Universal mobile electrochemical detector designed for use in resource-limited applications Alex Nemiroskia, Dionysios C. Christodouleasa, Jonathan W. Henneka, Ashok A. Kumarb, E. Jane Maxwella, Maria Teresa Fernández-Abedulc, and George M. Whitesidesa,d,e,1 aDepartment of Chemistry and Chemical Biology, bSchool of Engineering and Applied Sciences, dWyss Institute for Biologically Inspired Engineering, and eThe Kavli Insitute for Bionano Science, Harvard University, Cambridge, MA 02138; and cDepartamento de Química Física y Analítica, Universidad de Oviedo, 33006 Oviedo, Asturias, Spain Edited by Alexis T. Bell, University of California, Berkeley, CA, and approved June 30, 2014 (received for review March 30, 2014) This paper describes an inexpensive, handheld device that couples provides a pair of convergent paths toward a potential solution, the most common forms of electrochemical analysis directly to although, practically, technical and conceptual connections be- “the cloud” using any mobile phone, for use in resource-limited tween them are weak (5, 6). mHealth is the general term given to settings. The device is designed to operate with a wide range of health-related information technologies that depend on mobile electrode formats, performs on-board mixing of samples by vibra- wireless communication for connectivity. Although these net- tion, and transmits data over voice using audio—an approach that works and devices can capture information relevant to health guarantees broad compatibility with any available mobile phone (and other problems involving chemical and biological sensing) (from low-end phones to smartphones) or cellular network (sec- and transmit it globally over the web, they typically do not have ond, third, and fourth generation). The electrochemical methods the capability to collect data directly, and rely instead on (error- that we demonstrate enable quantitative, broadly applicable, and prone) data entry by the user, either alphanumerically or through inexpensive sensing with flexibility based on a wide variety of images. Conversely, although POC diagnostics (e.g., lateral flow important electroanalytical techniques (chronoamperometry, cy- immunoassays, urinalysis dipsticks, and handheld glucometers) clic voltammetry, differential pulse voltammetry, square wave provide examples of simple, inexpensive devices that enable voltammetry, and potentiometry), each with different uses. Four minimally trained users to perform chemical testing, these applications demonstrate the analytical performance of the de- devices are typically limited in function and cannot connect vice: these involve the detection of (i) glucose in the blood for easily to networks for mHealth. Many devices are now being explored that attempt to connect personal health, (ii) trace heavy metals (lead, cadmium, and zinc) mHealth with POC testing. Because these systems have been in water for in-field environmental monitoring, (iii) sodium in developed in, and often implicitly targeted toward, the de- urine for clinical analysis, and (iv) a malarial antigen (Plasmodium i ii falciparum veloped world, they typically require ( ) smartphones, ( ) custom histidine-rich protein 2) for clinical research. The com- applications (apps), (iii) third or fourth generation (3G/4G) data bination of these electrochemical capabilities in an affordable, networks, (iv) proprietary connectors for sophisticated sensors handheld format that is compatible with any mobile phone or that interface with diagnostic tests, and in some cases (v) a sub- network worldwide guarantees that sophisticated diagnostic test- stantial level of technical sophistication (7–13). As such, these ing can be performed by users with a broad spectrum of needs, first-generation hybrid mHealth/POC devices are often too ex- resources, and levels of technical expertise. pensive, too restricted to a single type of phone, too limited in function, and too reliant on advanced mobile telecommunication electrochemistry | mHealth | point-of-care diagnostics | technology to be practically applicable in resource-limited settings low-cost potentiostat | telemedicine Significance lectrochemistry provides a broad array of quantitative methods Efor detecting important analytes (e.g., proteins, nucleic acids, The ability to perform electrochemical testing in the field, and metabolites, metals) for personal and public health, clinical in resource-limited environments, and to transmit data auto- analysis, food and water quality, and environmental monitoring matically to “the cloud” can enable a broad spectrum of anal- — (1, 2). Although useful in a variety of settings, these methods yses useful for personal and public health, clinical analysis, with the important exception of blood glucose meters (3, 4)—are food safety, and environmental monitoring. Although the de- generally limited to well-resourced laboratories run by skilled veloped world has many options for analysis and web con- personnel. If simplified and made inexpensive, however, these nection, the developing world does not have broad access to