Controlled Drug Release Technology

Transcript of Part 3: Biomaterials for Drug Delivery Systems and Tissue Engineering

00:00:07.15	My name is Bob Langer,
00:00:09.02	and I'd now like to over my third lecture,
00:00:10.22	which is Biomaterials and Biotechnology:
00:00:12.20	the development of controlled drug delivery systems
00:00:15.05	and the foundation of tissue engineering.
00:00:18.17	In my last lecture, I went over the fact that
00:00:21.28	numerous angiogenesis inhibitors
00:00:24.07	were approved by regulatory authorities
00:00:26.16	and are now in clinical use,
00:00:28.09	and that controlled drug delivery systems
00:00:30.03	actually helped in creating the bioassays
00:00:32.09	that enabled many of them to be isolated.
00:00:35.29	Also, I went over the fact
00:00:37.27	that one could create new smart materials
00:00:39.25	like nanoparticles and even smart microchips
00:00:43.06	that could be externally activated
00:00:45.00	and used in the body.
00:00:46.29	Now, what I'd like to do
00:00:48.19	is turn to some of the materials themselves
00:00:51.07	and some of the issues with those.
00:00:53.06	So, as I mentioned in my second lecture,
00:00:56.16	I worked in a hospital for a number of years,
00:00:58.22	and one of the things that I was curious about
00:01:00.14	as a chemical engineer
00:01:02.05	was how did materials
00:01:04.21	find their way into medicine?
00:01:06.26	And I though, naively,
00:01:08.15	that it must be chemists and materials scientists
00:01:10.08	and engineers that did that,
00:01:12.05	but when I looked into this I found out
00:01:13.16	that was almost never the case.
00:01:15.13	It was almost always clinicians,
00:01:16.23	and what they did is they would usually go to their house
00:01:19.22	to find some object that resembled the organ or tissue
00:01:22.13	they were trying to fix,
00:01:24.07	and they'd use it in the person.
00:01:26.09	For example, in the case of the artificial heart,
00:01:28.21	in 1967 some of the clinicians at NIH
00:01:32.01	wanted to make a heart
00:01:35.12	and they wanted something with a good flex life
00:01:37.05	and they said, "Well, what object has that?"
00:01:38.29	And they said, "A ladies girdle."
00:01:40.17	So, they took the material in a ladies girdle
00:01:42.15	and made the artificial heart out of that,
00:01:44.11	and that's actually not only what was used in 1967,
00:01:47.23	it's what used today.
00:01:49.15	But, one of the problems is
00:01:51.27	that when one starts down that path from a regulatory standpoint...
00:01:54.16	you really... it's very hard to change it,
00:01:57.27	and when people designed the artificial heart,
00:01:59.28	many times is hasn't worked that well,
00:02:02.01	because when blood hits the surface of the artificial heart,
00:02:04.01	the ladies girdle material, it could form a clot,
00:02:06.18	that clot could go to the patient's brain,
00:02:08.12	they get a stroke and they may die.
00:02:10.26	And yet, to me, it's not that surprising
00:02:12.27	that something that was designed to be a ladies girdle material
00:02:15.09	might not be the optimal blood contacting material,
00:02:18.00	and this problem really pervades all of medicine.
00:02:20.28	Dialysis tubing was sausage casing.
00:02:23.04	Vascular graft, that's an artificial blood vessel,
00:02:25.10	was a surgeon in Texas going to a clothes store
00:02:27.26	to see what he could sew well with,
00:02:29.28	and breast implants, one of those was a lubricant,
00:02:32.10	another actually was a mattress stuffing.
00:02:35.08	Being a chemical engineer I thought,
00:02:37.05	well, maybe there's a different way.
00:02:38.24	One of the things you learn about in chemical engineering is design,
00:02:41.06	and so I thought, why couldn't we ask the question,
00:02:43.06	what do we really want in a material
00:02:44.29	from an engineering standpoint,
00:02:46.22	chemistry standpoint,
00:02:48.07	and biology standpoint,
00:02:49.27	and then could we synthesize it from first principles?
00:02:52.04	So, we picked an example.
00:02:53.27	When I started, the only material that was FDA approved
00:02:57.14	that was synthetic and degradable
00:03:00.07	were the polyester sutures,
00:03:02.09	and they dissolve by a process we call bulk erosion,
00:03:04.25	which means that as you look at the top part
00:03:07.28	it's intact, but then over time it gets spongy
00:03:10.11	all the way through,
00:03:12.11	and then it just breaks apart.
