Quantum microscopy and biosensing

Biology is a longstanding frontier for quantum metrology, where high optical intensities are frequently required to get sufficient signal, but lead to damage in the biological sample. Quantum optics based precision measurements allow getting the most signal with the lowest optical power. Therefore Queensland Quantum Optics Laboratory aims to translate the precision sensing techniques from quantum optics to biological measurements. This philosophy has recently been very successful in astronomy, allowing the LIGO collaboration to detect the first gravitational waves. Optical tweezers is a common tool in biological experiments that allow manipulation and tracking of single cells and small glass spheres in a live biological sample. Here in Queensland Quantum Optics Laboratory we have used the quantum optics philosophy to demonstrate tighter trapping in optical tweezers [1] and the first quantum enhanced measurement in biology [2].

Single molecule biosensors are designed to make measurement on biological processes which are too small to be seen in a normal microscope. We have developed the first quantum noise limited biosensor allowing us to detect and track single proteins down to 5 nanometre in size and track them with 1000 measurements per second [3]. Notably this is achieved using only a tiny fraction (1E-4) of power compared to other sensors, and thereby greatly reduces photodamage. We aim to use this sensor to uncover biological phenomena never directly seen before, such as the rotational steps of single motor molecules.

The above biosensor and several of our other experiments are based on optical nanofibres. We have developed unique fabrication methods including precision characterisation that can measure the nanofibre thickness with sub-nanameter resolution [4]. Raman microscopy allows measurement on biological samples where not only the contrast of the sample, but also the chemical composition is visible. However, measurements are generally slow and require a lot of power, which can damage the samples. To overcome these challenges we are developing the first quantum enhanced stimulated Raman microscope.



In biology at microscale, weak optical signals need to be detected in large level of background noise. A straightforward solution to this issue is to increase the probing optical intensity interrogating the sample. However, high optical intensities are known to induce photodamage to biological samples, which can affect their viability, growth and function. This greatly limits the sensitivity of biosensors and microscopes preventing the observation of rapid biological phenomena or processes that happened at smaller scales. In fact, most biosensors and microscopes operate at intensities known to be harmful to biological samples.

Quantum optics based precision measurements allow extracting the most information from the light emitted by the sample without using high intensities.  Therefore, one of the key aim of the Queensland Quantum Optics Laboratory is to translate the precision sensing techniques from quantum optics to biological measurements. By doing so, we have demonstrated improvement of sensitivity and measurement speed of biosensors, which provide paths towards the observation of new biophysical phenomena at safe intensity for extended periods of time.

Recent work:

Biosensing at the quantum noise limit

Biosensors that are able to detect and track single biomolecules without requiring labelling are an important tool to understand biophysics including biomolecular dynamics and interactions. They are as well as valuable tools for medical diagnostics and need to be operated at their ultimate detection limits. In the Queensland Quantum Optics Laboratory, we developed a biosensor free of all technical noise sources that operates at the fundamental precision limit due to the quantization of light. This was achieved by using an optical nanofiber in a dark-field illumination configuration combined with a quantum optics technique named heterodyne detection.  We demonstrated state-of-the-art sensitivity using only a tiny fraction of power compared to other sensors (four orders of magnitude reduction in optical intensity), and thereby greatly reduces photodamage dealt by detection. Our method enables, for the first time, quantum noise-limited tracking of single biomolecules as small as 3.5 nm, and monitoring of surface–molecule interactions over extended periods. We aim to use this sensor to uncover biophysical phenomena never directly observed before, such as the rotational steps of single motor molecules. Moreover, our sensing technique can be used for the development of new rapid detection platform for medical diagnostics, such as early stage cancer detection. By achieving quantum noise-limited precision, our approach provides a pathway towards quantum-enhanced single-molecule biosensors.

Darkfield heterodyne detection scheme. An optical nanofiber is illuminated from the top with a frequency shifted probe light. Interferences with the probe light (orange) and the light circulating in the fibre (red) are detected on a balanced detector.
Animation of the detection process. The probe light scattered by a nanoparticle is combined with the light guided by the fibre creating interferences.

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Quantum enhanced optical tweezers

Optical tweezers are a common tool in biological experiments that uses high intensity tightly focussed beams to manipulate and track single cells and small glass spheres in live biological samples. At the Queensland Quantum Optics Laboratory, we have demonstrated for the first time, using optical tweezers, that the fundamental limit due to the quantization of light can be overcome for measurements of living systems. To achieve this, a quantum engineered light was prepared for the measurement with noise characteristics reduced by 75% compared to classical light and used to perform microrheology experiments within yeast cells. Naturally occurring lipid granules were tracked in real time as they diffuse through the cytoplasm, and the quantum noise limit was surpassed by 42%. This laser-based microparticle tracking technique is compatible with non-classical light and is immune to low-frequency noise, leading the way to achieving a broad range of quantum-enhanced measurements in biology.

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Enhanced optical trapping via structured scattering

Interferometry can completely redirect light, providing the potential for strong and controllable optical forces. However, subwavelength particles do not naturally act like interferometric beamsplitters and the optical scattering from them is not generally thought to allow efficient interference. Instead, optical trapping is typically achieved via deflection of the incident field. In the Queensland Quantum Optics Laboratory, we show that a suitably structured incident field can achieve beamsplitter-like interactions with scattering particles. The resulting trap offers order-of-magnitude higher strength than the usual Gaussian trap in one axis. We demonstrate trapping with optical tweezers of 3.5–10.0 μm silica spheres, achieving a trap strength up to 30 times higher than was possible using Gaussian traps as well as a two-orders-of-magnitude higher measured signal-to-noise ratio. These results are highly relevant to many applications, including cellular manipulation, fluid dynamics, micro-robotics and tests of fundamental physics.

Trapping via Mie interference. The incident light is represented in blue and the scattered light in orange for a bead trapped by a Gaussian beam, for a beam splitter and for a bead trapped with structured light

Mechanical power spectra for a bead trapped with a Gaussian beam and with structured light showing the improvement in trapping strength and measurement bandwidth.

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Quantum enhanced Raman microscopy

Raman microscopy allows measurements on biological samples where not only the contrast of the sample, but also the chemical composition is visible. However, photodamages introduce hard limits on performances that theory predicts which can only be overcome using quantum photon correlations. We experimentally validate this, using quantum correlated light to reach signal-to-noise beyond the photodamage-free capacity of conventional microscopy. Our microscope is a quantum-compatible coherent Raman microscope that offers sub-wavelength resolution. Quantum correlations within it allow imaging of molecular bonds within a cell with a signal-to-noise ratio improved by 35%. This new method enables the observation of biological structures that would otherwise not be resolvable. Our work provides a path towards order-of-magnitude improvements in both sensitivity and imaging speed.

Raman quantum-enhanced images of polystyrene beads (left) and a yeast cell (middle). The background (coloured green) has no Raman signal, and is limited by measurement noise showing the increase in SNR. Right: A sequence of images in which two cells are illuminated with high optical intensities. Visible photodamages are observed after less than a minute of exposure.

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We gratefully acknowledge funding from:

Australian Research Council
Air Force Office of Scientific Research
ARC Centre of Excellence for Engineered Quantum Systems