The collective vibrational modes of dihydropyridine in nifedipine studied by terahertz spectroscopy.

Cardiovascular pharmaceuticals have drawn huge attention in drug development. Nifedipine (NFD) is an important member of calcium channel blockers (CCB) with the structural characteristic of dihydropyridine (DHP), but the binding mechanism to its target remains an open question. Even though several analytical techniques have been used for structural characterizations, the information of collective vibrational behavior is still lacking. In this work, we use terahertz (THz) spectroscopy to investigate the spectral fingerprints of NFD, and quantitatively evaluate the temperature-induced frequency shifts. Combined with quantum chemical calculations, each THz fingerprint is attributed to specific collective vibrational modes. The collective vibrations of DHP are mainly distributed below 2.5 THz, which provides complementary information to understand the behavior of rigid DHP ring. The rotation of methyl group and the wagging of nitrophenyl group are widely distributed in the range of 1.0-4.0 THz, which is helpful for the conformational recognition between NFD and target molecule. THz spectroscopy is demonstrated to be suitable for characterizing the collective vibrational modes of DHP and elucidating the drug-target binding behavior from the perspective of noncovalent interactions. It has the potential to become a non-invasive technology for conformational analysis and pharmaceutical development.

Detection of biomarkers using terahertz metasurface sensors and machine learning.

To achieve classification and concentration detection of cancer biomarkers, we propose a method that combines terahertz (THz) spectroscopy, metasurface sensors, and machine learning. A metasurface sensor suitable for biomarker detection was designed and fabricated with five resonance frequencies in the range of 0.3-0.9 THz. We collected biomarkers of five types and nine concentrations at 100 sets of time-domain spectra per concentration. The spectrum is processed by noise reduction and fast Fourier transform to obtain the frequency-domain spectrum. Five machine learning algorithms are used to analyze time- and frequency-domain spectra and ascertain which algorithm is more suitable for the classification of the biomarker THz spectrum. Experimental results show that random forest can better distinguish five biomarkers with an accuracy of 0.984 for the time-domain spectrum. For the frequency-domain spectrum, the support vector machine performs better, with an accuracy of 0.989. For biomarkers at different concentrations, we used linear regression to fit the relationship between biomarker concentration and frequency shift. Experimental results show that machine learning can distinguish different biomarker species and their concentrations by the THz spectrum. This work provides an idea and data processing method for the application of THz technology in biomedical detection.

Detection of Asthma Inhaler Use via Terahertz Spectroscopy.

Inhaled medications are commonplace for administering bronchodilators, anticholinergics, and corticosteroids. While they have a defined legitimate use, they are also used in sporting events as performance-enhancing drugs. These performance enhancers can be acquired via both legal (i.e., at a pharmacy through over-the-counter medications or through a prescription) and illicit (i.e., black market and foreign pharmacies) means, thus making monitoring procurement impossible. While urine tests can detect these pharmacological agents hours after they have been inhaled, there is a significant lag time before they are observed in urine. Direct detection of these inhaled agents is complicated and requires a multiplexed approach due to the sheer number of inhaled pharmacological agents. Therefore, detection of propellants, which carry the drug into the lungs, provides a simpler path forward toward detection of broad pharmacological agents. In this paper, we demonstrate the first use of terahertz spectroscopy (THz) to detect inhaled medications in human subjects. Notably, we were able to detect and quantitate the propellant, HFA-134a, in breath up to 30 min after using an asthma inhaler, enabling the use of a point-of-care device to monitor exhaled breath for the presence of propellants. We also demonstrate via simulations that the same approach can be leveraged to detect and identify next-generation propellants, specifically HFA-152a. As a result, we provide evidence that a single point-of-care THz sensor can detect when individuals have used pressure-mediated dose inhalers (pMDIs) without further modification of the hardware.

[Research Progress in the Application of Terahertz Spectroscopy and Imaging Technology in Stomatology].

Terahertz waves, the electromagnetic waves in the range of 0.1 to 10 THz, has the advantages of being damage-free, causing no ionizing radiation injury, and being capable of recognizing the fingerprint spectrum of molecular characteristics, thus holding encouraging prospects for wide applications in the field of biomedicine. Terahertz spectrum can be used to identify and characterize biological structures of different levels, from biomolecules such as proteins to cells and tissues, through the spectral signals and/or restored images of the samples. Herein, we summarized the current stomatogical application of and research progress in terahertz spectroscopy and imaging in dentistry, reported the latest research findings, strengths and limitations from three perspectives, tooth anatomical structure, the extent of caries progression, and oral soft tissue, and suggested possible directions for future exploration.

