Ellen Roche, PhD - Innovations in Cardiac Devices

She's collaborated with many surgeons here at Boston Children's, uh, and done some interesting work on, um, extra cardiac compression devices that can increase cardiac output in a failing heart animal model. She's also, uh, taken, um, an interest in, um, in collaborating with, uh, people also across the street at Brigham, um, and here at Children's to, uh, design a light reflecting catheter that can close tissue defects automatically. I think more importantly, uh, particularly to this auditorium, she's been the recipient of the Judah Folkman Award. She has many publications in the area and she has a very interesting talk to share with us about innovation in cardiac devices. So please welcome her. Thank you, Ellen. Thank you so much. Thanks so much. Thank you for the kind introduction and thanks for having me here. Um, I did a lot of my PhD work here at Children's, it's always a pleasure to come back and to talk about my work. Um, so just a brief introduction. Currently, I'm an assistant professor at MIT since last September. I have a dual position between mechanical Engineering and IAMS, which is the Institute for Medical Engineering Science. Um, before, um, a my academic life, I worked in industry. I worked in Mednova first to design, um, a distal embolic protection device, worked in Abbott on stent development for a couple of years, and then in Medtronic on a transapical valve system. my. I. Um, so this audience doesn't need any introduction to the heart and what it does, so I'll skip through this slide, but, uh, when the heart fails, it can be broadly categorized into vessel disease, structural defects, rhythm disorders, and cardiomyopathies. And uh cardiac device engineering has helped a lot with um rectifying or treating these diseases, but the trends in general seem to be moving from rigid, metallic permanent devices like these total artificial hearts, pacemakers, stents, and And occluder devices to more biological, um, bioprosthesis, resorbable stents, uh, tissue-engineered valves, um, and even cell delivery where, where people are trying to deliver cells to regenerate the heart and using biomaterials to do so. Um, I'll talk about 3 case studies from my own work. Um, again, all of these were done with some level of involvement with, uh, with, um, collaborators here at Boston Children's Hospital. Um, so I'll start with my work on a direct cardiac compression device. Uh, upfront, I'll acknowledge, uh, a lot of people that helped us, um, Dave and Connor at Harvard, some other engineers. Um, the work was done with Doctor Frank Pegula, who, who was here at the time, um, and Doctor Nikolai Vasiliev, who's still working here in Doctor Delnido's group. So, uh, we wanted to look at heart failure and, um, alternative therapies for treating heart failure. Uh, heart failure is the impaired ability of the heart to fill with or eject blood, um, and it's a huge problem. It affects 26 million people worldwide and it's growing in prevalence. Uh, the current gold standard is left ventricular assist devices, um, while people wait for transplants, um. And these are, these act as a bridge to transplant, but they're very invasive, so blood is routed from the apex of the heart up to the aorta and the blood passes through mechanical components. So one of the big risks there is clotting and the patient will be on anticoagulation, um. So we wanted to take this and look and see if we could make um an alternative um that ideally wouldn't contact the blood. Uh, the VA market is growing. There's been big acquisitions recently, um, and they're expected to boost research in different areas in, in vas like a transcutaneous energy transfer for charging of the vats and, um, and so on. So we wanted to really Understand the problem in order to come up with the different ways to solve it. So we looked at the way the heart moves, um, and these images show, um, MRI or speckcal tract echo images, and they show the twisting motion of the heart. So, um, as you all know, when the heart contracts, it doesn't just compress, it also twists and there's, um, there's counter rotation at the apex and the base of the heart. They twist in opposite ways. Um, at the time, there was a huge growth in the area of soft robotics. At the time I was, um, starting out my research in Harvard, um, So soft robotics use elastomeric materials and smartly designed fluidic channels to achieve complex motion. Um, so the example here shows a fiber reinforced, um, segmented actuator that can, can, that can rep or simulate the motion of the finger. But these are lightweight, cheap to build, um, and they're a traumatic, so they, they have application for implantable devices. So the vision was to replace these EVA, existing LVADs with a sleeve, a soft robotic sleeve that wrapped around the heart, um, so it would be non-blood contacting and it would provide external assistance to the failing heart. And what we wanted to do was to replicate the twisting motion as well as the squeezing motion. So