Implanted sensors

Developing chemical sensors that can be placed in the bloodstream or under the skin to continuously monitor oxygen, acidity (pH), or glucose levels is a major challenge for analytical chemists and biomedical engineers.

The problem is, the body responds to these foreign objects in ways that interfere with their ability to accurately measure blood chemistry. In the bloodstream, clots form on the surface of implanted sensors or blood vessels contract around them. Sensors implanted under the skin may become walled off by cells that flock to the site as part of the inflammatory response.

A University of Michigan team that previously demonstrated improved accuracy with intravascular sensors that were coated with nitric oxide-releasing polymers has promising preliminary results with a new strategy: creating polymer coatings that generate nitric oxide from components already in the blood.

"The idea we had, when we started working on this problem about eight years ago, was to try to mimic what occurs in the human body to prevent clotting on the walls of your own blood vessels," said U-M chemistry professor Mark Meyerhoff.

"Your endothelial cells---the cells that line all of your blood vessels---generate nitric oxide. The nitric oxide produced in this layer of cells diffuses back into the blood vessel walls, where it relaxes surrounding muscle cells and increases blood flow. It also diffuses into the lumen of the blood vessel, where it plays another important role: it inhibits platelet function and prevents platelets from sticking to the surface of the blood vessels."

Over the years, Meyerhoff and collaborators have developed nitric oxide-releasing polymers, then coated sensors with the polymers and implanted the sensors into the arteries of laboratory animals. "We always see an improvement in the accuracy of the sensors and fewer clots on the sensor surfaces when we use nitric oxide-releasing polymeric coatings," said Meyerhoff.

However, those materials have some characteristics that may limit their usefulness. "In some instances, the chemistry in the polymer is sensitive to moisture and heat, so whether it can be easily commercialized is one of the big issues," he said. In addition, the polymer coating must be very thin for most biomedical applications, which limits the amount of nitric oxide that can be stored and released from the thin coating on the sensor surface.

The new approach is to make polymers that generate nitric oxide from compounds called nitrosothiols found in the bloodstream. The key to doing this, the researchers found, is copper.

"It turns out that copper ions can act as catalysts to take nitrosothiols and generate nitric oxide from them," said Meyerhoff.

So the U-M team has been creating polymers that include a copper ion-containing complex. They've demonstrated that complexed copper ions do have the desired catalytic effect when incorporated into a polymer and that they remain effective even after soaking in blood for up to three days, suggesting that sensors coated with nitric oxide-generating polymers might have longer lifespans than those that release nitric oxide. Next, the researchers plan to test the new polymers to see if these materials are as effective at preventing clots as the nitric oxide-releasing polymers they developed earlier.

Other questions to explore are how much of the raw materials for generating nitric oxide are present in blood, and whether the amount varies from one person to another. "The device might work with me, but if you don't have enough of the reactive species in your blood, then it may not generate adequate nitric oxide levels and it may not prevent clotting," said Meyerhoff. To get at these questions, the researchers have developed a way of measuring the amount of nitrosothiols in blood samples, and they're working on a way to do the same thing in fluid under the surface of the skin.

Much work remains to be done, "but the concept of using immobilized copper ions is what we're putting a lot of thought into these days," said Meyerhoff. "It's a speculative idea, but if it works, it will be very exciting."