…with NanoMission, but believe it or not, you might learn something, too

Gaming for the greater good is the higher purpose of PlayGen’s managing director Kam Memarzia, one of the founding members of the London-based interactive media company that uses game technology for learning rather than just entertainment. That goal recently brought PlayGen into the world of nanotech when it released the beta version of its latest game, NanoMission.

Dubbed by its creators as “the world’s first scientifically accurate interactive 3D learning game based on understanding nanosciences and nanotechnology,” NanoMission aims to transform young gamers’ visions of nanotechnology from one of miniature robots to a practical science with applications in the real world.

“While most teenage gamers are familiar with nanotechnology, very few have a realistic understanding of what it can do, or realize its impact on the world around them,” says Memarzia. “Coupled with declining numbers of physics, chemistry, and engineering students, this is a major cause for concern.”

PlayGen hopes to change that with its NanoMission series. Half Tomb Raider and half science class, NanoMission features an alluring Lara Croft-like scientist named Lisa who, in the first module, fights to save a young colleague, Jacob, from cancer by selecting and maneuvering a cancer-killing vesicle through his bloodstream to the site of the tumor.

Fantastic voyage it’s not. NanoMission tries to stick to the science, as in this scene where Dr. Goodlove informs Lisa that people can’t possibly operate at the size of a single protein molecule.Click here to enlarge image

One of the most gratifying aspects of the game is the simple yet effective plot setup in which the lead scientist, an elder Dr. Goodlove, ridicules the absurdity of shrinking people and placing them into tiny submarines that are injected into people’s bloodstream – as is the typical scheme in classic sci-fi movies.

“Nanoscience is a billion-dollar industry and its connection to science fiction can be unhealthy,” Memarzia says of the introduction.

Dr. Goodlove then explains the real solution, in which they will inject highly toxic cancer-killing molecules into Jacob’s body. Lisa must guide the nanomolecules to the tumor while avoiding all particles in the bloodstream and detection by Jacob’s immune system.

Once players select which type of vesicle they want – fast but easy to detect or slow but stealthy – they are immersed in a spooky network of blood cell tunnels where they must steer clear of sticky antibody proteins and lumbering red blood cells while following an onscreen map to the tumor, all while a heartbeat throbs in the background, adding a sense of menace to the game.

Memarzia’s team made a point to work with scientific advisors to make sure the game is scientifically correct. Eventually the game will have several modules, released every couple of months beginning in April 2007, that will allow gamers to play against each other while learning about nanotech.
– Sarah Fister Gale

The fifth category – work force – of our state rankings shows few surprises. The density of the East Coast and the engineering clusters around national labs play a big factor in pushing certain states ahead.

Click here to enlarge image

The map above and the charts on the facing page comprise the fifth installment of our ongoing series that ranks the U.S. states for their micro- and nanotechnology development.

The category presented here – work force – is one of five categories used to generate a state’s overall score. In the previous four issues, analyses of venture capital investment, micro- and nanotech density, research, and innovation were presented. A compilation of the current series of individual categories is scheduled for the July/August 2007 issue of Small Times magazine.

1. Massachusetts

The Bay State maintained its top spot for work force for the fourth year in a row. The state benefits from a deeply rooted tech cluster that is fed by some of the nation’s top universities. Sounds like California – except that on a per-capita basis Massachusetts is the denser of the two. The state’s work force is highly educated, ranking third behind just Maryland and New Mexico for its density of science and engineering doctorate holders. And those well-educated workers are oriented in the right direction: Massachusetts tops the charts for the number of engineers who call it home, relative to its overall number of workers.

2. Maryland

Maryland benefited from two things in the work force category: its overall size and its highly disproportionate number of science and engineering doctorate holders. The result? A top position in the measure that tracks the density of doctorates in the state as a percentage of overall workers. On the engineering side, the state is still strong, but not as strong as it had been. It ranked seventh in the measure that tracks the density of engineers in the state.

