Dr. Kassem Ashe and Duane Cronin
Dr. Kassem Ashe (KA), Cardiovascular Surgeon at St. Mary’s General Hospital in Kitchener, Ontario, Canada, and Duane Cronin (DC), Professor of Mechanical and Mechatronics Engineering at University of Waterloo, recently leased a ViVitro Pulse Duplicator for early design work in their Autologous Pericardial Tissue valve project. ViVitro Lab Manager Rob Fraser (RA) spoke with them recently about the project, their experience leasing the equipment, and future plans.
RF: Please tell us about the work you are doing.
DC: We’re looking at a version of an aortic heart valve that can be created from autologous pericardium. Our goals were to understand the effects of changes in dimension on the functionality and performance of the valve, and ultimately to optimize the geometry of the valve.
KA: In terms of background, the limitations of using biological aortic valves with respect to durability are well known. The issues relate to early calcification, accessibility, and cost. We have seen early failures in patients–in non high risk patients, meaning no renal failure, no calcium drugs for osteoporosis, not a young patient– and we have to explant these valves because they have failed.
We are looking to solve this issue with autologous pericardium. To date most attempts to use autologous pericardium have been to reconstruct the valve free hand, (Duran, Osaki). Autologous pericardium is much more durable and resists calcification when compared with bovine or porcine pericardium. Despite the anti-calcification modalities developed and used today there still is a propensity to early calcification in many subgroups, namely the young patient, renal failure. We are also looking at an ideal valve design. The idea is that a valve could be fashioned as soon as the patient’s chest was opened and before the patient was put on pump. We started off with something that was going to be created by hand (stentless) and we moved to a valve that is stented with design features that potentially are superior to existing valves on the market. We are at the stage of fine tuning our computer modelling with the aim of creating a prototype that we can mold or 3D print and then have something that can be easily put in by the majority of surgeons.
We’re utilizing both experimental and computational methods to understand the challenges and functionality of these valves in order to optimize them. We’re taking a new and different approach in terms of construction and materials in order to address the well-known challenges, including calcification and durability, which exist today.
RF: Calcification is certainly an issue everyone is looking to resolve. How is the work going?
KA: We leased the pulse duplicator back in August and we had a number of technical difficulties, not so much in the case of the Pulse Duplicator—it worked perfectly. We had some initial ideas in terms of the concept of the valve we were going to use and then we had some difficulty implementing it and getting consistent numbers. We were implanting a free hand sewn valve into a Valsalva graft. The issue related to significant leakage through multiple needle holes that significantly affected closing volume. Towards the end of our two month rental with ViVitro, we were able to generate a number of great results that at least matched or could be superior to existing valves in terms of hemodynamics. We’re at the stage of completing the computational model that Duane is working on, and then, hopefully, we will revise the design further and get some more funding so we can take it further.
DC: We’ve been working in experimental and computational modelling for many years and found that the fusion of those two areas has enabled us to answer a lot of challenging questions. We know that for something as critical as a heart valve, we can’t just live in the computational world. There has to be some real physical testing and prototypes to understand what’s going on in order to use and even to validate these models. However, as a starting point the models can give us some insight into the effective geometric variations, without material and other variabilities that may creep into experimental testing. Each aspect of this initial phase of work had a benefit in terms of the modelling giving us really good insights into the physics, what we wanted to achieve and how we could choose an optimization path. And then on the physical side, being able to actually test the valves themselves in a realistic condition and understand how these effects were supplemented by real world aspects as well.
RF: What challenges have you faced with this project?
KA: We spent a considerable amount of time getting ethics approval to use human tissue. Unlike using porcine and bovine tissue that are readily available and don’t need the same hurdles, we had to get ethics approval to use live human pericardium. We now have ethics approval to test our various designs.
RF: What is next for this project?
DC: There are still many technical challenges to solve in this space. We think we’re on the right path moving forward. We have good potential for success by identifying what are the critical areas. Without focusing on the other valves that are out there today, we know that there are some good valves and some that are having some challenges and have a solid plan to address those challenges.
ViVitro has been very understanding and helpful in terms of allowing us to achieve some very significant goals in a very, very short period of time– which was the intent of our initial funding. Our goal now is to secure additional funding to continue our studies.
KA: What started off as research project, has now expanded on to something entrepreneurial.
Because of some of the travels I’ve done, I have seen firsthand that the developing world requires an ideal tissue valve. If you look at the world at large, there is an incredible population that requires these valves because rheumatic heart disease and congenital valvular disease continue to be endemic in these third world countries. These people need a valve that doesn’t require any anti-coagulation because they are going back into their tribes or communities, and due to the distance, follow-up is limited. The practice has been primarily to put in the tissue valve of choice, the people go back into their community and they are lost to follow up. Unfortunately, they go on to early valve failure from calcification.
Another problem with tissue valves is shortage of heart valves in certain sizes. That’s because emerging markets have created such a demand that we’re seeing these shortages. So there is need to have an alternative material with potentially better durability.
RF: You mentioned the lack of available valve sizes. Is this the smaller sizes that don’t fit the North American population norms?
KA: Surprisingly, it’s primarily the most popular sizes, the 23-25 mm size valves are very hard to get now. We’re back ordered because we’re using them so much. We have the same problem with grafts. Having said that, when the market leader is having problems meeting the expanding market demands (primarily it’s the Asian market), companies that are not the market leaders are now seeing this incredible window to come in. Unfortunately, I think that some of the valve designs that exist with these other competitors may not be ideal. Without mentioning names, there’s a company that we’ve implanted a significant number of valves that we are seeing coming back today. I am also old enough to remember the Ionescu Shiley valve and early failure, because of a design flaw. Today’s generation of tissue valves are not ideal. I think the very fact that when I open up the ViVitro website and you are advertising a device/methodology to measure calcification extent and location to effect design speaks to the fact that there have been hundreds of millions of dollars invested to look at anti-calcification methods and to date nobody has solved that problem yet. We believe with autologous pericardium and looking at a different type of design that can be fashioned quickly and with the engineering expertise that Duane brings to the table, hopefully we will be able to fill that void.
RF: Any advice for readers?
KA: Persistence and get a great team partner like Duane. Collaborate and persistence. And when you fail, collaborate and continue persisting.
