Fictional secret agent Maxwell Smart, of the 1960s TV series “Get Smart,” may have been an early adopter of mobile phones that do more than make calls—he often dialed his colleagues on a shoe phone. Of course, today’s smartphones, with their integrated cameras and advanced computational power, wouldn’t work well as footwear. But they have turned out to be powerful platforms for a new wave of point-of-care medical diagnostic devices.
Diagnostic devices that can be used in conjunction with a smartphone could allow health care workers to diagnose diseases or monitor a patient’s health on the spot, without the need to send off a sample to some remote laboratory. This, researchers say, could change the way people attend to their own health, putting a tool to monitor disease literally in their hands.
Such devices could also prove useful in the developing world, where smartphones are becoming common yet hospitals can be few and far between. In these regions, opportunities to diagnose easily treated disease are often missed. And for infectious diseases, such as influenza or Ebola virus, a point-of-care system combined with a smartphone’s ability to provide a geographical location could track a disease’s movement in real time and even identify and isolate patients to slow the spread of the disease.
“These days, smartphones are everywhere, and smartphones are getting more and more powerful in terms of their computational power and their imaging capabilities,” says Hakho Lee, director of the biomedical engineering program at Massachusetts General Hospital’s Center for Systems Biology. “A smartphone is really a minicomputer that happens to have telecommunications abilities.”
Lee is one of many researchers trying to take advantage of these devices and bring them to market as diagnostics. Last month, researchers in his lab, working with colleagues in Ralph Weissleder’s group at Massachusetts General Hospital, reported a smartphone attachment and related technology that allow them to detect precancerous and cancerous cells, as well as cancer-associated DNA (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1073/pnas.1501815112).
The researchers use immunobeads, little plastic beads about 7 μm across that are coated with antibodies that recognize proteins on the surface of specific cells. They add the beads to a sample from a patient, such as blood or Pap smear cells, and then place the treated sample on a slide. The antibodies make the beads glom on to cancer cells but not other cells that may be present, creating a distinctive fringe pattern around the cells when imaged.
The slide then goes into a device the researchers built that snaps onto the smartphone. Light from a light-emitting diode in the attachment shines through the sample and creates a diffraction pattern that’s imaged by the smartphone’s camera. This image gets sent off to a remote server, which analyzes it and sends the results back to the phone in about two minutes. The whole process—from taking samples to receiving the results—takes less than an hour.
Lee and Weissleder’s team used the device clinically to screen for cervical cancer in a small group of patients. Their results were comparable to those from a conventional cervical cancer test. The researchers also used a modified version of the technique to detect specific DNA sequences, which opens the door to using the system to screen for viruses or other pathogens, Lee explains.
Developing such portable diagnostics for pathogens has long been a goal of biomedical engineering professor Samuel K. Sia’s group at Columbia University. “We’ve actually been working on this before the smartphone was even invented,” Sia says.
Years ago, his team created a portable diagnostic device essentially from scratch, building an operating system, a user interface, and communications features. “It was a lot to build,” Sia says. “When it was clear that smartphones were going to revolutionize the way everyone does things, including in the most remote regions of the world and in developing countries, we started thinking that it might make sense to pair up our microfluidics technology with this really powerful device.”
Earlier this year, Sia reported a new diagnostic device his lab created that screens for HIV and syphilis (Sci. Transl. Med. 2015, DOI: 10.1126/scitranslmed.aaa0056). Syphilis is a problem in the developing world and can cause stillbirths. The disease can be treated with a single injection of penicillin, Sia explains, but many pregnant women don’t realize they’re infected.
These women often get screened for HIV, so Sia’s lab set out to build a device that diagnoses HIV and syphilis simultaneously with just 2 μL of blood. The device they came up with uses an enzyme-linked immunosorbent assay—also known as ELISA—to detect the pathogens.
The ELISA technology, Sia explains, has been established for more than a decade, but incorporating it into a portable device that operates in conjunction with a smartphone wasn’t trivial. Sia’s device plugs into the audio jack of a smartphone, where it draws all the power it needs to run the test. Health care workers simply take a drop of blood, put it on a microfluidic chip, place the chip in the device, and press a button. The device performs the entire ELISA analysis. An app Sia’s group developed gives them the test results in about 15 minutes.
