YORKTOWN HEIGHTS, N.Y.—Lab-on-a-chip technology, devices that combine several traditional laboratory capabilities such as high-throughput screening onto chips that can be just a few centimeters large, offer scientists greater freedom in terms of automation and analysis. They allow evaluation on a small scale, which is helpful for small batch analysis or when working with microscopic particles such as individual cells.
Researchers everywhere might soon be able to work with even smaller objects—ones at the nanoscale—thanks to new lab-on-a-chip technology from scientists at IBM.
With the aid of nanoscale deterministic lateral displacement, or nano-DLD, Drs. Joshua Smith and Benjamin Wunsch spearheaded development of a lab-on-a-chip technology that would enable a liquid sample to be passed in a continuous flow through a silicon chip with an asymmetric pillar array, which allows the sorting of nanoparticles by size. The pillars deflect the larger particles, but the smaller particles can flow through the array, thereby sorting them by size. The chip has already been scaled down to 2cm by 2cm.
The team was able to detect and separate particles as small as 20 nm from smaller particles, and found that exosomes of 100 nm and larger could be separated from smaller exosomes. In addition, they discovered that separation can occur in spite of diffusion, which is a key trait of particle dynamics at such small scales.
“The ability to sort and enrich biomarkers at the nanoscale in chip-based technologies opens the door to understanding diseases such as cancer as well as viruses like the flu or Zika,” explained Gustavo Stolovitzky, program director of Translational Systems Biology and Nanobiotechnology at IBM Research. “Our lab-on-a-chip device could offer a simple, noninvasive and affordable option to potentially detect and monitor a disease even at its earliest stages, long before physical symptoms manifest. This extra amount of time allows physicians to make more informed decisions and when the prognosis for treatment options is most positive.”
The team detailed their work in a Nature Nanotechnology piece—titled “Nanoscale Lateral Displacement Arrays for Separation of Exosomes and Colloids Down to 20nm”—in which they explained that “exosomes, a key target of liquid biopsies, are secreted by cells and contain nucleic acid and protein information about their originating tissue.” A particular challenge when dealing with exosomes, the paper notes, is “to sort exosomes by size and surface markers,” as exosomes can range in size from 20 nm to 140 nm.
The challenge could be worth it, however, given the potential and functions of exosomes. Joshua Smith, IBM researcher in the Nanobiotechnology group, says this advancement could enable noninvasive diagnosis and monitoring of cancer, which is the eventual goal. Exosomes, he explains, “can be found in abundance in bodily fluids such as blood, urine or saliva, and in principle, cancer cells are constantly shedding exosomes as they are very active. Therefore, by having a less-invasive and cheap way of separating out exosomes for analysis, our lab-on-a-chip technology can give physicians a view into the origin of a cancer or if a cancer has metastasized before physical symptoms appear in the patient. Also, physicians may be able to use the technology as a point-of-care device to see how the patient is doing after treatment.”
Moving this discovery forward, IBM is collaborating with scientists from the Icahn School of Medicine at Mount Sinai to continue developing the technology and test it in prostate cancer. Mount Sinai is optimistic that this technology could enable them to follow exosomes’ cell-to-cell communication, which could be useful for learning more about disease pathology and progression. The Mount Sinai and IBM teams will seek to determine if the device can register exosomes with cancer-specific biomarkers from liquid biopsies. The scientists at IBM will continue working to scale up sample volumes and develop different surface chemistries targeted toward other bioparticles like viruses, Smith tells DDNews, and will also aim to “push the size limit of particle separation to access the sub-10nm particle regime.”
Smith notes that current methods for separating nanoscale particles are “cumbersome” and require compromise—“Centrifugation and chromatography can be very precise but require expensive machinery and trained technicians, whereas gels and filter media are cheap and easy to use but are less precise and more difficult to recover sample from,” he explains. In their approach, they take advantage of IBM's experience with silicon nanotechnology, he says, as “Piggy-backing on silicon technology lends itself to high-volume manufacturing, which lowers costs and allows more ubiquitous use in medicine and diagnostic technologies. In addition, nanoscale DLD provides high-fidelity separation of nano-colloids and requires minimal training to operate. This lowers the barrier-to-entry for researchers wanting high-precision separation technology.”
As for what kind of clinical applications this technology could improve, IBM explained in an infographic that in addition to more options with exosomes, this advancement could offer “increased efficiency in purification of DNA from enzymatic reactions for next-generation DNA sequencing libraries” and also “opens the possibility of remote and affordable point-of-care screening checks for individuals with viruses such as the flu, HIV and Zika.”
“When we are ahead of the disease we usually can address it well; but if the disease is ahead of us, the journey is usually much more difficult. One of the important developments that we are attempting in this collaboration is to have the basic grounds to identify exosome signatures that can be there very early on before symptoms appear or before a disease becomes worse,” Dr. Carlos Cordon-Cardo, professor and chairman for the Mount Sinai Health System Department of Pathology, stated in a press release. “By bringing together Mount Sinai’s domain expertise in cancer and pathology with IBM’s systems biology experience and its latest nanoscale separation technology, the hope is to look for specific, sensitive biomarkers in exosomes that represent a new frontier to offering clues that might hold the answer to whether a person has cancer or how to treat it.”