SciCafe: Mending a Broken Heart

SciCafe: Patching a Broken Heart - Transcript

Jeffrey Karp (Principal Faculty, Harvard Stem Cell Institute):

What I wanted to do tonight was tell you about some of the projects in the lab, but actually go beyond that and tell you a little bit about the process that we engage in to attack these problems. We have two types of projects in the lab. One is basic discovery and the other is translation. I want to focus tonight on translation, but I want to highlight something important about just doing science in general and that is that it's extremely challenging. Often, nine times out of ten, when we conduct an experiment, we fail and so, to then take that science and translate it into products that can help patients is even more challenging.

And I find that when we try to do this, we tend to approach the problem the same way every time and yet we expect different outcomes and I think there's many reasons for this. There's many reasons why our brains have actually been trained to be anti-creative, to kind of anticipate what comes next and to just do the same thing over and over again. So the question is, how do we break free from this repetitive process. How do we hijack our brains to bring in fresh ideas? And I would argue that there are many ways to do this and tonight, I'm going to share some examples.

In particular, one of the ways that we try to intercept this repetitive thought process is to turn to nature for inspiration. Every living thing, every plant, every animal, everything that's living that exists today is here because it has overcome an insurmountable number of challenges and those that haven't have quickly become extinct. So, in many ways, we're actually surrounded by solutions, which are ideas for solving problems. Evolution is truly the best problem-solver. Hundreds of millions of years of research and development happening all around us. Let me share with you an example of a project that we were pursuing when we encountered what seemed to be an insurmountable barrier and we turned to nature for inspiration.

This is Dr. Pedro del Nido. He's Chief of Cardiac Surgery at Boston Children's Hospital and he approached me one late summer evening and he said, "You know, I'm trying to treat kids who have septal defects." These are holes in between the chambers of the heart. He said, "Sometimes we try to suture that tissue, but it's so fragile, it just tears." He said, "There's devices that work in adults, but the challenge is you can't just downsize those devices because they're permanent and you'd have to come back over and over for revision procedures because that child's heart is growing over time." He said, "Isn't it possible, based on some of the work you've done before that we could develop a patch, a patch that you could place inside a beating heart, put up against the hole, immediately seal it. Cells would migrate over this patch, form tissue. The material would fully degrade and the patient would be left with their own tissue sealing that hole, which could then grow over time."

So, we were really excited to work with Dr. del Nido, but we knew that this tissue adhesive that we were going to develop would have to work in potentially the harshest environment inside the human body, where you have sheer forces. You know, the heart is beating at least 60 beats per minute. You have blood. There's multiple cells in there. There's enzymes. Everything is working against you. And so, what we did is we put together design criteria for the ideal solution. And I'll tell you, this is probably one of the hardest things that we do because it's easy to come up with a shopping list of 20 or 30 things. The challenge is how do you narrow it down to five or six and then, narrow it down to one or two to drive a completely differentiated solution that no one has ever tried before.

So, we came up with the short list. We said, you know, a lot of materials that people have developed, they actually react with blood. They become fouled with blood. They just don't work in the presence of blood. Ours has to work in the presence of blood. It has to be biodegradable. It has to be elastic. It has to match the material properties of the tissue that we're applying it to. It also has to be biocompatible so cells can migrate onto it and form tissue, that tissue bridge that I spoke of. And then, when you put it in place, we have to think of the surgeons. They're not just going to put it in place and they're done. They're going to want to position it to the right location and it can't wash out during this procedure.

And then, Dr. del Nido and other clinicians that we spoke to said, "You know, there's some materials in the clinic that cure within a minute or 10 minutes," but they said, "We don't want to be at the mercy of the technology. We want to be in control of the technology. We want on-demand adhesion. We want to place this thing and when we're ready, we want to cure it to its final state." And we had developed a number of materials that could address a lot of these criteria, even the on-demand because we have light-activate-able materials.

But there were two criteria that we really had no idea how to get around: resistant to blood and resists wash-out. And so, we turned to nature for inspiration. We said, "What creatures exist in nature within wet, dynamic environments that may mimic the environment where this adhesive would have to work?" And so, we turned to sandcastle worms in the sea and slugs and snails on the land and what we noticed is that these creatures actually had two things in common. One was viscous secretions and we know that viscous things like honey, for example, honey on a plate, will stay put. If I put honey here and try to wash it away, it's actually going to take some time because of these viscous adhesive interactions.