00:03:13.26	Which is okay for some drugs, but for others
00:03:15.21	it could lead to bursts of drug release
00:03:17.17	and that could be fatal if you had
00:03:19.21	a possibly dangerous drug like an anti-cancer drug.
00:03:22.15	So we said, and others have said,
00:03:25.22	what you really want in a polymer
00:03:30.27	to degrade is not bulk erosion, but surface erosion.
00:03:33.23	That would be layer by layer erosion,
00:03:35.14	and if that could happen kind of the way a bar of soap might dissolve
00:03:38.12	then you wouldn't have this problem of dose dumping.
00:03:40.27	The challenge was, how could you do that?
00:03:43.05	How could you create a polymer to do this?
00:03:45.28	So, we went through
00:03:48.06	a very detailed engineering design analysis
00:03:50.25	to try to figure that out.
00:03:52.15	We'd start out with different design questions,
00:03:54.12	like what should cause the polymer degradation?
00:03:57.04	Should it be enzymes?
00:03:58.20	Should it be water or something else?
00:04:00.12	Our thinking is, well, everybody may have different enzyme levels,
00:04:02.09	but everybody has excess water,
00:04:04.06	so let's build into the polymer
00:04:06.08	the ability to be degraded by water
00:04:09.03	as a first step.
00:04:10.21	And then what we did is we figured out
00:04:12.08	what the right building blocks are
00:04:14.12	to make those polymers
00:04:15.25	that would keep water out,
00:04:17.20	because you want to keep water confined to the surface.
00:04:20.00	And then we tried to figure out
00:04:21.16	what would be the right chemical bonds
00:04:23.10	that would break apart in the right way
00:04:24.19	and we came up with the anhydride bond.
00:04:26.20	And then we tried to figure out
00:04:28.14	what would be the specific units in the polymer
00:04:31.00	that would be safe in the body,
00:04:34.13	and ultimately we came up with this polymer.
00:04:37.11	It's what's called a copolymer,
00:04:38.28	there's two units to it:
00:04:40.26	PCPP, that's carboxyphenoxy-propane,
00:04:43.09	and sebacic acid.
00:04:45.02	And our thinking was
00:04:47.06	that by changing the ratios of these
00:04:49.06	we could make the polymer last for different times,
00:04:51.01	and if we used this anhydride bond
00:04:53.04	to connect everything,
00:04:55.09	then we might be able to get the surface erosion.
00:04:58.11	We made some of these;
00:05:00.17	we synthesized these polymers.
00:05:02.17	It's a good deal of work but we synthesized them,
00:05:05.00	and what you see is
00:05:07.23	they actually did come quite close to this surface erosion,
00:05:09.23	but if you change the ratio of one to the other...
00:05:12.04	the 79, 55, 15, and 0
00:05:17.01	all referring to the amount of sebacic acid,
00:05:19.04	what happens is you can make these last
00:05:21.15	for almost any length of time.
00:05:23.03	You can go from the 79% one
00:05:25.16	that lasts for about 2 weeks.
00:05:27.03	The 0% one will last for 3 or 4 years.
00:05:29.20	So, you can simply dial in the ratio of these
00:05:32.09	and make them last for almost any length of time you want.
00:05:35.19	Well, one of the things that I always want to try to do
00:05:38.12	is not just write the paper,
00:05:40.11	but to try to see if we can use these materials that we create
00:05:44.04	to do something useful,
00:05:46.09	and in 1985, Henry Brem,
00:05:47.27	a young neurosurgeon at Johns Hopkins,
00:05:49.21	came to visit me
00:05:51.20	and wanted to see if we might be able to help him
00:05:53.25	come up with a different way to treat brain cancer.
00:05:56.27	Henry is now chairman of neurosurgery at Johns Hopkins.
00:06:00.05	But just briefly,
00:06:02.06	these were some of the statistics at the time.
00:06:04.14	With glioblastoma multiforme
00:06:06.10	it was a uniformly fatal disease.
00:06:08.23	The mean lifespan,
00:06:10.10	regardless of how you treated it,
00:06:11.29	was generally less than a year.
00:06:13.24	The drug that people used at that time
00:06:16.01	in the 1980s was this one, BCNU.
00:06:19.11	It's effective but very,
00:06:22.19	you know, toxic drug.
