Design and characterization of a hyperbolic-elliptical lens pair in a rapid beam steering system for single-pixel terahertz spectral imaging of the cornea.

Terahertz (THz) time-domain spectroscopy has been investigated for assessment of the hydration levels in the cornea, intraocular pressure, and changes in corneal topography. Previous efforts at THz imaging of the cornea have employed off-axis parabolic mirrors to achieve normal incidence along the spherical surface. However, this comes at the cost of an asymmetric field-of-view (FOV) and a long scan time because it requires raster-scanning of the collimated beam across the large mirror diameter. This paper proposes a solution by designing a pair of aspheric lenses that can provide a larger symmetric spherical FOV (9.6 mm) and reduce the scan time by two orders of magnitude using a novel beam-steering approach. A hyperbolic-elliptical lens was designed and optimized to achieve normal incidence and phase-front matching between the focused THz beam and the target curvature. The lenses were machined from a slab of high-density polyethylene and characterized in comparison to ray-tracing simulations by imaging several targets of similar sizes to the cornea. Our experimental results showed excellent agreement in the increased symmetric FOV and confirmed the reduction in scan time to about 3-4 seconds. In the future, this lens design process can be extended for imaging the sclera of the eye and other curved biological surfaces, such as the nose and fingers.

Polarimetric imaging of back-scattered terahertz speckle fields using a portable scanner.

Speckle patterns observed in coherent optical imaging reflect important characteristic information of the scattering object. To capture speckle patterns, angular resolved or oblique illumination geometries are usually employed in combination with Rayleigh statistical models. We present a portable and handheld 2-channel polarization-sensitive imaging instrument to directly resolve terahertz (THz) speckle fields in a collocated telecentric back-scattering geometry. The polarization state of the THz light is measured using two orthogonal photoconductive antennas and can be presented in the form of the Stokes vectors of the THz beam upon interaction with the sample. We report on the validation of the method in surface scattering from gold-coated sandpapers, demonstrating a strong dependence of the polarization state on the surface roughness and the frequency of the broadband THz illumination. We also demonstrate non-Rayleigh first-order and second-order statistical parameters, such as degree of polarization uniformity (DOPU) and phase difference, for quantifying the randomness of polarization. This technique provides a fast method for broadband THz polarimetric measurement in the field and has the potential for detecting light depolarization in applications ranging from biomedical imaging to non-destructive testing.

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.

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.

Terahertz PHASR Scanner with 2 kHz, 100 picosecond Time-Domain Trace Acquisition Rate and an Extended Field-of-View Based on a Heliostat Design.

Recently, we introduced a Portable HAndheld Spectral Reflection (PHASR) Scanner to allow THz Time-Domain Spectroscopic (THz-TDS) imaging in clinical and industrial settings using a fiber-coupled and alignment-free telecentric beam steering design. The key limitations of the version 1.0 of the PHASR Scanner were its field-of-view and speed of time-domain trace acquisition. In this paper, we address these limitations by introducing a heliostat geometry for beam scanning to achieve an extended field-of-view, and by reconfiguring the Asynchronous OPtical Sampling (ASOPS) system to perform Electronically Controlled OPtical Sampling (ECOPS) measurements. The former change improved the deflection range of the beam, while also drastically reducing the coupling of the two scanning axes, the combination of which resulted in a larger than four-fold increase in the FOV area. The latter change significantly improves the acquisition speed and frequency domain performance simultaneously by improving measurement efficiency. To accomplish this, we characterized the non-linear time-axis sampling behavior of the electro-mechanical system in the ECOPS mode. We proposed methods to model and correct the non-linear time-axis distortions and tested the performance of the high-speed ECOPS trace acquisition. Therefore, here we introduce the PHASR Scanner version 2.0, which is capable of imaging a 40×27 mm2 FOV with 2000 traces per second over a 100 picosecond TDS range. This new scanner represents a significant leap towards translating the THz-TDS technology from the lab bench to the bedside for real-time clinical imaging applications.

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.

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

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.

Multiresolution spectrally-encoded terahertz reflection imaging through a highly diffusive cloak.

Turbid media, made of wavelength-scale inhomogeneous particles, can give rise to many significant imaging and spectroscopy challenges. The random variation of the refractive index within such media distorts the spherical wavefronts, resulting in smeared and speckly images. The scattering-induced artifacts can obscure the characteristic spectral fingerprints of the chemicals in a sample. This in turn prevents accurate chemical imaging and characterization of the materials cloaked with a diffusive medium. In this work, we present a novel computational technique for creating spatially- and spectrally-resolved chemical maps through a diffusive cloak using terahertz time-domain spectroscopy. We use the maximal overlap discrete wavelet transform to obtain a multiresolution spectral decomposition of THz extinction coefficients. We define a new spectroscopic concept dubbed the "bimodality coefficient spectrum" using the skewness and kurtosis of the spectral images. We demonstrate that broadband wavelet-based reconstruction of the bimodality coefficient spectrum can resolve the signature resonant frequencies through the scattering layers. Additionally, we show that our approach can achieve spectral images with diffraction-limited resolution. This technique can be used for stand-off characterization of materials and spectral imaging in nondestructive testing and biological applications.

