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Microfluidic diagnostics for the developingworldXiaole Mao ab and Tony Jun Huang * ab

DOI: 10.1039/c2lc90022j

For more than a decade, it has beenexpected that microfluidic technologywould revolutionize the healthcare industrywith simple, inexpensive, effective, andubiquitous miniature diagnostic devices. Todate, however, microfluidics has not yetbeen able to live up to these expectations.This fact has led to the recent developmentof new philosophies and methodologies formicrofluidic diagnostics. In this Focusarticle, we will discuss some of the latestbreakthroughs that could significantlyimpact medical diagnostics in thedeveloping world.

IntroductionCost-effective, high-performance diag-nostic methods are vital to providing citi-zens with accessible, affordable, and high-quality healthcare in both developed anddeveloping countries. It was estimated thatdiagnostics comprises only 35% of healthcare spending, yet it impacts about70% of healthcare decisions. Therefore,a relatively modest investment in diag-nostic technology could potentially lead todrastic improvement of the overall health-careoutcome.Thisis particularlyattractivefor developing countries where nancialresources areextremely limited.As a result,an important question has been presentedto biomedical researchers: how to developand leverage innovative diagnostic

technologies to create exponential impactfor healthcare in developing countries?

Obviously there is a major difference interms of the needs of diagnostics between

developing countries and developedcountries. While the top killer diseases indeveloped countries such as the US areheart diseases and cancers, the leadingcause of death in developing countries areinfectious diseases, the majority of whichcould be prevented with proper diagnosisand treatment. 1 Therefore, infectiousdiseases have been identied as the top-priority in terms of the development of cost-effective diagnostic methods. Fig. 1demonstrates the impact of variousinfectious diseases in terms of disability-

adjusted life years (DALYs), which is theyears of life lost by a persons prematuredeath. Among the infectious diseases lis-ted, lower respiratory infections, HIV/AIDS, malaria, measles and tuberculosiscontribute the highest burden to devel-oping countries. Others such as syphilisalso cause signicant capital andeconomical losses. Common diagnosticprocedures for these diseases include

chemical/biological assays such asenzyme-linked immunosorbent assay(ELISA) and assays that heavily rely oninstruments such as ow cytometry.

For a diagnostic technology to besuccessful in the developing world, it isimportant to follow the guidelinesprovided by World Health Organization(WHO) which include a set of criteriasuch as affordability, accessibility, sensi-tivity, specicity, ease-of-use, speed, androbustness. 2 In light of these require-ments, it is natural for researchers to turnto microuidics, because microuidictechniques inherently use compact, low-cost, low-power, mass-producible uidicchips designed for sensitive, rapidanalysis

of minute sample sizes. In addition,various on-chip diagnostic modules havebeen integrated within the same uidicchips, providing devices with excellentexibility and functionality. Therefore,microuidics could be an extremelyattractive platform for providing diag-nostic solutions for the developing world.

The expectation that microuidictechnology could revolutionize the

Fig. 1 Disability-adjusted life years (DALYs) for infectious and parasitic diseases. Image repro-duced from ref. 1 with permission from Nature publishing.

a Department of Engineering Science and Mechanics, The Pennsylvania State University,University Park, PA 16802, USA. E-mail: [email protected] Department of Bioengineering, ThePennsylvania State University, UniversityParkPA 16802, USA

1412 | Lab Chip , 2012, 12 , 14121416 This journal is The Royal Society of Chemistry 2012

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healthcare industry with simple, inex-pensive, effective, and ubiquitous minia-ture biomedical diagnostic devices hasexisted since the conception of micro-uidics. Despite tremendous progress inthe eld in the past decade, it seems thatmicrouidics has yet to live up to theseexpectations. Signicant challenges still

exist. For example, while many researchteams have demonstrated complex bio/chemical processes that are necessary forvarious diagnostic procedures withina singlemicrouidicchip, in practice theseon-chip processes are not possiblewithout the support of bulky and expen-sive external components, such as pumpsand switches for uid actuation andoptical detectors for signal measurement.Therefore, new philosophies for simpli-ed microuidics are required to make

microuidic-based systems more prac-tical. In addition, transformative tech-nologies are needed to provide solutionsfor medical diagnostic applications whichcurrently seem unobtainable.