DC: Our rule of thumb is: “Experimental testing always takes longer than you plan for”. It’s just the nature of experimentation. I’ve been doing it for a number of years and it’s always that way. Take a nice progressive and step-wise approach to development. Start with something you know and then evolve or gradually evolve towards your intended design. I think that’s a classical experimental mechanical approach that always serves well in these complex environments like a heart valve.
RF: I was laughing to myself when you said that experiments always take longer than you think.
DC: I always tell my graduate students to use the rule of Pi. If you budget 2 hours, multiple it by Pi and that’s how long it will take you. I used to say 3-4X, but engineers always believe a formula if there is Pi in it.
Dr. Rouzbeh Amini (RA) is an assistant professor in the Department of Biomedical Engineering at The University of Akron. The goal of his research laboratory is to improve human health by studying the multi-scale biomechanics and biotransport in cardiovascular, ocular, and reproductive systems. Dr. Amini’s group has been extending the scope of experimental techniques (e.g. small-angle light scattering, planar biaxial testing, and ex vivo beating heart) to quantify mechanical and microstructural properties of soft tissues. They have also been developing computational models based on experimentally quantified responses of these tissues.
ViVitro’s Lab Manager, Rob Fraser (RF), recently spoke with Dr. Amini about his research.
RF: Please tell us about your current work in the research laboratory.
RA: We are conducting experiments and building models to study tricuspid valves, which are located between the right ventricle and the right atrium on the pulmonary side of the heart. This is probably the most understudied of the four cardiovascular valves. Some clinicians call it the “forgotten” valve because of how much work has been conducted on the other three valves.
We are trying to understand how the biomechanics of the valve affect its physiology and pathophysiology. We are hoping to study the influence of different surgical procedures on the valve and look at the changes the surgical procedure causes on the biomechanics of the leaflets at the tissue and sub-tissue levels.
RF: How is the work going?
RA: So far, good. We just published a paper on some of the work we did on mechanical testing of the valves and another paper on the ex vivo beating heart setup where we used the ViVitro SuperPump. In the latter study we have been looking at the deformation of the leaflets when the right ventricle of the heart is passively beating. It is pressurized using the ViVitro pump.
RF: How is the right heart model working for you?
RA: Clearly I saw some major limitations of the model because the muscles are not actively working as they do in vivo. But if you look at most of the work studying the mechanics of valves, specifically the studies where the leaflet strains and deformations have been measured experimentally, most of the times researchers remove the entire valve and mount it on a rigid annulus. Then they put the valve that has been mounted on the rigid annulus on to some sort of simulator that simulates the pressure environments of the ventricle whether it is on the right or left side, mitral or aortic or tricuspid valve doesn’t matter.
That is what’s done a lot. In recent years the whole idea of using an entire intact heart and actually pressurizing the ventricles and letting the annulus deform as the valve opens and closes has been shown to be important. The reason it is important in my opinion is that if you use surgical annuloplasty rings and put them on the valves and technically eliminate that motion, you find different strain on the valve in the in vivo set-up. So by fixing the annulus of the valve you are removing a major contribution of the surrounding tissues that let the valves deform more freely. I think the ex vivo beating heart is one step closer to the in vivo case. A lot of the ethical issues that come with in vivo studies don’t exist with ex vivo studies. We can use hearts we get from slaughter houses. Or if later on you want to use human tissues we can get cadaver hearts and use them in studies on surgical procedures and models without ethical issues. Also, some of the in vivo study hearts are too far away to get into the clinical set-up. It has to be first verified in the ex vivo setup.
I used to think the lack of contraction of the heart was a limitation, but it could actually be beneficial in certain cases, say where you want to develop a computational model of the valve and the muscular tissue around it. The advantage of having the actual ex vivo heart is that it allows us to better define the actual boundary conditions on our model and lets us have a slightly more simplified computational model and validate the computational model from something where all the mechanical forces are generated primarily by this pressure change not by the internal stresses from the muscle contraction. That is an important step for verification and validation of the computational model, also a very important task of the computational work which is another aspect of our research lab. We are trying to use this for validating our computational model.
RF: That’s an interesting point. I too see that having the ventricle walls not contracting has limitations, but had not considered the advantages of defining boundary condition, and then validating CFD code. That’s an interesting advantage.
RF: You were the first group that used our ex vivo simulator. How was the experience?
RA: Overall, it’s fantastic. We’re very happy. My former assistant spent a lot of time trying to play around with things. You guys were very helpful and we are very appreciative. Another thing I want to thank you for is when I was submitting the paper I needed a reference for the waveform we were using over a holiday and I got a response back from you in a short period of time.
RF: Glad we could help. Earlier you mentioned the tricuspid is a forgotten valve for research. That’s also true for product development. Many of the technologies that came to market were for the aortic valve. Now they’re switching to the mitral valve and it seems people are going after all four valves of the heart. What do you think has caused this increase in study and then treatment for all the valves of the heart?
RA: There are a lot of new, interesting hypotheses developing in the minds of the surgical and clinical community. For the longest time there was a lot of effort on just removing the valve and replacing it with a prosthetic valve. Nowadays, a repair procedure is preferable to a total valve replacement. The patient doesn’t have to take a lot of medications. The success of repair procedures has been improved by the work of surgeons. Most of this work has been done on the mitral and aortic valves. Now that the success of the systemic side of the heart is being improved, more and more attention is going to the pulmonary side. Other diseases that cause secondary regurgitation to the tricuspid valve such as pulmonary hypertension, which is another disease we know little about, affects the biomechanics of the tricuspid valve and leads to regurgitation of the tricuspid valve. So a combination of improvements on the mitral and aortic side has led to more investigation on tricuspids.
RF: What are your future plans and goals with this work?
RA: We are currently working on a couple of interesting studies. One is looking at the biomechanics of the normal leaflet. We are measuring the deformation of the valve in response to the normal pressure. Then we plan on repeating the same study by increasing the pressure and seeing how the biomechanic changes in a “pulmonary hypertension” environment. We’re very excited because we believe having this sort of information will help people doing studies on the cellular level of the valve. They try to understand how much the mechanical environment of the valve actually changes when you expose them to a higher level of pressure. Then hopefully they can answer why changes in pressure lead to changes in the valve that lead to regurgitation.
