Age related macular degeneration (AMD) is one of several retinal diseases that can lead to vision loss and, ultimately, blindness. Dr. Bhisitkul explains that the class of anti-VEGF biologic drugs (Lucentis, Avastin, Eylea) can treat AMD, however, ongoing, monthly injections into the eye are required for the drugs to be fully effective. There are a number of drawbacks to this treatment regime, many of which could be mitigated by the development of a drug delivery device for implantation in the eye. Dr. Desai describes the work done in her lab to develop an injectable, biocompatible and biodegradable device that has the right release kinetics to successfully deliver needed drugs to the retina of patients with AMD.
Advancing the Treatment of Retinal Diseases
Concepts: Retinal diseases, vision loss, implantable devices for drug delivery, age-related macular degeneration
00:00:07;07 This is a project to develop a new technology for an ocular drug delivery device.
00:00:13;18 And since this is a collaboration between ophthalmology and bioengineering,
00:00:18;15 we'll have the presentation in two parts.
00:00:20;11 I'm Robert Bhisitkul.
00:00:21;16 I'm a retina surgeon at the University of California, San Francisco.
00:00:25;12 And I will introduce this with a clinical background, with a description of the diseases
00:00:30;16 that we're trying to treat, and with the unmet clinical need that we have currently
00:00:35;25 in the way that we treat patients with these retinal diseases.
00:00:38;15 And this will serve as an introduction for my colleague, Tejal Desai,
00:00:42;20 in Bioengineering at UCSF,
00:00:45;08 who will give a description of the translational research project that we have
00:00:49;22 and the progress that we've made with translating this technology to an ocular drug delivery device.
00:00:57;14 As background, I'll give... for some members of the audience that might not be ophthalmologists,
00:01:03;06 we'll give a brief description of the basic anatomy of the eye.
00:01:06;21 The eye of course is a small spherical structure.
00:01:09;10 The front part of the eye is to allow light to enter into the eye, to be focused
00:01:15;08 onto the retina.
00:01:16;10 And the retina is the neural tissue of the eye that's sensitive to light that sends
00:01:20;02 an image back to the brain.
00:01:21;24 The retina is... can be thought of as the wallpaper that lines the inside of the eye.
00:01:27;11 And the space inside the vitreous cavity is filled with a clear gel.
00:01:34;13 And it's that space that we use to inject a lot of the drugs that I'll des...
00:01:39;03 that I'll describe later to treat retinal diseases.
00:01:42;01 Now, the center of the retina, the bull's eye of the retina, is known as the macula.
00:01:46;17 And that's what we see here, as you... as you look through the pupil, straight back
00:01:51;01 into the center of the retina.
00:01:52;25 And if this postage sty... postage stamp-sized area of the retina that is really responsible
00:01:58;16 for all of our high-resolution vision, the vision that we need for daily function.
00:02:03;06 There's even a small area with a depression that's shown alongside here, where it's only
00:02:07;25 200 microns in size.
00:02:09;09 That's the fovea, and that's really where we get our 20/20 vision, our high-resolution vision.
00:02:14;11 So, this is the part of the retina that we're trying to protect with these retinal diseases
00:02:17;24 that I'll describe next.
00:02:20;02 Some of these retinal diseases that we see every day in clinic, that are... that are...
00:02:24;24 that affect many patients in the United States are shown here.
00:02:28;18 The first is age-related macular degeneration, or AMD.
00:02:31;28 The "wet" form of this disease causes blood vessels to grow underneath the retina,
00:02:37;08 causes bleeding and leakage of fluid underneath the retina and into the retina, and can cause
00:02:41;09 a blind spot and severe vision loss.
00:02:43;15 It's the most common cause of severe vision loss in the elderly population.
00:02:48;02 And it's estimated to affect about 200,000 people every year in the United States alone.
00:02:53;08 Another large disease category here is diabetic retinopathy.
00:02:57;26 It's thought that this is a disease that affects the working-age population mostly.
00:03:02;08 And there's 25,000 new cases of blindness from diabetic retinopathy.
00:03:06;08 And there's millions of patients that remain at risk for this every year.
00:03:09;19 In this disease, the blood vessels are abnormal again.
00:03:12;22 They leak fluid.
00:03:14;00 They leak blood into the retina.
00:03:15;05 And they cause macular edema.
00:03:17;08 A third category of disease that's very common, that we're treating every day,
00:03:21;03 is retinal vein occlusion.
