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June 11, 2009: Scientists have identified for the first time a mechanism by which nanoparticles cause lung damage and have demonstrated that it can be combated by blocking the process involved, taking a step toward addressing the growing concerns over the safety of nanotechnology.

Although nanoparticles have been linked to lung damage, it has not been clear how they cause it.

In a study published online today in the newly launched Journal of Molecular Cell Biology, Chinese researchers discovered that a class of nanoparticles being widely developed in medicine – ployamidoamine dendrimers (PAMAMs) — cause lung damage by triggering a type of programmed cell death known as autophagic cell death. They also showed that using an autophagy inhibitor prevented the cell death and counteracted nanoparticle-induced lung damage in mice.

“This provides us with a promising lead for developing strategies to prevent lung damage caused by nanoparticles. Nanomedicine holds extraordinary promise, particularly for diseases such as cancer and viral infections, but safety concerns have recently attracted great attention and with the technology evolving rapidly, we need to start finding ways now to protect workers and consumers from any toxic effects that might come with it,” said the study’s leader, Chengyu Jiang, a molecular biologist at the Chinese Academy of Medical Sciences in Beijing, China.

The first nanomaterial was developed by German scientists in 1984. Nanomaterials are now used in a variety of products, including sporting goods, cosmetics and electronics. The fact that unusual physical, chemical, and biological properties can emerge in materials at the nanoscale makes them particularly appealing for medicine. Scientists hope nanoparticles will be able to improve the effectiveness of drugs and gene therapy by carrying them to the right place in the body and by targeting specific tissues, regulating the release of drugs and reducing damage to healthy tissues. They also envision the possibility of implantable nano devices that would detect disease, treat it and report to the doctor automatically from inside the body. The U.S. Food and Drug Administration has approved some first generation nanodrugs. One example is Abraxane, a nanoformulation of the anti-cancer chemotherapy paclitaxel.

Lung damage is the chief human toxicity concern surrounding nanotechnology, with studies showing that most nanoparticles migrate to the lungs. However, there are also worries over the potential for damage to other organs.

In the study, the researchers first showed, through several independent experiments, that several types of PAMAMs killed human lung cells in the lab. They did not observe any evidence that the cells were dying by apoptosis, a common type of programmed cell death. However, they found that the particles triggered autophagic cell death through the Akt-TSC2-mTOR signalling pathway. Autophagy is a process that degrades damaged materials in a cell and plays a normal part in cell growth and renewal, but scientists have found that sometimes an overactivity of this destruction process leads to cell death.


Top: Percentage of cells containing autophagic vesicles after treatment with control, PAMAM G5.5, PAMAM G3 ,and PAMAM G3 plus 3MA. Bottom: Percentage of cells tested positive for light chain 3 (LC3) — a marker protein for autophagy — after control, PAMAM G5.5, PAMAM G3, and PAMAM G3 plus 3MA treatment. [**P < 0.01 and *P < 0.05.] (Source: Journal of Molecular Cell Biology)

The researchers also found that treating the cells with an autophagy inhibitor known as 3MA significantly inhibited the process, increasing the number of cells that survived exposure to the nanoparticles.

“Those results, taken together, showed that autophagy plays a critical role in the nanoparticle-induced cell death,” said Jiang.

The scientists then tested their findings in mice. They found that introducing the toxic nanoparticles significantly increased lung inflammation and death rates in the mice, but injecting the mice with the autophagy inhibitor 3MA before introducing the nanoparticles significantly ameliorated the lung damage and improved survival rates.

“These experiments indicate that autophagy is indeed involved in lung damage caused by these nanoparticles and that inhibition of this process might have therapeutic effects,” Jiang said. “We will likely need to look for additional new inhibitors to block lung damage as this particular compound is not stable in humans, but this gives us a promising lead for the first time.”

“Our study has identified the principle for developing such compounds. The idea is that, to increase the safety of nanomedicine, compounds could be developed that could either be incorporated into the nano product to protect against lung damage, or patients could be given pills to counteract the effects,” Jiang said, adding that the findings could also provide important insight into how nanopaticles cause other toxic effects.

It is not clear whether other types of nanoparticles would cause lung damage via the same mechanism, but some may, Jiang said. The group’s research also suggests that blocking autophagic cell death could perhaps be useful in combating other causes of lung damage.