3. New Mexico

New Mexico lacks the proximity to bigger brethren states and the resulting cross-border pollination that breeds so much tech development. However, it is buttressed by government laboratories, universities, and growing tech clusters in Albuquerque and elsewhere in the state. As a result, it offers an extremely well-educated work force, ranking second in the measure that tracks science and engineering doctorate holders. And on the engineering side, a strong fourth-place showing put it in third overall for the work- force category for a total score just a little over half a point behind Maryland.

4. Connecticut

Connecticut benefits from major engineering installations both along the Atlantic coast and inland near its capital of Hartford, as well as a location that tucks it neatly between the hotbeds of Massachusetts and New York. It was strongest in the measure tracking engineer density, with a third-place showing, but it also placed a solid fifth in the science and engineering doctorate density measure.

5. Colorado

Colorado is one of only two southwest states to make the top 10 for work force (along with New Mexico). It fared reasonably well in the doctorate density measure, netting an eighth-place showing and coming in ahead of California and Washington. But it really pulled out all the stops in engineer density, with a second-place position. The state benefits from a number of high-tech corridors, including a cluster built around computer memory development.

6. Virginia

Virginia wasn’t tops in either measure, but secured its sixth-place showing by virtue of netting the sixth spot in both science and engineering doctorate density as well as engineer density. The state’s strong defense-related ties don’t show up in all our categories since much of the data about the industry is not disclosed – but it shows up clearly in the work-force category.

7. California

Juggernaut California doesn’t fare as well in the work- force category as it does in other categories used in Small Times’ rankings – in large part due to its overall size. Despite world-leading tech clusters in both the northern and southern parts of the state, California’s overall size and diversity conspire to work against its showing. Now if only the rankings were done on an absolute basis…

8. Washington

Washington notched a seat in the top 10 for work force by placing tenth in the science and engineering doctorate density and eighth in the engineer density. The state benefits from Seattle area biotech and software clusters.

9. Rhode Island

Little Rhode Island benefits from its size and its location on the eastern seaboard as well as from the presence of some world-class educational institutions. It placed seventh on the science and engineering doctorate density and ninth in the engineer density measure.

10. Delaware

An East Coast location, proximity to both the mid-Atlantic states and the Chesapeake region, and some major industrial centers supporting the headquarters of global corporations put Delaware into the mix. It was an impressive fourth in science and engineering doctorate holders, and tenth in engineers.
– David Forman

Two measures are used to generate the work-force scores reflected in the map. Individual scores for the top-10 in each measure are reflected in the charts below.

The two measures are used to evaluate the work force in each state based on education as well as employment – in each case relative to the overall work force in that state. Additional details are available under each chart.

The final scores on the map are calculated by taking the average of the two scores shown here, then normalizing the result on a 100-point scale.

Sources: Small Times uses data from the National Science Foundation, as well as other proprietary data sources.

A percent score is calculated by dividing the number of science and engineering doctorate holders in the state by the number of workers in that state. To generate the final score, the result was then normalized on a 100-point scale.Click here to enlarge image

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A percent score is calculated by dividing the number of engineers in the state by the number of workers in that state. To generate the final score, the result was then normalized on a 100-point scale.Click here to enlarge image

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As Goliath Ltd. prepares to debut its nanotech-enabled product, the David Co. brandishes its slingshot full of patents

By Richard Acello

Each January, the Consumer Electronics Show in Las Vegas plays host to the latest in high-tech wizardry. This year, SED Inc., a joint venture of Canon Inc. and Toshiba Corp., was said to have its 55-inch television set ready for display. But the SED TV never made it to Vegas.

The IP factor

Toshiba issued a press statement that read, in part, “After many months of planning for CES 2007, it is with deep regret that we inform you that Toshiba is forced to cancel the 55-inch panel exhibition. The reason is neither [a] technical nor [a] business issue but we are not allowed to disclose details due to [a] confidentiality obligation.”