Deep neural network classification of in vivo burn injuries with different etiologies using terahertz time-domain spectral imaging.

Thermal injuries can occur due to direct exposure to hot objects or liquids, flames, electricity, solar energy and several other sources. If the resulting injury is a deep partial thickness burn, the accuracy of a physician's clinical assessment is as low as 50-76% in determining the healing outcome. In this study, we show that the Terahertz Portable Handheld Spectral Reflection (THz-PHASR) Scanner combined with a deep neural network classification algorithm can accurately differentiate between partial-, deep partial-, and full-thickness burns 1-hour post injury, regardless of the etiology, scanner geometry, or THz spectroscopy sampling method (ROC-AUC = 91%, 88%, and 86%, respectively). The neural network diagnostic method simplifies the classification process by directly using the pre-processed THz spectra and removing the need for any hyperspectral feature extraction. Our results show that deep learning methods based on THz time-domain spectroscopy (THz-TDS) measurements can be used to guide clinical treatment plans based on objective and accurate classification of burn injuries.

Supervised machine learning for automatic classification of in vivo scald and contact burn injuries using the terahertz Portable Handheld Spectral Reflection (PHASR) Scanner.

We present an automatic classification strategy for early and accurate assessment of burn injuries using terahertz (THz) time-domain spectroscopic imaging. Burn injuries of different severity grades, representing superficial partial-thickness (SPT), deep partial-thickness (DPT), and full-thickness (FT) wounds, were created by a standardized porcine scald model. THz spectroscopic imaging was performed using our new fiber-coupled Portable HAndheld Spectral Reflection Scanner, incorporating a telecentric beam steering configuration and an f-[Formula: see text] scanning lens. ASynchronous Optical Sampling in a dual-fiber-laser THz spectrometer with 100 MHz repetition rate enabled high-speed spectroscopic measurements. Given twenty-four different samples composed of ten scald and ten contact burns and four healthy samples, supervised machine learning algorithms using THz-TDS spectra achieved areas under the receiver operating characteristic curves of 0.88, 0.93, and 0.93 when differentiating between SPT, DPT, and FT burns, respectively, as determined by independent histological assessments. These results show the potential utility of our new broadband THz PHASR Scanner for early and accurate triage of burn injuries.

In Vivo Assessment and Monitoring of Burn Wounds Using a Handheld Terahertz Hyperspectral Scanner.

The accuracy of clinical assessment techniques in diagnosing partial-thickness burn injuries has remained as low as 50-76%. Depending on the burn depth and environmental factors in the wound, such as reactive oxygen species, inflammation, and autophagy, partial-thickness burns can heal spontaneously or require surgical intervention. Herein, it is demonstrated that terahertz time-domain spectral imaging (THz-TDSI) is a promising tool for in vivo quantitative assessment and monitoring of partial-thickness burn injuries in large animals. We used a novel handheld THz-TDSI scanner to characterize burn injuries in a porcine scald model with histopathological controls. Statistical analysis (n= 40) indicates that the THz-TDSI modality can accurately differentiate between partial-thickness and full-thickness burn injuries (1-way ANOVA, p< 0.05). THz-TDSI has the potential to improve burn care outcomes by helping surgeons in making objective decisions for early excision of the wound.

Development of a terahertz time-domain scanner for topographic imaging of spherical targets.

Topographical abnormality in corneal tissue is a common diagnostic marker for many eye diseases and injuries. Using an asynchronous optical sampling terahertz time-domain spectroscopy setup, we developed a non-contact and normal-incidence imaging system to measure topographic changes along the surface of spherical samples. We obtained orthogonal 1D scans of calibration spheres to evaluate the minimum axial resolution of our system. We determined the axial and spatial resolution of the scanner using 3D-printed spherical cross and Boehler star targets. Furthermore, we characterized the asymmetrical performance of the scanner due to the use of an off-axis parabolic mirror. Finally, we developed an edge-detection filter to aid with improving the topographic scans. We showed that when imaging samples were comparable in size to the human cornea, the axial and spherical spatial resolutions were limited to about 15 µm (∼λ/67) and 1 mm, respectively.

Design and characterization of telecentric f-θ scanning lenses for broadband terahertz frequency systems.

