Effect of transdermal drug delivery patches on the stratum corneum: in vivo inspection with a handheld terahertz probe.

Transdermal drug delivery patches are a good alternative to hypodermic drug injection. The drug delivery efficiency depends strongly on the hydration of the skin under treatment, and therefore, it is essential to study the effects on the skin induced by the application of these medical-grade patches. Terahertz (THz) spectroscopy shows great promise for non-invasive skin evaluation due to its high sensitivity to subtle changes in water content, low power and non-ionizing properties. In this work, we study the effects of transdermal drug delivery patches (three fully occlusive and three partially occlusive) applied on the upper arms of ten volunteers for a maximum period of 28 h. Three different levels of propylene glycol (0 %, 3 % and 6 %) are added to the patches as excipient. By performing multilayer analysis, we successfully retrieve the water content of the stratum corneum (SC) which is the outermost layer of skin, as well as its thickness at different times before and after applying the patches. This study demonstrates the potential of using THz sensing for non invasive skin monitoring and has wide applications for skin evaluation as well as the development of skin products.

Spectroscopic insight on impact of environment on natural photoprotectants.

Biomimicry has become a key player in researching new materials for a whole range of applications. In this study, we have taken a crude extract from the red algae Palmaria palmata containing mycosporine-like amino acids - a photoprotective family of molecules. We have applied the crude extract onto a surface to assess if photoprotection, and more broadly, light-to-heat conversion, is retained; we found it is. Considering sunscreens as a specific application, we have performed transmission and reflection terahertz spectroscopy of the extract and glycerol to demonstrate how one can monitor stability in real-world applications.

Quantitative evaluation of transdermal drug delivery patches on human skin with in vivo THz-TDS.

Transdermal drug delivery (TDD) has been widely used in medical treatments due to various advantages, including delivering drugs at a consistent rate. However, variations in skin hydration can have a significant effect on the permeability of chemicals. Therefore, it is essential to study the changes in skin hydration induced by TDD patches for better control of the delivery rate. In this work, in vivo terahertz (THz) spectroscopy is conducted to quantitatively monitor human skin after the application of patches with different backing materials and propylene glycol concentrations. Changes in skin hydration and skin response to occlusion induced by other patches are investigated and compared. Our work demonstrates the potential application of in vivo THz measurements in label-free, non-invasive evaluation of transdermal patches on human skin and further reveals the mechanism behind the effect.

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.

Simulated and Experimental Verification for a Terahertz Specific Finite Rate of Innovation Signal Processing Method.

Recently, finite rate of innovation methods have been successfully applied to achieve low sampling rates in many areas, such as for ultrasound and radio signals. However, to the best of our knowledge, there are no journal publications applying this to real terahertz signals. In this work, we mathematically describe a finite rate of innovation method applied specifically to terahertz signals both experimentally and in simulation. To demonstrate our method, we applied it to randomized simulated signals with and without the presence of noise and to simple experimental measurements. We found excellent agreement between the simulated signals and those recreated based on results from our method, with this success also being replicated experimentally. These results were obtained at relatively low sampling rates, compared to standard methods, which is a key advantage to using a finite rate of innovation method as it allows for faster data acquisition and signal processing.

Monitoring the Effect of Transdermal Drug Delivery Patches on the Skin Using Terahertz Sensing.

Water content of the skin is an important parameter for controlling the penetration rate of chemicals through the skin barrier; therefore, for transdermal patches designed for drug delivery to be successful, the effects of the patches on the water content of the skin must be understood. Terahertz (THz) spectroscopy is a technique which is being increasingly investigated for biomedical applications due to its high sensitivity to water content and non-ionizing nature. In this study, we used THz measurements of the skin (in vivo) to observe the effect of partially and fully occlusive skin patches on the THz response of the skin after the patches had been applied for 24 h. We were able to observe an increase in the water content of the skin following the application of the patches and to identify that the skin remained hyper-hydrated for four hours after the removal of the fully occlusive patches. Herein, we show that THz spectroscopy has potential for increasing the understanding of how transdermal patches affect the skin, how long the skin takes to recover following patch removal, and what implications these factors might have for how transdermal drug patches are designed and used.