New philosophies inmicrofluidics

Microuidics started out with the conceptto manipulate minute volumes of samplereagents within a monolithic uidic chip.Traditionally, most research efforts havebeen focused on realizing uidic controlwithin the chip, while uid-drivingmechanisms (such as pumps, switches,and pressure sources) largely existedoutside of the chip. This is ratherconvenient for demonstrating technol-ogies in the laboratories; however, it has

become increasingly obvious that theentire microuidic community couldsuffer from the inability to launch thesetechnologies into a practical setting.Many devices developed so far remain asthe Chip-in-a-Lab systems rather thanthe Lab-on-a-Chip systems whichmany of us have hoped for. Fortunately

this issue has been seriously examinedandseveral new and quite intriguing philoso-phies have emerged in the past few years.

Paper microfluidics

Paper microuidics, pioneered by theWhitesides group, is a perfect example of how innovative low-cost uidic manipu-lation methods can free microuidicdevices from the limitation of activepumping and enable extremely low-cost

Fig. 2 (A) Schematic of the fabrication process for a paper-based microuidic channel. (B) Three-dimensional (3D) paper microuidic channel networkand multiplex detection. Image reproduced from ref. 3 and 4 with permission from ACS and the National Academy of Sciences.

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microuidic diagnostics. In a paper-basedmicrouidic device, the ow is driven bycapillary forces (paper wicking). Hydro-phobic barriers such as wax can be easilyprinted onto the paper to dene a micro-uidic channel network (Fig. 2A). Besidesthe benets of pump-free uid manipula-tion, paper is advantageous in many other

aspects, such as its light weight, biocom-patibility, disposability, compatibilitywith various biological assays, all of which are ideal for a diagnostic platform. 3

Paper is particularly suitable for colori-metric tests which can be detected by thenaked eye or simple devices such asa cellular phone. As the smart devices(such as smart phones) equipped withhigh-resolution cameras become more

readily accessible and affordable, papermicrouidics could become a powerfultool to perform many diagnostic tests inthe developing world. So far only a fewrelatively simple laboratory tests havebeen demonstrated in paper microuidicssuch as glucose or protein detection;however a plethora of existing colori-

metric technologies used in various test-strips can be leveraged to expand theportfolio of diagnostics using paper mi-crouidics. In addition, three-dimen-sional uidic networks were fabricated inpaper 4 by patterning multiple layers of paper with uidic networks (Fig. 2B). It isworth noting that creating a 3D uidicnetwork in paper is much more conve-nient than in traditionally monolithic

microuidic devices. This 3D congura-tion has further expanded the capabilitiesof paper microuidics with multiplefunctional zones and multiplexing tests.

Creating microfluidic diagnosticdevices with a practical mind-set

Solving the current issues of microuidicdiagnostic devices for the developingworld does not always mean that oneneeds to make drastic changes in thetechnology platform as in paper micro-uidics. There is still a great potential intraditional microuidics, if the tech-nology can be implemented with a prac-tical mind-set. For example, the Sia grouprecently developed a microuidic

Fig. 3 (A) Images of the microuidic chip. (B) Schematic diagram of passive delivery of multiple reagents. (C) Illustration of biochemical reactions indetection zones at different immunoassay steps. (D) Absorbance traces of a complete HIV-syphilis duplex test as reagent plugs pass through detectionzones. Image reproduced from ref. 5 with permission from Nature Publishing.


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platform for the diagnosis of infectiousdiseases specically for developing coun-tries. 5 In this device (Fig. 3), theydemonstrated how new manufacturing,uid handling, and signal detectionprocedures can be leveraged to overcomethe challenges that we are facing in real-world applications. The authors present

a series of innovations in chip develop-ment. Firstly, a cost-efcient, high-throughput manufacturing process formicrouidic cassettes (material cost: 1US dollar) was developed. Secondly,a meandering channel design togetherwith a silver-reduction amplicationmethod were used to amplify the ELISAsignal yielded by gold nanoparticle-conjugated antibodies to the extent that itcan be easily read by the naked eye or lost-cost optical components such as LEDsand photodetectors (cost per unit: several

US dollars). Finally, a simple, elegant,and cost-effective method to delivermultiple reagents into the chip for ELISAtests was achieved by preloading variousreagents into a tube as discrete droplets.The sequential loading of samples was aseasy as pulling the reagents through theuidic chip using the vacuum generatedmanually with a disposable syringe. Sucha method is simple yet reliable, andeffectively eliminates the need for externalpumps and switches, resulting ina dramatic reduction in cost and

complexity. These three measures resultin a low-cost diagnostic device for ELISAdetection of HIV and syphilis that issimple to operate and provides results

that can be easily interpreted. The chiphas been eld-tested in Rwanda onhundreds of locally collected humansamples for HIV and syphilis detection,and the results are very promisingwithsensitivities and specicities that rivalthose of reference bench-top assays. 5

