Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> Abstract We report an investigation of the temperature-dependent far-infrared spectrum of liquid water. We have employed a new experimental technique based on ultrashort electromagnetic pulses (THz pulses). This technique allows for fast and reliable data of both index of refraction and absorption coefficient for highly absorbing liquids. The temperature dependence reveals an enthalpy of activation corresponding to 2.5 kcal/mol, in agreement with recent Raman experiments, but lower than the enthalpy observed in dielectric relaxation experiments. This demonstrates that part of the orientational relaxation in liquid water takes place without breaking of hydrogen bonds with bonding energy of 5 kcal/mol, as suggested in recent theoretical model. <s> BIB001 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> The use of terahertz pulses for imaging has opened new possibilities for scientific and industrial applications in the terahertz frequency range. In this article, we describe the technology necessary to perform terahertz "T-ray" imaging, novel imaging techniques, and commercial applications of T-ray imaging. <s> BIB002 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> We review recent progress in the field of terahertz “T-ray” imaging. This relatively new imaging technique, based on terahertz time-domain spectroscopy, has the potential to be the first portable far-infrared imaging spectrometer. We give several examples which illustrate the possible applications of this technology, using both the amplitude and phase information contained in the THz waveforms. We describe the latest results in tomographic imaging, in which waveforms reflected from an object can be used to form a three-dimensional representation. Advanced signal processing tools are exploited for the purposes of extracting tomographic results, including spectroscopic information about each reflecting layer of a sample. We also describe the application of optical near-field techniques to the THz imaging system. Substantial improvements in the spatial resolution are demonstrated. <s> BIB003 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> We present Terahertz Pulse Imaging (TPI) results of different human tissue types. Our results are part of an initial study to explore the potential of TPI for biomedical applications. A survey of different tissue types has demonstrated the various contrast mechanisms that are available in TPI, allowing different tissue types to be readily identified. This encourages the pursuit of further studies of TPI for a variety of biomedical applications. <s> BIB004 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> Summary form only given. The use of Terahertz Pulse Imaging (TPI) for the analysis of skin cancer has been investigated. Our initial experiments have focused on the analysis of basal cell carcinoma (BCC), the most common form of skin cancer. BCC seldom metastasize but can be locally very invasive. The current diagnosis of carcinomas is by visual examination, where suspicious lesions require biopsy and subsequent histological diagnosis, which is painful, time consuming and may require additional tissue removal. The use of TPI as a diagnostic tool for skin cancer is of particular interest as its long wavelengths lead to a reduction in Rayleigh scattering and a resultant axial resolution of approximately 80 /spl mu/m. The spectroscopic information of TPI may prove to be advantageous in the discrimination between tumor types, which is unattainable using other methods such as ultrasound. Through the use of TPI, unnecessary biopsies could be avoided, by providing in-vivo measurements before surgery to identify the type and depth of tumor present. <s> BIB005 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> We discuss the use of terahertz time domain spectroscopy for studies of conformational flexibility and conformational change in biomolecules. Protein structural dynamics are vital to biological function with protein flexibility affecting enzymatic reaction rates and sensory transduction cycling times. Conformational mode dynamics occur on the picosecond timescale and with the collective vibrational modes associated with these large scale structural motions in the 1-100 cm(-1) range. We have performed THz time domain spectroscopy (TTDS) of several biomolecular systems to explore the sensitivity of TTDS to distinguish different molecular species, different mutations within a single species and different conformations of a given biomolecule. We compare the measured absorbances to normal mode calculations and find that the TTDS absorbance reflects the density of normal modes determined by molecular mechanics calculations, and is sensitive to both conformation and mutation. These early studies demonstrate some of the advantages and limitations of using TTDS for the study of biomolecules. <s> BIB006 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> We report on a promising approach for the label-free analysis of DNA molecules using direct probing of the binding state of DNA with electromagnetic waves at THz frequencies. Passive THz resonator devices based on planar waveguides are used as sample carriers and transducers for THz transmission analysis. In comparison to a formerly used free-space detection scheme, this method provides a drastically enhanced sensitivity enabling analysis down to femtomol levels. We examine the potential of our approach on biologically relevant DNA samples and demonstrate the detection of single base mutations on DNA molecules. <s> BIB007 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> We demonstrate the application of Terahertz Pulse Imaging (TPI) in reflection geometry for the study of skin tissue and related cancers. The terahertz frequency regime of 0.1-100THz excites the vibrational modes of molecules, allowing for spectroscopic investigation. The sensitivity of terahertz to polar molecules, such as water, makes TPI suitable for studying the hydration levels in the stratum corneum 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). Measurements on scar tissue, which is known to contain less water than the surrounding skin, and on regions of inflammation, show a clear contrast in the THz image compared to normal skin. We discuss the time domain analysis