June 10, 2009: Nanoparticle films are no longer a delicate matter: Vanderbilt physicists have found a way to make them strong enough so they don’t disintegrate at the slightest touch.

In the last 25 years, ever since scientists figured out how to create nanoparticles — ultrafine particles with diameters less than 100nm — they have come up with a number of different methods to mold them into thin films which have a variety of interesting potential applications ranging from semiconductor fabrication to drug delivery, solid state lighting to flexible television and computer displays.

Until now these films have had a common problem: lack of cohesion. Nanoparticles typically consist of an inorganic core coated with a thin layer of organic molecules. These particles are not very sticky so they don’t form coherent thin films unless they are encapsulated in a polymer coating or mixed with molecules called chemical “cross-linkers” that act like glue to stick the nanoparticles together.

“Adding this extra material can complicate the fabrication of nanoparticle films and make them more expensive. In addition, the added material, usually a polymer, can modify the physical properties that make these films so interesting,” says James Dickerson, assistant professor of physics at Vanderbilt, who headed the research group that developed freestanding nanoparticle films without any additives.

The properties of the new films and the method that the researchers use to create them is described in the article “Sacrificial layer electrophoretic deposition of freestanding multilayered nanoparticle films” published online in the journal Chemical Communications on May 27.

“Our films are so resilient that we can pick them up with a pair of tweezers and move them around on a surface without tearing,” says Dickerson. “This makes it particularly easy to put them into microelectronic devices, such as computer chips.”

Dickerson considers the most straightforward applications for his films to be in semiconductor manufacturing to aid in the continued miniaturization of digital circuitry and in the production of flexible television and computer screens.


AFM image of the surface of an iron oxide nanoparticle film, showing individual nanoparticles. (Source: Vanderbilt/Dickerson Lab)

A key component in the transistors in integrated circuits is an insulating layer that separates the gate, which turns current flow on and off, from the channel through which the current flows. Traditionally, semiconductor manufacturers have used silicon dioxide for this purpose. As transistors have shrunk, however, they have been forced to make this layer thinner and thinner until they reached the point where electrons leak through and sap the power from the device. This has led semiconductor manufacturers to retool their process to use “high-k” dielectric materials, such as hafnium oxide, because they have much higher electrical resistance.

“We have made high-k nanoparticle films that could be cheaper and more effective than the high-k materials the manufacturers are currently using,” Dickerson says.

In addition, the physicist argues that the films have properties that make them ideal for flexible television and computer screens. They are very flexible and don’t show any signs of cracking when they are flexed repeatedly. They are also made using a technique called electrophoretic deposition (EPD) that is well suited for creating patterned material and is compatible with fluorescent materials that can form the red, green and blue pixels used in flat panel television screens and computer displays.

EDP is a wet method. Nanoparticles are placed in a solution along with a pair of electrodes. When an electric current is applied, it creates an electrical field in the liquid that attracts the nanoparticles, which coat the electrodes. Using colloids, mixtures with particles 10×-1,000× larger than nanoparticles, EDP is widely used to apply coatings to complex metal parts such as automobile bodies, prosthetic devices, appliances and beverage containers. It is only recently that researchers like Dickerson have begun applying the technique to nanoparticles.


Illustration of the electrophoretic deposition process. (Source: Vanderbilt/Dickerson Lab)

“The science of colloidal EDP is well known but the particles are substantially larger than the solvent molecules. Many nanoparticles, however, are about the same size as the solvent molecules, which makes the process considerably more complicated and difficult to control,” Dickerson explains.

To get the method to work, in fact, Dickerson and his colleagues had to invent of new form of EDP, which they call sacrificial layer electrophoretic deposition. They added a spun-cast layer of polymer to the electrodes that serves as a pattern that organizes the nanoparticles as they are deposited. Then, after the deposition process is completed, they dissolve (sacrifice) the polymer layer to free the nanoparticle film.

According to the researchers, films made in this fashion stick together because the electrical field slams the nanoparticles into the film with sufficient force to pack the particles together tightly enough to allow naturally attractive inter-particle forces to bind the particles together.

So far the Dickerson group has used the technique to make films out of two different types of nanoparticles — iron oxide and cadmium selenide — and they believe the technique can be used with a wide variety of other nanoparticles.

