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Session 8: Controlled Drug Release Technology
With Robert Langer
The traditional way of taking a drug, such as a pill or injection, often results in plasma drug levels that cycle between too high and too low. To better maintain drug levels in the effective range, scientists have developed a variety of systems that release drugs at a steady rate for days or even years. In his first talk, Bob Langer gives an overview of many of these controlled release technologies, including polymer and pump systems.
Langer begins Part 2 with the story of how he became interested in drug release technologies, which is also a story of the power of perseverance. As a post-doc with Judah Folkman, and after much trial and error, Langer developed a polymer system that provided a slow and constant release of an anti-angiogenesis factor. Initially, his results were met with skepticism, by both scientists and the patent office. Today, many, many companies have developed peptide delivery systems based on that original work. Langer also describes ongoing research in areas such as targeted drug delivery and externally controlled microchips designed for drug delivery.
In Part 3, Langer focuses on the materials used in drug delivery and medical devices. Many of the original materials used in medicine were adapted from completely unrelated uses and often generated their own problems. Langer describes work by his lab and others to make polymers designed for specific medical uses. For instance, a porous polymer can be shaped into an ear or nose and act as a scaffold onto which a patient's cells can be seeded to grow a new structure. Different polymers have been successfully used as scaffolds to grow new blood vessels or artificial skin for burn victims.
Controlled Drug Release Technology
Concepts: Plasma drug levels, optimizing drug release, drug release technologies
00:00:07.14	So, my name is Bob Langer.
00:00:09.07	I'm a professor at MIT,
00:00:10.27	and I'm going to be discussing,
00:00:13.03	in this first lecture,
00:00:14.19	to give you an overview
00:00:16.10	of this area of controlled drug delivery technology,
00:00:20.18	and in the second lecture...
00:00:23.05	I've listed the lectures here...
00:00:25.01	I'll be talking about
00:00:27.00	some of our own work
00:00:29.27	that lead to some of these drug delivery systems
00:00:32.07	and also some future work
00:00:34.15	in nanotechnology and other areas
00:00:36.09	that I think will be exciting for the future of drug delivery.
00:00:38.23	And, in the third and final lecture,
00:00:40.08	I'll be talking about biomaterials and biotechnology
00:00:43.13	and I'll give an example, in particular,
00:00:46.06	of how one can create new materials,
00:00:48.02	and I also will discuss
00:00:49.29	how one can combine materials with cells,
00:00:52.07	which helped to lay the foundation
00:00:53.28	of tissue engineering.
00:00:56.03	So, I'll start out by just going over,
00:00:59.06	as is mentioned here,
00:01:01.04	this whole field of controlled release technology,
00:01:03.05	and it's a field that actually
00:01:05.02	now affects hundreds of millions of patients
00:01:08.09	around the world
00:01:10.01	and yet it's still a very new field.
00:01:11.22	Maybe the easiest way to start
00:01:13.12	is to just go over how people generally take drugs.
00:01:15.26	Generally, you take a pill
00:01:18.05	or you might take an injection,
00:01:21.05	but whenever you take any of these drugs
00:01:24.17	what happens is, as we can see in the slide...
00:01:28.14	there are these blue lines
00:01:30.14	which give you a desired range...
00:01:32.17	if you're above that range the drug could be toxic,
00:01:34.28	if you're below it's not effective.
00:01:37.13	One example I sometimes just use is a sleeping pill.
00:01:39.29	If somebody took too much
00:01:43.00	they would die - that's obviously toxic.
00:01:44.26	And, if you took too little then it doesn't work,
00:01:46.28	you don't fall asleep.
00:01:49.05	So, for any drug,
00:01:51.05	you have this desired range,
00:01:53.06	and what happens in a lot of cases
00:01:55.21	is you get this what I'll call peak-and-valley delivery
00:01:58.24	which you see here,
00:02:00.14	meaning that when you first take the drug
00:02:02.10	it starts out at a very low level,
00:02:04.04	then it keeps going up,
00:02:06.05	and then it goes down.
00:02:07.26	And so, you would have to take it again,
00:02:10.13	and there are really two or three problems with this.
00:02:12.13	One is the problem that I just mentioned,
00:02:14.08	that you could get these toxic effects
00:02:15.29	or it may not work.
00:02:17.28	The second effect, the big effect
00:02:20.00	is that people have what are called very poor compliance.
00:02:23.13	People usually don't do what they're supposed to do
00:02:25.23	and they often don't take the drugs
00:02:28.09	when they're supposed to,
00:02:30.07	and that has led to hospitalizations
00:02:32.07	and all kinds of other kinds of problems.
00:02:34.20	So, what somebody would like to do is,
00:02:37.28	when you look at those lines,
00:02:40.00	is to have a pill or an injection or whatever
00:02:43.29	that starts out low but then goes into the desired range.
00:02:47.19	In a way, people have tried to do this for over 100 years.
00:02:52.18	The earliest examples of these
00:02:54.28	are what we called sustained release.
00:02:57.08	Sustained release systems,
00:02:58.23	and people have heard about these probably,
00:03:00.14	are things like tiny time pills
00:03:02.04	and things like that,
00:03:04.00	so rather than what you might have seen in the last slide,
00:03:06.11	where you took, say, a pill maybe every four hours,
00:03:08.25	sustained release probably it lasts for twelve hours,
00:03:11.26	and it kind of blunts those peaks.
00:03:13.25	But, what happens is that you still...
00:03:18.20	you still have to keep taking them,
00:03:21.05	and also you really are not in the desired range.
00:03:24.28	I mean, you're in the desired range
00:03:26.16	maybe longer, but not long enough.
00:03:29.02	So, the way these have been achieve,
00:03:32.00	these sustained release systems,
00:03:34.01	involves different types of chemistry and chemical engineering,
00:03:37.20	like you can have what's called a complex.
00:03:39.23	For example,
00:03:41.20	you want to slow the release down,
00:03:43.13	and the way you might slow the release down
00:03:45.22	is by adding a salt or even complexing it
00:03:48.09	to what's called an ion-exchange resin.
00:03:50.20	Another way of slowing it down
00:03:52.26	is to put what are called slowly dissolving coatings around it.
00:03:55.21	For example, there's something called an enteric coating,
00:03:57.22	and if you have a pill with an enteric coating,
00:04:01.16	the stomach, which often has a lot of acid,
00:04:04.15	will not dissolve that coating,
00:04:07.04	so you won't get release until later...
00:04:10.15	wait until you go past the stomach
00:04:12.21	and the acidity is neutralized.
00:04:16.16	You can also do things like suspensions or emulsions,
00:04:19.25	that decreases the availability of the drug
00:04:22.22	to the body,
00:04:24.22	and even something as simple as a compressed tablet
00:04:26.23	slows release down because the drug
00:04:28.29	won't dissolve as fast.
00:04:30.24	Still, as we look at the bottom part of this slide,
00:04:34.01	what sustained release systems...
00:04:36.07	release drugs generally for short periods of time, like hours,
00:04:39.19	and they require repeated administration.
00:04:41.24	Also, the release rates are very strongly influenced
00:04:44.02	by your environmental conditions.
00:04:46.15	For example, I mentioned,
00:04:48.09	you know, release in the stomach.
00:04:50.05	Well, your stomach pH
00:04:52.03	is very dependent on when you ate your last meal,
00:04:53.25	so there's a lot of variability
00:04:55.23	when you take these kinds of systems.
00:04:57.17	And, with that in mind,
00:04:59.05	what's happened over the last 40 years
00:05:01.04	is the advent of what we now call
00:05:03.02	controlled release formulations.
00:05:04.22	These are often polymers or pumps.
00:05:08.08	They can release the drug
00:05:09.27	for really long periods of times,
00:05:11.23	like not only days but in some cases, as I 'll go over,
00:05:14.19	up to 5 years from a single tiny system.
00:05:17.16	Also, the release rates are only weakly
00:05:19.28	or not at all influenced by the environmental conditions,
00:05:23.01	so you get a fixed predetermined release pattern
00:05:28.05	for a definite period of time.
00:05:30.23	This is just a graph
00:05:32.23	that shows you an idealized case of that.
00:05:35.03	So, rather than getting this kind of peak-and-valley delivery
00:05:38.10	that I mentioned before,
00:05:40.07	what you can get is the drug starts out
00:05:42.15	in a low range, then it goes to the desired range,
00:05:45.09	and it stays there for as long as you want.
00:05:47.24	This is kind of the ideal case.
00:05:50.02	One other thing that I wanted to mention,
00:05:53.08	that's very exciting in this area of drug delivery,
00:05:56.08	is not only the idea of controlling the duration
00:05:59.00	of the drug and controlling its level,
00:06:02.10	but actually in some cases
00:06:04.09	targeting it right to where you want it to go,
00:06:06.17	and there's a lot of research going on in that area.
00:06:10.05	It's still very early,
00:06:11.24	but I'll mention some of this in my second talk,
00:06:15.06	but what people are doing
00:06:17.29	is they're looking at the little fatty particles called liposomes
00:06:21.09	that you can direct to certain cell types.
00:06:24.12	They're also looking at microspheres and microcarriers
00:06:28.00	that you can decorate in certain ways
00:06:30.12	to target them to specific places in the body.
00:06:33.04	And finally,
00:06:35.03	you can attach a drug to a carrier,
00:06:36.28	which might be an antibody or a polymer,
00:06:38.18	to hopefully, again,
00:06:40.12	target it to where you want to go.
00:06:42.12	So, all these are very exciting areas of
00:06:45.04	how you can take drugs
00:06:47.12	and make them do things they could never do before.
00:06:50.13	I thought in this lecture
00:06:52.13	what I want to do is go over
00:06:56.01	the general mechanisms by which this takes place,
00:06:58.13	and generally there's three mechanisms.
00:07:00.26	Diffusion is the first one,
00:07:02.13	and there are two geometries that people often use.
00:07:05.02	What's called a reservoir,
00:07:06.22	and I'll show you a picture of that in a minute,
00:07:08.18	and what's called matrix.
00:07:10.05	The second mechanism involves a chemical reaction,
00:07:14.00	and in the case of the chemical reaction
00:07:15.25	it might cause the polymer to erode, bioerode,
00:07:18.22	which will enable the drug to come out,
00:07:20.20	or you might have what we call a pendant chain system,
00:07:23.22	where the drug is attached to a polymer,
00:07:26.05	let's say,
00:07:28.08	and something comes along and cleaves it off.
00:07:30.14	The third mechanism is the solvent does something.
00:07:33.04	The solvent might cause the polymer to swell,
00:07:36.04	so the drug might be locked into place,
00:07:37.29	but when it swells,
00:07:39.19	now the drug comes out.
00:07:41.06	Or, as I'll show you,
00:07:42.14	there's some very clever ways using what's called osmosis
00:07:44.19	to actually deliver drugs.
00:07:47.04	Finally, and on top of all that,
00:07:49.23	you can actually in some cases
00:07:51.12	make even a smart delivery system,
00:07:53.07	where you can activate it externally
00:07:55.05	and make more drug come out at certain periods of time,
00:07:57.27	and I'll go over that...
00:08:02.08	a little bit of an example of that in my second lecture.
00:08:04.11	So, I'll just go over each of these three fundamental mechanisms.
00:08:08.19	First, diffusion,
00:08:11.11	and the most common way that people set up drug delivery
00:08:14.19	by diffusion is what's shown here,
00:08:16.16	a reservoir.
00:08:18.03	A reservoir,
00:08:19.18	and people have probably seen these,
00:08:21.06	could be a capsule, could be a microcapsule,
00:08:23.23	could be hollow fibers,
00:08:25.13	or the drug could be placed in between two membranes,
00:08:27.29	but basically what we see,
00:08:29.16	and the little dots in this slide
00:08:31.17	illustrate the drug,
00:08:33.03	the blue illustrates the membrane, let's say,
00:08:35.26	or the capsule,
00:08:37.15	and this is just a cross-section.
00:08:39.05	So, what you see is if you go
00:08:47.00	from the left-hand one to the right-hand one
00:08:49.14	is that the little dots...
00:08:52.13	the left-hand one is the system at time 0,
00:08:57.04	but what happens is over time,
00:08:59.07	the dots keep coming out by diffusion.
00:09:01.01	They diffuse through the polymer,
00:09:02.26	and that will keep coming out over really long periods of time.
00:09:06.27	There are a number of polymers that are very commonly
00:09:09.17	used to make these systems,
00:09:11.07	like silicone rubber, EVA,
00:09:12.20	which is ethylene-vinyl acetate copolymer,
00:09:15.09	or different hydrogels.
00:09:17.19	For polymer chemists,
00:09:19.08	one good example would be
00:09:21.12	poly(2-hydroxyethyl methacrylate),
00:09:23.10	but just in general, hydrogels are materials
00:09:25.15	that are used in soft contact lenses
00:09:27.15	and they're very biocompatible.
00:09:29.21	These systems have a number of advantages,
00:09:32.08	you can make them release at relatively constant rates,
00:09:35.24	but one possible disadvantage
00:09:38.02	is if you had a leak,
00:09:39.23	let's say there was a tear in the blue,
00:09:41.23	the drug could dump out.
00:09:43.24	So, what that might mean is if you had a potentially toxic drug
00:09:46.13	like a cancer drug or insulin,
00:09:48.28	you wouldn't probably use a reservoir system,
00:09:51.16	but if you were delivering...
00:09:53.14	let's say you were delivering human growth hormone,
00:09:55.14	or things like that,
00:09:57.13	this would probably be fine.
00:09:59.12	The second system
00:10:01.11	that's also diffusion-based
00:10:03.25	is what we call a matrix system,
00:10:05.20	and again the blue dots represent the drug,
00:10:09.14	and the yellow that you see there,
00:10:12.08	the yellow-green,
00:10:14.22	that's the outside of the polymer matrix.
00:10:17.14	So, in the case of a non-erodible matrix,
00:10:20.08	the drug is uniformly distributed through that matrix,
00:10:23.09	and we see that on the top,
00:10:25.01	but then when we go to the bottom
00:10:27.01	we see the drug diffusing out.
00:10:29.11	And again,
00:10:31.15	it diffuses out through the polymer,
00:10:33.10	but now, because this geometry is different,
00:10:35.11	other things happen.
00:10:37.04	For example, this is not as easy to get steady release,
00:10:39.24	but on the positive side,
00:10:41.24	let's say there was a tear in this matrix...
00:10:44.26	not much more drug would come out
00:10:46.27	because it's embedded throughout this entire matrix.
00:10:49.27	So, this is the first mechanism, is diffusion.
00:10:52.04	The second mechanism, as I mentioned,
00:10:53.25	is a chemical reaction,
00:10:56.06	and one of the very common ways of doing this
00:10:58.20	is a bioerodible system.
00:11:01.15	So, in the case of a bioerodible system,
00:11:04.15	it basically would look, in the beginning,
00:11:06.25	essentially identical to what I showed you on the matrix,
00:11:10.25	but now the yellow, rather than staying the same,
00:11:16.14	in other words, rather than the matrix staying the same size,
00:11:19.26	it actually shrinks and ultimately completely dissolves,
00:11:23.01	and as it dissolves
00:11:25.00	what we see is all those blue dots come out and are released.
00:11:27.22	So, bioerosion
00:11:30.01	provides a whole second mechanism of being released,
00:11:32.13	and the big advantage of bioerosion,
00:11:34.13	thinking about it from the patient's standpoint,
00:11:36.15	if you had an implant and it didn't dissolve,
00:11:40.04	you have to go in and take it out.
00:11:42.24	That's gonna be done in some cases,
00:11:44.05	as I'll mention later,
00:11:46.19	but that's still a disadvantage.
00:11:48.18	It certainly would be preferable for the patient
00:11:50.11	to just have one injection or one implant
00:11:52.10	and never have to worry about it again.
00:11:54.26	So, one mechanism for chemical reaction is erosion.
00:12:00.20	The second mechanism is the idea of the polymer
00:12:03.14	containing a pendant chain,
00:12:05.23	and now what happens is the drug is attached
00:12:08.03	to the polymer backbone,
00:12:10.03	but water or enzyme, as we see in the bottom,
00:12:12.28	comes along and basically breaks the bond
00:12:15.26	and then the drug is released.
00:12:18.06	One of the advantages of this
00:12:19.26	is that you can add a lot of drug to these,
00:12:22.29	but a possible disadvantage
00:12:25.17	is that these are what are called new chemical entities.
00:12:28.13	We've chemically modified the drug by attaching it,
00:12:30.29	so it's a new chemical entity,
00:12:32.14	so you'd have to do a lot more toxicology
00:12:34.13	to eventually get approval,
00:12:36.06	whereas the earlier systems that I talked about,
00:12:38.10	there is no change in the drug,
00:12:39.27	it's just physically embedded.
00:12:42.15	The third mechanism
00:12:44.26	is the solvent does something,
00:12:47.14	and so here we're looking at swelling having an effect,
00:12:50.08	and the idea of swelling is you,
00:12:53.20	again, if we look at the left-hand panel,
00:12:56.18	the drug is dissolved in the polymer
00:12:58.23	and we see it just looking blue,
00:13:00.27	but now, as we go the right-hand panel,
00:13:04.28	what happens is the water goes in
00:13:08.15	and the outer part of the matrix actually swells.
00:13:11.27	So, the drug was locked into place,
00:13:14.02	but now since it's swelling, it can come out,
00:13:18.02	and that takes place over time
00:13:20.15	and that gives you the opportunity
00:13:25.06	to deliver the drug simply based on water.
00:13:27.13	Also, one of the other things
00:13:29.07	that people have sometimes done in the case of swelling systems
00:13:31.17	is make them swell so much
00:13:33.21	that they might stay in the stomach a little longer,
00:13:35.21	and that might also give you a way, if you took an oral system,
00:13:38.25	of maybe making it act longer as well.
00:13:42.07	And, the final mechanism for solvents,
00:13:45.07	and of the one's I'm gonna talk about,
00:13:48.08	is osmotic pressure.
00:13:50.09	And, the idea of osmosis is that what happens is,
00:13:53.04	if you have... let's just say I had two sites,
00:13:58.22	I have site 1 where I have water and a lot of salt in it,
00:14:02.08	like table salt,
00:14:04.16	and I have site 2 that just has water in it,
00:14:07.26	and then they're connected by a membrane.
00:14:10.04	There's a whole field called thermodynamics
00:14:12.20	where what happens is,
00:14:14.16	if you have these two sites
00:14:16.10	and they're separated by the membrane
00:14:18.11	and water can permeate,
00:14:20.03	what they wanna do is have what's called
00:14:22.03	the same thermodynamic activity,
00:14:23.14	so what happens is water will actually
00:14:26.24	rush in from one to the other to actually dilute it,
00:14:29.04	so you'll actually hopefully someday
00:14:31.06	have the same salt concentration on both sides.
00:14:34.12	But, when that happens,
00:14:35.29	that is what leads to osmotic pressure,
00:14:39.21	because water is actually rushing in
00:14:41.18	and there's a certain amount of pressure
00:14:43.23	that is caused by that.
00:14:45.21	That same thing is manifested here in this final mechanism
00:14:48.12	of osmosis,
00:14:50.23	where the drug is dissolved in the polymer,
00:14:53.07	but now water rushes in
00:14:55.08	because the drugs not on the outside and water wants to...
00:14:58.24	the water wants to come in to dilute that drug,
00:15:01.04	and you see these cracks form, these porous openings,
00:15:04.00	and those permit release.
00:15:05.26	Now, one of the issues with this particular system
00:15:08.27	is it's not so reproducible.
00:15:12.07	It's getting cracks...
00:15:13.24	it's not easy to make reproducible cracks,
00:15:15.28	but I want to show you what I think is a very clever approach
00:15:19.06	that has been done
00:15:21.18	where you can actually make an osmotic pump,
00:15:23.26	and what's interesting about this pump...
00:15:25.21	I think when people generally think about pumps
00:15:27.28	you think about pumps that involve mechanical parts
00:15:31.28	and electricity and things like that.
00:15:34.03	The pump I'm gonna show you here
00:15:35.25	has none of that.
00:15:37.15	It's a totally-driven pump,
00:15:39.24	and it can actually give you very, very precise release rates.
00:15:42.12	So, when we look at this slide,
00:15:45.06	let's take a look first at the top left,
00:15:47.23	that's a front cross-section,
00:15:50.03	and the way this has been designed
00:15:52.19	is you've got an outer membrane
00:15:55.02	that's rigid but it's water permeable,
00:15:57.13	so water can go through it
00:15:59.08	and yet the system won't expand.
00:16:01.20	Immediately below that
00:16:04.12	there's another chamber where you see the salt.
00:16:06.17	That salt could be like sodium chloride or potassium chloride.
00:16:10.08	That salt is, again,
00:16:12.11	what's going to cause the osmotic pressure,
00:16:14.10	because there's not much salt on the outside,
00:16:16.03	so water is going to want to rush in to that salt.
00:16:19.17	And, actually you load the salt
00:16:21.18	at a pretty high level
00:16:23.18	so that it's always going to be above it's solubility level,
00:16:26.17	so water will actually rush in at a constant rate.
00:16:29.22	Now, the next chamber,
00:16:31.24	as we keep going to the inside,
00:16:33.29	is a compressible membrane,
00:16:35.24	but that compressible membrane is exactly the opposite
00:16:38.06	of the rigid membrane on the outside.
00:16:40.18	That compressible membrane is water impermeable,
00:16:42.23	in other words water can't get through it,
00:16:44.27	and yet it's compressible, it's not rigid.
00:16:47.17	You might of it like a balloon.
00:16:49.27	And, inside that chamber,
00:16:53.15	you have the dissolved drug.
00:16:55.23	So, the only other thing
00:16:57.23	that I wanted to point out as we look at this top section
00:17:01.20	is now if we looked at a side view,
00:17:03.20	there's actually a laser-drilled hole
00:17:05.13	in the very front of this system,
00:17:07.11	and that is how the drug's gonna come out.
00:17:09.19	But, let me just now go over how it works,
00:17:11.14	and it's really going to be looking at the bottom part
00:17:14.18	of this slide that shows you how that happens.
00:17:18.03	So, what happens is,
00:17:20.12	as I mentioned before, water is going to want to rush in
00:17:23.06	at a constant rate through that rigid membrane
00:17:25.27	and what happens is,
00:17:27.19	as water rushes in at a constant rate,
00:17:30.25	the outer membrane doesn't expand,
00:17:32.14	the whole system doesn't expand, but...
00:17:35.29	so the only thing that can happen
00:17:38.08	is the chamber where we have the salt,
00:17:40.07	that does expand inward
00:17:42.25	because that's the only place the water can go.
00:17:45.16	So, water rushes in at a constant rate,
00:17:48.11	diluting the salt,
00:17:50.13	and it compresses that compressible membrane.
00:17:52.17	It can't get inside that membrane, but it can compress it,
00:17:55.07	and it gets smaller and smaller,
00:17:57.15	and it's kind of almost like squishing a tube of toothpaste,
00:18:00.06	and as you squish it
00:18:02.07	the only thing that can happen
00:18:04.08	is the contents in the center, the solution,
00:18:06.08	go out that laser-drilled hole
00:18:08.16	where you see the drug coming out at the bottom.
