Instead of searching for a needle in a haystack, what if you were able to sweep the entire haystack to one side, leaving only the needle behind? That’s the strategy researchers in the University of Georgia College of Engineering followed in developing a new microfluidic device that separates elusive circulating tumor cells (CTCs) from a sample of whole blood.
CTCs break away from cancerous tumors and flow through the bloodstream, potentially leading to new metastatic tumors. The isolation of CTCs from the blood provides a minimally invasive alternative for basic understanding, diagnosis and prognosis of metastatic cancer. But most studies are limited by technical challenges in capturing intact and viable CTCs with minimal contamination.
“A typical sample of 7 to 10 milliliters of blood may contain only a few CTCs,” said Leidong Mao, a professor in UGA’s School of Electrical and Computer Engineering and the project’s principal investigator. “They’re hiding in whole blood with millions of white blood cells. It’s a challenge to get our hands on enough CTCs so scientists can study them and understand them.”
Leidong Mao (right) and graduate student Yang Liu stand in Mao’s lab at UGA.
Circulating tumor cells are also difficult to isolate because within a sample of a few hundred CTCs, the individual cells may present many characteristics. Some resemble skin cells while others resemble muscle cells. They can also vary greatly in size.
“People often compare finding CTCs to finding a needle in a haystack,” said Mao. “But sometimes the needle isn’t even a needle.”
To more quickly and efficiently isolate these rare cells for analysis, Mao and his team have created a new microfluidic chip that captures nearly every CTC in a sample of blood - more than 99% – a considerably higher percentage than most existing technologies.
The new device could be “transformative” in the treatment of breast cancer, according to Melissa Davis, an assistant professor of cell and developmental biology at Weill Cornell Medicine and a collaborator on the project.
“Physicians can only treat what they can detect,” Davis said. “We often can’t detect certain subtypes of CTCs, but with the iFCS device we will capture all the subtypes of CTCs and even determine which subtypes are the most informative concerning relapse and disease progression.”
Davis believes the device may ultimately allow physicians to gauge a patient’s response to specific treatments much earlier than is currently possible.
While most efforts to capture circulating tumor cells focus on identifying and isolating the few CTCs lurking in a blood sample, the iFCS takes a completely different approach by eliminating everything in the sample that’s not a circulating tumor cell.
The device, about the size of a USB drive, works by funneling blood through channels smaller in diameter than a human hair. To prepare blood for analysis, the team adds micron-sized magnetic beads to the samples. The white blood cells in the sample attach themselves to these beads. As blood flows through the device, magnets on the top and bottom of the chip draw the white blood cells and their magnetic beads down a specific channel while the circulating tumor cells continue into another channel.
The device combines three steps in one microfluidic chip, another advance over existing technologies that require separate devices for various steps in the process.
“The first step is a filter that removes large debris in the blood,” said Yang Liu, a doctoral student in UGA’s department of chemistry and the paper’s co-lead author. “The second part depletes extra magnetic beads and the majority of the white blood cells. The third part is designed to focus remaining white blood cells to the middle of channel and to push CTCs to the side walls.”
Wujun Zhao is the paper’s other lead author. Zhao, a postdoctoral scholar at Lawrence Berkeley National Laboratory, worked on the project while completing his doctorate in chemistry at UGA.
“The success of our integrated device is that it has the capability to enrich almost all CTCs regardless of their size profile or antigen expression,” said Zhao. “Our findings have the potential to provide the cancer research community with key information that may be missed by current protein-based or size-based enrichment technologies.”
The researchers say their next steps include automating the iFCS and making it more user-friendly for clinical settings. They also need to put the device through its paces in patient trials. Mao and his colleagues hope additional collaborators will join them and lend their expertise to the project.
Graphene has emerged as one of the most promising two-dimensional crystals, but the future of electronics may include two other nanomaterials, according to a new study by researchers at the
In research published Monday (July 4) in the journal Nature Nanotechnology, the researchers described the integration of three very different two-dimensional (2D) materials to yield a simple, compact, and fast voltage-controlled oscillator (VCO) device. A VCO is an electronic oscillator whose oscillation frequency is controlled by a voltage input.
Titled “An integrated Tantalum Sulfide—Boron Nitride—Graphene Oscillator: A Charge-Density-Wave Device Operating at Room Temperature,” the paper describes the development of the first useful device that exploits the potential of charge-density waves to modulate an electrical current through a 2D material. The new technology could become an ultralow power alternative to conventional silicon-based devices, which are used in thousands of applications from computers to clocks to radios. The thin, flexible nature of the device would make it ideal for use in wearable technologies.
Graphene, a single layer of carbon atoms that exhibits exceptional electrical and thermal conductivities, shows promise as a successor to silicon-based transistors. However, its application has been limited by its inability to function as a semiconductor, which is critical for the ‘on-off’ switching operations performed by electronic components.
To overcome this shortfall, the researchers turned to another 2D nanomaterial, Tantalum Sulfide (TaS2). They showed that voltage-induced changes in the atomic structure of the ‘1T prototype’ of TaS2 enable it to function as an electrical switch at room temperature—a requirement for practical applications.
