The accurate tracking of medical devices is a key clinical requirement that currently requires the use of ionising X-ray radiation and / or contrast agents. These essential procedures have potential long term detrimental effects, especially on babies, and also causes significant disruption (and therefore cost) due to both the need to protect staff and waiting for the availability of, or transport to, X-ray equipment. There are therefore significant clinical drivers to develop alternative tracking methods. Very recently, we have demonstrated a ground breaking approach to tracking medical devices located deep in tissues using single photon imaging [1]. Our approach exploits the fact that if a point source of light is placed inside the body, a tiny fraction of the light will emerge from the body with a close to line-of-sight path. Crucially, these line-of-sight photons (particles of light) hold precise information about the spatial location of the point source inside the tissue, but extracting this information is not trivial. The key to accessing it is the fact that the line-of-sight photons exit the body with a shorter transit time than the more diffuse photons - a fact that allows us to exploit a technique known as time-correlated single-photon counting (TCSPC) to detect and distinguish them from more diffuse photons. In contrast to "normal" cameras, which do not record the arrival time of the photons on the detector array, TCSPC-based imaging relies on using a source of light that produces short pulses of light at precisely known times, together with a single-photon sensitive detector array that can record the arrival times of individual photons. In this manner, TCSPC imaging allows us to design an imaging system that can selectively detect and image the location of the emerging line-of-sight photons before the diffuse photons start to emerge, and this allows us to locate the precise position of the source. Although we have now demonstrated the potential of this technique for medical device tracking, the clinical translation has been hampered by the low fill-factor (how much of the detector array is light-sensitive) of commercially available TCSPC detector arrays. This low fill-factor (~1%) effectively means that we lose 99% of the light reaching the detector array, limiting the maximum frame rate to ~0.05 Hz - too low to provide adequate feedback to the clinician during catheter placement. Recently, through STFC funding, we have demonstrated that so-called "photonic lantern" transitions provide a new and powerful route to addressing the low fill-factor of commercially available SPAD arrays [2]. The overarching goal of this project will therefore be to work with our commercial partners, Photon Force, to exploit this capability, and develop a TCSPC system capable of tracking catheters with video frame rates. We will then work with clinician scientists to translate the technology towards clinical exploitation by demonstrating the tracking capability using relevant models. The results of this project will then be used to support translational clinical studies, and to work with Photon Force to develop a TCSPC tracking system suitable for the medical market. [1] M. G. Tanner et al, Biomed. Opt. Express 8, 4077-4095 (2017) [2] H. K. Chandrasekharan et al. Nat. Commun. 8, 14080 (2017).

Working at the very forefront of microscope development, this multidisciplinary research team aim to explore the four dimensions of space and time within live neurons. Using bioengineering, we have developed novel ways of training neurons to grow within specially created channels in biomaterials. The neurons make connections in these channels which enable us to investigate cell-to-cell communication in real-time as it would in the brain - in an entirely controllable way. Once we have grown these "wetware artificial neural networks" we can image their complex signalling behaviour using advanced microscopy. In this proposal, a new microscope concept will be developed which pushes the envelope of what can be seen at the cellular level. By creating a 3-dimensional lattice of optical foci in the sample and, in parallel, reading them out, we can create a 3D representation of the sample. Using ultra-sophisticated camera technology which was developed principally for 3D detection and ranging (LIDAR) in the automotive industry, called SPAD sensor arrays, we will measure the speed at which biological processes such as energy metabolism occur using a technique called fluorescence lifetime imaging microscopy (FLIM). FLIM is incredibly powerful for detecting changes in fluorescent molecules and can be used to measure protein-protein interactions or changes in protein conformation - essential processes for control of cellular behaviour. By adding fluorescent tags to proteins and illuminating them with a laser we can visualise them in a cell using SPAD sensor arrays. Energy transfer occurs when two of these tags with different colours come within a certain distance of each other, changing the amount of light that they emit. This Fluorescence Resonance Energy Transfer (FRET) can be measured to detect protein interactions. FLIM measures how the fluorescence lifetime changes during FRET and is not dependent on how much protein is present, making it a robust method for detecting protein interactions in live cells. The second difficulty in measuring FRET in moving cells, is that many imaging techniques are too slow and the amount of light from the laser can damage the cell. Our new microscopy method, ISO-FLIM (since it generates a isotropic resolution image), generates beams in a sheet of light that is shone onto the sample, which is recorded by a sensitive camera, making it fast and non-damaging to the cell. Our new method combines these techniques to create a new microscope to accurately and rapidly measure protein interactions in living neurons, allowing researchers to look at the 'real time' mechanics of protein function.

