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Not Your Father’s Microscope

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In the not-too-distant future, clinical microscopy will look a lot less like it does now. Here, we look at several examples of the next generation of microscopes being developed for health applications (or at least with one eye on health applications), from light, compact instruments designed for limited-resource settings to digital pathology systems that can send images to servers for remote viewing.

Gary Boas, News Editor, [email protected]

Researchers have devoted increasing effort to developing microscopes that can be used in the field for global health applications. Some have started with the conventional microscope design, condensed it and replaced many of the existing components with less expensive alternatives – for example, webcams and digital cameras that have come on the market in recent years.

Others investigators, however, are looking to develop unconventional microscopy modalities. “If my goal is really to create a tool that works in the field – if I really want to engineer something that’s affordable, compact and lightweight – then trying to simplify the conventional design can never be optimal,” said Aydogan Ozcan, an assistant professor of electrical engineering at the University of California, Los Angeles (UCLA), Henry Samueli School of Engineering and Applied Science.

Ozcan and colleagues are developing cell phone-based lens-free digital microscopy for global health applications. Weighing less than 1.4 oz, the technology attaches to the camera unit of a phone. Samples are loaded from the side of the device and vertically illuminated by an LED. The LED light is scattered by the sample and interferes with the background light, thus creating a lens-free hologram.

Researchers at UCLA are developing cell phone-based microscopes for global health applications. The instruments are affordable and lightweight, taking advantage of cell phones that are already widely available in the developing world to send images to remote PCs for analysis. Courtesy of Lab on a Chip.

They have also demonstrated cell phone-based wide-field fluorescence and dark-field imaging, with similarly compact and lightweight optical components.

Ozcan points to the robust cell phone market as a major enabler of this work. The hardware is phenomenally sophisticated, he said, and for no reason, companies are introducing cell phone cameras with ever higher resolution. “That creates an opportunity for scientists like me to get our hands on 8- and 12-megapixel CMOS sensor arrays. Without the cell phone market, these would be 200- to 1000-fold more expensive than what I am paying today.”

Even more important, perhaps, is the cell phone itself – that is, its connectivity. Within a few years, 90 percent of the planet will carry at least one cell phone, and a great many of these phones are already in use in the developing world. As a result, health care workers can carry very simple, cost-effective hardware into the field and link it to advanced algorithms running remotely on a simple PC.

A third component, Ozcan said, is the extremely fast graphics processing that has become available in recent years, thanks to the needs of the gaming industry. Advanced units specifically optimized for graphics applications are playing an important role in the development of microscopes for global health care applications.

In many cases, the technology is nearly ready to go. “I don’t see any reason why it can’t be implemented at the consumer product level within two years,” Ozcan said of the cell phone-based technology that he and colleagues are developing. There are still hurdles to be overcome, however. It is not a question of science but rather one of developing a business plan that will foster sustainability.

“People like myself are realizing more and more that, while it’s extremely important to use the technology in the developing world, sustainability of that model is a bit difficult,” Ozcan said.

mBio Diagnostics is developing technology for infectious disease diagnosis. The technology can be used in a variety of resource-limited settings.

One of the ways to achieve such sustainability is to leverage the technology against other, similar application areas – or even to view these as all of a piece. “We look at point-of-care, home testing and world health together as resource-limited settings, where users are not formally trained medical technicians and the ‘lab’ facilities are not sophisticated,” said Chris Myatt, founder and CEO of mBio Diagnostics, which is developing solutions for infectious disease diagnosis and research. “This is true of a clinic in Mozambique, a mobile STD van in San Diego, or in a home in New York.”

The researchers demonstrated the performance of a cell phone-based fluorescence microscope by imaging labeled white blood cells. Images of the same sample, obtained with a conventional fluorescence microscope, are shown for comparison. FOV = field of view. Courtesy of Lab on a Chip.