00:03:23;02 This happens most frequently in patients with high blood pressure or with cardiovascular disease.
00:03:27;26 And it's estimated it affects about over 10 million people globally.
00:03:30;15 And here you have a blocked circulation in the back of the eye, near that macula.
00:03:35;13 And this causes fluid and hemorrhage to build up in the... in the macula, again causing
00:03:39;15 macular edema.
00:03:42;24 In the past ten years or so, we've had expanding drugs that we can use to treat these diseases
00:03:47;10 very effectively.
00:03:48;13 And we have a range of diseases, not only the ones that I talked about there,
00:03:52;19 but many other diseases that we're now able to treat for the first time.
00:03:56;22 Because of drugs that we are injecting into the eye... this is a class of drugs against
00:04:02;01 vascular endothelial growth factor.
00:04:05;09 The first one that became available was Lucentis and there's also Avastin and Eylea in this class,
00:04:10;11 and some other drugs, all of which we're injecting into the eye to treat these diseases.
00:04:15;05 And every year in the United States alone we're doing millions of these treatments.
00:04:20;02 This is what the treatment looks like from the patient's perspective.
00:04:24;09 It's done in the office with local anesthesia that you can see is being injected here.
00:04:28;28 And the eye is held open with this lid speculum; washed off with a sterilizing solution -- iodine;
00:04:35;27 and then we can give the injection of the drug that we're using directly into the eye.
00:04:41;20 And you can see this is difficult for the patient.
00:04:44;02 The eye is irritated afterwards.
00:04:45;20 It's painful.
00:04:47;07 The eye can have some unsightly hemorrhage afterwards for a few days.
00:04:51;20 But at the same time it's a very effective solution.
00:04:53;13 We can take a tiny amount of the drug, we inject it into the eye right at the target tissue,
00:04:58;12 and it's sequestered somewhat in the eye so that it doesn't get into the bloodstream
00:05:03;01 and cause unwanted effects, systemic effects, but is contained within the eye.
00:05:10;04 Other drawbacks... when we give these treatments for these diseases, they are frequent injections
00:05:14;24 that we have to do.
00:05:15;24 It's not a one-time treat... once treat... one treatment and you're done,
00:05:19;13 but it looks like we have to treat these patients as often as monthly.
00:05:22;17 And for a disease like macular degeneration, it's on average seven to eight times a year.
00:05:26;28 And unfortunately it's not just for one or two years.
00:05:29;22 As we learn more about these treatments, we see that we have to maintain this
00:05:33;11 regimen of treatment for many years, perhaps lifelong.
00:05:35;25 There are some other drawbacks from this therapy as well.
00:05:39;27 There's risks with this injection.
00:05:41;20 You can get a low risk of a serious infection inside of the eye.
00:05:45;05 And then there's the treatment burden.
00:05:47;01 It's un... it's painful and uncomfortable for the patient, but also the patient
00:05:51;06 and their family have to come into the office for frequent, ongoing visits.
00:05:55;03 The doctors and their staff have to handle this workload.
00:05:59;02 And so it's a significant treatment burden that I think we've... we still have not completely
00:06:03;26 adapted to.
00:06:05;23 From the... from the pharmacologic standpoint, when we inject these drugs into the eye
00:06:10;03 we have peaks and troughs.
00:06:11;16 When we initially inject it into the eye as a bolus, we have an order of magnitude
00:06:15;22 too much drug that's in the eye that's not needed.
00:06:18;07 And then it rapidly begins to decline so that there's a subtherapeutic tail that occurs,
00:06:22;21 and there's not enough drug left in the eye at somewhere around a month.
00:06:26;09 So, those... these are all our motivations to try to find a new way to deliver drugs
00:06:31;00 into the eye besides just injecting them directly into the eye as fluids.
00:06:35;14 From here, we'll concentrate on one of the diseases that I talked about,
00:06:38;13 wet macular degeneration, wet AMD.
00:06:41;16 And this is for elderly patients.
00:06:43;05 And this is a depiction of what it's like from their standpoint.
00:06:45;26 The patients, once they have the onset of the disease, develop blurriness.
00:06:49;10 They develop a blind spot.
00:06:50;18 They develop distortion in the center of the vision, so that they can have severe vision loss.
00:06:55;25 About seven or eight years ago, we had a major breakthrough in treating macular degeneration
00:06:59;15 with a drug called Lucentis.