And then, when we looked at these viscous secretions, we also noticed that they contained hydrophobic agents and hydrophobic agents can repel water. So, we said aha. What if we developed a precursor glue that we could put inside a beating heart that was hydrophobic? As soon as it contacted the tissue, it would repel the blood away from the tissue and because it's viscous, it would stay in place long enough for the clinician to shine light to cure it.

So that was great, but how are we going to make the thing adhesive? When you walk around Boston, as I'm sure some places here in New York, you see buildings like this, covered in ivy and I don't know if anybody has gone up to the ivy and tried to pull it off, but it's remarkable the amount of force that's required and lucky for us, the mechanism through which ivy attaches so strongly was recently elucidated and it's amazing. Ivy has these root hairs, which are almost like heat-seeking missiles. They go up and down the building and they look for crevices and when they find a crevice, they insert the root hair in, they shrivel up and they mechanically interlock. And so, that gave us an idea. If we could develop a glue that upon contact with tissue, if it could infiltrate into the tissue, and then, we cure it with light, we would have a tissue-like Velcro and it potentially would work on almost any tissue in the body. So, after about two or three years of multiple iterations, we were able to address all the design criteria.

Now we have a glue, but there's another challenge because often, if you go to CVS, for example, or Walgreen's to get a Band-Aid, you don't just have cotton gauze with glue. There's actually a backing layer, which is paper or plastic to provide structural support. We needed a backing layer. This is a very harsh environment in the heart. We had to design a completely new material and this material had to have an additional design criteria. In addition to being degradable and elastic, it also had to be transparent because we're going to shine light through it to activate an adhesive on the opposing side. There are no recipes in the literature, the academic literature, for how to do this. We just had to do brute force, but we were able to come up with another material that was completely transparent, as you can see here, and also, elastic. We could stretch it over and over again and it wouldn't lose its properties.

After performing multiple experiments, we moved to an extraordinarily challenging experiment, one that would mimic the exact application of where this patch would go. We had to put this inside a beating heart, right on the septum where you have these holes. And so, what we did is working with Dr. del Nido, he had developed this cardio-port device. We put our patch on the very end of the device and then, we made a small incision in the myocardium, the outside of the heart, in a pig model. This is a live pig. We pushed this up against the septum. We shined the light for 20 seconds and here's what happened.

What you can see directly after the procedure is we have the patch in the middle here that has attached. We came back after four hours and added epinephrine to increase the heart rate. We needed to test this at the full range and watch what happens. We see here the patch still remains attached in both of these pigs. We came back after 24 hours and the patch was still there. And since we've conducted this experiment, we've also partnered with another laboratory in Boston to develop a device so that we can place this patch through a blood vessel. We don't have to make an incision in the myocardium, which would be non-ideal, of course, for the patient. We can actually put a tube into a blood vessel, fish it into the heart and then, deploy it in a more minimally-invasive fashion.

We continue to advance this in the laboratory, but we've also been able to test this in multiple other models. We showed we could seal the carotid artery of a pig. We could seal the aorta of a pig. This attaches to almost every tissue in the body and because of that, we decided this is ready for translation. And so, we started a company called Gecko Biomedical in late 2013 and the company has now been able to manufacture this glue at large scale. It's shelf-stable and they're expected to be first in man in March of this year for vascular reconstruction.

[Applause]

In addition to bioinspiration, I wanted to share with you another tool that we've been harnessing in the lab and it's something that I've realized, in terms of looking at the full translational spectrum. I've realized that you can't help a patient unless you keep your solution extraordinarily simple. You have no idea how many technologies have been developed in laboratories and have been shown to work in animal models, but have not been translated to patients and often, these fail because they can't be manufactured. They're just too complicated. And so one of the principles that we have been trying to employ in the laboratory is one that we call radical simplicity and let me show you an example of how we've used this.

Patients that have ulcerative colitis, almost all patients, will require enema-based therapy at some point in their treatment regimen. And enemas have a lot of challenges. One, the patient needs to retain that for long periods of time to get good drug exposure. The systemic absorption of the drug is also very high and so, this can go throughout the body, causing systemic side effects and patients need to dose every day, which is extremely inconvenient. So, we were interested in asking the question, could we develop a solution to this that would address all three of these challenges and for this, to keep things as simple as possible, we turned to the Generally Recognized as Safe List by FDA. This is a list of agents that's on the FDA website that basically says, if you use these in certain concentrations and they're topical, then it's extremely safe. We're going to minimize technology risk if we can pick agents directly off this list and so, what we did is the following.