00:18:11.02	So, you squish this by osmotic pressure
00:18:13.03	at an exactly constant rate,
00:18:14.21	the drug comes out at an exactly constant rate,
00:18:17.25	and the patient gets steady delivery.
00:18:22.19	So, what's novel about this is
00:18:24.25	this is I think a very interesting example of
00:18:27.13	where different chemical and physical principles
00:18:29.24	are used to design a steady delivery system,
00:18:34.04	and it's actually been widely used.
00:18:36.06	These kinds of systems are used for delivery systems
00:18:38.25	and studying different biological things in animals,
00:18:41.26	and actually variations of it
00:18:43.28	are pills that most people probably take.
00:18:46.09	They may not realize it,
00:18:47.29	but sometimes if you look down
00:18:50.06	very carefully at the pill, you can see a little laser-drilled hole right
00:18:52.26	where they have the label.
00:18:55.01	So, what I've gone over so far
00:18:57.01	are some of the different mechanisms by which these work.
00:19:00.08	Now, I thought I'd turn and show you how they're actually used
00:19:02.08	in different applications.
00:19:04.20	Well, the eye was actually one of the earliest places
00:19:07.21	where people used controlled release.
00:19:10.02	They used it in glaucoma,
00:19:12.19	which is a leading cause of blindness,
00:19:14.11	and in artificial tears, which is very uncomfortable.
00:19:17.06	I'll go over each of these.
00:19:18.25	This was one of the earliest systems
00:19:20.25	developed in controlled release.
00:19:22.12	This was in the 70s, and it was called the Ocusert,
00:19:26.04	and it's a little device that you just put into your eye,
00:19:31.22	it's actually a reservoir system that lasts for one week.
00:19:38.04	Normally, somebody, it they had this disease,
00:19:40.10	would have had to take 28 eye drops.
00:19:44.21	The way it's designed is shown here.
00:19:47.01	It's a reservoir system,
00:19:48.27	just like the very first thing that I went over
00:19:50.28	on those three different types,
00:19:52.22	so you have pilocarpine, that's the drug.
00:19:55.01	It's surrounded by two membranes
00:19:57.00	that really control the rate of diffusion,
00:19:59.21	and what they've done,
00:20:01.09	just so people can visualize it better,
00:20:03.10	is they've put an annular ring right here
00:20:06.17	that's got titanium dioxide in it,
00:20:08.20	and that makes it easy for the patient to see.
00:20:11.03	That's why when you looked at it on the last slide
00:20:13.07	it had this little ring around it on the bottom.
00:20:16.18	So, depending on the thickness of those two membranes
00:20:20.25	that actually controls the rate of release,
00:20:22.22	so what's been done
00:20:24.24	is to make one that releases at 40 µg/hour
00:20:27.09	after an initial burst,
00:20:29.07	and another that releases at 20 µg/hour
00:20:31.17	after an initial burst.
00:20:33.06	But really, again, by using engineering
00:20:35.03	you can make them release at any rate you want,
00:20:37.00	just by controlling the thickness of those membranes,
00:20:39.18	so these are just two common ones that have been used.
00:20:43.17	The next system I wanted to mention was artificial tears.
00:20:46.09	If somebody had dry eye
00:20:48.07	that can be very painful,
00:20:50.12	and the goal is to put something in the eye
00:20:53.16	that might last for a long time,
00:20:55.12	rather than have somebody take eye drops, you know,
00:20:57.15	really every 20 minutes sometimes.
00:20:59.08	So, what's been done is to create an applicator,
00:21:01.24	shown here,
00:21:03.25	which you can use to pick up a little polymer
00:21:07.15	and then drop it in the eye
00:21:10.11	and basically, when you do,
00:21:13.18	it might last for up to 18 hours
00:21:15.23	and hold on to corneal moisture.
00:21:17.29	It's not a perfect system by any means,
00:21:19.28	because one of the things that happens sometimes
00:21:22.02	for some patients is they get blurred vision,
00:21:24.10	but it's an illustration of what you can do,
00:21:26.02	and actually I think it's a challenge for the future
00:21:28.21	to be able to do systems like this
00:21:32.01	that will not have any change in visual acuity.
00:21:36.19	Probably one of the biggest areas
00:21:38.11	where this whole field of controlled release
00:21:40.10	has been used worldwide
00:21:42.12	is in contraceptive systems.
00:21:44.06	There are a number of ways
00:21:46.01	that people have done this:
00:21:47.23	non-erodible subdermal implants, erodible ones,
00:21:52.01	steroid releasing intra-uterine devices,
00:21:53.22	and vaginal rings.
00:21:55.28	I'll go over them briefly.
00:21:57.27	Probably the most widely-known system
00:22:00.18	for contraception using controlled release
00:22:03.02	is a system called the Norplant.
00:22:05.12	It's actually shown here.
00:22:07.22	This is a woman's finger
00:22:09.20	and she has these six sticks,
00:22:11.17	now actually they've designed them so you can just have two of them,
00:22:14.28	but they're very small, they're like matchstick-size.
00:22:17.28	They can be placed underneath the skin
00:22:20.24	and they'll deliver the drug for 5 years.
00:22:22.24	It's just slow diffusion through the polymer,
00:22:25.08	through the reservoir system like I mentioned,
00:22:27.15	and it'll last for 5 years.
00:22:29.05	Here is an example of that,
00:22:31.00	where we're looking at release curves for different patients,
00:22:33.19	and it goes for 2000 days
00:22:35.26	even though it's as small as what I showed you.
00:22:38.16	Another system, also a reservoir system,
00:22:41.27	is what's called the Progestasert,
00:22:45.21	and this system...
00:22:47.22	again, very small, it's an intra-uterine device.
00:22:50.10	These again are a woman's fingers
00:22:52.16	and, again, you put the drug
00:22:55.22	in the center of the system,
00:22:57.29	just like I showed earlier
00:23:00.01	with the picture where the drug was the dots
00:23:03.10	and then it will diffuse out,
00:23:05.15	and here's an example of that,
00:23:07.19	where look at the core matrix.
00:23:09.17	The dots here, again, represent the drug,
00:23:11.19	and the drug will diffuse out
00:23:14.03	over a 365 day period.
00:23:17.01	This is just a curve, it's not exactly constant,
00:23:20.00	but it basically will vary from,
00:23:23.05	over a 400 day period,
00:23:26.05	it's pretty close to 50 µg/day over that period.
00:23:30.21	So, this is a second way that people do it,
00:23:33.14	and there are other controlled release systems as well
00:23:36.12	that have been worked on for contraception.
00:23:40.25	A third area that's been very important
00:23:43.14	is dentistry, actually,
00:23:45.18	that people use controlled release for.
00:23:47.22	If one looks at the percentage of patients
00:23:50.02	who have periodontal disease,
00:23:52.00	it's maybe 25% of the population.
00:23:55.13	To tell if you have periodontal disease,
00:23:57.07	the way I always know is if I go to the dentist
00:23:59.21	and, you know, they brush your teeth a lot harder
00:24:01.24	than we do, or I do at least,
00:24:03.20	and if they start bleeding
00:24:05.24	then you probably have some periodontal disease.
00:24:07.20	It's not pleasant, 2-3% of the people
00:24:10.02	who have periodontal disease require surgery.
00:24:12.19	If you have no treatment
00:24:14.25	the result is no teeth.
00:24:16.11	That's not a very good outcome.
00:24:18.03	If you do surgery, that's painful, it's expensive.
00:24:21.04	There are drugs that people use,
00:24:22.26	like tetracycline, but they make you incredibly sick
00:24:24.21	to your stomach.
00:24:26.20	So, what's been done
00:24:28.26	is to actually make fibers
00:24:32.04	with tetracycline or other drugs,
00:24:34.05	and here you're delivering the drug locally.
00:24:36.27	So, because you're delivering the drug locally,
00:24:38.24	rather than throughout the whole body,
00:24:40.16	the body doesn't get as much
00:24:42.24	and so it's effective,
00:24:45.03	but with much lower dosage,
00:24:46.24	like in this case it's effective with less than 1/1000-th the dose,
00:24:49.23	and the dentist can apply them very quickly,
00:24:51.22	like 3 minutes per tooth.
00:24:53.28	You can barely see them, I'll show you a picture.
00:24:55.26	They get rid of the problem, the spirochetes,
00:24:58.05	and they don't cause irritation.
00:24:59.24	I'll just show you a couple pictures.
00:25:01.26	Here is a picture of the general idea
00:25:05.15	of the hollow fiber in the bottom,
00:25:08.08	just covering the tooth,
00:25:10.12	and it will deliver the drug over time.
00:25:13.01	And, let me just even go further
00:25:15.01	and show you what was done.
00:25:17.06	Originally, they used a reservoir system,
00:25:19.15	this is a hollow fiber,
00:25:21.01	where the drug was placed in the center,
00:25:22.20	but they got some leaks.
00:25:24.13	So, then they went to the matrix system
00:25:26.02	where they uniformly distribute it,
00:25:27.29	and tetracycline is kind of a yellowish drug,
00:25:30.07	so now it's in these fibers
00:25:33.02	but they're uniformly distributed,
00:25:34.27	and what the dentist did,
00:25:37.00	and I'll just show you some pictures...
00:25:39.28	here's a patient with periodontal disease,
00:25:42.01	notice the red gums.
00:25:44.15	Then, what the dentist does
00:25:47.17	is he puts... she puts
00:25:50.13	the matrix systems that are on the teeth
00:25:54.00	like you see them here,
00:25:56.21	and so they are actually on several of the teeth,
00:25:59.12	and that will release the drug,
00:26:01.23	say, over a 10 day period,
00:26:03.12	and when you're done with that,
00:26:05.18	notice the difference in the gums.
00:26:07.17	The problem has gone away.
00:26:09.15	And, there have been many different variations
00:26:11.07	of these that people have used
00:26:13.06	to help people with this problem.
00:26:15.08	Another really powerful example of local delivery
00:26:18.10	is the drug-eluting stent.
00:26:20.26	If somebody has cardiovascular disease,
00:26:23.02	one of the most common ways
00:26:25.08	of treating cardiovascular disease today
00:26:27.19	is to basically prop open the blood vessel
00:26:29.21	with a system like this.
00:26:31.17	This is a stent,
00:26:33.10	and it basically looks like a Chinese finger puzzle.
00:26:35.18	It props open the blood vessel,
00:26:37.06	but unfortunately about 50% of the time
00:26:39.27	when you do this you get a lot of cells,
00:26:42.17	smooth muscle cells proliferating,
00:26:44.16	and they'll block off the blood vessel itself,
00:26:48.02	which isn't good and in the worst case somebody could die,
00:26:51.22	but even short of that
00:26:54.05	you'll have to go in and do another operation.
00:26:56.02	So, what's been done is to take some fairly toxic anti-cancer drugs
00:26:59.26	like Taxol,
00:27:01.27	coat them with a polymer on these stents,
00:27:05.07	and these anti-cancer drugs are anti-proliferative,
00:27:08.15	they prevent the smooth muscle cells
00:27:10.25	from dividing the same way,
00:27:13.26	and basically they keep the blood vessel open,
00:27:16.03	and probably close to a million patients use this every year.
00:27:20.26	Now, I'm gonna move a little bit
00:27:23.20	from local delivery like the teeth and stent
00:27:26.15	to systemic delivery,
00:27:28.20	and again go over a couple of examples.
00:27:31.04	One of the other I think really important areas
00:27:33.28	for controlled release
00:27:36.06	is a lot of times people have come up with new drugs
00:27:38.01	like peptides and proteins
00:27:40.01	in the last 20 or 30 years.
00:27:41.26	One of those was what's called
00:27:43.15	a luteinizing hormone-releasing hormone analog,
00:27:45.22	and that has been shown to be very effective
00:27:48.08	in treating certain diseases
00:27:50.05	like prostate cancer, endometriosis,
00:27:52.10	and other diseases.
