An Aqueous Scanning Thermal Microscope for nanoscale thermal biology

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The ability to measure and manipulate heat is a fundamental tool in any scientist's toolkit. Biological processes, chemical reactions and even fundamental physics are all intrinsically linked to temperature. By changing temperature, biological, chemical and physical processes can be sped-up, slowed-down or even stopped. Likewise, many processes result in the generation or consumption of thermal energy so can be monitored by measuring temperature. Modern science has responded to this by developing a wide range of heaters and thermometers that employ various underlying mechanisms, including optical, electrical and chemical. However, this shouldn't lead us to believe that temperature is a 'solved' problem that no longer requires innovation. A very clear example of this is the continuing push of scientists for tools that work at ever smaller length scales. Specifically, the accurate control and measurement of temperature at the micro- and nano-scale is very difficult, with no single approach offering a perfect solution.This project is to build an accurate nano-scale heater/thermometer microscope that can operate in cell-friendly, water based environments. The technology behind this tool means that it can measure the temperature of (or heat) a nano-sized region of a sample. In addition to this, it can be positioned at any site on a sample and make a measurement before being moved to another site to repeat the process indefinitely. The tool is completely compatible with other forms of microscopy, allowing optical, topographic and thermal measurements to be made simultaneously. This flexibility has a wide range of applications in biology but two examples that will be explored during this project are given below:In cell biology, control of temperature gives scientists a fascinating and flexible way to monitor or change cell behavior, even the ability to induce cell death. This last point has been exploited in a highly promising new approach to cancer treatment called 'nanoparticle-mediated photothermal therapy'. In this technique, gold nanoparticles specifically designed to target cancer cells absorb a light of specific wavelength and heat up. This heat can induce the death of the cancer cells directly or release pre-loaded therapeutic drugs. However, the mechanism of heat-induced death is poorly understood, mainly because of unknown nanoparticle temperature and their uncontrolled distribution in cells. Traditional methods would require a huge number of repeat experiments, together with indirect calculations of particle temperature to answer these questions. The tool we will develop can provide answers within one simple experiment by precisely locating its heater/thermometer at carefully chosen sites on different cells one at a time and delivering an exact quantity of heat to each.Another example is measuring the temperature of different living cells. It should be no surprise that a cell's temperature is dependent upon its metabolism and its activity in response to the surrounding environment. Traditionally, biologists have used a range of optical tools to measure the temperature in and around cells. However, interpreting these measurements is fraught with difficulty, resulting in scientific disagreement and no consensus. The thermometer we will use in this project is based on a very well understood, unambiguous way of measuring temperature. This coupled with the ability to precisely locate the measurement on different regions of a single cell will offer valuable data to this lively scientific debate. Ultimately, our instrument will provide a simple to use and flexible tool to measure and change temperature at length scales relevant to cutting edge research at the cellular and subcellular level.