Challenges
Datasets
Workspaces
Papers
Discussions
Leaderboard
Log inSign up
Challenges
Datasets
Workspaces
Papers
Discussions
Leaderboard
Blog
Job Board
Q3AS

© 2026 Aqora Quantum S.A.S.

TermsPrivacyLegal Notice

The Journal of Physical Chemistry B

Imaging Brain Tissue with Quantum Light at Low Power

Oleg P. Varnavski, P. Johnson, Tiecheng Liu, Dinesh Pal, George A. Mashour, Theodore G. Goodson III

Published Nov 13, 2024• 5 citations
Publisher

Abstract

Light-induced tissue damage is a crucial limitation for traditional microscopy of the living brain, underscoring the need for new techniques that minimize exposure of samples to light. Here, we tested the hypothesis that quantum light, i.e., entangled photons, could detect brain structures at a lower excitation energy. In a proof of principle, we show microscopic images of fixed brain tissue in the hippocampus area created by fluorescence selective excitation in the process of entangled two-photon absorption in a scanning microscope. Quantum-enhanced entangled two-photon microscopy (TPM) had brain imaging capabilities at an unprecedented low excitation intensity of ∼3.6 × 10 7 photons/s, orders of magnitude lower than the excitation level for the classical two-photon fluorescence image obtained in the same microscope. The extremely low light probe intensity demonstrated in entangled TPM is of critical importance in the investigation of neural activity to minimize heating and photobleaching during repetitive imaging. It may have important functional implications in optogenetic technology, removing unintended heating and accumulated photodamage effects. This technology also opens avenues in spatially resolved brain tissue investigations with quantum light, providing new capabilities in local spectroscopy.

DOI
10.1021/acs.jpcb.4c03225

Related papers

Quantum Light-Enhanced Two-Photon Imaging of Breast Cancer Cells

Oleg P. Varnavski, Carolyn E. Gunthardt, Aasia O. Rehman +2 more

Correct biological interpretation from cell imaging can be achieved only if the observed phenomena proceed with negligible perturbation from the imaging system. Herein, we demonstrate microscopic images of breast cancer cells created by the fluorescence selectively excited in the process of entangled two-photon absorption in a scanning microscope at an excitation intensity orders of magnitude lower than that used for classical two-photon microscopy. Quantum enhanced entangled two-photon microscopy has shown cell imaging capabilities at an unprecedented low excitation intensity of ∼3.6 × 10 7 photons/s, which is a million times lower than the excitation level for the classical two-photon fluorescence image obtained in the same microscope. The extremely low light probe intensity demonstrated in entangled two-photon microscopy is of critical importance to minimize photobleaching during repetitive imaging and damage to cells in live-cell applications. This technology opens new avenues in cell investigations with light microscopy, such as enhanced selectivity and time–frequency resolution.

The Journal of Physical Chemistry Letters•Mar 23, 2022•43 citations

Quantum Imaging of Bone Tissue Using Entangled Two-Photon Microscopy

Paloma Johnson, Bishal Saha, Oleg P. Varnavski +3 more

Tracking the progression of the bone resorption process is important for clinical research and development of pharmaceuticals for bone-related diseases. Although fluorescence imaging is found to be one of the powerful tools for studying bone, conventional fluorescence microscopy relies on extremely high excitation powers that induce photobleaching and phototoxic effects on biological samples, preventing long-term observations. To overcome these limitations, we propose a quantum light-based approach using entangled two-photon fluorescence microscopy (ETPFM). We demonstrate ETPFM for imaging fixed demineralized unstained and Hoechst- and DAPI-stained bone sections at photon fluxes nearly 6 orders of magnitude lower than classical two-photon excitation. This quantum-correlated light preserves tissue integrity, eliminates photobleaching, and reveals microstructures with high contrast. Endogenous fluorescence is detected without exogenous dyes, and osteoclast cells are clearly resolved in the stained bone sections. ETPFM thus provides a minimally invasive, quantum-enhanced approach for long-term imaging of bone microenvironments.

