Micromachined Nanocalorimetric Sensor for Ultra-Low-Volume Cell-Based Assays

Abstract

Current strategies for cell-based screening generally focus on the development of highly specific assays, which require an understanding of the nature of the signaling molecules and cellular pathways involved. In contrast, changes in temperature of cells provides a measure of altered cellular metabolism that is not stimulus specific and hence could have widespread applications in cell-based screening of receptor agonists and antagonists, as well as in the assessment of toxicity of new lead compounds. Consequently, we have developed a micromachined nanocalorimetric biological sensor using a small number of isolated living cells integrated within a subnanoliter format, which is capable of detecting 13 nW of generated power from the cells, upon exposure to a chemical or pharmaceutical stimulus. The sensor comprises a 10-junction gold and nickel thermopile, integrated on a silicon chip which was back-etched to span a 800-nm-thick membrane of silicon nitride. The thin-film membrane, which supported the sensing junctions of the thermoelectric transducer, gave the system a temperature resolution of 0.125 mK, a low heat capacity of 1.2 nJ mK(-1), and a rapid (unfiltered) response time of 12 ms. The application of the system in ultra-low-volume cell-based assays could provide a rapid endogenous screen. It offers important additional advantages over existing methods in that it is generic in nature, it does not require the use of recombinant cell lines or of detailed assay development, and finally, it can enable the use of primary cell lines or tissue biopsies.

Review of MEMS differential scanning calorimetry for biomolecular study

“…Since biomolecules are often resolved in liquid, there is serious evaporation problem without careful chamber system during the temperature scanning process [38]. Hence the simple open type structure which is utilized by most MEMS isothermal titration calorimeters cannot be applied to the MEMS DSC [39,40].…”

Bridging the Gap Between Micro and Nanotechnology: Using Lab-on-a-Chip to Enable Nanosensors for Genomics, Proteomics, and Diagnostic Screening

“…The relatively large size of these sensors limits the functional complexity of the pill for a given size of capsule. Adapting existing semiconductor fabrication technologies to sensor development [12][13][14][15][16][17] has enabled the development of highly functional units for data collection, whilst the exploitation of integrated circuitry for sensor control, signal conditioning and wireless transmission [18] has extended the concept of single channel radiotelemetry to remote distributed sensing from microelectronic pills.…”

Nanocalorimetric platform for accurate thermochemical studies in microliter volumes

“…In open-chamber nanocalorimeters, the sample is dispensed directly into a microwell that is placed on the sensor chip [17], [24]- [27]. For instance, Johannessen et al demonstrated the feasibility of monitoring heat production by a very small number of mammalian cells [17], [28] in sample volumes of hundreds of pl.…”