There’s a reason that polyethylene glycol (PEG) is used in so many biomedical and medical device applications: it’s a highly biocompatible polymer that doesn’t biofoul. That is, it doesn’t allow contamination by microbes such as bacteria.
However, there are structural and chemicalrelated properties of PEG that create instabilities – such as being easy to oxidise, possessing a low thermal stability, and being immunogenic (it can set off the body’s natural defences, causing an antibody response). This limits the lifetime of PEG-based devices – which is not ideal for a lot of applications, especially medical implants that go inside the body. Selecting other materials that are biocompatible and robust enough to withstand the biofluids and testing biological environments inside the body has been a challenge. “Non-specific adsorption of biomacromolecules on material’s surface – such as biofilm formation starting with the adsorption of organic molecules followed by bacteria – is a challenge for many materials being used in medical devices,” says Peng Zhang, professor in the Department of Polymer Science and Engineering at Zhejiang University. “PEG is the most studied nonfouling material for biological applications, but due to its structural instability and immunogenicity, its in vivo applications are limited in the long term.”
Zwitterionic polymers have emerged as a good option for overcoming the shortcomings of PEG in medical devices as they have an enhanced stability and high biocompatibility. Zhang notes that “zwitterionic polymers have gathered a lot of attention over the last couple of decades as the next generation of non-fouling materials for biomedical applications”.
What are zwitterionic polymers?
Zwitterionic polymers are a specialist type of polymer which have oppositely charged groups within the repeating unit of polymer. These oppositely charged groups are equally distributed at the molecular level along the chain of the polymer, meaning that zwitterionic polymers still have an overall neutral charge (i.e. a balanced molecular charge).
Plus, because they readily interact with water, this “forms the foundation for a range of exceptional properties, such as resistance to protein adsorption, promoting the stability of proteins, microbial resistance, high ionic conductivity, pH-responsiveness, and lubrication properties,” says Zhang. “Because of these properties, zwitterionic polymers are mainly used as surface coatings for medical devices. They are used for anticoagulant, anti-infection, and lubrication purposes”.
There are also several types of zwitterionic polymers, such as polybetaines, amino acid-derived zwitterionic polymers, and mixed charge pseudo-zwitterionic polymers. The types most used in medical devices are polysulfobetaine (PSB), polycarboxybetaine (PCB), and phosphorylcholine (PC)-based zwitterionic polymers (such as PMPC) because they all exhibit a good biocompatibility, strong hydrophilicity, strong resistance to non-specific adsorption, and anti-fouling capabilities. While the common polymers share key properties, they all also bring their own specific properties to a medical device (these vary from polymer to polymer and device to device) – which is why many different materials are used today. Thanks to the range of zwitterionic polymers available, they can be integrated into a wide range of medical devices to reduce the reliance on PEG.
A superior surface
The reason for using zwitterionic polymers so widely is directly related to their fundamental properties. And it’s these which set them apart from conventional PEG materials. For one, the regularity of cationic (positively charged) and anionic (negatively charged) groups along the polymer chain means that zwitterionic polymers retain water via ionic solubilisation (an ability that allows the polymer to absorb and ‘trap’ water in its polymer network using the groups on its surface).
PEG binds to water via hydrogen bonding methods, but the interactions in zwitterionic polymers provide a much better resistance to non-specific adsorption from proteins and bacteria. “Protein adsorption is the first step of many biofouling events, such as thrombosis, biofilm formation and foreign body reaction,” says Zhang. The anti-protein and anti-bacteria properties in zwitterionic polymers stem from their surface properties, he explains. “Zwitterionic polymers are super hydrophilic and super-biocompatible. They’re the best materials known to resist the nonspecific protein adsorptions at the material-tissue interface and have better surface hydration properties than PEG.”
Zwitterionic polymers have good anti-fouling properties because their enhanced surface hydration properties lead to superhydrophilicity. With water molecules held closer to the surface of the polymer, it makes it more difficult for proteins and bacteria to stick to that surface. This is why fouling occurs more in materials that have hydrophobic properties, as there is a drier solid interface that can easily be adhered to. Due to their positive and negatively charged regions, zwitterionic polymers have an enhanced electrostatic interaction, Zhang explains. “This improves the hydrogen bonding between water molecules and hydrophilic charged groups in zwitterionic materials, allowing water to be held more strongly…this strong hydration is key to their non-fouling properties”.
