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.
Non-electric Disposable Drug Delivery Device for Hemophilia.
Prof. David J. Beebe, Biomedical Engineering; Dr. Carol Diamond, Pediatrics; and Ben Moga, Biomedical Engineering.

Speaker: Prof. Robert Radwin, Chair of the Department of Biomedical Engineering. 
Our next speaker is Professor Dave Beebe. 
Dave is actually a PhD from the University of Wisconsin-Madison. 
He left the University of Wisconsin to take faculty positions at Louisiana State 
and then at the University of Illinois in Urbana-Champaign.
And we were fortunate enough to hire him back into our department 
when we were forming Biomedical Engineering.
Dave started out in the biomems and microfluidics area.
Today he has a much more far-reaching goal.
His goal is a holistic approach to understanding cell behavior 
that integrates in vivo cellular-scale engineering to recapitulate 
important in vivo microenvironmental characteristics 
in ways that provide biological insights 
that can be easily assimilated by biologists.
Professor Beebe ...

Speaker: Professor David Beebe.
Thank you, but I'm not going to talk about any of that today, actually.
So, what I'm going to talk about today is actually based on what my lab
sort of used to do a number of years ago, and so it really is translational 
in that we had sort of done all the basic research on this, 
and it was sort of perfect timing for a Coulter to come in
and really help us now try to translate this into clinical use.
The title is Non-electric Disposable Drug Delivery Device for Hemophilia.
The clinical collaborator is Dr. Carol Diamond
in pediatrics, and actually I have a video of her, and
she'll be part of the presentation via video
because I think she can do a much better job than I
of telling you about the clinical problem.
I'll get the acknowledgments out of the way. In the beginning
DARPA funded a lot of the technology development that this
drug-related auxiliary device is based on.
And of course Coulter is now helping us move this into translation.
Dave Edington is a former student in my lab who did a lot
of the initial work who is now on the faculty at the University of Illinois at Chicago.
And James Will in Vet Med here is actually the person that is
sort of overseeing the animal studies that we're going to
be beginning actually in a few weeks.
So the problem that we're trying to address here on a very broad level
is sort of a transformation that is taking place
in drugs that are being produced today, and that is,
the rate at which large-molecule drugs are being introduced
is much higher now, is increasing much more rapidly, 
than the rate at which small-molecule drugs are being introduced.
And, as I'm sure many of you know, large-molecule drugs have
the problem that they can't easily be taken orally 
and formulated in a fill.
So there is and will continue to be a very growing need 
for the ability to deliver drugs cheaply and safely through the skin -- 
get them into the body -- so that you can avoid the GI tract problems. 
And particularly, there's a need for sustained delivery --
both bolus injection and sustained delivery.
And the current sort of status of that -- is there a laser pointer
built into this? -- you have a very simple syringe, it has some
obvious issues, it's limited to bolus injection, 
you can't do it quickly, and on the other end very expensive $5,000
sort of catheter-based infusion devices. They can be programmed,
but they're very expensive and there's a very large percentage
of the market, of patient populations, that can't use them because of cost.
So, I'm going to let Carol here ... .

Carol Diamond via video:
... by Dr. Beebe for the application of a drug delivery device specifically for patients with hemophilia.
As you know, hemophilia is an inherited disorder -- affects about one in 5,000 patients with factor VIII deficiency, 
one in 50,000 for factor IX deficiency.
Hemophilia is manifest by spontaneous severe bleeding, particularly into the joints. 
If a patient suffers a bleed, or if they would like to protect
themselves from having a bleed, they must be infused 
with factor VIII, or factor IX if they have factor IX deficiency. 
Now, this administration of the factor is really our challenge
at this point, and it continues to be a particular challenge for 
the small child.
To illustrate this point, I'd like to tell you what a lot of my
patients go through.
So, a little boy is born; he is known to have factor VIII deficiency
because his mother is a carrier.
He's doing relatively well through infancy because he's immobile, 
but then, as he starts to become active, he starts to have bleeds.
So let's say it's a Saturday afternoon and he's out running around
the way a normal toddler will do, and he suddenly starts screaming,
his parents notice he has a red, hot, swollen knee.
They identify a hemarthroses.
They have their factor at home, because we make sure patients
have the drug available as it is not easy to obtain, frequently.
But they have to go to an emergency room.
So they go to the emergency room with their screaming child,
and they wait for two hours to be seen.
Then, they're seen, and they even start to mix their factor, 
assuming that they be infused soon,
but it takes six or seven people to access a vein.
Finally, the factor is infused, but this is now
four to five to six hours later than it should have been. 
Child is traumatized, the family is traumatized, the staff is traumatized, 
and lots of resources have been used. 
Patients will typically go through experiences like this two or three times 
before they decide that they want an in-dwelling catheter placed.
Now in-dwelling catheters, such as a port-a-catheter Hickman,
dramatically improve the lives of small children with hemophilia;
however, they, too, are not without risk. 
It's a surgical procedure, requires anesthesia,
requires a lot of factor in the perioperative period,
and it's an in-dwelling foreign body, so therefore, a risk of infection. 
So, the thing that I think is so exciting about this drug-delivery device (Beebe's), 
is that, first of all, it would allow a family to administer a drug immediately, 
in their home, safely. 
It is something that could be used in a prophylactic manner -- 
so that on a regular interval, to prevent bleeds for a child. 
It's something even for an older child -- if they knew they were going 
to play in a rigorous tennis match or a soccer game, 
they could infuse at home with this device, without intravenous access, 
without an in-dwelling catheter. 
This would dramatically improve the patient's quality of life.