00:07:01;11 This is a biologic drug.
00:07:02;27 It's an antibody fragment against VEGF.
00:07:06;23 This is a... this graph is showing a Phase 3 clinical trial over two years.
00:07:11;26 And on the y-axis we're seeing the change in vision.
00:07:14;28 So, above... going up... going upward is an improvement in vision, going downward is
00:07:20;04 a decline in vision, over time.
00:07:22;16 And you can see from the blue line in the control group, this is what it used to
00:07:26;02 be like for our patients.
00:07:27;06 With the onset of wet macular degeneration, there was a steady, inevitable decline in vision
00:07:32;06 for almost all of the patients, so that they had severe vision loss over a year
00:07:37;10 or two years, to the point where they would almost universally become legally blind.
00:07:42;22 The red line shows the dramatic benefit of using the Lucentis drug in these patients.
00:07:48;13 For the first time, we saw improvement in vision for these patients, where they
00:07:52;15 restored their visual function over three or four months, and this was maintained over two years.
00:07:56;26 Now, a couple of things to point out.
00:07:58;17 In this clinical trial, the patients received the injection of this drug every month
00:08:03;02 for two years, so a total of 24 injections.
00:08:06;08 That's a lot of treatments, so physicians and others immediately started looking for
00:08:11;06 ways that we could reduce this burden and make the treatment more manageable.
00:08:14;28 And this... this slide here, on the top, is showing that when we reduce the frequency
00:08:20;06 of the treatments compared to monthly injection, the lower frequency treatments also have
00:08:26;03 a lower benefit.
00:08:27;27 And the bottom frame, here, is showing a study that I conducted with 14 investigators
00:08:32;27 around the country.
00:08:33;27 And we looked at a cohort of patients from the original Phase 3 clinical trial,
00:08:38;15 and we did an update assessment on them seven years after... seven years afterwards.
00:08:43;22 And the red line shows this.
00:08:45;01 And you can see over the first two years, the patients with monthly injections had
00:08:48;15 a beautiful increase in their vision.
00:08:51;21 But once they stopped the monthly injections, there was a steady decline.
00:08:55;17 And so out... between year three and year seven, there was a very low treatment frequency,
00:09:02;06 that physicians were only electing to inject two times per year for these patients.
00:09:07;01 And on average, there was a loss of the initial benefit, and even a reversal of the benefit,
00:09:12;27 so the patients ended up with a vision that was below their starting baseline.
00:09:16;13 So, a couple things to point out here.
00:09:20;07 Doctors and patients have to face that we cannot limit the number of these injections
00:09:24;02 the way we'd like to.
00:09:25;23 And as this study shows, at least out to seven years, these patients are at risk to lose vision,
00:09:29;26 so that we're going to have to maintain this intensive treatment regimen for
00:09:34;14 at least many years and possibly for lifelong therapy.
00:09:37;17 So, how do we solve this problem?
00:09:40;08 In work... in collaborating with Tejal Desai, we have drawn up some target profiles
00:09:46;23 that we want for this device to have, from the clinician standpoint and from the patient standpoint.
00:09:51;28 We want this to be a device that when we put it into the eye it delivers the drug
00:09:55;24 effectively for at least four to six months.
00:09:58;18 We want to maintain precise concentrations with this drug, so both that we avoid
00:10:02;18 the peaks and we avoid the troughs.
00:10:04;06 But it has another benefit of precisely controlling the kinetics of the drug release with this device
00:10:09;24 in that, because the eye is such a small structure, there are real limits to
00:10:14;06 how much drug that we can put into these devices because the devices have to be kept so small.
00:10:20;17 So, we have to take a very small payload and stretch it out over many months by
00:10:26;21 precisely controlling the drug release.
00:10:27;24 And this is what allows us to maximize a small drug payload.
00:10:32;07 Some other characteristics that we want the device to have.
00:10:34;21 We want this to be an office procedure that's done pretty similarly to what all of us
00:10:38;20 are already doing, an injection... an injectable device that can be done in the office with local anesthesia.
00:10:44;28 The materials for the device should be degradable materials so that we don't have to go in later
00:10:48;28 and remove these devices, or we don't have accumulation of materials in the eye
00:10:54;17 as we treat these patients over the years.