The accurate tracking of medical devices is a key clinical requirement that currently requires the use of ionising X-ray radiation and / or contrast agents. These essential procedures have potential long term detrimental effects, especially on babies, and also causes significant disruption (and therefore cost) due to both the need to protect staff and waiting for the availability of, or transport to, X-ray equipment. There are therefore significant clinical drivers to develop alternative tracking methods. Very recently, we have demonstrated a ground breaking approach to tracking medical devices located deep in tissues using single photon imaging [1]. Our approach exploits the fact that if a point source of light is placed inside the body, a tiny fraction of the light will emerge from the body with a close to line-of-sight path. Crucially, these line-of-sight photons (particles of light) hold precise information about the spatial location of the point source inside the tissue, but extracting this information is not trivial. The key to accessing it is the fact that the line-of-sight photons exit the body with a shorter transit time than the more diffuse photons - a fact that allows us to exploit a technique known as time-correlated single-photon counting (TCSPC) to detect and distinguish them from more diffuse photons. In contrast to "normal" cameras, which do not record the arrival time of the photons on the detector array, TCSPC-based imaging relies on using a source of light that produces short pulses of light at precisely known times, together with a single-photon sensitive detector array that can record the arrival times of individual photons. In this manner, TCSPC imaging allows us to design an imaging system that can selectively detect and image the location of the emerging line-of-sight photons before the diffuse photons start to emerge, and this allows us to locate the precise position of the source. Although we have now demonstrated the potential of this technique for medical device tracking, the clinical translation has been hampered by the low fill-factor (how much of the detector array is light-sensitive) of commercially available TCSPC detector arrays. This low fill-factor (~1%) effectively means that we lose 99% of the light reaching the detector array, limiting the maximum frame rate to ~0.05 Hz - too low to provide adequate feedback to the clinician during catheter placement. Recently, through STFC funding, we have demonstrated that so-called "photonic lantern" transitions provide a new and powerful route to addressing the low fill-factor of commercially available SPAD arrays [2]. The overarching goal of this project will therefore be to work with our commercial partners, Photon Force, to exploit this capability, and develop a TCSPC system capable of tracking catheters with video frame rates. We will then work with clinician scientists to translate the technology towards clinical exploitation by demonstrating the tracking capability using relevant models. The results of this project will then be used to support translational clinical studies, and to work with Photon Force to develop a TCSPC tracking system suitable for the medical market. [1] M. G. Tanner et al, Biomed. Opt. Express 8, 4077-4095 (2017) [2] H. K. Chandrasekharan et al. Nat. Commun. 8, 14080 (2017).

From the earliest invention of the camera, humans have been seeking to observe processes that are too fast or too complex for the human eye to follow. The first time-lapse images of a running horse, taken by Eadweard Muybridge in the 19th century, allowed us to understand its motion, freezing a moment in time so that we can examine minute details. It showed that a horse's feet all leave the ground when galloping, a controversial question hotly debated at the time. Importantly, the time lapse images were a full-frame view - a key concept which we will also employ in the instrument to be developed here. Today, in cellular biology, our understanding of cellular function continues to evolve as we observe complex dynamic processes played out under a microscope. The optical microscope is a non-invasive, non-destructive and non-ionising tool which can be used to study living cells and tissues. No other method can study molecules in living cells with anything remotely approaching its combination of spatial resolution, selectivity, sensitivity and dynamics. Modern sensitive and sophisticated electronic cameras can capture dynamic processes at high speed, revealing intricate details of these processes. Indeed, detector development is a very important aspect of progress in the field of microscopy. The aim of our project is to develop extremely sensitive and fast full-frame view cameras which will allow us to observe molecules and proteins in their natural habitat, the cell, without disturbing them - in a way the 21st century equivalent of Muybridge's galloping horse. We are interested in molecules that play a role in inflammation, which is the body's response to some kind of harm or injury. These molecules are called proteins, and they are many different ones in our cells. We specialise in finding out about a protein called the coxsackie virus adenovirus receptor (CAR). We want to know how they move around in time, bump into each other and stick together. So we have labelled them with a fluorescent label to observe them under a microscope. The special cameras we are going to develop will be able to see them with a very high resolution, and also very quickly and very precisely, by measuring the polarization of the fluorescence emitted by its label. They will allow us to observe the moment a cell responds to a chemical stimulus at the level of single proteins. This will help us to understand how inflammation occurs, on a molecular basis - which, at the moment, is still unknown. Imaging living cells is the best available approach to study this kind of biological question, and others, and, ultimately, the knowledge and insight gained by doing this work will enable us to design and develop drugs against inflammation, for the benefit of all of humankind.

We have seen rapid development and growing interest in quantum technologies-based applications in the past decade and the overall global quantum technology market is expected to reach $31.57B by 2026. Most of these emerging quantum applications require single-photon avalanche diode (SPAD) detectors operating beyond the spectral range of silicon but with "silicon-like" performance. The use of "silicon-like" short-wave infrared (SWIR) SPAD detectors in the existing systems will immediately improve resolution and acquisition time for the existing imaging system and enhance the range and improve data rate for Quantum Key Distribution (QKD). However, the present commercially available InGaAs/InP based SPADs based on designs from more than two decades ago are unlikely to have a step change in their performance. Over the last five years, the advent of several innovations by way of novel III-V materials and semiconductor band structure engineering offers us the possibility of a paradigm shift in the performance of long wavelength detectors. The next revolution in the development of SPADs in the SWIR region will almost certainly be using novel materials and band structure engineered structures. Such a revolution will significantly enhance detection efficiency and fast timing. This new class of detectors will be evaluated on existing state-of-the-art testbeds for time-of-flight ranging/depth imaging and QKD. This Fellowship proposal has the ambition to sweep away the obstacles of material and processing problems that are hindering the development of affordable and easy operation SPADs, and to bridge gaps between material sciences, semiconductor physics, manufacturability and quantum technology applications in order to improve the scope and overall performance of next generation quantum technology-based applications.