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Immobilized liquid surfaces prevent device-associated infections

By Joseph Bennington-Castro December 7, 2016
SLIPS image
Scanning electron micrograph images of ePTFE (clinically used Teflon) retrieved after three days of being implanted in mice infected with Staphylococcus aureus. The unmodified implant on the left accumulated S. aureus (highlighted purple), as well as red blood cells, immune system cells, and extracellular matrix material. The SLIPS-modified implant on the right did not accumulate any of this biological material. SLIPS is “slippery liquid-infused porous surfaces.” Credit: Caitlin Howell

For various health issues, such as heart or liver failure, implanted biomedical devices are, literally, life savers. Yet, bacteria can colonize these implants and form hardy biofilms, potentially leading to device-associated infections. To help put an end to this common problem, researchers at Harvard University have now created self-healing immobilized liquid surfaces that prevent bacteria from adhering to Teflon-based implanted devices. Based on a previously developed system design called slippery liquid-infused porous surfaces (SLIPS), which was inspired by pitcher plants, the new technology is comprised of a membrane of expanded poly-tetrafluoroethylene (ePTFE) and one of three fluorinated lubricants. Described recently in the journal Biomaterials, implants modified with SLIPS showed nearly 100% reduction in adhesion of Staphylococcus aureus, without causing inflammation or affecting local immune function during in vitro and in vivo tests in a rat model.

“By learning from nature about how natural systems prevent their surfaces from fouling, we can design materials that are now proven to have potential applications in the medical field,” says study co-corresponding author and materials scientist Joanna Aizenberg of Harvard University. “In particular, we can create various devices that have no bacterial accumulation, develop no infection, do not affect immune response, and allow for operation in a biological medium.”

It is estimated that more than 50% of infections acquired in the hospital are associated with medical devices. Researchers have devised various strategies to prevent such infections, some of which are used in the clinic today, Aizenberg says. Most commonly, these strategies use antibiotics, silver ions, or other substances to combat bacteria. While seemingly effective at reducing device-associated infections, these devices generally only work in the short term—they have a finite “reservoir” of antibacterial agents—and can lead to antibiotic-resistant bacterial strains. Other technologies take a structural approach (such as using nanoscale superhydrophobic surfaces), but often lose efficacy over time as secondary layers of biomolecules or minerals develop, allowing biofilm formation on top of them.

To develop a system that prevents bacterial adhesion on medical implants, Aizenberg and her team turned to nature as a guide—specifically they explored organisms that use liquid layers to prevent adhesion. The carnivorous Nepenthes pitcher plant has a porous inner surface that immobilizes water. “By creating this liquid interface on top of its surface, it makes the surface so slippery that ants cannot attach to the interface and they slide into the ‘stomach’ of this plant and are digested,” Aizenberg says. Similarly, she says, our gut uses a mucus layer to protect intestinal walls from microbial attachment and fish use a slippery interface on their scales to reduce drag while they swim.

This inspiration lead to SLIPS, in which a liquid layer coats a porous material—the presence of the liquid layer creates an interface that prevents adhesion. To create such immobilized liquid surfaces, devices must be able to physically trap liquid within a porous or nanostructured substrate and have a high chemical affinity between the substrate and liquid or lubricant. Since first developing the system design in 2011, Aizenberg and her colleagues have produced SLIPS-modified substrates for a range of applications, such as ice and frost-repellent industrial materials and anti-fouling wearable fabrics. In the last year, the researchers have developed SLIPS applications for the medical field, including SLIPS coatings that work with metals (for use on scalpels and other medical tools) or endoscopic devices that have tiny lights and cameras (requiring the coatings to work on glass and be transparent). But these applications only require slippery surfaces for short periods of time, unlike implanted devices.

To fashion SLIPS-modified implanted devices, the team began by looking at existing medical materials, settling on Teflon-membranes (specifically ePTFE), which are currently used in grafts for cardiovascular reconstruction, among other things. They then had to find a lubricant with a high affinity for the porous ePTFE material. “Since Teflon is a fluorinated material, we looked at the range of perfluorinated oils,” Aizenberg says. “We always try to use not just any lubricant, but those that are likely to be accepted by the FDA [Food and Drug Administration] later on or ones that are already allowed for some other medical application.” They chose perfluoropolyether (PFPE), perfluoroperhydrophenanthrene (PFPH), and perfluorodecalin (PFD)—PFPH has been tested clinically and PFD is currently undergoing human clinical trials in certain applications. Unlike with most other SLIPS, which require surface functionalization to adhere the lubricants to the substrates, ePTFE membranes needed only to be dipped in one of the perfluorinated oils to become SLIPS-modified because of the very high chemical affinity between the solid and lubricant.

The researchers first tested the efficacy of their “ePTFE-SLIPS” in vitro. Compared with control ePTFE membranes, ePTFE-SLIPS reduced adhesion of S. aureus by up to 99.7%. The material still held its 100-fold reduction in bacterial adhesion after being incubated in rat serum for 21 days. Tests also showed that while SLIPS reduced the ability of macrophages (white blood cells that engulf foreign bodies, such as bacteria) to accumulate on ePTFE, it did not compromise the macrophages’ ability to fight the bacteria. “Just removing bacteria from the equation is a great success, but that coupled with the fact that innate immune responses aren’t compromised is extremely important,” Aizenberg says.

They then moved on to in vivo tests with a rat model. They implanted ePTFE or ePTFE-SLIPS test samples subcutaneously and then injected S. aureus into the implant pocket a day later. Again, SLIPS prevented bacteria from accumulating on the devices. The team looked at whether the bacteria instead colonized and infected neighboring tissue and found that the SLIPS system allowed for the elimination of bacteria both on the implant surface and in the region around the implant. Furthermore, ePTFE-SLIPS significantly reduced inflammation at the implant site over seven days.

“This is interesting work,” says Morgan Alexander, a professor at the University of Nottingham who works on biomedical surfaces and who was not involved in the research. “Existing materials-based strategies, such as silver incorporation, are often ineffectual. The more potential solutions to this problem we can investigate, the more likely we are to find an effective strategy for use in humans.” And while the animal model data is convincing, Alexander says, the real test will be clinical trials. “Hopefully this pre-clinical work will get them the funding to get FDA approval for devices and the clinical trial data!”

Read the article in Biomaterials.