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In January, Clarivate Analytics released its listing of the Top 100 Global Innovators, based primarily on prolific and successful patenting activity. Among such renowned commercial firms as Apple, 3M, Google, Sony, and Microsoft, an outlier made its mark: The University of California (UC) system was the only academic entity to make the list.

Of course, with 10 campuses, almost a quarter-million students and nearly as many faculty and staff, the UC system defies any effort to determine a single factor in its success at innovation. Similarly, attempting to characterize any one portion of UC research as “representative” would exclude far too much.

Nevertheless, Clarivate resources such as the Web of Science and Derwent World Patents Index can point in interesting directions, offering a sampling of the work that has placed UC at the forefront of worldwide innovation. Here, we highlight one particular lab, on the Los Angeles campus, where the lead researcher and his colleagues have transformed an everyday object into a powerful and versatile tool for microscopy.

Portable Microscopy

Aydogan Ozcan, UCLA

 

UCLA’s Aydogan Ozcan, who leads a research group in the Electrical Engineering and Bioengineering department, ranks among UC’s most-prolific filers of patents. Early in his career, he decided to take his engineer’s interest in physics and optics in an unconventional direction: into the realm of biomedicine.

“Toward the end of my Ph.D.,” he says, “while focusing on nonlinear optics, fiber optics, and the like, I realized this interesting parallelism between some of the tools I’d been creating and their synergies with biomedical optics.”

So, with his doctorate complete, Ozcan made the risky decision to accept a post at Massachusetts General Hospital, part of the Harvard Medical School. There, working with doctors, he learned about navigating the area between the engineer’s obsession with novelty and the physician’s interest in invention as a means of helping patients.

With a growing interest in computational imaging and sensing, Ozcan grasped the pressing need to simplify the tools used for medical measurement and diagnosis. Microscopes and sensors used in clinical settings are expensive, bulky, and difficult to miniaturize without affecting performance. Ozcan set out to create instruments that would be lightweight, portable, and cost effective, while also capable of matching the performance of their benchtop counterparts.

Ozcan realized that a potential platform, with imaging and processing power built in, already existed: the typical smartphone. Even with the earlier-generation, less-smart phones of a decade ago, the concept proved itself. Ozcan and his colleagues fashioned a cylindrical attachment that combined LEDs and optical fibers, with a slot to receive a small slide holding the sample to be analyzed. The housing contains no lens or other bulky optical devices.

With the device attached to the smartphone’s camera module, the LEDs illuminate the sample. In lieu of conventional focusing, a series of algorithms repeatedly analyze the shapes, which in fact are holograms, ultimately creating higher-resolution images.

In 2007, as Ozcan notes, the cellphone microscope could barely image a red blood cell – roughly one-tenth of a human hair. Subsequently, given improvements in processing power and the mobile interface, as well as refinements to the phone attachment, the lens-free apparatus now permits views of viruses and even smaller objects.

“Imagine a mobile phone that has a very lightweight and cost-effective 3D-printed attachment,” says Ozcan, describing some of the lab’s recent work. “With the use of fluorescent tagging, the device allows you to see a single DNA molecule, about 2 nanometers in width. We’ve used this mobile technology to examine genetic mutations in tissue samples, including a mutation that causes cancer in humans. With mobile phones increasing in terms of optics, computational power and connectivity, even if you don’t have the power on your phone, you can use a 4G network and have a server work for you.”

In addition to targeted gene sequencing, Ozcan and colleagues have used the cellphone-based technology and assorted variations for vaccination screening, investigation of antimicrobial resistance, and many other applications. The advantages of the devices for on-site diagnostics, particularly in the developing world and other underserved areas, are obvious.

“Literally,” says Ozcan, “you are replacing a benchtop instrument, which may cost $20,000 or more and is the size of a printer, with a handheld, lightweight, cost-effective device.”

Proceeding Swimmingly

Meanwhile, Ozcan and colleagues are advancing their work in other areas of optics. Their refinements of “on-chip,” computational microscopy have permitted views that surpass those of traditional, high-end microscopic tools. For example, their 3D examination of the locomotion of human and horse sperm over a large sample volume has yielded new discoveries of motion that had eluded light microscopes. These swimming behaviors, involving a “chiral ribbon” pattern, had been predicted theoretically, but the extremely fast motion had previously escaped clear resolution.