Myatt points to the Pima analyzer as an example of a device that can be applied in multiple resource-limited settings. Marketed by Alere, the instrument uses microscopy, image analysis and cell counting to offer an analysis of CD4 cells that rivals existing flow cytometer analysis, all in a portable, robust package. This allows for management of HIV patients in point-of-care locations, delivering an absolute count of T-helper cells in whole blood in 20 min.

Devices such as this – not generic microscopes, but still capable of imaging cells and analyzing them on small, internal processors – can also serve for global health applications. The instrumentation isn’t going to be as low-cost as a cell phone-based device, Myatt said, but there is no need to send images to a remote PC for analysis since the “computation is not that troublesome.”

“In many ways, the underlying technology has been driven by the cell phone revolution,” he added. Here, though, the developers have decided to incorporate all of the advances into a single, stand-alone device to avoid some of the snags one might encounter when relying on cell phones – rapidly changing models, occasionally having to reinstall drivers, etc.

Olympus’ cellSens software is helping to improve work flow by enabling users to control many aspects of the imaging process from within the software.

Researchers are eyeing a number of potential home testing applications. Among these are ovulation monitoring and male fertility tests. In a recent issue of Analytical Chemistry, for example, Ozcan and colleagues reported a compact and lightweight platform with which to conduct automated semen analysis using a lens-free on-chip microscope. In addition to home testing, the device could find use in fertility clinics and in veterinary medicine – for example, in stud farming and animal breeding applications.

Head in the cloud

The field of microscopy is generally moving toward digitization of the acquired images. Researchers can achieve this simply by taking field-of-view images with a camera positioned on top of a microscope, or by implementing virtual microscopy techniques in which the entire specimen is digitized for remote viewing and a variety of other uses.

A number of companies are developing technologies for virtual microscopy – automated technologies that enable digitization of the specimen at high resolution and subsequent storing and sharing of the images. Olympus America has been working with such a technology. Originally developed by Bacus Laboratories of Chicago (Olympus America acquired Bacus just over four years ago), the technology allows users to create large data sets – images upward of 2 to 4 GB in size – and share them via the Internet. It can scan slides at true 20x/0.75 numerical aperture (NA) and 40x/0.95 NA, and can be outfitted with a slide loader for high-capacity and automatic throughput.

In clinical research applications, many users are interacting more with a computer and software than with the microscope itself. Recognizing this shift, Olympus is offering a digital pathology system that automatically scans slides. The system also can transfer images to a server for remote viewing.

Currently, the technology is designed to aid in research, such as with brain mapping efforts. But Olympus America is looking toward clinical applications. “Every indication is, this is a direction in which the technology will evolve,” the company’s Lorne Davies said. “It could offer tremendous benefits within the clinical environment.”

He noted, for example, how a small lab might use it. The pathologist might not have the degree of expertise needed for a particular reading, or might just need an opinion. Today, he or she would pack up a glass slide, put it in a courier box and send it to a pathologist who could help. The turnaround time could be days. Using virtual microscopy technology, this could be done digitally in real time, speeding up diagnosis considerably.

The FDA is exploring the possible use of virtual microscopy for clinical applications. It is seeking to determine the safety and effectiveness of the technique, looking at the differences between viewing and navigating on a computer screen vs. on a light microscope, for example.

Feb 2011
AlereAnalytical Chemistryautomated semen analysisAydoganAydogan OzcanBacus LaboratoriesBasic ScienceBiophotonicsBoasbrain mappingBX3BX3 seriescamera phonecamerascell phonecellSenscellSens softwareChrisChris Myattclinical microscopyCMOSdarkfield imagingDaviesdigital microscopyFeaturesfertility clinicsGaryGary BoasGlobal healthHenry Samueli School of Engineering and Applied ScienceHome testingimagingimaging and sensingimproved workflowlens-freeLorneLorne DaviesmBio DiagnosticsMicroscopyMyattNewport Corp.Olympus AmericaOzcanphonePimapoint of careresource-limited settingsSensors & DetectorsUCLAupright microscopesveterinary medicinevirtual microscopyVision IsoStationwide-field fluorescent imaging

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