how to fix a broken heart

>>dr. jeffrey karp: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 alittle 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 importantabout 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 andso, to then take that science

and translate it into products that can helppatients is even more challenging. and i find that when we try to do this, wetend to approach the problem the same way every time and yet we expect different outcomes and ithink there's many reasons for this. there's many reasons why our brains haveactually been trained to be anti-creative, to kind of anticipate what comes next andto just do the same thing over and over again. so the question is, how do we break free fromthis repetitive process. how do we hijack our brains to bring in freshideas? and i would argue that there are many waysto do this and tonight, i'm going to share some examples.

in particular, one of the ways that we tryto 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 insurmountablenumber of challenges and those that haven't have quickly become extinct. so, in many ways, we're actually surroundedby solutions, which are ideas for solving problems. evolutionis truly the best problem-solver. hundreds of millions of years of researchand development happening all around us. let me share with you an example of a projectthat we were pursuing when we encountered

what seemed to be an insurmountable barrierand we turned to nature for inspiration. this is dr. pedro del nido. he's chief ofcardiac surgery at boston children's hospital and he approached me one late summer eveningand he said, "you know, i'm trying to treat kids whohave septal defects." these are holes in between the chambers ofthe heart. he said, "sometimes we try to suture thattissue, but it's so fragile, it just tears." he said, "there's devices that work inadults, but the challenge is you can't just downsize those devices becausethey're permanent and you'd have to come back over and overfor revision procedures

because that child's heart is growing overtime." he said, "isn't it possible, based onsome of the work you've done before that we could develop a patch, a patch thatyou could place inside a beating heart, put up against the hole, immediately sealit. cells would migrate over this patch, form tissue. the material would fully degradeand the patient would be left with their own tissue sealing that hole, whichcould 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 towork in potentially the harshest environment insidethe human body, where you have sheer forces.

you know, the heart is beating at least 60beats per minute. you have blood. there's multiple cells inthere. there's enzymes. everything is working against you. and so, what we did is we put together designcriteria for the ideal solution. and i'll tell you, this is probably oneof the hardest things that we do because it's easy to come up with a shoppinglist of 20 or 30 things. the challenge is how do you narrow it downto five or six and then, narrow it down to one or two todrive 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 becomefouled with blood. they just don't work in the presence ofblood. 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 canmigrate 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 placeand they're done.

they're going to want to position it tothe right location and it can't wash out during this procedure. and then, dr. del nido and other cliniciansthat we spoke to said, "you know, there's some materials in theclinic that cure within a minute or 10 minutes," but they said, "we don't want to be atthe 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'reready, we want to cure it to its final state." and we had developed a number of materialsthat could address a lot of these criteria, even the on-demand because we have light-activate-ablematerials.

but there were two criteria that we reallyhad 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 thisadhesive would have to work?" and so, we turned to sandcastle worms in thesea and slugs and snails on the land and what we noticed is that these creaturesactually had two things in common. one was viscous secretions and we know thatviscous things like honey, for example, honey on a plate, will stay put. if i puthoney here and try to wash it away,

it's actually going to take some time becauseof these viscous adhesive interactions. and then, when we looked at these viscoussecretions, we also noticed that they contained hydrophobic agents andhydrophobic agents can repel water. so, we said aha. what if we developed a precursorglue that we could put inside a beating heart that was hydrophobic? as soon as it contactedthe 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 tomake the thing adhesive? when you walk around boston, as i'm suresome places here in new york,

you see buildings like this, covered in ivyand i don't know if anybody has gone up to the ivy and tried to pull it off, butit's remarkable the amount of force that's required and lucky for us, the mechanism through whichivy attaches so strongly was recently elucidated and it's amazing. ivy has these root hairs, which are almostlike heat-seeking missiles. they go up and down the building and theylook for crevices and when they find a crevice, they insert the root hair in, they shrivelup and they mechanically interlock. and so, that gave us an idea. if we could develop a glue that upon contactwith tissue, if it could infiltrate into the tissue,

and then, we cure it with light, we wouldhave a tissue-like velcro and it potentially would work on almost anytissue in the body. so, after about two or three years of multipleiterations, we were able to address all the design criteria. now we have a glue, but there's anotherchallenge because often, if you go to cvs, for example, or walgreen'sto get a band-aid, you don't just have cotton gauze with glue. there's actuallya backing layer, which is paper or plastic to provide structural support. we needed abacking layer. this is a very harsh environment in the heart.