00:06:25.09	And, what Henry and I talked about was this idea:
00:06:28.07	rather than give it intravenously,
00:06:30.14	which was always what was done before,
00:06:33.01	could we introduce this paradigm
00:06:34.28	of what I'lll call local chemotherapy?
00:06:37.04	Could we allow the neurosurgeon, like Dr. Brem,
00:06:40.04	to operate on the patient
00:06:43.12	to remove as much of the tumor as he could,
00:06:45.24	but before he closes the patient,
00:06:47.18	could he line the surgical cavity
00:06:49.14	with little wafers containing this drug and polymer?
00:06:53.26	Now, this polymer, the drug I should say,
00:06:57.09	normally lasts just for 12 minutes,
00:06:59.17	but if you put it in the polymer it's protected.
00:07:01.05	It'll last as long as the polymer lasts.
00:07:03.10	So, the neurosurgeons like Dr. Brem,
00:07:06.07	they wanted it to last for a month,
00:07:09.05	and we could do that by changing the chemistry.
00:07:11.15	So basically, what we were able to do
00:07:14.02	is make these wafers,
00:07:16.05	make it last for a month,
00:07:17.29	and also what was important to the neurosurgeons
00:07:20.20	is they're putting the wafers in the brain,
00:07:22.24	so they're exposing only the cells, largely,
00:07:25.13	they wanted to to the drug,
00:07:27.10	and the rest of the body is really spared these high concentrations
00:07:29.08	of chemotherapy.
00:07:31.09	So...
00:07:33.24	so, that was the idea and,
00:07:36.18	well, what happened is that
00:07:39.16	whenever you're in academia, a professor,
00:07:41.11	you have to raise money,
00:07:42.27	and so what we would do to try to raise money
00:07:44.29	to move this forward,
00:07:46.22	first to create the new materials and everything,
00:07:48.11	is I'd write grants and I'd write them
00:07:50.21	to like the National Institutes of Health of other places, a
00:07:52.13	nd then they'd have professors at other universities
00:07:54.18	review them and say what they thought.
00:07:56.22	And we did terribly.
00:07:58.16	We did very, very badly.
00:08:00.18	When I first wrote the grants,
00:08:02.25	the reviewers, the chemists said,
00:08:05.06	well, we'll never be able to synthesize the polymers.
00:08:07.28	But, I had a very good graduate student at the time
00:08:10.00	named Howie Rosen.
00:08:11.21	Howie later became president of the ALZA corporation,
00:08:13.08	a 12 billion dollar corporation,
00:08:15.16	and also has been elected to the National Academy of Engineering,
00:08:18.10	and he synthesized the polymers.
00:08:20.14	So, we sent the grant back
00:08:22.07	and the reviewers said, well,
00:08:23.24	we still shouldn't fund it even if you can synthesize them.
00:08:26.22	The polymers are gonna...
00:08:28.15	they have these anhydride bonds,
00:08:29.13	they'll react with whatever drug you put in.
00:08:30.00	But, another couple postdocs,
00:08:32.19	Bob Linhardt, who's now Constellation Professor of Chemistry
00:08:35.28	at RPI,
00:08:37.20	and Kam Leong, who's a James Duke Professor of Bioengineering
00:08:40.05	at Duke University,
00:08:41.18	also was elected to the National Academy of Engineering,
00:08:44.02	and they showed there was no reaction.
00:08:46.08	So, we sent it back again,
00:08:47.26	and the reviewers said,
00:08:49.26	well, you know, okay...
00:08:51.10	that's not a problem,
00:08:52.13	but these polymers are low molecular weight,
00:08:54.18	they're fragile, they'll break in the body.
00:08:57.18	But I had another couple postdocs,
00:08:58.28	Edith Mathiowitz, she's now a full professor of Bioengineering
00:09:01.25	at Brown University,
00:09:03.15	she's been elected to the National Academy of Inventors,
00:09:05.25	and Avi Domb,
00:09:07.01	who later became Chairman of Medicinal Chemistry
00:09:09.09	at Hebrew University,
00:09:10.28	and they made polymers that were very strong,
00:09:13.05	high molecular weight polymers
00:09:14.20	and, you know, wouldn't break.
00:09:16.29	So then we sent it back again
00:09:18.23	and the reviewers said, well, you know,
00:09:20.12	new materials are certainly gonna be toxic,
00:09:22.16	but I had another graduate student,
00:09:24.08	Cato Laurencin,
00:09:26.04	Cato later became Dean of Medicine at the University of Connecticut,
00:09:28.12	and he's been elected to actually both the
00:09:30.22	Institute of Medicine of the National Academy of Sciences
00:09:33.10	as well as the National Academy of Engineering,
00:09:36.00	and he showed that they were very, very safe.