00:27:53.24	The problem was,
00:27:55.17	since it's a peptide of 1200 molecular weight,
00:27:57.22	there was no good way to give it to the patient.
00:28:00.02	If the patient tried to swallow it,
00:28:02.02	it's destroyed in the stomach and the GI tract
00:28:05.14	by enzymes.
00:28:06.23	Also, it's too big to get absorbed.
00:28:08.25	They also tried to give it through the nasal passages
00:28:10.24	and other things but, again,
00:28:12.06	none got into the body.
00:28:14.08	So, they injected it,
00:28:16.04	but the problem when you inject it is that enzymes
00:28:18.08	destroyed it right away,
00:28:19.27	so what's now done
00:28:21.20	is to put it in little microspheres
00:28:23.10	like one of those matrix systems,
00:28:24.27	actually a bioerodible matrix system,
00:28:26.24	and what happens is you can actually release it for many days.
00:28:29.25	This is a graph of it,
00:28:31.23	but now Lupron Depot,
00:28:33.08	which has been used by many, many millions of patients...
00:28:36.15	most of these last for about four months.
00:28:39.02	So, you give a single injection every four months
00:28:41.20	for the patient and it will deliver the drug.
00:28:44.23	Another example that's widely used
00:28:48.09	is for patients that have schizophrenia.
00:28:50.19	If somebody has schizophrenia
00:28:52.07	there are also drugs like Risperdal
00:28:54.23	which are quite good for the patient,
00:28:56.29	but a lot of times people forget to take them,
00:29:00.26	and so what's been done
00:29:03.02	is to put them in another type of microsphere,
00:29:06.23	bioerodible system like I was talking about,
00:29:09.20	and they're injected every two weeks.
00:29:11.28	Now, actually, they've come up with one
00:29:14.01	that will be injected every four weeks,
00:29:15.24	again using these kind of principles
00:29:17.12	that I mentioned earlier.
00:29:19.01	And, that's had a huge effect
00:29:22.01	on helping patients that have schizophrenia.
00:29:25.23	It's decreased the amounts of hospitalizations,
00:29:29.21	it's decreased suicides,
00:29:32.08	and probably about five million patients have taken these.
00:29:37.00	Another example, recently approved,
00:29:39.02	is another molecule
00:29:41.08	that may be useful in this case for type 2 diabetes.
00:29:43.10	This is a glucagon-like peptide,
00:29:45.20	and what happened was when it came out
00:29:48.27	it was effective in terms of improving blood sugar
00:29:51.16	after food intake,
00:29:53.24	but you had to give injections twice a day.
00:29:56.05	Now it's put into one of these microspheres,
00:29:58.03	again, one of these bioerodible systems
00:29:59.27	that I mentioned,
00:30:01.23	and it's given once a week
00:30:03.20	from a degradable system called PLGA,
00:30:05.19	which is poly(lactic-glycolic acid).
00:30:10.02	The last area that I wanted to talk about
00:30:13.02	to illustrate some of these points
00:30:14.17	are what are called transdermal systems.
00:30:16.10	For many years, people would have never thought
00:30:18.17	that you could deliver drugs through the skin
00:30:20.22	because you'd think that that might be...
00:30:23.00	you know, if things could get through the skin easily
00:30:25.09	that might be very bad,
00:30:26.25	like somebody could get infected.
00:30:28.15	But what's been found out
00:30:30.28	is that some molecules can actually get through the skin,
00:30:32.22	and what's been done is to make, again,
00:30:35.29	another reservoir system,
00:30:37.15	diffusion-based system, shown here,
00:30:39.22	and the way this is designed
00:30:41.18	is you've got a backing membrane,
00:30:43.13	a drug reservoir which is shown in the middle,
00:30:45.27	a rate controlling membrane,
00:30:47.27	and finally an adhesive.
00:30:49.16	And you just put this reservoir system,
00:30:51.19	diffusion controlled reservoir,
00:30:53.22	on the skin and it will release the drug,
00:30:56.00	and these may last anywhere
00:30:58.11	from a day to a week.
00:31:00.20	The key issue in terms of getting drugs
00:31:03.13	through the skin
00:31:05.09	is pretty much all the resistance
00:31:07.05	in terms of getting the drugs through the skin
00:31:08.25	is the outermost skin layer.
00:31:10.09	It's called the stratum corneum,
00:31:12.10	and actually if you looked at it under a microscope
00:31:14.07	it looks like a brick wall.
00:31:16.09	There are dead cells called keratinocytes
00:31:18.05	and then there are lipid bilayers in between them,
00:31:20.28	and that provides a very tight barrier
00:31:23.10	that makes it very hard for things to get through,
00:31:26.04	but if some molecule has just the right characteristics,
00:31:29.10	like the right molecular size
00:31:31.06	and the right, let's say lipophilicity,
00:31:33.10	meaning how fat soluble it is,
00:31:35.05	actually it can get through.
00:31:37.10	So, I though I'd make a few general comments
00:31:39.12	about transdermal systems.
00:31:41.11	The skin, as I mentioned,
00:31:42.26	is generally impenetrable
00:31:44.20	and the principle resistance
00:31:46.27	is the stratum corneum,
00:31:49.03	which is actually dead skin,
00:31:51.03	but it has this tight sheath, as I mentioned,
00:31:53.19	of keratinocytes and lipid bilayers.
00:31:57.22	The permeability of a drug
00:32:01.16	correlates with its water solubility,
00:32:03.09	its molecular weight,
00:32:05.01	you'd like it to be fairly small,
00:32:06.24	and its oil/water partition coefficient,
00:32:09.07	because if the drug is more what's called lipid-like
00:32:11.09	it's more likely to, you know,
00:32:13.16	if you take the principle "like-dissolves-like",
00:32:15.19	it's more likely to be able to penetrate through the lipid bilayers
00:32:17.25	that I showed you in the last slide.
00:32:20.08	And finally, it's useful...
00:32:22.05	transdermal systems are useful for drugs
00:32:24.01	that have a low dose requirement,
00:32:26.04	the lower the better because of this permeability issue,
00:32:28.06	and also for drugs that have high skin permeability.
00:32:32.09	One of the big areas of transdermal research
00:32:35.10	is the fact that
00:32:37.27	you can enhance permeability by using certain compounds,
00:32:41.07	chemical compounds,
00:32:42.28	and just to give an example,
00:32:44.28	when people have put estradiol in a patch,
00:32:47.23	for postmenopausal women,
00:32:50.20	the flux is not very high,
00:32:52.11	but what they found is that you can take ethanol
00:32:55.10	and you can put it in it,
00:32:57.05	and that will increase the flux by a factor of 20,
00:32:59.13	and what that means for the patient
00:33:01.14	is that they can go from having this giant patch
00:33:03.14	to a much smaller patch,
00:33:05.06	a factor of 20 smaller,
00:33:07.00	and that makes it practical.
00:33:08.16	Also, these transdermal systems
00:33:11.06	are easy to apply and easy to remove.
00:33:15.12	One of the biggest advantages
00:33:17.05	is the fact that when you do something transdermally,
00:33:20.10	rather than orally,
00:33:22.09	you really tremendously reduce the first pass effect.
00:33:25.01	For example, there's lots of drugs that,
00:33:26.15	when you take them orally,
00:33:28.11	they're destroyed by the liver,
00:33:30.17	and that leads to low amounts in the blood
00:33:32.14	and also variability,
00:33:34.19	but transdermal systems can reduce that tremendously.
00:33:38.20	One possible drawback, however, of a transdermal system
00:33:41.26	is that it takes time to reach a steady state,
00:33:44.09	like maybe 2-6 hours in some cases,
00:33:47.17	and what that means is that
00:33:49.14	probably if you had an acute problem,
00:33:51.04	like say, sudden pain,
00:33:52.27	an oral system would be better than a transdermal system,
00:33:55.15	but if you have a chronic situation
00:33:58.03	transdermal is actually quite good.
00:34:01.04	This slide simply shows
00:34:04.13	the flux of different drugs
00:34:07.05	and melting points,
00:34:08.28	but in particular what I wanted to note
00:34:10.29	is if you look at the drug on the top,
00:34:12.19	like say nitroglycerin, scopolamine, fentanyl...
00:34:14.16	all of which are used clinically
00:34:17.21	in transdermal systems,
00:34:19.07	their fluxes are pretty high,
00:34:21.06	but if you go down closer to the bottom
00:34:23.14	and you look at estradiol,
00:34:25.15	estradiol has a lower flux,
00:34:27.11	so the only way to really get that to
00:34:29.24	become a useful transdermal system
00:34:31.18	is you have to have a permeation enhancer,
00:34:34.21	and that would move estradiol up higher
00:34:38.25	so it would be more like the scopolamine,
00:34:40.15	fentanyl, and nitroglycerin fluxes.
00:34:44.14	On the final slide,
00:34:46.04	I just wanted to expand that point a little bit further
00:34:48.18	and go over methods of enhancement.
00:34:51.03	This is a big area probably for the future,
00:34:54.16	because most drugs...
00:34:55.28	right now there's only about 20-25 drugs
00:34:57.21	or drug combinations
00:34:59.19	that are given transdermally,
00:35:01.17	even though they're used by millions of patients.
00:35:04.09	We'd like to expand the numbers of drugs
00:35:07.16	that could be given this way,
00:35:09.26	so one way of doing it
00:35:12.05	that people are looking at is electric fields
00:35:14.05	like by iontophoresis.
00:35:15.29	Could you actually take an electric field
00:35:18.21	and apply it to a drug
00:35:21.18	so that the drug could go through the hair follicles or sweat ducts?
00:35:24.29	And, this is experimental,
00:35:26.28	but may some time be useful for delivering peptides,
00:35:30.01	for example, in patches.
00:35:31.25	Electroporation, that's a second method,
00:35:34.11	and it also involves electricity,
00:35:36.06	but it involves creating new pathways,
00:35:37.29	new pores in the skin that are just temporarily there,
00:35:41.01	and even though it's an early stage
00:35:43.07	it's shown very, very large increases,
00:35:45.09	like 10^4 increases in permeation
00:35:48.08	and is in clinical trials in some situations.
00:35:51.06	The third are is ultrasound.
00:35:52.25	Ultrasound... actually
00:35:54.13	there has already been an ultrasound system approved by the FDA
00:35:57.07	for delivering pain medications,
00:35:59.08	and one of things the ultrasound does
00:36:01.21	is it gets rid of any type of lag time,
00:36:04.03	but also tremendously increases permeation of drugs,
00:36:07.24	and people are exploring it for
00:36:10.19	different types of large molecules.
00:36:13.02	For all of these three,
00:36:14.24	iontophoresis, electroporation,
00:36:16.05	and ultrasound,
00:36:18.08	one of big challenges is engineering
00:36:20.08	and miniaturizing
00:36:22.14	and making less expensive the units,
00:36:24.09	so that you could make a small patch
00:36:26.09	that the patient could conveniently wear.
00:36:28.17	In addition to these methods,
00:36:30.08	there are chemical methods like making a drug more lipophilic
00:36:33.27	by making what's called a prodrug,
00:36:35.23	that means attaching something lipophilic to the drug
00:36:38.18	and, as I mentioned, penetration enhancers.
00:36:41.00	So, drug delivery, in summary,
00:36:43.26	is actually a very, very broad area.
00:36:45.13	It involves a lot of chemical
00:36:47.22	and physical and biological principles.
00:36:49.15	It's been very, very important
00:36:51.01	for delivering all kinds of drug up until now,
00:36:54.09	and I believe it will probably be even more important
00:36:56.15	in the future as we come up with...
