Smart lasers could make cancer biopsies painless, help speed new drugs to market

To test forskin cancer, patients today must endure doctors cutting away a sliver of skin, sending thebiopsyto a lab and anxiously awaiting the results. Usinglasermicroscopes that deploy rapid, ultra-short pulses to identifymolecules, doctors may soon have the tools to painlessly scan a patient's troublesome mole and review the results on the spot, said Marcos Dantus.

The results touting this new molecule-selective technology can be found in the current issue ofNature Photonics, which Dantus co-authored with Sunney Xie of Harvard University.

"Smart lasers allow us to selectively excite compounds– even ones with small spectroscopic differences,"said Dantus."We can shape the pulse of the lasers, excite one compound or another based on their vibrational signatures, and this gives us excellent contrast."

In the past, researchers could approach this level of contrast by introducing fluorescent compounds. With the breakthrough using stimulated Raman scattering microscopy, fluorescent markers are unnecessary.

"Label-free molecular imaging has been the holy grail in medicine,"Dantus said."SRS imaging gives greater specificity and the ability to map a particular chemical species in the presence of an interfering species, such as cholesterol in the presence of lipids."

Additional potential applications include allowing researchers to closely examine howcompoundspenetrate skin and hair. Smart lasers also can better identify how drugs penetrate tissue and how drugs and tissue interact, thus mitigating the chances of potential side effects and helping reduce the time required to bring new drugs to market.

Dantus also is using smart laser imaging technology at MSU for detecting traces of hazardous substances from a distance.

"The ability to image with molecular specificity and sensitivity opens a number of applications in medicine as well as in homeland security,"he said.

Collaboration for the paper began when Harvard graduate student Christian Freudiger contacted BioPhotonic Solutions, a high-tech company Dantus launched in 2003 based on his research at MSU. Dantus was not only able to provide the laser pulse shaper Harvard needed to conduct the research, but he also was able to lend his expertise as well as the support of his MSU laboratory, Dantus said.

"I like to say that we enable technology,"he said."Controlling ultrashort pulses, which once required Ph.D. experts, can now be done with push-button simplicity by a small computer-controlled box. This instrument is now being used in the most prestigious research laboratories in the world."

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New center aims to dramatically lower barrier to making silicon photonic chips

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In a ceremony today on the UW campus, Michael Hochberg, a UW assistant professor of electrical engineering; Justin Rattner, chief technology officer atIntelCorp.; Carver Mead, professor emeritus at the California Institute of Technology; and Matt O'Donnell, dean of the UW College of Engineering, kicked off the initiative to support startups and academic researchers.

"We would like the photonics industry, 10 years from now, to function in a way that's very similar to the electronics industry today,"Hochberg said."People building optoelectronic systems will send designs out to an inexpensive, reliable third party for manufacturing, so they can focus on being creative about the design."

The new center aims to create for silicon photonics what Mead and colleague Lynn Conway did for silicon electronics in the 1970s. The"Mead and Conway Revolution"is widely credited with ushering in the current era of integrated circuit computing technology.

Optoelectronics Systems Integration in Silicon, or OpSIS, will offer a service similar to theMetal Oxide SemiconductorImplementation Service, or MOSIS, an organization based at the University of Southern California that helped combine many different circuits, based on Mead and Conway's design principles, onto a single silicon wafer.

"More than 15 years ago, we had a collaboration that allowed my group to design custom integrated circuits that would have been totally impossible for us to do from scratch,"said O'Donnell, who then worked at the University of Michigan."It's now clear that silicon photonics is becoming an integral part of the electronics world, and so it's critical to have that type of capability."

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This is a graphic of a recently built silicon photonic chip measuring 1 cm by 2 cm. At the bottom is a photograph of the chip. Above it, in green, is the original chip design. The rectangle on the upper left shows how layers of silicon (blue), metal (gray) and electrical insulator (orange) combine to create channels, or waveguides, for light to pass through. Credit: A. Spott, University of Washington

The OpSIS project will permit"shuttle runs"in which researchers cut costs by sharingsilicon wafersbetween multiple projects. A single circuit design might use only a few square millimeters. Enabling shuttle runs, Hochberg said, can reduce costs by more than 100 times.

In developing the rules and protocols, Hochberg aims to create a system analogous to Mead and Conway's so that even non-specialists can begin to design and build functioning chips that integrate photonics and electronics.

Creating these rules requires striking a fine balance.