Paper Citations
D. Tseng, et al., “Lensfree microscopy on a cellphone,” Lab on a Chip, 10 (14): 1787-92, 2010. 192
H.Y. Zhu, et al., Optofluidic fluorescent imaging cytometry on a cell phone,” Analytical Chemistry, 83 (17): 6641-7, 2011. 164
O. Mudanyali, et al., “Compact, lightweight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab on a Chip, 10 (11): 1417-28, 2010. 160
O. Mundanyali, et al., “Integrated rapid-diagnostic-test reader platform on a cellphone,” Lab on a Chip, 12 (15): 2678-86, 2012. 151
H.Y. Zhu, et al., “Cost-effective and compact wide-field fluorescent imaging on a cell phone,” Lab on a Chip, 11 (2): 315-22, 2011. 145

TABLE 1: Aydogan Ozcan: Most-Cited Papers Published Since 2010
(According to citations tallied in the Web of Science Core Collection)
Source: Clarivate Analytics Web of Science

The adjoining table lists the most-cited papers by Ozcan and colleagues published since 2010 – a small portion of his nearly 200 reports indexed in the Web of Science Core Collection.

Ozcan’s work has also demonstrated its centrality in a specialized area of investigation marked by a Clarivate Analytics “research front.” Research fronts are self-organizing nodes of activity that are identified by analysis of citation patterns. Specifically, a front forms when a foundational group of “core” papers are frequently cited together by later papers, indicating a common theme or thread in the cited work. Together, the core papers and the later citing papers constitute the front, denoting a discrete and often fast-moving area of research.

Of the 32 foundational papers in a research front devoted to microfluidics and point-of-care diagnostics, 10 papers by Ozcan and colleagues form nearly a third of the core.

With a View to Viruses

Smartphone with attachment for screening water-borne pathogens

 

In continuing to refine his lab’s work on diagnostic devices for locations that might be remote from medical resources, Ozcan’s current interests include what he calls “the intersection of machine learning and general imaging.” Working with water-borne pathogens, his lab compiled the statistical signatures of known samples of the chlorine-resistant parasite Giardia. In the scenario that Ozcan and colleagues are developing, a data server is “trained” to recognize the shape of the pathogen. Samples from the field can be transmitted via a microscope-equipped cellphone to the server, which in turn can perform the detection and return results, all without the necessity for a microbiologist.

His lab also recently demonstrated a similar platform that merges computational imaging and machine learning for air-quality mapping, determining the particulate matter density in air.

Ultimately, Ozcan hopes to turn the power of computational imaging to an extremely daunting challenge: viewing viruses as they move freely and infect cells. Given the vanishingly small size of his quarry – “a million times smaller than a typical cell,” notes Ozcan – it’s a tall order. This is particularly true of the scale envisioned by Ozcan: Not just viral activity captured within a single cell, but hundreds of thousands of cells, all in parallel. Despite the high-risk prospects in terms of success, Ozcan views the rewards  the insights into the dynamic processes by which viruses enter cells and replicate  as worthwhile.

On Fostering Innovation

Confirming Ozcan’s status as a significant contributor to the UC’s record of innovation, Derwent World Patents Index records his more than 130 patents and patent applications filed worldwide.

Ozcan also fosters innovation as leader of a research group that usually includes 40 to 45 undergraduates. His strengths as an educator were recognized by the Howard Hughes Medical Institute, which in 2014 selected him as an HHMI Professor. As the Institute notes, the five-year grant “empowers research scientists who can convey the excitement of science to undergraduates” [and who have] “developed new educational resources and implemented novel mentoring programs to support students.” The program in Ozcan’s lab is sufficiently immersive that a few undergrads, by the time of their graduation, have received royalty checks for their contributions to patented work.

For undergrads and all those in his charge, Ozcan favors a hands-off approach. “I don’t like to micro-manage,” he says. “I like to leave students free – to give them room to think, to learn, to make mistakes. Of course, we meet periodically, but in between they should have some bold ideas without a lot of deadline pressure. Failure is one of the best things. Without failure you can’t invent anything.”

Ozcan has particular appreciation for what he terms “false alarms.”

“It’s when you think you’ve invented something,” he says, “and you think it’s big and you’re very excited, and then you realize that it’s not working as you imagined or, worse, you learn that it’s already been done. But then you think, at least I was correct in that ‘a-ha!’ moment. I’ve enjoyed all of those false alarms.”