David Beebe:
So I'm going to actually take out a few slides so we can stay on schedule here, 
but just give you a very quick overview of what we're doing.
So our solution to this is sort of a cross between the drug pump and a patch. 
It's low-cost, disposable.
It's capable of both bolus delivery and sustained delivery.
It's very small.
It can be configured with either microneedles or a single needle,
simple to use, less pain.
And what I want to show you a little bit about is the basic technology 
upon which this is built, and then I'll skip over some of the details in the interest of time.
So, our goal here was to try to make a device that's cheap and disposable.
If we wanted to do that, we wanted to stay away
from traditional way of engineering devices, and that is
electronics, pumps and valves, in a traditional sense.
So, a number of years ago, we developed this method of using 
stimuli-responsive hydrogels to make, for example, valves.
So these are hydrogels that change their shape in response 
to temperature changes or pH changes.
And here's a video of a responsive hydrogel
being exposed to a solution that changes in pH,
and you can see it shrinking and swelling, in real time, actually,
in response to this change in the environment around it.
So, Dave Edington, a former student of mine,
had taken this basic concept and incorporated it into some very crude
prototypes to make a non-electronic pump. 
So it's a membrane-based device that has a flexible membrane, 
a drug reservoir, if you will, on the bottom and on the top we have these swellable hydrogels.
So, then, just by triggering the response of these hydrogels 
by exposing them to a change in pH, for example, in the solution, 
you then expand the volume of these hydrogels and just simply push the drug out. 
The nice thing about this is that by controlling the chemistry and the geometry 
of these gels you can control what the profile of delivery looks like, 
whether it happens in five minutes or 24 hours.
In theory, we can actually make specific profiles,
so that the drug would be at one rate for a few hours and then
drop down to another rate.
So this is a platform technology.
And I'm just going to say this and skip over the next couple slides in the interest of time.
We've actually also demonstrated that this can be used for closed-loop delivery, 
which is really the Holy Grail of drug delivery. 
So we think this is just the first step of a platform technology
upon which we'll first start with open-loop system, and ultimately move
to closed-loop systems.
So let me skip over and really just summarize and conclude
so we can stay on time.
Just to give you a sense, because this is very translational,
and there is a startup company that is looking at this:
Where we think about positioning this sort of a product
is in this sort of space.
So it is a very crowded space, but if you look here at cost on this axis and sustained delivery, so from bolus to sustained,
there's not much in this space that is very low-cost sustained delivery
and that's the space that we're interested in capturing. 
So, just to summarize, and then we'll actually be on time:
This is a very cheap, disposable, sustained delivery device. 
The initial application that was described by Dr. Diamond
is hemophilia, although again, there's a growing market 
for devices that can do sustained delivery on large-protein drugs, 
so we envision that this might be a technology licensed widely to pharmaceutical companies.
The status of our project -- and I sort of skipped over some of the details of this, 
but just to summarize: 
So we have a benchtop prototype that we have done extensive testing on.
We can now do very repeatable delivery over multiple devices.
We have also completed a first baseline animal experiment on pigs
so that we have essentially all the experimental details worked out.
And we will be beginning our first animal study in the next few weeks
with a bolus delivery prototype. 
And then the next step will be to design the chemistry and geometries 
for a sustained delivery device.
And the commercialization, then, we think once we have these animal
studies, animal data, in hand, we think we would then be in a position
either to license it, or partner it with pharmaceutical company, 
or to license it to a startup who could then take this data 
and then move forward on it.
And I'll stop there in the interest of time. Thank you.

Radwin: Thanks very much, Dave. We have a few minutes for questions
if there are any questions for speakers before we take our break.
Not seeing any questions, we'll take about a 15-minute break.

Copyright 2007 The Board of Regents of the University of Wisconsin System.
Last modified: 19 May 2009.
Created: 26 July 2007.