Mr. Kenneth Chan Zhi Wei is working on the design of a novel prosthetic heart valve for the treatment of Mitral Regurgitation (MR) under the supervision of Assoc. Prof. Leo, and Dr. Elynn Phang Hui Qun of MERCI, who is managing the commercialization of the invention. The lab has used a ViVitro SuperPump since 2010. Mr. Chan Zhi Wei (CZW) recently spoke with our Product Manager, Joe McMahen (JM), about the unique features of the VeloX minimally invasive prosthetic heart valve and other research activities underway at MERCI.
JM: Please describe what MERCI is and how you are associated with NUS.
CZW: MERCI stands for Medical Engineering Research & Commercialization Initiative. We are a bridge between the clinicians and the Faculty of Engineering at National University of Singapore (NUS). We find unmet needs that the clinicians want solved. Sometimes they bring an unmet need to us, and sometimes we see an unmet need which can potentially improve healthcare in general. We assess the data landscape and if there is an area worth going into, we link the relevant clinician up with relevant professors of engineering to further develop the idea by applying for a government grant and finding joint investors.
Finding first stage investors is something that MERCI does to move a technology forward. We lay the baseline framework for technology to grow and to mature to the next stage, which is either a start-up, or a licensing approach with bigger companies like Edwards or Boston, who take on the license and further develop the device or technology. MERCI exists to reduce redundant risk development within the Faculty of Engineering. Most of the time the Faculty of Engineering comes up with a lot of innovation and technology. Then they look to find a huge void. We are trying to do it the other way around. We try to find a need before a solution. We feed it with a solution that is ready to develop. That way we avoid going off in a direction which may not have a useful outcome.
JM: Could you please discuss your current work with mitral valves and explain what is unique about the valve?
CZW: We are researching a novel transcatheter mitral valve device. What’s unique is the mode with which we anchor the device. Typically, transcatheter mitral valve devices use quite invasive methods of anchoring because the lack of mounting zones on the mitral valve annulus itself. What this means is that we would typically require invasive anchor mechanisms such as barbs. This would risk damaging the myocardial tissues around the annulus region, injuring the heart and increasing mortality risk. With our device, we use atraumatic anchors that minimize this risk. Coupled with a unique sealing mechanism, we are able to minimize the risk of paravalvular leakage significantly. This is reflected in the pre-clinical studies. In the bench model, we see less than 10% paravalvular leakage which is reflected the pre-clinical models. This validates what we saw in the bench model. We have completed most of the bench testing phase and are going into the pre-clinical phase.
JM: How is ViVitro testing equipment or services helping your efforts?
Currently we are validating bench model results using a SuperPump AR Series model. In the bench, we created a custom flow chamber to house our device in an anatomically correct silicone model to reflect what we would see in the human model. We were able to program the pump to output physiological and pathological flow and pressure waveforms to obtain the desired flow output needed. For instance, having 100 mmHg of systolic blood pressure and 80 mmHg of diastolic blood pressure. In addition, the ease of programming the pressure waveform through the ViViGen software was a real plus.
We also conducted Particle Image Velocimetry (PIV) during our verification study in-vivo. The interoperability of the pump with the PIV system and the high-speed camera system through its Sync Pulse function really helped us a lot. We got flow data that helped us examine how our valve affected the flow profile within the left ventricle and the left atrium. We could see how the flow generated within the left atrium differed from the physiological state as well as how it compared to existing valves– the commercial tri-leaflet and mechanical heart valve. This helped us benchmark our device at a level of confidence where we are able to make important decisions and design changes to the device even before going into the pre-clinical stage. By reducing the need to iterate between in-vivo and in-vitro phases of the project, we were able to reduce the number of cases required for the pre-clinical phase and that is in line with the ethical mandate of the animal use and care committee. This helped us a lot through the protocol approval process in the pre-clinical phase. At present, short-term acute implant data proved to be promising, with the device exhibiting good anchorage capabilities. Also, the team is still collecting data for further analysis.