The other thing we are doing is building a computational model of the right side of the heart. We are trying to use the same type of data that we get from an ex vivo beating heart to validate our model. We are also interested in looking at a mitral surgical procedure that is currently being conducting and first understand how they affect the biomechanics of the leaflet, and what we can do to maintain the “normal” physiological deformation of the leaflet of the heart using this surgical procedure. Hypothetically if we do a procedure that is going to deviate the stresses and strains on the leaflet, from its normal physiological response, then in the long term we should expect that it’s going to affect the quality of the valve surgical procedure. So what can we do? Can we use a different annuloplasty ring shape? Can we use a more flexible annuloplasty ring? Or maybe the sizing should change or something like that? How about percutaneous procedures? That’s the other advantage. We can use the connectors that we used to send our endoscopic camera to perform percutaneous procedures on the valve to see how that affects the stresses and strains on the leaflets and the general quality of the valve repair.
RF: It sounds like there is more than enough to keep you busy for years to come. Do you have any advice for academics and people doing similar work?
RA: My piece of advice to people in the research realm is to be persistent and if they think they have a good idea and when they face hard times, there comes a point where all of the hard work will be fruitful. For us the whole idea of using the ex vivo beating heart and combining it with some other tools such as sonomicrometry using piezoelectric transducers was really challenging initially. But we didn’t give up and were excited to make these things happen. I think in this case we were very excited when we managed to collect our first set of data. If you refer to the Journal of Biomechanical Engineering paper you can see we got a pretty consistent data set with a good level of variability even though these are pig hearts and we didn’t have any specific criteria to select the hearts form a specific group of animals. We collected them from a local slaughterhouse. For our lab, we have received funding from the American Heart Association and we are really grateful that we can continue our work. As we talked, I mentioned 4-5 different research ideas and we hope to have more funding to be able to continue these studies.
Read more interviews with Cardiovascular Pioneers.
Founded by a cardiothoracic surgeon and a mechanical engineer whose family members suffered from CHF, Endotronix is developing a single platform digital health medtech solution that provides comprehensive health management tools for patients suffering from advanced heart failure. The solution includes a cloud-based disease management data system and outpatient hemodynamic monitoring with an implantable wireless pulmonary artery sensor for early detection of worsening heart failure. ViVitro’s Lab Manager, Rob Fraser (RF), recently spoke with Michael L. Nagy (MN), VP Engineering, about the Endotronix Care Management Solution, a recent $32m Series C funding for Heart Failure Solutions, and healthcare transformation in the Internet of Things and Digital Health world.
RF: What is unique about the work Endotronix is doing?
MN: We are focused on an end-to-end solution for patients with heart failure. It’s been known for a long time that daily measurement of pulmonary artery pressures (that are very different from your arterial pressure) allows a clinician to proactively manage heart failure much more effectively and avoid hospitalization. This exciting technology is combined with a comprehensive patient management system that includes individualized clinical care protocols and improves physician, patient, and caregiver communication. We’re on the cusp of a movement to transform healthcare from being clinic-based, that is, very reactive to symptoms to a home-based model that tests and treats these states before symptoms appear. And we’re doing it with heart failure, which is an enormous market.
RF: That certainly sounds appealing for a lot of reasons. How is Endotronix addressing this opportunity/challenge?
MN: We have an implantable pressure sensor. It’s very simple, but it has to be quite small because the sensor fits within the pulmonary artery via a catheter based, minimally invasive delivery procedure. The procedure has to be cost-effective and safe. We designed a sensor that will exist for the lifetime of the patient in the pulmonary artery and is powered from the outside. The patient picks up a reader approximately the size of a cell phone, holds it against their chest for 15-30 seconds each day. And that’s all they have to do. The reader records the pulmonary artery pressure, sends it up to the internet, and a clinician reviews the information. Trends in this data provide early detection of worsening heart failure that allows the clinician to intervene by adjusting the medications a patient is taking. With the feedback data they can adjust meds more intelligently. It’s been shown that this can reduce hospitalization of heart failure patients by 40%.
RF: You just recently received another round of funding. I assume that’s a good sign. Do you want to give an update on how you are doing in the development of your device?
MN: It’s going very well, but remains a big project. We’ve established the basic technology for our cloud-based patient management system and our sensor system, which includes the implant, the delivery system and the reader. Management of the data is a very important piece of the puzzle because it is a lot of data and the clinic staff often don’t have time to sort through and analyze all of it in great detail. Presenting the data in an organized and useful fashion is a big part of this job. We are now moving steadily towards commercialization. The C round funding really enables us to execute on the activities we need to do in order to verify and validate the system.
RF: I believe CardioMEMS™ HF System is the only predicate device on the market right now. How do you differ from that product?
MN: We’re similar in many ways – the basic measurement and what we do with it is similar to CardioMEMS. For the sensor system, our main differentiator is our reader unit. We have a different kind of reader technology that allows us to make a very small, handheld reader unit versus the CardioMEMS interrogator unit, which is built into a mattress and is a fairly large piece of capital equipment that has to go into a patient’s home. We realize that a very important part of the process is designing a reader that people will want to use. Our reader looks like a piece of consumer equipment that belongs in the home rather than a large piece of medical equipment that dominates the room and that you have to lay down on. That’s one big aspect of it.
We’ve also developed an entire care strategy, a care platform to simplify home based individualized care protocol management. The care community includes the patient, their loved ones and the clinicians. They can work together in a way that is effective and doesn’t take a lot of anybody’s time, yet gets the therapy done correctly and gets the data managed in an efficient way. I think those are two of our biggest differentiators from CardioMEMS.
RF: There must be a fair amount of excitement about this new technology. What are reactions from colleagues/industry regarding those differentiators?
MN: Yes, we got a $32 million reaction that was very positive! The industry is behind our strategy and heart failure is such a pervasive disease state. It’s an enormous market: 20 million people in just the United States and Europe with millions more elsewhere and several million new patients coming on the rolls every year. As a medical device engineer you might brag about a product you are working on that is going to help out 50,000 or 80,000 people. But 20 million people! Economically and from a personal level, it’s very satisfying.
Everybody in the world has been affected by heart failure: if not yourself, then a loved one, a relative, a colleague, or a neighbor. This makes my work very personal. To be on a project where we have the opportunity to improve the lives of millions of people in such a big way is a once in a lifetime experience for a lot of engineers. I think of all the heart failure victims I’ve known in my life and it’s a real motivator to get this out to the market. It’s going to be something that’s affordable for payers and easy to use for patients and clinicians.