00:09:38.19	Anyhow, this kept going on and on until 1996,
00:09:41.07	when the FDA approved the treatment.
00:09:43.05	It was actually the first time
00:09:45.01	in over 20 years they approved a new treatment for brain cancer,
00:09:47.28	and the first time they ever approved
00:09:49.28	this idea of polymer-based chemotherapy for cancer.
00:09:53.28	You can probably tell from the way I'm speaking
00:09:56.15	that I'm very proud of...
00:09:58.05	well, all the graduate students and postdocs
00:10:00.08	that they became chairpeople of departments,
00:10:03.17	presidents of large corporations,
00:10:05.29	received all kinds of honors,
00:10:07.23	whereas the reviewers...
00:10:09.29	they haven't done that well.
00:10:12.13	Now, I'd like to actually show
00:10:15.09	what the operation looks like,
00:10:16.15	but these are gonna be fairly bloody slides,
00:10:18.25	so people shouldn't look
00:10:20.28	if they don't want to,
00:10:22.21	but this is gonna be a little wafer going into the human brain,
00:10:26.14	and you can see that here,
00:10:28.18	it's the white part,
00:10:30.00	and usually they put 6 or 7 in and then close up the brain.
00:10:33.17	So, I should point out that,
00:10:37.28	you know, it's very hard to get good advice when I give a talk,
00:10:40.24	but my wife once came to one of the talks I gave
00:10:42.28	and I asked her about it...
00:10:44.19	this was a talk to a group of engineers at MIT,
00:10:46.16	and she told me that
00:10:48.23	I had left those two bloody slides on for 10 minutes
00:10:51.06	explaining all the details,
00:10:53.09	and unfortunately all of the engineers got,
00:10:55.10	I guess, very ill,
00:10:57.11	and I should have noticed that.
00:10:59.05	So, now I don't leave them on very long
00:11:01.11	when I talk to engineers, so I apologize for that.
00:11:04.20	At any rate,
00:11:07.11	this was some of the clinical data
00:11:09.05	that was published in Neurosurgery
00:11:11.06	and from the European clinical trials.
00:11:13.12	It's what called a Phase 3 clinical trial,
00:11:15.29	and what you see is at the end of two years
00:11:20.18	you do see significantly increased survival.
00:11:24.00	It's not a cure by any means,
00:11:26.03	but what's been exciting is that now...
00:11:31.09	for patients who have, you know, sometimes localized tumors,
00:11:34.20	this treatment has been approved by the FDA,
00:11:36.23	it's been used in over 30 countries
00:11:38.21	for the last 18 years,
00:11:40.07	and it created a new paradigm
00:11:41.25	for how one would think about local chemotherapy.
00:11:45.17	Not only might you use it in cancer,
00:11:48.01	and people are studying it in other kinds of cancer,
00:11:50.06	but you might also use it in other diseases,
00:11:52.14	and in fact one of my other graduate students,
00:11:54.27	former graduate students,
00:11:56.14	Elazer Edelman, who's now a professor at Harvard and MIT,
00:11:59.29	as well as a number of companies
00:12:01.19	like Boston Scientific,
00:12:03.14	have used these ideas in the area of drug-eluting stents,
00:12:06.08	and that's been a huge area in interventional cardiology.
00:12:09.17	Today, if somebody has heart disease,
00:12:11.18	one of the things that are often done
00:12:14.04	is to prop open the blood vessel
00:12:16.12	by putting a stent in,
00:12:18.07	it's like a Chinese finger puzzle,
00:12:20.02	but about half the time
00:12:22.06	what happens is it closes off
00:12:24.06	because of smooth muscle cell proliferation.
00:12:26.23	And now what's done is to coat these stents
00:12:29.02	with a polymer
00:12:31.00	that locally delivers a drug like another anti-cancer drug by Taxol,
00:12:35.01	and that prevents that proliferation,
00:12:37.00	and these are used in about a million patients every year
00:12:39.07	and have had very profound effects.
00:12:41.20	Now, what I'd like to do
00:12:45.12	is go the second part of the talk,
00:12:47.01	where I'd like to talk to you about
00:12:49.05	using materials to create new tissues and organs
00:12:51.23	by combining materials with cells.