At the same time, Canon found itself involved in legal action with Nano Proprietary Inc., an Austin, Texas-based technology company. Nano Proprietary is not a rival electronics manufacturer, but describes itself as “first and foremost a research and development company.” The company explains, “We have an extensive portfolio of intellectual property that we have developed over the years and our goal is to develop a portfolio of recurring revenue streams by licensing our intellectual property to others.”

The advent of intellectual property (IP) litigation indicates maturity of the nanotech industry, says Jim Peterson, partner at the law firm Jones Day.Click here to enlarge image

Nano Proprietary has an agreement with Canon to license its technology; the agreement extends to Canon’s subsidiaries, but not, Nano Proprietary contends, to the Canon-Toshiba joint venture SED.

In April 2005, Nano Proprietary filed suit against Canon, and its wholly owned subsidiary Canon USA, in the U.S. District Court for the Western District of Texas, seeking a declaratory judgment that SED’s products were not covered by Nano Proprietary’s licensing agreement with Canon. “We allege that SED Inc. is not covered under a license we gave to Canon in 1999, a license that extended to Canon subsidiaries, but prohibited Canon from sub-licensing the patents to others,” says Tom Gilbertsen, a partner with New York firm Kelley, Drye and Warren. SED Inc., says Gilbertsen, is not covered under the 1999 license and Canon breached the license contract by sublicensing SED Inc., entitling Nano Proprietary to damages that may range into the hundreds of millions of dollars.

In November 2006, an Austin District Court judge denied Canon’s motion for summary judgment in the case. Canon argued that SED was a subsidiary of Canon, but Judge Sam Sparks disagreed. “To put it bluntly, Canon’s characterization of SED as a subsidiary simply can’t pass the smell test,” Sparks wrote. “Canon has bargained away its voting rights in SED. Dead fish don’t swim, dead dogs don’t hunt, and Canon’s dead voting rights don’t give it a majority of the shares entitled to vote in SED. This court declines to recognize a corporate fiction designed for the sole purpose of evading Canon’s contractual obligations.”

Patton Lochridge of the Austin firm of McGinnis, Lochridge and Kilgore, who responded in court to the Nano Proprietary complaint on behalf of Canon, referred questions about the case to New York attorney Nicholas Cannella of Fitzpatrick, Cella, Harper and Scinto, who did not return calls about the matter.

Gilbertsen said the case was headed to trial, but in the meantime, Nano Proprietary was open to a settlement. “We’ve had dialogue with them, so Canon knows what we want them to do,” he said. “We’re open to Canon and Toshiba obtaining a license with us.”

Then on January 12, Toshiba said it had reached an agreement to have Canon purchase from Toshiba all of its outstanding shares in SED, so that SED would become a wholly owned subsidiary of Canon.

Another battlefield

Nano Proprietary is not the only nanotech “David” to trot out its IP portfolio before a well-known manufacturer. In December 2006, DA Nanomaterials, a Tempe, Ariz.-based joint venture of chemical giant DuPont and Lehigh Valley-based Air Products, went to court in Arizona federal district court against Cabot Microelectronics, based in Aurora, Ill. DA Nanomaterials sought a judgment that it is not infringing on Cabot’s intellectual property.

Cabot says DA Nanomaterials is infringing the process Cabot uses to make and sell slurry polishing and pad products used in the manufacture of semiconductor chips. The chips go into electronics products from cell phones to servers.

Unlike Nano Proprietary, Cabot is a manufacturer of the products in dispute and does not necessarily want to negotiate a license with DA Nanomaterials. In fact, Cabot says the suit results from Cabot’s refusal to grant DA Nanomaterials a license to the disputed technology. “We don’t think it’s appropriate to ask or demand that they be given a license,” said H. Carol Bernstein, Cabot’s general counsel.

In June 2006, Cabot was successful in an action before the U.S. International Trade Commission against Korea-based Chiel Industries involving some of the same technology at issue in the DA Nanomaterials case, said Bernstein.

Natural progression

What the Nano Proprietary and Cabot cases have in common is the willingness of companies with extensive nanotech portfolios to assess their intellectual property rights as nanotechnology products move from drawing boards to reality.