RF: You’re totally right. There are a lot of people in this industry that are here to help others. Helping with heart failure is a great way to serve the masses. Have ViVitro Labs and services helped in your efforts?
MN: Our implant is held in the pulmonary artery for the lifetime of the patient by nitinol anchors. It has to remain safe and function all of that time. We have to validate safety and efficacy long-term over many years of exposure to the endovascular environment, but we have to get that done quickly to get the development done quickly. Testing in an endovascular simulator is the way to go. Originally we planned to build our own test stand, but I have to tell you it is not trivial. For any new test stand, there’s a debug and a test stand qualification period before you can really believe the results, and that impacts project schedule. Having a ViVitro test stand that has already gone through this, and the turnkey solutions you offer, we believe are going to be a great timesaver and a quick, efficient way to get to that confidence level.
RF: You echo what a lot of people say. What are your future plans/goals beyond this project? What’s next for you and Endotronix?
MN: We patented a wireless technology that allows us to interrogate a very small sensor with an external wireless reader, across large distances deep in the body (i.e. the pulmonary artery), not just a centimeter or two. That technology has a lot of other potential applications across medicine. This technology will give clinicians the ability to take a daily reading and understand what’s going on in many areas of the body. Real-time, frequent, home-based information versus occasional readings in a clinical setting where the patient may not be feeling or reacting in a normal way, is going to open up vast new worlds in medical and pharmaceutical research.
RF: In other words, you can measure anything of clinical relevance?
MN: That’s right. Our sensor converts the measurement into a resonant frequency. It’s a pretty basic idea. If you can create a resonator that transduces whatever parameter you’re measuring into frequency, we can read it wirelessly. The measured parameter can be, for example, pressure, temperature, chemical presence, acceleration, strain, and there may be some applications for simple actuators as well.
RF: That’s very exciting. Hopefully those will be coming down the pipeline soon.
MN: We’re starting in what we believe is our biggest and most important market. But there are many more markets that might follow.
RF: Do you have any advice for cardiovascular researchers and start-ups that are just about to make it big?
MN: Yes. I’d love to see a wave of researchers and start-ups follow the effort that we’re spearheading. I think we need to stop thinking of healthcare as something that exclusively happens reactively and start proactively managing disease states. That care can be guided by frequent measurements of all kinds of data that matter- data from deep in the body that comes on a daily or hourly basis. We’ve got this great thing called the internet that can get data from people’s homes to the clinic and organize it well. Now let’s make some devices that get the data we really need. Let’s move beyond the systems out there now where you are just putting Bluetooth capability into a weigh scale, blood pressure cuff, or a glucometer. That’s almost a commodity now. Let’s get deep in the body and start measuring pressures and temperatures in all of the organs that matter. This opens up a new treatment paradigm for medicine.
RF: It’s great to see that people are finally getting treated in the home and that you are delivering an elegant example of personalized medicine.
MN: That’s what we’re all about. There are also ergonomic and economic factors. Home based equipment has to be very user-friendly and unobtrusive as well as cost effective. That’s something researchers are going to have to think more and more about as this shift occurs.
RF: That raises another question. Does the patient have any access to the data?
MN: Our plan is to make the data accessible to the patient via their own personalized website. How you present medical information to the patient and their family caregivers is very important. You want to present it in a way that they will understand it but not misinterpret it or overreact to it. You also want to make it effective. A lot of our job is to do the ergonomic studies and consult with front line clinicians – doctors and nurses who work with these people, to try to get that right.
RF: We know of the white coat syndrome where blood pressures increase because patients are stressed out. Have you noticed anything like that when patients conduct their own data collection? Are they more relaxed or is there a similar effect?
MN: I’ve read the research others have done, and I believe it is a real effect. I also believe that what the patient is doing when they take their measurement is important. There is a certain amount of training needed —everything from positioning the patient to did they just run up a flight of stairs? That is something we have to pay attention to. We do believe there will be a difference between getting measurements once or twice a year in the cath lab when they are laying down on the table with a catheter inserted versus each day at home in their normal routine.
RF: This was great. Thank you very much for the interview. We really appreciate you taking the time. I know our readers will be interested in your activities.
MN: Thank you. It’s nice talking to someone who is as much into this stuff as we are!
Read more interviews with Cardiovascular Pioneers.
Wei Sun, Ph.D.(WS) is an associate professor in Biomedical Engineering at Georgia Institute of Technology. He is an expert in the field of heart valve mechanics. He was previously employed by Edwards Lifesciences, LLC. He also serves as a member of the ISO/TC 150/SC 2 – Cardiovascular implants and extracorporeal systems working committee with Rob Fraser (RF), ViVitro Lab Manager.
Wei and Rob spoke recently about Wei’s work in the Tissue Mechanics Lab, the ISO committee, and TAVR durability.
RF: As an associate professor at Georgia Tech you’re involved in a variety of projects. Will you give our readers a summary of what’s unique about the work you’re doing.
WS: We study heart valve biomechanics, left ventricle mechanics, as well as the ascending aorta aneurysm rupture potential—basically cardiovascular biomechanics. We use experimental methods, such as biaxial, uniaxial, and fatigue testing to characterize the tissues’ mechanical properties, then we put them into computer models to simulate their biomechanical behaviors and responses. We would look at valve performance to study the mechanism of valve failure, valve repair, and procedural failure – like TAVR procedural failure- the mechanism. That’s our research focus.
RF: It sounds like basic material characterization with the biaxial and uniaxial testing to translate this into a TAVR model, are you also testing on the full TAVR systems?
WS: We don’t test a full commercial TAVR valve in our lab. Basically we test pericardial tissues and then put their properties in the computational model. We created a generic TAVR valve model. It’s a computational model that mimics the key features of transcatheter valves. We can run simulations in the nominal shape, elliptical shape or oval shape, and look at the valve stress and strain distributions. From numeric simulations we can also look at how the TAVR stent interacts with the calcified aortic root, whether it is placed too high or too low and whether it is expanded too much. Will it cause aortic rupture, paravalvular leak, coronary occlusion, or blood flow obstruction?
RF: How is the work going? What reactions have you had from colleagues in the industry?
WS: We have been publishing in this area extensively. Some of our papers have had a pretty good impact. For example, our 2010 publication talks about how elliptical deployment is going to increase TAVR stress and have implications on the durability. At that time it was new, now it is well accepted that the elliptical configuration is not good.
RF: Yes, certainly your elliptical findings were great results. Are there any other highlights?
WS: We also work on modeling aortic aneurysm. We look at the ascending aortic aneurysm and its rupture potential. We work with Dr. Elefteriades at Yale University Medical Center. He’s a cardiac surgeon. He provided us patient tissue samples and imaging data, and we built computational models and run simulations. We also collaborate with Dr. James Duncan at Yale. He’s an imaging expert. We recently worked on statistical shape models for population-based modeling of the aortic valve.
RF: What are some of your future plans or goals?
WS: I think fatigue damage is going to be an issue for the TAVR valves. The 5 year durability data for the SAPIEN device look very good. We’re waiting to see at 7-8 years if this type of valve is going to show some particular issues. We’re getting towards that 7 years now.
I think the TAVR durability is going to be a concern. As TAVR goes to younger patients and low risk patients and is competing somewhat with surgical valve replacement, the durability is going to be a big issue. We did some computational fatigue models, tissue fatigue testing, and we just don`t have clinical results yet so we are waiting. That`s one of the interesting research areas we are studying.
RF: Based upon this fundamental research you are conducting, do you see any issues coming up?
WS: It`s hard to say. It`s predicting into the future. I have a good confidence in the companies who have a lot of surgical valve fabrication experience. They have in-house expertise and are rigorous. For the new companies- we have so many new start-ups with new valve designs- for those companies I think it’s going to be an issue because durability will not show until many years down the road. In 5-6 years, “are they really building a valve as good and rigorously as a well-established valve company?” is a big unknown.
RF: You have a unique perspective working in both industry and academia.
WS: One difference is that in academia you have more time to look at more details. In a company you have product deadlines and have to hit those targets for a product launch. The goal is really the same: To improve the patient’s healthcare. For me, I enjoy doing more fundamental basic science research. That’s the reason I go for academia. But I think for the valve industry, this is probably the best time. There are a lot of R&D activities, a lot of start-ups and opportunities for young people to grow. If you are a grad student, going into the valve industry is probably a good idea at this moment.
RF: But not for you. You’re happy where you are.
WS: (laughs) Yes, I am.
RF: We met while working on the ISO committee. Has it helped or influenced your work?
WS: Not directly because a lot of my work is fundamental basic research. But I really like my ISO work because it gives me a different perspective. I feel ISO standards have very rigorous wording. We discuss every single line to make sure it makes sense. Sometime we argue, sometimes we agree. It’s nice working with the representatives from different companies. In terms of technical learning, not that much.
Read more interviews with Cardiovascular Pioneers.
Founded in 2012, PECA Labs is a Carnegie Mellon and UPMC spin-off dedicated to bringing better medical devices to orphan populations, with an initial focus on the pediatric cardiovascular system. Their first product, the MASA Valve, is a surgeon-created, engineer-optimized, clinically-implanted and validated heart valve that will save thousands of children every year from repeated open heart surgeries, with a significantly reduced input cost compared to the typical heart valve. PECA Labs recently completed a $2.8 Million Series A Financing Round.
Co-founder and CEO, Doug Bernstein (DB) and ViVitro Lab Manager, Rob Fraser (RF) discussed the unique challenges and methodologies of the pediatric cardiac space.
RF: What’s unique about the work PECA Labs is doing?
DB: We’re one of the few device companies solely focused on the pediatric space—especially for complex class III devices. Other companies have created pediatric devices in the heart valve space, but very few have taken it as their sole focus. A lot of that is because of the uniqueness of the pediatric cardiovascular system. The complexities that exist around pediatric cardiac surgery are not similar to adult cardiac surgery.
I think it’s an important niche to be filled. The fact that it is our sole focus has allowed us to approach the field differently and to build our relationships with surgeons and institutions differently in order to bring devices to the kids who need them at a greatly reduced cost compared to normal development.
RF: How is PECA Labs approaching this differently?
DB: We take an approach that starts with a high degree of collaboration with the surgeons doing these surgeries and with universities as well. Because there are often very few devices that are off the shelf applicable to patients, there’s a lot of off label use, a lot of customization and a lot of “in the suite innovation” by surgeons. Because of the market size associated with the pediatric market, these are often not taken up and acquired by larger device companies to be brought to market as a product. So you end up with a lack of standardization, a lack of quality controls, and ultimately more liability on the surgeon than should really be there and is often not there for other fields.
We work directly with the surgeons and the engineers at the university research level who are focused on this and all the time having to create new ideas to approach the complex problems of pediatric cardiac surgery. We work with them to translate those ideas and to productize them so we can get them back to the surgeons in a quality controlled, standardized and (eventually) FDA approved or CE mark approved fashion. We can take away a lot of the questions and non-standardization that go with custom and off label use and give them products that are still going to work with their patients.
RF: You are taking the big company approach and taking it to a market not being served by them.
DB: Yes. And because we are focused on such a small market and there are so few surgeons that do pediatric cardiac surgery compared to the adult market, we are able to build very strong relationships and collaborations directly with the surgeons that we work with. We are able to have relationships in a different way than you would see with the larger device companies. We‘re able to get closer and more collaborative. That’s a big benefit for us and eventually a big benefit for the surgeons and their patients.
RF: How is the work progressing?
DB: It’s going well. As anyone in this field knows, it’s never as quick as you would want it to be. There’s inevitably going to be some slowdowns and hiccups in the road. Over the three years the company has been around we’ve managed to move forward at a relatively quick pace for the industry. We started out with one product and we’re up to three products in development that are all moving down their FDA pipelines in a way that we’re very happy. Hopefully we’re going to see products on the market in the next year or two that will address certain pediatric populations.
RF: What reactions have you had from colleagues in the industry?
DB: Colleagues in the industry have had very mixed reactions. We’ve seen it change a lot from when the company started. When the company first started out and before it even started, it was more in the development stage and planning what the company would be and what our approach would be. We got much more negative feedback or people just not believing that we’re trying to do could be possible. Because of the historical time and cost of the types of devices that we’re developing and the past experiences of some of the larger companies in these markets, people tended to think it was not possible to be able to do what we’re doing. Let alone do it in such a way that you could raise the proper funds from investors to bring such products to market for these relatively niche groups.