"You want a minimum of rules because people are going to use the technology in ways that you never imagined,"Mead said."You want people to use it in ways that seem crazy."

The emerging field of photonics uses photons, or light, rather than electrons to carry information. Using photons provides a faster, lower-power means for moving data around; a single optical fiber or waveguide can carry many terabits per second of data, tens of thousands of times more than a copper cable does today. Using silicon as the base for the technology eases integration with existing devices and builds on the mature silicon chip manufacturing industry.

Combining photonics and electronics promises to improve radar and sensing technology, and the U.S. Air Force Office of Scientific Research funds Hochberg's UW research. There are also a number of emerging applications for silicon photonics: In the future, Hochberg said, chips that combine electronics and photonics could allow for biological sensors that can test hundreds of blood samples on a single inexpensive chip that combines lasers, sensors and electronics.

"OpSIS will enhance the education of U.S. engineering students, giving them the opportunity to learn the new optical design paradigm,"Intel's Rattner said."The ability to produce such low-costsiliconchips that manipulate photons, instead of electrons, will lead to new inventions and new industries beyond just data communications, including low-cost sensors, new biomedical devices and ultra-fast signal processors."

In August, Hochberg and Tom Baehr-Jones, a UW research scientist in electrical engineering, published aNature Photonicsarticle calling for a foundry forsilicon photonics.

"With such an organization in place, we predict that designing and building photonic-electronicsilicon chipswill constitute a multibillion-dollar industry within the next ten years,"they wrote.

The OPSIS organization already has a half-dozen early users who are participating in so-called"risk runs"that test the protocols now under development.

One early user is John Bowers, a professor of electrical and computer engineering at the University of California, Santa Barbara who has designed a circuit for the first run. While Bowers can build photonics circuits elsewhere, he sees himself as a potential user of the foundry.

"By focusing research of many different groups in one process line, that allows you to advance a library of components and processes faster than any one group could do on its own,"Bowers said."It enables a faster evolution of photonic devices."

Eventually, the UW center plans to offer three runs per year, each of which could accommodate 30 to 40 users. The chips will be built by BAE Systems Inc.

OpSIS will be based at the UW's new Institute for Photonic Integration.

"I'm just rooting for it,"Mead said."It's a wonderful thing and it needs to happen. I might even use it for some of my own research."

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Microtechnology: An alignment assignment

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One approach to achieve accurate alignment is to manufacture both the optical MEMS components and any other electronic or photonic components on the same silicon wafer. OpticalMEMS devices, however, are often ten times thicker than other optical components. This means that different fabrication techniques are needed for the different components, making alignment difficult.

Another approach is to fabricate MEMS and electrical components on two separate wafers that are then bonded together. Achieving good alignment in this scheme is made difficult, however, by the coarse bonding processes that are available. Qingxin Zhang and co-workers at the A*STAR Institute of Microelectronics have now refined the two-wafer approach by combining the final fabrication step for each component into a single process.

The research team aligned an optical MEMS structure with a silicon photonic structure (see figure). The two wafers bearing the respective components were processed independently in the first step: the MEMS structure was fabricated on a bulk silicon wafer and the photonic structure on a silicon-on-insulatorwafer. The wafers were then bonded together using benzocyclobutene—a commonly used bonding agent for MEMS—at 250°C, and the two structures were completed simultaneously using a single step of deep reactive ion etching.

The use of a single fabrication step to complete the final integrated device allowed Zhang and his co-workers to meet strict alignment specifications, achieving a misalignment of less than one micrometer laterally and less than half a micrometer vertically. They also used their strategy to construct and characterize a functioning optical switch in which a MEMS mirror is displaced by a driving voltage to connect and disconnect an optical pathway. The signal loss between a source optical fiber and the silicon waveguide in the device was just 2.4 decibels, which is well within acceptable limits.

The new approach allows scientists to merge photonic and MEMS components fabricated on two different wafers into a single device. Future work will focus on optimizing the MEMS design and fabrication process, and demonstrating reconfigurability.

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Insect eyes inspire improved solar cells

In a paper appearing inEnergy Express, a bi-monthly supplement toOptics Express, the open-access journal published by the Optical Society (OSA), the team describes how this film improves the performance of photovoltaic modules in laboratory andfield experiments, and they calculate how the anti-reflection film would improve the yearly performance of solar cells deployed over large areas in either Tokyo, Japan or Phoenix, Ariz.

