Simulating the response of terahertz radiation to basal cell carcinoma using ex vivo spectroscopy measurements

Studies of basal cell carcinoma using terahertz pulsed imaging have revealed a significant difference between regions of tumor and healthy tissue. These differences are manifested in the reflected pulse due to what is thought to be changes in refractive index and absorption. We present measurements of the refractive index and absorption coefficient of excised normal tissue and basal cell carcinoma using terahertz (THz) transmission spectroscopy. We extract Debye parameters from these data and enter them into a finite difference time domain simulation to predict the shape of the waveforms reflected off the normal tissue and basal cell carcinoma and compare them with published in vivo data. Simulating the interaction of terahertz radiation with normal and cancerous tissue is a key step toward understanding the origin of contrast in terahertz images of skin cancer.     

Towards functional 3D T-ray imaging

We review the recent development of T-ray computed tomography, a terahertz imaging technique that allows the reconstruction of the three-dimensional refractive index profile of weakly scattering objects. Terahertz pulse imaging is used to obtain images of the target at multiple projection angles and the filtered backprojection algorithm enables the reconstruction of the object's frequency-dependent refractive index. The application of this technique to a biological bone sample and a plastic test structure is demonstrated. The structure of each target is accurately resolved and the frequency-dependent refractive index is determined. The frequency-dependent information may potentially be used to extract functional information from the target, to uniquely identify different materials or to diagnose medical conditions.     

In vivo study of human skin using pulsed terahertz radiation

Studies in terahertz (THz) imaging have revealed a significant difference between skin cancer (basal cell carcinoma) and healthy tissue. Since water has strong absorptions at THz frequencies and tumours tend to have different water content from normal tissue, a likely contrast mechanism is variation in water content. Thus, we have previously devised a finite difference time-domain (FDTD) model which is able to closely simulate the interaction of THz radiation with water. In this work we investigate the interaction of THz radiation with normal human skin on the forearm and palm of the hand in vivo. We conduct the first ever systematic in vivo study of the response of THz radiation to normal skin. We take in vivo reflection measurements of normal skin on the forearm and palm of the hand of 20 volunteers. We compare individual examples of THz responses with the mean response for the areas of skin under investigation. Using the in vivo data, we demonstrate that the FDTD model can be applied to biological tissue. In particular, we successfully simulate the interaction of THz radiation with the volar forearm. Understanding the interaction of THz radiation with normal skin will form a step towards developing improved imaging algorithms for diagnostic detection of skin cancer and other tissue disorders using THz radiation.     

Terahertz sensing in corneal tissues

This work introduces the potential application of terahertz (THz) sensing to the field of ophthalmology, where it is uniquely suited due to its nonionizing photon energy and high sensitivity to water content. Reflective THz imaging and spectrometry data are reported on ex-vivo porcine corneas prepared with uniform water concentrations using polyethylene glycol (PEG) solutions. At 79% water concentration by mass, the measured reflectivity of the cornea was 20.4%, 14.7%, 11.7%, 9.6%, and 7.4% at 0.2, 0.4, 0.6, 0.8, and 1 THz, respectively. Comparison of nine corneas hydrated from 79.1% to 91.5% concentration by mass demonstrated an approximately linear relationship between THz reflectivity and water concentration, with a monotonically decreasing slope as the frequency increases. The THz-corneal tissue interaction is simulated with a Bruggeman model with excellent agreement. THz applications to corneal dystrophy, graft rejection, and refractive surgery are examined from the context of these measurements.     

Sielectric Properties of Terahertz Windows Materials for Bio-sample Measurement

We presented the dielectric properties of three materials for bio-sample measurement using THz transmission spectroscopy.The materials,PE,COC and PVDF,have sufficient transmittance.The results demonstrate that PVDF membranes are suitable media for THz transmission spectrum above 0.3 THz.However,it is not property to measure the solution sample because of the water existed after active processing by ethanol.In this paper,the refractive index,the absorption coefficient,and the complex dielectric functions in the THz region are compared for each material.From the measured dielectric properties,the loss mechanism of THz radiation for each material is also discussed.     

Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue

We demonstrate the application of terahertz pulse imaging (TPI) in reflection geometry for the study of skin tissue and related cancers both in vitro and in vivo. The sensitivity of terahertz radiation to polar molecules, such as water, makes TPI suitable for studying the hydration levels in the skin and the determination of the lateral spread of skin cancer pre-operatively. By studying the terahertz pulse shape in the time domain we have been able to differentiate between diseased and normal tissue for the study of basal cell carcinoma (BCC). Basal cell carcinoma has shown a positive terahertz contrast, and inflammation and scar tissue a negative terahertz contrast compared to normal tissue. In vivo measurements on the stratum corneum have enabled visualization of the stratum corneum-epidermis interface and the study of skin hydration levels. These results demonstrate the potential of terahertz pulse imaging for the study of skin tissue and its related disorders, both in vitro and in vivo.     

An introduction to medical imaging with coherent terahertz frequency radiation

Methods have recently been developed that make use of electromagnetic radiation at terahertz (THz) frequencies, the region of the spectrum between millimetre wavelengths and the infrared, for imaging purposes. Radiation at these wavelengths is non-ionizing and subject to far less Rayleigh scatter than visible or infrared wavelengths, making it suitable for medical applications. This paper introduces THz pulsed imaging and discusses its potential for in vivo medical applications in comparison with existing modalities.     

The analysis of human cortical bone by terahertz time-domain spectroscopy

Samples of cortical bone, derived from human femur, have been studied using terahertz time-domain transmission spectroscopy. The relationship between the broadband THz parameters and the previously acquired values of Young's modulus and x-ray attenuation (CT number), and the density of each bone sample, is investigated. The only significant correlation is that between THz transmission and sample density, suggesting that the potential use of THz radiation as a non-invasive probe of bone quality is limited. The spectra of absorption coefficient and refractive index are plotted over the frequency range 0.1-1.25 THz. There is evidence that the sample hydration state is a factor in the resultant THz parameters.     

Far-infrared vibrational modes of DNA components studied by terahertz time-domain spectroscopy

The far-infrared dielectric function of a wide range of organic molecules is dominated by vibrations involving a substantial fraction of the atoms forming the molecule and motion associated with intermolecular hydrogen bond vibrations. Due to their collective nature such modes are highly sensitive to the intra- and intermolecular structure and thus provide a unique fingerprint of the conformational state of the molecule and effects of its environment. We demonstrate the use of terahertz time-domain spectroscopy (THz-TDS) for recording the far-infrared (0.5-4.0 THz) dielectric function of the four nucleobases and corresponding nucleosides forming the building blocks of deoxyribose nucleic acid (DNA). We observe numerous distinct spectral features with large differences between the molecules in both frequency-dependent absorption coefficient and index of refraction. Assisted by results from density-functional calculations we interpret the origin of the observed resonances as vibrations of hydrogen bonds between the molecules.     

The effects of internal refractive index variation in near-infrared optical tomography: a finite element modelling approach

Near-infrared (NIR) tomography is a technique used to measure light propagation through tissue and generate images of internal optical property distributions from boundary measurements. Most popular applications have concentrated on female breast imaging, neonatal and adult head imaging, as well as muscle and small animal studies. In most instances a highly scattering medium with a homogeneous refractive index is assumed throughout the imaging domain. Using these assumptions, it is possible to simplify the model to the diffusion approximation. However, biological tissue contains regions of varying optical absorption and scatter, as well as varying refractive index. In this work, we introduce an internal boundary constraint in the finite element method approach to modelling light propagation through tissue that accounts for regions of different refractive indices. We have compared the results to data from a Monte Carlo simulation and show that for a simple two-layered slab model of varying refractive index, the phase of the measured reflectance data is significantly altered by the variation in internal refractive index, whereas the amplitude data are affected only slightly.     