00:36:58.13	and the world comes up with new drugs
00:36:59.29	like siRNA, mRNA, DNA, gene editing,
00:37:05.21	all kinds of approaches
00:37:08.01	where really I think the delivery
00:37:10.03	will end up being critical
00:37:12.15	to getting these important molecules
00:37:14.10	into the cells where you want them.
00:37:16.10	Thank you very much.
Why is drug delivery design an important field of study for advancing therapeutics
In the last minute of his lecture, Dr. Langer suggests that drug delivery technology is imperative to expand the scope of possible therapeutics to include DNA, RNA, and gene editing. Why is the method of delivery particularly important for these therapeutic options?
What are some remaining issues with the drug delivery systems discussed in this lecture?
Drug Delivery Technology: Present and Future
Concepts: Drug release technologies, targeted drug delivery, drug delivery using microchips
00:00:07.17	My name is Bob Langer
00:00:08.28	and I'd like to now go over the second lecture,
00:00:11.19	which is Drug Delivery Technology:
00:00:13.13	Present and Future,
00:00:15.15	but I should briefly summarize
00:00:17.28	what I went over in my first lecture.
00:00:19.27	And, in that first lecture,
00:00:21.08	I discussed the fact that controlled release systems
00:00:23.02	offer long-term drug release
00:00:25.10	with release rates primarily determined
00:00:27.09	by the system itself,
00:00:28.29	and I went over some different ways that one could achieve that,
00:00:32.04	and I in particular went over
00:00:34.20	how one might design certain polymer systems
00:00:37.10	or pump-based systems to do that.
00:00:40.17	Now what I'd like to do is actually go back in time
00:00:42.17	and tell you how I got involved in this area in the first place,
00:00:46.13	and then talk to you about
00:00:49.07	some of the systems we developed
00:00:50.28	and even some of the ones we're developing for the future.
00:00:54.03	So, when I got done with my doctorate it was 1974
00:01:00.05	and I was in chemical engineering,
00:01:01.26	and most of my friends at the time
00:01:03.28	went into the oil industry, there was a gas shortage then
00:01:06.09	and they had lots of jobs,
00:01:08.12	but I got a lot of job offers from the oil companies
00:01:10.24	but I wasn't very excited about it,
00:01:12.28	and I was looking for a way to try to use my chemically engineering background
00:01:16.01	to either help in education or human health,
00:01:19.17	and I was very fortunate that Judah Folkman,
00:01:21.28	who was a surgeon,
00:01:23.25	offered me a job in his lab
00:01:26.14	on something very, very different,
00:01:28.06	but that I felt was incredibly exciting.
00:01:30.10	And I though I'd start out and just show you a picture,
00:01:34.08	actually from the New York Times, in 1971,
00:01:37.07	of Dr. Folkman's vision of how tumors grow,
00:01:40.29	and what he proposed is that a tumor cell
00:01:45.18	would somehow be created
00:01:47.29	and it would grow to a 3-dimensional mass,
00:01:49.25	and it would never get larger than say about a millimeter cubed,
00:01:53.12	because it ran into a nutrition problem.
00:01:55.17	Cells in the center would die
00:01:57.15	because they couldn't get nutrients or get rid of wastes.
00:02:01.07	Well, what he said is that somehow the tumor
00:02:04.02	is able to solve that problem
00:02:06.12	because the tumor would create a chemical signal
00:02:08.21	which he called TAF, tumor angiogenesis factor,
00:02:12.08	that would diffuse to the surrounding blood vessels
00:02:14.23	which normally didn't do anything,
00:02:16.22	but when the TAF was there
00:02:19.02	it would cause them to multiply and grow,
00:02:21.11	and grow right to the tumor,
00:02:22.29	and that would cause a second phase of growth,
00:02:25.14	which you see here.
00:02:27.05	And, in that second phase of growth,
00:02:29.07	the tumor is vascularized
00:02:31.00	and that solves the nutrition problem for the tumor.
00:02:34.03	It gets bigger and bigger
00:02:36.10	and ultimately can spread through those blood vessels,
00:02:38.03	a process called metastasis,
00:02:39.29	and eventually kill.
00:02:41.24	Dr. Folkman's idea, which is I didn't realize
00:02:44.10	but was very controversial at the time,
00:02:46.08	was that it you could stop the blood vessels from growing,
00:02:48.17	achieve anti-angiogenesis,
00:02:51.04	maybe that would be a whole new way of thinking
00:02:53.05	about stopping cancer.
00:02:55.18	So, when I came to his lab in 1974
00:03:01.02	there was no such thing as an angiogenesis inhibitor,
00:03:03.20	and he asked me to isolate, actually,
00:03:06.03	what would become the first of these.
00:03:09.03	How do you think about a problem like that?
00:03:11.05	Well, we kind of broke it up into two parts.
00:03:13.06	First, where could you find something
00:03:15.13	that might stop blood vessels from growing,
00:03:17.13	and one of the things that we thought about was cartilage,
00:03:19.24	which is in your nose and your knee,
00:03:21.24	and cartilage doesn't have blood vessels.
00:03:24.04	So, I was able to get some cartilage
00:03:28.11	from the little rabbits we had in the lab,
00:03:30.00	but I couldn't get that much.
00:03:31.29	So then, I started thinking,
00:03:34.07	you know, well where can I get more?
00:03:35.27	...you know, and I found a slaughterhouse
00:03:38.07	that had cows and I got some of their bones,
00:03:41.03	but still I could only get a couple bones.
00:03:43.08	So, I found out, where do all of the cow bones
00:03:47.09	in the Northeast go,
00:03:49.02	and they go it turns out to a slaughterhouse,
00:03:51.01	to some meatpacking places in south Boston.
00:03:53.08	So I made an arrangement with them to get all their bones
00:03:55.10	and I'd bring them back to the lab
00:03:57.20	and I would process them,
00:03:59.15	meaning that I would scrape meat off of the bones,
00:04:03.26	I'll actually just show you one.
00:04:06.07	Here's a bone and if you look at the top of it,
00:04:07.23	that's where the cartilage it.
00:04:09.13	And so I'd scrape the meat off the top,
00:04:11.09	which I did in this case,
00:04:13.00	and then I'd slice off the cartilage,
00:04:15.11	and then I'd put it through various extraction
00:04:17.26	and purification procedures
00:04:19.14	so that at the end of several years
00:04:21.08	I maybe had 50 or 100 different what are called fractions
00:04:24.04	that I wanted to study
00:04:26.01	and test to see if they would stop blood vessels from growing.
00:04:28.11	But, that then brings up the second problem.
00:04:30.12	How do you study something
00:04:32.01	like blood vessel growth?
00:04:33.25	And, if you look back at the history of medicine,
00:04:37.23	one of the biggest challenges
00:04:39.29	whenever somebody comes up with a new factor
00:04:41.24	or substance
00:04:43.20	is often finding a bioassay, a way to study it.
00:04:46.24	And there was no such bioassay,
00:04:48.21	really, for studying angiogenesis,
00:04:50.17	so we had to create one.
00:04:53.05	And, one of the things that we thought about was,
00:04:57.03	as we started to think about creating them, was...
00:05:00.04	one of the big issues was that almost everywhere you go
00:05:02.08	in the body or any organism there are background blood vessels,
00:05:05.07	so we wanted to find a place where there weren't,
00:05:07.05	and so we thought about the eye of a rabbit.
00:05:09.16	And, it turns out that Michael Gimbrone had shown
00:05:12.13	that if you put tumors, certain types of tumors like B2 carcinomas
00:05:16.12	in the eyes of rabbit,
00:05:18.17	they will cause, over about a 2-3 month period,
00:05:21.02	blood vessels to grow from the edge of the cornea,
00:05:23.11	the limbus, to the tumor.
00:05:25.07	So, we thought we could take an ophthalmic microscope
00:05:27.13	and actually measure the length of the longest blood vessel,
00:05:31.10	but the problem was,
00:05:32.18	if we wanted to now find an inhibitor,
00:05:34.16	we had to also put the inhibitor in the eye
00:05:37.04	and the inhibitors would quickly diffuse away.
00:05:39.16	So, we thought a way to solve that
00:05:41.18	is to have what we call a controlled release polymer
00:05:43.27	that could take any of the things we isolated from cartilage,
00:05:46.24	all of which were fairly large molecules,
00:05:49.07	and deliver them to the eye and to the tumor
00:05:53.10	and to the blood vessels over this 2-3 month period.
00:05:57.14	So, one of the big challenges, then,
00:05:59.21	became to try to develop such a polymer...
00:06:02.28	and they didn't exist,
00:06:05.11	and in fact Dr. Folkman, he was on the board of the one company, ALZA,
00:06:08.23	working in this area,
00:06:11.06	and he went out to ask them if they could help us.
00:06:13.01	But they said no, they said
00:06:15.17	that large molecules can't slowly diffuse through solid polymers.
00:06:19.18	It's kind of like saying, could any of us walk through a wall?
00:06:22.25	In fact, the literature said similar things,
00:06:25.23	that the use of polymer matrices
00:06:27.19	has been virtually restricted to small molecules.
00:06:30.11	The only thing I really had going for me is
00:06:32.26	I just didn't know any of that,
00:06:35.06	so I went ahead and tried to do it anyhow.
00:06:37.09	I experimented in the lab and I...
00:06:40.20	kind of almost Edisonian-like...
00:06:42.29	and I actually found over 200 different ways
00:06:45.04	to get this to not work.
00:06:47.18	But eventually, I was able to make little microspheres,
00:06:51.16	those shown here and one shown here
00:06:54.14	and then the other's cut in half,
00:06:57.10	and we were able to show
00:06:59.22	that by making these the right way
00:07:01.19	we could actually get release,
00:07:03.12	this is from a paper in Nature in 1976,
00:07:05.25	for over 100 days,
00:07:08.08	for really any molecule.
00:07:10.15	And that enabled us to start to
00:07:13.20	think about doing these bioassays
00:07:18.01	and to do controlled release as well.
00:07:21.05	Later on, one of the challenges
00:07:23.05	was to get constant release,
00:07:25.04	and we worked out some ways, using some engineering models
00:07:28.06	where we could predict certain shapes or drug distributions,
00:07:30.26	where we could get constant release,
00:07:32.17	and here's an example of that.
00:07:36.04	When I first presented some of this work,
00:07:40.03	people were very, very skeptical about it.
00:07:42.28	I remember giving a talk at a major meeting in 1976,
00:07:48.24	and I practiced this talk for many weeks before
00:07:53.12	because I was a very young guy,
00:07:55.01	I was a postdoc and there were all these very famous
00:07:58.00	polymer chemists and engineering in it,
00:08:00.05	and when I got done with the talk
00:08:02.06	I actually felt I did alright,
00:08:04.03	but what happened was all these older scientists,
00:08:06.01	when I got done,
00:08:07.16	they came up to me and they said,
00:08:08.27	"We don't believe anything you said."
00:08:10.22	They were just very skeptical
00:08:12.09	that you could release these large molecules.
00:08:14.23	But what happens, of course, in science
00:08:16.26	is the key is whether people reproduce what you do,
00:08:19.05	and it turned out that over the next couple of years
00:08:21.00	a number of groups did,
00:08:22.23	and the question shifted to how could this happen.
00:08:24.23	So, to understand the way this happened,
00:08:27.25	I had a graduate student, Rajan Bawa,
00:08:30.01	when I was at MIT,
00:08:31.12	and we cut thin sections through the polymer with a cryomicrotome.
00:08:34.29	Here, for example, is one of those thin sections.
00:08:37.12	It's a 5 micron thin section of a polymer we used
00:08:40.11	called ethylene-vinyl acetate copolymer.
00:08:43.07	And, if you had a molecule that was
00:08:46.04	300 molecular weight or greater,
00:08:48.02	it would not be able to diffuse from one side of this to the other.
00:08:51.00	So, how could the molecules get through?
