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U Michigan Researchers Develop Wearable Microfluidic Device for CTC Detection, Monitoring


NEW YORK (360Dx) – A group of researchers led by the University of Michigan has developed a wearable device that can continually collect circulating tumor cells (CTCs) in an individual's bloodstream and monitor the amount of cancer cells over time in the person.

While only tested in canine models at this point, the researchers believe that clinicians could potentially use the microfluidic chip-based system attached to a vein to detect cases of cancer and track the number of cancer cells in patients with minimal residual disease and relapse.

According to U Michigan breast cancer research professor Daniel Hayes, he and his colleagues have "made a miniature cytapheresis machine based on a dual-lumen system that is about the size of an iPod. The tool will give us more cells to … genotype and phenotype, which is our real interest here."

In a proof-of-principle study published earlier this month in Nature Communications, Hayes and his team collaborated with Colorado State researchers on an in vivo method using an indwelling intravascular aphaeretic system to continually isolate and capture CTCs from a peripheral vein.

According to Hayes, the four-part system consists of a microcontroller, a peristaltic pump, heparin injector, and a microfluidic CTC capture chip. Using a dual-lumen catheter, the researchers route whole blood through the CTC capture module and back into the systems' circulatory system.

Hayes explained that the ends of the catheter are connected to a silicone tube, treated with anticoagulation reagents, and forms a closed loop structure. The peristaltic pump drives the blood flow with a pre-programmed flow rate and overall processing volume. The system also implements a flow rate sensor to monitor and maintain a constant flow through the feedback loop.

To prevent blood clots during the collection process, the module continually infuses a small amount of heparin into the blood through an injection pump.

Designing the herringbone graphene oxide CTC microfluidic chip (CTC chip) to maximize the contact frequency of cells, the researches coated the CTC chip's functional graphene oxide sheets with anti-EPCAM antibodies on its surface to capture cancer cells. Hayes said the extraction and capture techniques are based on Menarini-Silicon Biosystems' Cellsearch technology. Hayes noted that he currently receives royalties for his past efforts to develop the tool. However, he explained that the new system uses antibodies to carry the cell along the chip, rather than the magnetic beads used in Cellsearch.

"At the same time, we've designed [the chip] so that if we have a better technique to capture cells in the future, as long as it’s the same size, we're agnostic with the best way to grab the cells," Hayes said.

In the study, the researchers initially evaluated the CTC chip's ability to capture fluorescently marked cultured human breast cancer cell lines. Comparing the CTC chip to a flat channel graphene oxide chip, the group found that the CTC chip maintained a higher target yield and improved cell surface interactions.

After validating the approach on ex vivo samples, Hayes and his team tested the device's feasibility in three canine subjects. Testing on one beagle at a time, the group sedated and injected 20 million fluorescently marked human breast cancer (MCF7) cells into the veins of each canine.

Hayes explained that his team selected canine models because they had large enough vascular sizes to allow easy and dependable access to the subjects' veins, as the researchers sought to collect as many MCF7 cells as possible.

Attaching the device to the canine's veins, the researchers then identified and tracked the amount of MCF7 cells in the dog's bloodstreams over two hours. In order to estimate the cell distribution in the bloodstream, the researchers sampled blood via venipuncture before and after one, five, 15, 30, 60, and 120 minutes following injection. They processed the blood through the CTC chip ex vivo at a flow rate of 100 μl per minute, quantifying the cells using positive cytokeratin staining.

"Over time, as we expected, the number of cells went up over the first hour," Hayes explained. "The tumor cells typically disappeared within two hours since the dog's immune system normally eliminated the xenographic cells after a while."

To compare and evaluate the system's ability to extract CTCs, the team drew 2 ml of blood through the catheter every 20 minutes and searched for the presence of MCF7 cells using ex vivo CTC capture.

The study authors noted that despite the drop in CTC count over time, they were able to detect the cells throughout the experiment's duration and did not observe any short-term or long-term adverse issues in the animals. Hayes also noted that the group performed the test through an internal revenue board at Colorado State to ensure animal safety, in addition to monitoring the subjects for several weeks following the experiment.

In total, Haynes and his colleagues isolated and enumerated 212 MCF7 cells from the 6 ml of whole blood collected in 1 ml increments over two hours. In contrast, the team collected a total of 762 MCF7 cells in vivo using the CTC chip system — or about 3.5 times as much in the blood draw — over two hours.  

The researchers noted that cell viability significantly decreased when they applied flow rates higher than 200 μl per minute. The higher flow rate became a limiting factor of the CTC chip, and Hayes noted that the chip currently cannot handle a dramatic flow rate increase: Either the cells don't have enough time to stick to the antibodies or the chip will break down.

"We're working on a way to get around that limitation, as right now we are looking at about 2 percent of the dog's total blood volume," he said. "In humans, that would [only] give us about 200 ml, but we're trying to get to 2 liters over a couple of hours."

In order to minimize CTC saturation and clogging, Hayes noted that fellow author and U Michigan chemical engineer professor Tae Hyn Kim developed a clever method to instantly replace the capture module by swapping out the chips while maintaining sterility. At the same time, Hayes acknowledged that his team is attempting to figure out a way of avoiding clogging issues without having to manually swap out the chip.

In addition, Hayes noted his colleagues will need to understand how CTCs circulate within the subject's bloodstream. They believe that the cells are being released from their injection point episodically, rather than in a continual flow that can tracked normally.

"We don't think it's a constant function, but rather increases or decreases over time for a variety of reasons," Hayes explained. "If this pans out, we hope to monitor the release of cells over hours, if not days, and ultimately better understand how cells are released from original sites and move to other areas."

Hayes said that the group will continue to perform animal studies in order to optimize the platform for eventual human clinical use. The team will try to increase the collection time and volume of blood that it can interrogate so that it can collect a higher number of cancer cells.

"We're going to try to increase the number of cells we capture up to the thousands in these experiments," Hayes explained. "Once we can do that, we'd perform additional dog studies to see if its effective and safe, and hopefully apply it in human studies."

Despite being unable to file patents on miniaturizing the apheresis method used to extract the CTCs, Hayes noted that his group is filing for certain limited-use patents for various components of the system. His team is currently in preliminary discussions with the US Food and Drug Administration regarding use in potential clinical trials.

However, Hayes highlighted that the tool would only be for diagnostic and prognostic use, rather than for therapeutic options. He envisions that a patient would eventually be able to walk into a doctor's office, have the IV strapped to their arm, and then find out about their CTC levels identified within a couple of hours.

At the same time, Hayes emphasized that the tool is nowhere ready for clinical use. He estimated that his team would need at least another four to five years to develop a product ready for clinical testing.

"Right now, [the platform] would be for people who already have established metastasis and figuring out how to better treat those patients," Hayes said. "In the short run, we want to identify patients who have been treated for a cure, who seem to be doing well, and see if we can detect imminent recurrence or dormant cells that we could do something about."