We scoured that list for agents that are amphiphiles. These have a hydrophobic group that doesn't like water and a hydrophilic group that likes water In addition, we also looked for agents that had an enzyme-cleavable bond between the hydrophobic and hydrophilic moieties. What's amazing is if you take an amphiphile that has this hydrophobic and hydrophilic properties and you put it into water, it doesn't dissolve, but with the right solvents and the right temperature, you can get it to dissolve. As you cool that, what we can do is coax that system, those molecules, to assemble, to stack one on top of the other. The groups that don't like water will point inward and the groups that like water will point outward. And we can coax this system to form a hydrogel that looks like this. This is an electron-micrograph of that hydrogel system. It's nanofibrous. This looks just like butter or margarine at room temperature and has very similar consistency. But what you're looking at here is a single molecule that is stacked over and over and over again. There's nothing else present except that molecule. And that molecule was taken from the Generally Recognized as Safe List. What we can do during that assembly process is we can entrap drugs, all kinds of different drugs. We've tried many and then, in the presence of inflammation at sites of ulcers, you have high concentrations of degradative enzymes and so, what will happen is that if this gel, if this material reaches the ulcer, it'll be disassembled and the drug will be released. So, we've developed an inflammation-responsive material that's extremely simple.

And we went one step beyond that. We knew at sites of ulcers that typically you have positive charge and to increase the potential for targeting to minimize systemic absorption, to minimize potential for this gel to disassemble at a site of healthy tissue, we target it by selecting an amphiphile from that list that had negative charge. We then broke this gel into small particles and we did enema infusion into a number of animal models. We were able to show with this system that we could selectively target the ulcers. These gel-based particles attach specifically to the diseased tissue, whereas we didn't see any attachment to the healthy tissue. We also were able to show, because when you infuse this gel in particle form, it attaches to the ulcer so quickly, the patient wouldn't have to hold in- they wouldn't have to retain that enema. And then, it sticks to the ulcers and it continuously releases in the presence of those enzymes. In fact, we saw that it could remain attached to the ulcers for long periods of time and because we're not getting release of the drug at the healthy tissue, we were able to reduce the systemic exposure of the drug by five- to ten-fold with our system, meaning less potential systemic side effects.

And then, we moved to a model where we dosed the enema to the animals every other day and when you do this with a drug alone, it doesn't work. You have to dose every day, but with our gel, because it attaches to the ulcers and stays there and continuously releases the drug, we're able to dose every day and get a major improvement in the healing of the tissue. And now, I'm working with a number of gastroenterologists to try to bring this forward to the clinic.

Another example of where we've tried to harness this concept of radical simplicity can be shown here. This is my hand and one day, I was wondering why do I have this burning, itching, red reaction next to my wedding ring. Am I allergic to my marriage, maybe? I don't know. It was bothersome.

This is 24-carat gold and so, I started to wonder, you know, what was going on. This wasn't happening on any of the other fingers and I read that maybe this was a nickel allergy. And so, what I did is what I think all of you would do if you had access to a laboratory, was I brought my ring to the lab and analyzed for nickel and sure enough, the substrate turned red, meaning that this wedding ring, which we got from a family friend, 24-carat gold, contains a good amount of nickel, which is extremely cheap and is used as a filler. And then, I realized I'm part of the 9% of the population that has a nickel allergy, 9% of the world population and it's one of these things that when you reach a certain exposure level, then you become allergic and you're allergic for life and it's almost impossible to avoid. It's everywhere. It's in belt buckles. It's in coins. It's in eyeglass frames. FitBit had to recall one of their product lines because it was leaching a lot of nickel. And so, when we looked to see what was currently available in the clinic, there was nothing to prevent these reactions for people who are allergic and nothing to prevent someone from becoming allergic. Only steroids, which were administered after the reaction to resolve it.