Telecentric beam scanning using f-θ lenses offers nearly uniform spot size, linear beam displacement, and normal incidence angle over a planar surface. These unique properties allow for the minimization of imaging distortion over a wide field-of-view. In this article, we present a numerical method for designing custom f-θ lenses in the THz regime. We fabricated three lenses made from different commonly used polymer materials in the THz optics. We demonstrated their optical performance metrics compared to a conventional plano-convex lens over the broadband 0.3 THz-1 THz range. We find that the f-θ lens designed using the optical properties of high-density polyethylene achieved superior performance by maintaining a constant phase over a wide field of view of about 34°. We demonstrate this isophase property by measuring a constant time of arrival of the THz time-domain pulses over a reference mirror with a standard deviation of ∼19 fs, in excellent agreement with simulation predictions. This work will pave the way for the design and implementation of highly precise and fast telecentric imaging systems in the THz frequencies.

Terahertz time-domain spectral imaging using telecentric beam steering and an f-θscanning lens: distortion compensation and determination of resolution limits.

We report on the development and performance characterization of a telecentric terahertz spectroscopic scanner using an f-θ objective lens and a single gimballed scanning mirror for image formation. We derived a beam steering transform to compensate for the intercoupling of the gimballed mirror axes and the distortions caused by an imperfect scanning lens. We characterize the optical performance of the system in both the time and spatial domains, demonstrating a constant diffraction-limited imaging resolution over the entire field of view. Finally, given the large depth of focus of the objective lens, we demonstrate the broadband imaging capability at different depths using a Boehler star target. This imaging setup has the potential to be miniaturized into portable form factors for field-deployable scenarios.

Comparison of comparable scald and contact burns in a porcine model: A preliminary report.

Whether the depth and healing of scalds and contact burns are similar is controversial. Due to water's greater heat capacity, we hypothesized that when exposed to similar temperatures and durations of exposure, burns caused by hot water would be deeper than those caused by contact with hot metal. Forty standardized burns were created in two anesthetized female domestic pigs using a brass bar or circulating heated water. In one pig, the temperature was kept constant (95°C) while the duration of exposure varied (5, 10, 15 seconds) In the second pig, the exposure time was kept constant (10 seconds) while the temperature of exposure varied (70°C, 80°C, 98°C). Periodic punch biopsies were taken to determine burn depth immediately after injury, percentage burns reepithelialized within 21 days, and depth of scar at 28 days. The analysis was performed using analysis of variance. When the temperature was held constant, duration of exposure (5, 10, and 15 seconds) was associated with scar depth (2.1 vs 3.8 vs 5.0 mm, respectively, P = 0.001) but not with burn depth (2.0 vs 2.2 vs 2.3 mm, respectively, P = 0.10). When exposure duration was held constant, temperature (70°C, 80°C, 98°C) was associated with scar depth (0.6 vs 1.7 vs 3.6, P < 0.001) but not with burn depth (1.2 vs 1.5 vs 1.7 mm, respectively, P = 0.21). Burn depths were greater for scald than contact burns although not significantly greater. After controlling for temperature, the difference in scar depth between scalds and contact burns was statistically significant (marginal means 3.0 for contact burns, 4.3 for scalds, P = 0.008). We conclude that burns created in swine with circulating hot water result in deeper scars than those created by contact with a brass bar when controlling for temperature and duration of exposure.

Investigation of water diffusion dynamics in corneal phantoms using terahertz time-domain spectroscopy.

Perturbation of normal corneal water content is a common manifestation of many eye diseases. Terahertz (THz) imaging has the potential to serve as a clinical tool for screening and diagnosing such corneal diseases. In this study, we first investigate the diffusive properties of a corneal phantom using simultaneous THz time-domain spectroscopy (THz-TDS) and gravimetric measurements. We will then utilize a variable-thickness diffusion model combined with a stratified composite-media model to simulate changes in thickness, hydration profile, and the THz-TDS signal as a function of time. The simulated THz-TDS signals show very good agreement with the reflection measurements. Results show that the THz-TDS technique can be used to understand water diffusion dynamics in corneal phantoms as a step towards future in vivo quantitative hydration sensing.

Terahertz Portable Handheld Spectral Reflection (PHASR) Scanner.

We report on the development and characterization of a handheld terahertz (THz) time-domain spectroscopic scanner for broadband imaging between approximately 0.25 and 1.25 THz. We designed and fabricated a 3D-printed fiber-coupled housing which provides an alignment-free strategy for the placement and operation of the THz optics. Image formation is achieved through telecentric beam steering over a planar surface through a custom f-θ scanning lens. This design achieves a consistent resolution over the full 12 × 19 mm field of view. Broadband spectral imaging is demonstrated using a 1951 United States Air Force Resolution Test Target. The consistency of the resolution over the wide field is validated through Boehler Star resolution measurements. Finally, a practical scenario of subsurface imaging on a damaged section of an aircraft wing is demonstrated. The THz PHASR is a field-deployable imaging system with the versatility to be applied to a much broader range of targets and imaging scenarios than previously possible, from industrial non-destructive testing to clinical diagnostic imaging.