we looked at the way the the muscle fibers were oriented in the heart, and there's 3 layers. The outer and inner layers are organized in um opposing helices and the middle layer is a circumferential arrangement. So we wanted to design a soft sleeve that um that did both of these actions. So we had an inner sleeve that squeezed. They were where um small actuators or contractile elements were arranged circumferentially and an outer sleeve where the actuators were arranged helically to um induce twisting motion. So we had to first of all develop actuators. Um, we went with a different technology called actuators that manic artificial muscles. They consist of an inner elastic er and an outer braid. So when the inner balloon is pressurized, it senses expand so the brain, the radial expansion get linear contraction, and this can be failored by the brain. I to. Linear expansion you get. So we made multiple. And we embedded them in a soft material, um, a silicone elastomer in this case, and then when we selectively actuated, um, these, these individual elements, you could get more complex motion, um, so it was like a 3D, um, smart kind of active material. We did a lot of engineering characterization on this, um, using computational models and experimental, um, testing. So we looked at embedding different numbers of these elements in different types of matrices and we characterized both the strain that they induce and the force that they can, um, transmit and we matched this to computational models so we could optimize the spacing and the number of these actuators needed to achieve certain motions and forces. Um, so this video just shows testing on a mechanical tester where we track dots and we can quantify the strain in the vertical and horizontal direction and match it to a computational model. Then we wanted to extend this to a three-dimensional space. So we 3D printed a reconfigurable mold and the mold allowed us to um cast an outer sleeve in elastomer and then insert these elements, actuatable elements in the exact pattern that we wanted to and then embed the entire structure in elastomer. Um, there were different layers of the mold so that we could get, you know, the right, the right, um, architecture that we, that we wanted in, in the sleeve. So we ended up simulating the motion of just the left ventricle in a simplified model. So when you pressurize these elements, you get a twisting motion and we compared this to um our finite element computational model. And we published this in advanced materials, but this is the prototype of the, of the ventricle simplified. So. an airline. if you look at it. The twisting and then you get the posterior twisting. That we want to stimulate. But really what we wanted to do was move this technology all towards an implantable device. So we developed two sleeves here, they're shown on a silicone lab heart model, and the inner sleeve compresses and the outer sleeve twists, and when you put them together, you get the combination of both motions. We had to build a control system to control this, um, so we had an electronic pneumatic control unit that consists of multiple regulators and valves, um, a data acquisition system, and a custom-built software interface, so we could individually open and close valves at the correct timing so we could get really controlled motion of the sleeve. Um, and some of the control systems we could implement, we could trigger from the ECG wave, so sense the ECG and trigger based on a part of that, usually the top of the, um, the QRS complex, um, and we could actuate, for example, from the apex up with milliseconds in between, so you got a kind of a peristaltic motion which helped eject blood. Uh, we can also actuate from the hemodynamics, so we can, uh, measure pressure and flow and, uh, trigger from a point on these, um, these waves. Another control system could be to actuate the twisting, uh, motion first and then the circumferential motion and then turn them off sequentially as well. So we had to do a lot of testing on this, uh, device. We did this in vitro ex vivo and in vivo, a lot of this again was done here. The in vitro testing was a simple silicone cup that we, where we could measure output, um, volume. Metric output and we could also have a flow sensor, an ultrasonic flow sensor attached to measure flow. Here we could really hone in on the design, um, which kind of actuators gave most ejection, um, what kind of material worked best. I. Yeah. We don't need. We also built a sensing sleeve that would go at the interface of the device in the heart. This had small barometric sensors that could measure the compression at individual points on the heart, um, so we knew exactly how much force the sleeve was, was, um, was transmitting to the epicardial surface. And we looked at fabricating the sleeve in a flat pattern because this allowed the surgeons more um versatility when they were wrapping it around the heart and they could adjust tightness accordingly. Um, so we made it out of very thin silicone layers where we