00:08:53.18	Well, now we cut a second section.
00:08:55.23	This section has a red drug in it,
00:08:58.03	actually a red protein, myoglobin,
00:09:00.14	and this is cut before any release has taken place.
00:09:04.01	And we see what we call, in this case,
00:09:05.27	a phase separation.
00:09:07.19	You see the red myoglobin chunks here,
00:09:10.23	and then you see the white polymer here,
00:09:14.04	and you see that throughout.
00:09:16.14	So, this is what happened before any release.
00:09:18.27	Now, let's say you released it for a year
00:09:21.03	and then you cut a thin section.
00:09:22.28	What you'd see is left behind...
00:09:25.16	where the drug was,
00:09:27.19	are these pores,
00:09:29.29	and these pores are large enough so that molecules even millions of
00:09:32.12	molecular weight can get through,
00:09:34.05	but what happens is...
00:09:35.21	we did a lot of serial sectioning
00:09:37.13	and also scanning electron microscopy...
00:09:39.12	and what happens is it turns out that these pores
00:09:41.21	are interconnected, they have tight constrictions between them,
00:09:45.01	and they're incredibly winding and tortuous,
00:09:47.21	so it takes a really long time
00:09:49.20	for the molecules to get through them.
00:09:51.20	One way, when I try to explain this to people
00:09:53.27	when I give lectures around the world,
00:09:55.17	is I sometimes say it's kind of like driving a car through Boston.
00:09:59.04	Boston has,
00:10:01.18	what we call in chemical engineering terms,
00:10:03.20	which I'm a chemical engineer,
00:10:05.11	is Boston and these structures
00:10:07.07	have what we call a very high tortuosity.
00:10:09.19	And, if you have a high tortuosity,
00:10:11.23	that you can use to slow release down,
00:10:13.26	and over the years our graduate students and postdocs
00:10:16.19	have worked out ways
00:10:18.27	to create all kinds of these porous tortuous structures
00:10:21.20	and to even develop mathematical models
00:10:23.27	to predict how to make these,
00:10:25.23	and so you can make these last anywhere
00:10:27.20	from days to years, or any time in between.
00:10:33.11	So now, we were able to go back
00:10:35.22	and try to address the problem,
00:10:37.16	the angiogenesis problem,
00:10:40.04	because now we have these polymers that could deliver
00:10:42.06	molecules of any size
00:10:44.03	and we also were able to make these polymers in a way
00:10:46.18	that would not cause irritation to the eye,
00:10:48.11	which was also a big challenge.
00:10:50.15	So this was the assay I mentioned we wanted to create.
00:10:53.08	The tumor is there
00:10:55.25	and the polymer,
00:10:58.03	and what we did is we put different fractions,
00:11:00.16	we probably did close to 2000 eyes,
00:11:03.02	and when we did...
00:11:06.15	most of them didn't work.
00:11:08.05	There were all different fractions that we isolated
00:11:09.22	and most of them didn't work.
00:11:11.15	I should also almost all but one didn't work.
00:11:14.05	And I'll just show you some pictures
00:11:15.22	of what they look like.
00:11:17.13	So, this is from a paper we wrote in Science in 1976
00:11:21.11	with this what's called rabbit corneal pocket assay.
00:11:23.23	If you didn't have the cartilage-derived inhibitor,
00:11:26.00	that's what I call CDI,
00:11:27.28	if you didn't have it...
00:11:30.28	over, this is about 9 weeks after the start of the experiment,
00:11:34.01	you get a sheet of blood vessels
00:11:36.03	growing from the bottom of the eye
00:11:38.24	over the polymer to the tumor.
00:11:40.19	You can actually see the tumor...
00:11:42.19	where the tumor is it's a little bit cloudy.
00:11:44.26	And, if you looked at this eye,
00:11:46.26	or any eye like it 2-3 weeks after this,
00:11:49.15	what would happen is it would be...
00:11:53.01	the tumor would be 3-dimensional.
00:11:54.16	It would be out of the orbit of the eye...
00:11:56.14	we sacrificed the animals before that,
00:11:58.13	but nonetheless you see the rapid blood vessel growth.
00:12:01.07	In contrast, if you look at the next panel
00:12:04.24	where we put the CDI in the polymer,
00:12:06.19	the cartilage-derived inhibitor,
00:12:08.06	notice how the blood vessels are lower:
00:12:10.10	they avoid the polymer,
00:12:12.12	they don't grow into the tumor.
00:12:14.09	This is at exactly the same time,
00:12:16.04	and it turns out that about 40-50% of the time,
00:12:19.00	the tumors on the right will never grow,
00:12:21.03	whereas 100% of the time the tumors grew on the left,
00:12:24.09	and like I say, we did hundreds, thousands of eyes
00:12:27.26	over the years to look at this.
00:12:31.07	So, that actually enabled us
00:12:33.13	to isolate the first angiogenesis inhibitor.
00:12:35.16	It did a couple of important things,
00:12:37.09	I like to think.
00:12:39.00	One, is that we did develop an assay
00:12:42.09	that people could use in the future
00:12:44.25	for all future angiogenesis inhibitors.
00:12:46.23	Secondly, I like to think that this
00:12:48.22	really established there were angiogenesis inhibitors
00:12:51.05	that were chemical, and they did exist.
00:12:53.22	And then we had this first one.
00:12:56.09	Now, what happened is of course it took...
00:12:59.12	this was just the start.
00:13:01.04	It took the work of many companies,
00:13:03.16	particularly Genentech and others,
00:13:06.04	to really move this field forward,
00:13:09.17	so it's wasn't...
00:13:11.24	you know, many years later.
00:13:13.09	So, it wasn't until 2004
00:13:15.21	when the first angiogenesis inhibitor got approved,
00:13:19.07	and this is just a list of angiogenesis...
00:13:22.18	and it's not even a complete list,
00:13:24.12	that have gotten approved since 2004.
00:13:28.15	Avastin, which is a Genentech drug,
00:13:30.09	is one of the biggest, most widely-used
00:13:33.19	biotech drugs in history,
00:13:35.07	but there are many others as well
00:13:37.08	and they've been, as we can see in this slide,
00:13:39.00	been used for all kinds of cancers.
00:13:41.08	And, not just cancer,
00:13:43.01	but many people have different...
00:13:44.27	of what's called...
00:13:46.13	an eye disease called macular degeneration,
00:13:48.09	where you get blood vessels
00:13:50.02	growing into the back of the eye
00:13:51.21	causing hemorrhage.
00:13:53.11	And, before this, the only way to treat them
00:13:55.01	was to use lasers to do what's called photocoagulation.
00:13:58.15	Now, you can use these inhibitors
00:14:02.01	like Eylea or Lucentis or Macugen
00:14:04.25	to actually stop the blood vessels from growing
00:14:07.16	and even reverse macular degeneration.
00:14:10.01	What's happened is angiogenesis,
00:14:14.01	this whole area
00:14:15.25	has become a quite large area.
00:14:17.19	Now, about 20 million patients
00:14:19.05	have been treated with angiogenesis inhibitors
00:14:21.07	and the FDA has said that there are four kinds of ways of treating cancer:
00:14:25.23	angiogenesis treatment,
00:14:27.02	chemotherapy,
00:14:28.18	surgery,
00:14:29.22	and radiation,
00:14:31.05	and sometimes these are used together.
00:14:33.04	But it also seemed to me that not only might this be useful...
00:14:36.06	the controlled release systems for angiogenesis,
00:14:38.06	but they might be useful...
00:14:40.08	studies...
00:14:42.17	but they might be also useful in their own right,
00:14:44.25	for delivering all kinds of drugs.
00:14:48.18	And, as a proof of principle, Larry Brown,
00:14:50.20	one of my graduate students,
00:14:52.12	just took a molecule, insulin,
00:14:54.06	and again I'm simplifying this,
00:14:56.12	it was actually his whole doctoral thesis,
00:14:58.24	but he put insulin in these pellets,
00:15:00.17	designed a certain way,
00:15:02.28	and was able to get three months release
00:15:06.06	of a fairly large molecule.
00:15:08.07	So, we thought, both Dr. Folkman and I,
00:15:10.16	that this might be, you know...
00:15:12.22	really open up the door
00:15:17.18	to all kinds of new delivery systems.
00:15:19.20	So, I was working at Children's Hospital
00:15:21.04	when I started this work
00:15:23.06	and Dr. Folkman said to me one day,
00:15:24.25	he said, "Bob, we should file for a patent on this."
00:15:27.06	And, it's interesting,
00:15:29.08	I'd never had a patent before at the time,
00:15:31.14	and Dr. Folkman actually said
00:15:33.13	the entire Children's Hospital never had a patent at the time.
00:15:36.02	So, we worked with a lawyer and filed the patent,
00:15:39.09	and five years in a row
00:15:41.00	the patent examiner turned it down
00:15:43.03	and, you know, we felt he didn't understand it,
00:15:44.23	but it really didn't matter.
00:15:46.02	The patent examiner was the one calling the shots.
00:15:48.08	So, the lawyer said to me around 1982,
00:15:51.17	we started this process in 1976,
00:15:54.10	the lawyer said to me, he said,
00:15:55.21	"Bob, you know, you're wasting a lot of money for the hospital,
00:15:57.22	you should just give up."
00:15:59.14	But, I don't like to give up,
00:16:01.07	so I was thinking,
00:16:02.25	how could we convince the examiner,
00:16:04.29	you know legally of course,
00:16:07.05	that the patent... you know that this was novel.
00:16:10.08	And I thought, you know, when I first started talking about this work
00:16:13.27	everybody told me it was impossible, it couldn't work.
00:16:16.10	I remember getting my first nine grants turned down.
00:16:19.29	There was just this enormous skepticism
00:16:22.03	about whether it could work,
00:16:23.18	and I wondered whether anybody ever wrote anything down.
00:16:26.06	So, I actually did what's called the science citation search,
00:16:29.12	meaning that I could go back to our original paper,
00:16:31.08	which we wrote in Nature in 1976,
00:16:33.27	and see who wrote stuff about it
00:16:35.13	and what they said,
00:16:37.05	and it was actually fascinating.
00:16:38.29	I found a number of quotes,
00:16:40.25	but this one in particular was very useful,
00:16:42.25	and I'll just read this.
00:16:44.25	It was by five of the leading polymer scientists in the world,
00:16:50.15	and they were describing this field is,
00:16:52.04	"Generally the agent to be released
00:16:53.23	is a relatively small molecule
00:16:55.13	with a molecular weight no larger than a few hundred.
00:16:58.16	One would not expect that macromolecules,
00:17:01.02	e.g. proteins,
00:17:02.29	could be released by such a technique
00:17:05.01	because of their extremely small permeation rates
00:17:07.14	through polymers.
00:17:09.01	However, Folkman and Langer
00:17:10.28	have reported some surprising"
00:17:12.14	... that surprising word is a very good word for a patent examiner...
00:17:16.14	"have reported some surprising results
00:17:18.09	that clearly demonstrate the opposite."
00:17:20.20	So, I showed this to our lawyer
00:17:22.13	and he was very excited.
00:17:23.22	He said, "I'm gonna fly down to Washington
00:17:25.05	and show it to the examiner."
00:17:26.24	And he did, and the examiner said,
00:17:28.24	he said, "I had no idea".
00:17:30.08	He said, "I'll tell you what,
00:17:31.25	I will allow this patent if Dr. Langer
00:17:33.22	can get written affidavits from these five authors
00:17:35.27	that they really wrote that quote."
00:17:38.07	So, I did that.
00:17:39.15	I wrote each of them, and they were all kind enough to write me back
00:17:41.05	that they really did write that,
00:17:43.04	and then we got this very broad patent issued,
00:17:46.01	and that was the first one in the history of Children's Hospital
00:17:49.00	and then the hospital would license that out
00:17:51.22	to other people
00:17:53.18	and, today, many companies have developed all kinds of products
00:17:55.28	based on either the patent or these ideas,
00:17:59.10	and these are just a few of them shown here.