The Journal of Physical Chemistry B•Sep 4, 2026•0 citations

Two-Photon Fluorescence Microscopy at Extremely Low Excitation Intensity: The Power of Quantum Correlations

Oleg P. Varnavski, Theodore G. Goodson III

Quantum entanglement has been shown to imply correlations stronger than those allowed by classical models. The possibility of performing tasks that are classically impossible has made quantum entanglement a powerful resource for the development of novel methods and applications in various fields of research such as quantum computing, quantum cryptography, and quantum metrology. There is a great need for the development of next generation instrumentation and technologies utilizing entangled quantum light. Among the many applications of nonclassical states of light, nonlinear microscopy has the potential to make an impact in broad areas of science from physics to biology. Here, the microscopic image created by the fluorescence selectively excited by the process of the entangled two-photon absorption is reported. Entangled two-photon microscopy offers nonlinear imaging capabilities at an unprecedented low excitation intensity 10 7, which is 6 orders of magnitude lower than the excitation level for the classical two-photon image. The nonmonotonic dependence of the image on the femtosecond delay between the components of the entangled photon pair is demonstrated. This delay dependence is a result of specific quantum interference effects associated with the entanglement and this is not observable with classical excitation light. In combination with novel spectroscopic capabilities provided by a nonclassical light excitation, this is of critical importance for sensing and biological applications.

Journal of the American Chemical Society•Jul 9, 2020•91 citations

Experimental observation of enhanced quantum-entangled two-photon absorption fluorescence at milliwatt pump power levels

Tadashi Kasamatsu, Kengo Hisamatsu, Masahiro Toida

Optical technologies based on two-photon absorption can provide high resolution and deep tissue penetration but require very high peak power intensities because of the extremely small absorption cross sections associated with this phenomenon. The use of quantum-entangled photon pairs has been reported to increase the two-photon absorption rate compared with that obtainable using classical coherent laser sources. However, the enhancement that can possibly be obtained using entangled two-photon absorption (ETPA) has thus far been realized only at low photon rates, typically ranging from 107 (on the pW level) to 1013 (on the μW level) photons/s. For this reason, ETPA has been regarded as impractical. The present work demonstrates an experimental evaluation of ETPA-excited fluorescence at both low (μW) and relatively high (mW) pump power levels, using a high-gain parametric down-conversion source. Both an increase in the absorption rate and a linear correlation between rate and power were observed within both power ranges. This work also compared quantum and coherent sources. Assessments of the crossover photon flux suggest that the larger spatial-mode diameter of the present quantum source at the focal point (relative to values used in prior research) may have contributed to the rate enhancement seen at high-power levels. The results presented herein are expected to provide a new route to the mitigation of damage often associated with two-photon imaging and photodynamic therapies.

Applied Physics Letters•Mar 9, 2026•2 citations

Quantum confocal imaging based on entangled photons

Wen-Zhuo Tang, Hongwei Wang, Yuhang Luo +4 more

Laser confocal imaging technology has become an important analytical tool in biological, biomedical, and materials science research, offering high imaging precision. However, this technology still has some limitations, especially in imaging biological samples (such as living tissues or cells), where the high intensity of the laser may cause irreversible photodamage. It has been proposed that quantum entangled light sources, instead of laser, can be used to avoid this drawback. In this paper, we experimentally demonstrated a quantum confocal imaging technology employing entangled photon sources with high brightness and stability. In the experiment, we obtained the point-by-point scanning imaging of a targeted area, in which a resolution of 3.91 µm is achieved and the signal-to-noise ratio (SNR) degradation is suppressed. We also theoretically analyzed the potential of quantum confocal imaging to improve SNR performance in photodamage-free imaging. Our results could widen the application fields of confocal imaging technology and pave the way for applying the quantum technology in biological imaging.