“Nanotech intellectual property exists in thousands of patents that have been out there for a while,” says Jim Peterson who heads up the nanotechnology practice at the Bay Area law firm Jones Day. “It’s an indication of the maturation of the nanotech industry.”

Peterson says the trend of IP-rich firms using their portfolios to win licensing agreements is reminiscent of what happened in the development of biotechnology. “First comes the innovation, then comes the ‘so what’ component, or how you go from innovation to something that is useful, and that involves wrapping your arms around it and creating intellectual property, so you have something to license,” he adds.

Companies with extensive IP portfolios will set out to try and license their technologies, and while legal action may be part of the scenario, their main goal will be to get paid for their IP.

“You’ll see people trying to license their technology to larger companies, set out to be licensing companies, and developing strategies toward that,” Peterson says. “But I think litigation is an expensive proposition, and the substance behind it is the licensing because nobody makes money on litigation except the lawyers.”

Editor’s note: As this issue was going to press, Judge Samuel Sparks ruled in the Canon/Nano Proprietary case, saying that Nano Proprietary has the right to terminate its licensing agreement with Canon, keep its original licensing fee of $5.56 million, and seek damages for material breach of contract.

A new breed of sophisticated, low-cost microscopes is enabling new vision for industry and academe

BY CHARLES CHOI

Electron and scanning probe microscopes-those wonderful machines that allow us to peer at objects on the atomic and nano scales-have traditionally been large and expensive. Increasingly, however, toolmakers are introducing versions of these devices that are smaller (sometimes even portable) and less expensive than ever before as they begin to serve a potentially enormous market.

“It’s part of the same trend you see with all electronics. Instruments are now getting smaller and getting more capabilities squeezed into them,” says Mark Flowers, co-founder of Nanoscience Instruments in Phoenix, Ariz., U.S. distributor of Nanosurf’s portable and tabletop AFMs.

Students, start-ups, and industry

With this new generation of instruments, toolmakers are targeting primarily the education niche that optical microscopes typically fill. “The optical microscope market is about three to four times larger than the electron microscope market worldwide,” says Robert Gordon, vice president of Hitachi High Technologies America nanotechnology business development. Hitachi entered the desktop imaging market in 2006 with its tabletop scanning electron microscope (SEM) TM-1000.

“Before, a lot of these instruments were really off-limits in the lab, only for Ph.D. students and professors and postdocs to use, and often only at the universities with research facilities-the MITs and Stanfords,” says Agilent AFM operations manager Jeff Jones. “One trend we now see is these instruments finding use at state universities that want students to have broader capabilities, teaching universities that aren’t necessarily research-oriented but want to apply for nanotechnology research grants. They want to include AFMs in courses at the undergrad and grad level and want more-advanced instrumentation.”

Hitachi has “over the past one-year period concentrated heavily on the high school, small college, and university markets, and we are a major player and supporter of the government’s initiative to further develop our workforce and enhance our science and technology programs,” says Gordon. “We had always focused on pretty expensive electron microscopes, but now we’re looking into smaller microscopes with higher volumes to compete with optical microscopes and with a very big audience of people.”

Hitachi’s TM-1000 is allowing more schools to compete for nanotech research grants.Click here to enlarge image

Entering the academic market is also a way of training generations of students in the use of advanced instruments they might use later in their careers. “We’re helping spread the infrastructure,” says Jones.

One key consideration behind entering the academic market, besides price, is ease of use. “Ease of use is not a consideration when you have a Ph.D. student who will spend five years on an instrument, but it is when you have a student for three or six weeks,” adds Jones. “You need something to get students up to speed quickly. You want something like an optical microscope, where anyone can walk up to it and see what he or she is looking for without being an expert in the technique.”

“We’ve also included a curriculum with our instruments that professors can use as part of a microscopy course,” Jones says.

Ease of use is also important in the industrial environment, “where technicians are running samples over and over for quality metrics,” continues Jones.