The overall neutral charge of zwitterionic polymers plays a role here, too, as adhesion is favoured in materials with a net charge. This is because there are more active sites to form electrostatic interactions, hydrophobic interactions, and Van der Waals interactions (intermolecular forces that are based on attraction and repulsion between molecules and atoms).
Improving medical devices
The versatility of zwitterionic polymer structures, coupled with their excellent superhydrophilicity, are useful for a number of medical devices used both inside and outside the body – and particularly for devices that directly interface with blood and other biofluids.
“All devices in contact with blood can use zwitterionic polymer surface coatings,” says Zhang. This is because these devices – like stents, catheters, and ventricular assist devices (VADs) – need to interact with blood without causing toxicity, a property called haemocompatibility. Zwitterionic polymers have been shown to inhibit thrombosis, control the degradation rate of stent coatings, and prevent the corrosion of stent alloys compared to other materials. Meanwhile, their haemocompatibility has helped in the development of better artificial vascular grafts that are not affected when they contact with blood – other coatings, such as oligo(ethylene glycol) (OEG), have allowed blood to coagulate, leading to thrombosis. Plus, the surface properties of zwitterionic polymers have also helped to prevent the adsorption of non-specific proteins in artificial heart valves.
This is helpful for extracorporeal membrane oxygenation (ECMO) devices, too – these are respiratory support systems that pump blood through an artificial lung and back into the patient’s bloodstream. So, they’re constantly in contact with blood. “Zwitterionic polymer coatings resist the protein adsorption and platelet adhesion from human plasma, without the coating having an effect on the permeation of oxygen in the gas filtration membrane,” says Zhang.
Another system in contact with blood is dialysis machines. Here, zwitterionic polymers have shown an ability to decrease cell adhesion and reduce protein adsorption, which leads to improved protection against toxins. They could also increase utilisation of VADs, which Zhang notes are often not an option due to their low haemocompatibility.
Other implantable medical devices could benefit from zwitterionic polymers, too – such as neuroprosthetics. “The low fouling, anti- [foreign body reaction] properties allow zwitterionic polymers to be used in implantable neuroprosthetics, to improve their performance and reduce inflammation to the brain once implanted,” says Zhang.
Implantable biosensors, such as glucose sensors, could also benefit. “For biosensing and detection, preventing non-specific protein adsorption increases the signal-to-noise ratio and improves the sensitivity of different biosensors,” Zhang explains.
Another application for zwitterionic polymers is improving the performance and biocompatibility of different drug delivery vessels. Zwitterionic polymers can improve anti-cancer drug delivery because their anti-fouling and pH response properties enable the vessels to stay in the body longer, which in turn allows them to target the tumour properly while inhibiting its growth. Zwitterionic polymers also enhance cancer diagnosis processes by improving different medical imaging approaches – such as CT scans, MRI, and optical imaging. The zwitterionic coating prevents protein absorption on the contrast agents used in tumour imaging, which enables the agents to last longer in the body. This makes them easier to image.
Then there’s ionic skins, which provide non-invasive health monitoring and diagnosis: zwitterionic polymers can be combined with hydrogen bonding networks to create stretchy, flexible materials that function as a wearable ‘skin’. Here, the strong hydration properties of the polymer surface can be used to form ion migration channels using an applied electric field. When this field is applied, cations and anion-resistant ions can be separated easily within the channel, ensuring the skin has a high ionic conductivity, and therefore, a higher sensitivity when monitoring.
Finally, among other things, “zwitterionic polymers are being used to improve contact lenses, to mitigate their surface contamination and as a lubricating surface in artificial joints,” says Zhang. Their superhydrophilicity and anti-fouling properties prevent bacterial contamination and inflammatory reactions during use, making the lenses last longer.
More polymers on the market
While there are many different types of zwitterionic polymers, they’re increasingly being used to improve the capabilities and longevity of various medical devices.
But when talking about disrupting the status quo – in this case, using PEG – we also have to talk about the commercial and clinical potential of new materials. Indeed, the only disadvantage of zwitterionic polymers that Zhang could think of is the cost and difficulties in processing them. Zwitterionic polymers are good coating materials, he says, but available coating technologies “may not always be [sophisticated] enough to ensure that the final coating performs to its potential”.
Some devices with zwitterionic polymers have already made it to market, yet others are still a work in progress, Zhang adds. “Most of those [on the market] use PMPC polymer, as PMPC was commercialised two decades ago. Other types of zwitterionic polymers are relatively new, and I believe they will be successfully commercialised soon.”
With the advantages of these materials gaining steam, it probably won’t be long before we see more of them in real-world settings.