“The technique is liberating because you can make these films from the materials you want and use them where you want,” Dickerson says.

June 10, 2009: The US Food and Drug Administration can regulate nanotechnology using its existing authority, but questions remain over the size of food ingredients, according to an FDA official.

Food Production Daily reports that Annette McCarthy, of the office of food additive safety at the FDA’s Center for Food Safety and Applied Nutrition, is warning that food ingredients on the nanoscale could change the “identity” and the toxicity of the ingredient.

“We believe that the regulatory authority is sufficient to address nanotechnology but there are further questions we need to address,” McCarthy said, speaking at the IFT International Food Nanoscience Conference in Anaheim.

She said that manufacturers looking to petition the FDA for acceptance of a nanotech food additive or coloring’s safety should examine its “impact on identity and toxicity.”

She also said the FDA is in the process of developing a guidance document for nanotechnology, scheduled to be available before the end of 2010.

June 9, 2009: NanoString Technologies, a privately held life sciences company advancing technologies for expression profiling, has closed a $30 million Series C equity financing. This financing, structured in two tranches, will allow NanoString Technologies to accelerate the commercialization of the nCounter Analysis System in the research tools and diagnostics arenas.

The round was led by Clarus Ventures, a global life sciences venture capital firm, and was joined by existing investors OVP Venture Partners and Draper Fisher Jurvetson. In connection with the financing, Nicholas Galakatos, co-founder and managing director of Clarus Ventures, will join the NanoString Technologies’ Board of Directors.

“We believe that NanoString Technologies has the best-in-class platform for expression profiling. Their uniquely user-friendly technology that does not require sample purification or use of PCR constitutes a breakthrough in the field, as evidenced by the excitement of the scientific community towards their products. We are delighted to be part of the success of this emerging leader,” said Galakatos.

“Completion of this financing in this tough economic environment is an important validation of the differentiation of the NanoString technology platform, the success with key customers and the insight and determination of Clarus Ventures and our other investors. Our products have received tremendous interest from commercial and clinical researchers in a relatively short amount of time. The new funds will fuel our growth in manufacturing and product development and enhance our commercialization capabilities,” said Wayne Burns, CFO and Acting CEO of NanoString Technologies, in a statement.

NanoString Technologies is a life sciences tool company that is commercializing a novel and uniquely user-friendly technology for characterizing and quantifying expression profiles in complex biological samples.

June 9, 2009: For car designers, secret agents in the movies and jet fighter pilots, data eyeglasses — also called head-mounted displays (HMDs) — are everyday objects. They transport the wearer into virtual worlds or provide the user with data from the real environment. At present these devices can only display information.

“We want to make the eyeglasses bidirectional and interactive so that new areas of application can be opened up,” Michael Scholles, business unit manager at the Fraunhofer Institute for Photonic Microsystems IPMS in Dresden.

A group of scientists at IPMS is working on a device which incorporates eye tracking — users can influence the content presented by moving their eyes or fixing on certain points in the image. Without having to use any other devices to enter instructions, the wearer can display new content, scroll through the menu or shift picture elements.

Scholles believes that the bidirectional data eyeglasses will yield advantages wherever people need to consult additional information but do not have their hands free to operate a keyboard or mouse.


Data eyeglasses display information and respond to commands. (Source: Fraunhofer IPMS)

The Dresden-based researchers have integrated their system’s eye tracker and image reproduction on a CMOS chip. This makes the HMDs small, light, easy to manufacture and inexpensive.

The chip, measuring 19.3mm × 17mm, is fitted on the prototype eyeglasses behind the hinge on the temple. From the temple the image on the microdisplay is projected onto the retina of the user so that it appears to be viewed from a distance of about one meter.

The image has to outshine the ambient light to ensure that it can be seen clearly against changing and highly contrasting backgrounds. For this reason the research scientists use OLEDs, organic light-emitting diodes, to produce microdisplays of particularly high luminance.

In industry and in the medical field, the interactive data eyeglasses could enable numerous tasks to be performed more simply, efficiently and precisely. Many scenarios are possible, including patients’ vital functions, MRT and x-ray images for the operating surgeon, construction drawings for erection engineers and installation instructions for service technicians.

Some users have already tried out conventional HMDs, but the results were not very impressive. In most cases they were found to be too expensive, too heavy, too bulky and not very ergonomic.

