Stimulated Raman Scattering (SRS) enables label-free imaging by probing the vibrational responses of molecules. SRS offers high specificity and sensitivity; however, its signal-to-noise ratio (SNR) is constrained by photodamage to the sample. To address this limitation, high-power, quantum-enhanced SRS microscopes have recently been developed and applied to both polymers and biological samples. Using squeezed light for illumination, these microscopes suppress noise below the shot noise level, improving the SNR without increasing the illumination intensity. In this work, we highlight the advantages of using squeezed light over other sources of quantum correlations when operating at the high optical powers required for precision microscopy limited by photodamage. We then present the latest developments a photodamage-evading quantum microscope where both the quality of the quantum probe and the classical SNR are improved on compared to the previous single-beam SRS imaging experiments. These improvements led to a fast, multispectral quantum imaging system with noise levels below the shot noise limit of state-of-the-art classical SRS microscopes.

Stimulated Raman scattering (SRS) microscopy is a powerful label-free imaging technique that probes the vibrational response of chemicals with high specificity and sensitivity. High-power, quantum-enhanced SRS microscopes have been recently demonstrated and applied to polymers and biological samples. Quantum correlations, in the form of squeezed light, enable the microscopes to operate below the shot noise limit, enhancing their performance without increasing the illumination intensity. This addresses the signal-to-noise ratio (SNR) and speed constraints introduced by photodamage in shot noise-limited microscopes. Previous microscopes have either used single-beam squeezing, but with insufficient brightness to reach the optimal ratio of pump-to-Stokes intensity for maximum SNR, or have used twin-beam squeezing and suffered a 3 dB noise penalty. Here we report a quantum-enhanced Raman microscope that uses a bright squeezed single-beam, enabling operation at the optimal efficiency of the SRS process. The increase in brightness leads to multimode effects that degrade the squeezing level, which we partially overcome using spatial filtering. We apply our quantum-enhanced SRS microscope to biological samples and demonstrate quantum-enhanced multispectral imaging of living cells. The imaging speed of 100×100 pixels in 18 seconds allows the dynamics of cell organelles to be resolved. The SNR achieved is compatible with video-rate imaging, with the quantum correlations yielding a 20% improvement in imaging speed compared to shot noise-limited operation.

Quantum technologies leverage the laws of quantum physics to achieve performance advantages in applications ranging from computing to communications and sensing. They have been proposed to have a range of applications in biological science. This includes better microscopes and biosensors, improved simulations of molecular processes, and new capabilities to control the behaviour of biomolecules and chemical reactions. Quantum effects are also predicted, with much debate, to have functional benefits in biology, for instance, allowing more efficient energy transport and improving the rate of enzyme catalysis. Conversely, the robustness of biological systems to disorder from their environment has led to proposals to use them as components within quantum technologies, for instance as light sources for quantum communication systems. Together, this breadth of prospective applications at the interface of quantum and biological science suggests that quantum physics will play an important role in stimulating future biotechnological advances. This review aims to provide an overview of this emerging field of quantum biotechnology, introducing current capabilities, future prospects, and potential areas of impact. The review is written to be accessible to the non-expert and focuses on the four key areas of quantum-enabled sensing, quantum-enabled imaging, quantum biomolecular control, and quantum effects in biology.

The performance of light microscopes is limited by the stochastic nature of light, which exists in discrete packets of energy known as photons. Randomness in the times that photons are detected introduces shot noise, which fundamentally constrains sensitivity, resolution and speed 1 . Although the long-established solution to this problem is to increase the intensity of the illumination light, this is not always possible when investigating living systems, because bright lasers can severely disturb biological processes 2 – 4 . Theory predicts that biological imaging may be improved without increasing light intensity by using quantum photon correlations 1 , 5 . Here we experimentally show that quantum correlations allow a signal-to-noise ratio beyond the photodamage limit of conventional microscopy. Our microscope is a coherent Raman microscope that offers subwavelength resolution and incorporates bright quantum correlated illumination. The correlations allow imaging of molecular bonds within a cell with a 35 per cent improved signal-to-noise ratio compared with conventional microscopy, corresponding to a 14 per cent improvement in concentration sensitivity. This enables the observation of biological structures that would not otherwise be resolved. Coherent Raman microscopes allow highly selective biomolecular fingerprinting in unlabelled specimens 6 , 7 , but photodamage is a major roadblock for many applications 8 , 9 . By showing that the photodamage limit can be overcome, our work will enable order-of-magnitude improvements in the signal-to-noise ratio and the imaging speed.

In the Acknowledgements section of this Article, the sentence “This work was supported primarily by the Air Force Office of Scientific Research (AFOSR) grant FA2386-14-1-4046.” should have been “This material is based upon work supported by the Air Force Office of Scientific Research under award number FA9550-17-1-0397.”. The original Article has been corrected online.

State-of-the-art microscopes use intense lasers that can severely disturb biological processes, function and viability. This introduces hard limits on performance that only quantum photon correlations can overcome. In this talk I will report recent work from my laboratory which demonstrates this absolute quantum advantage [1]. We show, specifically, that quantum correlations enable signal-to-noise beyond the photodamage-free capacity of conventional microscopy. Broadly, this represents the first demonstration that quantum correlations can allow sensing beyond the limits introduced by optical intrusion upon the measurement process. We achieve this in a coherent Raman microscope, which we use to image molecular bonds within a cell with both quantum-enhanced contrast and sub-wavelength resolution. This allows the observation of nanoscale biological structures that would otherwise not be resolved. Coherent Raman microscopes allow highly selective biomolecular finger-printing in unlabelled specimens, but photodamage is a major roadblock for many applications. By showing that this roadblock can be overcome, our work provides a path towards order-of-magnitude improvements in both sensitivity and imaging speed.

Viscosity is an important property of out-of-equilibrium systems such as active biological materials and driven non-Newtonian fluids, and for fields ranging from biomaterials to geology, energy technologies and medicine. Non-invasive viscosity measurements typically require integration times of seconds. Here, we demonstrate measurement speeds reaching 20 μs, with uncertainty dominated by thermal molecular collisions for the first time. We achieve this using the instantaneous velocity of a trapped particle in an optical tweezer. To resolve the instantaneous velocity we develop a structured-light detection system that allows particle tracking over femtometre length scales and 16-ns timescales. Our results translate viscosity from a static averaged property to one that may be dynamically tracked on the timescales of active dynamics. This opens a pathway to new discoveries in out-of-equilibrium systems, from the fast dynamics of phase transitions to energy dissipation in motor molecule stepping and to violations of fluctuation laws of equilibrium thermodynamics. A structured-light-based detection of a particle trapped in optical tweezers enables ultrafast velocity and viscosity determination.

State-of-the-art microscopes use intense lasers that can severely disturb biological processes, function and viability. This introduces hard limits on performance that only quantum photon correlations can overcome. Here we demonstrate this absolute quantum advantage, achieving signal-to-noise beyond the photodamage-free capacity of conventional microscopy. We achieve this in a coherent Raman microscope, which we use to image molecular bonds within a cell with both quantum-enhanced contrast and sub-wavelength resolution. This allows the observation of nanoscale biological structures that would otherwise not be resolved. Coherent Raman microscopes allow highly selective biomolecular finger-printing in unlabelled specimens, but photodamage is a major roadblock for many applications. By showing that this roadblock can be overcome, our work provides a path towards order-of-magnitude improvements in both sensitivity and imaging speed.