New technologies by fusingmicrofluidics withoptoelectronics

Examples shown in the previous sectionwere mainly focused on the chemical/bio-logical assays. Another area of particularinterest is the development of affordableand miniature diagnostic instrumentsby combining microuidic and optoelec-tronic technologies. By utilizing theuniqueproperties of uids and piggybacking onthe latest optoelectronic advance-ments, these technologies make it possibleto provide cost-effective diagnosticinstruments for the developing world.

Recently the Ozcan group shed somelight into hownovelinstrumentdesign cantake advantage of both microuidics andoptoelectronic technology to performdiagnosis in the developing world. 6 Ina recent study, they invented a new tech-nology route that is signicantly differentfrom that of traditional ow cytometry.Their device is composedof a fairly simplemicrouidic device and a camera systemfrom a cellular phone. By pairing the mi-crouidic device with the cellular phone,the device is capable of performing uo-rescent cell imaging cytometry. Fig. 4

demonstrates theprinciple of thedevice.Amicrouidic channel is positioned abovethe cell phone camera. During the opera-tion, uorescently labeled cells are injectedthrough the channel. Within the uidicchannel, cell suspension is sandwichedbetween theglass/polymersubstrates. Dueto the refractive index difference, the cell

suspension and glass/polymer effectivelyform an optouidic slab-waveguidestructure that connes the light within theuid layer. An inexpensive LED providesthe illumination light that is coupled fromthe sidewalls of thechannel andexcites theuorescently labeled cells. Due to the lightconnement of the optouidic slab-wave-guide, the illuminationlight fromthe LEDonly propagated laterally along the mi-crouidic channel, producing an almostperfectly dark background for uorescentimaging of the cells. Due to the low

intensity of the background excitationlight, only an inexpensive plastic adsorp-tion lter was needed in front of the cellphone camera lens to completely eliminatethe background noise for uorescentimaging. The uorescent movies of thecells are captured by the cell phoneCMOS and the data can be further pro-cessed via a cell phone application todeterminethe counts of cells in thesample.This cell phone-based imaging cytometerweighs about half an ounce and costs lessthan ve dollars (excluding the cell

phone). It has been tested with whiteblood cells in human blood and the resultsare comparable to those from a commer-cial hematology analyzer. Further work isongoing to evaluate the potential of thissystem for HIV monitoring in resource-limited countries.

Conclusions

In summary, the microuidics communityis in need of transformative solutions todramatically impact the healthcare

systems in the developing world. The eldof microuidics is no longer youngenough to continue boasting aboutpotential without delivering truly mean-ingful solutions. In this aspect, recentlymany innovative researchers have beenstepping up to this challenge. We haveseen that drastically rethinking whatwe consider microuidic technology, asin paper microuidics, can push theeld into new directions. However,approaches that are less dramatic canalso

Fig. 4 (A)(C) Various schematic diagrams of the designed optical attachment for optouidicuorescent imaging cytometry on a cell phone are illustrated. (D) The picture of the optouidicuorescent imaging cytometer on a cell phone. Image reproduced from ref. 6 with permission fromACS publishing.

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go a long way, as we have seen throughthe integration of microuidics witheveryday/common devices such as cellphones and syringes. The recent advancesoutlined in this article are intriguing andwill continue to inspire others in the eldto take bold steps to move microuidicsinto a new era in which we produce real-

istic devices that could truly impact theworld.

All opinions are those of the authorsand do not reect the views of Lab ona Chip or the Royal Society of Chemistry.

Acknowledgements

This research was supported by NationalInstitutes of Health (NIH) Directors

New Innovator Award (1DP2OD007209-01). The authors thank Michael Lapsley,Sz-Chin Steven Lin, and Brian Kiraly forhelpful discussions.

References

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4 W. W. Martinez, S. T. Phill ips andG. M. Whitesides, Three-dimensionalmicrouidic devices fabricated in layeredpaper and tape, Proc. Natl. Acad. Sci.USA , 2008, 19(105), 606611.

5 C. D. Chin, T. Laksanasopin,Y. K. Cheung, D. Steinmiller, V. Linder,H. Parsa, J. Wang, H. Moore, R. Rouse,

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