In laboratories ranging from medical complexes to sprawling R&D centers, expensive benchtop instruments such as spectrometers, flow cytometers and blood analyzers still hold sway. However, in recent years a whole new category of instruments has steadily gained ground: the lab-on-chip (LOC).
On these tiny microfluidic platforms, researchers dispense, mix and analyze minute amounts of chemicals in fluid channels whose diameters are measured in microns and even nanometers. Also on board these LOCs, depending on the design, are components such as electronic and fluid connectors, sensors, valves, thermal elements—even pumps and on-chip microscopes. Compared to traditional benchtop instruments, these miniature labs often can achieve faster analytic results with far less fluid consumption, thus trimming the costs of reagents and other chemicals.
Designing these microfluidic devices typically demands the talents of teams made up of engineers, chemists, material experts, biologists and even medical clinicians. Their efforts have spawned an array of new tools in applications such as gene study, drug discovery, point-of-care diagnostics, biofuels development and environmental monitoring.
“The field now has two solid decades under its belt,” says chemistry professor Aaron Wheeler of the University of Toronto, whose lab develops LOCs for biology, chemistry and medicine. “Like any new technology, there was the initial hype and then a bit of a crash. But now we are seeing some real successes.”
Biomedical Leads the Way
Much of this LOC activity targets medical and pharmaceutical applications, says Wheeler, who points to funding support from government entities such as the National Institutes of Health (NIH) and the Defense Advanced Research Projects Agency (DARPA). A report from BCC Research predicts that the global market for LOCs and related microarrays in the biomedical field will increase from $3.9 billion in 2013 to $14.4 billion in 2018, a compound annual growth rate of 30%.
Typical of the many new microfluidic LOC advances in biomedical is engineering professor Tony Jun Huang’s work at Pennsylvania State University. Huang has designed a LOC device for diagnosis and personalized treatment of asthma and tuberculosis that requires a patient’s sputum sample to be 100 times smaller than usual in conventional labs. The self-contained design, featuring a disposable component that relieves users from handling contagious samples, features an on-chip acoustofluidic pump powered by a piezoelectric transducer about the size of a 25-cent piece.
Huang says that low-cost, reliable micro-pumps are essential to the commercialization of microfluidics, especially in point-of-care diagnostics. He estimates that his total LOC system, including off-the-shelf electronics, could be made for as little as $30, with the disposable chip costing about $0.20. Huang says the device does not require highly trained operators, and it takes the place of lab instruments like flow cytometers and blood analyzers that can cost tens of thousands of dollars. The professor has established a startup company called Ascent Bio-Nano Technologies to bring his technology to commercial partners.
“Both the number of applications and the quality of research in microfluidics has increased significantly in the last 10 years,” says Huang. “About 70% of our body is comprised of fluids, so biology can be better mimicked and understood by a network of microfluidic devices than by Petri dishes.”
With support from NIH and diagnostics giant Roche, University of North Carolina biomedical engineering professor Steve Soper also has launched a LOC startup called BioFluidica. It seeks to market a microfluidic platform for analyzing circulating tumor cells (CTCs) that are important biomarkers for cancer.
The disposable plastic cartridge for this instrument features sinusoidal-shaped microchannels coated with antibodies that can isolate CTCs from whole blood in less than 30 minutes. Its design includes a sensor that counts single cells and determines their viability without expensive optical detection. The cartridge, about the size of a standard microscope slide, can be injection molded for about $1 per unit and using the same technology that produces CDs and DVDs. This not only enables high production at low cost, but improves replication fidelity, as well as the reproducibility of assays. The platform can also be used for other applications, such as isolating bacterial cells from whole blood or pathogens from waste water.
“This device is fully automated, so you don’t have to be a specialist in flow cytometry to operate it,” says Soper. The platform has already gone through clinical validation and has had the first round of investment, with product launch targeted for the first quarter of 2016.
New Resources for Pharma
To help address global concerns about “super bugs” that are resistant to existing classes of antibiotics, engineering professor Tza-Huei Wang of Johns Hopkins University is leveraging NIH funds to develop a portable dual-module microfluidic device. One module, already designed, uses magnetic manipulation of microfluidic droplets to process a culture and identify the specific strain of bacteria that is causing an infection. A second module, still under development, relies on the same platform to determine the precise antibiotic needed, as well as the correct dose to fight an infection. By using microfluidics, researchers can achieve high concentrations of bacteria in a droplet, allowing much faster analysis of a drug’s potential impact.
Contrast to this approach, says Wang, with current methods in which emergency room physicians prescribe an antibiotic based on a patient’s symptoms, rather than on lab evidence. Result: Patients are sometimes prescribed antibiotics unnecessarily or are prescribed an antibiotic that is not the best choice for their condition.
In effect, Wang’s LOC automates the complex, multi-step polymerase chain reaction (PCR) tests that labs now perform to detect infectious diseases. “We believe that our microfluidic device will give the appropriate answers within three hours, rather than two or three days under the present system of analyzing cultures in a centralized lab,” says Wang. That is particularly important, he says, in cases where deadly pathogens are present.
Typical of the collaboration that is taking place on many LOC projects, Wang is working with research partners at the University of Arizona as well as with Stanford University urologist Joseph Liao, who is helping to validate that the technology works on bacteria associated with urinary tract infections. Another partner, GE Global Research, is exploring production methods that would meet federal Food and Drug Administration manufacturing requirements.