00:12:53.27	Here, I've worked very closely with Jay Vacanti.
00:12:56.02	Jay is head of the pediatric surgery program
00:12:58.20	at Massachusetts General Hospital,
00:13:00.24	and he and I have been working on this
00:13:04.02	for, now, over 30 years,
00:13:06.05	and the reason this came about is he would see patients
00:13:08.07	who had liver failure, like this little boy,
00:13:11.06	who were dying,
00:13:12.24	and there was no way to treat them other than a transplant
00:13:14.27	and there weren't nearly enough transplants.
00:13:17.13	And so, he and I started talking about this
00:13:19.12	and asked, could we come up with a way
00:13:22.00	to maybe use the patients own cells
00:13:24.02	or a relative's cells or someone's cells,
00:13:27.00	combined with materials,
00:13:28.18	to create new tissues and organs?
00:13:30.25	The specific idea we had is shown here.
00:13:33.17	This is from a paper we wrote in Science many years ago,
00:13:36.24	and the idea was you could take these cell types,
00:13:40.07	you see osteoblasts, which are bone cells,
00:13:42.11	or chondrocytes, which are cartilage cells,
00:13:44.18	hepatocytes, which are liver cells,
00:13:46.14	and so forth,
00:13:47.28	and you'd dissociate them...
00:13:49.27	today, you might also consider using stem cells
00:13:52.16	and converting them to one of these,
00:13:54.19	but if you take these cells
00:13:56.10	and inject them at random in the body,
00:13:58.04	not much happens.
00:13:59.16	But, the cells are small and people,
00:14:01.04	for example at Berkeley,
00:14:03.05	have shown that you can take mammary epithelial cells
00:14:05.09	and put them close together
00:14:07.09	and when you do that, they're smart enough
00:14:08.29	to actually make acini and make milk,
00:14:11.16	and our theory was that if we could create
00:14:14.02	the right kind of polymer
00:14:15.22	and biodegradable scaffold,
00:14:17.11	and the cells would be close enough together,
00:14:19.09	and they were grown under the right in vitro tissue culture conditions
00:14:23.01	in what we call bioreactors,
00:14:24.22	maybe we could make a new tissue
00:14:26.12	and ultimately put it in the body.
00:14:28.20	There are a number of components to this,
00:14:31.09	as one sees on this slide.
00:14:32.24	The first component was having the right materials,
00:14:34.20	and we would generally use degradable materials
00:14:37.06	that had been shown to be safe in people,
00:14:38.26	and in many cases we synthesized new materials ourselves.
00:14:42.23	We might then convert them to fibers,
00:14:44.21	where we could put cells on
00:14:46.19	like you can see in this scanning electron micrograph,
00:14:49.06	but also the way this field is going,
00:14:51.21	we also thought that you might someday
00:14:53.27	be able to even use techniques
00:14:56.08	like CAD/CAM techniques,
00:14:58.17	computer-aided design is what I basically mean,
00:15:01.14	and just to illustrate that,
00:15:03.12	this is work that Prasad Shastri, who was a postdoc with us, did.
00:15:07.02	He basically was thinking about
00:15:10.09	making new structures like a nose, which you see here,
00:15:13.14	and so he basically designed a nose
00:15:16.01	with a foaming technique...
00:15:17.27	you could also use 3-D printing,
00:15:19.28	other ones of my former postdocs like Linda Griffith
00:15:22.12	have done things like that,
00:15:24.10	she's a professor at MIT now...
00:15:26.14	and the idea is that
00:15:29.12	you could make basically a nose.
00:15:33.09	It's 98% porous,
00:15:36.09	but it's made of a polymer of, in fact, poly(L-lactic acid),
00:15:40.06	and you could make this nose into any shape,
00:15:41.19	so I've just speculated 30 or 40 years from now,
00:15:44.19	maybe they'll be a computer printout
00:15:47.13	that somebody could pick,
00:15:49.03	when they're going to a plastic surgeon,
00:15:51.10	whatever nose shape they want.
00:15:52.24	So, they could have a regular nose shape,
00:15:55.01	or maybe they'd want an upturned nose shape,
00:15:57.04	which wouldn't be hard, you'd just take a little bit of this off.
00:15:59.28	You can even give a hooked nose shape...
00:16:02.02	probably nobody would want that, but you could do it.
00:16:04.03	And then maybe you take the patients own cells
00:16:06.11	and put that on the scaffold,
00:16:08.16	and so these are just some examples.