In vivo terahertz imaging of rat skin burns

A reflective, pulsed terahertz (THz) imaging system was used to acquire high-resolution (d(10-90)/λ~1.925) images of deep, partial thickness burns in a live rat. The rat's abdomen was burned with a brass brand heated to ~220°C and pressed against the skin with contact pressure for ~10 sec. The burn injury was imaged beneath a Mylar window every 15 to 30 min for up to 7 h. Initial images display an increase in local water concentration of the burned skin as evidenced by a marked increase in THz reflectivity, and this likely correlates to the post-injury inflammatory response. After ~1 h the area of increased reflectivity consolidated to the region of skin that had direct contact with the brand. Additionally, a low reflecting ring of tissue could be observed surrounding the highly reflective burned tissue. We hypothesize that these regions of increased and decreased reflectivity correlate to the zones of coagulation and stasis that are the classic foundation of burn wound histopathology. While further investigations are necessary to confirm this hypothesis, if true, it likely represents the first in vivo THz images of these pathologic zones and may represent a significant step forward in clinical application of THz technology.     

The impact of hydration changes in fresh bio-tissue on THz spectroscopic measurements

We present a study of how residual hydration in fresh rat tissue samples can vastly alter their extracted terahertz (THz) optical properties and influence their health assessment. Fresh (as opposed to preserved) tissue most closely mimics in vivo conditions, but high water content creates many challenges for tissue handling and THz measurement. Our THz measurements of fresh tissue over time highlight the effect of tissue hydration on tissue texture and dimension, the latter directly influencing the accuracy of calculated optical properties. We then introduce lyophilization (freeze drying) as a viable solution for overcoming hydration and freshness problems. Lyophilization removes large amounts of water while retaining sample freshness. In addition, lyophilized tissue samples are easy to handle and their textures and dimensions do not vary over time, allowing for consistent and stable THz measurements. A comparison of lyophilized and fresh tissue shows for the first time that freeze drying may be one way of overcoming tissue hydration issues while preserving tissue cellular structure. Finally, we compare THz measurements from fresh tissue against necrotic tissue to verify freshness over time. Indeed, THz measurements from fresh and necrotic tissues show marked differences.     

Label-free probing of genes by time-domain terahertz sensing

A label-free sensing approach for the label-free characterization of genetic material with terahertz (THz) electromagnetic waves is presented. Time-resolved THz analysis of polynucleotides demonstrates a strong dependence of the complex refractive index of DNA molecules in the THz frequency range on their hybridization state. By monitoring THz signals one can thus infer the binding state (hybridized or denatured) of oligo- and polynucleotides, enabling the label-free determination the genetic composition of unknown DNA sequences. A broadband experimental proof-of-principle in a freespace analytic configuration, as well as a higher-sensitivity approach using integrated THz sensors reaching femtomol detection levels and demonstrating the capability to detect single-base mutations, are presented. The potential application for next generation high-throughput label-free genetic analytic systems is discussed.     

Terahertz spectroscopy of liver cirrhosis: investigating the origin of contrast

We have previously demonstrated that terahertz pulsed imaging is able to distinguish between rat tissues from different healthy organs. In this paper we report our measurements of healthy and cirrhotic liver tissues using terahertz reflection spectroscopy. The water content of the fresh tissue samples was also measured in order to investigate the correlations between the terahertz properties, water content, structural changes and cirrhosis. Finally, the samples were fixed in formalin to determine whether water was the sole source of image contrast in this study. We found that the cirrhotic tissue had a higher water content and absorption coefficient than the normal tissue and that even after formalin fixing there were significant differences between the normal and cirrhotic tissues' terahertz properties. Our results show that terahertz pulsed imaging can distinguish between healthy and diseased tissue due to differences in absorption originating from both water content and tissue structure.     