we had to design a completely new materialand this material had to have an additional design criteria. in additionto being degradable and elastic, it also had to be transparent because we'regoing to shine light through it to activate an adhesive on the opposing side. there are no recipesin the literature, the academic literature, for how to do this. we just had to do bruteforce, but we were able to come up with another material that was completely transparent, as you cansee here, and also, elastic. we could stretch it over and over again andit wouldn't lose its properties. after performing multiple experiments, wemoved to an extraordinarily challenging experiment, one that would mimic the exact applicationof 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. delnido, he had developed this cardio-port device. we put our patch on the very end of the deviceand 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 shinedthe light for 20 seconds and here's what happened. what you can see directly after the procedureis we have the patch in the middle here that has attached. we came back after fourhours and added epinephrine to increase the heart rate. we needed to test this at the full range andwatch what happens. we see here the patch still remains attachedin both of these pigs.

we came back after 24 hours and the patchwas 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 thispatch through a blood vessel. we don't have to make an incision in themyocardium, which would be non-ideal, of course, for thepatient. 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 inmultiple other models. we showed we could seal the carotid arteryof a pig. we could seal the aorta of a pig. this attaches to almost every tissue in thebody and because of that, we decided this is ready for translation. and so, we started a company called geckobiomedical in late 2013 and the company has now been able to manufacturethis glue at large scale. it's shelf-stable and they're expectedto be first in man in march of this year for vascular reconstruction. [applause]

in addition to bioinspiration, i wanted toshare 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 patientunless you keep your solution extraordinarily simple. you have no idea how many technologies havebeen 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'tbe manufactured. they're just too complicated. and so one of the principles that we havebeen trying to employ in the laboratory is one that we call radical simplicity and let meshow you an example of how we've used this.

patients that have ulcerative colitis, almostall 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 forlong periods of time to get good drug exposure. the systemic absorption of the drug is alsovery 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 challengesand for this, to keep things as simple as possible, we turned to the generally recognized as safelist by fda. this is a list of agents that's on the fdawebsite 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 riskif 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'tlike water and a hydrophilic group that likes water. in addition, we also looked for agents thathad an enzyme-cleavable bond between the hydrophobic and hydrophilic moieties. what's amazing is if you take an amphiphilethat 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 itto dissolve. as you cool that, what we can do is coax thatsystem, those molecules, to assemble, to stack one on top of the other. the groupsthat don't like water will point inward and the groups that like water will pointoutward. and we can coax this system to form a hydrogelthat looks like this. this is an electron-micrograph of that hydrogelsystem. it's nanofibrous. this looks just like butter or margarine atroom temperature and has very similar consistency. but what you're looking at here is a singlemolecule that is stacked over and over and over again.

there's nothing else present except thatmolecule. and that molecule was taken from the generallyrecognized as safe list. what we can do during that assembly processis we can entrap drugs, all kinds of different drugs. we've tried many and then, in the presenceof inflammation at sites of ulcers, you have high concentrations of degradativeenzymes and so, what will happen is that if this gel, if this material reaches theulcer, it'll be disassembled and the drug will be released. so, we've developed an inflammation-responsivematerial that's extremely simple. and we went one step beyond that. we knewat sites of ulcers that typically you have

positive charge and to increase the potentialfor targeting to minimize systemic absorption, to minimize potential for this gel to disassembleat a site of healthy tissue, we target it by selecting an amphiphile fromthat list that had negative charge. we then broke this gel into small particles andwe did enema infusion into a number of animal models. we were able to show with this system thatwe could selectively target the ulcers. these gel-based particles attach specificallyto the diseased tissue, whereas we didn't see any attachment tothe healthy tissue. we also were able to show, because when youinfuse this gel in particle form, it attaches to the ulcer so quickly, the patientwouldn'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 presenceof those enzymes. in fact, we saw that it could remain attachedto the ulcers for long periods of time and because we're not getting release ofthe drug at the healthy tissue, we were able to reduce the systemic exposureof 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 dosedthe enema to the animals every other day and when you do this with a drug alone, itdoesn'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'reable to dose every day and get a major improvement in the healingof the tissue. and now, i'm working with a number of gastroenterologiststo try to bring this forward to the clinic. another example of where we've tried toharness this concept of radical simplicity can be shown here. this is my hand and oneday, i was wondering why do i have this burning, itching, red reactionnext to my wedding ring. am i allergic to my marriage, maybe? i don'tknow. it was bothersome. this is 24-carat gold and so, i started towonder, you know, what was going on. this wasn't happening on any of the otherfingers and i read that maybe this was a nickel allergy.