techniques used to classify the different tissue types. Basal cell carcinoma shows a positive terahertz contrast, and inflammation and scar tissue shows a negative terahertz contrast compared to normal tissue. This demonstrates for the first time the potential of TPI both in the study of skin cancer and inflammatory related disorders. <s> BIB008 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> Terahertz (THz) frequency spectroscopic imaging studies of teeth are reported. The aim is to establish the characteristic properties of the enamel and dentine at these high frequencies. Changes to the THz characteristics as a result of various types of tooth decay are reported showing the potential of this technique for dental diagnosis. <s> BIB009 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> We present a THz investigation of histo-pathological samples including the larynx of a pig and a human liver with metastasis. Our measurements show that different types of tissue can be clearly distinguished in THz transmission images, either within a single image or by a comparison of images obtained for different frequency windows. This leads to the problem that images obtained for different frequencies inherently have a different spatial resolution. An image obtained from two such images by a simple mathematical operation may contain artefacts. We discuss measures to deal with this problem. Furthermore, we investigate the possibility of improving the spatial resolution of THz images. Finally, we present a cw THz imaging system based on a photomixer and an external cavity semiconductor laser that allows for simultaneous two-mode operation. The cw system is less expensive and more compact than conventional time-domain imaging systems. <s> BIB010 </s> Medical applications of terahertz imaging: a review of current technology and potential applications in biomedical engineering <s> III. CURRENT AND FUTURE USES OF THZ RADIATION <s> 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. <s> BIB011
THz radiation has found two fundamental modes of application in medicine and biology -spectroscopy and imaging, though far more use has been made of the latter in medical applications. Here we will limit our discussion to imaging, though it is worth noting that THz time-domain spectroscopy has been shown to be capable of detecting mutations and conformational modes of biomolecules provided a reference sample is available for calibration BIB006 . In addition, T-rays have been used as a method of label-free probing of the binding state of DNA with good results  BIB007 . An unavoidable issue when imaging with THz radiation is absorption by water. The entire THz band is strongly absorbed by water (or any polar liquid) BIB001 and consequently does not penetrate moist tissue to any significant depth. It has been reported that a THz pulse can be detected through 1.5 mm of skin when the signal to noise ratio is 500:1  , this is low penetration but still better than through water alone BIB002 BIB001 . Researchers have circumvented this in two ways, firstly by performing transmission imaging on thin, clinically prepared tissue samples, and secondly by imaging surface features using reflection geometry imaging. Transmission imaging, for obvious reasons, can only be carried out in vitro, whereas a reflection geometry set-up allows the possibility of in vivo imaging BIB008  . The limited penetration depth of THz radiation has focused medical imaging research into the areas of dermatology and dentistry. In dentistry, in vitro experiments using THz imaging and spectroscopy have already been carried out to determine the characteristic THz properties of enamel and dentine in human teeth BIB009 . THz radiation has been shown to be capable of the early detection of dental carries BIB004 . Since in vivo THz imaging is currently limited to surface features, it would seem that dentistry should be a suitable field of application. However, in practice THz imaging systems are large and cumbersome -even structures as obvious as teeth can make a challenging target. In this respect THz imaging is still some way off offering a non-ionizing alternative to x-rays in dentistry. Imaging with THz radiation has been most successful when dealing with illnesses of the skin. Work in this area initially focused on identifying previously diagnosed basal cell carcinomas (a cancer of the lowest layer of the epidermis). At first this was accomplished in vitro using both transmission and reflection modes BIB008 BIB005  , where THz showed promising tissue differentiating abilitiesbeing able to distinguish between diseased and normal but inflamed tissue. More recently reflection geometry techniques have been used to take the first in vivo THz images of skin cancers, showing surface features and depth information  . In both the in vivo and in vitro tests, THz radiation has been shown to perform well when compared to the standard in vitro histological test. The potential usefulness of THz imaging in this case cannot be over stated. The treatment for this type of cancer is surgical removal of the tumor, the object being, to remove as little healthy tissue as possible while ensuring all cancerous material has been removed. Histological examination of the excised tissue indicates whether the tumor has been successfully removed. THz imaging allows the size, shape and depth of the diseased tissue to be accurately viewed prior to surgery. The exact reason for THz radiation's ability to differentiate between cancerous and healthy tissue is not known. While one might suspect that water absorption may play a part in the in vivo cases -water is removed from samples prior to histological testing and on such samples THz still performs well. Since cancerous and healthy tissue do not differ greatly in density, it has been suggested that the cause of the differentiation is down to chemical composition BIB010 . Another area where THz imaging will likely find use is wound assessment. The potential of THz imaging as a burn diagnostic has been demonstrated using chicken breast BIB002 BIB003 . It is also conceivable that THz imaging could be of use in monitoring treatment of skin conditions (like psoriasis), since THz imaging is cheaper than MRI and does not necessitate contact with the skin like ultrasound. (See BIB011 and the references therein.)