Chiral enantiomer recognition of amino acids enhanced by terahertz spin beam separation based on a Pancharatnam-Berry metasurface.

The highly sensitive detection and identification of chiral biochemical substances have attracted extensive attention. Terahertz (THz) spectroscopy and sensing technology have obvious advantages in non-contact and label-free biochemical detection, but the THz chiral spectral response of chiral biochemical substances is too weak to realize highly sensitive chiral enantiomer recognition. Herein, we propose a method of spin beam deflection and separation by using a Pancharatnam-Berry (PB) metasurface to enhance the THz chirality response of chiral amino acids, realizing the identification of chiral enantiomers of the same kind of amino acid. The conjugate spin transmittances and circular dichroism (CD) spectra of d- and l-tyrosine samples on the PB metasurface were measured by an angle-resolved THz time-domain polarization spectroscopy system, and their CD values reached 16.4° and -11.6° at a deflection angle of ±33°, respectively, which were enhanced by about 9.3 and 11.9 times compared with the maximum CD values of the sample without the metasurface. Therefore, this THz chiral sensing method based on a PB metasurface has great potential in highly sensitive chirality identification and enhancement for chiral substances.

Terahertz Spectroscopic Molecular Sensor for Rapid and Highly Specific Quantitative Analytical Gas Sensing.

Quantitative analytical gas sampling is of great importance in a range of environmental, safety, and scientific applications. In this article, we present the design, operation, and performance of a recently developed tabletop terahertz (THz) spectroscopic molecular sensor capable of rapid (minutes) and sensitive detection of polar gaseous analytes with near "absolute" specificity. A novel double-coil absorption cell design and an array of room-temperature sorbent-based preconcentration modules facilitate quantitative THz detection of light polar volatile compounds, which often challenge the capabilities of established gas sensing techniques. Acetone, ethanol, methanol, acetaldehyde, formaldehyde, and isoprene are detected at low parts-per-billion to high parts-per-trillion levels. This work evaluates performance-limiting factors for THz spectroscopy-based chemical identification: (1) spectral signal to noise and (2) preconcentrator efficiency.

Assessing Corneal Endothelial Damage Using Terahertz Time-Domain Spectroscopy and Support Vector Machines.

The endothelial layer of the cornea plays a critical role in regulating its hydration by actively controlling fluid intake in the tissue via transporting the excess fluid out to the aqueous humor. A damaged corneal endothelial layer leads to perturbations in tissue hydration and edema, which can impact corneal transparency and visual acuity. We utilized a non-contact terahertz (THz) scanner designed for imaging spherical targets to discriminate between ex vivo corneal samples with intact and damaged endothelial layers. To create varying grades of corneal edema, the intraocular pressures of the whole porcine eye globe samples (n = 19) were increased to either 25, 35 or 45 mmHg for 4 h before returning to normal pressure levels at 15 mmHg for the remaining 4 h. Changes in tissue hydration were assessed by differences in spectral slopes between 0.4 and 0.8 THz. Our results indicate that the THz response of the corneal samples can vary according to the differences in the endothelial cell density, as determined by SEM imaging. We show that this spectroscopic difference is statistically significant and can be used to assess the intactness of the endothelial layer. These results demonstrate that THz can noninvasively assess the corneal endothelium and provide valuable complimentary information for the study and diagnosis of corneal diseases that perturb the tissue hydration.

Terahertz Time-Domain Spectroscopic Study of Tricalcium Silicate.

In this study, the terahertz (THz) spectra of C3S were obtained in the 0.4-2.3 THz frequency range using different sample preparation methods. In the spectra, a sharp absorption peak of C3S was found at 2.03 THz. Under controlled conditions, the mass ratio of C3S was the most critical factor affecting the strength of the absorption peak, and the absorption coefficient followed the Beer-Lambert law, exhibiting a linear relationship with the mass ratio of C3S. The intrinsic dielectric constants of C3S and polyethylene (PE) were calculated in accordance with the Maxwell-Garnett (MG), Bruggeman (BM), and Landau-Lifshitz-Loovenga (LLL) models, using two-phase composite samples. The results show that the LLL model had the highest accuracy.

Boosting the terahertz absorption spectroscopy based on the stretchable metasurface.

