Tiny needles yielding big results

Microneedles measure only two to three times the diameter of human hair and about a millimeter long. But their impact is significant, from helping U.S. service members in the field diagnose infections earlier, to helping individuals monitor their own health. Sandia is at the forefront of microneedle research. A microneedle is a minimally invasive way to sample interstitial fluid from under the skin. Interstitial fluid shares many similarities with blood, but there is still much to learn about it.

“When we started work in this field in 2011, our goal was to develop microneedles as a wearable sensor, as an alternate to blood samples,” said Ronen Polsky, who has led Sandia’s work in microneedles. Microneedles can access interstitial fluid for real-time and continuous measurements of circulating biomarkers.

“People wear continuous glucose monitors for blood sugar measurements. We want to expand this to a whole range of other conditions to take advantage of this minimally invasive sampling using microneedles,” Ronen said.

A collaboration between Sandia and an external partner has helped speed up interstitial fluid extractions. That could help get microneedle sensors to the market quicker for other uses including viral detection and electrolyte levels. Sandia recently received a patent for a microneedle sensor that Ronen and his team are trying to commercialize.

“We basically will bring the diagnostic lab to the patient in the form of a wearable device,” Ronen said.

Sandia has current partnerships with SRI, Adaptyx Biosciences and the University of California, Berkeley, to expand microneedle work.

Faster extraction

One of the projects with SRI, an independent nonprofit research institute, has significantly improved the extraction of interstitial fluid. “The previous technique was highly variable. It took one to two hours to get enough fluid to do the analysis,” Ronen said.

That technique involved using four or five arrays of needles, each with five needles.

“Through our new project with SRI, we improved the technique using a single microneedle to get enough fluid for a test in about 10 minutes. The new technique works faster, and we get higher volumes of fluid,” Ronen said.

The microneedles penetrate the outer skin layer, but they don’t reach nerve endings and are hollow. Engineers made a couple of changes to improve the extraction technique, including modifying the shape of the needle holders, which are 3D-printed by year-round intern Mychal Taylor at Sandia’s Advanced Materials Laboratory.

“With microneedles, we have engineering and comfort concerns, which play into how we design them. We get feedback from participants as we’re updating the design,” said Adam Bolotsky, an engineer in Sandia’s Biological and Chemical Sensors group. “We believe we’ve found the optimal depth for collecting the most fluid with the least discomfort.”

Viral or bacterial?

Will Brubaker is the principal investigator for SRI on the microneedles project. He said improving the interstitial fluid extraction method helps potentially expand the use of microneedles.

“When we collect more samples in a shorter amount of time, we can recruit more people to these kinds of studies. The improvement in the collection method opens up a lot of doors to other applications,” Will said.

One such application involves using microneedles to distinguish between bacterial and viral infections. It’s another project that Sandia and SRI are collaborating on.

“Making a distinction as to whether an infection is bacterial or viral would help doctors make informed decisions much quicker to get you treated at the earliest possible stage,” Ronen said.

The Defense Threat Reduction Agency is funding the project.

“It’s a potentially useful diagnostic for a service member who is feeling sick and symptomatic,” Will said, adding that the test is a step toward a device that could perform continuous health monitoring using interstitial fluid. He said there’s still a lot of work that needs to be done before seeking Food and Drug Administration approval. “There’s a very clear place where this test could eventually be used for the general public,” Will said.

The current work with SRI is expected to wrap up in October.

Adaptyx Biosciences

Sandia is also working with Adaptyx Biosciences under a Cooperative Research and Development Agreement. Adaptyx is hoping to get a better understanding of what biomarkers are in interstitial fluid.

“We want to broadly understand the components in interstitial fluid and how those components correlate to blood measurements. We’re leveraging Sandia’s existing technology for foundational physiological studies,” Alex Yoshikawa, co-founder of Adaptyx, said.

As part of this collaboration, Sandia is extracting interstitial fluid on-site from volunteers using the improved method developed with SRI.

“It’s much easier to recruit volunteers who only need to dedicate 15 minutes of their time versus two hours,” said Sandia’s Brittany Humphrey, who coordinates and oversees the extractions. “The extraction basically requires little to no work on their part.”

Adaptyx is analyzing the fluid collected with the goal of developing continuous monitoring devices for public use, Alex said.

Electrolyte sensors

Sandia also has a partnership with the University of California, Berkeley, to develop microneedle electrolyte sensors with professor Ana Arias and graduate student Carolyn Schwendeman.

“In this case, we are functionalizing the microneedle to be sensitive to electrolytes such as sodium, potassium or calcium,” Ronen said. Work just started on the second year of the three-year-long project. Continuous electrolyte monitoring, like a wearable glucose meter, could help manage cardiovascular functions, hydration levels and electrolyte imbalances for a variety of conditions.

“Studying interstitial fluid is not easy. Sandia has made a mark in this area, and we are known as world leaders for this work. It’s turned into this interdepartmental collaborative effort with a lot of other people,” Ronen said.

A closer look at the whys behind Sandia’s microneedle successes

Listening to how the end-user could use microneedles is part of the reason for Sandia’s success in this field – especially in soldier defense.

“We’ve had amazing interactions with customers and sponsors,” said Ronen Polsky, who leads Sandia’s microneedle work. “We have traveled to special operation commands of the military. A Navy Seal Medic explained what kind of medical response equipment they have available, and what they need. We learned directly how the Sandia technology had to be adapted for military use in the field, as opposed to making a sensor for commercial use.”

Ronen said management has been key to those interactions and helping guide research for use-case scenarios.

Adam Bolotosky, an engineer who works closely with Ronen, said another key to success is collaboration among Sandians.

“We had quick turnarounds on printing needle fixtures so we could work on optimizing extractions of interstitial fluid,” Adam said. “Brittany Humphrey was getting volunteers and performing extractions. Then she was providing extraction output data that helped us come up with the final design of the microneedle holders. A great team effort helped us get tangible results.”

Ronen said the interdisciplinary effort, which is often hard to find in academia and private industry, stands out to him. “This really is a cross section of chemistry, engineering and biology. Interdisciplinary collaboration is promoted within Sandia’s culture,” he said.

He added that Laboratory Directed Research and Development is another reason for innovation and optimization of microneedles.

“There’s a huge sense of satisfaction when the work we do is taken out of Sandia. You can see it in research reports around the world and when people contact us that they want to work together. We’re helping expand this work to the broader science community. It makes us extremely happy with what we’re doing,” he said.