selectively bonded parts together. Using, you know, a novel process with a flat 3D printed mold in this case. And we also sewed the device out of textiles, so I had to learn my sewing machine skills weren't really up to scratch, but uh we took medical mesh and sewed in the patterns of the channels and inserted the actuators into it afterwards. Um, one of the big things we were looking is that, looking to, uh, satisfy is that the device conformed well to the heart. So this is a CT scan of, um, one of the flat silicone devices wrapped around the heart, and you can see at different cross sections that it does conform very well to the outside of the heart. I Uh, Sam, do you wanna like turn the radar? I just want to show in this video. Oh, there synchronized the device using a pacing system. So we had, um, a large control system developed here where we would, um, in this case for these studies, we pace the heart and pace and then triggered the device at the same rate so that they were exactly synchronized. Um, but here we had a, um, Data logging system that would record aortic and pulmonary flow from our uh ultrasonic flow sensors. We measured ECG, SPO2, a lot of different parameters so that we could um monitor after the fact, the effect that the device had on performance. Um. So here we used um Esmol to reduce contractility. This was um a cardiac arrest model where you can show with the active assist on and then off. uh you get a big difference in the pressure and the flow um in the pulmonary and aortic um arteries respectively. Um, when you turn the activists back on, you can, um, restore it somewhat. We also looked at the uh interface between the device and the heart and we did some animal studies and some histology at uh first of all, characterizing whether there was any um inflammation or injury at the myocard at the epicardial surface because of the device and then we implanted a hydrogel which reduced the friction between the sleeve and the heart, um, and reduced the level of inflammation. So we would put a, a, a hydrogel around the heart and then the device over it. Yeah from. Yeah. And this was published in Science Translational Medicine last year. The, uh, the movie here on the left also shows a sequential actuation, so you can see that we actuate from the apex up so you can really control, uh, timing of that to get maximum output. And since then, we've looked at diastolic coupling, so we've looked at individual actuators and coupling them to the epicardium so that as well as systolic assistance, you can help um the heart fill. Um, and achieve diastolic assistance. Um, we optimized the timing when, when was best to um start the assistance. So, you know, if it was 120 milliseconds, 150 milliseconds, or 180 milliseconds after the peak of the um or after the start of um the uh rising pressure. Um, so there's a lot of um understanding that we can gain from these, these studies and we're working on optimizing the device um and implanting it in animals for chronic studies. So the next project I'll talk about is a uh device we developed for ventricular septal defect repair. Um, this was a collaboration with Doctor Del Ndo here at Children's and Professor Jeffrey Karp, who has a lab between the Brigham and MIT. Um, we did a lot of our testing here downstairs, um, in arch as well, um, with some of the surgical fellows, um, that were working with Delnido at the time. So the problem here is intracardiac defects when there's a hole, um, in this case in the septum between the two ventricles. Um, current existing treatments are uh surgical repair which is invasive and open heart and requires the patient. To go on bypass or there are some existing occluder devices and they have been shown to cause some tissue damage and, uh, there are reports of conduction block and friction. There's a permanent metallic object left in the heart, um, you know, for permanently, um. So we worked with Dr. Delnido and Professor Karp on this. At the time when I started working on it, they had just published a paper about a light-activated adhesive. They call it HLAA, a hydrophobic light-activated adhesive, and they had showed that this, this adhesive along with the patch made of um PGSA and PGSU, they could seal a defect in the heart, but they used um Uh, relatively large light guide to apply the, uh, light and pressure to the, to cure the patch. And at the time they were looking to develop a minimally invasive device so that they could do this, um, all through a cat a minimally invasive catheter. So we came up with this set, we brainstormed all together between the three kind of teams and came up with a set of challenging design requirements. Uh, we wanted it to be minimally invasive, so less than 18 French to deliver a patch that was at least 20 millimeters. Um, deliver glue, 100 micron coating, deliver UV light to activate the glue, and the glue also requires a certain compressive load to actuate. Um, and then we wanted to retrieve everything apart from the patch and leave a minimal residual shunt between the