Stimulated Raman photothermal microscope
Inventors
Assignees
Publication Number
US-12196682-B2
Publication Date
2025-01-14
Expiration Date
2044-01-26
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Abstract
A stimulated Raman photothermal (SRP) microscope for imaging a sample. A first optical source omits an intensity-modulated pump beam. A second optical source omits an intensity-modulated Stokes beam. The Stokes beam is combined with the pump beam to form a combined beam. The combined beam is directed to the sample to induce a thermal effect caused by the stimulated Raman process. A third optical source emits a probe beam, the probe beam is directed to the sample. An optical detector detects modulation of the probe beam after modulation by the sample to measure an SRP signal.
Core Innovation
The invention relates to systems and methods for a stimulated Raman photothermal (SRP) microscope capable of imaging a sample with enhanced sensitivity and spatial resolution. The core innovation is the use of intensity-modulated pump and Stokes beams that are combined and directed to the sample to induce a thermal effect via the stimulated Raman process, alongside a third probe beam that detects the resulting thermal lensing through changes in local refractive index. The probe beam, after modulation by the sample, is detected by an optical detector, providing a much higher modulation depth and sensitivity than conventional SRS methods.
The problem addressed by the invention is the inherent limitations of conventional SRS microscopy, particularly its low detection sensitivity due to small modulation depths and susceptibility to noise, as well as the technical complexity associated with noise-reduction methods and enhancement techniques that require special molecular labels or structures. Previous approaches to boost sensitivity were either limited in scope or introduced operational complexity, such as the need for auto-balance detection in fiber laser systems or the use of plasmonic nanostructures that constrain applicability.
The present disclosure overcomes these limitations by introducing low duty cycle coherent Raman excitation, which nonlinearly benefits from high laser peak power and amplifies the stimulated Raman-induced thermal effect. This process creates a significant local temperature rise and refractive index change, forming a detectable thermal lens, which is then optically interrogated with a probe beam. The integration of a simplified fiber laser probe beam and an air condenser for light collection further improves usability and broadens the practical application of the system, facilitating high-sensitivity, label-free, and bond-selective imaging in various biological and material environments.
Claims Coverage
The patent includes two independent claims, each covering distinctive inventive features related to the structure and methods of an SRP microscope.
SRP microscope using modulated pump, Stokes, and probe beams with detection of probe modulation
The SRP microscope comprises: - A first optical source emitting an intensity-modulated pump beam. - A second optical source emitting an intensity-modulated Stokes beam, with the Stokes and pump beams combined and directed to the sample to induce a thermal effect via the stimulated Raman process. - A third optical source emitting a probe beam that is directed to the sample. - An optical detector configured to detect modulation of the probe beam, after modulation by the sample, for measuring an SRP signal.
SRP microscope employing a fiber laser for probe beam and photodiode detection
The SRP microscope comprises: - A first optical source emitting an intensity-modulated pump beam. - A second optical source emitting an intensity-modulated Stokes beam, combined with the pump beam and directed to the sample to induce a thermal effect via the stimulated Raman process. - A fiber laser emitting a probe beam directed to the sample. - A photodiode configured to detect modulation of the probe beam after modulation by the sample to measure an SRP signal.
These inventive features define an SRP microscope that utilizes modulated pump and Stokes beams to induce a thermal effect, probed by a third beam whose modulation is detected to provide imaging data, with embodiments specifying the use of a fiber laser and photodiode detection for improved sensitivity and operational simplicity.
Stated Advantages
Provides superior sensitivity compared to conventional SRS, with much higher modulation depth and lower detection limits.
Achieves high-quality, high-contrast imaging of nanoparticles, single viruses, sub-cellular structures, and tissue samples.
Eliminates the need for balance detection systems, simplifying setup and operation, especially when using fiber lasers.
Improves spatial resolution through the use of a third probe beam and shorter wavelengths.
Offers enhanced signal-to-noise and signal-to-background ratios compared to SRS.
Reduces susceptibility to laser noise and allows use of high-power, noisy lasers for vibrational imaging.
Facilitates user-friendly, robust setup by allowing use of air condensers and compatibility with long working distance optics.
Enables real-time, label-free, and bond-selective imaging across various Raman bands and in different sample media.
Documented Applications
Label-free imaging of live and fixed biological samples, including cancer cells and tissue sections.
Hyperspectral chemical mapping and analysis of sub-cellular structures, such as lipid droplets, endoplasmic reticulum, and nuclei.
Detection and imaging of individual viral particles.
Screening and chemical mapping of large area tissues, including cancer tissues.
Analysis of cellular uptake of molecules (e.g., deuterated palmitic acid in cells).
High-sensitivity imaging and detection of nanoparticles and weak Raman bands in materials.
Quantitative decomposition of chemical content in biological samples.
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