Terahertz (THz) technology has experienced rapid development in the past two decades. Growing numbers of interdisciplinary applications are emerging, including materials science, physics, communications, and security as well as biomedicine. THz biophotonics involves studies applying THz photonic technology in biomedicine, which has attracted attention due to the unique features of THz waves, such as the high sensitivity to water, resonance with biomolecules, favorable spatial resolution, capacity to probe the water–biomolecule interactions, and nonionizing photon energy. Despite the great potential, THz biophotonics is still at an early stage of development. There is a lack of standards for instrumentation, measurement protocols, and data analysis, which makes it difficult to make comparisons among all the work published. In this article, we give a comprehensive review of the key findings that have underpinned research into biomedical applications of THz technology. In particular, we will focus on the advances made in general THz instrumentation and specific THz-based instruments for biomedical applications. We will also discuss the theories describing the interaction between THz light and biomedical samples. We aim to provide an overview of both basic biomedical research as well as pre-clinical and clinical applications under investigation. The paper aims to provide a clear picture of the achievements, challenges, and future perspectives of THz biophotonics.

https://aip.scitation.org/doi/pdf/10.1063/5.0068979

Terahertz (THz) biophotonics technology: Instrumentation, techniques, and biomedical applications

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.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.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.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.The THz PHASR scanner promises a robust, high-speed, and accurate diagnostic modality to improve the clinical triage of burns and their management. 

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

The initial assessment of the depth of a burn injury during triage forms the basis for determination of the course of the clinical treatment plan. However, severe skin burns are highly dynamic and hard to predict. This results in a low accuracy rate of about 60 - 75% in the diagnosis of partial-thickness burns in the acute post-burn period. Terahertz time-domain spectroscopy (THz-TDS) has demonstrated a significant potential for non-invasive and timely estimation of the burn severity. Here, we describe a methodology for the measurement and numerical modeling of the dielectric permittivity of the in vivo porcine skin burns. We use the double Debye dielectric relaxation theory to model the permittivity of the burned tissue. We further investigate the origins of dielectric contrast between the burns of various severity, as determined histologically based on the percentage of the burned dermis, using the empirical Debye parameters. We demonstrate that the five parameters of the double Debye model can form an artificial neural network classification algorithm capable of automatic diagnosis of the severity of the burn injuries, and predicting its ultimate wound healing outcome by forecasting its re-epithelialization status in 28 days. Our results demonstrate that the Debye dielectric parameters provide a physics-based approach for the extraction of the biomedical diagnostic markers from the broadband THz pulses. This method can significantly boost dimensionality reduction of THz training data in artificial intelligence models and streamline machine learning algorithms.

Triage of in vivo burn injuries and prediction of wound healing outcome using neural networks and modeling of the terahertz permittivity based on the double Debye dielectric parameters.

Terahertz reflectometry technique is applied for noninvasive precorneal tear film assessment. The results of the receiver operating characteristic analysis show a good applicability of the proposed method. The direct comparison of the results obtained by reflectometry approach and results of Norn testing shows a good correlation. The in vivo measurement of the dynamic of tear film thinning could be useful for clinical diagnosis of dry eye syndrome.

Potential clinical applications of terahertz reflectometry for the assessment of the tear film stability

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.

/pdf/investigating-the-impact-of-synchrotron-thz-radiation-on-the-26u2uz7u.pdf

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

https://iopscience.iop.org/article/10.1070/QEL17213/pdf

Assessment of the degree of hydration of ocular surface tissues using THz reflectometry

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Assessment of the degree of hydration of ocular surface tissues using THz reflectometry