left and right chambers of the heart. So we came up, brainstormed and came up with a lot of broad concepts, um, various types of ideas, and we settled in on a light reflecting balloon. The way it works is there's an internal UV fiber optic. This is a small, uh, low profile fiber optic, um, and when, when you, um, Place the fiber optic and shine the light in this distal balloon, and there's a reflective coating on the balloon that reflects the fiber optics back onto a patch that has been pre-coated with the glue and adheres it to the to the left side of the heart. There's a second proximal balloon there for stabilization while the while the glue is being cured. Researchers from 4 top institutions in Boston have designed a specialized catheter that can repair holes in the heart without invasive open heart surgery. Let me go back. This video was developed by Children's and it really nicely describes an overview of the project. Researchers from 4 top institutions in Boston have designed a specialized catheter that can repair holes in the heart without invasive open heart surgery. First, a clinician inserts the catheter, which is equipped with a UV light and biodegradable adhesive patch, through a vein and guides it to the hole in the patient's heart. Next, the adhesive patch and two balloons, one on each side of the hole, are released from the catheter. The balloons apply pressure from both sides of the heart wall securing the patch in place. Then the clinician turns on the catheter's UV light, which reflects off the balloon's interior and activates the glue on the side of the patch facing the heart wall. Finally, the clinician deflates the balloons and removes the catheter, leaving behind the biodegradable patch. In time, tissue will grow over the patch and the patch will dissolve, leaving no foreign material in the body. So one of the key um advantages of this technology is that the patch is biodegradable. So uh once you get tissue repair, there's no permanent object left behind. It's an elastomeric patch as well, so it doesn't um interfere with the motion of the heart. So to, to realize this, we had to um innovate a lot in manufacturing technologies. We had to develop a process to coat a balloon with reflective coating, which, which wasn't as easy as it sounds. Um, so we took urethane balloons and we sputter coated them with aluminum particles in a sputter coer um that's shown on the bottom left, a rotating chamber. Um. But to get the uh aluminum to adhere, this is um a 100 nanometer layer of aluminum. To get it to adhere properly, we had to surface treat the balloons with plasma pre-treatment and then place a layer of urethane over um to prevent the aluminum coming in contact with the blood. We did a lot of testing as well to determine the best kind of coating to use. So we compared aluminum with different pre-treatments to palladium and various other types of coating with this um custom-built optical test um set up so that we could really get the best reflectivity of the light we, that we could. Um, we did some light simulations. When you advance the fiber optic here along the catheter, you reflect the rays in different ways and you kind of spread the light out over the entire patch. So, um, thereby curing the glue in the whole, um, area of the patch. So the red there shows the, where the maximum, uh, light reflection is on the patch, which is here. And as you advance the catheter, that changes. You can spread the light right to the edges and make sure the glue is um adhered um throughout the whole patch. So again, we did our testing here. Um, We did in vivo testing in a swine model again and we used echo guidance, um, inserted the catheter, created the VSD with the catheter in this case, um, and then deployed the device, um, on the left ventricle. Here you can see it with echo, um, and this is grossly postmortem. It's, it's optically transparent. It has to be to allow the light to reflect through or to, um, be transmitted through to cure the glue, so it's difficult to see, um, on the heart after explant. Um, but in, again, in, in 6 cases, we were able to implant this and reduce the uh residual shunt. Um, we also looked at broader applications for this technology. Um, on a cadaver, we tried, uh, adhering it to the abdomen, which works really well. It could be a potential candidate for hernia repair, um, and for peptic ulcer repair, we, uh, directed the catheter down the esophagus of an explanted stomach. Uh, stuck the patch on, um, to a defect and then, um, overinflated the, the stomach and, um, the, the patch and the glue and maintained a seal. So there's a lot of broader applications that this device could also be used for. So the final um device that I'll talk to you about is a therapeutic epicardial reservoir. Um this is ongoing work that, that we're doing um in the lab at the moment. Uh, we call it therapy. It's therapeutic epicardium, and the idea is that it delivers drug or proteins or cells locally to the epicardium, and it's refillable through an implanted refill line