“There are many charge-density wave materials that have interesting electrical switching properties. However, most of them reveal these properties at very low temperature only. The particular polytype of TaS2 that we used can have abrupt changes in resistance above room temperature. That made a crucial difference,” said Alexander Balandin, UC presidential chair professor of electrical and computer engineering in UCR’s Bourns College of Engineering, who led the research team.
To protect the TaS2 from environmental damage, the researchers coated it with another 2D material, hexagonal boron nitrate, to prevent oxidation. By pairing the boron nitride-capped TaS2 with graphene, the team constructed a three-layer VCO that could pave the way for post-silicon electronics. In the proposed design, graphene functions as an integrated tunable load resistor, which enables precise voltage control of the current and VCO frequency. The prototype UCR devices operated at MHz frequency used in radios, and the extremely fast physical processes that define the device functionality allow for the operation frequency to increase all the way to THz.
Balandin said the integrated system is the first example of a functional voltage-controlled oscillator device comprising 2D materials that operates at room temperature.
“It is difficult to compete with silicon, which has been used and improved for the past 50 years. However, we believe our device shows a unique integration of three very different 2D materials, which utilizes the intrinsic properties of each of these materials. The device can potentially become a low-power alternative to conventional silicon technologies in many different applications,” Balandin said.
The electronic function of graphene envisioned in the proposed 2D device overcomes the problem associated with the absence of the energy band gap, which so far prevented graphene’s use as the transistor channel material. The extremely high thermal conductivity of graphene comes as an additional benefit in the device structure, by facilitating heat removal. The unique heat conduction properties of graphene were experimentally discovered and theoretically explained in 2008 by Balandin’s group at UCR. The Materials Research Society recognized this groundbreaking achievement by awarding Balandin the MRS Medal in 2013.
The Balandin group also demonstrated the first integrated graphene heat spreaders for high-power transistors and light-emitting diodes. “In those applications, graphene was used exclusively as heat conducting material. Its thermal conductivity was the main property. In the present device, we utilize both electrical and thermal conductivity of graphene,” Balandin added.
More information: Guanxiong Liu et al, A charge-density-wave oscillator based on an integrated tantalum disulfide–boron nitride–graphene device operating at room temperature, Nature Nanotechnology (2016). DOI: 10.1038/NNANO.2016.108
The human body operates under a constant state of martial law. Chief among the enforcers charged with maintaining order is the immune system, a complex network that seeks out and destroys the hordes of invading bacteria and viruses that threaten the organic society as it goes about its work.
The immune system is good at its job, but it’s not perfect. Most cancerous cells, for example, are able to avoid detection by the immune system because they so closely resemble normal cells, leaving the cancerous cells free to multiply and grow into life-threatening tumors while the body’s only protectors remain unaware.
“What we are working on is specifically geared toward breast cancer,” said Dhar, the study’s co-author and an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences. “Our paper reports for the first time that we can stimulate the immune system against breast cancer cells using mitochondria-targeted nanoparticles and light using a novel pathway.”
In their experiments, Dhar and her colleagues exposed cancer cells in a petri dish to specially designed nanoparticles 1,000 times finer than the width of a human hair. The nanoparticles invade the cell and penetrate the mitochondria?the organelles responsible for producing the energy a cell needs to grow and replicate.
They then activated the nanoparticles inside the cancer cells by exposing them to a tissue-penetrating long wavelength laser light. Once activated, the nanoparticles disrupt the cancer cell’s normal processes, eventually leading to its death.
The dead cancer cells were collected and exposed to dendritic cells, one of the core components of the human immune system. What the researchers saw was remarkable.
“We are able to potentially overcome some of the traditional drawbacks to today’s dendritic cell immunotherapy,” said Sean Marrache, a graduate student in Dhar’s lab. “By targeting nanoparticles to the mitochondria of cancer cells and exposing dendritic cells to these activated cancer cells, we found that the dendritic cells produced a high concentration of chemical signals that they normally don’t produce, and these signals have traditionally been integral to producing effective immune stimulation.”
Dhar added that the “dendritic cells recognized the cancer as something foreign and began to produce high levels of interferon-gamma, which alerts the rest of the immune system to a foreign presence and signals it to attack. We basically used the cancer against itself.”
She cautions that the results are preliminary, and the approach works only with certain forms of breast cancer. But if researchers can refine the process, this technology may one day serve as the foundation for a new cancer vaccine used to both prevent and treat disease.
“We particularly hope this technique could help patients with advanced metastatic disease that has spread to other parts of the body,” said Dhar, who also is a member of the UGA Nanoscale Science and Engineering Center, Cancer Center and Center for Drug Discovery.
If the process were to become a treatment, doctors could biopsy a tumor from the patient and kill the cancerous cells with nanoparticles. They could then produce activated dendritic cells in bulk quantities in the lab under controlled conditions before the cells were injected into the patient.
Once in the bloodstream, the newly activated cells would alert the immune system to the cancer’s presence and destroy it.
“These are the things we can now do with nanotechnology,” Dhar said. “If we can refine the process further, we may be able to use similar techniques against other forms of cancer as well.”