00:10:56;19 And finally, we want this to be a platform for a number of drugs, both for the drugs
00:11:00;20 that we have already available for a number of different diseases and also some of
00:11:05;11 the drugs that are in the pipeline that will allow us to treat... will allow us to treat other diseases
00:11:09;16 in the very near future.
00:11:12;06 So, all of this is by way of an introduction in the clinical background here.
00:11:17;05 And it sets the table for my colleague, Tejal Desai, who will now come in and talk about
00:11:21;20 some of the progress we've made in this translational project.
00:11:24;15 Hi, I'm Tejal Desai, and I'm a professor in Bioengineering and Therapeutic Sciences at UCSF.
00:11:31;16 And I want to continue our discussion on developing new ocular drug delivery systems.
00:11:37;11 As suggested in Part 1, we really have an unmet need in how to develop treatment strategies
00:11:44;17 for delivering drugs to the back of the eye.
00:11:47;18 And my colleague, Dr. Robert Bhisitkul, eloquently described what our unmet need is,
00:11:55;10 in terms of how to get drugs effectively and safely to that region in the eye.
00:11:59;08 What was interesting is that we actually met because he was describing how there were
00:12:05;12 these wonderful drugs that are able to improve ocular vision.
00:12:10;23 And that, really, the way that they administer them are sort of dating back from the 19th century
00:12:16;00 in terms of injecting them with a needle.
00:12:18;25 And so we started talking at a forum that brought together clinical ophthalmologists
00:12:24;05 as well as bioengineers, and realized that there really was a unique opportunity to develop
00:12:30;01 a technology that could more effectively... and have better safety and compliance for
00:12:36;10 the patient.
00:12:37;16 So, where are we in terms of thinking about drug delivery for the eye?
00:12:42;10 There actually are a lot of technologies that have been developed.
00:12:46;02 We have everything from what we call nondegradable implants.
00:12:51;22 These are large devices or cages that are put into the eye.
00:12:56;11 But as you can see, they range from everything from a reservoir to an actual screw that gets
00:13:04;04 screwed into the eye.
00:13:06;13 And they stay there for the lifetime of the patient.
00:13:09;28 So, once you put these types of devices into the eye, they are basically there for the
00:13:16;09 rest of your lifetime.
00:13:17;26 So, one of the things, as Bob mentioned, we wanted to actually develop something
00:13:22;14 that was degradable.
00:13:23;19 So, there also were some advances in biodegradable implants that were placed in the eye.
00:13:30;02 Some of the things like microspheres and smaller pellets have been developed.
00:13:33;27 But all of these systems actually had only been developed for very small molecules
00:13:38;28 being delivered to the eye and could only really last for very short time periods.
00:13:44;00 So as Bob mentioned, we actually needed to develop something that would last at least
00:13:48;15 four to six months, and be able to be... deliver this drug in a very, very precise manner,
00:13:55;24 but then degrade at the end.
00:13:58;06 And none of these systems actually did that.
00:14:00;22 And finally, we saw that there were also some cell-based implants being developed.
00:14:05;12 And again, this was an idea that potentially could have merit in the future, but for
00:14:10;26 actually treating today's patient there was nothing already developed that would treat the unmet need.
00:14:18;09 So, when we think about the landscape and how people are approaching the delivery of
00:14:24;09 drugs to the eye, we really decided that there was an unmet need in developing long-term
00:14:31;25 biologic delivery devices that could be degradable and also injectable.
00:14:38;00 And if you look at this graph, what I'm pointing out here is that topical eye drops
00:14:43;10 -- we sort of think about that as a way to deliver drugs -- can really only last on the order of hours to days.
00:14:50;25 When you think about putting an eye drop into your eye, very little of that medicine actually
00:14:56;04 penetrates deep within the eye.
00:14:58;06 And in fact, eye drops are really limited to very, very small molecules, things that
00:15:03;20 can easily pass through the junctions of the cornea.
00:15:08;08 If we think about things that are being currently injected -- those are the drugs that Bob mentioned,
00:15:15;00 they're the larger antibodies or proteins -- and of course we can deliver them
00:15:20;14 with fairly large amounts, but we do that in a very invasive way.
00:15:26;19 And this is something that, again, we talked about.
00:15:29;02 These are delivered monthly.
00:15:30;08 So, an injection every single month in order to get these larger proteins into the eye.
00:15:36;24 And finally, there are these larger delivery devices that I mentioned.
00:15:41;03 But to date, there is nothing available that can actually deliver large proteins as well as
00:15:48;13 be biodegradable.