THz Sensing of Human Skin: A Review of Skin Modeling Approaches.

The non-ionizing and non-invasive nature of THz radiation, combined with its high sensitivity to water, has made THz imaging and spectroscopy highly attractive for in vivo biomedical applications for many years. Among them, the skin is primarily investigated due to the short penetration depth of THz waves caused by the high attenuation by water in biological samples. However, a complete model of skin describing the THz-skin interaction is still needed. This is also fundamental to reveal the optical properties of the skin from the measured THz spectrum. It is crucial that the correct model is used, not just to ensure compatibility between different works, but more importantly to ensure the reliability of the data and conclusions. Therefore, in this review, we summarize the models applied to skin used in the THz regime, and we compare their adaptability, accuracy, and limitations. We show that most of the models attempt to extract the hydration profile inside the skin while there is also the anisotropic model that displays skin structural changes in the stratum corneum.

Gold nanoparticle enhanced detection of EGFR with a terahertz metamaterial biosensor.

The epidermal growth factor receptor (EGFR) plays an important role in the proliferation of various cancers, and the expression level of EGFR in tumor tissues can provide a basis for the diagnosis and prognosis. Improving the detection technology of EGFR to achieve high sensitivity and faster speed will benefit the diagnosis of many types of tumors. Trace biological samples can be sensitively measured with terahertz (THz) metamaterial devices. Here, a bow-tie array THz metamaterial biosensor is presented and modified with gold nanoparticles (GNPs) and EGFR antibodies for specific EGFR detection. The effect of the size of the GNP on the sensitivity enhancement was also analyzed. Enhanced sensing for EGFR was achieved with the assistance of GNPs and EGFR antibodies. Importantly, the metamaterial functionalized by GNPs and antibodies with a bigger GNP diameter achieves a greater resonance frequency shift. The proposed metamaterial biosensor can also realize tiny-volume EGFR solution detection. Our proposed technique can therefore sense EGFR sensitively with high speed, and can potentially be applied to achieve quick and accurate detection of EGFR related tumors.

Deep THz modulation at Fabry-Perot resonances using graphene in periodic microslits.

Potential applications of terahertz (THz) radiation are constantly being investigated for high-speed communication due to its large bandwidth. For example, frequency hopping communication technology would benefit from the large bandwidth. To attach the information to the carrier wave, THz modulators with deep and stable modulation at different frequencies are crucial, yet are still lacking. Here a THz modulator, designed by integrating a non-resonant field enhancement effect of periodic metal microslits to assist a Fabry-Perot resonance structure (MS-FP) is proposed and demonstrated. New equations are developed to describe the superior performance of the novel design. The >95% modulation depth is achieved by a SiO2/Si gated graphene device at 14 Fabry-Perot resonant frequencies across 1.4 THz bandwidth, outperforming the recently reported 75% modulation depth THz modulator with a similar Fabry-Perot structure.

Low cost and long-focal-depth metallic axicon for terahertz frequencies based on parallel-plate-waveguides.

In this work we demonstrate a triangular surface lens (axicon) operating at frequencies between 350 and 450 GHz using parallel-plate-waveguide technology. The proposed axicon offers longer focal depth characteristics compared to conventional plastic lenses, surpassing common TPX lenses by one order of magnitude. Additionally, due to the triangular surface of the axicon, this device is able to focus THz radiation onto smaller areas than TPX lenses, enhancing the resolution characteristics of THz imaging systems. The frequency range of operation of the proposed axicon can be easily tuned by changing the space between plates, making this approach a very attractive candidate for low-cost, robust and easy to assemble solutions for the next generation of active THz devices.

Evaluation of transdermal drug delivery using terahertz pulsed imaging.

Transdermal drug delivery (TDD) is widely used for painless dosing due to its minimally invasive nature compared to hypodermic needle injection and its avoidance of the gastrointestinal tract. However, the stratum corneum obstructs the permeation of drugs into skin. Microneedle and nanoneedle patches are ways to enhance this permeation. In this work, terahertz (THz) imaging is utilized to compare the efficacy of different TDD methods including topical application and via a needle patch. Our work shows the feasibility and potential of using THz imaging to quantify and evaluate different transdermal application methods.

Super Sub-Nyquist Single-Pixel Imaging by Total Variation Ascending Ordering of the Hadamard Basis.

Single pixel imaging (SPI) captures images without array detectors or raster scanning. When combined with compressive sensing techniques it enables novel solutions for high-speed optical imaging and spectroscopy. However, when it comes to the real-time capture and analysis of a fast event, the challenge is the inherent trade-off between frame rate and image resolution. Due to the lack of sufficient sparsity and the intrinsic iterative process, conventional compressed sensing techniques have limited improvement in capturing natural scenes and displaying the images in real time. In this work, we demonstrate a novel alternative compressive imaging approach employing an efficient and easy-implementation sampling scheme based on reordering the deterministic Hadamard basis through their total variation. By this means, the number of measurements and acquisition are reduced significantly without needing complex minimization algorithms. We can recover a 128 × 128 image with a sampling ratio of 5% at the signal peak signal-to-noise ratio (PSNR) of 23.8 dB, achieving super sub-Nyquist sampling SPI. Compared to other widely used sampling e.g. standard Hadamard protocols and Gaussian matrix methods, this approach results in a significant improvement both in the compression ratio and image reconstruction quality, enabling SPI for high frame rate imaging or video applications.

Real-time terahertz imaging with a single-pixel detector.

Terahertz (THz) radiation is poised to have an essential role in many imaging applications, from industrial inspections to medical diagnosis. However, commercialization is prevented by impractical and expensive THz instrumentation. Single-pixel cameras have emerged as alternatives to multi-pixel cameras due to reduced costs and superior durability. Here, by optimizing the modulation geometry and post-processing algorithms, we demonstrate the acquisition of a THz-video (32 × 32 pixels at 6 frames-per-second), shown in real-time, using a single-pixel fiber-coupled photoconductive THz detector. A laser diode with a digital micromirror device shining visible light onto silicon acts as the spatial THz modulator. We mathematically account for the temporal response of the system, reduce noise with a lock-in free carrier-wave modulation and realize quick, noise-robust image undersampling. Since our modifications do not impose intricate manufacturing, require long post-processing, nor sacrifice the time-resolving capabilities of THz-spectrometers, their greatest asset, this work has the potential to serve as a foundation for all future single-pixel THz imaging systems.

Broadband amplitude, frequency, and polarization splitter for terahertz frequencies using parallel-plate waveguide technology.

In this Letter, we report a broadband frequency/polarization demultiplexer based on parallel-plate waveguides (PPWGs) for terahertz (THz) frequencies. The fabrication and experimental validation of this polarization sensitive demultiplexer is demonstrated for the range from 0.2 to 1 THz. Upgrading the demultiplexer by adding a second demultiplexer stage, a fifty-fifty amplitude splitter is also demonstrated in the same frequency range. The multiplexer is based on a stainless-steel traveling-wave antenna, exhibiting strong mechanical robustness. This unique device exhibits three splitting mechanisms in the same device: amplitude, polarization, and frequency splitting. This is a significant improvement for the next generation of THz passive components for communication purposes.

A Sensitive and Versatile Thickness Determination Method Based on Non-Inflection Terahertz Property Fitting.

The accuracy of thin-film characterization in terahertz spectroscopy is mainly set by the thickness uncertainty. Physical thickness measurement has limited accuracy for thin-film samples thinner than a few hundreds of micrometers and is sometimes even impossible. The temporal resolution of time-domain terahertz spectrometers is not sufficient to resolve such thin films. Previously reported numerical methods mainly only work for materials with low dispersion and absorption. Here, we propose a novel method for thickness determination by fitting a non-inflection offset exponential function to the material optical properties. Theoretical analysis predicts the best fitting to only be achieved when the correct thickness is given. Transmission measurements on a thin-film polymer, water, and a lactose pallet verify the theory and show the accurate thickness determination and property characterization on materials which are either achromatic or dispersive, transparent or absorptive, featureless or resonant. The measurements demonstrate the best versatility and sensitivity compared to the state-of-art. The method could be widely adapted to various types of research and industrial applications.

In vivo terahertz imaging to evaluate scar treatment strategies: silicone gel sheeting.

