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Rob Fraser MSc. (RF), Interim General Manager at ViVitro Labs, met Dr. Sotiris Korossis (SK), Director of Biomedical Engineering, Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School during a training session at Hannover Medical School. Rob asked to share Dr. Korossis’s work and use of the Pulse Duplicator in his research as part of our series of interviews with Cardiovascular Pioneers.
RF: Please tell me about your current research.
Currently, our work conducted in the Department of Cardiothoracic, Transplantation and Vascular Surgery, which is headed by Professor Axel Haverich, is heavily focused on tissue engineered heart valves that involve the use of decellularised valvular scaffolds with a view to attracting endogenous cell repopulation following implantation. Another strategy that we follow involves seeding decellularised and polymeric valvular scaffolds with endothelial or stromal cells and then condition them in a bioreactor with a view to these constructs achieving valve-equivalent functionality prior to implantation. Recently we have also started working on the computational modelling of the left heart, incorporating the mitral and aortic valves, and aortic arch using patient specific geometries. The purpose is to create a virtual platform for assisting surgeons in the pre-operative planning of valve repair and replacement. Moreover, we work on developing extracorporeal and intracorporeal biohybrid oxygenators both as a bridge to transplantation, as well as a destination therapy. More specifically, currently available extracorporeal membrane oxygenators suffer from thrombotic events, due to the contact of the blood with their artificial materials, which limit their usage to 4-6 weeks. Our strategy for improving the haemocompatibility of these artificial oxygenators is to endothelialise their blood-contacting surfaces, while also focusing on the miniaturisation and optimisation of the biohybrid membrane oxygenator for intracorporeal operation.
RF: It sounds like there are two big fronts. How is the work going?
SK: Our cardiothoracic surgeon team, led by Professor Axel Haverich, have already implanted decellularised human aortic and pulmonary valves into patients. Our surgeons in Hannover Medical School, have implanted more than 140 decellularised pulmonary homografts since 2005, and more than 80 decellularised aortic homografts since 2008, with excellent outcomes that were superior to conventional pulmonary and aortic valve replacements. These decellularised homografts also demonstrated signs of significant cell repopulation following explanation of one of them. Moreover, we have successfully decellularised the very complicated and inhomogeneous mitral valve apparatus and we are in the process of optimising the design of transcatheter valves made of decellularised pericardium and a novel polymeric scaffold. In addition, we currently work on the optimisation of the in vitro cell seeding and bioreactor conditioning of valvular scaffolds prior to implantation, our progress indicates that in the next 5-7 years we will be able to implant decellularised and in vitro cell-repopulated homograft valves into patients. In terms of the biohybrid lung, we have successfully endothelialise the gas-exchange membrane of oxygenators and we have developed computational models for optimising the design and performance of extracorporeal and intracorporeal membrane oxygenators. In the next 4-5 years we will be able to implant one of these biohybrid oxygenators in a first in man study. In the case of our virtual surgery platform, we are currently seeking industrial partners for translating the concept in a surgeon-friendly software platform, suitable for clinical use.
RF: Am I correct in hearing that the longest decellularised human valve has been implanted for more than 10 years?
SK: Yes, that is correct.
RF: That’s great that they are lasting that long. What sort of reactions are you getting to this work?
SK: The concept of tissue engineering is quite sexy and will remain sexy for years to come. Tissue engineering enjoyed substantial hype in the early 2000s. However, the hype did not substantiate into producing clinically tangible solutions for restoring tissue and organ function. Now that we’re in the position to demonstrate that the decellularised valvular scaffolds provide a clear edge over conventional valvular prosthesis for our patients, people, especially the patients, are really quite excited about it.
RF: It sounds like the technology is finally catching up with the hype?
SK: Yes, absolutely. It also seems that this technology can actually be translated into a profit-making product. Although, and rightfully so, you cannot actually sell human tissue, you can actually make a profit by selling the technology of decellularising the homograft valves. However, things get rather challenging in the case of cell-seeded constructs, since the regulatory and logistics hurdles for this type of product are rather tremendous.
RF: Correct me if this is wrong, but there are no other products using cells like that. It would be a huge paradigm shift for the regulators.
SK: I don’t know how successful they were, but in the past there have been companies trying to market cell-seeded scaffolds for applications such cartilage repair. I’m not sure how this has worked out in terms of regulation and logistics. Remember, you are marketing something that is alive; preparing and shipping it to different locations across the world would be very difficult. This industry is still very young and there are a lot of regulatory and logistics issues that still need to be resolved.
RF: Good points. How is ViVitro helping you with these projects?
SK: We’re trying to break an old habit of surgeons that whenever they have an idea, they just have to put it in an animal. In vitro systems, such as the ViVitro simulators, present a disruptive technology, placed between the conceptual idea of a medical device and animal testing. Following rigorous testing in a near-physiological simulator, animal testing can be done on a much more educated and cost-effective basis. In our case, we conduct pre-animal assessment of decellularised scaffolds and tissue-engineered heart valves in ViVitro benchtop models, which are also invaluable for validating our computational models. We also use the ViVitro pulse duplicator as a phantom circulation for testing our biohybrid intracorporeal and extracorporeal membrane oxygenated prototypes.
RF: You’ve also used the equipment in a past position when you were in the UK?
SK: Yes, at the University of Leeds at the Institute of Medical and Biological Engineering.
RF: What has been the most exciting moment in your career to date?
SK: When I started feeling and becoming independent in my research. I still remember the day that I received the acceptance letter of my first research grant. That, together with the graduation of my first PhD student, would be two of the big moments of my career. Moreover, my first patent was also one of the exciting moments of my career.
RF: I can see those as being exciting moments. Do you have any advice for other cardiovascular researchers who have yet to achieve similar moments?
SK: At the end of the day, I’m an engineer, and as an engineer I’m quite fond of simulations; whether it is in vitro simulations of organs and tissue environments, or computational simulations, I regard them as important tools. I think that it is quite important to conduct animal testing only after you have narrowed down your test parameters; there is no need to test animal after animal after animal in order to understand and optimize parameters that can be reliably and easily assessed in vitro. It’s quite expensive to go to animal testing without having optimized at least some of your parameters, and frankly, I think it is quite unethical.
RF: That’s great advice. Some of our clients don’t realize that quite sophisticated bench top models can be done.
SK: In vitro simulations will never replace animal testing, but you can go to your animal model much more educated and with an optimised parameter set. Sophisticated benchtop simulations allow you to controllably study a parameter of interest either in isolation or in conjunction with other controllable parameters, without interference. In animal models, the only option is to test your device systemically with the inevitable interplay of a multi-cohort of relevant and non-relevant parameters, and with limited controllability. This makes things much more complicated for understanding the fundamental role of each one of the parameters that might be involved in the problem.
RF: I agree completely.
Read about other Cardiovascular Pioneers here.
View Dr. Korossis’ research involving ViVitro equipment and services here: