New Blood Analysis Chip Could Lead to Disease Diagnosis in Minutes

The researchers have dubbed the device SIMBAS, which stands for Self-powered Integrated Microfluidic Blood Analysis System. SIMBAS appeared as the cover story March 7 in the peer-reviewed journalLab on a Chip.

"The dream of a true lab-on-a-chip has been around for a while, but most systems developed thus far have not been truly autonomous," said Ivan Dimov, UC Berkeley post-doctoral researcher in bioengineering and co-lead author of the study."By the time you add tubing and sample prep setup components required to make previous chips function, they lose their characteristic of being small, portable and cheap. In our device, there are no external connections or tubing required, so this can truly become a point-of-care system."

Dimov works in the lab of the study's principal investigator, Luke Lee, UC Berkeley professor of bioengineering and co-director of the Berkeley Sensor and Actuator Center.

"This is a very important development for global healthcare diagnostics," said Lee."Field workers would be able to use this device to detect diseases such as HIV or tuberculosis in a matter of minutes. The fact that we reduced the complexity of the biochip and used plastic components makes it much easier to manufacture in high volume at low cost. Our goal is to address global health care needs with diagnostic devices that are functional, cheap and truly portable."

For the new SIMBAS biochip, the researchers took advantage of the laws of microscale physics to speed up processes that may take hours or days in a traditional lab. They note, for example, that the sediment in red wine that usually takes days to years to settle can occur in mere seconds on the microscale.

The SIMBAS biochip uses trenches patterned underneath microfluidic channels that are about the width of a human hair. When whole blood is dropped onto the chip's inlets, the relatively heavy red and white blood cells settle down into the trenches, separating from the clear blood plasma. The blood moves through the chip in a process called degas-driven flow.

For degas-driven flow, air molecules inside the porous polymeric device are removed by placing the device in a vacuum-sealed package. When the seal is broken, the device is brought to atmospheric conditions, and air molecules are reabsorbed into the device material. This generates a pressure difference, which drives the blood fluid flow in the chip.

In experiments, the researchers were able to capture more than 99 percent of the blood cells in the trenches and selectively separate plasma using this method.

"This prep work of separating the blood components for analysis is done with gravity, so samples are naturally absorbed and propelled into the chip without the need for external power," said Dimov.

The team demonstrated the proof-of-concept of SIMBAS by placing into the chip's inlet a 5-microliter sample of whole blood that contained biotin (vitamin B7) at a concentration of about 1 part per 40 billion.

"That can be roughly thought of as finding a fine grain of sand in a 1700-gallon sand pile," said Dimov.

The biodetectors in the SIMBAS chip provided a readout of the biotin levels in 10 minutes.

"Imagine if you had something as cheap and as easy to use as a pregnancy test, but that could quickly diagnose HIV and TB," said Benjamin Ross, a UC Berkeley graduate student in bioengineering and study co-author."That would be a real game-changer. It could save millions of lives."

"The SIMBAS platform may create an effective molecular diagnostic biochip platform for cancer, cardiac disease, sepsis and other diseases in developed countries as well," said Lee.

Other co-lead authors of the study are Lourdes Basabe-Desmonts, senior scientist at Dublin City University's Biomedical Diagnostics Institute, and Jose L. Garcia-Cordero, currently post-doctoral scientist atÉcole Polytechnique Fédérale de Lausanne (EPFL Switzerland). Antonio J. Ricco, adjunct professor at the Biomedical Diagnostics Institute at Dublin City University, also co-authored the study.

The work was funded by the Science Foundation Ireland and the U.S. National Institutes of Health.

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Extremely Fast Magnetic Random Access Memory (MRAM) Computer Data Storage Within Reach

An invention made by the Physikalisch-Technische Bundesanstalt (PTB) changes this situation: A special chip connection, in association with dynamic triggering of the component, reduces the response from -- so far -- 2 ns to below 500 ps. This corresponds to a data rate of up to 2 GBit (instead of the approx. 400 MBit so far). Power consumption and the thermal load will be reduced, as well as the bit error rate. The European patent is just being granted this spring; the US patent was already granted in 2010. An industrial partner for further development and manufacturing such MRAMs under licence is still being searched for.

Fast computer storage chips like DRAM and SRAM (Dynamic and Static Random Access Memory) which are commonly used today, have one decisive disadvantage: in the case of an interruption of the power supply, the information stored on them is irrevocably lost. The MRAM promises to put an end to this. In the MRAM, the digital information is not stored in the form of an electric charge, but via the magnetic alignment of storage cells (magnetic spins). MRAMs are very universal storage chips because they allow -- in addition to the non-volatile information storage -- also faster access, a high integration density and an unlimited number of writing and reading cycles.

However, the current MRAM models are not yet fast enough to outperform the best competitors. The time for programming a magnetic bit amounts to approx. 2 ns. Whoever wants to speed this up, reaches certain limits which have something to do with the fundamental physical properties of magnetic storage cells: during the programming process, not only the desired storage cell is magnetically excited, but also a large number of other cells. These excitations -- the so-called magnetic ringing -- are only slightly attenuated, their decay can take up to approx. 2 ns, and during this time, no other cell of the MRAM chip can be programmed. As a result, the maximum clock rate of MRAM is, so far, limited to approx. 400 MHz.

Until now, all experiments made to increase the velocity have led to intolerable write errors. Now, PTB scientists have optimized the MRAM design and integrated the so-called ballistic bit triggering which has also been developed at PTB. Here, the magnetic pulses which serve for the programming are selected in such a skilful way that the other cells in the MRAM are hardly magnetically excited at all. The pulse ensures that the magnetization of a cell which is to be switched performs half a precision rotation (180°), while a cell whose storage state is to remain unchanged performs a complete precision rotation (360°). In both cases, the magnetization is in the state of equilibrium after the magnetic pulse has decayed, and magnetic excitations do not occur any more.

This optimal bit triggering also works with ultra-short switching pulses with a duration below 500 ps. The maximum clock rates of the MRAM are, therefore, above 2 GHz. In addition, several bits can be programmed at the same time which would allow the effective write rate per bit to be increased again by more than one order. This invention allows clock rates to be achieved with MRAM which can compete with those of the fastest volatile storage components.

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'Nano-Velcro' Technology Used to Improve Capture of Circulating Cancer Cells

Metastasis is the most common cause of cancer-related death in patients with solid tumors and occurs when these marauding tumor cells leave the primary tumor site and travel through the blood stream to set up colonies in other parts of the body.

The current gold standard for determining the disease status of tumors involves the invasive biopsy of tumor samples, but in the early stages of metastasis, it is often difficult to identify a biopsy site. By capturing CTCs in blood samples, doctors can essentially perform a"liquid" biopsy, allowing for early detection and diagnosis, as well as improved monitoring of cancer progression and treatment responses.

In a study published this month and featured on the cover of the journalAngewandte Chemie,the UCLA researchers announce the successful demonstration of this"nano-Velcro" technology, which they engineered into a 2.5-by-5-centimeter microfluidic chip. This second-generation CTC-capture technology was shown to be capable of highly efficient enrichment of rare CTCs captured in blood samples collected from prostate cancer patients.

The new approach could be even faster and cheaper than existing methods, and it captures a greater number of CTCs, the researchers said.

The prostate cancer patients were recruited with the help of a clinical team led by physicians Dr. Matthew Rettig, of the UCLA Department of Urology, and Dr. Jiaoti Huang, of the UCLA Department of Pathology and Laboratory Medicine.

The new CTC enrichment technology is based on the research team's earlier development of 'fly-paper' technology, outlined in a 2009 paper in Angewandte Chemie. The technology involves a nanopillar-covered silicon chip whose"stickiness" resulted from the interaction between the nanopillars and nanostructures on CTCs known as microvilli, creating an effect much like the top and bottom of Velcro.

The new, second-generation device adds an overlaid microfluidic channel to create a fluid flow path that increases mixing. In addition to the Velcro-like effect from the nanopillars, the mixing produced by the microfluidic channel's architecture causes the CTCs to have greater contact with the nanopillar-covered floor, further enhancing the device's efficiency.

"The device features high flow of the blood samples, which travel at increased (lightning) speed," said senior study author Dr. Hsian-Rong Tseng, an associate professor of molecular and medical pharmacology at the UCLA Crump Institute for Molecular Imaging and the California NanoSystems Institute at UCLA.

"The cells bounce up and down inside the channel and get slammed against the surface and get caught," explained Dr. Clifton Shen, another study author.

The advantages of the new device are significant. The CTC-capture rate is much higher, and the device is easier to handle than its first-generation counterpart. It also features a more user-friendly, semi-automated interface that improves upon the earlier device's purely manual operation.

"This new CTC technology has the potential to be a powerful new tool for cancer researchers, allowing them to study cancer evolution by comparing CTCs with the primary tumor and the distant metastases that are most often lethal," said Dr. Kumaran Duraiswamy, a graduate of UCLA Anderson School of Management who became involved in the project while in school."When it reaches the clinic in the future, this CTC-analysis technology could help bring truly personalized cancer treatment and management."

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Nanofabrication Tools May Make Silicon Optical Chips More Accessible

Silicon optical chips are critical to the Air Force because of their size, weight, power, rapid cycle time, program risk reduction and the improvements they can offer in data communications, lasers and detectors.

The Air Force Office of Scientific Research is funding this effort in silicon photonics called"Optoelectronic Systems Integration in Silicon" at UW's Nanophotonics Lab in Seattle. OpSIS is hosted by UW's Institute for Photonic Integration. Hochberg is in charge of the OpSIS research program, the Nanophotonics Lab and the Institute for Photonic Integration.

Hochberg emphasizes that the funding from the Air Force Research Laboratory and AFOSR is a critical component in getting the effort off the ground because it provides both a strong technical validation, and the resources to get started on the project.

Unlike most research groups that are designing, building and testing silicon photonic devices or optical chips in-house rather than by using commercial chip fabrication facilities, the UW researchers are using shared infrastructure at the foundry at BAE Systems in Manassas, Virginia. There they are working toward creating high-end, on-shore manufacturing capabilities that will be ultimately made available to the wider community. In the past few years, complex photonic circuitry has not been accessible to researchers because of the expense and a lack of standard processes.

The UW researchers are working on system design and validation so they can imitate what's been done in electronics by stabilizing and characterizing some processes so that the transition from photonics to systems can be smooth.

"The OpSIS program will help advance the field of silicon photonics by bringing prototyping capability within reach of startup companies and researchers," said Hochberg."They will provide design rules, device design support and design-flow development so that even non-experts will be able to design and integrate photonics and electronics."

Silicon photonics has developed over the last decade, and the transition from using devices to systems is something that has only recently occurred.

"The digital electronics revolution over the past 40 years has had a transformative effect on how the Air Force systems are built, and we're hoping to have a similar impact on photonic systems," he said.

The researchers' current goal is to work first on test runs for the new optical chips for commercial uses and on developing some software tools that will make the design process easier.

AFOSR program manager, Dr. Gernot S. Pomrenke, agrees with Prof. Hochberg."Integrating silicon photonics will impact Air Force, DoD and commercial avionics," he said."AFRL has been a leader in developing and supporting this technology over the last two decades and the OpSIS program will help in transitioning silicon photonics into new system capabilities."

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Surgical Instruments With Electronic Serial Numbers

Be it a heart transplant or a Cesarean section, every operation requires a wide variety of surgical instruments, from simple retractors, clamps, scalpels and scissors to more specialist devices such as cerclage wire passers, which surgeons employ to repair long, oblique fractures in bones. These are shaped in such a way as to half encircle the broken bone, and incorporate a hollow channel. In a process not unlike stringing a parcel for posting, thread or wire is fed through the channel around the damaged bone and then knotted in place, both to support the bone and to hold the broken parts together."Until now, it has always been time-consuming and expensive to manufacture surgical instruments featuring this kind of channel," says Claus Aumund-Kopp of the Fraunhofer Institute for Manufacturing Technology and Advanced Materials IFAM in Bremen. Because it is nigh-on impossible to machine curved channels, shaped tubes have traditionally had to be cast, or else welded or soldered retrospectively.

At the MEDTEC Europe trade show in Stuttgart from March 22 through 24, the Bremen-based scientists will be presenting a technique that enables the manufacture of surgical instruments of any shape, even those with complex interiors like channels, or those with integrated RFID chips. The technique in question is laser melting. Originally developed for the production of industrial prototypes, this manufacturing method uses an extremely fine laser beam to melt a powder material into almost any desired form, one layer at a time.

"Nowadays, laser melting is a mature technology, which has already proved its worth in the manufacture of medical implants," states Aumund-Kopp. Like all generative -- i.e. bottom-up -- manufacturing techniques, it has two major advantages: First, unlike in turning, drilling or milling, hardly any material is wasted; and second, there are no production-related restrictions on the shape or interior structure of the workpiece."The designer can focus exclusively on the surgeon's stated requirements," says the engineer. For surgical instruments, either cobalt-chromium steel or titanium powders could be used -- both are standard materials in generative manufacturing. Although no-one has yet begun using the laser melting technique to produce surgical instruments, Aumund-Kopp believes it would be an ideal manufacturing method:"Even small quantities of customized surgical instruments incorporating completely new functions could easily be produced in this way," he reports. 3-dimensional model on a computer is the only template needed; intermediate stages, including the production of special tools or casting molds, are eliminated.

Steel components that are produced using laser melting technology also demonstrate particular electrical properties. Normally, metals shield against electromagnetic radiation such as radio waves, so whenever an RFID chip is cast in metal, a small opening must be left above it, otherwise it will not be readable. But this is not necessary with laser-melted instruments; even though they are completely shrouded in metal, the integrated RFID chips are still able to transmit and receive over short distances."We assume that the layered structure of the material shapes the field in such a way that the chips remain readable despite their metal covering," explains Aumund-Kopp. This could prove advantageous in the operating room: After every operation, all surgical instruments have to be cleaned, sterilized and counted; if they had integrated RFID chips, quantities and individual numerical codes could be checked quickly and easily and could be electronically linked to the operation report or to specific instrument data such as date of manufacture, protocols for use or current state of cleanliness.

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