Technique enables development of viable diagnostic tests and instruments in fight against cancer
Cancer is the second leading cause of death in the U.S., making early, reliable diagnosis and treatment a priority for researchers. Genomic biomarkers offer great potential for diagnostics and new forms of treatment, such as immunotherapy. Miniaturized lab-on-chip approaches are prime candidates for developing viable diagnostic tests and instruments because they are small, need only limited test volumes, and can be cost-effective.
A team of scientists and engineers from the University of California, Santa Cruz and Brigham Young University have developed just such an approach capable of processing biomolecular samples from blood. Their method can analyze and identify multiple targets on a silicon-based molecular detection platform and is described this week in Biomicrofluidics, from AIP Publishing.
Laboratory–on-a-chip describes the miniaturization of laboratory functions such as blood testing on a chip. Instead of transferring relatively large (micro- to milliliters) samples between test tubes or using bulky analytical equipment, samples and reagents are handled on chip-scale devices with fluidic microchannels. This requires much smaller test volumes, and multiple functions can be integrated on a single device, improving speed, reliability and portability of these lab processes.
“Our approach uses optofluidic chips where both fluid processing and optical sensing are done on a chip, allowing for further miniaturization and performance enhancements of the chip system,” said Holger Schmidt, a Narinder Kapany professor of electrical engineering at the University of California, Santa Cruz.
The entire process of testing was a challenge for the team, led by Schmidt and Aaron Hawkins, a physics professor at Brigham Young University. Each of the chips had to be developed and tested for multiple functions, from filtering of blood cells without clogging the filter to reliably analyzing optical data to create the right excitation patterns on the silicon chip. However, the process worked as envisioned, and the team was pleasantly surprised to see just how powerful the multi-spot optical excitation method actually was.
The next step to realizing the potential of this research is to move toward real clinical samples and to detect individual DNA biomarkers.
“We have shown single nucleic acid analysis in the context of on-chip Ebola detection and would like to transfer that to this application,” said Schmidt.
Other goals for the team include increasing the speed of the analysis process, and integrating more optical elements on the chip. They also want to expand their capabilities to analyzing protein biomarkers in addition to nucleic acids and whole virus particles already demonstrated.
This research is expected to have a wide range of applications because the underlying principle of this kind of on-chip optical analysis and manipulation is very general.
“In the near term, we hope to build new diagnostic instruments for molecular diagnostics with applications in oncology and infectious disease detection, both viruses and (drug-resistant) bacteria,” Schmidt said. “In addition, these chips could be very useful for fundamental research in molecular biology and other life sciences since they can provide analysis of single nano- and microparticles without the need for expensive equipment. And they require a relatively low amount of experimental skills.”
“Morphing” wing could enable more efficient plane manufacturing and flight.
When the Wright brothers accomplished their first powered flight more than a century ago, they controlled the motion of their Flyer 1 aircraft using wires and pulleys that bent and twisted the wood-and-canvas wings. This system was quite different than the separate, hinged flaps and ailerons that have performed those functions on most aircraft ever since. But now, thanks to some high-tech wizardry developed by engineers at MIT and NASA, some aircraft may be returning to their roots, with a new kind of bendable, “morphing” wing.
The new wing architecture, which could greatly simplify the manufacturing process and reduce fuel consumption by improving the wing’s aerodynamics, as well as improving its agility, is based on a system of tiny, lightweight subunits that could be assembled by a team of small specialized robots, and ultimately could be used to build the entire airframe. The wing would be covered by a “skin” made of overlapping pieces that might resemble scales or feathers.
The new concept is described in the journal Soft Robotics, in a paper by Neil Gershenfeld, director of MIT’s Center for Bits and Atoms (CBA); Benjamin Jenett, a CBA graduate student; Kenneth Cheung PhD ’12, a CBA alumnus and NASA research scientist; and four others.
A test version of the deformable wing designed by the MIT and NASA researchers is shown undergoing its twisting motions, which could replace the need for separate, hinged panels for controlling a plane’s motion. (Kenneth Cheung/NASA)
Researchers have been trying for many years to achieve a reliable way of deforming wings as a substitute for the conventional, separate, moving surfaces, but all those efforts “have had little practical impact,” Gershenfeld says. The biggest problem was that most of these attempts relied on deforming the wing through the use of mechanical control structures within the wing, but these structures tended to be so heavy that they canceled out any efficiency advantages produced by the smoother aerodynamic surfaces. They also added complexity and reliability issues.
By contrast, Gershenfeld says, “We make the whole wing the mechanism. It’s not something we put into the wing.” In the team’s new approach, the whole shape of the wing can be changed, and twisted uniformly along its length, by activating two small motors that apply a twisting pressure to each wingtip.
