Each year, there are almost two million healthcare-associated infections due to medical devices or implants, according to the National Institutes of Health. Latching onto the surface of a medical device implanted in the body, these bacteria trigger a foreign body reaction and lead to infection. This can lead to discomfort, patients needing more treatment, and surgery to replace the implant. To fight infection, medical devices usually have a coating that contains antimicrobial properties to fight bacteria and help reduce infection. One such coating is silver, which is traditionally quite a common material used in medical devices to help prevent complications due to its antimicrobial and antibacterial qualities, as well as being a biocompatible and cost-effective option.

The mechanism of action of nitric oxide device coatings and its interaction with the human body. Image Credit: USTAN Technology

challenge to these types of coatings, however, is that bacteria are increasingly becoming resistant to antibiotics. Not to mention that not all coatings are suitable for every device, and in the case of silver coatings, they can also run the risk of elements leaking into the body. Melissa Reynolds, Boettcher investigator and chemistry professor at Colorado State University (CSU), knows the complications of implant infections all too well; having been diagnosed with hydrocephalus as a child, she has had to have her shunt replaced multiple times due to bacteria and infections. She puts this as an undoubted influence behind her interest in the subject and her work on creating materials that interact better with the body for longer-lasting medical devices.

“To address infection, current medical devices, either release some type of antibiotic or they can release some other type of silver or other type of species that will interrupt or kill bacteria on the surface,” she explains. Reynolds also points to recent work on hydrophilic coatings that cause bacteria to almost “bounce” off the surface.

Fighting infection

With this in mind, researchers have been investigating different coatings that could prevent and fight infection. In a joint effort between researchers at CSU and the University of St Andrews in Scotland, they combined their metal-organic frameworks to develop a flexible antimicrobial material that slowly releases nitric oxide into the body. “We were interested in how we could mimic what the body does to produce nitric oxide in the right amounts so that we could use it for beneficial things,” explains Russell E Morris, Bishop Wardlaw professor, School of Chemistry, University of St Andrews.

Nitric oxide offers several benefits to the body, including controlling blood pressure by relaxing blood vessels, preventing blood clots inside blood vessels and is the first line of defence against bacteria. “If you cut yourself, one of the first things the body does is produce some nitric oxide to kill the bacteria,” Morris continues. “So, we’ve been looking at various different ways of either storing and delivering or producing nitric oxide from actual materials for medical devices, whether it be dressing on wounds or catheters that go into the bloodstream.” While some of these are short-term, longer-lasting medical devices such as indwelling catheters or surfaces that might attract bacteria could benefit from this material.

At CSU, Reynolds and her students discovered that they could prevent bacteria from sticking to surfaces over a prolonged period of time through a metalorganic framework technology that could be an additive for medical devices. “Unlike drug-eluding coatings where eventually the drug runs out because it has to be eluted to have it in effect, ours just keeps on going,” she adds. By combining the research from both universities, both teams have combined their two frameworks to create a single thin-filmed membrane that can release nitric oxide slowly over an extended period and have long-term NO generation from the catalytic MOF. This collaboration was published in ACS Applied Materials & Interfaces, ‘Mixed Metal-Organic Framework Mixed-Matrix Membranes: Insights into Simultaneous Moisture-Triggered and Catalytic Delivery of Nitric Oxide using Cryo-scanning Electron Microscopy’, with both Reynolds and Morris authors on the paper.

Antimicrobial coatings provide a non-drugbased route to device infection prevention. Image Credit: USTAN Technology

MOFs (metal-organic frameworks), as detailed in the paper, are porous polymers that Morris describes as “sponges” that can soak up gases. “MOFs are probably some of the most exciting types of material developed over the last 25–30 years or so,” says Morris. “And we’re interested in using them to act like mini gas tanks to deliver the gas the body uses to do lots of things.” By delivering nitric oxide to help kill bacteria from the material’s reservoir, which is great for short-term applications. But once that runs out, Morris continues, the materials act as a catalyst to produce nitric oxide at the surface of the materials, which keeps it protected from bacteria.

“What we have found is that while we do kill the bacteria that adhere to the surface, we are killing everything around in the whole body because we are having that localised effect,” adds Reynolds. This is a real benefit, she explains, as the coating offers targeted treatment to impact the root of the problem with no worry of systemic side effects. Follow-up studies are needed, however, to determine what happens to additional bacteria and whether they become more susceptible to antibiotic treatment she explains, but the main focus for her is localised treatment.

An additional benefit that both point to is its anti-platelet activity. “[If] you put something into the blood, it tends to set off the platelets and start clots – nitric oxide stops that happening,” says Morris. Using just one technology, the antimicrobial coating can release and produce nitric oxide on the surface of a medical device to fight bacteria and prevent infection while also preventing platelet activation and the clotting process.

Nothing new

The antimicrobial coating offers a non-drug-based route to prevent infection from medical devices due to its specific mechanism. “This is not a drugbased approach because we’re not eluting any drugs out of the surface,” Reynolds emphasises. “We’re not introducing anything into the body that’s going to go into circulation and cause any type of toxicity because there is nothing in circulation at a measurable level.”

“It’s one that’s been around for millions of years and biology that still works, right? So, it’s less prone to drug resistance,” adds Morris. This is partly why Reynolds believes it’s a safe technology, as there is no additional concern over where the drug or active agent goes after it has done its job, whether it’s functioning correctly and at the surface and if there are any side effects. That is not to say that the MOF doesn’t work as a drugeluting material, as Morris points, out, as various drugs can be stored inside the material’s pores and deliver drugs for various applications.

As with any material though, there are some challenges. While Reynolds is quick to point out that with the MOF they are working with, the material and device do not have to deal with delamination like other coatings where they are made from a different material from the device. “That’s another advantage; we aren’t trying to add a material to another,” she says. “We can actually make one functional device out of the materials that are already used.”

Despite Reynolds’ confidence, Morris points out that with any new medical device, it still needs to get through all the different efficacy and safety trials. “There are lots of things we’ve got to do. It’s still at a stage where we know these materials work really well in the lab,” he continues. “Now the next stage of course is to prove that they work really well out in the real world in real people, so that’s obviously a big challenge.”

Challenges aside, the collaboration from both universities has exciting potential for tackling medical device infection in a localised way. With both Reynolds and Morris expecting the coating to combat these types of bacterial infections and complications in a big, non-drug-based approach, their antimicrobial material could be a powerful weapon in medical device coating’s arsenal.