Device innovation is sorely needed to improve the treatment of cardiovascular disease, the world's leading cause of death. Credit: Yuichiro Chino/ Getty Images
A viscous mass of bespoke ‘ink’ is placed with precision. Under the nozzle of the 3D bioprinter, a form is beginning to take shape. At just over a centimetre across, it is round, flat and pliable, with a translucent ivory tinge. This is a prototype cardiac patch; a sliver of bioengineered material, which one day could be sutured on to the surface of an injured human heart to help repair it.
For now, this patch contains a mix of silk, for stretch, and a protein-rich extract derived from human placenta, modified to give the structure added mechanical strength. In the future, however, it could be infused with human cells, and laced with ‘off-the-shelf’ bioengineered or 3D-printed blood vessels, to create a living material that moves with the beating human heart. The artificial tissue matrix will mimic the intricate structure of the surrounding tissue, and encourage the patient’s own cells to grow into the area and regenerate it. Then, when it is no longer needed, the patch will biodegrade. “Our focus is to produce biomaterials and 3D-bioprinted artificial tissue parts that can move into preclinical and then clinical studies as soon as possible,” says bioengineer Karl Schneider, who is developing the prototypes.
The work is part of a diverse research portfolio at the Medical University of Vienna’s (MUV) Center for Biomedical Research, where a new bioprinting facility will be up and running in 2023. Bruno Podesser, who leads the centre, is a researcher and surgeon with more than 25 years of experience, and is deeply familiar with the constraints posed by current cardiovascular surgical techniques.
There are vast limitations in the choice of materials to replace small arteries in the body. If a blood vessel becomes damaged, it can sometimes be replaced with a graft taken from the patient’s own vasculature, but this is not always feasible. The same is true when a surgeon needs to do a bypass surgery on a limb or the heart. Synthetic alternatives are an option, but they often get clogged shortly after implantation, especially when repairing small, thin vessels. Larger bore grafts, which can be used to replace sections of bigger vessels, such as the ascending aorta (the part of the aorta that is next to the heart), are too stiff.
“People have been using the same plastic-based materials to make these synthetic grafts for more than 50 years,” says Podesser. “Improving the design and composition of these devices is the only way to move things forward." The Center for Biomedical Research aims to break this innovation bottleneck. But as new patches, grafts and other technologies emerge, they will need to be tested in relevant animal modelss, raising questions about how this research can be conducted as efficiently and ethically as possible.
Cardiac insights from the imaging lab
Down the corridor from the bioprinting facility, a small animal operating room (OR) sits across from the MUV’s preclinical imaging laboratory, replete with echocardiography, CT, PET and MRI scanners for the assessment of cardiac morphology, structure, function and metabolism. This new hybrid PET-MRI system will enable Podesser and his team to assess disease activity in the heart while MRI scanning provides detailed anatomic imaging and tissue characterization. “It’s really state-of-the-art,” says Attila Kiss, a researcher in the lab. “It’s very unusual to find this equipment in a preclinical setting for small animals.”
The set-up enables researchers to image the same animals across time, so they can refine their models and assess new interventions without having to use different animals at multiple time points. Using MRI, Kiss and colleagues have shown¹ that when the ascending aorta is constricted in mice, the heart also changes. This ‘adverse remodelling’ can be at least partially reversed.
The same effect observed by the researchers in animal models is seen in patients who either have long term high blood pressure or aortic valve stenosis. Critically, the team has also shown that when the constriction is mechanically reversed, the structure and function of the heart substantially improve. “This is exactly what we see in patients undergoing aortic valve replacement,” Podesser says.
A European first
Bioengineers continue to improve the biomechanics² of synthetic grafts, raising the hope that these devices will go on to replace their outdated counterparts in the human OR. Before this happens, the grafts will need to be tested in large animals³ such as sheep and pigs.
In recognition of this, the Center for Biomedical Research will soon open a large animal facility just outside Vienna. It contains a hybrid OR that combines surgery with angiograms and CT, so each animal can be operated on and imaged under a single dose of anaesthesia. There are in-house vets, nurses, radiographers and carers, as well as a barn and a meadow, where the animals will spend most of their time. “The set-up is the only one of its kind in Europe,” says Podesser.
In alignment with the centre’s ongoing commitment to replace, reduce and refine the use of animals in its research, the sheep and pigs here will be followed and imaged over time, maximizing the data obtained from each. There’s a dearth of detailed information on large animal vasculature, so with every scan, the team will record basic information about the size and shape of various vessels.
This will be fed into an open-access database. If a researcher needs to know, for example, what size graft fits the ascending aorta of a 90-kilogram pig, this information will be readily available to them. The facility, which will be open to MUV researchers and external collaborators, will also contain simulators. This way, surgeons can practice interventions in the virtual world long before they pick up a scalpel in reality.
It’s the perfect environment to test new technologies as they emerge from small animal studies, while conforming to the highest standards of humane research. At the Center for Biomedical Research, new materials and designs are being tested, and new cardiac devices are in the pipeline. Podesser is looking forward to validating them in animal studies, and then, hopefully, moving them towards the clinic and his patients. If the devices need further tweaking, his clinical experience will help to guide further refinement in the lab.
It’s an ongoing, iterative process. Cardiovascular diseases remain the leading cause of death globally, and innovations here could have untold impacts on public health. “We know, as a field, that to do better in the clinic, we have to do better in the lab,” says Podesser. “We’re working on that right now.”
This advertisement appears in Nature Index Biomedical sciences 2022 an editorially independent supplement. Advertisers have no influence over the content of the editorial articles within this supplement.