At Cornell University, chemical engineering professor Michael Shuler and his colleagues are working on what he calls “body-on-chip” microfluidic devices that can mimic organ function and help in evaluating possible drugs to treat cancer and other diseases. One such device features microfluidic silicon chips with separate chambers containing different tissues analogs in the form of cell cultures. It recreates the interactions between the gastrointestinal tract and the liver. The device, which provides a miniaturized model of a section of the body, helps researchers better understand how digestion affects a drug.
Shuler says he believes that this body-on-chip concept is an effective, lower-cost way for pharmaceutical companies to increase their chances of bringing new drugs to market. It also can reduce or eliminate the need for animal studies. His startup, Hesperos Inc., already has garnered interest from drug firms. “The cost of clinical trials for new drugs is huge,” says Shuler. “Only 11% of drugs that go into clinical trials reach the commercial market. If you could increase that success rate to 33%, consumers would reap big benefits in the form of lower prices and expanded drug choices.”
From Biofuels to Water Monitoring
Beyond medical, LOC technology is infiltrating all sorts of applications. Aaron Wheeler’s lab at the University of Toronto has used a microfluidic chip to assess environmental conditions such as light exposure that promote maximum lipid production from algae for biofuels. Also in the energy field, he says that firms are using microfluidic devices on probes used in oil exploration. Others are building microfluidic-based models to evaluate techniques for hydraulic fracturing operations. Wheeler also sees good opportunities for microfluidics in agriculture, such as portable sensors to better control pesticide applications or to determine the extent of pollination.
Among other recent examples of LOCs in fields beyond biomedical:
- Toronto-based Micromem Technologies has developed a LOC that is housed in a vehicle’s oil pan drain plug and measures the real-time condition of engine oil to prevent breakdowns.
- The U.S. Department of Energy’s Joint Center for Artificial Photosynthesis has designed a tiny microfluidic test bed to evaluate new catalysts and materials for electrochemical energy conversion. The device reduces the need for expensive full-scale prototypes.
- Seoul National University in South Korea has created a LOC-based “bioelectronic nose” that can detect traces of bacteria in water by smelling it. The key components of the chip: a lab-grown human olfactory receptor and a carbon nanotube field-effect transistor.
Wanted: Better Building Blocks
Even while LOC applications are multiplying, researchers are looking for ways to speed the design of these miniature labs while enhancing their capabilities. For example, University of California Los Angeles engineering professor Aydogan Ozcan has created a series of LOC devices to diagnose diseases, and has pioneered the concept of linking those devices to cell phones, both to capture and process results and to communicate them instantly (see “Your Cell Phone as Lab Instrument,”
In addition, Ozcan has freed his LOC devices from dependence on lab-based microscopy by making a “lens-free” microscope an integral component of his system. In this design, a light-emitting-diode illuminates a tissue or blood sample that has been placed on a slide and inserted into a portable diagnostic device. A sensor array on a microchip captures and records the pattern of shadows created by the sample. The device then processes these patterns as a series of holograms, forming 3D images of the specimen and giving medical personnel a virtual depth-of-field view. An algorithm color codes the reconstructed images, making the contrasts in the samples more apparent than they would be in the holograms and making any abnormalities easier to detect.
Ozcan’s team has tested the lens-free microscope on several specimens, such as Pap smears indicating cervical cancer, tissue containing cancerous breast cells and blood samples showing sickle cell anemia. A pathologist who analyzed images of these specimens created by the lens-free technology and by conventional microscopes found that diagnoses made using the lens-free microscopic images proved accurate 99% of the time.
“In research labs, we are seeing all kinds of beautifully engineered tests performed on microfluidic devices as small as a credit card,” says Ozcan, “But unless you also include imaging capability on these devices, you don’t really have a complete LOC design.”
Meanwhile, at the University of Southern California, electrical engineer Krisna Bhargava wants to make it easier for engineers and scientists to design LOCs. “Building a microfluidic system can require a lot of time and money, as well as many iterations,” says Bhargava. His solution: Use 3D printing to construct a modular system for encapsulating and connecting the major components that make up a microfluidics system, much like snapping together LEGO components.
Working with colleagues from the chemical engineering, materials science and biomedical fields, Bhargava designed a helix component that can mix two fluid streams as well as a component that contains an integrated optical sensor for measuring the size of small droplets. He envisions a whole library of standard components to accommodate the key elements of microfluidic systems, such as chemical reservoirs, sensors and pumps.
Bhargava says he believes that this modular approach, including sharing designs via an open-source data base, could speed the design of new LOC devices, as well as move the industry closer to the standardization being called for by bodies such as the U.S. National Institute of Standards and Technology. Along with finding the funds to commercialize innovative LOCs being designed all around the world, experts say that developing widely recognized industry standards is essential to ensure future growth of LOC technology.
Despite these challenges, researchers specializing in the field see bright days ahead. “Microfluidic devices hold great promise, especially in such applications as point-of-care diagnostics in developing countries where lab resources are scarce,” says biomedical engineer Soper of the University of North Carolina. As the technology matures, production costs decline and engineers are learning that “a device doesn’t have to be complicated to be effective,” he says. “It’s a matter of finding the right niche.”
For more information:
Wheeler Microfluidics Laboratory, University of Toronto
Acoustofluidics research at Penn State
BioFluidica Circulating Tumor Cell analysis
Microfluidics devices at Johns Hopkins University to detect bacteria
Ozcan Research Group at UCLA:
USC “Lego” concept for building LOCs