“We have now overcome these hurdles,” says Scholles. With his team and colleagues from other Fraunhofer institutes he is already working on the next development stage of the bidirectional eyeglasses.

June 9, 2009: Xradia Inc., a developer and manufacturer of high-resolution 3D X-ray imaging systems, has announced a partnership with NanoLab Technologies Inc.

The companies will offer 3D X-ray imaging as part of a service model which enables customers in the electronics and semiconductor industry to address semiconductor packaging development and failure analysis challenges while evaluating the purchase of their own systems.

As part of the agreement, NanoLab Technologies purchased an Xradia MicroXCT-200, a platform for 3D X-ray imaging.

This new class of X-ray computed tomography scanner features sub-micron pixel resolution and impressive high contrast imaging capabilities for a larger range of sample sizes and shapes. In addition, the Xradia MicroXCT-200 detectors provide superior contrast, even for low absorption materials.

The system comes equipped with multiple magnification detectors for easy zoom-in during imaging. 3D X-ray capabilities eliminate the need for physical cross sectioning and delayering for many applications, which reduces analysis time and prevents method induced artifacts.

“The MicroXCT-200 is the ideal solution for semiconductor package and electronic materials imaging”, said John Traub, president of NanoLab Technologies.

“Giving our customers the ability to visualize fine embedded structures in 3D within the intact chip package offers insight that’s not possible with typical surface analysis tools like the AFM, SEM or conventional 2D X-ray systems. The Xradia system is a critical addition to our state-of-the-art lab offering — providing our customers with solutions to their advanced packaging technology challenges such as flip chip packages, BGA, multi-chip packages and wafer level packaging solutions.”

The results suggest that graphene could out-perform copper for use as on-chip interconnects — tiny wires that are used to connect transistors and other devices on integrated circuits. Use of graphene for these interconnects could help extend the long run of performance improvements for silicon-based integrated circuit technology.

“As you make copper interconnects narrower and narrower, the resistivity increases as the true nanoscale properties of the material become apparent,” said Raghunath Murali, a research engineer in Georgia Tech’s Microelectronics Research Center. “Our experimental demonstration of graphene nanowire interconnects on the scale of 20nm shows that their performance is comparable to even the most optimistic projections for copper interconnects at that scale. Under real-world conditions, our graphene interconnects probably already out-perform copper at this size scale.”

Beyond resistivity improvement, graphene interconnects would offer higher electron mobility, better thermal conductivity, higher mechanical strength and reduced capacitance coupling between adjacent wires.

“Resistivity is normally independent of the dimension — a property inherent to the material,” Murali noted. “But as you get into the nanometer-scale domain, the grain sizes of the copper become important and conductance is affected by scattering at the grain boundaries and at the side walls. These add up to increased resistivity, which nearly doubles as the interconnect sizes shrink to 30nm.”

The research was supported by the Interconnect Focus Center, which is one of the Semiconductor Research Corporation/DARPA Focus Centers, and the Nanoelectronics Research Initiative through the INDEX Center.

Murali and collaborators Kevin Brenner, Yinxiao Yang, Thomas Beck and James Meindl studied the electrical properties of graphene layers that had been taken from a block of pure graphite. They believe the attractive properties will ultimately also be measured in graphene fabricated using other techniques, such as growth on silicon carbide, which now produces graphene of lower quality but has the potential for achieving higher quality.


Figure 1. A graphene material sample that was tested for its properties is shown against an image in a test station. (Source: Georgia Tech/Gary Meek)

Because graphene can be patterned using conventional microelectronics processes, the transition from copper could be made without integrating a new manufacturing technique into circuit fabrication.

“We are optimistic about being able to use graphene in manufactured systems because researchers can already grow layers of it in the lab,” Murali noted. “There will be challenges in integrating graphene with silicon, but those will be overcome. Except for using a different material, everything we would need to produce graphene interconnects is already well known and established.”

Experimentally, the researchers began with flakes of multi-layered graphene removed from a graphite block and placed onto an oxidized silicon substrate. They used electron beam lithography to construct four electrode contacts on the graphene, then used lithography to fabricate devices consisting of parallel nanoribbons of widths ranging between 18 and 52nm. The three-dimensional resistivity of the nanoribbons on 18 different devices was then measured using standard analytical techniques at room temperature.