00:15:50;26 So, where are we trying to go?
00:15:53;24 We're trying to develop a device that will really marry the best of all of these different technologies,
00:15:58;27 which is something that will sit in the back of the eye, deliver these
00:16:03;03 large and small molecules, but do so in a way that is as easy and safe for the patient,
00:16:10;25 and relatively low invasiveness.
00:16:13;25 Okay, so the question is, how do we control drug levels?
00:16:19;09 It sounds easy.
00:16:20;09 We just want to get the right drug in the right concentration to the right place.
00:16:24;15 But it's not so trivial.
00:16:25;24 And in fact, most drug delivery systems actually give you a lot of drug right away and then
00:16:32;23 over time give you very little amounts of drug.
00:16:35;20 And that's sort of what we think about when we think about conventional drug delivery systems.
00:16:40;19 You have a reservoir with your given drug.
00:16:45;01 And drug comes out of that reservoir based on Fick's law, which essentially says that
00:16:50;24 diffusion is concentration-dependent.
00:16:54;11 So, if I have a lot of molecules on one end, the molecules will diffuse out based on the
00:17:01;24 concentration difference.
00:17:04;11 That tends to give us profiles that look like this, where you have a burst release followed
00:17:09;06 by a plateau.
00:17:11;11 And in the case of the eye, this is not what we want.
00:17:14;23 We actually want a very small amount of drug to be given over a long period of time.
00:17:20;18 So, how can we change these sort of kinetics?
00:17:23;15 Well, it turns out that if you shrink down your reservoir such that you're 1-2 times
00:17:31;20 the molecular diameter of your drug of interest -- so, looking at a panel number two --
00:17:38;28 you can actually constrain the drug molecules such that they can only come out one at a time.
00:17:45;06 So, if you do that, instead of having burst release, where all the drugs try to get out
00:17:51;20 at the same time, you can only have one drug molecule coming out at any given one time.
00:17:58;22 And the analogy that I like to use is one of a movie theater, where if you have
00:18:04;18 a hundred people in the audience or you have a thousand people in the audience, if there's only
00:18:09;25 one exit door and somebody yells fire and everybody races to get out, actually, the rate of escape
00:18:17;00 or the rate of getting out of that movie theater is not dictated by how many people are concentrated
00:18:23;13 in the theater.
00:18:24;13 It's really dictated by how many people can escape out that door.
00:18:28;26 And if only one person can come out, then only... the rate is only dependent on
00:18:35;09 how long it takes for all of those people to get out.
00:18:38;24 So, we apply that same principle, and we are able to get these very linear release rates.
00:18:44;18 And if we create very many tiny nanoscale pores, what we can then do is tune that
00:18:51;03 release rate up and down.
00:18:53;16 And that's what we employ for designing our drug delivery systems.
00:18:57;24 So, how do we do that?
00:18:59;28 Well, my lab and many of my colleagues have been working to develop materials in which
00:19:05;14 we can precisely create nanopores.
00:19:09;04 And just an example, these are some of the materials that we've worked on in the past,
00:19:13;17 ranging from nanoporous alumina, nanoporous silicon, as well as titanium.
00:19:20;17 And as you can see, there are very, very defined architectures that are made in all of these materials.
00:19:27;16 And we can control the pore size from anything from a couple of nanometers up to
00:19:32;09 hundreds of nanometers or even microns.
00:19:35;05 And what's unique about these materials is that they don't have what we call a pore size
00:19:40;19 So, whatever we design, every single pore has the same size.
00:19:45;25 And this is important for sort of taking advantage of that effect I mentioned and getting
00:19:50;24 a very, very linear profile.
00:19:55;06 How linear is this profile?
00:19:57;06 Well, for example, if we wanted to deliver something like albumin
00:20:01;27 -- this is a protein that has a molecular weight of about 66,000 --
00:20:06;27 we can essentially design pore sizes that
00:20:09;15 are anywhere from 30 nanometers down to 13 nanometers.
00:20:15;03 And if you take a look at the graph on the top, what that's showing you is just the difference
00:20:20;14 from going from a sort of conventional Fickian type of arrangement, where you actually see
00:20:28;11 this burst release, to something that's much more linear.
00:20:34;14 And when you get down to interferon, which is even smaller
00:20:38;14 -- down to about 19,000 molecular weight --
00:20:41;02 we have to really go down to nanometer-sized pores that are on the order of 10-13 nanometers
00:20:47;03 to get that linear release.
