Detection Limits for Nanoscale Biosensors

Abstract

We examine through analytical calculations and finite element simulations how the detection efficiency of disk and wire-like biosensors in unmixed fluids varies with size from the micrometer to nanometer scales. Specifically, we determine the total flux of DNA-like analyte molecules on a sensor as a function of time and flow rate for a sensor incorporated into a microfluidic system. In all cases, sensor size and shape profoundly affect the total analyte flux. The calculations reveal that reported femtomolar detection limits for biomolecular assays are very likely an analyte transport limitation, not a signal transduction limitation. We conclude that without directed transport of biomolecules, individual nanoscale sensors will be limited to picomolar-order sensitivity for practical time scales.Tremendous progress is being made in the development of microanalytical systems for biosensing, driven by parallel advances in biotechnology, microtechnology, and microfluidics. 1,2 The advantages of small, highly integrated systems include more rapid and multiplexed analysis and reagent sample volumes reduced to the microliter range. When combined with innovative signal transduction technology, microsystems have recently achieved specific biomolecular detection at roughly femtomolar (fM) concentrations, corresponding to just a few thousand (or even a few hundred) analyte molecules in the sample volume. [3][4][5] Concurrently, many research groups have been developing micrometer or nanometer scale sensing elements based on novel transduction mechanisms. [5][6][7][8][9][10][11] Many researchers of nanometer-scale phenomena focus on the fact that miniaturizing a sensor often increases its signal-to-noise ratio (S:N), an inherent advantage for signal transduction, but the effect of nanoscale miniaturization on the overall sensitivity, which includes mass transport effects, has not been widely considered. For example, whether nanometer-scale sensors are intrinsically more sensitive overall than micrometer-scale sensors has not been fully examined. In this letter, we use experimentally verified [12][13][14] analytical solutions to examine the maximum sensitivity with which micro-to-nanoscale sensors of various geometries can detect biomolecules from solution. Our principal goal is to explicitly examine mass transport effects on biosensing at the nanoscale; however, the calculations also lead us to conclude that reported femtomolar detection limits for bioassays are likely an analyte transport limitation, not a signal transduction limitation. The implication is that, without methods to actively direct biomolecules to a sensor surface, individual nanoscale sensors will be subject to picomolarorder detection limits for practical time scales. 15 In the past decade, several papers have analyzed the effect of flow, 16-18 size, 13 or adsorption isotherms 19 on biomolecular adsorption; however, none have explicitly examined the effect at nanometer length scales. This effect is most easily examined using a simple geometrysa singl...

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