For field tests, Sia’s lab sent the device to Rwanda, where local health care workers watched a 20-minute training app and then used the app to screen 96 patients. The test performed as well as standard tests, and because it required only a finger stick rather than drawing blood, nearly all the patients preferred it.
“Sometimes people don’t fully appreciate how much of a challenge it is to come up with a device like this,” Sia says. “Anytime you’re dealing with chemical reagents and biological specimens, there is a degree of variability that becomes much harder to control. And you still have to deal with the hardware and software issues because at the end of the day, people expect to be able to run the tests as easily as they run apps on their phones.”
Still, Warren C. W. Chan believes smartphone diagnostics could bring big changes to the way we monitor infectious disease. Chan says he started thinking about using mobile devices to track disease outbreaks back in 2003, around the time he joined the chemistry and biomedical engineering departments at the University of Toronto.
Back then, he says, severe acute respiratory syndrome, or SARS, was taking its toll on Toronto. Chan thought that cell phones, which had become widespread, could be used to track an infectious agent moving around the world in real time. The problem, however, was that cell phones back then just weren’t good enough to do what Chan wanted.
He says it wasn’t until Apple’s iPhone 4 came out in 2010 that the phone’s built-in camera was finally good enough to provide images on par with modern instrumentation. The camera and optics were important to Chan’s research team because they wanted to use them to image quantum-dot-containing polystyrene beads that are just 3 μm across.
Chan calls these beads bar codes. His team coats the beads with pieces of DNA that have a sequence corresponding to that of some target virus. Different beads have different sequences and different colors of quantum dots. For example, a bead bar-coded to detect DNA from HIV might have green dots.
To detect a virus, Chan’s team mixes the beads with DNA from a patient’s sample along with a bit of DNA attached to a fluorophore. If the viral DNA is present, all the pieces will assemble, and when illuminated by a laser, the beads will light up with the color of the fluorophore and the color of the bead’s quantum dot. If researchers see just the quantum dot color, that means no viral DNA is around.
Because quantum dots come in different colors, Chan’s team can screen for multiple viruses simultaneously by using a different-colored quantum dot bar code for each virus. The whole test takes less than an hour. All the sample preparation can be done in a single device Chan’s group built using a lens positioning system they found in a child’s telescope and a $2.00 laser.
The researchers recently demonstrated that the device can screen for HIV and hepatitis B (ACS Nano 2015, DOI: 10.1021/nn5072792). But Chan says the bar codes can be used to detect many types of pathogens, including malaria, influenza, and tuberculosis.
When it comes to mobile diagnostic devices, Aydogan Ozcan, an electrical engineering professor at the University of California, Los Angeles, has proven to be something of an aficionado. Ozcan’s group has made smartphone accessories that allow them to visualize red blood cells, lone virus particles, and even single strands of DNA. His group pioneered the use of diffraction patterns to image microscale objects on smartphones. Ozcan’s team also developed smartphone accessories that can detect certain allergens, albumin in urine, waterborne pathogens, and mercury ions in water (Lab Chip 2014, DOI: 10.1039/c4lc00010b).
Ozcan even cofounded a company, Holomic, to bring these technologies to market. And he’s been looking into making diagnostic devices out of other mobile technologies, including Google Glass and smartwatches. It’s not uncommon for the Ozcan lab to get a new mobile device before it’s even available to the public.
Ozcan says he’s amazed at the progress that mobile phones have made. His group started working with phones that struggled to image single cells roughly 10 μm across. “In a matter of seven years, we’ve been able to see single DNA molecules that are 2 nm in width,” Ozcan marvels.
But those same rapid changes in hardware and software can make it tough for those who make diagnostic accessories for smartphones. Most diagnostic devices, he says, need to be able to last for five to 10 years, which is an eternity in the smartphone market.
Even so, Ozcan says, designing medical diagnostics and other types of scientific instruments that are mobile makes science more democratic. “Now, many other researchers in the world will be able to do experiments that they could not do before, even in remote locations,” he points out. “That could offer some interesting opportunities for education, for training, and for generating high-quality data on a much larger scale.”