That’s one reason why start-ups comprise another potentially ripe area for these instruments. About 15 years ago, “AFMs were complicated and expensive. There was no market for ones that were easier to use, because people who used them were experts in the area,” says Paul West, CTO and founder of Pacific Nanotechnology in Santa Clara, Calif. “People now want microscopes to solve problems, as opposed to the microscopes being the project itself.”

“Many start-ups cannot afford the traditional electron microscopes, which cost at least $150,000. So a tabletop microscope is a good entry-level microscope for them to start using,” says Gordon.

“We’re looking into new areas for us, servicing companies in the fields of nanomaterials, the biosciences, such as pharma, and in cosmetics. There’s a lot of business we can gather there,” adds Gordon. “We’ve even found that major semiconductor customers are embracing it, for improving throughput in their failure analysis labs, for instance.”

Pioneers paved the way

One of the earliest companies to produce lower-cost, smaller-size advanced microscopes is Nanosurf in Liestal, Switzerland, spun off from the University of Basel in 1997. Nanosurf’s latest entry-level device, the easyScan 2 AFM, is portable. Its scanner fits in the palm of your hand and has a resolution of 150 x 27 picometers.

“At the time we started, there were only big, complex instruments on the market, operated by very experienced scientists,” says Nanosurf CEO Robert Sum. “We had been approached by high school teachers who had the need for small, easy-to-use microscopes, and we saw the potential there.”

The easyScan can be used on samples other microscopes might find it hard to access, “such as an airplane wing,” Sum says. “When it’s difficult to get the sample to the microscope, you bring the microscope to the sample.”

The easyScan is upgradeable with a variety of different scan heads and software packages, as well as vibration isolation attachments. Other microscopes Nanosurf offers are the portable Mobile S AFM, which includes multiple modes, and the tabletop Nanite, an automated system.

“The easyScan 2 is modular and can start below $15,000, and the Mobile S and Nanite can get closer to $100,000, depending on how they’re configured,” says Nanoscience Instruments’ Flowers.

Nanosurf’s easyScan can work on samples inaccessible to other microscopes.Click here to enlarge image

NASA researchers have approached Nanosurf to adapt the company’s AFMs for the Phoenix mission to Mars, scheduled for launch in August 2007. “The goal is a 300-gram microscope and 8-watt power consumption to analyze soil and ice samples,” Sum says.

So far Nanosurf has sold more than 1,000 of its STMs and 300 of its AFMs. “We’ve mainly looked at academic customers for the last 10 years,” Sum says.

Flowers adds that more and more industrial customers are emerging. “Time is money, and having an instrument that’s easy to use and accessible at different skill levels is very attractive for industrial quality control and industrial research.”

Another company that entered early into the advanced, lower-cost desktop imaging field is Pacific Nanotechnology. Its Nano-R2, the second generation of the Nano-R SPM for research and educational purposes, can accommodate samples up to a square inch. The Nano-I is a more-specialized tabletop system that uses the same scanner and software, but can accommodate samples as large as 12 inches for industrial applications, such as inspection of wafers, disks, and technical samples.

Pacific Nanotechnology’s systems have a vertical resolution of 0.5 angstroms and a horizontal resolution of 0.5nm. The Nano-R2 sells for $80,000, while the Nano-I retails at $120,000.

Veeco introduced its Caliber to attract a growing market it was not reaching.Click here to enlarge image

“Our systems are about 50 percent smaller than conventional AFMs and SPMs, at 12 inches x 12 inches x 12 inches,” says West. “They weigh maybe 100lbs.”

One of the main requirements for a desktop AFM or SPM is vibration isolation. “One of the things we incorporate into our devices is a heavy granite block, which helps protect the microscope against vibrations,” West says. Other vibration engineering safeguards remain proprietary information.

Pacific Nanotechnology also provides attachments to help users scan in gaseous environments, as well as heating stages and modes that allow scanning for electrical conductivity, magnetic fields, and other physical properties of samples. These can cost $1,000 to $5,000.