that attaches to a subcutaneous port. Um, so there are a lot of clinical trials ongoing for cardiac cell therapies, um, but one of the huge disadvantages of, of all of these trials, um, is that retention of cells in the heart is very low. An engraftment of cells. Um, typically they're, they're injected into the myocardium, um, just with a needle and, and because of the incessant beating of the heart, they get ejected and they don't stay where they're meant to to exert their therapeutic effects, um. So they have poor retention at the pathological site. They lose their biological activity rapidly and typically because of the invasiveness of this epicardial injection, most of these trials have only had one direct injection of therapy to the heart, and there's been recent studies that show that if you can Administer repeated doses of cell therapy over time that um you can improve or increase the clinical benefit that the cells have on um left ventricular function. So by, uh, by repeated administration, you can uh improve the outcomes and that's the premise that the device is based on. Um, so we know that biomaterials increase cardiac cell retention. Um, the, these show that there's, um, methods to deliver um cells using biomaterials that are placed on the epicardium of the heart or by injecting hydrogels into the myocardium, and this has been shown to increase retention. So we went a step further and used a biomaterial reservoir that was refillable from um from a subcutaneous port. So it allowed targeted delivery, epicardial retention, and localized release, but the main advantage was that it was replenishable so we could do it again and again without a further invasive procedure. Um, this is the biomaterial reservoir design so we can um deliver anything from small molecules to proteins to bacteria cells through the line. Um, for cell therapy, it's been shown that um even if the cells don't migrate into the heart, they can release paracrine factors that can exert a therapeutic effect and that's the idea behind the device that Uh, the cells stay localized in a biomaterial release factors which, um, which cross the membrane and, and have an effect on the myocardium. Um, this is mainly for post MI heart failure, um, patients. The biomaterial increases the retention of cells. The cells release therapeutic agents, but again they do not cross the membrane, and the membrane protects the transplanted cells from the host immune response. So the, this um refill port goes underneath the skin. There's an implantable refill line that goes to biomaterial reservoir. We miniaturize this for animal studies and a rat model. And there's a semi-permeable membrane uh dyed here for clarity that contacts the tissue on the heart. So we did an animal study where we looked at delivering drugs, proteins, and cells to the heart in a rat model, um, created a thoracotomy, retracted the chest. Um, removed the pericardium and placed, um, this reservoir on the epicardium after, uh, ligating the LAD permanently. So we tried to um place the reservoir on the border zone um which is easily identified by um the blanching of the tissue once you ligate the, the LAD. So once you attach this, um, you can close up the uh chest again and then deliver cells in situ or deliver different proteins and therapies to the heart. Um, here we attach the subcutaneous port to the back. This is because the animal can't, um, pull it out. And then over time we can, uh, oh, sorry, we can easily refill. So, We delivered adrenaline or epinephrine um to the heart and we could show um an instantaneous increase in systolic pressure um because it was localized, we compared it to um an intraperitoneal injection and we could see an instant uh response. We also looked at replenishable cell delivery. So this uses bioluminescence, um, to quantify how many cells are localized in the reservoir. Uh, we use luciferase expressing mesenchymal stem cells here, and the light produced is proportional to the cell number. On day 4, we refilled and you can see here that there's a huge amount more, a huge, um, increase in the number of cells, um, on the heart. So it shows the proof of concept that the Um, you know, that the system is working and this quantifies bioluminescence over time. So on day 4 you get a huge increase. They do, um, decrease over time and that's something that we're looking at in more detail, um, really protecting the cells from the host immune response and figuring out how to maintain the cells over, over longer periods of time. But the area, if you calculate the area under both of these curves, it indicates the dose of the um. Therapeutic um factors that are, are coming from the cells and it's much higher with the um with the device compared to with uh injection. um So we did an animal study looking at no treatment after MI with a simple cell injection with a device without any cells, with one dose of cells and then with cells plus refill, and we tracked ejection fraction using a PV catheter and using echo, and what we showed was that over 