Among many interesting talks at this year’s Till and McCulloch Meetings in Toronto, Canada, there were a couple related to biomaterials, which I’d like to focus on. In the first talk, professor Milica Radisic, University of Toronto, talked about two recent developments in her lab. Her research focus is on designing biomaterials that can be used in regenerative medicine strategies for cardiac tissue repair.
In a classic tissue engineering setting, researchers combine cellular populations and biomaterials to develop a specific tissue in the lab to replace or restore an injured tissue in patients. However, an abundant source of cells is needed and, in the case of human heart cells or cardiomyocytes, there aren’t any available. Adding to the challenge, cardiomyocytes are not easy to differentiate, or isolate and proliferate from a human heart biopsy.
Over the years, scientists have overcome this hurdle by producing millions of cardiomyocytes in vitro by using stem cells and mimicking pathways that result in cardiac cell development in an embryo. They do this with timed applications of growth factors to the cell cultures inside devices such as bioreactors. However, this approach results in immature cells that are smaller in size and have less striations or sarcomeric structures. An adult cardiomyocyte is a sheet like cell with well-developed striations on it called sarcomeres. Human heart cells are elongated, and they follow capillaries in parallel, and each cell is only a few tens of microns away from a nearby vessel.
Professor Radisic’s team has created a microdevice called the Biowire to recreate some of the aspects of the cardiac tissue. The Biowire is a poly(dimethylsiloxane) (PDMS) polymer seeded with cardiomyocytes derived from human pluripotent stem cells. This polymer is formed around sterile surgical sutures with collagen gels added to serve as cellular protective matrix.
When grown on this construct, the cells align along the suture with a very high cell density. The size of the Biowire stabilizes around 600 micrometers and it beats both continuously and in response to electrical stimulation or drugs, such as epinephrine. The cells grown on the Biowire have a closer morphology to heart cells compared to cells grown in cultures with growth factors; they are bigger, have a rod like appearance and very well developed sarcomeres.
An important physiological property of cardiac cells is their coordinated beating. The activities of a microscopic potassium ion channel has a major role in this ability and can be measured in the lab. Compared to the cells grown in growth factors alone, Biowire cells show a much higher activity of this channel: 20% of the normal value, compared to 1%.
To capture more physiological aspects of cardiac tissue, the team decided to redesign the Biowire with two parallel wires made of biodegradable elastomere polymer. They also replaced PDMS with plastic, since it has been shown to absorb small biomolecules and proteins from the solution, which can bias the results of the study for drug screening. They used a 96 well plate with electrodes in each well to be able to introduce electrical stimulation. The tissue will be in the middle of each plate. This design has been picked up by Tara Biosytems to be commercialized.
Shape Memory Scaffold
The second innovation Dr. Radisic talked about was a shape memory scaffold that can be injected into the desired tissue through a minimally invasive approach. The scaffold is seeded with cardiomyocytes derived from pluripotent stem cells and delivered to the heart tissue in an animal model.
The designed scaffold ensures connectivity between all the cells that are seeded, and has immediate function upon delivery – two very important factors in cardiac tissue engineering. The cells seeded on this scaffold remain viable with unchanged shape and electrophysiological properties. This construct has been successfully inserted into a pig model and, after six hours post insertion, host cardiac cells covered the scaffold.
Furthermore, inspired by the hooks and loops design of VelcroTM, Radisic’s team has created a new generation of 3D scaffolds. They designed a honeycomb shaped polymer to contain structures similar to tiny hooks and were able to stack the layers on top of each other. Interestingly, in a multilayer cardiomyocyte seeded construct, all the stacks have the ability to beat together and on their own, similar to what is seen in cardiac tissue. The disassembly of the construct did not have any effect on the shape, function and viability of the cells. You can read more about this innovation in the original paper published in Science Advances.
The next step in these developments would be long-term in vivo studies in animal models.
If you are wondering about vascularization of the scaffold system when stacked, you will have to wait to hear about another new technology, designed by her team, called the Angiochip. I’m hoping Dr. Radisic talks about the Angiochip at the 2016 Till & McCulloch Meetings. See you there!
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