Here come the big guns

Increasingly, microscope giants are entering the field.

For instance, Veeco introduced a new handheld AFM in 2006. “We were seeing a market where we were losing, and now we have the Caliber AFM, which literally sits in the palm of your hand,” says David Rossi, vice president of Veeco’s Nano-Bio Business Unit marketing and business development. The Caliber has near-atomic-level resolution, he adds.

The list price for the Caliber is $57,000 in the U.S. “We’ve already shipped 25 to universities and materials development companies since the September timeframe,” says Rossi. “Our customers at this point are probably about two-thirds academia and one-third industry. It’s interesting: We’re seeing education institutions that would not have purchased a $200,000 instrument buying four or five Calibers for their teaching labs.”

Tabletop AFMs from Veeco include the CP2 and the MultiMode, “the highest-resolution AFM commercially available,” according to Rossi. The MultiMode costs $125,000 to $175,000, depending on the modes it comes with and what size scanner it has, while the CP2 costs from $80,000 to $110,000, also depending on the configuration.

Another industry leader, Agilent, announced its own tabletop imaging system-Agilent 5400 AFM/SPM-in December 2006, “which looks about the size of a classic optical microscope,” says Agilent’s Jones.

“We’ve targeted the market for instruments from $50,000 to $100,000, for both universities, who want more functionality than microscopes costing less than $50,000, but don’t need the bells and whistles for the $100,000 to $200,000 microscopes,” says Jones. “We saw this trend of people getting grants under $100,000, and it seemed like a good market. We’re also shooting for industry, where very pretty high performance is required in testing the same things over and over again but [where they are] not conducting hero experiments.”

Agilent designed its 5400 AFM/SPM for ease of use.Click here to enlarge image

When compared to the more-expensive Agilent 5500, the 5400 “doesn’t have some environmental control aspects, such as full environmental control or being able to do some of the more-difficult temperature changes, but we do have the ability to upgrade the 5400 to the 5500,” Jones says. “We’ve also completely rewritten the software to make it easier to use and so it can get set up easier.”

“We’re happy with sales. We’ve almost reached double the initial targets for the first quarter,” Jones says.

The 5500 imaging modes, such as the magnetic AC mode, which allows better imaging in fluids, are compatible with the 5400. These modes range in price from a few thousand dollars to $30,000.

Electronics giant Hitachi introduced its TM-1000 last year at a price of $60,000. “That’s similar to an expensive imaging analysis optical microscope from a price standpoint,” says Hitachi’s Gordon. “At the same time, our microscope offers imaging at up to 10,000X, about 1,000 times past the point after which optical microscopes run into difficulties. It also provides much better depth of field and surface topography detail than optical does.”

Hitachi achieved its shrinking trick by miniaturizing the electron column and optics at the heart of an SEM using computer-aided design (CAD). Also, the company used smaller pumps to provide the same quality vacuum as other SEMs. A laptop that contains the software to run the microscope is included.

Intriguingly, unlike conventional SEMs, the TM-1000 does not require metal coatings to observe nonconductive samples. Cutting out this elaborate preparatory step is part of Hitachi’s strategy to make the microscope as simple to use as a digital camera.

“When electron beam-sensitive samples start to charge, which could damage them, the variable pressure mode bleeds a little air into the system to minimize the charge put on any noncoated materials,” Gordon explains.

The TM-1000 does have much lower magnification than more-expensive SEMs. It also has fewer software capabilities, “keeping with the idea that it should be simple to use,” Gordon says. Moreover, unlike other SEMs, the TM-1000 operates only at a fixed voltage of 15kV.

Total production volume for the TM-1000 on a worldwide basis is approaching about 400 units, Gordon says. “We’re interested in going to much higher volumes-possibly 200 units per month,” he adds. In the future, Hitachi will consider attachments that add functionality, such as energy dispersive x-ray analysis or software packages allowing image archiving and database management, while not making the microscope too complicated to use.