JM: What are the greatest challenges you’ve faced in the studies to date?
CZW: Primarily, anchorage and the prevention of paravalvular leakage are the two main challenges. The mitral valve annulus isn’t circular and has an irregular shape. In addition, its saddle shaped landing zone changes based upon the systolic phase and diastolic phase, making it a very fluid landing zone. Without much calcification present around the annulus region, it is difficult to anchor a valve stent device conventionally, like in the case of transcatheter aortic valve implantation (TAVI) procedures. There, we can use a radial force anchor mechanism and abut the stent frame of the prosthetic valve against the native calcified leaflet to give a strong circular hold. We have to come up with novel, rather unconventional anchoring method by means of an array of angled flares around the main stent frame bent to varying angles. This makes sure that the device is able to withstand the systolic pressure experienced by the leaflets when they are fully coapted. This pressure typically ranges between 130 mmHg to 150 mmHg depending on the pathological state of the heart. This is something we cannot really test in the bench model. In the bench model, silicone doesn’t reflect the softness or fluid nature of real tissue. Also, the device is always fixated with zero migration because of the way we anchor the device to test its functionality. It is permanently attached to the native annulus. In physiological models of pre-clinical studies we are faced with the challenges of not just anchor, but how and where the anchor is positioned. The mitral valve is located at such an angle that it makes imaging difficult. It’s not as clearly seen as in the aortic valve.
JM: I understand that MERCI is involved in other types of cardiovascular research. Are you involved in those activities?
CZW: We do research on the right heart- primarily to address the issue of severe tricuspid regurgitation. Many patients with mitral valve regurgitation have co-competent right heart disease. Conventionally, when the surgeon opens the heart in order to fix the left side, they will also fix the right side. With the advent of left heart transcatheter solutions and the move towards the transcatheter era, transcatheter treatment of the right heart would be the next developmental step to provide a comprehensive transcatheter therapy to patients. We are currently tackling the issue of tricuspid regurgitation by implanting novel valve devices at both of the vena cava atrial junction. This prevents regurgitant blood from leaving the heart, thereby restoring a forward unidirectional flow of blood within the right heart. This will improve cardiac output, alleviate the symptoms associated with tricuspid regurgitation and protect vital organs distal to the heart such as the brain and liver.
Due to the angle at which the tricuspid valve is natively oriented, it is very challenging for a transcatheter solution to be implemented at the native valve site. Even more so, the native tricuspid valve is significantly more compliant compared to the native mitral valve. Also, the tricuspid valve is the largest valve in the heart and exhibits very little calcification. As such, we are exploring a way to circumvent the need to implant a valve stent device at the native valve site by means of heterotopic ally implanting the valve stent device at the vena cava-atrial junctions of the heart. In-vitro studies using a bench top pulsatile flow model showed that implantation of a valve stent device at this alternative location yielded similar performance as implanting a valve at a native site.
Currently, we are in the design and concept verification and validation phase of the project. This is where the ViVitro software helped us a lot. Typically, the SuperPump is pre-loaded with waveforms for the left heart. We modified them extensively to cater to the low pressures of the right heart. The ViVitro software allowed us to easily modify and upload these modified waveforms into the pump controller rather than having to feed the waveform data into the pump via an external waveform input. This allowed us to efficiently perform extensive in-vitro tests in the bench and address device related design, performance and reliability issues.
JM: That’s definitely a good approach to tackling engineering problems. One last question – do you have any advice for researchers undertaking similar work.
CZW: My advice is to constantly review the patent landscape. The cardiovascular research domain is a long stretch – anything between 5 – 10 years. The first year some things might be novel, but 5 years down the road, people may have caught up. It is wise to be up to date with the patent landscape because new patents are published every day. This is a real challenge we are facing in the research and development area. And although you have to publish the patent early, filing it at the right time is also very critical. This is because the cost to publish a national phase patent can be quite significant. Thus, it is advisable for researchers to only file a patent when a reasonable amount of data has been gathered and/or obtained.