Computed terahertz near-field mapping of molecular resonances of lactose stereo-isomer impurities with sub-attomole sensitivity

Abstract

Terahertz near-field microscopy (THz-NFM) could locally probe low-energy molecular vibration dynamics below diffraction limits, showing promise to decipher intermolecular interactions of biomolecules and quantum matters with unique THz vibrational fingerprints. However, its realization has been impeded by low spatial and spectral resolutions and lack of theoretical models to quantitatively analyze near-field imaging. Here, we show that THz scattering-type scanning near-field optical microscopy (THz s-SNOM) with a theoretical model can quantitatively measure and image such low-energy molecular interactions, permitting computed spectroscopic near-field mapping of THz molecular resonance spectra. Using crystalline-lactose stereo-isomer (anomer) mixtures (i.e., α-lactose (≥95%, w/w) and β-lactose (≤4%, w/w)), THz s-SNOM resolved local intermolecular vibrations of both anomers with enhanced spatial and spectral resolutions, yielding strong resonances to decipher conformational fingerprint of the trace β-anomer impurity. Its estimated sensitivity was ~0.147 attomoles in ~8 × 10−4 μm3 interaction volume. Our THz s-SNOM platform offers a new path for ultrasensitive molecular fingerprinting of complex mixtures of biomolecules or organic crystals with markedly enhanced spatio-spectral resolutions. This could open up significant possibilities of THz technology in many fields, including biology, chemistry and condensed matter physics as well as semiconductor industries where accurate quantitative mappings of trace isomer impurities are critical but still challenging.

Photonic Bragg waveguide platform for multichannel resonant sensing applications in the THz range

“…A powder analyte named α-lactose monohydrate (molecular structure shown in Fig. 3(a)) is chosen as the target analyte, since it has fingerprint in THz region [40]. Such powder is captured on the waveguide inner core surface via the centrifugal force by employing a rotating setup shown in Fig.…”

“…As a reference, we also plot the reference spectrum of the waveguide with an empty core. The absorption peak at ∼0.53THz is the absorption signature of α-lactose monohydrate in THz range due to intermolecular interactions [40]. The other absorption peak at ∼0.57THz is one of the water lines in THz range [41].…”

Towards broadband THz spectroscopy and analysis of sub-wavelength-size biological samples

“…The scattering Scanning Near-field Microscopy (s-SNOM) [10,11], uses the oscillating tip of an Atomic Force µscope (AFM) to concentrate the incident light on its nm-sized apex enabling to probe the dielectric constant of a material at a resolution similar to the apex radius (today's record ~ 15 nm [12]). It can be used as a nano-spectroscopy system [13], for instance in the recent report of the characterization of lactose [14]. Although, in this case, due to a relatively low signal to noise ratio, the resolution is ~2 µm using complex experiments and very long integration time.…”

On the influence of water on THz vibrational spectral features of molecular crystals

“…1b. Also, due to its wide availability and low cost, lactose samples are often used to test THz spectroscopy equipment, 34,67 serving as a “first-try” sample in minor-volume detection techniques, 68–70 and is used as a mixture compound in approving methods for content quantification. 71,72 Furthermore, the study of lactose is important for pharmacology, 73,74 medicine 75–77 and food industry.…”