Sub-nanowatt microfluidic single-cell calorimetry

Abstract

Non-invasive and label-free calorimetry could become a disruptive technique to study single cell metabolic heat production without altering the cell behavior, but it is currently limited by insufficient sensitivity. Here, we demonstrate microfluidic single-cell calorimetry with 0.2-nW sensitivity, representing more than tenfold enhancement over previous record, which is enabled by (i) a low-noise thermometry platform with ultralow long-term (10-h) temperature noise (80 μK) and (ii) a microfluidic channel-in-vacuum design allowing cell flow and nutrient delivery while maintaining a low thermal conductance of 2.5 μW K −1. Using Tetrahymena thermophila as an example, we demonstrate on-chip single-cell calorimetry measurement with metabolic heat rates ranging from 1 to 4 nW, which are found to correlate well with the cell size. Finally, we perform real-time monitoring of metabolic rate stimulation by introducing a mitochondrial uncoupling agent to the microchannel, enabling determination of the spare respiratory capacity of the cells.

Design and analysis of magnetostrictive sensors for wireless temperature sensing

“…[50]- [52], implantable biomedical devices [4], [53], etc., and for concurrent temperature and fouling measurements in industrial pipelines [34], especially in low-temperature heat exchangers [54]- [56] to ensure profitable heat recovery. Overall, new or existing magnetostrictive sensor packages can be suitably adapted to measure temperatures remotely, using either the TCF-or TCVbased technique.…”

Cellular Thermometry Considerations for Probing Biochemical Pathways

“…We use finite element simulations that were validated for interfacial resistance modeling in our previous work [40], [54], [61] and for modeling transients in the supplementary material. A nominal volumetric heat of 2.5 nW is assumed to be released per cell, which corresponds to a typical cell metabolism rate [41], [62]. We plot in Figure 2 the volume-averaged temperature change (Δ − ) in the cell stack against the number of cells, , in the stack.…”

“…The former is more likely since it supports the reduction in the effective thermal conductivity to values below that of typical proteins (Figure 3). Typical calorimetry techniques [41], [42] for biological cells measure the temperature of the surrounding medium to estimate the total heat released from a cell. Such techniques inherently assume an effective thermal conductivity for the cell and the surrounding medium during the calibration of the thermal resistance of the calorimetry cell using an external heater.…”

“…We discussed in this section that the effective thermal conductivity is a function of the location of the heat source, the location of the measured temperature, and the local interface resistance network (Figure 4). Since the resistance to heat flow for an external heater may be different in comparison to any intracellular heat sources, previously reported calorimetry techniques [41], [42] may not be able to capture the true intracellular heat release via externally measured temperatures.…”

“…In this section, we estimate the localized temperature changes in sub-cellular compartments due to endogenous heating. Endogenous heat release in individual cells is typically in the range of 1-10 nW in a 50 μm diameter cell (~1-20 kW/m 3 ) [28], [41], [62]. We consider a few different scenarios (listed in Figure 5) each representing different sub-cellular compartment sizes, but all producing the same 10 nW of total heat.…”