00:20:48;21 So, by thinking about what molecule we're interested in, we can design a pore size
00:20:54;18 that precisely fits that molecule and gives us this linear profile.
00:20:58;13 So, why do we care?
00:21:03;02 As we keep mentioning, getting into this precise rate of release gives us what we call a therapeutic window.
00:21:12;24 So, instead of giving a lot of drug, and having wastage of drug, and actually having
00:21:19;18 side effects from overdosing, what we get is something that gives us just enough drug to be
00:21:27;03 physiologically effective and treat the disease but doesn't give us the toxicity that's associated
00:21:32;15 with a lot of drug, and also is not subtherapeutic.
00:21:35;08 So, we're actually giving something that's right in the region that we want.
00:21:40;21 So, forgetting the highs and lows that are associated with injection, and really going
00:21:46;00 into what we call the therapeutic window.
00:21:49;17 So, one of the challenges with sort of thinking about the eye was mentioned by Bob as well,
00:21:58;15 and that was that this is a pretty small space.
00:22:02;01 We really can't think about a large implant that sits in the eye and bounces around.
00:22:08;02 It has to be an implant that's relatively thin, transparent, flexible, and can be injected
00:22:15;04 via a needle.
00:22:16;26 And most of the work that people have done in terms of creating nanoporous materials
00:22:20;25 has conventionally been done in inorganic materials, so the ceramics and some of
00:22:26;20 the metal oxides that I mentioned earlier.
00:22:29;14 And so our challenge was, how could we actually create very small pores in a thin, flexible material,
00:22:36;12 almost like a contact lens type of material?
00:22:39;23 So, what we ended up doing is actually developing... developed a technique called nanotemplating.
00:22:46;22 And so this is actually pretty simple to understand.
00:22:50;08 It's really sort of creating a replica of a mold.
00:22:54;04 But instead of something on a large scale, what we're doing is creating a very, very
00:22:58;11 small structure and then replicating that off of a different material.
00:23:03;07 So, for example, in this image what we're showing is an inorganic porous material
00:23:11;23 -- so, this is the picture shown here, this is nanopores -- and then if we press another material,
00:23:19;27 a polymer or a soft material on those pores, what we get is the inverse of that structure.
00:23:26;09 And in this case, these are nanowires that project out of the surface.
00:23:31;01 And so, we.... as you can see, we get very precise structures by using this method.
00:23:36;23 So, we can do the opposite, which is we can create nanowires and then template off
00:23:45;01 a soft material and create nanopores.
00:23:49;12 And this is what we did.
00:23:50;28 We actually developed a process where we can create very thin films of nanoporous polymers
00:23:57;13 from nanorod templates.
00:24:00;02 And the details of this process are not necessarily important except for the fact that
00:24:07;14 if you look here what we're essentially doing is we're growing these rods.
00:24:12;14 And these rods can be controlled in terms of their width, their diameter, their spacing.
00:24:19;10 We then spin a thin film.
00:24:22;07 This can be any polymer of interest.
00:24:24;03 We've been using something called polycaprolactone.
00:24:27;11 This is a biodegradable polymer, and it's very flexible and robust.
00:24:32;22 And then we basically sandwich that between a structural layer that will hold it in place,
00:24:39;05 because if we have a very, very porous layer it may be too fragile.
00:24:42;17 So, we sort of sandwich multiple layers to create something that a surgeon can actually manipulate.
00:24:49;08 One of the things within our field of nanotechnology is that we want to create things that are
00:24:55;07 easily adaptable by the clinician.
00:24:58;23 And so, again, really thinking about creating a structure but then adapting that structure
00:25:03;17 in a way that could be administered in the clinic.
00:25:07;14 What does this look like?
00:25:08;26 Well, before, if you look at the rods, you can see they have all of this morphology of
00:25:15;09 things sticking out of the surface.
00:25:19;09 But when you look at the pores, it's the inverse of that.
00:25:22;10 So, we can do that essentially with any structure.
00:25:27;10 And after we do that, what we get are these thin films.
00:25:31;03 And you can see from looking at the image, the actual nanoporous region is this one
00:25:36;07 that's sort of the opaque area within the film.
00:25:39;26 When it gets hydrated, it actually becomes transparent.
00:25:43;00 But the nice thing about these films is they're actually very rollable or foldable.
