Michigan Engineering News

Two GO chips are laying on a benchtop lined with a paper towel. The chips resemble rectangular microscope slides encased in glass. The inlet line is red with crimson blood, which has also flown into the chip and completely fills the top portion of the chips' internal compartments. Along the chip, a gradient of red to gold-gray shows that the blood has only progressed halfway through the chip.

Is lung cancer treatment working? This chip can tell from a blood draw

By trapping and concentrating tiny numbers of cancer cells from blood samples, the device can identify whether a treatment is working at the four-week mark.

Experts

Shruti Jolly

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Professor of Radiation Oncology at the University of Michigan

Associate Chair of Community Practices at the University of Michigan

Sunitha Nagrath

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Professor of Chemical Engineering at the University of Michigan

Professor of Biomedical Engineering at the University of Michigan

Using a chip to process blood samples, doctors can monitor the amount of cancer cells in a patient’s blood to determine how well a treatment is working by the fourth week, according to a new study published in Cell Reports this week by University of Michigan researchers.

Such data could allow clinicians to adapt cancer treatments to patients’ needs and improve treatment outcomes.

Both scientists are wearing white lab coats, latex gloves, and safety glasses while standing in a lab. Jolly is handing a glass tube filled with crimson blood to Nagrath.
Shruti Jolly (left) delivers a patient blood sample to Sunitha Nagrath (right) to analyze in the latter’s lab. They hope to test if Nagrath’s GO chips can help clinicians notice whether a cancer treatment is working early in the process. Having this information could allow clinicians to make any necessary adjustments to their cancer treatments sooner, helping patients have better outcomes and avoid unnecessary side effects. Photo credit: Brenda Ahearn, Michigan Engineering.

“Currently, there’s typically a wait of weeks to months before we can fully assess the effectiveness of cancer treatment,” said Shruti Jolly, a professor of radiation oncology, associate chair of community practices at the University of Michigan, and a co-corresponding author of the study.

“However, with this chip, we may be able to sidestep prolonged, ineffective therapy and quickly pivot to alternatives, thus saving patients from needless side effects. This technique has the potential to shift cancer diagnostics, moving from a delayed single assessment to a more continuous surveillance and facilitating the delivery of personalized cancer treatment,” she added.

Today, clinicians use CT scans to see if a tumor shrank or grew, but only large changes in size are easily noticed. Tumor biopsies provide more exact information, but they can’t be done frequently enough to get regular updates.

A pair of yellow gloved hands hold a blue wafer, which looks like a glossy, flat circle. Three gold rectangles are arranged vertically on the wafer. Each rectangle is framed by a thin, gold line.
Part of the GO chip manufacturing process takes place in Nagrath’s lab. They start with silicon wafers, on which a tight array of gold dots have been etched into a rectangle pattern at the Lurie Nanofabrication Facility. The gold attracts the graphene oxide frame, which is added with more chemical steps in the lab. Further chemical processing attaches the antibodies to microscopically thin sheets of graphene oxide. These antibodies are what allow the chips to trap cancer cells. Photo credit: Brenda Ahearn, Michigan Engineering.

That’s why many clinicians are turning to liquid biopsies, or tests that look for signs of cancer in the patient’s blood, such as cancer cells that tumors have shed. Blood samples can be collected frequently, but they are only useful if the cells are present in high enough levels for biomedical instruments to detect. 

Lung cancer is a particular problem. Other FDA-approved tools for detecting cancer cells in blood samples have proven ineffective for monitoring lung cancer treatments—likely because they targeted a single protein on the cells’ surfaces that is less common in lung cancers, the researchers say.

“We were looking for more sensitive markers of cancer that we could use to closely monitor treatments,” said Sunitha Nagrath, a professor of chemical and biomedical engineering and one of the study’s corresponding authors.

“In some cases, only about half of cancer patients respond to the treatments, leaving the rest with poor outcomes,” Nagrath added. “Treatments may also be expensive and cause adverse reactions in some patients, so it’s important for clinicians to know early on whether a treatment is going to be effective—or whether they may be better off with a different treatment.”

Bright purple, lightning-like plasma arcs from the tip of the metal wand onto the blue chip. The plasma stands in stark contrast with the dark background and illuminates the wand, causing them to appear redder than usual.
To attach the GO chips’ covers, the engineers use a “corona wand,” which creates a high-voltage electric current that heats air into plasma. The plasma adds an electric charge to the chip that forms a permanent bond with the materials on the chip cover. The result is a tight seal that doesn’t allow any fluid to escape from the microscopic channels in the chip. Photo credit: Brenda Ahearn, Michigan Engineering.

The “GO chip” developed by Nagrath’s team, first demonstrated in 2013, succeeded where others fell short. It traps cancer cells like a piece of flypaper traps flies. But unlike fly paper, the chip only catches its target. Antibodies mounted on microscopically thin sheets of graphene oxide in the chip—which give the device its name—recognize a wide array of cancer-specific protein markers found on the surfaces of cancer cells.

As the blood is pushed through channels in the chip, the antibodies trap cells, eventually concentrating enough to work with. With the cells locked in place, the researchers can not only count them but confirm that they are indeed cancerous and determine how the cells’ biochemistry varies between patients and treatment stages.

To test that the GO chip could monitor lung cancer treatments, the researchers used it to collect cancer cells from the blood of 26 patients receiving both chemo- and immunotherapy for stage III lung cancer. The researchers took samples before cancer treatment and after the patients’ first, fourth, tenth, 18th and 30th weeks of treatment.

A thin, transparent syringe is filled with crimson blood and connected to GO chips by a thin plastic thread. The syringe is held in a gloved hand over the chips, which rest on a benchtop.
Once the GO chips are completely assembled, it’s time to add the blood samples. The researchers add the blood to a syringe, which is loaded into a programmable syringe pump. Plastic lines connect the syringe to the chips, providing a path for the blood to enter the chips. As the pump squeezes the syringe’s plunger closed, it forces blood to flow through the chip and out the other end into a waste collection tube. Photo credit: Brenda Ahearn, Michigan Engineering.

Their experiment revealed that when the number of cancer cells in a patient’s blood doesn’t decrease by at least 75% by the fourth week of treatment, their cancer is more likely to persist after treatment. The study also showed that cancer cells collected from patients whose cancer did not respond to treatment had activated genes that may have made the cancer resilient. These genes might be good targets for future cancer therapies, but further study is required to test this idea.

The research was funded by the National Institutes of Health. The GO chips were built in the Lurie Nanofabrication Facility. Shruti Jolly is also the chief clinical strategy officer for cancer services at Michigan Medicine. Sunitha Nagrath is also a co-director of Liquid Biopsy Shared Resources for U-M’s Rogel Cancer Center.

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