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The challenge: Secure Food and Drug Administration approval to put a new type of device or material inside the human body.
The approach: Both CardioMEMS and AcryMed combined rigorous trials with early and constant communication with the FDA.
The result: CardioMEMS’ EndoSure Wireless AAA Pressure Measurement System received FDA approval in November. A catheter using AcryMed’s SilvaGard coating was approved in December.

By David Forman

Developing a new product – matching design and functionality with a real market need – is difficult enough. But when it comes to working inside the human body, it’s doubly so. Devices and materials used in vivo must undergo rigorous clinical trials in what is essentially a make-or-break process. Two recent success stories, one a MEMS company and the other a nanotech company, highlight some of the practices companies use to navigate the trials process.

Both companies – CardioMEMS of Atlanta and AcryMed of Portland, Ore. – saw their products receive FDA approval late last year. CardioMEMS makes implantable MEMS medical sensors. AcryMed makes antibacterial nanoparticle coatings for medical devices. In both cases, said executives at the firms, getting in touch with the FDA early on proved critical, as did clear communication and a collaborative attitude.

CardioMEMS’ implantable sensor is designed for use with stents that treat an aneurism of the lower abdominal aorta. In the condition, a weakened aortal wall begins to bubble out, a potentially catastrophic problem if it bursts. Currently, stents with a fabric coating are implanted within the artery to create a sort of tube-within-a-tube. When functioning correctly, the blood flows through the tube and the pressure on the arterial wall is alleviated.

However, leaks appear periodically when blood finds its way around the stent, putting pressure back on the damaged wall. Currently, patients must undergo CT scans on a regular basis to test for leaks. With CardioMEMS’ sensor, however, a doctor merely has to move a handheld antenna over the patient’s abdomen to determine whether there is any pressure on the sensor, which has been implanted into the aneurysm sac during the same procedure in which the stent was placed in the body.

CardioMEMS’ wireless pressure sensor is implanted in a patient along with an arterial stent. By measuring pressure, it can determine whether the stent is leaking. Photo courtesy of CardioMEMSClick here to enlarge image

In addition to the challenge of developing an innovative technology that combines MEMS sensors, wireless connectivity and proprietary software, “we also had to demonstrate to the FDA that the product is both safe and effective since we are a medical device company,” said David Stern, CardioMEMS’ chief executive.

To streamline the process, Stern said his company stayed in constant communication with the FDA and hired a director of regulatory affairs to be responsible for the effort. Clinical tests began in March 2004 in Brazil and ultimately also included Argentina, Canada and the United States.

For starters, CardioMEMS’ sensor is built on a ceramic silica substrate, he said. To prove its product’s safety, the company had to do extensive research to show that all the materials it used were biocompatible and also extremely stable.

Meanwhile, interesting questions popped up – like, how do you confirm that the device is always functioning correctly? After all, if the stent is doing its job, there may be little or no pressure in the aneurysm sac. It is important that physicians do not misinterpret a “zero” pressure reading as a non-responsive sensor.

Stern explained that as long as the antenna is receiving a frequency signal from the sensor, the physician can be assured that the device is working properly. Just the same, the company still developed a simple test to use during the follow-up pressure measurements: The patient coughs and the sensor responds by showing a pressure change.

AcryMed found success with a similar strategy even though it is ultimately AcryMed’s customers who must file for FDA approval rather than AcryMed itself. The company’s SilvaGard coating is intended to prevent the buildup of films on medical devices. Such “biofilms,” said Bill Gibbins, AcryMed founder and chief technology officer, can provide bacteria with a safe haven from which to launch repeated infections against their hosts.

“It turns out organisms are more coordinated (than we thought),” Gibbins said. “They will turn on a gene that makes them sticky and form a tightly adhering colony on a surface. …When a critical mass forms, it will release a chemical signal to make a polysaccharide coating that blankets the organisms.”

Catheters coated with AcryMed SilvaGard, at left, both look and act different from the uncoated ones at right. The yellowish coating helps prevent the buildup of biofilms that can lead to infections. Photo courtesy of AcryMedClick here to enlarge image

If you can keep biofilms from forming on devices, said Gibbins, you can keep many infections from forming, too. The company’s SilvaGard, a silver nanoparticle technology, is designed to do just that.

The surfaces of implanted medical devices are perfect for the formation of biofilms, Gibbins said, and the longer they are implanted, the likelier they are to create infection-related problems. “If a Foley (bladder) catheter is implanted three to five days, there is less than a 5 percent chance of an infection,” he said. But after that, he said, the infection rates begin to rise precipitously.

Since he knew his licensees would need FDA approval, Gibbins made sure his company was also working closely with the agency from the start. Concerted efforts included developing specifications for using devices, making sure their materials would meet with approval, establishing a baseline for what kind of antimicrobial performance to expect and determining whether there were any known side effects – of which they found none. In December, I-Flow Corp. of Lake Forest, Calif., received FDA clearance for its ON-Q SilverSoaker antimicrobial catheter, the first medical device to use AcryMed’s SilvaGard.

The payback for both CardioMEMS and AcryMed is not just the initial product, but also the momentum of a successful FDA clearance. Stern said CardioMEMS is now transitioning production of its sensors to a large-scale commercial fab, and the company plans to commence clinical trials on a second product within months. Meanwhile, Gibbins said AcryMed has received inquiries from more than a dozen new potential customers.

While I’ve never resorted to putting a Canadian flag on my luggage, I understand why Americans do it. People are nicer to Canadians than Americans. Canadians have a well-deserved reputation as being good, honest and nice. And nice doesn’t include pushy. Unfortunately.

