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, firstname.lastname@example.org
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
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
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
“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
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.