Microfluidic chip calorimeters for biological applications

Abstract

The usage of calorimeters is limited due to its long measurement time and large sample consumption, despite its many advantages including universal applicability and simple sample preparation. Miniaturization of calorimeters not only resolves these problems, it also enables high-throughput measurements with array operations. We have developed microfluidic chip calorimeters with high sensitivity and reliable microfluidics-based sample handling. Immense sensitivity improvements are attained through reduction of the thermal conductance via on-chip vacuum insulation. This is enabled by Parylene thin-film microfluidic systems. Polydimethylsiloxane microfluidic systems, combined with the Parylene microfluidic system, gives easy and accurate control of picoliter-scale sample volume in a manner that is easily scalable to large, complex systems. Two device classes have been realized. Heat conduction calorimeters for biochemical reactions with 3.5 nL sample volume were built and validated by measurements of the heat of mixing and of enzyme activity. The thermal conductance of these devices was 15.5 µW/K and their power sensitivity was 4.2 nW. These devices can be built as calorimetric arrays to enable high-throughput heat of reaction measurements upon libraries of biomolecular interactions. Flow calorimeters were designed for sensor applications and measurements of cellular metabolism. The thermal conductance of these devices was 4.7 µW/K and their power sensitivity was 1.5 nW. Further reduction of thermal conductance and optimal thermocouple materials will deliver sensitivity of order ~1 pW, which will enable real-time measurement of single cell metabolism.