28 days, the refill group was significantly higher. The ejection fraction in the refill group was significantly higher. Then no treatment at all and then cell injection and also then the um group where the cells were just delivered once. um so it shows promise for this kind of system where you can repeatedly uh administer cells. And this device can be delivered minimally invasively, uh, deployed from a catheter, and so, you know, for potential translation, we could do it minimally invasively. We've also looked at developing a sleeve with multiple reservoirs that could be placed on the heart, maybe inside the active sleeve, so that you'd have multiple depots of drug that could be released on demand. Um, and then one of the main challenges, um, is adhesion of any of these devices to the heart. So we also worked on, um, a tough adhesive for, for wet surfaces. This was, um, in collaboration with the Mooney Lab, and this is an adhesive tough gel that can be used to attach either the drug delivery device or the active sleeve to the heart, uh, with an atraumatic, uh, gel. So that's pretty much all I have to talk about today. I'm happy to um answer any questions that you might have on any of the work. These are further acknowledgments on, on the therapy work. So thank you for your time. I'll just acknowledge my funding sources there. Thanks. Thank you very much. That's very fascinating work. So I had a question about the cell delivery system. So when you put the patch on the, on the heart, then the cells were just going in passively? Um, so the idea is that the cells stay in the reservoir. They're, um, in a biomaterial, and they, um, They secrete paracrine factors and the, the trials have shown that it's that effect that um that has a clinical benefit. So the cells don't migrate across the membrane at all. It's just their sacrotome that comes across. So they, they stay in the, they stay localized vessel if you will, and then they affect regeneration of cells in the in the myocardium, yeah, yeah, so they, it will be placed at the border zone. Um, and there's been a lot of studies showing that even if you deliver conditioned media with, um, you know, with these paracrine factors, that that's what affects the, um, You know, the ejection fraction, not the cells. So the idea that the cells themselves migrate and differentiate into cardiomyocytes, um, hasn't really been shown to be effective. It's more, um, their modulation of the healing response that helps clinically. So they're affecting the cells that are in the ischemic area that have not died then, yeah, exactly, yeah, they're, so they're, um. Salvaging, I guess, the border zone tissue that is, is not um completely infected. Fascinating. Additional questions this morning. Uh, I was fascinated by the last adhesive, uh, that in a wet environment adhesives. How does that work? Yeah, yeah, um, so it's a tough gel that's functionalized so that the surface, uh, adheres to wet tissue. Um, this is work done in the Mooney lab, not my area really. So the chemistry behind it, I, I'm not like entirely sure of, but it's UV activated as well. Um, so there's some kind of cross-linking with the, I believe it's the collagen in the tissue. Um, so when you place it on and UV cure it, there's cross-linking between the, the functionalized surface of the gel and, and the tissue. Um, so there, there's a a recent publication in Science that describes the exact, um, chemistry. Yeah, but it has a lot of uh potential applications, I think um for, you know, defect closure, vascular sealants, um, interfaces between any devices contacting tissue. It's promising. So, so one additional question I had is you showed that. Device when it was in and secured in in place for the ventricular defect and what, what stimulates the, the tissues to grow over it. Yeah, it basically acts as a scaffold um to encourage ingrowth. We didn't functionalize the patch at all to, you know, further encourage cells to grow. I think it's just that there's a membrane there, so there's, you know, um, a matrix that cells can grow across. We haven't done long-term studies to, um, You know, to fully characterize how long this takes, but what happens when you put any foreign, uh, material in the heart, you get a fibrous capsule form over it, and that in itself would, uh, close the defect. Um, so, you know, we showed in small animal models up to 6 months. Um, within maybe a week or two, you get a fibrous capsule that forms over the top of the implant. Um, and that grows over time, so that would, that would close it, and the, um, the patch itself is tunable, the degradation rate. So depending on how long it takes for the capsule to form, you could tune the degradation rate so that it degrades after that happens. So it has a matrix to it that then stimulates to, yeah, yeah, exactly, yeah. Fascinating. Any additional questions on this remarkable work? If not, thank you so much for joining us. Thanks so much for having me. Sure, yeah. Thanks so much. Thanks for having me. Yeah, yeah. Hey, how are you? I