00:25:48;18 They can actually fit into a needle.
00:25:51;22 And that's the same needle that is used today in the clinic.
00:25:54;27 So, we can take... con... you know, conceptually, we can take these films and put them
00:25:59;18 into a needle that every ophthalmologist is already familiar with using.
00:26:06;01 Now, if we take an electron microscope and we zoom into what that structure is,
00:26:14;04 of that porous area, what we see is that we have a whole region which is essentially
00:26:23;01 a microporous region, this sort of area, here.
00:26:26;23 And then if you zoom in, what you see is there is this nanoporous region.
00:26:31;26 And this nanoporous region is really the rate-limiting... limiting region.
00:26:36;09 That's the region that's going to constrain our molecules and keep our molecules
00:26:39;25 coming out one at a time at a very precise rate.
00:26:47;15 How do we make this a device?
00:26:49;06 Well, we spent a lot of time thinking about, how do you put in a drug, keep that drug stable,
00:26:56;13 maintain bioactivity, and then have this as a device that can be put into the body?
00:27:01;20 And so what we came up with was a method to take two of those thin films that we create
00:27:07;26 through that templating technique, basically encapsulate a drug around that film
00:27:14;08 -- so, the red dot in this schematic is the drug that we can either pellet or we can put that
00:27:19;21 in a powder or a liquid solution -- and we then bring the two films together,
00:27:26;15 and we do that, basically, by holding two weights and bringing the films and then heat sealing those films.
00:27:32;27 And what we end up with is basically a device that has the drug cargo in the middle,
00:27:40;11 but it's essentially a very thin, flexible film.
00:27:43;04 The shape, the size, the actual morphology of the film can be changed very easily.
00:27:51;26 And so, as we sort of talked about earlier, this can be adapted to a range of
00:27:57;00 different drugs and a range of different durations.
00:27:59;14 If we want something to last for one month versus four months versus two years, we can
00:28:05;10 simply change the size or the porosity of those films.
00:28:12;17 What does that get us, doing all this nanotemplating?
00:28:15;09 Well, what it does is it gives us that very, very precise control of drug release.
00:28:22;22 So, these are two graphs.
00:28:24;27 This is just showing a model protein, which is bovine serum albumin.
00:28:29;24 And what I'm showing you is, on top, basically release date... release rate per day.
00:28:36;07 So, this is over 200 days, so greater than 4 months.
00:28:41;20 And essentially what you're seeing is that the release rate of these devices stays between
00:28:47;23 1 and 2 micrograms per day.
00:28:51;14 And that goes out all the way across those 200 days.
00:28:55;09 So, if we want 10 micrograms per day, we can dial it in to make it 10 micrograms
00:29:00;22 being released over that duration.
00:29:02;10 If we want something smaller, we can dial it in.
00:29:05;04 But the important thing is that we can take what was a once-a-month payload,
00:29:11;12 which is 500 micrograms, and essentially make that last for 4 to 6 months.
00:29:17;13 So, given the current clinical standard of care, where we're injecting a bolus of
00:29:24;15 500 micrograms, this is the same amount of drug -- so we don't worry about toxicity --
00:29:29;13 but we're extending or stretching as was mentioned in the earlier presentation the drug profile
00:29:35;17 out to several months.
00:29:40;03 We can do this with Lucentis.
00:29:41;06 So, this is that great drug that is able to actually improve visual acuity.
00:29:48;01 And again, you see this linear release.
00:29:51;02 The release is shown over about 120 days, but it continues up until the end of the payload.
00:29:58;15 And one of the things that's very nice about this approach is that we're decoupling
00:30:03;19 the formulation of the drug with the actual kinetics of the drug delivery system.
00:30:08;18 And so that allows us to have a very, very high stability.
00:30:11;22 And we can keep the drug stable and pure.
00:30:16;00 And we can release it at a predetermined rate.
00:30:21;12 How would this be administered?
00:30:23;00 Well, again, knowing that in the clinic Lucentis is injected via a needle, we really wanted
00:30:30;02 to make this device flexible and able to be placed in those same types of needles.
00:30:36;22 And so, here is an example where we're actually taking our device, we're putting it into a needle,
00:30:41;11 and we're injecting it into the back of the eye, in this case in rabbits.
00:30:46;22 And you can see what that looks like.
00:30:50;03 Keep in mind this is a graduate student who's trying to get that film into... into the needle.