International Conference on Optical Communication and Optical Information Processing (OCOIP)•Mar 17, 2025•0 citations

Quantum-optimal nonlinear microscopy with classical light

Joshua L. Reynolds, S. C. Burd, Tzu-Chieh Yen +3 more

Nonlinear optical processes are used in biological microscopy to surpass the diffraction limit on resolution, image deeper into brain tissues, and identify biomolecules without exogenous labels. These techniques typically require high optical intensities to increase the strength of the nonlinear interactions, which can perturb native biochemistry and damage or kill living samples. Stimulated Raman scattering (SRS) microscopy visualizes the spatial distribution of molecules using a nonlinear interaction between light and chemically specific molecular vibrations. However, the detection of biomolecules at low concentrations is limited by the total photon dose that can be applied before photodamage alters the sample, and photon shot noise sets the minimum achievable noise floor for most microscopes. Here we demonstrate a cavity-enhanced SRS microscope that is more sensitive than an equivalent conventional SRS microscope by up to 8.3(7) dB in spectroscopy and 8.6(1) dB in cell imaging. These results approach quantum limits on sensitivity and demonstrate that quantum states of light are sufficient but not necessary to enhance the sensitivity of microscopy techniques that are limited by photodamage.

arXiv:2512.04328•Dec 3, 2025•0 citations
Light-induced tissue damage is a crucial limitation for traditional microscopy of the living brain, underscoring the need for new techniques that minimize exposure of samples to light. Here, we tested the hypothesis that quantum light, i.e., entangled photons, could detect brain structures at a lower excitation energy. In a proof of principle, we show microscopic images of fixed brain tissue in the hippocampus area created by fluorescence selective excitation in the process of entangled two-photon absorption in a scanning microscope. Quantum-enhanced entangled two-photon microscopy (TPM) had brain imaging capabilities at an unprecedented low excitation intensity of ∼3.6 × 10 7 photons/s, orders of magnitude lower than the excitation level for the classical two-photon fluorescence image obtained in the same microscope. The extremely low light probe intensity demonstrated in entangled TPM is of critical importance in the investigation of neural activity to minimize heating and photobleaching during repetitive imaging. It may have important functional implications in optogenetic technology, removing unintended heating and accumulated photodamage effects. This technology also opens avenues in spatially resolved brain tissue investigations with quantum light, providing new capabilities in local spectroscopy.
Correct biological interpretation from cell imaging can be achieved only if the observed phenomena proceed with negligible perturbation from the imaging system. Herein, we demonstrate microscopic images of breast cancer cells created by the fluorescence selectively excited in the process of entangled two-photon absorption in a scanning microscope at an excitation intensity orders of magnitude lower than that used for classical two-photon microscopy. Quantum enhanced entangled two-photon microscopy has shown cell imaging capabilities at an unprecedented low excitation intensity of ∼3.6 × 10 7 photons/s, which is a million times lower than the excitation level for the classical two-photon fluorescence image obtained in the same microscope. The extremely low light probe intensity demonstrated in entangled two-photon microscopy is of critical importance to minimize photobleaching during repetitive imaging and damage to cells in live-cell applications. This technology opens new avenues in cell investigations with light microscopy, such as enhanced selectivity and time–frequency resolution.
Tracking the progression of the bone resorption process is important for clinical research and development of pharmaceuticals for bone-related diseases. Although fluorescence imaging is found to be one of the powerful tools for studying bone, conventional fluorescence microscopy relies on extremely high excitation powers that induce photobleaching and phototoxic effects on biological samples, preventing long-term observations. To overcome these limitations, we propose a quantum light-based approach using entangled two-photon fluorescence microscopy (ETPFM). We demonstrate ETPFM for imaging fixed demineralized unstained and Hoechst- and DAPI-stained bone sections at photon fluxes nearly 6 orders of magnitude lower than classical two-photon excitation. This quantum-correlated light preserves tissue integrity, eliminates photobleaching, and reveals microstructures with high contrast. Endogenous fluorescence is detected without exogenous dyes, and osteoclast cells are clearly resolved in the stained bone sections. ETPFM thus provides a minimally invasive, quantum-enhanced approach for long-term imaging of bone microenvironments.