Terahertz (THz) absorption spectroscopy is widely used for molecular label-free fingerprinting detection, but it is not capable of efficiently analyzing trace-amount sample materials. For improving the efficiency of terahertz absorptance spectroscopy detection, we propose a sensing strategy by treating the geometry sweeping spoof surface plasmon polariton (SSP) of the stretchable metasurface. For the first time, the geometry sweeping can be realized by dynamically stretching the polydimethylsiloxane (PDMS) flexible substrate, leading to the resonant frequency variation of the unit cell. This design provides a significant absorption enhancement factor about 270 times for a 0.1 µm lactose film in a broad terahertz band, enabling the unambiguous identification of different trace-amount samples. The designed method exhibits a novel solution for the enhancement of broad-band terahertz absorption spectroscopy and great application potential in the field of detecting trace-amount samples.

Subwavelength Terahertz Resonance Imaging (STRING) for Molecular Fingerprinting.

Subwavelength terahertz (THz) imaging methods are highly desirable for biochemical sensing as well as materials sciences, yet sensitive spectral fingerprinting is still challenging in the frequency domain due to weak light-matter interactions. Here, we demonstrate subwavelength THz resonance imaging (STRING) that overcomes this limitation to achieve ultrasensitive molecular fingerprinting. STRING combines individual ring-shaped coaxial single resonators with near-field spectroscopy, yielding considerable sensitivity gains from both local field enhancement and the near-field effect. As an initial demonstration, we obtained spectral fingerprints from isomers of α-lactose and maltose monohydrates, achieving sensitivity that was enhanced by up to 10 orders of magnitude compared to far-field THz measurements with pelletized samples. Our results show that the STRING platform could enable the development of THz spectroscopy as a practical and sensitive tool for the fingerprinting and spectral imaging of molecules and nanoparticles.

Accurate and early prediction of the wound healing outcome of burn injuries using the wavelet Shannon entropy of terahertz time-domain waveforms.

SignificanceSevere burn injuries cause significant hypermetabolic alterations that are highly dynamic, hard to predict, and require acute and critical care. The clinical assessments of the severity of burn injuries are highly subjective and have consistently been reported to be inaccurate. Therefore, the utilization of other imaging modalities is crucial to reaching an objective and accurate burn assessment modality.AimWe describe a non-invasive technique using terahertz time-domain spectroscopy (THz-TDS) and the wavelet packet Shannon entropy to automatically estimate the burn depth and predict the wound healing outcome of thermal burn injuries.ApproachWe created 40 burn injuries of different severity grades in two porcine models using scald and contact methods of infliction. We used our THz portable handheld spectral reflection (PHASR) scanner to obtain the in vivo THz-TDS images. We used the energy to Shannon entropy ratio of the wavelet packet coefficients of the THz-TDS waveforms on day 0 to create supervised support vector machine (SVM) classification models. Histological assessments of the burn biopsies serve as the ground truth.ResultsWe achieved an accuracy rate of 94.7% in predicting the wound healing outcome, as determined by histological measurement of the re-epithelialization rate on day 28 post-burn induction, using the THz-TDS measurements obtained on day 0. Furthermore, we report the accuracy rates of 89%, 87.1%, and 87.6% in automatic diagnosis of the superficial partial-thickness, deep partial-thickness, and full-thickness burns, respectively, using a multiclass SVM model.ConclusionsThe THz PHASR scanner promises a robust, high-speed, and accurate diagnostic modality to improve the clinical triage of burns and their management. Significance: Severe burn injuries cause significant hypermetabolic alterations that are highly dynamic, hard to predict, and require acute and critical care. The clinical assessments of the severity of burn injuries are highly subjective and have consistently been reported to be inaccurate. Therefore, the utilization of other imaging modalities is crucial to reaching an objective and accurate burn assessment modality. Aim: We describe a non-invasive technique using terahertz time-domain spectroscopy (THz-TDS) and the wavelet packet Shannon entropy to automatically estimate the burn depth and predict the wound healing outcome of thermal burn injuries. Approach: We created 40 burn injuries of different severity grades in two porcine models using scald and contact methods of infliction. We used our THz portable handheld spectral reflection (PHASR) scanner to obtain the in vivo THz-TDS images. We used the energy to Shannon entropy ratio of the wavelet packet coefficients of the THz-TDS waveforms on day 0 to create supervised support vector machine (SVM) classification models. Histological assessments of the burn biopsies serve as the ground truth. Results: We achieved an accuracy rate of 94.7% in predicting the wound healing outcome, as determined by histological measurement of the re-epithelialization rate on day 28 post-burn induction, using the THz-TDS measurements obtained on day 0. Furthermore, we report the accuracy rates of 89%, 87.1%, and 87.6% in automatic diagnosis of the superficial partial-thickness, deep partial-thickness, and full-thickness burns, respectively, using a multiclass SVM model. Conclusions: The THz PHASR scanner promises a robust, high-speed, and accurate diagnostic modality to improve the clinical triage of burns and their management.