00:16:11.22	So, I thought I would go through a few examples
00:16:14.23	just to illustrate some of the challenges
00:16:16.18	and some of what we and others do.
00:16:19.00	So, let's say you want to make a new blood vessel.
00:16:20.28	That's been very challenging;
00:16:22.10	there's not been a way to make small diameter blood vessels.
00:16:25.11	So, one of our students,
00:16:27.02	David Mooney, who is now a professor at Harvard,
00:16:30.03	made these little tubes
00:16:31.28	out of a polymer that are also about 97-98% porous,
00:16:36.14	and then Jinming Gao, another postdoc,
00:16:39.27	he's now a professor at Texas Southwestern,
00:16:42.15	modified polyglycolic acid (PGA)
00:16:45.24	so that you could get a high attachment density
00:16:48.07	of what are called smooth muscle cells,
00:16:51.02	and the person who led this project
00:16:53.17	was Laura Niklason,
00:16:55.10	she was a fellow with us and now is a full professor at Yale,
00:16:58.07	and her idea was,
00:17:00.05	you know, nobody had ever been able to make a blood vessel before
00:17:02.24	and we and others had tried making these to try to grow them,
00:17:06.12	but the way you actually culture something is important.
00:17:09.08	Normally, when people grow cells
00:17:11.08	it's sitting in a petri dish that's stationary,
00:17:13.04	maybe there's a little bit of movement,
00:17:15.05	but what Laura said, you know,
00:17:16.24	that's not what happens in the body.
00:17:18.13	In the body, a blood vessel doesn't just stay there,
00:17:20.11	it's actually hooked up to a pulsatile pump,
00:17:22.13	your heart.
00:17:23.26	So she said, to get this to work,
00:17:25.13	we're gonna need to make a bioreactor
00:17:27.09	that really mimics that,
00:17:28.21	and so would create what we call pulsatile radial stress.
00:17:31.28	So, she did that.
00:17:33.13	She figured out the right medium
00:17:35.05	and had the pulsatile pump,
00:17:36.19	and over a several month period,
00:17:38.11	would pump that media in this pulsatile fashion,
00:17:40.15	165 beats per minute,
00:17:43.08	and try to make blood vessels.
00:17:45.05	And she was able to do that,
00:17:46.26	this was published in Science,
00:17:48.25	and made these tiny little blood vessels,
00:17:51.14	and when she characterized them
00:17:53.24	they were very, very similar
00:17:55.29	to regular blood vessels:
00:17:57.16	50% collagen,
00:17:59.01	their rupture strengths are greater than 2000 mm of mercury,
00:18:02.11	you can suture them in
00:18:04.20	and they're very strong,
00:18:06.09	and they show the same pharmacology
00:18:08.09	as a regular blood vessel.
00:18:12.23	We worked with Bill Abbott to try to put these into pigs,
00:18:15.24	which is considered the best model for blood vessels,
00:18:18.08	and here you see an angiogram
00:18:20.08	where the blood vessels are open, months later.
00:18:24.09	And Laura has actually taken this work a lot farther,
00:18:26.18	she actually started a company on this
00:18:28.27	and actually they're in multiple clinical trials,
00:18:31.05	actually using a variation of this,
00:18:33.16	a decellularized construct,
00:18:36.15	meaning she's taken the cells off
00:18:38.27	after she's made it,
00:18:42.27	and so that's now been used in a number of patients.
00:18:49.04	Now, I want to move on to cartilage as another tissue,
00:18:54.00	and this work was done with Lisa Freed,
00:18:56.06	Gordana Vunjak,
00:18:57.12	Chuck Vicanti,
00:18:58.23	and Jay Vicanti,
00:19:00.10	and here what we did is we took nude mice
00:19:03.19	and basically mimicked what someday might
00:19:06.10	happen in a person.
00:19:09.00	So, what happened here
00:19:11.05	is that you could take the cartilage,
00:19:13.06	and you could take it from an animal and redo it,
00:19:16.10	and if you look at the animal on the right,
00:19:18.07	we've redone his skull.
00:19:21.10	If you go to the next set of animals
00:19:22.27	and you look at the animal on your left,
00:19:25.13	we've redone his cheek.
00:19:27.03	If you open the animal and look at it,
00:19:28.17	it's pure white, glistening cartilage.