00:18:01.25	For example, if somebody has certain peptides
00:18:07.00	that you might want to take, l
00:18:10.00	ike leuprolide acetate...
00:18:12.00	people have not figured out ways to give it orally
00:18:14.01	or by skin patches because the molecule is just so big.
00:18:18.01	If it's injected it's destroyed right away.
00:18:20.15	So now, what happens is
00:18:23.14	it's put in little microspheres, just like I showed you,
00:18:25.22	that are injected under the skin
00:18:27.16	and actually deliver the drug for four months.
00:18:29.25	And there are many other too.
00:18:31.24	This is just pictures of different ones.
00:18:33.27	There's systems that can deliver
00:18:37.07	anti-schizophrenic drugs for several weeks.
00:18:40.00	There's systems that can deliver drugs
00:18:41.22	to treat alcoholism for a month,
00:18:43.16	to treat narcotic addiction for a month,
00:18:45.21	so you give the injections once a month,
00:18:47.23	to treat type 2 diabetes,
00:18:50.18	for where you give an injection once a week,
00:18:52.23	and this is really just the start of this.
00:18:54.17	There are many, many others
00:18:56.12	that end up affecting the lives of tens of millions
00:18:58.23	of patients around the world.
00:19:01.03	So, so far what I've done is I've gone over, now,
00:19:04.20	how you can take systems like this,
00:19:07.21	deliver them at steady rates
00:19:09.21	or maybe slightly decreasing rates
00:19:12.09	over long periods of time.
00:19:14.01	And so, what these systems allow you to do
00:19:16.14	is it allows you to control the level of the drug
00:19:18.24	and the duration of the drug,
00:19:20.24	and generally these are given intramuscularly or subcutaneously.
00:19:25.04	But we want to even go further,
00:19:26.16	and now I'd like to sort of turn to nanotechnology
00:19:29.10	and even some of the systems for the future,
00:19:31.15	or at least that I hope will be the future.
00:19:34.07	So, could you actually make these...
00:19:36.21	use a lot of the same principles...
00:19:38.14	but make these even smaller,
00:19:40.29	so that you could put them in the bloodstream
00:19:42.22	so they'll be able to go around the bloodstream
00:19:44.11	and find their way to particular cells
00:19:46.09	that you want them to go to.
00:19:48.24	How could you do this?
00:19:51.04	So, what we published,
00:19:53.23	this was about 20 years ago,
00:19:55.29	it was one of the earliest papers on medical nanotechnology,
00:19:59.07	is that the challenge is
00:20:01.10	if you make a particle
00:20:03.05	that you want to put drugs in,
00:20:04.20	and you inject it into the bloodstream,
00:20:06.20	almost always what will happen quite quickly
00:20:08.29	is macrophages, cells in the body,
00:20:11.01	will eat those particles.
00:20:13.04	So, what we had to do
00:20:14.20	was figure out a disguise for those particles, the nanoparticles,
00:20:17.26	so that that wouldn't happen,
00:20:19.11	and of course you need to get past the macrophages.
00:20:21.09	In a way, you can think of the macrophages
00:20:23.06	as kind of like the guardian.
00:20:24.23	If you could get past the macrophages
00:20:26.20	then maybe you can get to the cells you want,
00:20:28.11	if you can figure out the right other things
00:20:30.14	to add to the nanoparticle.
00:20:33.04	So, what we did is we made this disguise.
00:20:35.06	We picked a substance called polyethylene glycol
00:20:38.28	that we could add to the outside of the nanoparticles,
00:20:42.21	and our thinking was
00:20:44.19	is that takes up a lot of water,
00:20:46.23	and if the cell sees water, well,
00:20:48.22	it's used to seeing water
00:20:50.22	and it doesn't eat water up.
00:20:52.13	So, that was our hope,
00:20:54.01	that we could disguise these particles,
00:20:56.08	you know, to do that.
00:20:58.07	And then what we did
00:21:00.06	is Omid Farokhzadb, who was a postdoctoral fellow in our lab,
00:21:03.10	actually now is a clinician
00:21:06.07	and associate professor at Harvard Med. School,
00:21:08.24	took it even one step further.
00:21:11.00	We not only put the PEG on the nanoparticles,
00:21:13.08	but he put targeting molecules on
00:21:16.12	that might go to a tumor, for example.
00:21:18.07	Examples could be antibodies or aptamers
00:21:21.08	or things that could target things.
00:21:23.15	I realize sometimes
00:21:25.08	I don't always explain this perfectly,
00:21:27.13	but I was fortunate that
00:21:29.25	about a year or two ago Nova, the TV show,
00:21:31.21	they came to our lab and they filmed some of what we did,
00:21:34.03	and they made this video
00:21:36.02	that explains it much, much better than I do,
00:21:37.12	so I thought I'd...
00:21:39.02	I've gotten their permission to use that video,
00:21:40.16	so I thought I'd use it and show it to you
00:21:42.23	because I think it explains pretty well
00:21:44.22	how this kind of technology works.
00:21:46.24	So, let me just go to that video.
00:21:48.27	"He starts with a nanoparticle of anti-cancer drugs.
00:21:53.15	That gets incased in a plastic
00:21:55.14	that releases the drug over time.
00:21:57.28	That, in turn, gets a special wrapping
00:22:00.04	that disguises the package as a water molecule,
00:22:03.08	to fool the body's immune system.
00:22:05.22	And, last but not least,
00:22:07.26	the address where it should be delivered,
00:22:10.09	a key that will only fit the lock of cancer cells."
00:22:20.10	I should say that a lot of the clinicians
00:22:22.03	I work with tell me
00:22:24.01	it doesn't blow the cell up quite that way,
00:22:26.05	but I think it gives you an idea of what's happening.
00:22:28.19	And, then, what we did...
00:22:33.14	we actually, Omid and I got involved in even helping set up a company
00:22:37.17	that created a whole manufacturing plant to make nanoparticles,
00:22:40.13	which was a huge challenge,
00:22:43.02	and this is just a picture of that plant,
00:22:45.22	and then moved it from test tubes
00:22:48.21	to small animals
00:22:50.01	to large animals
00:22:51.16	to humans, where it is now.
00:22:53.24	And, it's been interesting and exciting, the compound...
00:22:58.10	one of the first compounds is one called BIND-014,
00:23:00.19	which is basically putting Docetaxel,
00:23:03.20	a common anti-cancer drug with some side effects, normally,
00:23:08.20	in the nanoparticles.
00:23:12.15	this is a semi-log plot,
00:23:14.22	but if you look at the red dots and the red curve,
00:23:17.16	if you put the drug in by itself,
00:23:22.07	it goes to zero very, very quickly.
00:23:24.22	But, if you put just the same amount of drug
00:23:26.24	in the nanoparticle
00:23:28.20	it lasts for days, so it keeps pounding the tumor.
00:23:32.06	The consequence of that maybe
00:23:33.21	can be seen even better by looking at human pharmacokinetic data,
00:23:37.22	and in particular the thing to focus on might be,
00:23:41.19	let's look at the dose just to make these absolutely equivalent,
00:23:45.08	of BIND-014 at 30 mg
00:23:49.07	and Taxotere, the same drug, also at 30 mg.
00:23:52.17	Well, what you see when you look at the third panel,
00:23:55.12	the area under the curve,
00:23:57.13	is you could take the same drug
00:23:59.09	but we've changed it dramatically.
00:24:01.11	When you put it in the long-circulating nanoparticle,
00:24:03.15	the area under the curve is 127,280.
00:24:07.16	When you don't put it in the nanoparticle it's 512.
00:24:10.25	So, you get something that's almost
00:24:13.04	250 times higher
00:24:15.18	when you put it in the nanoparticle,
00:24:17.05	so it's just pounding the tumor,
00:24:19.05	and it's early yet but the consequence of this,
00:24:21.15	this is from some papers
00:24:23.28	we published in Science Translational Medicine,
00:24:26.21	show that there's at least some hints of efficacy.
00:24:31.24	If you look a the top CAT scan,
00:24:34.07	you look at the patient's lung before
00:24:36.17	and then maybe 42 days after.
00:24:38.27	If you look at the bottom, that's another example
00:24:41.14	where you look at the lung before and 42 days after,
00:24:44.18	and notice that the nodules, that are circled in yellow,
00:24:48.22	go away after this treatment.
00:24:51.06	Now, of course, what's happening is hundreds of patients
00:24:53.25	are being done and we'll get a better feel for where this may work,
00:24:57.13	where it may not work,
00:24:59.10	but I think it's the dawn of a whole new era
00:25:00.27	of using nanotechnology to deliver drugs.
00:25:04.09	This is a small molecule drug. W
00:25:06.08	e're also using nanotechnology
00:25:08.01	in this form and in the form of different lipid systems,
00:25:11.00	to deliver DNA,
00:25:13.05	to deliver siRNA,
00:25:15.18	to deliver mRNA,
00:25:16.29	and all these things I think are
00:25:18.21	a very, very exciting opportunity for the future
00:25:21.12	and, again, I think the problems are still unsolved,
00:25:23.22	but I hope that this is the start
00:25:26.07	of solving some of them
00:25:29.12	and bringing them into patients.
00:25:31.14	I want to mention one other idea
00:25:33.11	that also might be somewhat futuristic,
00:25:35.24	but I think also will be a part
00:25:38.08	of how drug delivery can change
00:25:40.05	how people do things.
00:25:42.16	I was watching this television show
00:25:44.17	a number of years ago
00:25:46.11	about how they made microchips in the computer industry,
00:25:49.03	and I thought when I watched it,
00:25:50.23	you know, that would be a great way
00:25:52.01	to make a drug delivery system.
00:25:53.12	Now, of course, I've spent 34 years of my life
00:25:55.25	working on drug delivery systems,
00:25:57.10	so somebody might think, you know,
00:25:59.00	any TV show I say I might think that,
00:26:00.19	and they may be right.
00:26:03.09	But, I just want to show the idea I had.
00:26:07.27	The idea I had when I watched the show
00:26:10.01	was that maybe what you could do
00:26:13.02	is make a chip,
00:26:15.06	but rather than put electrical things in it,
00:26:17.05	you could also put chemical things in it,
00:26:19.05	and what we see in this chip,
00:26:21.02	this is just a schematic
00:26:24.23	and it's a cut-away where we're just looking at...
00:26:27.05	the chip itself is fully whole
00:26:29.07	and I'll show you some in a minute...
00:26:31.12	but, when you look at it,
00:26:33.03	we have these wells
00:26:34.18	where you could put active substances in.
00:26:36.22	So, you could put different doses of the same substance in,
00:26:39.15	or your could literally, theoretically,
00:26:41.12	have what we call a pharmacy on a chip.
00:26:42.24	You could put multiple drugs in
00:26:44.21	and have them come out whenever you want,
00:26:46.24	and they're really stored in these chips indefinitely.
00:26:49.12	But, notice that the chips
00:26:51.03	have a cover which looks like a gold cover here,
00:26:53.09	it could be gold or it could be a platinum alloy,
00:26:57.16	and they are hermetically sealed
00:27:00.03	and the drugs are underneath them
00:27:02.09	but, as I'll show you, when we apply,
00:27:04.11	by remote control...
00:27:06.25	we can actually take those covers off
00:27:09.29	and the drug could come out
00:27:12.01	whenever we want to make it do so.
00:27:13.24	Let me just show you some of the work that was done.