versatile methods could become broadly applicable tools in the either the expensive equipment necessary to perform these hands of healthcare workers, clinicians, farmers, and military tests or the advanced technologies required for network con- personnel who need accurate and quantitative results in the field, nectivity. To overcome these limitations, we have developed especially in resource-limited settings. Furthermore, if results of a simple, affordable, handheld device that can perform all the testing were directly linked to “the cloud” through available mo- most common electrochemical analyses, and transmit the results bile technology, expertise (and archiving of information) could be of testing to the cloud from any phone, over any network, any- geographically decoupled from the site of testing. To enable where in the world. electrochemical measurements to be performed and communi- cated in any setting, a useful technology must be (i)abletoper- Author contributions: A.N., D.C.C., J.W.H., A.A.K., E.J.M., and G.M.W. designed research; A.N., D.C.C., J.W.H., A.A.K., and E.J.M. performed research; A.N., D.C.C., J.W.H., A.A.K., form complete electrochemical analyses while remaining low in and E.J.M. contributed new reagents/analytic tools; A.N., D.C.C., J.W.H., A.A.K., E.J.M., cost, simple to operate, and as independent of infrastructure M.T.F.-A., and G.M.W. analyzed data; and A.N., D.C.C., J.W.H., A.A.K., E.J.M., M.T.F.-A., as possible; and (ii) compatible with any generation of mobile and G.M.W. wrote the paper. telecommunications technology, including the low-end phones and The authors declare no conflict of interest. 2G networks that continue to dominate communications in much This article is a PNAS Direct Submission. of the developing world. 1To whom correspondence should be addressed. Email: [email protected]. — The parallel development of two successful technologies This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. mobile health (mHealth) and point-of-care (POC) diagnostics— 1073/pnas.1405679111/-/DCSupplemental. 11984–11989 | PNAS | August 19, 2014 | vol. 111 | no. 33 www.pnas.org/cgi/doi/10.1073/pnas.1405679111 Downloaded by guest on October 1, 2021 where 3G/4G networks and smartphones are still not widely used. A B Mobile Network Although mobile connectivity has spread rapidly across the world, low-end mobile phones and second generation (2G) networks Data Results dominate the telecommunications infrastructure (especially in rural Over by areas) in the developing world (14, 15) and will continue to do so Voice SMS Medical for the foreseeable future (Fig. S1). This lack of advanced mobile Center technologies in much of the developing world, coupled with myriad 2G 3G 4G operating systems, generations of software, and types of connecting Public ports among all mobile phones, presents a major challenge to any Health device that requires a specific phone or application to communicate Database the results of testing. To provide a system that combines broad flexibility in electro- Electrodes chemical capability with connectivity to the web through widely ISE available technology, we have developed a low-cost (∼US$25), uMED SPE handheld device that (i) performs all of the most common elec- trochemical methods; (ii) interfaces with a variety of commercially Test Strip available electrodes; (iii) provides on-board vibration to mix C uMED To Phone D Potentiostat V iv 2 to 3 R samples when necessary; and ( ) is simple to operate. For com- 16-bit SPI Buttons LCD Audio Jack Elec munication of data, we exploited the ubiquity of the hands-free DAC Mic Aud Switch audio port, a nearly universal interface to mobile phones, and 16-bit - R Filters C ADC V DAC + designed a protocol to transmit digital data over a live voice Digital I/O R V i C W connection. This approach guarantees that ( ) any phone can Vibration Filt Switches function as a modem to link the results of testing to a remote CPU Motor V Rf W DAC DAC V facility through any available mobile network (2G, 3G, or 4G), and VW VR O VC ii 10-bit I/V that ( ) the device does not require any specific software appli- Potentiostat VR ADC Clock Switch V - to cation, operating system, or connector (beyond an audio cable). W (Crystal) DAC Microcontroller VW + We refer to our device as a universal mobile electrochemical VO ADC detector (uMED) because of (i) its universal compatibility with Test Battery Strip V DAC andV DAC set by DAC mobile technology; (ii) the broad range of electrochemical R W techniques that it can perform, including various forms of amperometry, coulometry, voltammetry (e.g., cyclic, differential Fig. 1. (A) An image of the uMED interfaced to a commercial glucose test pulse, square wave), and potentiometry; and (iii)itsbroad strip and a low-end mobile phone through a standard audio cable, for compatibility with different commercially available and paper- transmission of data over voice. (B) A schematic of the connections and flow based electrodes. Fig. 1 A and B shows the uMED connected to of data from the electrodes through the uMED to the remote back end.