Experimental Detection and Simulation of Terahertz Spectra of Aqueous L-Arginine.

Terahertz (THz) wave is a good candidate for biological sample detection, because vibration and rotation energy levels of biomolecule are in THz band. However, the strong absorption of THz wave by water in biological samples hinders its development. In this paper, a method for direct detection of THz absorption spectra of L-arginine suspension was proposed by using a strong field THz radiation source combined with a polyethylene cell with micrometer thickness in a THz time-domain spectroscopy system. And the THz absorption spectrum of L-arginine solution was simulated by the density functional theory and the simulation result is in good agreement with the experimental results. Finally, the types of chemical bond interaction that cause the absorption peak are identified based on the experimental and simulation results. This work paves a way to investigate the THz absorption spectra and intramolecular interactions of aqueous biological samples.

Investigating the Impact of Synchrotron THz Radiation on the Corneal Hydration Using Synchrotron THz-Far Infrared Beamline.

Due to increasing interest in imaging, industrial, and the development of wireless communication operating at THz frequencies, it is crucial to ascertain possible health impacts arising from exposure to THz radiation. This paper reports on the pilot study of transmittance and absorbance spectra of the porcine cornea following THz frequency irradiation at a synchrotron THz/Far-IR beamline. The exposure period was 4 hours. One cornea was exposed to the radiation, with a second cornea acting as a control. An Attenuated Total Reflection (ATR) apparatus was used, and the frequency range of 2.4 to 8 THz was selected to evaluate any changes. It was found that the synchrotron THz radiation intensities are too low to produce induced corneal injury, but may lead to subtle changes in the state of water. Our results suggest that THz spectroscopy is a promising modality for corneal tissue hydration sensing.

Analysis of the multilayer organization of a sunflower leaf during dehydration with terahertz time-domain spectroscopy.

We apply reverse engineering techniques (RET) to analyze the dehydration process of a sunflower leaf with terahertz time-domain spectroscopy. The multilayer structure of the leaf is extracted with accuracy during the entire process. Time variations of thickness and the complex index are emphasized for all leaf layers (2 cuticules, 2 epiderms, and 2 mesophylls). The global thickness of the sunflower leaf is reduced by up to 40% of its initial value.

Terahertz spectroscopy detection of zinc citrate in flour and milk powder mixtures.

Zinc citrate (ZC) has been widely used in food as an important nutritional supplement. Accurate detection of ZC in food is important for health and safety. In this study, THz time-domain spectroscopy (THz-TDS) is used to quantitatively detect ZC in flour and milk powder mixtures. In our research, 15 different contents of ZC in flour and milk powder mixtures were prepared and measured by THz-TDS. A partial least squares (PLS) model was established based on the quantitative analysis of the absorption coefficient data of these two mixtures at 0.5-3.0 THz. The R2 and rms error (RMSE) given by the PLS model prediction were, respectively, 0.999 and 0.14% ZC in flour and 0.999 and 0.20% ZC in milk mixtures, indicating the predictions of the PLS model are in excellent agreement with the experimental measurements. The results show that combining THz-TDS with the PLS model can be used for accurate, quantitative analyses of ZC in food mixtures.

Route to flexible metamaterial terahertz biosensor based on multi-resonance dips.

A flexible terahertz (THz) metamaterial biosensor is theoretically and experimentally investigated. The metamaterial unit cell of the periodic structure array was simply composed of three non-overlapping cut wires with different length parameters on a flexible thin-film (parylene-C) to improve sensitivity. The biosensor sample was fabricated using a lithography process and characterized by a THz time-domain spectroscopy (TDS) system. The metamaterial exhibited multi-resonance dips in transmission spectrum at 0.6-2.0 THz, which can self-correct errors in biosensing. Numerical results show that the Q-factor, figure of merit (FOM) and sensitivity can change in dynamic ranges with the geometric parameters (space and width) of three-cut-wire metamaterial. When space distance was 40 µm and other parameters were default, the sensitivity, FOM and Q-factor reached 710 GHz/RIU (Refractive Index Unit), 9, and 20, respectively. Therefore, through proper design and preparation, the metamaterial can be applied to biochemical detection.

Optimized multilayer structure for sensitive THz characterization of thin-film glucose solutions.