"Surface reflections are an essential loss for any type of photovoltaic module, and ultimately low reflections are desired,"says Noboru Yamada, a scientist at Nagaoka University of Technology Japan, who led the research with colleagues at Mitsubishi Rayon Co. Ltd. and Tokyo Metropolitan University.

The team chose to look at the effect of deploying this antireflective moth-eye film on solar cells in Phoenix and Tokyo because Phoenix is a"sunbelt"city, with high annual amount of direct sunlight, while Tokyo is well outside the sunbelt region with a high fraction of diffusesolar radiation.

They estimate that the films would improve the annual efficiency of solar cells by 6 percent in Phoenix and by 5 percent in Tokyo.

"People may think this improvement is very small, but the efficiency ofphotovoltaicsis just like fuel consumption rates of road vehicles,"says Yamada."Every little bit helps."

Yamada and his colleagues found the inspiration for this new technology a few years ago after they began looking for a broad-wavelength and omnidirectional antireflective structure in nature. The eyes of the moth were the best they found.

The difficulty in making the film, says Yamada, was designing a seamless, high-throughput roll-to-roll process for nanoimprinting the film. This was ultimately solved by Hideki Masuda, one of the authors on the Energy Express paper, and his colleagues at Mitsubishi Rayon Co. Ltd.

The team is now working on improving the durability of the film and optimizing it for many different types ofsolar cells. They also believe the film could be applied as an anti-reflection coating to windows and computer displays.

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New wave: JILA develops efficient source of terahertz radiation

JILA is a joint institute of the National Institute of Standards and Technology (NIST) and the University of Colorado at Boulder.

Terahertz radiation—which falls between the radio and optical bands of the electromagnetic spectrum—penetrates materials such as clothing and plastic but can be used to detect many substances that have unique absorption characteristics at these wavelengths. Terahertz systems are challenging to build because they require a blend of electronic and optical methods.

The JILA technology, described inOptics Letters, is a new twist on a common terahertz source, asemiconductorsurface patterned with metal electrodes and excited by ultrafast laser pulses. Anelectric fieldis applied across the semiconductor while near-infrared pulses lasting about 70 femtoseconds (quadrillionths of a second), produced 89 million times per second, dislodge electrons from the semiconductor. The electrons accelerate in the electric field and emit waves of terahertz radiation.

The JILA innovations eliminate two known problems with these devices. Adding a layer of silicon oxide insulation between the gallium arsenide semiconductor and the gold electrodes prevents electrons from becoming trapped in semiconductor crystal defects and producing spikes in the electric field. Making the electric field oscillate rapidly by applying a radiofrequency signal ensures that electrons generated by the light cannot react quickly enough to cancel the electric field.

The result is a uniform electric field over a large area, enabling the use of a large laser beam spot size and enhancing system efficiency. Significantly, users can boost terahertz power by raising the optical power without damaging the semiconductor. Sample damage was common with previous systems, even at low power. Among other advantages, the new technique does not require a microscopically patterned sample or high-voltage electronics. The system produces a peak terahertz field (20 volts per centimeter for an input power of 160 milliwatts) comparable to that of other methods.

While there are a number of different ways to generate terahertz radiation, systems using ultrafast lasers and semiconductors are commercially important because they offer an unusual combination of broad frequency range, high frequencies, and high intensity output.

NIST has applied for a provisional patent on the new technology. The system currently uses a large laser based on a titanium-doped sapphire crystal but could be made more compact by use of a different semiconductor and a smaller fiber laser, says senior author Steven Cundiff, a NIST physicist.

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Fastest movie in the world recorded: Scientists develop a method to film nanostructures

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German scientists at Helmholtz-Zentrum Berlin fur Materialien und Energie (HZB) and the Technische Universitat Berlin (TUB) now present a method that takes us a good step towards producing a"molecular movie". They can record two pictures at such a short time interval that it will soon be possible to observemoleculesand nanostructures in real time.

A"molecular movie"that shows how a molecule behaves at the crucial moment of a chemical reaction would help us better understand fundamental processes in the natural sciences. Such processes are often only a few femtoseconds long. A femtosecond is a millionth of a billionth of a second.

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The imaged Brandenburg Gate is only a few micrometers in size. The scientists took the green and red pictures of the model merely 50 femtoseconds apart. Credit: HZB/Eisebitt

While it is possible to record a singlefemtosecondpicture using an ultra-short flash of light, it has never been possible to take a sequence of pictures in such rapid succession. On a detector that captures the image, the pictures would overlap and"wash out". An attempt to swap or refresh the detector between two images would simply take too long, even if it could be done atspeed of light.