00:27:16.17	I did this work with my collaborator
00:27:18.09	Michael Cima at MIT,
00:27:19.25	and we had a very good graduate student
00:27:21.14	John Santini,
00:27:23.23	and we made these chips using techniques
00:27:25.22	that were never used in the pharmaceutical industry,
00:27:27.26	but using techniques
00:27:29.19	that we adapted from microelectronics.
00:27:32.02	And here you see in the top two pictures,
00:27:36.26	which is both a top view and a bottom view
00:27:38.28	of one of these chips,
00:27:40.25	and it's got something like 34 wells in it,
00:27:43.09	and these are tiny little wells,
00:27:46.04	but they don't have to be.
00:27:47.20	They can be bigger or smaller,
00:27:49.08	and they don't have to be short, flat chips.
00:27:51.03	We've actually made sort of cylindrical chips
00:27:52.23	that could be injected into the body and so forth,
00:27:55.08	but just to give you a size idea,
00:27:57.27	here's a United States dime.
00:27:59.20	Let me just show you how they work.
00:28:02.00	So, here's a well, it's covered with the metal
00:28:04.11	and you can see this,
00:28:06.02	this is a scanning electron micrograph of it,
00:28:07.19	it would actually stay in the body like this for years,
00:28:09.21	but if you come along
00:28:11.22	and just give one volt by remote control,
00:28:15.21	in nanoseconds the cover comes off
00:28:18.07	and you see that happening here.
00:28:20.27	And when the cover comes off the drug comes out.
00:28:24.01	So, this is from another paper
00:28:25.28	we wrote in Nature,
00:28:27.26	where we put different amounts of drug
00:28:29.15	in different wells
00:28:31.09	and the drug comes out at different times.
00:28:32.18	This is in test tubes, in vitro.
00:28:35.00	Along the lines of the pharmacy on a chip idea,
00:28:38.19	we put multiple model drugs in
00:28:41.26	and triggered release at different times
00:28:43.21	and that's shown here.
00:28:45.23	But over time,
00:28:47.15	what John and Mike
00:28:49.21	and a little company, Microchips, that we were involved with did,
00:28:52.27	is take this all the way from test tubes,
00:28:54.22	to small animals,
00:28:56.06	to large animals,
00:28:57.17	to humans.
00:28:59.03	And what I'm going to mention now
00:29:00.22	might almost sound like space-age medicine,
00:29:02.06	but we actually did it.
00:29:03.24	What was done is you put the chips in the human body
00:29:05.11	and you can communicate with them
00:29:07.02	over a special radiofrequency
00:29:08.24	called the Medical Implant Communications Service Band.
00:29:11.22	It's been approved by both the FCC and the FDA,
00:29:15.24	and sometimes people think about tampering,
00:29:17.16	I mean... I doubt that that's going to be a problem,
00:29:21.05	and that should be the biggest problem we'd face,
00:29:22.25	but to that extent
00:29:24.26	we even can have a special computer code
00:29:27.23	that we built in
00:29:29.16	that only the patient or doctor could know,
00:29:31.07	if they want to change or administer the dose.
00:29:33.11	Also, what we have,
00:29:35.14	what we built in is in a bidirectional communications link
00:29:40.04	between the chip itself and the receiver.
00:29:42.09	The receiver, by the way, could be a cell phone,
00:29:45.06	it could be something like this,
00:29:46.25	and it can give you all kinds of information like, did you take the drug?
00:29:49.07	I have to admit, as I've gotten older,
00:29:50.25	that's something I sometimes forget about,
00:29:52.27	so, did you take the drug, the battery life, and so forth.
00:29:56.25	Okay, let me tell you about the clinical trial that we did.
00:29:59.01	We did 8 patients,
00:30:01.10	this was done in Denmark,
00:30:03.23	and thinking about what kind of trial we wanted to do,
00:30:06.20	one of the things that happened as we'd send our grants in
00:30:09.07	is people would keep telling us
00:30:11.09	why our approach wouldn't work,
00:30:12.26	and the biggest reason they told us it wouldn't work
00:30:14.16	is you'd get what's called fibrous encapsulation
00:30:16.24	around the chip and that would mean that molecules
00:30:18.29	couldn't diffuse through that fibrous capsule
00:30:22.00	and wouldn't get into the bloodstream.
00:30:23.23	So we felt, let's give ourselves a hard test
00:30:26.02	to really see if they're right.
00:30:27.24	Let's give us...
00:30:30.00	let's pick a large molecule,
00:30:31.23	and if that got through certainly
00:30:33.10	we'd expect smaller molecules to get through.
00:30:35.04	So, what we chose was parathyroid hormone,
00:30:37.06	which is a large peptide,
00:30:39.18	and it's used in osteoporosis,
00:30:42.17	and we also chose it because we felt
00:30:45.07	this is a place where someday, maybe,
00:30:47.04	we could even make an impact.
00:30:49.09	In the case of osteoporosis,
00:30:51.04	women are supposed to take parathyroid hormone
00:30:53.16	by injections once a day,
00:30:55.16	but one of the additional problems with this
00:30:58.04	is that the women don't do it.
00:31:01.14	There's actually a 77% dropout rate
00:31:05.10	of the women who have to take these shots.
00:31:07.16	And you can't take it continuously, either,
00:31:09.11	with the little microspheres.
00:31:11.04	Continuous is bad
00:31:13.02	because that'll actually cause bone resorption.
00:31:14.29	So, you really have to give an injection once a day apparently,
00:31:18.10	and that just has been fraught with problems.
00:31:21.22	So, what was done is the trial is a small office procedure
00:31:25.01	in the doctor's office to do the implant,
00:31:27.05	and the results were very positive.
00:31:28.28	The women preferred this to some of the other methods.
00:31:32.03	You got the same pharmacokinetics,
00:31:33.20	I'll go over what I mean by that
00:31:35.19	in a second and show you some of the data,
00:31:38.01	with less variability,
00:31:39.23	which may not be important in this case
00:31:41.17	but could be important in others,
00:31:43.10	and the three major measures
00:31:45.13	of whether you're treating this disease
00:31:49.01	are Ca, PINP, and CTX,
00:31:51.23	and they were the same as daily injections.
00:31:54.05	Just to show you the data, on the next to final slide,
00:31:58.20	the top curve is human data
00:32:02.04	where what you see is data
00:32:05.01	for the woman at day 60, 68, 76, and 84.
00:32:09.17	Notice how the points really are pretty much
00:32:11.26	superimposed on top of each other.
00:32:13.26	It's very reproducible.
00:32:15.06	On the bottom right,
00:32:17.06	what you see are pictures of the chip itself.
00:32:19.17	In this case what we did is we made these little chips
00:32:23.04	and in them we also put electrical components,
00:32:26.25	a battery, a power source,
00:32:31.26	and even a computer program.
00:32:33.18	What you can't see on these chips
00:32:35.12	is on the back end of it
00:32:38.10	we actually built in an antenna,
00:32:41.06	we imprinted an antenna right into the back end of the chip,
00:32:44.01	and that's how you can communicate with it.
00:32:45.27	You can communicate with it by, depending on your device,
00:32:48.20	it could be a cell phone,
00:32:50.11	it could be something like this, and so forth.
00:32:54.15	As you can also see from these pictures,
00:32:56.17	the amount of fibrous encapsulation...
00:32:58.15	it's not zero, we definitely get some,
00:33:00.10	but it's very small
00:33:02.17	and obviously it's small enough
00:33:05.13	so that it has no effect on the release rate of this large molecule
00:33:08.11	and it's also, I'd say maybe 1/20th of what a pacemaker gets.
00:33:12.06	We also did histology,
00:33:14.02	that's actually taking sections of the tissue
00:33:16.10	and seeing whether you got inflammatory cells.
00:33:20.02	And, in the panels on [the left]
00:33:22.02	we see that there are no inflammatory cells
00:33:24.07	over the implant.
00:33:27.02	So, it ended up being very safe,
00:33:30.00	and effective,
00:33:31.25	and now we're moving this project in at least three directions.
00:33:34.19	One is we're making a two-year device.
00:33:38.02	Two, we've been working with the Gates Foundation,
00:33:41.15	where they've been interested in a...
00:33:44.01	for family planning in the third world,
00:33:46.13	that you could have a contraceptive device
00:33:48.14	that you could turn on and off whenever...
00:33:50.07	a woman could turn on and off whenever she wanted.
00:33:51.27	That can't be done with conventional technology,
00:33:54.09	but with this you can,
00:33:56.07	so we're actually designing a 16-year device
00:33:58.20	that could be turned on and off
00:34:00.28	whenever the woman wanted it to.
00:34:03.05	And finally, what we're doing...
00:34:05.02	one of my colleagues, Michael Cima,
00:34:06.23	he's been putting little sensors in these chips,
00:34:08.21	and someday our hope is we'll be able
00:34:10.21	to sense signals in the human body
00:34:12.20	and then tell the chip how much to deliver
00:34:14.17	in response to those signals.
00:34:16.21	So, that's what I wanted to largely go over in this lecture.
00:34:19.24	Just to summarize where we are,
00:34:22.01	in the first lecture I've gone over
00:34:24.25	advances in controlled release technology
00:34:26.18	and gave an overview.
00:34:28.13	Here I've given some examples of both current and possibly future technology.
00:34:32.23	And, in my third lecture,
00:34:34.11	I'll go over biomaterials and biotechnology
00:34:36.20	and talk about how one might use...
00:34:38.22	create new biomaterials for drug delivery,
00:34:40.17	and also how one might use biomaterials
00:34:42.17	to help lay the foundation for tissue engineering.
00:34:45.16	Thank you.
To screen for angiogenesis inhibitors, Dr. Langer used approximately 2000 rabbit eyes (11:03). With stricter modern rules around the use of animals in research, how would this bioassay differ today for a screen of this size?
Why is the targeting of anti-cancer drugs so important for cancer treatment?
In Dr. Langer's microchip example, a radio frequency is used to communicate with the microchip. To open a reservoir, the radio frequency signals for an electrical current to pass over the cover of the reservoir, melting it and allowing drug to be released. What are some other possible methods that could be used to communicate with the microchip or to open the reservoir? What are the advantages and disadvantages of your new method?
What are some possible ethical issues that could arise with the delivery of certain drugs, such as drugs for schizophrenia or contraceptives, from long lasting externally-controlled microchips?
Biomaterials for Drug Delivery Systems and Tissue Engineering
Concepts: Drug delivery and medical devices
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.
00:04:28.14	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.
00:04:47.06	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.
00:12:45.12	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,
00:22:59.26	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
00:23:37.24	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
00:25:11.12	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.
During his talk (7:37-7:57), Dr. Langer touches on the grant review process that exists in academia. What is a grant? Who is a reviewer? How does the process work?
Throughout the lecture, many animal models are discussed, including rodent, pig, and monkey. How do researchers choose which animal model to use for their research?
What is the advantage of using the patient's own cells for engineering a tissue replacement?
What is the purpose of a sham operation (23:22)?
Timko, B.P., Arruebo, M., Shankarappa, S.A., McAlvin, J.B., Okonkwo, O.S., Mizrahi, B., Stefanescu, C.F., Gomez, L., Zhu, J., Zhu, A., et al. (2014). Near-infrared-actuated devices for remotely controlled drug delivery. Proceedings of the National Academy of Sciences 111, 1349–1354.
What is the unfilled need in drug delivery that this paper is attempting to address?
How is the drug released from the reservoir in this design?
Compare this drug delivery device to injections. Which method for drug delivery is a better treatment for diabetes? Is this true in all instances?
How would you change or add to this product in order to apply this concept to another disease or advance its use for diabetes?
Robert Langer
Robert Langer is the David H. Koch Institute Professor at the Massachusetts Institute of Technology. Research in Langer's lab focuses on the development of polymers for use in drug delivery devices that will release molecules such as drugs, proteins, RNA or DNA at controlled rates and for extended periods of time. His lab also is… Continue Reading