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The Point of Care

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Editor's note: This article has been modified from an earlier version, which misstated Dan Luo's given name. GT regrets the
error.

In some parts of the developing world, you'd be hard-pressed to find refrigerators — which need a consistent supply of electricity — and clean water — or, in some cases, water at all. But, both electricity and water are required to perform most diagnostic tests for infectious diseases.

"The only things you have, actually, are Coca-Cola and cell phones," says Cornell University's Dan Luo.

Like globalization brought soda to places without potable water and mobile phones to areas not connected by landlines, Rick Henrikson at the University of California, Berkeley, says resource-poor settings are suited for point-of-care diagnostic tests because they lack centralized labs.

For most diagnostic testing in developed nations, "you go get blood taken and [that is] sent to a lab, and a few days later, get a result," Henrikson says. "Point-of-care diagnostics are competing with that, so you have to prove that your results are as good as these tests in the centralized labs, and also prove that there's some benefit for you to take that out of the centralized lab."

Theoretically, then, "the easier entry-point is in developing nations — sort of like the leapfrog effect we saw with cell phones," he says. Since, for the most part, there are no centralized labs in developing nations, resource-poor settings are "in a lot of cases a better target where you can develop these point-of-care diagnostics and not necessarily have to be directly competing with that infrastructure," Henrikson says. Plus, he adds, "there's motivation to apply these in developing nations where there's no other solution that exists right now that's practical."

For Brown University's Anubhav Tripathi, the main drive to develop amplification-based point-of-care infectious disease diagnostics is -access. "[It's] to get low-cost diagnostics to small clinics, [so that] not only big hospitals or rich clinics have access," he says.

Samuel Yang at Johns Hopkins Medicine also says access is the primary driver. "There is certainly a great clinical need to get some of the advances of PCR-based diagnostics technology that are right now only available in hospital-based laboratory settings available to the resource-limited settings to allow more timely diagnoses to be made for those who are unable to get to your traditional hospital-based setting," he says.

Market matters

Movement within the point-of-care diagnostics market is yet another driver. A January report from market-research firm BCC Research said that the global market for point-of-care tests — valued at $13.8 billion in 2011 — is projected to reach $16.5 billion in 2016. Of course, infectious disease testing is but one of several spheres within that total market. Taken on its own, the point-of-care infectious disease diagnostics space would expand at a compound annual growth rate of more than 10 percent for the next five years, BCC Research projected.

Still, there are questions as to who will cover the cost of bringing diag-nostic tests to resource-poor settings and whether developing point-of-care infectious disease tests for developed nations is also worth the hefty R&D price tag.

"A lot of people say that there is just not a market that can support a lot of these technologies because ... who's going to pay for it?" Berkeley's Henrikson says. "It will take a creative business model [for these tests] to be successful in the developing world." Financially speaking, "it seems more likely that niche point-of-care markets will be created in the developed world initially, and then those technologies will later be ported to developing nations," he adds.

But Hopkins' Yang is confident there is a solid market for point-of-care infectious disease diagnostics in both settings, particularly because "diseases are migrating very rapidly," he says. "We need to be able to detect existing or emerging infectious diseases early, wherever they are."

Push or pull?

It's not yet clear which amplification-based approach is best for infectious disease detection, nor which is most suitable for mass production and commercialization. Several labs seek to take PCR to the point of care, but continue to face challenges. Others are putting the principles of PCR toward alternative amplification-based diagnostics.

"There is this sense in the field that something will take off within the next five or 10 years, but the killer application hasn't been found yet," Berkeley's Henrikson says. "Right now, you've got all these labs developing some kind of technology that, in a lot of cases, isn't necessarily problem/pull, it's more technology/push. People are trying to develop technologies and push them to fit a particular application instead of saying: 'Here's the problem, let's build something specifically for this.'" Compounding the issue, he adds, is that at present there still is "not really a good bridging of the gap between academic labs and industrial production of these devices."

Brown's Tripathi says many mobile PCR devices developed to date have disappointed due to their complexity and limited repeatability. Because of "the number of steps that go into performing that assay, they don't repeat well in the field [even though] they work really well in the lab," he says. "Sometimes those assays are coded to be very sensitive and selective, but in the real application, the performance becomes dependent upon a lot of other environmental conditions."

In an Analytical Chemistry preprint posted online in February, Tripathi, his student Stephanie Angione, and their colleague Anuj Chauhan at the University of Florida report on a tablet platform they developed to perform temporal PCR in microliter droplets. Because this droplet-based approach "does not require extensive processing or external equipment ... [it] allows for a greater ease of use and integration as a point-of-care-diagnostic," the team writes.

