A New Pico-Calorimeter Detects Heat Signals from Living Cells Too Small to Measure Before

When cells grow, divide, or respond to drugs, they release tiny amounts of heat that reflect what is happening inside them. Capturing those signals directly has long been out of reach, but a device developed at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) can now do exactly that.

The pico-calorimeter measures metabolic heat signals on the order of 100 picowatts, or trillionths of a watt, making it the most sensitive bio-calorimeter of its kind. The research, from the lab of Joost Vlassak is published in Proceedings of the National Academy of Sciences.

Most approaches to studying cellular metabolism rely on indirect measurements, oxygen consumption, for example, or chemical byproducts. The pico-calorimeter bypasses those proxies entirely. "Heat is a direct measure for cellular metabolism," said Vlassak. "As the cells are going about their business, we see very nice exponential growth, depending on the media."

The device consists of three microscopic glass capillaries mounted on a thin micromachined membrane, housed inside a vacuum chamber for thermal isolation. One capillary holds the biological sample in liquid growth medium while the other two serve as references. As cells grow and consume nutrients, they release heat, creating minute temperature differences that a nearby thermopile—a heat-to-electricity converter—reads out. The vacuum-sealed, microfluidic design improves sensitivity by an order of magnitude over earlier versions and is easier to operate than its predecessors, which used liquid droplets on a suspended membrane.

To demonstrate the device, the team used it to track E. coli growth starting from just 30 to 40 individual bacteria. They also tested its potential as an antibiotic resistance probe by measuring how three drugs with distinct mechanisms—chloramphenicol, rifampicin, and ampicillin—altered bacterial metabolic activity at various concentrations. Because the measurements are direct, changes can be detected well before standard culture-based methods would show anything.

The researchers also envision using the device for sepsis monitoring, where patients may have only tens of bacteria per milliliter of blood. The pico-calorimeter could, in principle, assess metabolic activity and drug response from such small populations within hours rather than the days required for larger colonies to grow.

"It's very difficult to measure dynamic information from small living systems," said first author Juanjuan Zheng. "With this platform, we can begin to monitor cell viability, growth rate, proliferation, and drug response in real time. More broadly, it gives us an early functional readout of what a biological system is doing—whether it is growing, stressed, responding to treatment, or changing its metabolic state."