasons that people can develop a cerebral aneurysm. 
However, when they do fail, it is a serious, serious problem. 
The consequences of rupture can be hemorrhage in the brain, or a stroke, or death. 

2:07
So, the preferred method of treating a cerebral aneurysm -- and they can be treated prior to rupture if they are deemed to be a risk -- they can be detected via various imaging methods, and then treated via an endovascular route, which is not very invasive. 
This is a crude animation, showing how coil embolization is done in order to treat these.
So, delivered via an intervascular catheter, shape memory coils are deployed within the aneurysm until they actually fill up the aneurysm with essentially a ball of wire. 
And I was actually pretty surprised, when I first heard about this, because this doesn't seem like a great way to block off the aneurysm. 
But the idea is you fill it with this very tight bundle of wires that you just keep pushing in there, and the hope is that this bundle of wire is going to instigate this wound-healing response, sort of a scar formation, around the aneurysm that will then sort of wall this part off from the blood vessel and no longer have a risk of rupture and hemorrhage, etc. 

3:18
Now, there are many problems with this, including one of the main problems is compaction of the coils. 
So, as blood is flowing past here, the coils get sort of pushed up. 
And the coils aren't exactly elastic, and so when the coils get compacted, it just pushes out the aneurysm more.  
And so that could lead to increased risk of rupture or enlargement; you could end up with something worse than what you started with. 
There's also very unpredictable wound healing in terms of how long is it going to take the scar formation to occur. 
There's actually been very little analysis and study of how the fibrotic response happens around the aneurysm coils. 
And lastly, and probably most importantly from our clinical collaborator's point of view, is the very long procedure time. Our clinical collaborator, Dr. Moftakhar, has stories of spending, you know, upwards of eight hours placing coils in aneurysms, in some of these large aneurysms, because it is a very imprecise procedure in that they are just putting coils in and imaging while they're doing this, in order to decide when the aneurysm is essentially full of coils.

04:33
So, the project I'm going to discuss today is actually something that was suggested by Dr. Moftakhar and was not previously investigated in my lab or Dr. Crone's lab. 
So, this is something that we have been doing entirely from scratch and is entirely clinician driven in terms of the idea of it.  
And his idea was that he just wants to shorten the time that it takes for surgeons, for himself, to occlude the aneurysm. 
In addition, if possible, on top of that, make the occlusion better and safer, and possibly even more predictable wound-healing response. 
And so his idea was to have a single coil and have that inside of a polymer shell. This is actually how our team was built, is that Dr. Moftakhar had this idea, and so he went searching -- he wanted to find someone who was an expert on shape memory alloys and coils. 
And so that's how he found Wendy Crone in the Department of Engineering Physics. Her research lab does a lot of work with shape memory alloys. 
She's an expert in that field. And then, he went looking for someone who could build a shell, and that is how he found me. 

05:45
So, his idea is, you start out with the same intravascular delivery, except for here, this blue part is a coil that is straightened, because it is in the catheter, and it can't coil up while in there, and then, it is surrounded by a shell that is essentially like a balloon that is going to expand as it is delivered and pushed out by the coil. 
So, the idea is that this coil, as it is exiting from the catheter, expands the balloon to then create sort of intimate contact with the surrounding aneurysm shell. 

06:22
And so, the advantages of this approach -- and this is again is a very crude drawing in Ovation of how this would work -- that the polymeric shell is now the barrier to blood flow. 
And there is decreased risk of compaction because this is going to be a little bit more elastic than the coils, and so the likelihood of this being pushed up and then staying up is very, very low, and we've done tests on our prototypes to prove that, and therefore decreased risk of enlargement and rupture. 
There's a precise delivery of a single coil, and probably one of the most important things to our surgeon is that this only involves putting in a single coil. 
It could dramatically, by orders of magnitude, decrease the time to occlude these aneurysms. And because I like to make fun new biomaterials, we also discussed making this polymeric shell bioactive in order to not just simply be this inert surface, where scar formation just sort of happens around it because it's there, but rather a material that will actively promote or guide wound healing and scar formation, so that we can perhaps even get this, aside from just putting the device in, get this walled off biologically from the body now over a faster time frame.

07:45
So, the first part of our design is the coil part. 
And this all being done in Dr. Crone's lab in Engineering Physics and done using nickel-titanium shape memory alloys. And the shape memory alloys are trained to essentially remember a specific shape when they are above phase transformation temperature. 
And so, via various heat or mechanical treatments, they can form a shape that the coil will then assume above its phase transformation temperature. 
And in our case, the phase transformation temperature is somewhat below normal body temperature. 
So what happens is, when wire is cooled, you can straighten it out very, easily and that facilitates putting it into a very small catheter. 
And then when it warms up, it wants to coil, but it can't coil because it's in that very narrow-diameter catheter. 
But when it is pushed out, the nice thing about this is also we can use the same sort of delivery methods that are currently used for coil delivery in endovascular coiling. 
When it is pushed out of the catheter, it assumes that coiled shape that it was trained to remember during the previous treatment. 
And another nice thing about these materials is that they are already used in aneurysm coiling; they're actually one of the materials used in that little pack of coil that I showed on one of the first slides. 