Development of a compact terahertz time-domain spectrometer for the measurement of the optical properties of biological tissues

Terahertz spectrometers and imaging systems are currently being evaluated as biomedical tools for skin burn assessment. These systems show promise, but due to their size and weight, they have restricted portability, and are impractical for military and battlefield settings where space is limited. In this study, we developed and tested the performance of a compact, light, and portable THz time-domain spectroscopy (THz-TDS) device. Optical properties were collected with this system from 0.1 to 1.6 THz for water, ethanol, and several ex vivo porcine tissues (muscle, adipose, skin). For all samples tested, we found that the index of refraction (n) decreases with frequency, while the absorption coefficient (μ(a)) increases with frequency. Muscle, adipose, and frozen/thawed skin samples exhibited comparable n values ranging between 2.5 and 2.0, whereas the n values for freshly harvested skin were roughly 40% lower. Additionally, we found that the freshly harvested samples exhibited higher μ(a) values than the frozen/thawed skin samples. Overall, for all liquids and tissues tested, we found that our system measured optical property values that were consistent with those reported in the literature. These results suggest that our compact THz spectrometer performed comparable to its larger counterparts, and therefore may be a useful and practical tool for skin health assessment.     

Wavelet compression in medical terahertz pulsed imaging

This paper concerns the robustness of discrete wavelet transform (DWT) compression in terahertz pulsed imaging (TPI). TPI datasets consist of terahertz time-domain series which are sampled at each 'pixel' of the image, leading to file sizes which are typically of the order of several megabytes (MB) per image. This makes efficient compression highly desirable for both transmission and storage. However, since the data may be required for diagnostic purposes it is essential that no relevant information is lost or artefacts introduced. We show that for a nylon step wedge the estimates of refractive index and absorption coefficients are not significantly altered when the terahertz data are reconstructed from only 20% of DWT coefficients.     

Terahertz near-field imaging

A near-field probe is described that enables high spatial resolution imaging with terahertz (THz) pulses. The spatial resolution capabilities of the system lie in the range of few microns and we demonstrate a resolution of 7 microm using broad-banded THz pulses with an intensity maximum near 0.5 THz. We present a study of the performance of the near-field probes in the collection mode configuration and discuss some image properties.     

Terahertz wave imaging: horizons and hurdles

Terahertz (THz) science will profoundly impact biotechnology. It has tremendous potential for applications in imaging, medical diagnosis, health monitoring, environmental control and chemical and biological identification. THz research will become one of the most promising research areas in the 21st century for transformational advances in imaging, as well as in other interdisciplinary fields. However, terahertz wave (T-ray) imaging is still in its infancy. This paper discusses the uniqueness and limitations of T-ray imaging, identifies the major challenges impeding T-ray imaging and proposes solutions and opportunities in this field. It also concentrates on the generation, propagation and detection of T-rays by the use of femtosecond optics.     

The development of terahertz sources and their applications

The terahertz region of the electromagnetic spectrum spans the frequency range between the mid-infrared and the millimetre/microwave. This region has not been exploited fully to date owing to the limited number of suitable (in particular, coherent) radiation sources and detectors. Recent demonstrations, using pulsed near-infrared femtosecond laser systems, of the viability of THz medical imaging and spectroscopy have sparked international interest; yet much research still needs to be undertaken to optimize both the power and bandwidth in such THz systems. In this paper, we review how femtosecond near-infrared laser pulses can be converted into broad band THz radiation using semiconductor crystals, and discuss in depth the optimization of one specific generation mechanism based on ultra-fast transport of electrons and holes at a semiconductor surface. We also outline a few of the opportunities for a technology that can address a diverse range of challenges spanning the physical and biological sciences, and note the continuing need for the development of solid state, continuous wave, THz sources which operate at room temperature.     

Terahertz-wave water concentration and distribution measurement in thin biotissue based on a novel sample preparation

The measurement of water concentration and distribution in thin biotissues with terahertz (THz)-wave has been proposed. In this paper, a novel sample preparation approach was introduced to effectively preserve tissue freshness at room temperature. Excellent stability of this method was demonstrated by measuring the transmittance spectroscopy and imaging many times within a certain time. Moreover, the reliability of water volume concentration measurement with THz-wave was evaluated. Measurement results using THz-wave were in good agreement with volume concentration measurement results based on other quantitative methods. The results suggest that water concentration and distribution measurement in thin biotissues using THz-wave will be a potential modality for medical and biological diagnosis.