Nightingale-EOS Ltd.

Full article reprinted from Start Up - October/November 2009

Nightingale-EOS Ltd.'s Beam Profile Reflectometry technology evaluates coatings on medical devices by measuring the interference effects caused by the interaction of light reflecting from the coating surface with that from the substrate surface. The company's first focus is on implanted cardiac devices, primarily drug-eluting stents, where BPR can measure the concentration of the drug within the film of the coating. Read more...

Nightingale-EOS Ltd.

Full article reprinted from Start Up - October/November 2009

For 10 years before starting Nightingale-EOS Ltd., British-born Stephen Morris worked for a firm in the semiconductor industry in Silicon Valley that made coating thickness monitoring equipment for semiconductors. Therma-Wave Inc. had been the first company back in 1992 to launch a groundbreaking optical technology for measuring thin films on semiconductor wafers.

"This technology proved extremely successful," says Morris, who joined Therma-Wave in 1996 as an applications scientist. "It propelled the company very quickly to market leader within the semiconductor metrology industry." By 2005, Morris had advanced to Therma-Wave's director of marketing, around which time he began to contemplate broadening the use of the company's technology beyond the semiconductor arena. "After conducting market research, I concluded that a good opportunity existed within the medical sector for measuring drug coatings on medical implants," he says. Morris homed in on cardiac devices—primarily drug-eluting stents--because of their high value and the demanding nature of the application due to their small size, complex geometry and tight tolerances.

Nightingale's core technology, Beam Profile Reflectometry (BPR), reflects a laser beam off a surface and analyzes the laser reflectance as a function of geometry (the angle of the laser beam upon the surface). "Our technology is the only method I'm aware of that allows coatings to be measured accurately on actual medical devices," states Morris, who holds a PhD in physics (specifically the optical properties of semiconductors). He also notes that medical device manufacturers have been slow to adopt "the same sort of quality control practices that are well established in other industries."

The overall market for cardiac implants (stents and other coated cardiac implants) is $28 billion worldwide, of which $5 to $10 million could potentially be devoted to evaluating cardiac implants for their coating properties. CE mark approval of Nightingale's first product, the n-Gauge, a process control tool, is expected mid-2010, whereas FDA approval is not necessary because the tool is not a medical device itself. Morris expects stent manufacturers to be early adopters of the company's technology.

Morris was employed at Therma-Wave from 1996 to the end of 2005, whereas Alistair Taylor, Nightingale's chairman, is a chartered accountant with 45 years of experience in the pharmaceutical and medical device industries. Taylor founded Lombard Medical Technologies PLC in 2000 and served as executive chairman until 2007. During his tenure, the company became two divisions: Anson Medical Ltd. (abdominal and thoracic stent grafts) and PolyBioMed Ltd. (biocompatible and drug delivery coatings). In addition, from 1993 to 1999, Taylor was CEO at Biocompatibles International PLC, a biocompatible and drug-delivery coatings company that developed the first biocompatible-coated coronary stent in the world. The coronary stent division was sold to Abbott Laboratories Inc. in 2002 for $160 million. Taylor also acted as CEO of Schneider Worldwide, which developed the first coronary stent (acquired by Boston Scientific Corp. for $2.5 billion in 1994).

Nightingale has a total of 20 patents (17 issued, three pending), including some licensed under an agreement with California-based KLA Tencor (which acquired Therma-Wave in May 2007), for which Nightingale will pay a nominal royalty fee.

Nightingale's BPR technology evaluates the interference effects caused by the interaction of light reflecting from the coating surface with that from the substrate surface. "When you have a coating upon a surface, laser light reflects off the upper surface of the coating; in other words, the interface between the coating and the surrounding air," Morris explains. "Other light, however, penetrates the surface and travels down to the buried interface where the coating meets the underlying device and is reflected back. By analyzing this reflected light, you can infer the properties of the coating."

The two primary properties measured are thickness and the refractive index (closely correlated with chemical composition and density). "You need to measure the refractive index in order to achieve an accurate measurement of the thickness of the coating," Morris says. "Other technologies can measure coating thickness, if the refractive index is already known. Our technology enables manufacturers to characterize both thickness and refractive index on actual devices at the same time."

In the case of a cardiac stent, the refractive index correlates with the density or concentration of the drug within the film of the coating, which determines the dose rate that a patient receives.

Nightingale's technology is ideal for in-line process control, with every individual device able to be measured. "Up until now, this hasn't been possible," Morris says. As envisioned, a device manufacturer's employee would take the implant off the line and place it on the Nightingale process control tool. BPR would then be performed, largely automated and taking one or two minutes to characterize the device fully. Initially, though, the user will need to locate the laser beam on the sample, using a microscope, then press a button to acquire all the relevant data automatically.

In addition to coating thickness and refractive index, the Nightingale system is sensitive to coating roughness, and also to birefringence, which is related to the strain (tensile or compressive) in the film caused by the substrate properties.

A joint project with three partners (Nightingale, Lombard Medical Technologies PLC, and the United Kingdom's National Physical Laboratory), whose findings were released in October 2008, concluded that Nightingale's technology is accurate compared with the best-practice techniques currently available.

The three closest competitors, according to Morris, are Veeco Instruments Inc. (white light interferometry), Mikropack GMBH (spectrophotometry), and Olympus Industrial (confocal microscopy). "With white light interferometry, you need to know the refractive index before you can take a thickness measurement. Also, this technique does not work well on films less than 2 microns thick, while our technology can measure well below 1 micron--in fact, down to a few nanometers," Morris says. Similarly, spectrophotometry also requires prior information about the refractive index, and the measurement area "needs to be uniform over a fairly large area: no smaller than 10 microns. Nightingale technology is able to measure a very small area upon the surface. Our probe beam size is about 1 micron." Confocal microscopy also requires the refractive index beforehand and "is slower because you need to physically move the sample up and down along the Z axis relative to the lens," Morris points out. "You are unable to take an instantaneous measurement. With Nightingale technology, you simply point and shoot. It is a single data-acquisition event."

—Bob Kronemyer

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Companies mentioned in this article:

Boston Scientific Corp.

Schneider Worldwide

Nightingale-EOS Ltd.

Lombard Medical Technologies PLC

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