Quantum entanglement has been shown to imply correlations stronger than those allowed by classical models. The possibility of performing tasks that are classically impossible has made quantum entanglement a powerful resource for the development of novel methods and applications in various fields of research such as quantum computing, quantum cryptography, and quantum metrology. There is a great need for the development of next generation instrumentation and technologies utilizing entangled quantum light. Among the many applications of nonclassical states of light, nonlinear microscopy has the potential to make an impact in broad areas of science from physics to biology. Here, the microscopic image created by the fluorescence selectively excited by the process of the entangled two-photon absorption is reported. Entangled two-photon microscopy offers nonlinear imaging capabilities at an unprecedented low excitation intensity 10 7, which is 6 orders of magnitude lower than the excitation level for the classical two-photon image. The nonmonotonic dependence of the image on the femtosecond delay between the components of the entangled photon pair is demonstrated. This delay dependence is a result of specific quantum interference effects associated with the entanglement and this is not observable with classical excitation light. In combination with novel spectroscopic capabilities provided by a nonclassical light excitation, this is of critical importance for sensing and biological applications.
Optical technologies based on two-photon absorption can provide high resolution and deep tissue penetration but require very high peak power intensities because of the extremely small absorption cross sections associated with this phenomenon. The use of quantum-entangled photon pairs has been reported to increase the two-photon absorption rate compared with that obtainable using classical coherent laser sources. However, the enhancement that can possibly be obtained using entangled two-photon absorption (ETPA) has thus far been realized only at low photon rates, typically ranging from 107 (on the pW level) to 1013 (on the μW level) photons/s. For this reason, ETPA has been regarded as impractical. The present work demonstrates an experimental evaluation of ETPA-excited fluorescence at both low (μW) and relatively high (mW) pump power levels, using a high-gain parametric down-conversion source. Both an increase in the absorption rate and a linear correlation between rate and power were observed within both power ranges. This work also compared quantum and coherent sources. Assessments of the crossover photon flux suggest that the larger spatial-mode diameter of the present quantum source at the focal point (relative to values used in prior research) may have contributed to the rate enhancement seen at high-power levels. The results presented herein are expected to provide a new route to the mitigation of damage often associated with two-photon imaging and photodynamic therapies.
Laser confocal imaging technology has become an important analytical tool in biological, biomedical, and materials science research, offering high imaging precision. However, this technology still has some limitations, especially in imaging biological samples (such as living tissues or cells), where the high intensity of the laser may cause irreversible photodamage. It has been proposed that quantum entangled light sources, instead of laser, can be used to avoid this drawback. In this paper, we experimentally demonstrated a quantum confocal imaging technology employing entangled photon sources with high brightness and stability. In the experiment, we obtained the point-by-point scanning imaging of a targeted area, in which a resolution of 3.91 µm is achieved and the signal-to-noise ratio (SNR) degradation is suppressed. We also theoretically analyzed the potential of quantum confocal imaging to improve SNR performance in photodamage-free imaging. Our results could widen the application fields of confocal imaging technology and pave the way for applying the quantum technology in biological imaging.
Nonlinear optical processes are used in biological microscopy to surpass the diffraction limit on resolution, image deeper into brain tissues, and identify biomolecules without exogenous labels. These techniques typically require high optical intensities to increase the strength of the nonlinear interactions, which can perturb native biochemistry and damage or kill living samples. Stimulated Raman scattering (SRS) microscopy visualizes the spatial distribution of molecules using a nonlinear interaction between light and chemically specific molecular vibrations. However, the detection of biomolecules at low concentrations is limited by the total photon dose that can be applied before photodamage alters the sample, and photon shot noise sets the minimum achievable noise floor for most microscopes. Here we demonstrate a cavity-enhanced SRS microscope that is more sensitive than an equivalent conventional SRS microscope by up to 8.3(7) dB in spectroscopy and 8.6(1) dB in cell imaging. These results approach quantum limits on sensitivity and demonstrate that quantum states of light are sufficient but not necessary to enhance the sensitivity of microscopy techniques that are limited by photodamage.