Silicone gel sheeting (SGS) is widely used for scar treatment; however, studies showing its interaction with skin and efficacy of scar treatment are still lacking. THz light is non-ionizing and highly sensitive to changes in water content and thus skin hydration. In this work, we use in-vivo THz imaging to monitor how SGS affects the THz response of human skin during occlusion, and the associated THz reflectivity and refractive index changes are presented. We find that SGS effectively hydrates the skin beneath it, with minimal lateral effects beyond the sheeting. Our work demonstrates that THz imaging is able to detect the subtle hydration changes on the surface of human skin caused by SGS, and it has the potential to be used to evaluate different scar treatment strategies.

Design and fabrication of 3-D printed conductive polymer structures for THz polarization control.

In this paper, we numerically and experimentally demonstrate the inverse polarization effect in three-dimensional (3-D) printed polarizers for the frequency range of 0.5 - 2.7 THz. The polarizers simply consist of 3-D printed strip lines of conductive polylactic acid (CPLA, Proto-Pasta) and do not require a substrate or any further metallic deposition. The experimental and numerical results show that the proposed structure acts as a broadband polarizer between the range of 0.3 THz to 2.7 THz, in which the inverse polarization effect is clearly seen for frequencies above 0.5 THz. In the inverse polarization effect, the transmission of the transverse electric (TE) component exceeds that of the TM component, in contrast to the behavior of a typical wire-grid polarizer. We show how the performance of the polarizers depends on the spacing and thickness of the CPLA structure; extinction ratios higher than 20 dB are achieved. This is the first report using CPLA to fabricate THz polarizers, demonstrating the potential of using conductive polymers to design THz components efficiently and robustly.

Utilizing multilayer structures to enhance terahertz characterization of thin films ranging from aqueous solutions to histology slides.

We propose a multilayer geometry to characterize thin-film samples in reflection terahertz time domain spectroscopy. Theory indicates that this geometry has higher sensitivity compared to ordinary transmission or reflection geometries when characterizing both low- and high-absorption samples. Pure water and water-ethanol mixtures are measured to verify the characterization accuracy of the proposed geometry and its capability to measure trace liquids. Paraffin-embedded oral cancer tissue is imaged to further show how the proposed geometry enhances the sensitivity for solid low-absorptive films.

In vivo estimation of water diffusivity in occluded human skin using terahertz reflection spectroscopy.

Water diffusion and the concentration profile within the skin significantly affect the surrounding chemical absorption and molecular synthesis. Occluding the skin causes water to accumulate in the top layer of the skin (the stratum corneum [SC]) and also affects the water diffusivity. Scar treatments such as silicone gel and silicone sheets make use of occlusion to increase skin hydration. However with existing techniques, it is not possible to quantitatively measure the diffusivity of the water during occlusion: current methods determine water diffusivity by measuring the water evaporated through the skin and thus require the skin to breathe. In this work, we use the high sensitivity of terahertz light to water to study how the water content in the SC changes upon occlusion. From our measurements, we can solve the diffusion equations in the SC to deduce the water concentration profile in occluded skin and subsequently to determine the diffusivity. To our knowledge, this is the first work showing how the diffusivity of human skin can be measured during occlusion and we envisage this paper as being used as a guide for non-invasively determining the diffusivity of occluded human skin in vivo.

Graphene controlled Brewster angle device for ultra broadband terahertz modulation.

Terahertz modulators with high tunability of both intensity and phase are essential for effective control of electromagnetic properties. Due to the underlying physics behind existing approaches there is still a lack of broadband devices able to achieve deep modulation. Here, we demonstrate the effect of tunable Brewster angle controlled by graphene, and develop a highly-tunable solid-state graphene/quartz modulator based on this mechanism. The Brewster angle of the device can be tuned by varying the conductivity of the graphene through an electrical gate. In this way, we achieve near perfect intensity modulation with spectrally flat modulation depth of 99.3 to 99.9 percent and phase tunability of up to 140 degree in the frequency range from 0.5 to 1.6 THz. Different from using electromagnetic resonance effects (for example, metamaterials), this principle ensures that our device can operate in ultra-broadband. Thus it is an effective principle for terahertz modulation.