"What we really tried to do was make something really simple," Angione says. "A lot of other PCR chips [require] a lot of fabrication, are time-consuming to make, and are difficult to operate. What we really did was shoot for simplicity — to keep it really basic so that it is easy to use, repeatable, and the results are very reproducible."

In their paper, the team applied its platform to both standard DNA amplification and RT-PCR to detect H3 influenza RNA in real time. "We're also looking at clinical samples for subtyping of influenza, especially with swine flu and seasonal flu," Angione adds.

Still, this work is at an early stage. Tripathi says his group is now writing a small business grant with Rhode Island-based healthcare product development firm Ximedica to refine their platform further. Along with integrating a detection system, Angione says the group is working to streamline the assay, so that untrained individuals can successfully operate it. The group also intends to develop a sample prep device to accompany the platform, Tripathi adds.

Point-of-care tests have not yet made it into the field because they are still too complicated, Cornell's Luo says. His lab is one of several groups funded by the Bill and Melinda Gates Foundation to develop a portable pathogen detection device.

As an alternative to PCR — which Luo is not convinced is the best choice for point-of-care tests — Luo's signal amplification approach is enzyme- and equipment-free. It's based on chemistry known as target-driven polymerization, in which weighty polymer aggregates form only in the presence of pathogenic DNA, RNA, or antibodies. To detect the polymer aggregates, Luo teamed up with Cornell electrical engineer Edwin Kan, who is developing a complementary-symmetry metal-oxide semiconductor, or CMOS, device for this purpose. "He developed a CMOS system that's really, really small, but can weigh our polymer aggregates and also sense the charges," Luo says. "The beauty here is that all our design is based on DNA, so the charge in the mass ratio is constant for DNA — no matter how big the aggregate is, the ratio is always constant. And that will give us a great standard to distinguish between the aggregates and dust particles or any contaminants."

A key advantage of Luo's target-driven polymerization approach is that it can be run using soiled water. "Our polymer doesn't work in Coca-Cola," he jokes, "but in all other unpurified water. That shows the robustness of our chemistry." Luo adds that because the assay can be run at any temperature and in a matter of minutes, it is well-suited for the point-of-care setting.

Plug and play

For Luo, the Gates Foundation's approach — which separates point-of-care diagnostic development into steps — is the best route to successful R&D efforts. "They actually divide point-of-care into modules: sample preparation, signal amplification, readouts, and then legal and implementation, manufacturing issues," Luo says. "That's a very clever way; it's a very, very good strategy to separate them because very few labs are good at all of them."

Still, "integrating [the modules] will be one of the greatest challenges," Luo says, adding that the foundation is "trying to establish a so-called plug-and-play type of modular strategy, where you are not spending time developing one point-of-care assay and then you have to start again for another disease. It would be great to have some kind of universality, combined with the flexibility to put them together."

Hopkins' Yang also says integration is the greatest single technological hurdle facing point-of-care diagnostics. "There have been a lot of advances made in ... technology from an individual device standpoint. Right now, we've been able to do fairly well in terms of miniaturizing lone devices that carry out specific functional tasks. But the integration of these devices into a diagnostic system is where the challenges are," he says. "That's the major obstacle at this point — system integration of these devices to make them efficient enough to be clinically relevant."

Because of this, he says a modular R&D approach is best. "I don't think there's a system that is a one system that fits all," Yang says. "Depending on your sample type, I think the sample preparation module may be different depending on your needs, as well as say the amplification or the detection part, or even post-amplification, depending on your application. The module approach makes a lot of sense."

Deployment

Based on the Gates Foundation's funding strategy, Luo expects to have worked out all aspects of his group's target-driven polymerization approach within three years. "And then [the foundation] will try to integrate — to pick the best of all the modules and then integrate them together for the next, I would say, three to five years," he says. Overall, Luo adds, "you're talking six to eight years hopefully [when] you have a workable unit that can be mass-produced and can be dispersed in developing countries. ... I don't think that we will have a perfect product, but anything would be better than nothing."

Berkeley's Henrikson says he is optimistic about the deployment of point-of-care infectious disease -diagnostics in the near term. "A lot of it is in finding the right application for your technology," he says. "People are taking different approaches to this. But I think there will be some good devices on the market that are somewhere in between lateral flow tests and centralized labs in the next five years."

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