In spite of these difficulties, members of the joint research group"FunctionalNanomaterials"of HZB and the Technische Universität Berlin have now managed to take ultrafast image sequences of objects mere micrometres in size using pulses from the X-ray laser FLASH in Hamburg, Germany. Furthermore, they chart out a path how their approach can be scaled to nanometer resolution in the future. Together with colleagues from DESY and the University of Münster, they have published their results in the journalNature Photonics.

The researchers came up with an elegant way to descramble the information superimposed by the two subsequent X-ray pulses. They encoded both images simultaneously in a single X-ray hologram. It takes several steps to obtain the final image sequence: First, the scientists split the X-ray laser beam into two separate beams. Using multiple mirrors, they force one beam to take a short detour, which causes the two pulses to reach the object under study at ever so slightly different times– the two pulses arrive only 0.00000000000005 seconds apart. Due to a specific geometric arrangement of the sample, the pulses gen-erate a"double-hologram". This hologram encodes the structure of the object at the two times at which the X-ray pulses hit., Using a mathematical reconstruction procedure, the researchers can then simply associate the images with the respective X-ray puses and thus determine the image sequence in correct temporal order.

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This is the central part of the recorded hologram of the Brandenburg Gate micro-model. Credit: HZB/Eisebitt

Using their method, the scientists recorded two pictures of a micro-model of the Brandenburg Gate, separated by only 50 femtoseconds."In this short time interval, even a ray of light travels no further than the width of a human hair,"says PhD student Christian Günther, the first author of the publication. The short-wavelength X-rays used allow to reveal extremely small detail, since the shorter the wavelength of light you use, the smaller the objects you can resolve.

"The long-term goal is to be able to follow the movements of molecules and nanostructures in real time,"says project head Prof. Dr. Stefan Eisebitt. The extremely high temporal resolution in conjunction with the possibility to see the tiniest objects was the motivation to develop the new technique. A picture may be worth a thousand words, but a movie made up of several pictures can tell you about an object's dynamics.

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Extracting cellular 'engines' may aid in understanding mitochondrial diseases

The scientists reached into these cells and extracted their"engines"—themitochondriathat are in large part responsible for our metabolism. Many human cells contain hundreds of mitochondria, which were thought to be free-swimming organisms millions of years ago and which still possess their own DNA. Mutations in this mitochondrial DNA (mtDNA) are directly related to a large class of mitochondrial-based diseases, which have a range of symptoms that include early onset blindness, seizures, hearing loss, dementia, etc. In the general population, one out of every 200 people possesses a mtDNA mutation that may develop into a mitochondrial disease.

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Extracting mitochondria from a human cell (larger object on bottom right) is a tricky process. NIST researchers recently developed techniques that can surgically remove these tiny cellular engines, potentially enabling new ways to explore the link between mitochondrial DNA and a host of diseases. This short video clip (.mov format) demonstrates the process. Credit: NIST

Investigating more deeply has been problematic, though, because the way mitochondria mix and spread their DNA within and among cells is poorly understood."The trouble is that it's very difficult to extract single mitochondria from an individual cell,"says NIST physicist Joseph Reiner."For years, the best technique has been to break open a group of cells and collect the mitochondria from all of them in a kind of soup. As you might guess, it's hard to determine which mitochondria came from what cells—yet that's what we need to know."

The research team, which also includes scientists from Gettysburg College, has potentially solved this problem by realizing that several devices and techniques can be used together to extract a single mitochondrion from a cell that possesses a genetic mutation. They employed a method** previously used to extract single chromosomes from isolated ricecellswhere a laser pulse makes an incision in a cell's outer membrane. Another laser is used as a"tweezer"to isolate a mitochondrion, which then can be extracted by a tiny pipette whose tip is less than a micrometer wide.

This approach allowed the team to place a single mitochondrion into a small test tube, where they could explore the mitochondrion's genetic makeup by conventional means. The team found the mutation present throughout the entire cell was also found within individual mitochondria, a find suggesting that broad genetic research on mitochondrial disease may be possible at last.

"Getting an object as tiny as this from tweezer to test tube is not easy,"says Koren Deckman, a biochemist from Gettysburg College."But by building on more than a decade of work that has gone on at NIST and elsewhere, we now have a way to see the mitochondria we extract all the way through the transfer process, meaning we can be sure the sample came from a very specific cell. This could give medical scientists the inroad they need for understanding these diseases."

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