00:19:30.20	And actually, biochemically,
00:19:32.01	it looks like cartilage,
00:19:33.17	but it's still not of a good enough mechanical strength
00:19:36.25	that you can help people,
00:19:38.19	at this point at least in our research,
00:19:40.11	that if they had a weight-bearing injury,
00:19:42.09	that you could do anything.
00:19:43.29	So... but it is able to help people
00:19:46.03	with various cosmetic issues,
00:19:47.28	and so we actually had been approached...
00:19:50.04	have worked with the army,
00:19:51.22	the United States Armed Forces
00:19:53.02	Institute for Regenerative Medicine,
00:19:54.25	and they have patients that come back
00:19:57.12	from like Iraq or Afghanistan,
00:19:58.28	say, without certain body parts like an ear.
00:20:01.01	So Linda Griffith, one of our former postdocs,
00:20:03.16	and I mentioned she's now a professor at MIT,
00:20:05.11	actually made a scaffold in the form of the ear.
00:20:08.03	You see that on the top,
00:20:09.16	and on the bottom you see a scanning electron micrograph of it,
00:20:12.08	and you actually see the cells
00:20:13.25	and the matrix growing,
00:20:15.14	and over time you'll see more cells and matrix growing,
00:20:18.01	and the fibers that you see, they'll disappear,
00:20:20.25	and you'll actually get an ear.
00:20:22.08	And in fact, this has not been put on patients,
00:20:26.01	but it has been put on animals and it's been shown to work.
00:20:29.09	And in fact, Jay, my colleague,
00:20:31.20	has even put some of these systems on human beings,
00:20:37.10	in what are called physician-sponsored INDs.
00:20:40.14	Here's a 12-year old boy at the time,
00:20:42.19	and if you look at him he's got no chest covering his heart,
00:20:46.03	but he, like other 12-year olds,
00:20:47.17	likes to play baseball.
00:20:49.10	But you can imagine, if he ever got hit in the chest with a baseball,
00:20:51.08	he could die.
00:20:53.07	So actually, Jay operated on him,
00:20:54.26	we made a scaffold for him,
00:20:56.12	and Jay created a whole new chest for him
00:20:58.02	and he's doing fine.
00:21:00.07	Also, we licensed the technology
00:21:02.19	that we developed to different companies,
00:21:06.04	and some of them have now made artificial skin
00:21:08.08	for burn victims,
00:21:09.22	and let me just show you that.
00:21:11.17	Here, for example, is a 2-year old boy.
00:21:14.04	He's very badly burned,
00:21:18.05	and you can create a product which has now been done,
00:21:20.26	and it's actually approved by the FDA
00:21:23.16	and been used in many patients,
00:21:25.18	but the idea is that you have a polymer scaffold,
00:21:28.15	you can put on neonatal skin fibroblasts,
00:21:32.17	and you can actually cryopreserve these,
00:21:34.22	but then you come back and you put it in the child at the time of injury,
00:21:38.25	like this.
00:21:40.29	We'll come back three weeks later
00:21:43.02	and he looks better,
00:21:45.03	and six months later he's pretty much healed.
00:21:47.05	So, these have been approved now by the FDA
00:21:49.27	for patients who have been burned
00:21:51.18	and patients who have diabetic skin ulcers.
00:21:55.01	And, the final example I wanted to give you,
00:21:57.07	which is very early,
00:21:59.08	but could you someday even help people
00:22:01.12	who have paralysis - spinal cord repair?
00:22:03.22	And this project was led...
00:22:05.23	it was started in our lab by a woman named Erin Lavik,
00:22:08.13	who's now a professor at Case Western Reserve,
00:22:11.05	and this was done in collaboration with Ted Teng,
00:22:13.14	who's a neurosurgeon,
00:22:15.06	and Evan Snyder, who's a neuronal stem cell expert at the Burnham,
00:22:18.21	and basically the idea was,
00:22:21.12	could we make a scaffold that would mimic the grey and white matter
00:22:24.13	of the spinal cord?
00:22:25.28	And have an outer part that would be
00:22:28.20	sort of microfabricated or nanofabricated in a certain way
00:22:31.28	to provide axonal guidance,
00:22:33.26	and an inner part where we could create pores
00:22:36.25	where we could put neuronal stem cells
00:22:38.27	that we got from Evan.
00:22:41.01	And, just to show some pictures,
00:22:43.25	on the top-left hand panel
00:22:45.17	you see the scaffold, macroscopically.