The best of the graphene nanoribbons showed conductivity equal to that predicted for copper interconnects of the same size. Because the comparisons were between non-optimized graphene and optimistic estimates for copper, they suggest that performance of the new material will ultimately surpass that of the traditional interconnect material, Murali said.


Figure 2. SEM image showing 22nm wide graphene nanoribbons between the middle electrode pair. (Source: Georgia Tech/Raghunath Murali)

“Even graphene samples of moderate quality show excellent properties,” he explained. “We are not using very high levels of optimization or especially clean processes. With our straightforward processing, we are getting graphene interconnects that are essentially comparable to copper. If we do this more optimally, the performance should surpass copper.”

Though one of graphene’s key properties is reported to be ballistic transport — meaning electrons can flow through it without resistance — the material’s actual conductance is limited by factors that include scattering from impurities, line-edge roughness and from substrate phonons — vibrations in the substrate lattice.

Use of graphene interconnects could help facilitate continuing increases in integrated circuit performance once features sizes drop to approximately 20nm, which could happen in the next five years, Murali said. At that scale, the increased resistance of copper interconnects could offset performance increases, meaning that without other improvements, higher density wouldn’t produce faster integrated circuits.

“This is not a roadblock to achieving scaling from one generation to the next, but it is a roadblock to achieving increased performance,” he said. “Dimensional scaling could continue, but because we would be giving up so much in terms of resistivity, we wouldn’t get a performance advantage from that. That’s the problem we hope to solve by switching to a different materials system for interconnects.”

May 29, 2009: Members of a USC-led research team say they’ve made a big improvement in a new breed of electronic detectors for viruses and other biological materials — one that may be a valuable addition to the battle against epidemics.

It consists of a piece of synthetic antibody attached to a nanowire that’s attached to an electrical base, immersed in liquid.

If the protein the antibody binds to is present in the liquid, it will bind to these antibodies, immediately creating a sharply measurable jump in current through the nanowire.

The basic principle of nanotube and nanowire biosensors for protein detection was first demonstrated in 2001, but the new design by a team headed by Zhongwu Chou and Mark Thompson of the University of Southern California uses two new elements.

First, it takes advantage of bioengineered synthetic antibodies, much, much smaller versions of the natural substances that are designed to bind with a specific protein and only that protein.

Second, it uses indium oxide (In2O3) nanowires instead of silicon and other materials previously tried. Metal oxides, according to a new study published in ACS Nano, do not, unlike silicon, develop “an insulating native oxide layer that can reduce sensitivity.”

The result, according to the paper, is a device that can detect its target molecules with a sensitivity as great as the best alternative modes, do so more rapidly and without use of chemical reagents.

It is also potentially considerably cheaper than alternatives.


Antibody mimic protein is tailored to attach to nanowire base at one end, leaving biologically active area open for detection. (Source: University of Southern California)

“We believe,” the authors write, “that nanowire bisensor devices functionalized with engineered proteins … can have important applications ranging from disease diagnosis to homeland security.”

Additionally, the system can be useful in basis research, in helping to establish certain important parameters for two-part biological systems like the antibody/target protein pair.

The protein the prototype system detects is the SARS (severe acute respiratory syndrome) virus n-protein, which infected more than 8,000 people in 2002-2003, killing nearly 10% of them.

Commercial systems using enzyme-linked immunosorbent assay (ELISA) now exist to test for SARS, but the new system has advantages in time, cost and portability.

The first step was the creation, by Richard Roberts and Mark Thompson, chemists, and their team of the synthetic antibody, including both the active area, design to interact with the protein and, at the other end, a chemical “hook” that would bind it to nanowire at this point and only this point. “This … strategy allows every bound [detector molecule] to retain full activity, a clear advantage over antibodies, which [in earlier biosensor designs] are often bound to nanowire surface via amine containing residues randomly distributed over the antibody surface.”

The Zhou lab, which has specialized in nanowire and nanotube technology for years, performed the complex set of procedures to synthesize the wires, attaching

In tests, the group performed if anything better than predictions, showing a standard and low level of activity when no SARS protein was present, leaping quickly to a higher level when the protein was introduced, in response patterns that varied consistently according to concentration of the SARS protein. Devices complete except for the detector molecule showed no response at all.