As we’ve been moving forward and as we’ve seen the results of our devices be really excellent compared to anything else that’s out there, we’ve shown that we are able to move forward along our pipeline with costs that are significantly lower than the normal medical device company. The conversations with either industry partners, potential investors or previous investors has changed a lot. It went from “this isn’t really possible” to “Oh wow, this might actually happen.” And that’s definitely a nice change in attitude to see.
RF: Yes, it would be tough to start out knowing you have such a noble cause to bring these devices to children and to be met with such pessimism at the start. I’m glad to hear that’s turning around.
DB: Especially in the last year or so, it’s started to change dramatically.
RF: Is that when you started to secure funding, when the attitudes shifted that this was actually possible?
DB: Yes. The last pushes of our funding round, closing the funding round and sort of accelerating afterwards has really changed the way people looked at what we’ve been doing and what we’re going to do.
RF: How has ViVitro Labs services helped you and your efforts?
DB: We haven’t started our testing protocols or testing yet, but we’ve been looking around the field and getting ready for testing. Because our space is in the pediatric space, we end up having these unique anatomies that in a lot of ways are vastly different than in adult devices. It’s crucial to be working with a partner that’s able to customize, develop and adapt to our needs.
After this interview we’re going to continue our conversation about the customizations we need in order to test the devices. That’s something we’ve had good experiences working with ViVitro. It’s been really important to us because when you’re dealing with the regulatory side, you need to show these things and prove these things, and whether it’s easy or not to get the machine to do that isn’t part of the conversation. It’s important to work with fine industry partners like ViVitro that are able to adapt and work with you to meet your needs.
RF: You mentioned already you have three novel devices in the pipeline. What are the next steps for PECA Labs?
DB: The MASA valve is the most visible and the furthest along. The other two we’re keeping a bit quiet. They’ve gone through their benchtop and ex-vivo studies. We’ve been working with a number of surgeons and institutions to get them into realistic in-vivo animal studies that are going to be happening over the next few months. The results have been looking great and we’re excited to show that when we put them in animals, we maintain the results that we’ve seen. They’re not late stage, but they’re moving forward. If they continue to show what we’ve shown in our testing data, they have the opportunity to revolutionize the field of pediatric cardio-thoracic surgery. We’re very excited about this, but will have to wait a bit longer to go into the details.
RF: Do you have any advice for cardiovascular researchers or start-ups?
DB: Yes. Especially in the pediatric space, direct collaboration with surgeons is key. If you’re a researcher and you’re not talking with the surgeons doing it, you’re going to have a hard time even attacking the proper concept. When you read these things in textbooks, or even when you look in the publications, the reality of doing these surgeries– and every patient with a congenital heart defect has a different anatomy than the last one with the same congenital heart defect– is a big thing to take into account when you’re trying to develop devices that are going to be applicable to all of these differences in the patients that have it. Talking with surgeons that have hands on experience is crucial.
Separate from that, a huge amount of persistence is necessary. If you’re working in the pediatric field as an entrepreneur, you’re inevitably going to face people not believing what you’re trying to do is possible. Often times that’s because of their past experiences with larger markets and different markets than your own. The fact that people don’t think it is possible doesn’t mean that it isn’t. Being stubborn and very persistent is critical in this field.
RF: How did you choose cardiovascular and pediatric?
DB: I was born with a congenital defect. When I was born, my life was saved by a pediatric cardio-thoracic surgeon. That certainly had a part to play in my getting involved in this research. I had an opportunity to be involved in a project looking at right ventricular outflow tract reconstruction trying to develop a better methodology while I was at Carnegie Mellon University. Because of my own history, I jumped on that opportunity. Luckily, it was a great collaboration between engineers and surgeons that produced some promising results that led to PECA Labs. A little bit of serendipity, a little bit of personal history definitely went into that.
Read more interviews with Cardiovascular Pioneers.
Dr. M.Sc. Bassil Akra
Dr. M.Sc. Bassil Akra (BA), Director Clinical Centre of Excellence (cCE) at TÜV SÜD Product Service GmbH, was in Vancouver BC for a recent ISO meeting and took the opportunity to visit customers and ViVitro Labs.
ViVitro Labs and TÜV SÜD participate together on several ISO committee meetings with regards to standardization of cardiovascular devices. TÜV SÜD is the biggest notified body in the world that approves devices for the European market.
Rob Fraser (RF), Lab Manager, MSc. at ViVitro Labs, spoke with Dr. Akra about the differences in North American and European regulations. Here is a portion of their conversation:
RF: Are companies prepared for the new ISO 17025 requirements?
BA: ISO 17025 is not new and presents a method allowing acceptance of testing and calibration results over borders. This standard is used by accreditation bodies to recognize the competence of testing and calibration laboratories that operate in accordance with well-known quality management systems by complying with this standard.
Accredited test labs have the opportunity to market services globally because their test results are deemed trustworthy by international standards. It should be noted that this is just applicable in cases where labs obtain accreditation from bodies which have entered into mutual recognition agreements. This provides higher trust and easier market access.
For example, in Germany since approximately 10 years MPG § 15 (5) it is a requirement for notified bodies to involve recognized and accredited test labs when fulfilling their obligations. In cases where no test lab is accredited for specific test methods, we review the full validation report of the testing methods, challenge the methods and the obtained results and audit the lab to understand how the data was collected and documented.
RF: So the added value of working with an independent test lab that has ISO 17025 accreditation is that you can follow the results?
BA: That is correct. Inaddition to the quality of the results, you gain recognition all over the globe. Because test results, if they are not done by a quality test lab that is following the rules, could be challenged.
RF: Where do you see the European requirements heading?
BA: They are evolving because we are not done yet in Europe. The number of notified bodies and the scope of some of these will be reduced more in the next 12 months. A large number of these bodies will not be able to do what they are doing today and this is based on the internal clinical and technical competence level with specific devices. The requirements in Europe are facing big changes. In the clinical field there will be much more scrutiny on the assessment of the manufacturer’s clinical evaluation report.
The Essential requirements will be adopted in the proposed new medical device regulation. This will influence the whole market. Regulatory strategies that were fulfilling requirements in the past will not fulfill the new requirements; gap analysis and update of the technical documentation is required. In summary, this means that a large number of devices available in the European market, or other markets that rely on the CE marking, will disappear in the near future if they do not fulfil the new expected Medical Device Regulation.
This will start happening latest after 3 years of the publication of the new Medical Device Regulation (MDR). The MDR will be immediately applicable (upon publication), but in the transition phase, medical device manufacturers can still deal with the old applicable directives. At the end of three years, new applications must follow the new regulations. If manufacturers do not conform, they will not get a new approval according to the requirements of this MDR.