00:22:47.26	Next to that,
00:22:49.09	you see a scanning electron micrograph
00:22:50.29	that shows you the pores,
00:22:52.24	and you see another vision of that right next it.
00:22:55.23	Below it,
00:22:58.05	you see a scanning electron micrograph
00:22:59.26	of the outer part that Erin created,
00:23:02.01	and notice the nanopatterning
00:23:04.02	to aid in the axonal guidance.
00:23:05.28	And finally, this, on your...
00:23:09.15	here, is the experiment.
00:23:12.09	Basically, you take the spinal cord,
00:23:15.00	you remove a portion of it,
00:23:16.29	and then you do one of four things in our studies.
00:23:19.23	We basically did nothing, that's a sham operation,
00:23:23.00	or you put cells in, that's the second set of controls,
00:23:26.17	the scaffold by itself, that's third,
00:23:28.24	and the scaffold/cell combination,
00:23:31.08	which would be the experiment.
00:23:33.05	And these animals, Erin and Ted followed them
00:23:35.05	for over 400 days,
00:23:37.24	and really looked at behavioral studies
00:23:40.03	and track tracing and other things.
00:23:42.25	So, let me just show some of the results.
00:23:45.29	So first,
00:23:47.21	I'll just show a typical control animal,
00:23:50.09	and notice that he's not able to move his...
00:23:54.26	support his weight very well on the backside,
00:23:57.15	and as you'll see,
00:24:00.05	the paws are splayed are in a rather awkward fashion.
00:24:02.22	So he'd get what's called a BBB score
00:24:05.00	of about 5 out of a possible 20.
00:24:07.00	This is done 100 days
00:24:09.03	after the start of the experiment,
00:24:11.04	and we'll just look at this for a little while longer.
00:24:16.12	Now, if we go to a typical treated animal,
00:24:20.01	the mean of the treated group...
00:24:22.01	this is not a cure by any means,
00:24:23.27	but he is able to bear his own weight,
00:24:27.01	and notice how the paws
00:24:29.06	are splayed in a much more normal way.
00:24:32.08	You'll see this more clearly in a second,
00:24:35.24	and he gets a BBB score of about 14 out of 20.
00:24:38.25	Like I said, it's not a cure, but it's an improvement.
00:24:41.01	There are the paws.
00:24:44.03	And so, we basically did 52 animals,
00:24:46.15	13 in each group,
00:24:48.18	and got, you know,
00:24:51.19	good data with both the cell/polymer scaffold
00:24:53.26	and the scaffold actually by itself.
00:24:56.24	Then, this went to monkeys,
00:24:58.19	African green monkeys,
00:25:00.10	and this was done by Eric Woodard
00:25:01.28	and John Slotkin
00:25:03.11	and InVivo Therapeutics,
00:25:05.01	and here's the monkeys.
00:25:06.25	They're put on a treadmill test
00:25:08.22	and what happens is,
00:25:11.12	in the controls they're not able to move the one leg
00:25:14.02	that's been injured,
00:25:15.28	but when you give the scaffold or scaffold/cells
00:25:19.05	they do much better.
00:25:21.05	It's again not a cure,
00:25:22.17	but it's a significant improvement,
00:25:25.09	and what's happened now is, based on this,
00:25:27.21	the FDA has actually given the go-ahead
00:25:29.19	for the start of human clinical trials
00:25:31.21	at a number of hospitals around the United States,
00:25:34.04	so we'll learn more about what happens in humans,
00:25:38.27	I believe, in the next year.
00:25:40.28	So, in summary,
00:25:43.14	what I've tried to go over in this lecture
00:25:45.25	is how one can create new materials
00:25:48.22	to solve different medical problems,
00:25:51.07	and how one can create materials
00:25:53.17	and combine them with cells
00:25:55.13	to someday make new tissues and organs.
00:25:57.20	All this work in all these slides
00:25:59.25	really was made possible
00:26:01.26	by the terrific funding agencies
00:26:04.00	that have been very kind to us,
00:26:05.29	like the National Institutes of Health
00:26:07.16	and National Science Foundation,
00:26:09.04	the Gates Foundation,
00:26:10.19	and other foundations,
00:26:12.10	different companies,
00:26:13.27	and most of all, really,
00:26:15.19	it's been the terrific work
00:26:17.24	of really a wonderful group of student and postdocs
00:26:20.26	at MIT and Children's Hospital over the years
00:26:22.16	that have made this possible.
00:26:24.14	Thank you very much for having me.