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 ten-fold 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.
Highlights
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
Abnormal metabolic activities of cancer cells can be probed by calorimetry, and a large amount of research has been devoted to elucidating the relationship between the metabolic heat of cells and cancer[5]
Calorimetry has a unique advantage for the investigation of these metabolic heterogeneities compared with other methods; for instance, it can provide the overall metabolic information including that for anaerobic metabolism, which cannot be detected by oxygen consumption rate analysis
Summary
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. Calorimetry has a unique advantage for the investigation of these metabolic heterogeneities compared with other methods; for instance, it can provide the overall metabolic information including that for anaerobic metabolism, which cannot be detected by oxygen consumption rate analysis These heterogeneities have been widely investigated using optical[13], chemical[14], electrical[15], and mechanical[10] cytometry techniques, a method that can measure single-cell heat production rate has yet to be developed. This is mainly because the sensitivity of state-of-the-art calorimeters is insufficient to measure the metabolic heat from a single cell. The poor sensitivity is attributed to the inherent difficulty in measuring heat; various parasitic heat loss mechanisms such as conduction, convection, and radiation dissipate the small amount of heat produced from a single cell, which is usually less than a few nW
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