New optical glucose sensor could mean help for diabetics

Researchers at the University of California, Santa Cruz, have developed a novel optical glucose sensor that could be used to provide continuous monitoring of glucose levels in diabetics and hospitalized patients. Recently published studies showed that the sensor detects glucose under physiological conditions, giving a reversible fluorescent signal that changes intensity in response to changes in the concentration of glucose.

Bakthan Singaram, a professor of chemistry and biochemistry at UCSC, has been working on the glucose sensor for the past four years, along with visiting scientist Rich Wessling and several graduate students. The team's latest results were published in December in the international journal Angewandte Chemie.

"We are very excited about the prospects for our optical glucose sensor to be used in a viable device for continuous glucose monitoring," Singaram said.

Diabetes is a chronic disease that affects the body's ability to produce or respond to insulin, the hormone that allows glucose to enter the body's cells and be stored or used for energy. Many diabetics require insulin injections, and all must carefully monitor and manage their blood glucose levels. For millions of diabetics, this means drawing blood several times a day, usually from finger pricks. But glucose levels can fluctuate widely throughout the day, making it difficult to know when to do the blood tests for optimal control of glucose levels.

A device that can provide continuous monitoring of blood glucose levels has been eagerly sought by many research groups for more than a decade, with limited success. Singaram started working to develop a glucose sensor at the suggestion of Paul Levin, founder of Palco Labs, a Santa Cruz company that makes products for diabetics. Palco funded the first two years of research on the optical glucose sensor, but was eventually unable to continue its support.

"The support from Palco Labs carried us through the early stages when we were stumbling around and trying to figure out how to do this," Wessling said.

Singaram's group is now collaborating with a local company, Glumetrics LLC, which is developing a line of products based on the optical glucose sensor. Glumetrics was founded by Singaram's colleague Todd Wipke, a professor of chemistry and biochemistry at UCSC, but not a member of Singaram's research team.

"I thought it was a good project and wanted to see if I could put together a group of investors and a management team to take it on and develop the applications," said Wipke, who chairs the Board of Directors of Glumetrics.

The optical glucose sensor consists of a fluorescent chemical complex immobilized in a "thin-film hydrogel." The hydrogel, a biocompatible polymer similar to that used to make soft contact lenses, is permeable to glucose. The sensing system has two components: a fluorescent dye and a "quencher" that is responsive to glucose. In the absence of glucose, the quencher binds to the dye and prevents fluorescence, while the interaction of glucose with the quencher leads to dissociation of the complex and an increase in fluorescence.

Singaram's team tested the sensor by mounting it in a flow cell and circulating a solution with varying concentrations of glucose through the cell. The results showed that the system functions as a continuous glucose monitor capable of operating under physiological conditions. The sensor shows outstanding glucose response over the full range of glucose levels that might occur in a diabetic, Singaram said.

"This is the first system to show reversible optical sensing of glucose with a thin-film hydrogel. We tested the sensor under conditions that are as close as possible to the physiological conditions under which a continuous glucose monitor would have to operate," he said.

In addition to Singaram and Wessling, the authors of the recent paper include Jeff Suri, now a postdoctoral researcher at Scripps Research Institute, and graduate students David Cordes and Frank Cappuccio.

The researchers have also applied the hydrogel to the end of an optical fiber, enabling the signal from the glucose sensor to be transmitted through the optical fiber.

The application of this technology that is closest to yielding a marketable product is a catheter device, called GluCath, for monitoring blood glucose levels in hospitalized patients, Wipke said. Glucose levels must be regularly monitored in patients in intensive care units and others being fed intravenously with glucose drips. Research has shown that tight control of blood glucose levels can significantly reduce mortality of ICU patients, but the only way to do this currently is by taking frequent blood samples for analysis, which is painful for the patient and expensive for the hospital.

"The GluCath catheter is inserted into a blood vessel and gives a continuous reading, and it can sound an alarm if the glucose level goes too high or too low. GluCath should reduce pain, reduce costs, and reduce deaths," Wipke said.

An implantable glucose monitor for diabetics is the next product in the pipeline, he said. Other companies have used different technologies to develop continuous glucose monitors for diabetics, but currently there is nothing on the market that is effective enough to be used in place of the standard blood tests.

"Every conceivable method of detection has been explored, with very limited success, even after years of intensive research and development," Singaram said.

In Singaram's sensing system, glucose modulates the fluorescent signal by binding reversibly to a boronic acid component attached to the quencher molecule. Singaram's team designed the fluorescent dye (an anionic pyranine sulfonamide monomer) and the quencher (benzyl viologen with a boronic acid functional group attached). The fluorescence is stimulated by light from an LED and can be easily measured because it occurs at a distinct wavelength from the LED light.

"This technology satisfies all of the requirements for a working optical glucose sensor--it operates in the physiological pH range in blood or water, it can be stimulated by LED light, the response time is very fast, and the compounds are stable and don't degrade over time," Wipke said.

One of the biggest challenges for an implantable device is the body's tendency to encapsulate any foreign substance. Encapsulation could affect the ability of glucose to reach the sensor. If this problem can be overcome, however, an implantable glucose monitor would provide the crucial "missing link" in the development of an artificial pancreas.

Insulin pumps are already available that diabetics can use to deliver their insulin doses instead of giving themselves injections. In concept, at least, an artificial pancreas is simply a continuous glucose monitor connected to an insulin pump that is programmed to deliver appropriate doses of insulin to maintain healthy blood glucose levels.

"That is the holy grail that many people have been pursuing. It won't cure diabetes, but it would make management of the disease a lot easier," Singaram said.

Singaram's research on the glucose sensor is funded by UC's BioStar Discovery Grant program in collaboration with Glumetrics.

"It is a great example of successful technology transfer from the university to a company that can commercialize on this," Wipke said. "The collaboration has enabled the research to flourish and supported graduate student education at the university, and it has enabled the start of a new company in the Santa Cruz area."

Glumetrics is based at the UC Monterey Bay Education, Science, and Technology (MBEST) Center in Marina, where UCSC is helping to establish a community of high-technology businesses through strategic partnerships with the education and research institutions in the Monterey Bay Area.