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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.

This material is based upon work supported by the National Science Foundation and the National Institute of General Medical Sciences under Grant No. 2122350 and 1 R25 GM139147. Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speakers and do not necessarily represent the views of the Science Communication Lab/iBiology, the National Science Foundation, the National Institutes of Health, or other Science Communication Lab funders.

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