This approach to the manufacture of aircraft, and potentially other technologies, is such a new idea that “I think we can say it is a philosophical revolution, opening the gate to disruptive innovation,” says Vincent Loubiere, a lead technologist for emerging technologies and concepts at Airbus, who was not directly involved in this research. He adds that “the perspectives and fields this approach opens are thrilling.”
Like building with blocks
The basic principle behind the new concept is the use of an array of tiny, lightweight structural pieces, which Gershenfeld calls “digital materials,” that can be assembled into a virtually infinite variety of shapes, much like assembling a structure from Lego blocks. The assembly, performed by hand for this initial experiment, could be done by simple miniature robots that would crawl along or inside the structure as it took shape. The team has already developed prototypes of such robots.
The individual pieces are strong and stiff, but the exact choice of the dimensions and materials used for the pieces, and the geometry of how they are assembled, allow for a precise tuning of the flexibility of the final shape. For the initial test structure, the goal was to allow the wing to twist in a precise way that would substitute for the motion of separate structural pieces (such as the small ailerons at the trailing edges of conventional wings), while providing a single, smooth aerodynamic surface.
Building up a large and complex structure from an array of small, identical building blocks, which have an exceptional combination of strength, light weight, and flexibility, greatly simplifies the manufacturing process, Gershenfeld explains. While the construction of light composite wings for today’s aircraft requires large, specialized equipment for layering and hardening the material, the new modular structures could be rapidly manufactured in mass quantities and then assembled robotically in place.
Side perspective of the test wing at Langley Research Center’s 12-Foot Low Speed Tunnel. (Kenneth Cheung/NASA)
Gershenfeld and his team have been pursuing this approach to building complex structures for years, with many potential applications for robotic devices of various kinds. For example, this method could lead to robotic arms and legs whose shapes could bend continuously along their entire length, rather than just having a fixed number of joints.
This research, says Cheung, “presents a general strategy for increasing the performance of highly compliant — that is, ‘soft’ — robots and mechanisms,” by replacing conventional flexible materials with new cellular materials “that are much lower weight, more tunable, and can be made to dissipate energy at much lower rates” while having equivalent stiffness.
Saving fuel, cutting emissions
While exploring possible applications of this nascent technology, Gershenfeld and his team consulted with NASA engineers and others seeking ways to improve the efficiency of aircraft manufacturing and flight. They learned that “the idea that you could continuously deform a wing shape to do pure lift and roll has been a holy grail in the field, for both efficiency and agility,” he says. Given the importance of fuel costs in both the economics of the airline industry and that sector’s contribution to greenhouse gas emissions, even small improvements in fuel efficiency could have a significant impact.
Wind-tunnel tests of this structure showed that it at least matches the aerodynamic properties of a conventional wing, at about one-tenth the weight.
The “skin” of the wing also enhances the structure’s performance. It’s made from overlapping strips of flexible material, layered somewhat like feathers or fish scales, allowing for the pieces to move across each other as the wing flexes, while still providing a smooth outer surface.
The modular structure also provides greater ease of both assembly and disassembly: One of this system’s big advantages, in principle, Gershenfeld says, is that when it’s no longer needed, the whole structure can be taken apart into its component parts, which can then be reassembled into something completely different. Similarly, repairs could be made by simply replacing an area of damaged subunits.
“An inspection robot could just find where the broken part is and replace it, and keep the aircraft 100 percent healthy at all times,” says Jenett.
Following up on the successful wind tunnel tests, the team is now extending the work to tests of a flyable unpiloted aircraft, and initial tests have shown great promise, Jenett says. “The first tests were done by a certified test pilot, and he found it so responsive that he decided to do some aerobatics.”
Some of the first uses of the technology may be to make small, robotic aircraft — “super-efficient long-range drones,” Gershenfeld says, that could be used in developing countries as a way of delivering medicines to remote areas.
“Ultralight, tunable, aeroelastic structures and flight controls open up whole new frontiers for flight,” says Gonzalo Rey, chief technology officer for Moog Inc., a precision aircraft motion-controls company, who was not directly involved in this work, though he has collaborated with the team. “Digital materials and fabrication are a fundamentally new way to make things and enable the conventionally impossible. The digital morphing wing article demonstrates the ability to resolve in depth the engineering challenges necessary to apply the concept.”
Rey adds that “The broader potential in this concept extends directly to skyscrapers, bridges, and space structures, providing not only improved performance and survivability but also a more sustainable approach by achieving the same strength while using, and reusing, substantially less raw material.”