RF: When do you expect the pending changes to occur?
BA: We’ve been waiting for this regulation for many years. Every year we say the new medical device regulation will be coming. Based upon the latest information, the pressures we are seeing towards implementation of the new regulation and the starting activities of the triolog (the European Commission, Parliament and Council), we are expecting to see the new medical device regulation published in Q2/Q3 2016.
If you put a device on the market today, next year we will have a new regulation. You don’t have to fulfill the new regulation requirements immediately. You have three years’ time to fulfill these new requirements. After three years, new applications for device approval must fulfill the new requirements. Let’s take an example: You have a device you are developing, next year the new regulation comes in. You have a three year transition period. You can decide when you submit the device whether you want to go with the old requirements or the current regulation. You can decide because both methods are applicable.
It makes much more sense to go with the new regulation. If you don’t, when your certificate deadline is reached you will have to apply for CE Mark showing compliance with the requirements of the new regulation or remove your device from the market.
RF: How long is the current approval time?
BA: It depends on the quality of your documentation. If a medical device manufacturer submits documentation that fulfills the requirements, everything is good and there will be just one route of assessment. The product relevant reviewer are going to write a report, everything is going to be prepared for a certification process in a predictable timeline. But if the manufacturer submits questionable documentation and evidence, then this manufacturer will get a list of open questions to resolve.
The first round of your assessment is a question list. Then the manufacturer comes back with answers that are in some cases deemed not acceptable leading to a second round of assessment combined with a lot of delays. Depending upon the quality of the manufacturers’ documentation and the submitted evidence, the review and approval process can be between 30 days and two years. Those are extreme cases. 30 days is very fast. It could happen for a device that was tested according to the requirements of the directive and that has sufficient clinical data showing safety, performance and positive benefit-risk ration of the device.
A really good plan and a review that was project managed from the beginning, allow having a predictable approval process. That means the manufacturer tells us, “I’m going to submit on this date”, and we get their submission so we can schedule resources to review the file on time. However, if they say they will submit on Monday, but submit on Friday (which happens most of the time), then you may not have free resources anymore that deliver predictable services. In summary, it should be said that project coordination is an important factor that must be considered critically by both sides (Manufacturer and Notified Body).
RF: You mentioned that the CE mark has become a gateway to the rest of the world. Will you comment further on why that is happening?
BA: The CE mark is gained by fulfilling the requirements in Europe, this means the current Applicable Medical Device Directive(s) (MDD and AIMDD) for a specific device. The requirements in the US differ from those in Europe, especially with regard to clinical data requirements. The FDA differs between pre-market notification (510k) and pre-market approval (PMA) and depending on the novelty of the device either requires prospective clinical trials or accepts published clinical data as clinical evidence. In Europe currently different routes are possible to show safety and performance of a device: The clinical investigation route, the equivalence route or the combination of both. This system is currently under review but it should be mentioned that Europe was always pragmatic and reasonable in its decisions leading to opening the door for innovations 3 to 10 years before the US market. The delays in approval in the US were mainly based on the amount of required evidence during the submission.
Europe takes case by case decisions by looking on the claims of the manufacturer, the targeted medical indication and patient population, the proposed benefit, the innovation created by the device, and last but not least, the benefit risk ratio of the device when compared to the current state of the art. Based on those criteria, and in combination with the post marketing plan of the manufacturer, European Notified Bodies decide whether a device should be approved or rejected.
It should be also mentioned that there are several evidence showing that devices approved in Europe according to the current medical device requirements are not less safe or less effective than devices approved in the US 3 to 10 years later. The big question that should be raised is what the expectation of the patient is and when this patient wants to profit from the new technology. The whole issue the US has is that innovation is not innovative any more by the time it gets to the US market. This is why other markets such as some of the Asian market see the European system as a reasonable system and rely during their approval process on the CE mark of a device.
RF: And where does Health Canada fit?
BA: Having quality management certification (EN ISO 13485) for Europe supports as well the fulfillment of the Canadian Requirements. Health Canada has their own audit processes– Canadian Medical Devices Conformity Assessment System (CMDCAS) now—but this will be changing in the future. CMDCAS also uses ISO 13485. A manufacturer must submit a CMDCAS certificate with their device license applications for Class II, III and IV devices. The MDSAP Program (Medical Device Single Audit Program) will be replacing the current CMDCAS Audit Process soon. We are authorized as a third party Auditing Organization for the MDSAP Pilot Program. With MDSAP you can avoid having several audits by different authorities or different bodies with one cycle that covers US FDA, Brazil, Australia, Canada and Japan. This is really helpful. Europe is currently observing this program. We are hopeful that Europe will adopt some of the MDSAP tools in the future. This could be a way to have common understanding, regulatory convergence and effective usage of high valuable resources all over the globe.
RF: You’ve already given some great information, do you have any additional advice for cardiovascular researchers and device companies in the region?
BA: I’m not allowed to give any inside information because of compliance requirements and confidentiality agreements with our customers. Nevertheless I can tell you that a lot of manufacturers are working on new innovative cardiovascular devices. I’m seeing the Asian market grow much more than in the past. Asia is now developing and testing their own Class III medical devices such as heart valves, stents, drug eluting stents, and Occluders with the intention to gain European market access. The main market for Asian Manufacturer is the Asian, Middle East and African market. Getting a CE mark allows them to get smoother market access in different regions of the world and support quality claims.
With a CE mark, the previously mentioned countries gain more trust on the quality of the device fulfilling European requirements. With the CE Mark, manufacturers are allowed to sell the device in Europe. What is not acceptable is a manufacturer that says “I want to get a CE mark, but I will not support you with evidence for every requirement of the medical device directive because I want to sell it in Asia.” This will not be accepted. If they want to get a CE mark, they have to have a device that is fulfilling the European medical device directive requirements.
Read more interviews with Cardiovascular Pioneers.
Dr. Dominik Obrist
Michel Labrosse Ph.D., P.Eng
Michel Labrosse Ph.D., P.Eng. is the Vice-Dean (Interim), Graduate Studies, and Associate Professor, Department of Mechanical Engineering, University of Ottawa, Canada. His team utilizes ViVitro Labs equipment in their research and cites it in research publications. Rob Fraser, Lab Manager at ViVitro Labs, recently spoke with Dr. Labrosse to learn more.