Having just returned from a whirlwind tour of Montreal and Toronto, I have a better appreciation of the micro and nanotechnology landscape in Eastern Canada. There are interesting happenings in the white belt, though I doubt many people outside Canada know. At a national level, the Canadian government is not visibly promoting its capabilities to a broad audience.

My trip was sponsored by a Canadian embassy as a way to showcase their nanotechnology development efforts. But this was the initiative of a strategic-thinking investment development officer, not a coordinated push from above. It’s hard to be taken as a serious player when no one knows you are in the game.

Although the promotion isn’t there, the activity certainly is. NanoQuebec, a non-profit organization funded by the governments of Quebec and Canada, organized two days with startups, universities, venture capitalists and a MEMS manufacturer. There is support, including funding, for building a competitive nano cluster in Quebec.

During my trip I was given the good and bad of nano in Canada. However, what I am discovering is that regions are finding ways to leverage their strengths to make the most of limited resources. In Canada’s case, it appears that the university system is the key driver of the nanotechnology sector. Researchers are securing funding for infrastructure, focusing on technology application and are moving their research into the marketplace.

The Neurological Institute at McGill proves how researchers are crossing traditional academic departments to solve real-world problems with nanotechnology. In open discussion forums, researchers talk about the problems they are trying to solve. Unique angles, new approaches and a common language are being discovered through this dialog – creating excitement and initiative to work together driven by the bottom up, not the top down.

Although the universities in Quebec are competing against one another, the provincial government has instituted a process to encourage cooperation and to facilitate resource sharing. University researchers/grant developers go through two approving bodies before their infrastructure proposal is recommended to a federal funding organization. Quebec’s technology research fund assesses the project’s scientific value and partners with NanoQuebec to evaluate the industrial strategic value.

While I was there, NanoQuebec was facilitating discussions between the University of Montreal and McGill, two strong nano research institutions looking for support of double-digit million dollar projects. The goal is to eliminate duplication of funding requests and encourage research and equipment use across boundaries while prioritizing an industrial agenda.

The coordinated efforts in Quebec are paying off. According to the Canadian research funding database, Quebec’s nanotechnology related expenditures in 2004 – a little more than $47.5 million – were the size of all the other provinces put together, with the exclusion of Ontario at about $35.5 million.

More informally, the interconnection of academia and the industrial community in Quebec and Ontario was clear in almost all of my meetings. Industry relies heavily on the research community for technology development and facility sharing. While there seems to be a solid base for seed funding of new companies, the dollars available for significant equipment investment are hard to come by. Companies use relationships with the universities to meet their short-term research and development needs.

At the Ecole Polytechnique at the University of Montreal, an incubator system in a new nanotechnology building provides access to facilities for companies like Nanometrix, which is commercializing technology for monolayer assembly, and Nova Plasma, which is trying to solve degradation and quality issues in flexible organic electronics manufacturing.

Waterloo holds an entrepreneurial/commercial center and a vibrant university with a large undergraduate nanotechnology program. While I’ve heard arguments against undergrad nanotechnology degrees, I believe the industry demand for skilled labor (this program also requires 24 months of co-op experience) will create a strong pull for these graduates.

While considered by some to be a minor player, Canada has more potential than is commonly recognized. Strong research programs, high-quality workforce, solid research, and equipment will all assist Canada in playing an important global role in emerging technologies, albeit probably a niche one.

But take a lesson or two from one of Canadian’s rising nano stars, Ted Sargent. Learn the art of self-promotion.

Click here to enlarge image

Patti Glaza is vice president and publisher at Small Times. She can be reached at [email protected].

Steven Jefferts knows better than to make lofty predictions about F2. After all, it took his colleagues and him almost a decade of tweaking to get F1 into the position as the world’s best timekeeper.

F1 is nothing like a traditional clock, though. It’s a laser-cooled cesium fountain, a device that determines the passing of a second by measuring the oscillations of cesium atoms. “Nine billion and change” oscillations add up to a second, said Jefferts, a physicist at the National Institute of Standards and Technology in Boulder, Colo., and designer of F1. F1 can so accurately track the oscillations that it is projected to neither gain nor lose a second in 60 million years. Jefferts and his team published their record results in the journal Metrologia last fall.

Since 1999, F1 has set the standard in the United States and is a contributor to the International Atomic Clock. The data is used to synchronize Global Positioning Systems, for instance, and for defense applications ranging from navigation to code breaking.

“Time applications are not the place where huge accuracy is needed,” Jefferts said. “It’s when you’re trying to synchronize at high speeds. With GPS, if you just let the clock wander off on its own, eventually it will tell you a wrong time and give a positioning error.”

From left, physicists Steven Jefferts, Elizabeth Donley and Tom Heavner are mastering the art of accuracy by improving NIST’s atomic clock. Photo courtesy of NIST.Click here to enlarge image

Jefferts and co-workers Elizabeth Donley and Tom Heavner think in terms of reducing uncertainties rather than increasing accuracy. “There’s a laundry list of things that can mess up the clock,” Jefferts said. “They add up to the uncertainties.”

The NIST group earned their title as having the most accurate of the clocks through incremental changes that improved reliability: Swapping Jefferts’ homemade laser apparatus for a commercial product and better monitoring of subsystems allowed them to conduct uninterrupted run times. They even found ways to overcome the shortcomings of their lab space, an add-on to the NIST facility.

“We’re the poster child for how bad an environment can be,” Jefferts joked.

That will change this year. Jefferts and his crew in the Time and Frequency Division are moving to better digs within NIST’s building. The new space will hold F2, a second-generation fountain that may be in place by the summer. F2 is expected to have capabilities that will whittle away some remaining uncertainties. But based on his experience, Jefferts cautions, it will take some time before F2 has a hope of besting its predecessor.
– Candace Stuart