and so, what i did is what i think all ofyou would do if you had access to a laboratory, was i brought my ring to the lab and analyzedfor nickel and sure enough, the substrate turned red, meaning that thiswedding 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 oneof these things that when you reach a certain exposure level, then you become allergic and you're allergicfor 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 productlines because it was leaching a lot of nickel. and so, when we looked to see what was currentlyavailable in the clinic, there was nothing to prevent these reactionsfor people who are allergic and nothing to prevent someone from becomingallergic. only steroids, which were administered afterthe 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 similarto some of the sunscreens that exist. so, some of the sunscreens have nanoparticlesin them that coat the skin and block the sun from going through. we thoughtwell, maybe we could create

particles on the skin, but instead of blockingthe sun, they could bind nickel and prevent that nickel from going into theskin and then, we could just wash it off. so, we went back to the generally recognizedas safe list. we scanned the list and we identified someagents that we had a hunch could bind nickel at high affinity when we formulated it asnanoparticles. and what we did is we applied this in manydifferent models in the lab. this is just one example where what you'reseeing is full-thickness skin, this is the top of the skin at the top andthe bottom of the skin, the underneath surface, at the bottom.

we put the particles onto the skin and weadded a very high concentration of nickel. this is calcium carbonate, chalk. the particleswe had put into a cream to apply it, just like a sunscreen and here you have thecream alone, the glycerin and what happens is, is that the nickel bindsto the particles that are on the skin and doesn't enter the skin, whereas if youdon'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 wepublished a paper

and cnn picked up this paper. they put iton the home page and they had a little blog at the bottom and people started writing in saying, "i'mdesperate. when is this going to be available?" and so, we launched a company called skintifiqueand brought this technology to market. and by harnessing this concept of radicalsimplicity, the company was able to have a clinical proof of concept within two yearsof the publication and a year later, we had a product on the market. and the company has been able to maintainthis concept of radical simplicity in new products - and let me just quickly show you one example.

so, this is a hydrating gel that the companydeveloped, where what they did is they looked for agents on the generally recognizedas safe list that could be formulated as three-dimensional nanostructures that couldbind a ton of water. and it keeps this water in close contact withthe skin and skin has natural repair mechanisms whereif you keep it hydrated and prevent irritating agents from interacting,it can actually self-heal in many cases. this product only has eight ingredients andwe can entrap active agents from the gras list in these nanostructures. let me just show you one example of a patientwho approached the company

who had psoriasis. he had tried everythingand he started using this cream multiple times a day and within weeks, his skin completely clearedup. and now, he's been using this cream for about a year-and-a-half and the skin conditionhas not come back. this has been tried now on multiple patientswith eczema, psoriasis and other skin conditions and it's been performing very well. this company has now been able to launch theseproducts across the globe. now, finally, i just want to tell you aboutone more problem that we've been working on where we've tried to employ this conceptof radical simplicity. we want the solution to get out there as quicklyas possible.

some of you may be familiar with the dangersof 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 hydroxideions, through the esophagus. so, we were determined to try to solve thisproblem and we made a simple observation. any time you put a battery in a device, there'salways the spring you need to push against. you don't just drop it in. you kind of haveto click it in and we did a number of calculations. we turned to the literature and we realizedthat the force that the esophagus exerts on a battery, a button cell battery, is much less than theforce required

to put the battery into a device against thisspring. and, so that gave us a design angle. so, weasked, "are there any off-the-shelf materials we could use to solve this problem?" becausewe 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 availablework by a pressure-sensitive action, where where you touch, you actually get acurrent that forms to describe that location. we purchased these materials. we attachedthem to the battery. we also added a silicon layer over the gasketthat 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 youdon't have the coating, you get significant damage. this damage occurswithin two hours. it's very fast. but with the coating, we get absolutely nodamage. we've put this into stomach acid for 48hours and nothing happens. there's no reactions. and so, when this coating is on the batteryoutside of a device, it's insulating. if you accidentally swallow it and it getstrapped in the esophagus, the forces can't convert that coating becauseit's pressure-sensitive, to a conductor, so it remains insulating. but when you putit into a device, the pressure converts

to an effective conductor and it works justnormally. and now, we're working with some of themajor battery manufacturers, as well as the u.s. government poison controland the u.s. consumer product and safety commission, to bring this technology to the market. so, in closing, i shared with you a coupleof 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 spokeabout bioinspiration. we're not doing bio-mimicry here where youmimic nature directly. we're doing bioinspiration, where you takea basic idea in nature and then,

improve on it for one's own purposes. and then, radical simplicity. how can we keepwhat we do as simple as possible at every single step, to maximize the potentialthat what we work on can help patients as soon as possible? thank you so much.