A native from France, Professor Labrosse received his Diplôme d’Ingénieur from the École Centrale de Nantes in 1993, with a specialization in structural engineering. He obtained a Ph.D. in Mechanical Engineering from the same institution in 1998, and pursued his research work on the finite element modelling of wire ropes and cord-rubber materials during a post-doc at the University of Akron, Ohio, in the United States.
Labrosse then spent 5.5 years with the Heineman Medical Research Laboratory at the Carolinas Medical Center in Charlotte, North Carolina, working on various problems in cardiovascular mechanics related to clinical topics.
Professor Labrosse joined the Department of Mechanical Engineering at the University of Ottawa in 2005. His research interests revolve around theoretical and computational structural analysis and its applications to the diagnosis and surgical treatment of cardiovascular diseases.
Rob Fraser: Please tell us about your current work:
Professor Labrosse: I collaborate with several clinicians at the University of Ottawa Heart Institute. The objective of my lab is to improve basic science in cardiovascular mechanics. For example, the description and understanding of soft tissue mechanics, cardiac valve geometry and function, as well as cell mechano-biology. We’d like to combine this knowledge with the development of new computational tools for use by the medical community. For instance we are developing a framework to help cardiac surgeons with the planning of repair procedures on the aortic and mitral valves. That’s basically the bulk of what we are doing right now, and it goes in so many directions.
We need to develop our own tools—for instance, to process medical imaging data. We’re also developing a new shell finite element specific to soft tissues and dynamics. But the clinical input is very important for us to stay relevant. We want our simulations to be as clinically meaningful as possible, and this forces us to carry out experiments as well, to validate our simulations. For example, we’ve run lots of experiments on the human aorta and on the aortic valve. We test the aortic valve in the ViVitro system. We want to see if what we see in the machine is comparable to what we are able to simulate in our finite element models.
Rob Fraser: How is the work going?
Professor Labrosse: We’re pushing the limits. We’ve been able to develop tools to use images from 3D ultrasound. We can now build finite element models of parts that actually are in patients or subjects. We want to reproduce their function as faithfully as possible. The geometries you see in vivo are pressurized, but if you are interested in stress and strain computations, you actually need to start from the unpressurized geometries. This comes with many technical challenges that we’ve recently started to overcome.
We’ve been successful in normal human valves, now we’re moving to diseased human valves and it’s another ballgame altogether because the material properties are potentially very different from the normal ones and they are difficult to figure out.
At the same time, with my clinician colleagues, we are interested in modelling the different procedures that are used to repair aortic valves. We can do that on a computer relatively easily, but we also need to get input from experimental work. Again, it’s done in the ViVitro system. For example, a cardiac resident runs a pig valve where a leaflet has been removed; we look at the AI, and then fix the leaflet according to different surgically relevant techniques, and we finally test how the valve is performing. From the ViVitro machine, we get information about cardiac output, leaflet dynamics, left ventricular work, speed of opening and closing of the leaflets, maximum effective orifice area—things like that. And from our simulations, we can get access to stress levels in the leaflets, etc. Of course, we check if the simulations are telling similar things to what we see in the experiments.
Rob Fraser: What are the reactions to this work?
Professor Labrosse: The clinicians are keen. They want the simulations done yesterday. Because we are getting there for the aortic valve, now we have to move toward the same things in the mitral valve. And the ViVitro machine should be able to help us there as well.
Rob Fraser: What are your plans for the future?
Professor Labrosse: We are pushing hard toward the modelling of the diseased aortic valves, whether they are dilated by an aneurysm or bicuspid valves. We want to simulate them properly and give advice to surgeons as to what procedures should work best for removing the AI. That’s a big goal we have. We are also planning to do similar work on the mitral valve. Our expectations from experiments have been growing, so now, we’re also very interested in an ex-vivo model to get better images. Right now, the ViVitro is working just fine for us, but when we try to image the valves that are running on the machine using the usual clinical imaging methods like 3D transesophageal echography, we don’t see the valves so well because there is interference with plastic objects and things like that. We’re really hoping that we can get better imaging from an ex vivo model, so that we could process the data in a completely similar way to what we do with human data. We have data coming from humans and we can simulate things from them. To close the loop, we’d like to have the same type of data coming from the lab as well so that we can control conditions much better and try out surgical things that wouldn’t be done on humans yet.
Rob Fraser: What has been the most exciting moment in your career to date?
Professor Labrosse: When I learned it was possible to extract data out of medical imaging machines. For years I had been getting information by making measurements off of monitors on heart valves. All of a sudden, in 2010, I could get access to the raw data when Philips opened up its equipment to the research community. The heavy work started there as well. I needed to create my own way of processing the data towards the goals I had. It has panned out beautifully, but it’s only the beginning. There’s so much more we can do with the data. It’s been super-exciting.
Rob Fraser: How has ViVitro helped in your work?
Professor Labrosse: It really is like an industry standard. I love the machine. The first time I saw the machine in action was at the Heineman Medical Research Laboratory in Charlotte where I was working with Dr. Mano Thubrikar—a pioneer in aortic valve research. I saw there that it was a fantastic machine. When I became an associate professor at U of Ottawa in 2005, the first thing I did was write a proposal to try and get that machine. I was lucky enough to get it in 2006. It’s really a fundamental tool for validation of whatever I’m doing in terms of simulation. That’s big.
Rob Fraser: Do you have advice for our readers in cardiovascular research working with clinicians?
Professor Labrosse: It’s very challenging, but you want to stick to what’s clinically relevant. Automatically, you will end up with beautiful, fundamental questions from that. If you don’t have the clinician teams excited about what you’re doing, they will lose interest and the collaboration will fizzle out fairly rapidly. It’s a win-win situation when you are trying to solve something that’s useful for the clinicians. Unfortunately for them, it takes a lot more time to solve than what they would like. But that’s the way research is.
Rob Fraser: How do you help set the expectation that this will take time?
Professor Labrosse: That’s a challenge but clinicians know they too can’t always get what they want. They are very busy in the clinic and they have night calls and things like that. They realize I may have limiting factors as well because of the admin work and the teaching I am doing and so on. We’re all just humans! It’s a bitter pill to swallow for everyone, so at the end of the day, we need to work with reasonable people.
Read more interviews with Cardiovascular Pioneers.