Detecting Tiny Changes in Light to Spot Single Molecules

At a Glance

Researchers at Colorado State University have developed a device and method that can measure extremely small shifts in the frequency of light pulses. This allows for much higher sensitivity than current Raman spectroscopy techniques, potentially detecting single molecules. This technology opens new possibilities for identifying molecules with unprecedented precision and can be used for chemical detection in nearly any industry or application that differentiates molecules or the chemical nature of compounds.

Background

Detecting very low levels of molecular impurities is essential in many scientific and industrial fields. Techniques like Raman scattering and mid-infrared (MIR) absorption are commonly used but have limitations. MIR suffers from low spatial resolution and weak light sources, while Raman spectroscopy is limited by weak signal strength and only works well at higher concentrations. Existing spectrometers cannot detect the extremely small frequency shifts required for detecting minute quantities, creating a need for more sensitive methods.

Overview

This innovation measures tiny changes in the optical frequency of pulses in a train of light pulses, reaching sensitivities far beyond traditional methods. Unlike standard interferometry, which cannot detect shifts below about 1 GHz, this method translates small frequency shifts into measurable time delays. This conversion allows detection of frequency changes as small as 1 kHz—improving sensitivity by six orders of magnitude.

Originally designed to enhance Raman spectroscopy, this technology can detect frequency shifts of pulse-to-pulse that were previously impossible to measure. By enabling “single molecule detection,” it promises a major leap forward in the sensitivity of vibrational spectroscopy techniques.

Data from the spectroscopy imaging — Figure 1. Time-resolved Raman spectra of biological molecules. The spectra are extracted from the time-resolved Raman response using either multitaper power spectral density estimation or linear prediction singular value decomposition (LPSVD). LPSVD model estimates are shown on the left, and reconstructed Raman spectra using LPSVD are shown on the right, with peaks corresponding to literature values indicated. Samples include: (a) 100 mM Flavin adenine dinucleotide (FAD) in phosphate-buffered saline (PBS), (b) 100 mM Adenosine triphosphate (ATP) in DI water, (c) 100 mM Nicotinamide adenine dinucleotide (NADH) in PBS, (d) 0.5 M L-Alanine in PBS, and (e) 1 M L-Cysteine in PBS.

Light scattering data — Figure 2. Raman spectra of Flavin adenine dinucleotide (FAD) at different concentrations, showing how signal intensity changes with concentration.

Benefits

Measures extremely small frequency shifts in optical pulses
Detects shifts unmeasurable by standard interferometric techniques
Converts frequency changes into time delays for precise electronic measurement
Applicable to any consistent pulse-to-pulse frequency shift
Dramatically improves Raman spectroscopy sensitivity to near single molecule detection levels

Applications

Forensic chemical analysis
Biomedical diagnostics and molecular detection
Neuroscience research requiring sensitive molecular sensing
Polymer and material manufacturing quality control
Trace chemical detection in environmental and industrial settings

Publications

D.R. Smith, et al. 2019. “Ultrasensitive Doppler Raman spectroscopy using radio frequency phase shift detection” https://doi.org/10.48550/arXiv.1912.04348

Last Updated: June 2026

Opportunity

Available for Licensing
TRL: 2

IP Status

US10488259

Inventors

Randy Bartels
David Winters

Reference Number

14-102

Licensing Manager

Aly Hoeher
Aly.Hoeher@colostate.edu
970-491-7100