Hot on Hitachi’s heels is FEI with its new Phenom, a tabletop electron microscope with magnification capability up to 20,000X. Designed to be easy to operate, Phenom offers a touch-screen monitor. It is currently being sold in the Netherlands, Belgium, Germany, and Luxembourg, with other countries added soon. Suggested applications for it include pharmaceuticals, metallurgy, manufacturing process, quality control testing, and basic research.

Rossi expects the market to grow as the semiconductor and other industries experience increasing metrology demands and the life sciences sector approaches the nano scale.

The devices will also continue toward trends of improved performance, capabilities, and ease of use, West adds.

“I’m very excited about how the market’s growing and about other companies entering it,” Sum says. “In the beginning, there was no competition, and so one wondered whether or not there was a big market here. If other companies are entering, that shows these technologies represent a good direction to go in. Competition’s good.”

Equity financing

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Acquisitions

Epion Corp., Billerica, Mass. Undisclosed amount
Acquirer: Tokyo Electron (TEL)
Description: TEL acquired Epion, a supplier of gas cluster ion beam (GCIB) technology for diverse semiconductor applications and emerging nanotechnology markets because it considers Epion’s GCIB a highly versatile atomic-scale processing technique that is ideal for production applications where surface and film quality are crucial. Key applications for GCIB include etching, smoothing, doping, and physical and chemical surface modification.

AMIA Labs, Leesburg, Va. Undisclosed amount
Acquirer: Evans Analytical Group LLC
Description: AMIA provides x-ray based analytical services to high-tech industries, including x-ray diffraction, x-ray fluorescence, and x-ray reflectometry. AMIA has developed proprietary techniques for the measurement of texture, stress, composition and thickness on thin films, as well as micro-diffraction capabilities for patterned wafers or specific areas on medical implants and many other manufactured parts. The companies said AMIA operations and staff will be integrated into EAG’s Round Rock, Texas, facility.

By John Carroll

A team of researchers at Johns Hopkins University has demonstrated a new way to slip drug-bearing nanoparticles through the body’s protective shields of mucus while surprising even themselves with just how big these microscopic delivery vehicles can be constructed.

By developing nanoparticles designed to mimic the appearance of viruses, they have opened up an appealing commercial opportunity for either licensing the technology to drug developers (who are eager to attack specific disease sites with more-effective therapies) or developing new therapies themselves. And previous research has proven that the nanoparticle pathway can be used to carry a large payload of sustained-release therapeutics.

“We actually thought that 500 nanometers would be so big that there was no way that it would go through,” says Justin Hanes, the associate professor of chemical and biomolecular engineering who supervised the team’s research project. “Based on the existing estimates of the mesh size of human mucus, we thought the largest particle that would go through would be at most a couple of hundred nanometers.”

Samuel K. Lai, a chemical and biomolecular engineering doctoral student at Johns Hopkins, was the lead author of the report, which appeared in the online edition of the Proceedings of the National Academy of Sciences on January 23.

Their work adds to the potential of nanomedicine in fighting disease, a subject that has attracted the attention of a variety of research groups around the globe. In fact, just earlier this year, researchers at Rice University announced that they had redesigned the Buckyball to include nontoxic peptides, giving it the appearance of a virus so that it could deliver medicine inside a cell.

Challenges and discoveries

The Johns Hopkins’ group started with an important insight from Richard Cone, a professor in the university’s department of biophysics, and co-workers. “Cone and his colleagues showed that a few of these small viruses could move in human mucus as fast as in water,” says Hanes.

To the eye, mucus appears to be a slimy, nonporous tissue. But using a high-powered microscope, the tissue comes into focus as a mesh. If you make the delivery vehicle small enough and build it to avoid sticking to the mucus, Hanes says, it can effortlessly slip through the sticky barrier used to trap pathogens and other material before they can harm the host.