The response was complete in less than ten minutes, compared to hours needed for results from ELISA tests — which are basically present/not present tests with relatively little quantitative elements.

Next steps are to enable detection in more complex environment, such as Serum and whole blood, by integrating the nanobiosensor with micro systems such as microfluidics chips and micro filters.

May 27, 2009: Rice University researchers announced that the first field tests of “nanorust,” the university’s low-cost technology for removing arsenic from drinking water, will begin later this year in Guanajuato, Mexico.

“Mexico’s debating the adoption of more stringent national standards for allowable levels of arsenic in drinking water, and officials in Guanajuato are looking ahead to explore ways they might meet stricter new standards,” said nanorust inventor Vicki Colvin, Rice’s Pitzer-Schlumberger Professor of Chemistry and director of Rice’s Center for Biological and Environmental Nanotechnology (CBEN)

Colvin and CBEN faculty, staff and students began visiting Guanajuato last fall to prepare for the upcoming tests. Guanajuato, which has a population of 80,000, is the capital of Guanajuato state. It is about 230 miles northwest of Mexico City.

Arsenic is a colorless, odorless, tasteless element, and prolonged exposure to dangerous levels of arsenic can lead to skin discoloration, sickness and cancer. Arsenic-poisoned drinking water is a global problem, affecting tens of millions of people in communities in Asia, Africa, North America, South America and Europe.

CBEN’s arsenic-removing technology is based on the unique properties of particles called “nanorust,” tiny bits of iron oxide that are smaller than living cells. In 2006, Colvin and CBEN colleague Mason Tomson, professor in civil and environmental engineering, published with their students the first nanorust studies. Their initial tests indicated nanorust — which naturally binds with arsenic — could be used as a low-cost means of removing arsenic from water.

Qilin Li, an assistant professor of civil and environmental engineering and CBEN faculty expert in water treatment, said Rice’s team plans to test nanorust-coated sand. The material will be used in sand filters to treat groundwater from wells. The water treated with nanorust will be kept separate from the water that is released for human consumption, Li said.

“Our studies of nanorust have progressed rapidly over the past three years, but in order to move this technology toward practical application there is really no substitute for this type of field test,” Li said.

Pedro Alvarez, the George R. Brown Professor of Engineering and chair of the Department of Civil and Environmental Engineering, said, “One collateral benefit of the nanorust filters is that they may also help remove water-borne viruses that are responsible for a wide variety of gastrointestinal diseases.”

May 26, 2009: RainDance Technologies Inc., which provides microdroplet-based solutions for human health and disease research, has received the first European order for its Sequence Enrichment Solution from ATLAS Biolabs GmbH of Berlin, a genomic services provider.

In an announcement at the European Society of Human Genetics (ESHG) Conference 2009, the company said ATLAS Biolabs’ purchase includes the RDT 1000 system, PCR primer libraries, consumables kits, and training services.

“ATLAS Biolabs is a renowned genomic services provider with an esteemed scientific team that is highly respected in the European research community,” Christopher McNary, RainDance’s president and CEO said in a prepared statement.

“We look forward to supporting their requirements with a solution that can dramatically enhance their genomic research services portfolio.”

McNary said the sale represents a key addition to the company’s global service provider network.

“With our Sequence Enrichment Solution in place at ATLAS Biolabs, European researchers will have immediate access to our technology. It will enable scientists to perform high-resolution analysis of genetic variation between individuals within populations at a level unmatched by current methodologies,” he said.

“RainDance’s massively parallel microdroplet PCR-based solution for sequence enrichment is superior to all others available in the market because it is less prone to the selection bias associated with targeted sequencing,” said Peter Nürnberg, co-founder and CEO of ATLAS Biolabs. “Using the RainDance technology, we can amplify up to 4,000 amplicons in a single PCR process with essentially no allelic amplification bias and a near 100 percent success rate of PCR primer pairs.”

Nürnberg said ATLAS Biolabs is discussing the RainDance Sequence Enrichment Solution with key customers and will invite them to perform proof-of-principle experiments once the instrument is installed.

“We are pleased to be the first in Europe to offer this innovative approach and will work with RainDance to explore additional applications for their promising new technology.” RainDance will immediately begin designing custom DNA primer libraries for ATLAS Biolabs’ customers and anticipates shipping the RDT 1000 system by July.