Terahertz time-domain spectroscopy (THz-TDS) has shown promise in biomedical sample characterization and high characterization sensitivity is in demand due to the thin-film (TF) feature of the sample. This paper proposes an optimized multilayer structure for sensitive characterization of TF aqueous solutions in reflection THz-TDS. Theoretical simulations are conducted for structural optimization and the 75 µm window-sample-mirror structure displays the best sensitivity compared to other sandwich structures and traditional THz measurement geometries. 0-20% TF glucose solutions are then measured; and a spectral peak introduced by the proposed structure is observed to result in the high sensitivity. Our work provides a new way of customizing multilayer structure for THz thin-film characterization.

Sub-terahertz silicon-based on-chip absorption spectroscopy using thin-film model for biological applications.

Spectroscopy in the sub-terahertz (sub-THz) range of frequencies has been utilized to study the picosecond dynamics and interaction of biomolecules. However, widely used free-space THz spectrometers are typically limited in their functionality due to low signal-to-noise ratio and complex setup. On-chip spectrometers can revolutionize THz spectroscopy allowing integration, compactness, and low-cost fabrication. In this paper, a low-loss silicon-based platform is proposed for on-chip sub-THz spectroscopy. Through functionalization of silicon chip and immobilization of bio-particles, we demonstrate the ability to characterize low-loss nano-scale biomolecules across the G-band (0.14-0.22 THz). We also introduce an electromagnetic thin-film model to account for the loading effect of the immobilized biomolecules, i.e. dehydrated streptavidin and immunoglobulin antibody, as two key molecules in the biosensing discipline. The proposed platform was fabricated using a single mask micro-fabrication process, and then measured by a vector network analyzer (VNA), which offers high dynamic range and high spectral resolution measurements. The proposed planar platform is general and paves the way towards low-loss, cost-effective and integrated sub-THz biosensors for the detection and characterization of biomolecules.

Clinical and experimental study of a terahertz time-domain system for the determination of the pathological margins of laryngeal carcinoma.

OBJECTIVE: Laryngeal cancer is a common malignancy in otorhinolaryngological head and neck surgery, accounting for approximately one-third of all head and neck malignancies. Terahertz time-domain spectroscopy (THz-TDS) has recently been found to be useful for the detection of tumors. This study was conducted to investigate the application of THz-TDS in the diagnosis of pathological resection margins of laryngeal cancer. METHODS: Fresh laryngeal cancer tissues from 10 patients with laryngeal cancer were extracted, and after simultaneous HE staining and terahertz imaging, the tumor area, paracancerous area, and normal tissue area of each laryngeal cancer tissue sample were located under a microscope according to the pathological results of HE staining. RESULTS: The shape contours of the tumor region revealed by terahertz imaging maps and HE staining were similar. In the terahertz spectrum in the frequency range of 0.5-1.9 THz, both the absorption coefficient and refractive index values followed the order tumor > para cancer > normal tissue, with statistically significant differences (P < 0.01). When the terahertz frequency was 1.5 THz, the absorption coefficient of terahertz light waves by laryngeal cancer tissue and the percentage of nuclei showed an extremely high positive correlation (P < 0.01, r = 0.971). In the frequency ranges of 0.5-1.2 THz and 1.6-1.9 THz, the absorption coefficients of the highly differentiated group were higher than those of the moderately differentiated group. In the frequency range of 1.2-1.6 THz, the results were reversed, with statistically significant differences (P < 0.05). In the frequency range of 0.5-1.9 THz, the highly differentiated group had a higher refractive index than the moderately differentiated group, with a statistically significant difference (P < 0.05). CONCLUSIONS: THz-TDS can be used to determine the pathological margins of laryngeal cancer based on the absorption coefficient and refractive index, and the magnitudes of the absorption coefficient and refractive index are related to the percentage of nuclei. The degree of differentiation of laryngeal cancer tissue can be assessed by THz-TDS. The study shows that the terahertz time-domain system is promising for applications in the diagnosis of laryngeal cancer, especially for the more accurate identification of intraoperative margins.

Monitoring MgCl2 hydrate formation from aqueous solutions using terahertz time-domain spectroscopy.

The interaction of MgCl2 with H2O is heavily involved in biological and chemical processes. In this work, freezing-induced hydrate formation from MgCl2 aqueous solution was monitored using terahertz time-domain spectroscopy. At low temperatures, two phase transitions from brine to hydrate formation could be clearly observed, and the formation of hydrate was accompanied by the emergence of new THz fingerprint peaks at 1.02, 1.56, and 1.84 THz, respectively. Integrating XRD and quantum chemical calculations, we attributed the absorption peaks to the vibrational modes of the formed MgCl2·12H2O. This demonstrates the potential of THz spectroscopy for application in the detection of biological processes in low-temperature environments, such as cell freezing.