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Case Study — Resolution Sciences Corporation, Inc.

Some think big. But for Russ Kerschmann, thinking small has made all the difference. He’s the scientist who invented a brand new imaging technology that allows microscopists to view the three-dimensional (3-D) architecture of objects.

His is a grass roots success story that began on his kitchen table 15 years ago. Kerschmann, an anatomic pathologist, began work on a project that would eventually become the core technology of his company, Resolution Sciences Corporation, Inc. (Resolution), based in Corte Madera, California.

This forward-thinking technology is called digital volumetric imaging (DVI) and has altered the way microscopists study images by transforming biological tissue and materials science into high fidelity, 3-D digital replicas.

Before the introduction of DVI, all scientists and researchers were bound by the traditional glass slide-based method that offered only a two-dimensional (2-D) perspective of images. The amount of distortion introduced made it nearly impossible to re-assemble the hundreds or thousands of tissue sections into one good image. Instead, with the introduction of DVI, the entire sample is now stained with a fluorochrome dye, embedded in a specially formulated polymer, and physically sectioned on a precision-controlled robotic microtome.

“When it comes to doing 3-D reconstruction on samples of many cubic millimeters, serial glass slides were the predominant way that people tried to do that. No one in the 150 years of optical microscopy had been successful in making a truly high-fidelity rendering of a biopsy-size piece of tissue in 3-D,” Kerschmann said. Thanks to his creation, scientists can see inside the 3-D structure of samples many cubic millimeters in volume, and can conduct accurate measurements and analyses by investigating the approximately 1,000 to 3,000 virtual sections in each DVI set, that are imaged at as little as 1/4 of a micron resolution. An important tool in this process is the company’s software program RESView, that enables researchers to rotate samples in 3-D space and digitally cut into the data, examining a 2-D image along any axis, effectively establishing integrated 2-D and 3-D information. The price tag on this Windows NT or 2000 workstation is just under $24,000, and includes all the hardware, software, initial licensing fees, and upgrades. Customers can expect to pay $1,000 per sample for processing and will receive their images on CD-Rom or DVD. The tissues are dyed with a multicolored stain and technicians capture the color and bring it all the way through to the data.

The technology is exciting for many of Resolution’s clients including Douglas Chinn, Principle Member of the Technology Staff for Sandia National Laboratories, California. Sandia has incorporated DVI into its research and development protocols for imaging of micromachine parts, and Chinn has designed special structures for inclusion on his micromachine wafers. “The idea of having a 3-D image of a mechanical part clicked immediately, so I sent them one of our gears made with lithography electroplating and molding (LIGA) and they sliced it up and imaged it, and demonstrated the new part with their computer. It was obvious this would allow us to see things that we really don’t have any technique to see,” said Chinn. “What we can do with Resolution Sciences data sets that we can’t do with any other technology is match the 3-D data sets to a computer-aided design (CAD) model–and that is very powerful for the designers. Here we have a technique that effectively measures the entire surface of the device at once, so we get a color map out of the computer and the colors indicate how the real object varies from the CAD model.” He added that designers normally prepare drawings, and through an arduous and complex process, produce a real part. “There’s always some kind of variance, but now we can see instantaneously how the part varies from the design. The next step is to match data sets from each wafer to the other, so we can compare wafer 1 to wafer 2 and see how consistent our manufacturing processing is. This is very powerful.”

“I was looking at blood vessel networks in skin that had been irradiated with therapeutic laser light,” Kerschmann said of his days in the late 1980s as a research fellow for Wellman Laboratories of Photomedicine at Massachusetts General Hospital, “and the research group wanted to know where the threshold damage was occurring. They were asking me, for example, if the first damage occurs at the vessel branch points and all I had at the time was standard glass slides. It became clear I could not answer that question because vessel branch points are very three-dimensional in their arrangement in skin.” It was time to put his B.A. in neuroscience, M.S. in microbiology, M.D. from the University of Massachusetts, and clinical fellowship in pathology from Harvard to the test. Kerschmann began to develop DVI while working at the University of Massachusetts and later went on to work at the University of California, always hoping it would someday be valuable enough to stand on its own.

That day finally arrived in 1997 when the first investors appeared, and the result continues to please the inventor. Resolution was later awarded a $1.6 million grant from The National Institute of Standards and Technology, that partially funds its National Digital Tissue Repository (NDTR), a web-based collection of standard digital, biological tissue images available for purchase online. The program features high quality, 3-D DVI images of commonly used biological tissue samples that can be previewed interactively on the web. Resolution also won 5th place in Nikon’s Small World Photography Competition last year, for the submission of an image containing a sample of a coated magazine cover. Another winning image will appear in Nikon’s Small World Calendar later this year.

Though Resolution originally thought they would launch the innovative technology to the clinical field, they ultimately decided that commercializing it within the research community would be their focus. Today, their primary goal is to introduce the technology to more pharmaceutical and material manufacturing companies. They’re currently working with Genentech, Genetics Institute/Wyeth-Ayerst Research, Sandia National Laboratories, and GlaxoSmithKline Pharmaceuticals, among others.

Resolution’s relationship with Sandia National Laboratories continues to develop, and Chinn’s expectations keep growing. “What we have got is conventional scanning electron microscopy (SEM), optical microscopes, various surface profilometers, and some interferometer-type scopes. The problem with all of these imaging techniques is that they’re 2-D. Even the interferometry scopes–I call them 2 1/2-D, not true 3-D. We need information about all sides of the part. We need precision of measurement to better than a micron over these very distances of, say, a thousand microns. We also need to know information about surface finish and how the front of the part relates to the back of the part.”

Science and technology develop simultaneously, and, according to Kerschmann, the electronic age has been “absolutely critical” for his research and development. “I sat on this technology for almost a decade before trying to commercialize it. The amount of information generated is immense.” His company takes pride in teaching customers about their own products and helping them save money by providing “a better understanding of how the components of material fit together.” Manufacturers can potentially reduce the amount of materials needed to produce their products, and drive down their operating costs.

The DVI technology has applications in numerous areas of science, including genome research. Resolution works closely with collaborator Scott Fraser, director of the Biomedical Imaging Center at California Institute of Technology. Of Fraser, Kerschmann says, “He’s doing a lot of imaging of embryos with our systems, including vertebrae embryos, and he’s using it [our technology] to look at knock-out mutation changes in the entire embryo. We have the only technology that can image an entire embryo at cellular level resolution.” We’ve been able to image gene expression distributions in entire embryos using fluorescent proteins. They can use it to track the migration of different cell types in the development of embryos.”

Though Kerschmann proclaimed his discovery of how to make the chemistry and tissue block work to get a sharp image a “Eureka moment”, he’s not done yet. What does the future hold for this scientist turned entrepreneur? This time, he’s thinking big: “I’m hoping our technology will be widely used in industry and academia and will be the standard practice for 3-D microscopy of large amounts of samples.”