Short Communication Flexible Rolled Thick-Film Miniaturized Flow-Cell for Minimally Invasive Amperometric Sensing Andrea Kagie, a,b Daniel K. Bishop, a,c Jared Burdick, a,d Jeffrey T. La Belle, a,c Robert Dymond, e Robin Felder, f Joseph Wang a,b,g,h * a Biodesign Institute, Arizona State University, Tempe 85287, AZ, USA b Department of Chemical Engineering, Arizona State University, Tempe 85287, AZ, USA c Harrington Department of Bioengineering,Arizona State University, Tempe 85287, AZ, USA d Department of Mechanical and Aerospace Engineering, Arizona State University, Tempe 85287, AZ, USA e Ibetics inc., Toronto, M5R 1N2 Canada f Medical Innovation and Transformation Institute, Leesburg,Virginia, USA g Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287, AZ, USA h Department of NanoEngineering, University of California, San Diego, La Jolla 92093, CA, USA (permanent address) *e-mail: Joseph.Wang@asu.edu Received: April 16, 2008 Accepted: May 8, 2008 Abstract Wedescribehereaminiaturizedflexiblethick-filmelectrochemicalbiosensorflowdetector,suitableforinsertioninto the lacrimal canaliculus towards minimally invasive amperometric monitoring of biomarkers in the tear fluid. Our focus here is on the microfabrication and in-vitro testing of the new laterally rolled screen-printed sensor. The new device responds rapidly and sensitively to dynamic changes in the levels of norepinephrine and glucose (the later in connection to glucose-oxidase containing ink). Coverage of the enzyme electrode with an electropolymerized polytyramine minimizes contributions from the common electroactive interferences ascorbic and uric acids. Such attractive performance indicates great promise for minimally invasive monitoring of health biomarkers in the tear fluid, or in alternative usage such as capillary microelectrophoresis, ultralow volume sampling, or in-flow (tubular) systems for batch processing of blood or culture media. Keywords: Glucose, Microfabrication, Rolled flow cell, Flexible substrate, Tears, Norepinephrine, Biosensor DOI: 10.1002/elan.200804253 With the rise of chronic diseases, new methodologies for disease detection and treatment are in high demand. The ability to continuously monitor the health status would enableaswiftandappropriatecorrectiveaction,througha closed-loopdrug-deliveringsystem,e.g.,releaseofinsulinin the case of diabetes management [1, 2]. By enabling personalized medicine, such feedback loop systems are expectedtorevolutionizepatientmonitoringinconnection to different diseases. A critical component of such closed- loop integrated medical systems is a reliable and robust sensor,providingcontinuouslytheanalyticalinformation. Electrochemical sensors have played a leading role in the move towards continuous health monitoring, and currently are the devices of choice for tight glycemic monitoring [1, 2]. Yet, despite extensive efforts, existing in-body electrochemical sensors are subject to major biofouling/biocompatibility problems [1] which impede practical in-vivo monitoring. Minimally invasive and non- invasive sensors offer an attractive alternative to implant- able devices as they minimize the biocompatibility chal- lenge,obviatetheneedforneedle-basedsystems,andutilize advantages of cleaner alternate sample sources (over protein-rich interstitial fluid and blood). Various body fluids, including saliva, tears and sweat, have been consid- ered as alternate sample sources for such noninvasive measurements[1,3]. This communication describes the design, fabrication, optimization and in-vitro testing of a minimally invasive electrochemicalbiosensorformonitoringhealthmarkersin tears, based on a miniaturized, flexible, thick-film ampero- metric enzyme electrode. The use of the tear fluid for noninvasive and minimally invasive monitoring has re- ceived considerable recent attention [4, 5]. Tear fluid is an advantageousfluidforbiodetectionasitflowscontinuously, and is a relatively clean body fluid compared to the relatively static interstitial fluid used in subcutaneous monitoring. Recent activity has led to flexible electro- chemical sensors for tear [6] or cardiac [7] monitoring fabricated by lithographic (thin-film) techniques. As illus- trated in Figure 1, our new sensing device consists of enzyme-containing thick-film carbon electrodes, printed on a flexible polyimide substrate and rolled into a 0.7 mm diameter flow cell. Such laterally rolled geometry and dimension make it suitable for insertion into the lacrimal canaliculus (through which the tear fluid passes), in a manner similar to the widely used insertion of punctum 1610 Electroanalysis 20, 2008,No.14,1610–1614 # 2008 WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim