The Heat-Transfer Method: A Versatile Low-Cost, Label-Free, Fast, and User-Friendly Readout Platform for Biosensor Applications Bart van Grinsven,* ,†,‡,⊥ Kasper Eersels, ‡ Marloes Peeters, ‡ Patricia Losada-Pe ́ rez, ‡ Thijs Vandenryt, ‡ Thomas J. Cleij, † and Patrick Wagner ‡,§ † Maastricht Science Programme, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands ‡ Institute for Materials Research IMO and § IMEC vzw, IMOMEC Division, Hasselt University, Wetenschapspark 1, B3590 Diepenbeek, Belgium ABSTRACT: In recent years, biosensors have become increasingly important in various scientific domains including medicine, biology, and pharmacology, resulting in an increased demand for fast and effective readout techniques. In this Spotlight on Applications, we report on the recently developed heat-transfer method (HTM) and illustrate the use of the technique by zooming in on four established bio(mimetic) sensor applications: (i) mutation analysis in DNA sequences, (ii) cancer cell identification through surface-imprinted polymers, (iii) detection of neurotransmitters with molecularly imprinted polymers, and (iv) phase-transition analysis in lipid vesicle layers. The methodology is based on changes in heat-transfer resistance at a functionalized solid-liquid interface. To this extent, the device applies a temperature gradient over this interface and monitors the temperature underneath and above the functionalized chip in time. The heat-transfer resistance can be obtained by dividing this temperature gradient by the power needed to achieve a programmed temperature. The low-cost, fast, label-free and user- friendly nature of the technology in combination with a high degree of specificity, selectivity, and sensitivity makes HTM a promising sensor technology. KEYWORDS: biosensors, heat-transfer method, DNA, cancer cells, neurotransmitters, lipid vesicles 1. INTRODUCTION In this Spotlight on Applications, we evaluate the recently developed heat-transfer method (HTM) as a versatile biosensor readout platform. The methodology can be combined with a wide range of functional interfaces, leading to the development of numerous applications. One of the major demands when developing a diagnostic application is the label-free, low-cost, fast, sensitive, and user-friendly nature of the proposed technology. To meet these requirements, research in the field of biosensors has become increasingly important in recent years. Biosensors have evolved from a canary in a coal mine to more complex, technological devices for a vast number of applications in areas as diverse as, for example, (bio)medical research, environmental analysis, or pharmacology. 1 Generally speaking, a biosensor can be defined as an analytical device that combines a biological receptor element with a physicochemical detector. 2 Biosensor platforms profit from the high degree of specificity that a natural receptor has for its target to detect the analyte of interest. This natural receptor layer can consist of nucleic acids (DNA or RNA), 3-5 enzymes, 6-8 cells, 9-11 or antibodies. 12,13 Biosensors based on biological recognition elements can be very sensitive and specific toward their target, but there are drawbacks associated with the use of biological receptors. They can be unstable in challenging physical and chemical environ- ments, display a limited shelf life, it is time-consuming and expensive to obtain these receptors in sufficiently large quantities, and some analytes do not have a natural receptor. 14 Many of these drawbacks can be overcome by using synthetic rather than natural receptors in so-called biomimetic sensors. Molecularly imprinted polymers (MIPs) 15-17 and surface- imprinted polymers (SIPs) 18 are often used as synthetic receptors in these devices. Bio(mimetic)sensor platforms can be combined with several readout techniques to detect target binding to the functional interface. These detection methods are often based on electrochemical detection methods including impedance spec- troscopy, 19,20 cyclic voltammetry, 21,22 field-effect, 23,24 potenti- ometry, 25,26 amperometry, 27,28 etc. Alternatively, biosensor applications have been developed based on optical, 29,30 microgravimetrical, 31,32 and thermal 33 detection. The under- lying principles of these sensing techniques are associated with several phenomena occurring at a solid-liquid interface including: target-receptor binding, changes in the total charge, mass, refractive index or dielectric constant at the interface, change in mechanical rigidity, or redistribution of counter- ions. 34-39 In this article, we review the use of a new readout technology based on thermal transport through a functionalized solid- liquid interface, the heat-transfer method. This method surfaced in 2012 and was originally used for the detection of single- Received: June 10, 2014 Accepted: August 8, 2014 Published: August 8, 2014 Spotlight on Applications www.acsami.org © 2014 American Chemical Society 13309 dx.doi.org/10.1021/am503667s | ACS Appl. Mater. Interfaces 2014, 6, 13309-13318