And Loubiere, from Airbus, suggests that many other technologies could also benefit from this method, including wind turbines: “Simply enabling the assembly of the windmill blades on the spot, instead of using complex and fuel-consuming transport, would enhance greatly the cost and overall performance,” he says.
Learn more: A new twist on airplane wing design
UC Santa Cruz engineers use flexible silicone material to build an integrated optofluidic platform for biological sample processing and optical analysis
For well over a decade, electrical engineer Holger Schmidt has been developing devices for optical analysis of samples on integrated chip-based platforms, with applications in areas such as biological sensors, virus detection, and chemical analysis. The latest device from his lab is based on novel technology that combines high-performance microfluidics for sample processing with dynamic optical tuning and switching, all on a low-cost “chip” made of a flexible silicone material.
In previous devices from Schmidt’s lab, optical functions were built into silicon chips using the same fabrication technology used to make computer chips. The new device is made entirely of polydimethylsiloxane (PDMS), a soft, flexible material used in microfluidics as well as in products such as contact lenses and medical devices.
“We can use this fabrication method now to build an all-in-one device that allows us to do biological sample processing and optical detection on one chip,” said Schmidt, the Kapany Professor of Optoelectronics and director of the W. M. Keck Center for Nanoscale Optofluidics at UC Santa Cruz.
The flexibility of PDMS allows for novel ways of controlling both light and fluids on the chip. Using multilayer soft lithography techniques, senior graduate student Joshua Parks built chips containing both solid-core and hollow-core waveguides for guiding light signals, as well as fluidic microvalves to control the movement of liquid samples. Schmidt and Parks also developed a special microvalve that functions as a “lightvalve,” controlling the flow of both light and fluids.
“That opens up a whole new set of functions that we couldn’t do on a silicon chip,” Schmidt said. “The lightvalve is the most exciting element. In additional to a simple on-off switch, we built a moveable optical trap for analysis of biological particles such as viruses or bacteria.”
Parks and Schmidt reported the results of initial experiments with the new device in a paper published September 6 in Nature Scientific Reports.
In a previous study, Schmidt, Parks, and colleagues at BYU and UC Berkeley demonstrated a hybrid device in which a PDMS microfluidic chip for sample preparation was integrated with a silicon-based optofluidic chip for optical detection of viral pathogens. The new device combines both functions on the same chip. In addition, Schmidt said, the materials are relatively inexpensive, allowing rapid prototyping of devices.
“We can do the full chain of fabrication here in our lab, and we can make new devices very quickly,” he said.
Schmidt said the potential applications for this technology include a wide range of biological sensors and analytical devices. For viral diagnostic assays, for example, fluorescently labeled antibodies can be used to tag specific viral strains for optical detection. In a recent paper, Schmidt and colleagues demonstrated detection and identification of different flu strains using fluorescence detection in a multi-mode interference (MMI) waveguide. With the new device, they showed that they can actively tune an MMI waveguide on the chip.
The dynamic tuning of the optofluidic device is achieved by applying pressure to the optofluidic channel, changing its dimensions and thereby altering its photonic properties. “We can actually tune the spot pattern made in the channel by the interference waveguide, which we couldn’t do with the silicon chip,” Schmidt said.
The University of California, Santa Cruz (also known as UC Santa Cruz or UCSC) is a public, collegiate university and one of 10 campuses in the University of California system.
Located 80 miles (130 km) south of San Francisco at the edge of the coastal community of Santa Cruz, the campus lies on 2,001 acres (810 ha) of rolling, forested hills overlooking the Pacific Ocean and Monterey Bay.
Founded in 1965, UC Santa Cruz began as a showcase for progressive, cross-disciplinary undergraduate education, innovative teaching methods and contemporary architecture. Since then, it has evolved into a modern research university with a wide variety of both undergraduate and graduate programs, while retaining its reputation for strong undergraduate support and student political activism. The residential college system, which consists of ten small colleges, is intended to combine the student support of a small college with the resources of a major university.
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Hybrid device integrates a microfluidic chip for sample preparation and an optofluidic chip for optical detection of individual molecules of viral RNA A team led by researchers at UC Santa Cruz has developed chip-based technology for reliable detection of Ebola virus and other viral pathogens.
The current gold standard for Ebola virus detection relies on a method called polymerase chain reaction to amplify the virus’s genetic material for detection.
“We’re detecting the nucleic acids directly, and we achieve a comparable limit of detection to PCR and excellent specificity.” In laboratory tests, the system provided sensitive detection of Ebola virus while giving no positive counts in tests with two related viruses, Sudan virus and Marburg virus.
The system combines two small chips, a microfluidic chip for sample preparation and an optofluidic chip for optical detection.