A loose analogy is that it’s like someone jumping on a trampoline, he adds. A person is too large to go through, but if you put sand on the net instead it will sift through as you jump on it. “In nature the thing that jiggles nanoparticles is thermal energy. The big difference is that mucus is not just a physical barrier-it is also sticky. So particles small enough to fit through the mesh still get stuck in mucus unless they have special coatings.

Johns Hopkins’ associate professor Justin Hanes (left) supervised the research, while doctoral student Samuel K. Lai served as lead author for the report. The team used nanoparticles to get past the body’s protective shields.Click here to enlarge image

“We started to see that particles coated with low molecular weight polyethylene glycol-PEG-move extremely fast in mucus,” adds Hanes. What was startling, he says, is that the larger 200 nanometer particles traveled even faster than the 100 nanometer particles. So they asked themselves a new question: Just how big could they make a nanoparticle and still have it slip through mucus?

Viruses that are capable of moving through mucus have surfaces that are densely coated with positive and negative charges, the scientist explains, but the surfaces are net-neutral, meaning that they don’t stick electrostatically. The coating with charged groups also makes the viral surface water-loving, meaning they do not stick by oily interactions. “PEG was shown to be mucus-adhesive,” says Hanes, “but the studies that showed this focused on high molecular weight PEG-the adhesion effect was thought due to the ability of PEG molecules to attach to mucus in a kind of Velcro-like fashion. We thought that coating particles with low molecular weight PEG would prevent any oily interaction between the particle and mucus and make the charge on the nanoparticle net neutral as well.”

The key was using PEG with a molecular weight high enough so that it wasn’t toxic-a well-known process in the drug development field-but not so high that it would stick to the mucus.

Important implications

Hanes is still a little amazed that it worked for the largest particles. He’s even more amazed by the implications. “The advantage is that a larger particle is able to provide a much more sustained release of a wide variety of therapeutic and diagnostic agents,” says Hanes, who is also the director of therapeutics for the Institute for NanoBioTechnology at Johns Hopkins. “The time it takes for drugs to be released from the particles doesn’t increase linearly as you increase particle size; it’s much more than linear.”

By delivering drugs through nano-particles, drug developers can reformulate existing therapies, extending patent protection on active ingredients with a proven safety profile and making the therapeutic more effective. That can add millions of dollars in revenue, potentially making the difference in turning a successful drug into a blockbuster.

The bigger nanoparticle size also accommodates a wider range of drugs, expanding its commercial applications.

“We would envision that the company that owns this technology could partner with quite a few pharmaceutical companies,” says Hanes. “We could license this to an independent company or more likely found a company based on this technology. A start-up company could develop its own line of drugs and also potentially partner with pharmaceutical companies.”

This technology could work with many chemotherapeutic agents by providing extended-release, or dispatching cancer-fighting drugs directly to the tumor site. Drugs could be directed to the lungs, the gastrointestinal tract and the cervicovaginal tract, and applied against a host of big diseases such as chronic obstructive pulmonary disorder, Cystic Fibrosis, Crohn’s disease, inflammatory bowel disease, chronic infections, and more.

Another whole class of drugs could be developed in delivering antibodies through mucosal sites such as the female reproductive tract “where you’re susceptible to infection from viruses. Think about a long-acting treatment to prevent sexually transmitted diseases or viral infection, anthrax, or this year’s flu. You can envision a lot of potential applications of the technology.”

Big, fast and commercial

For now, the researchers are back at pushing the envelope on this nanoparticle breakthrough. They want to see just how big they can make the particle without slowing its passage through mucus. And Hanes and his colleagues, including lead author Dr. Jie Fu, have recently reported on a PEG-coated biodegradable polymer particle version that can encapsulate and deliver a wide array of drug molecules. They have a patent covering the new material and a few patents pending related to the most recent findings reported in PNAS.

“We hope to get 1,000 nanometer particles moving fast,” he says.

Hanes can also envision founding a company that will explore the field even further.

“I’m not leaving Johns Hopkins,” says the researcher, but there’s a distinct commercial opportunity here.

“There are a lot of different avenues to go down on this.”