So, we were determined, I was determined, to find a solution to this. And the goal was to kind of do something similar to some of the sunscreens that exist. So, some of the sunscreens have nanoparticles in them that coat the skin and block the sun from going through. We thought well, maybe we could create particles on the skin, but instead of blocking the sun, they could bind nickelmand prevent that nickel from going into the skin and then, we could just wash it off. So, we went back to the Generally Recognized as Safe List. We scanned the list and we identified some agents that we had a hunch could bind nickel at high affinity when we formulated it as nanoparticles. And what we did is we applied this in many different models in the lab. This is just one example where what you're seeing is full-thickness skin, this is the top of the skin at the top and the bottom of the skin, the underneath surface, at the bottom. We put the particles onto the skin and we added a very high concentration of nickel. This is calcium carbonate, chalk. The particles we had put into a cream to apply it, just like a sunscreen and here you have the cream alone, the glycerin and what happens is, is that the nickel binds to the particles that are on the skin and doesn't enter the skin, whereas if you don't have the particles there, they can directly go into the skin. And then, if you wash the skin, we can wash off almost all the particles and all the nickel, but you can't do the same with the nickel that's gone into the skin.

We tested this in a number of models and we published a paper and CNN picked up this paper. They put it on the home page and they had a little blog at the bottom and people started writing in saying, "I'm desperate. When is this going to be available?" And so, we launched a company called Skintifique and brought this technology to market. And by harnessing this concept of radical simplicity, the company was able to have a clinical proof of concept within two years of the publication and a year later, we had a product on the market. And the company has been able to maintain this concept of radical simplicity in new products- and let me just quickly show you one example.

So, this is a hydrating gel that the company developed, where what they did is they looked for agents on the Generally Recognized as Safe list that could be formulated as three-dimensional nanostructures that could bind a ton of water. And it keeps this water in close contact with the skin and skin has natural repair mechanisms where if you keep it hydrated and prevent irritating agents from interacting, it can actually self-heal in many cases. This product only has eight ingredients and we can entrap active agents from the GRAS list in these nanostructures. Let me just show you one example of a patient who approached the company who had psoriasis. He had tried everything and he started using this cream multiple times a day and within weeks, his skin completely cleared up. And now, he's been using this cream for about a year-and-a-half and the skin condition has not come back. This has been tried now on multiple patients with eczema, psoriasis and other skin conditions and it's been performing very well. This company has now been able to launch these products across the globe.

Now, finally, I just want to tell you about one more problem that we've been working on where we've tried to employ this concept of radical simplicity. We want the solution to get out there as quickly as possible. Some of you may be familiar with the dangers of button cell, or coin cell, batteries. Kids under the age of six get a hold of them, accidentally ingest them. They get stuck in the esophagus. They short-circuit. A current forms and then, it can burn a hole through production of hydroxide ions, through the esophagus. So, we were determined to try to solve this problem and we made a simple observation.

Any time you put a battery in a device, there's always the spring you need to push against. You don't just drop it in. You kind of have to click it in and we did a number of calculations. We turned to the literature and we realized that the force that the esophagus exerts on a battery a button cell battery, is much less than the force required to put the battery into a device against this spring. And, so that gave us a design angle. So, we asked, "Are there any off-the-shelf materials we could use to solve this problem?" because we don't want to invent something new. It would just take too long. And that led us to touch screens.

Some of the touch screens that are available work by a pressure-sensitive action, where where you touch, you actually get a current that forms to describe that location. We purchased these materials. We attached them to the battery. We also added a silicon layer over the gasket that connects the anode to the cathode to completely waterproof the system and then, we fed those batteries to pigs. And we showed that with this coating, if you don't have the coating, you get significant damage. This damage occurs within two hours. It's very fast. But with the coating, we get absolutely no damage. We've put this into stomach acid for 48 hours and nothing happens. There's no reactions. And so, when this coating is on the battery outside of a device, it's insulating. If you accidentally swallow it and it gets trapped in the esophagus, the forces can't convert that coating because it's pressure-sensitive, to a conductor, so it remains insulating. But when you put it into a device, the pressure converts to an effective conductor and it works just normally. And now, we're working with some of the major battery manufacturers,as well as the U.S. government poison control and the U.S. Consumer Product and Safety Commission, to bring this technology to the market.

So, in closing, I shared with you a couple of tools that we've been using in my laboratory to try to focus on translational projects, to try to get over those hurdles and really break free from this repetitive thought process. I spoke about bioinspiration. We're not doing bio-mimicry here where you mimic nature directly. We're doing bioinspiration, where you take a basic idea in nature and then, improve on it for one's own purposes. And then, radical simplicity. How can we keep what we do as simple as possible at every single step, to maximize the potential that what we work on can help patients as soon as possible?

Thank you so much.

[Applause]

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