By Angus Dalton
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On a scientific poster inside the University of Sydney’s School of Chemical and Biomolecular Engineering, there are two photos of blood on a strip of plastic.
In the first photo, the blood sits evenly across the surface of the strip, behaving itself. On the other strip, the blood has gathered into a dark, wet clot.
A swirl, painted in a zwitterionic substance, reveals itself by clinging on to this food-dyed water, demonstrating the water-loving properties of the zwitterions which can be used to propel blood clots.Credit: Wolter Peeters
“That’s actually human blood,” polymer scientist Dr Sepehr Talebian says, referring to the experiments run by PhD candidate Matthew Crago. “The student has to use freshly drawn blood for each experiment.”
And why the difference in blood behaviour? The plastic without the clot has been treated with a weird, magic-sounding molecule: the zwitterion.
These curious molecules are both positively and negatively charged at the same time; the word “zwitter” in German means “hybrid” or “hermaphrodite”.
Their unusual nature affords zwitterions a superpower: they are extremely hydrophillic, or water-loving, molecules. They grab hold of H2O and they don’t let go.
The scientists I’ve come to meet are trying to harness that superpower to create a watery armour around medical devices – such as artificial heart parts – that stops the formation of clots, which is one of the biggest dangers associated with some types of implants.
Here’s how they’re doing it – and why these zany molecules you’ve never heard of until now could one day save your life.
Testing two decades’ worth of heartbeats
Talebian is working with Dr Sina Naficy, director of the polymeric heart valve replacement program, to improve treatment for the 600,000-odd Australians with heart valve disease.
Damaged valves are currently replaced with pig, cow or human tissue.
“They degrade over time because these are dead tissues,” Naficy says. “Usually, between two and seven years is the period that you would have a heart valve replacement working fine, and then you have to replace it.”
Replacing the valve becomes increasingly difficult; each operation makes the body more likely to reject foreign tissue.
Dr Sepehr Talebian with an artificial heart valve developed by biochemical engineers at the University of Sydney.Credit: Wolter Peeters
“Let’s say a patient had heart valve disease since birth; by the age of 40 or so, after five replacements, literally there is no solution for them,” Naficy says.
“The body starts to reject any tissue because of hypersensitivity, and after lots of operations there’s nothing left for the surgeon to suture.”
That’s why Naficy and his collaborators began pursuing a more durable polymer-based artificial heart valve.
But the criteria for an appropriate material was strict: blood is an “aggressive” media and these valves have to survive within the body for decades.
They must be soft to allow blood to pass through with each pump of the heart, but structurally sound enough to withstand high aortic pressure without collapsing. They have to resist being eaten away by enzymes, hardened by calcification and damaged by oxidation.
“The wishlist is strict. When you put them all together, there are not many materials that you can choose,” Naficy, who co-founded a company called LevTech Lifesciences to commercialise the artificial valves, says.
So Naficy and his colleagues at the University of Akron in Ohio crafted their own polymer. Their resulting artificial valve hasn’t been tested in humans, but it’s passed a big threshold test.
The valve was placed within a machine that emulates the fluid-pumping action of a heart and stress-tested with one billion pumps. That’s about 20 years’ worth of heartbeats – the machine can pump 10 times faster than a real heart, so the experiment took two years.
But the testing machine was pumping water, not blood. And blood’s much harder to deal with. When you introduce a foreign surface into the body, you also introduce the risk of blood clots.
Dr Naficy (foreground) and Dr Talebian with a machine that recreates the pumping of a heart so they can test the durability of replacement heart valves.Credit: Wolter Peeters
The scientists’ wonder polymer needed one more magic trick.
Enter the zwitterions.
Zwitterions, biofouling, and other less weird words
Zwitterions might sound alien, but they’re ubiquitous within our bodies.
The phospholipids within the membranes of our cells are zwitterionic, meaning they have equal numbers of positively and negatively charged regions within their structure.
“That is the main, unique feature of zwitterions, this nice harmony of these positive and negative functionalities makes them overall neutral,” Talebian says.
“That neutrality is really important, because if anything is charged, it could initiate interactions with the blood. But you still want the positive and negative regions because those are the entities that interact with water.”
Coating heart valve implants with zwitterions creates a layer of water that clings to the surface of the device. That layer of water – only a few nanometres thick – creates a kind of liquid armour that prevents clots.
When stents, heart valve or implants come into contact with blood, protein can begin to build up on their surface in a process called biofouling. That triggers a cascade of chemical interactions that eventually leads to clots.
Stop this biofouling, and you rein in the clots.
“That teeny tiny layer of bound water on top of your surface actually creates a repelling force against the blood that’s coming towards an implant surface,” Talebian says.
“It’s not free, loose water; it’s actually tightly bound to the zwitterions.”
The natural zwitterions in cell membranes have a similar role; they form a barrier of water to prevent protein build-up and keep blood flowing smoothly through our hearts and other organs.
The scientists have found a way to chemically bind the zwitterions to their implant materials using UV light, like the purple lamps used to cure nail gel at a salon.
Now they’re working on finding the perfect concoction of zwitterions; too little and it won’t work, too much and the chance of clots could actually increase.
And the scientists are jazzed about broader applications of zwitterions. They could be used, for example, to coat the nanoparticles which serve as the delivery vehicles of RNA vaccines, as in Pfizer and Moderna’s COVID vaccines, Talebian says.
A different particle-stabilising substance, polyethylene glycol, is used in those vaccines but has been linked to instances of extremely rare but severe anaphylaxis.
Zwitterions may work better and avoid such reactions because they’re “biomimetic”, which means they emulate a biological molecule within our cells.
Or, put simply: nature invented it first. And now we’re catching up.
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