09:11
So, the second part of the design, the shell, which is what my lab has mainly been focusing on, there are several constraints that we knew we had to follow. One, it has to be biocompatible, of course, and, more importantly, has to be hemocompatible. And when you specify that something has to be hemocompatible, that is going to greatly reduce your biomaterial options; there are very few polymers that are truly hemocompatible. 
By hemocompatible, I mean that it's not going to induce thrombosis or any sort of adverse events, when in contact with the blood, which obviously our material is -- in contact with blood. If we want it to be essentially expandable by this coil, it has to be highly elastic. 
We have to be able to make it into thin films, capsules, balloons, so we have that shell. 
And, ideally, not entirely necessary but in an ideal world, it would also contain some kind of element that actively stimulates the wound healing process. So, when we started thinking about this, we realized that there wasn't a good existing material to meet these criteria. 
It wasn't, well, we had an idea at the beginning of this project that we would have to make something new. 
It didn't become clear until a little bit into it that there really wasn't anything out there that was going to do the job and that we really had to do our own thing from scratch. 
And so, typical hemocompatible polymers, such as Teflon polytetrafluoroethylene and polyethylene terephthalate -- they are considered hemocompatible, but they are not highly elastic. 
They usually have less than 250% elongation at break, and they are poor stimulators of wound healing. Of course, there is a whole host of non-hemocompatible polymers that are, say, highly elastic and conform films, but again we need something hemocompatible. 

11:00
So, we decided to go the route of taking a polymer that's kind of hemocompatible -- but not quite all the way there, not as much as we'd like for this application -- and trying to make it more hemocompatible. 
So polyurethanes are used widely in medical devices. 
They're very easy to process. 
In other words, you can make them into all sorts of different shapes by different processing methods, etc. 
They are fairly elastic already, so we're already starting with something with pretty good, favorable mechanical properties for application. They are biocompatible, but they're not great when it comes to hemocompatibility. 
And so, what we decided to do was incorporate an anti-thrombotic molecule into the actual backbone of the polyurethane polymer. And, for this, we have chosen hyaluronic acid. 
Hyaluronic acid is viewed by a lot of people as sort of this wonder molecule, because it does so many fantastic things. 
It is non-thrombogenic, non-immunogenic. 
It's very viscoelastic, and it stimulates wound healing. 
And it also stimulates low-molecular-weight -- hyaluronic acid also stimulates the proliferation of endothelial cells and that also is promising for this, because if we could reendothelialsize that part of the blood vessel, that would be really nice.

12:17
So, we need a variety of these polyurethane hyaluronic acid copolymers. 
So, then, let's briefly review whether these materials actually met those constraints that we listed on the previous slide.  
So, first, these are done, here, I should note.
We need polyurethane hyaluronic acid-that's PU-HA -- polymers with the percent -- refers to the amount of PU-HA that we incorporated into these materials. 
So, can we form thin films? Yes, that was extremely easy. 
Just via regular solvent casting, we could form extremely thin films. 
We haven't tried anything less than 100 microns, but the materials are extremely easy to process. 
Did we have good mechanical properties? 
Yes, we do, and in fact, with all of our formulations, we have almost a couple 1,000% elongation. 
So, when you think about the type of stretching that's needed in order to expand a balloon, we are in a good range for doing that. 
And well, this isn't the percentile elongations, just our elastic modules, I also showed this just because I wanted to demonstrate that by changing the amount of HA that we incorporate into these materials, we can dramatically change the mechanical properties of these materials as well. 
And one of our most exciting and relevant results, are they hemocompatible? 
Yes, and dramatically so, in fact. 
So, control here is a collagen-coated surface, so collagen is known to be very thrombogenic. 
And this is just our plain polyurethane, which is a lot less thrombogenic than collagen, but still there is a lot of platelets adhere to that. 
We found that even at our lowest HA incorporation, we get complete elimination of platelet adhesion to these materials, so these are highly hemocompatible. 

14:04
And these results in particular are extremely promising. 
Wound healing -- does it stimulate wound healing? 
Looking promising right now. 
We have put endothelial cells on the materials. 
And what's really unique about these materials -- I'll get into more of their uniqueness in the next slide -- is that a lot of times, there is a trade-off between having something have no platelets adhere to it and wanting cells to adhere to it. 
So, for instance, if you make a material that is not ... where platelets do not adhere to it, most of the time it's going to be really, really hard to get cells to adhere to it.
So, it's hard to have both, but since hyaluronic acid is a molecule that is often directly recognized by cells, there's more of a chance that we can still retain cell adhesion of cells that we want on there, while still having no platelets adhere to it. 
And, in fact, ... we have had endothelial cells adhere and proliferate on these materials.

15:11
So, there's supposed to be a video here ... it's not really happening ... OK.
Anyway, so, our final prototype is this single shell inside a polymer coil. 
This is actually one of our earlier pictures.
Let's see what happened there ... we'll skip that slide for now.
Basically, we've made our prototype of a single coil inside of a polymeric shell and have been testing it or are currently testing it in vitro models of aneurysms. 
We can construct out of silicone, actually, models of in vitro aneurysms, and we are practicing deploying it in there. 
We'll be moving into an animal model in very near future. 

And, what I also wanted to mention is that, basically, because of this work, many other projects have come out of this. 
And of one of the, as you can tell, I'm very excited about the materials that we've developed, and sort of another project is born, and these materials that we've developed can be used for a lot more than just the shell of these aneurysm occlusion devices. 
And I do want to note that ... we are using native biomolecule to impart bioactivity. 
It's part of the material backbone, so that's not something that is eluting out of the material; this is something that is permanently there. 
We can really tailor the physical properties and biological properties of our materials based upon how much of the HA we put in there. 
And again, as I noted before, these materials resist protein adsorption, which makes them more likely to be very immunocompatible, but they actually allow endothelial cell adhesion and proliferation, which could be great for vascular contacting applications.

I would like to thank Coulter Foundation for their support of this work. Fangmin Xu, is the lab technician who did almost everything that I just showed you today. 
She is a fantastic lab technician. And Claire Flanagan, who is unfortunately not in this picture, but she is an undergraduate who has been working on this as well. 

Copyright 2007 The Board of Regents of the University of Wisconsin System

Last modified: 08 August 2007.
Created: 26 July 2007.