In 2007, Mehmet Toner and Daniel Haber and their collaborators at Massachusetts General Hospital and Harvard Medical School developed a microfluidic device capable of trapping rare circulating tumor cells (CTCs) from the blood of cancer patients. Since then, these investigators, working with Harvard Medical School colleague Shyamala Maheswaren, have shown that captured CTCs can be used to characterize tumors from patients with lung and prostate cancer. Based on those initial results, this team and others are working diligently to determine if CTCs can serve as early indicators of disease and therapeutic efficacy.
Going forward, those efforts should become easier thanks to the development of a redesigned version of the CTC-Chip that appears to be more effective and should be easier to manufacture than the original. Called the HB-(herringbone) Chip, the new device may also provide more comprehensive and easily accessible data from captured tumor cells. The device's construction and use are described in a paper published in the Proceedings of the National Academy of Sciences.
"The original CTC-Chip worked wonderfully in a small-scale laboratory setting, but limitations arose when we attempted to increase production for larger clinical studies. The new device performs as well or better than the previous technology with several additional benefits," says Shannon Stott, one of the authors of the PNAS paper. "It also was able to capture something that had never been seen using either the CTC-chip or the most prevalent previous technology - small clusters of CTCs, the significance of which we need to study."
CTCs are living solid tumor cells found at extremely low levels in the bloodstream. Until the 2007 development of the CTC-chip by researchers from the MGH Cancer Center and the Center for Engineering in Medicine, it was not possible to get information from CTCs that would be useful for clinical decision making. In the original CTC-Chip, patient blood samples pass over a silicon chip covered with microscopic posts coated with an antibody that binds to most tumor cells. Not only did this design prove challenging to manufacture reliably and cost-effectively, but the smooth flow of blood around the microposts also limited the number of CTCs that came into contact with the antibody-covered surfaces. In their search to increase the capture of CTCs, the researchers found that passing samples through a chamber lined with a herringbone pattern of grooves - an approach developed elsewhere for quickly mixing independent streams of fluid - would generate a more chaotic flow that could significantly increase the number of captured cells.
The HB-Chip can also process larger-volume blood samples, increasing the ability to find rare CTCs. The microchip is mounted on a standard glass slide, which allows the use of standard pathology tests to identify cancer cells; and the device can be easily opened, giving access to CTCs for additional testing and growth in culture. Experiments comparing the HB-Chip to the CTC-chip found the new device captured more than 90 percent of cancer cells introduced into blood samples - a 25 percent improvement over the older device. Tests of samples from cancer patients found the redesigned device at least as effective as the original.
The HB-Chip also captured clusters of 4 to 12 CTCs from several patient samples but not from samples to which cancer cells had been added. No previous technology for capturing CTCs has ever found such clumps of tumor cells. "These clusters may have broken off from the original tumor, or they might represent proliferation of CTCs within the circulation," explained Dr. Toner, a member of the MIT-Harvard Center of Cancer Nanotechnology Excellence Alliance, one of nine such centers funded by the National Cancer Institute's Alliance for Nanotechnology in Cancer. "Further study of these clusters could provide valuable insight in the metastatic process."
This work, which is detailed in a paper titled, "Isolation of circulating tumor cells using a microvortex-generating herringbone chip," was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal's website.