00:30:56;20 But as you see, we're holding open the eye.
00:31:00;19 We're doing an injection.
00:31:01;22 This is very similar to what is done in the clinic.
00:31:06;08 And we put that in there, we press it, and then we take the needle out.
00:31:11;21 And if you look very carefully through that magnifying glass that's sitting right on top
00:31:16;26 of the eye, you can make out the corner of that film.
00:31:20;08 It is transparent, but it sits in the peripheral vitreous, and it's able to elute drug over time.
00:31:30;11 In vivo, we also see that these things are able to release in that linear fashion.
00:31:36;06 So, these are, again, some examples in a study in which we basically took devices that were
00:31:42;26 sitting in vitro and releasing drug, and then we took those same devices and we put them
00:31:47;17 into the rabbit eye.
00:31:49;04 And we wanted to ask the question, can these devices release in a consistent manner to
00:31:54;04 what we saw in vitro?
00:31:55;26 And what we saw is, yes.
00:31:58;00 We can continue that profile out.
00:32:01;10 And as compared to an injection, as you see here, we're continuing to have drug
00:32:08;17 being released, whereas in an injection basically the drug amounts go back to zero very rapidly.
00:32:15;26 So, we're really excited about thinking about a new way that we can deliver these proteins
00:32:23;08 and biologics in a way that, again, is safe for the patient but also improves patient compliance.
00:32:31;04 And really, we think, might help the visual outcomes by having a continuous therapeutic dose
00:32:38;06 of our intended drug target.
00:32:42;12 One of the things that we have really focused on is the safety and biocompatibility of
00:32:48;05 this type of device.
00:32:49;22 And this is just a little bit of data showing that putting in a polymer film and
00:32:56;10 having it sit there for a period of 6 and even 12 months really minimally disturbs
00:33:03;01 the back of the eye in terms of the histology of the retina or any other parts of the eye.
00:33:08;27 And what we see is very similar to control eyes in which we place no device.
00:33:15;25 And this is important because, again, if we're going to release a drug that's supposed
00:33:20;13 to be therapeutic, we don't want to induce any other complications.
00:33:25;23 So, our goal with this collaboration, and I think again the beauty of bringing together
00:33:32;27 clinicians and engineers or other people interested in developing technologies, is that we can
00:33:39;01 focus on unmet clinical needs and, in this case, really improving how ocular drugs are delivered.
00:33:46;24 And do that in a way that can, we hope, change the course of administration for not
00:33:52;25 just drugs for the back of the eye but also drugs for other parts of the body.
00:33:57;26 This is a platform technology, and we hope it can be used for the delivery of biologics
00:34:03;13 as well as small molecules to many port... many different places in the body.
00:34:07;22 So, where is the future?
00:34:10;12 Well, we're actively seeking to scale this device up and hope that we can put this
00:34:17;00 into patients at some point in the near future.
00:34:20;09 We hope that this technology will really lead to a future where patients have access to
00:34:26;28 a better visual outcome.
00:34:30;08 And with this I'd like to thank our funders, including the NIH, the Coulter Foundation,
00:34:36;16 the Rogers Foundation, and the UCSF Catalyst Award for funding the collaboration
00:34:43;13 and the innovation that came through this.
- Lucentis is a drug used to treat wet age-related macular degeneration. It is an antibody fragment against VEGF. What is VEGF? From what Dr. Bhisitkul mentioned about wet age-related macular degeneration, how do you think that blocking VEGF would help treat this disease?
- Dr. Bhisitkul discusses the phase three clinical trial of Lucentis (7:08). What is a phase three clinical trial? What are the other phases of clinical trials?
- Dr. Desai shows that her drug delivery device can release drug more consistently than drug injections in rabbits, maintaining drug concentrations in the therapeutic window for longer periods of time. What are some next steps that should be taken to show that this method of drug delivery is more beneficial for patients?
- What are some possible safety concerns with Dr. Desai’s drug delivery device?
- The drug delivery device was designed so that it could be used in various situations. What are some other possible applications of this drug delivery technology in other body systems?
Dr. Robert Bhisitkul is a Professor of Clinical Ophthalmology at the University of California, San Francisco where he specializes in vitreoretinal surgery. Bhisitkul received his MD from Stanford University and his PhD in neurosciences from Yale University. Continue Reading
Professor, Bioengineering and Therapeutic Sciences
University of California, San Francisco Continue Reading
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