Ruth M. Woodward

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.

Terahertz Pulsed Imaging of Skin Cancer in the Time and Frequency Domain

Terahertz Pulsed Imaging(TPI) is a new medical imaging modality forthe detection of epithelial cancers. Overthe last two years this technique has beenapplied to the study of in vitrobasal cell carcinoma (BCC). Usingtime-domain analysis the contrast betweendiseased and normal tissue has been shownto be statistically significant, andregions of increased terahertz (THz)absorption correlated well with thelocation of the tumour sites in histology.Understanding the source of this contrastthrough frequency-domain analysis mayfacilitate the diagnosis of skin cancer andrelated skin conditions using TPI. Wepresent the first frequency-domain analysisof basal cell carcinoma in vitro,with the raw power spectrum giving aninsight into the surface features of theskin. Further data manipulation is requiredto determine whether spectral informationcan be extrapolated at depth. These resultshighlight the complexity of working inreflection geometry.

Terahertz pulsed imaging and spectroscopy for biomedical and pharmaceutical applications

Terahertz (THz) radiation lies between the infrared and microwave regions of the electromagnetic spectrum. Advances in THz technology have opened up many opportunities in this scientifically and technologically important spectroscopic region. The THz frequency range excites large amplitude vibrational modes of molecules as well as probing the weak interactions between them. Here we describe two techniques that utilize THz radiation, terahertz pulsed imaging (TPI) and terahertz pulsed spectroscopy (TPS). Both have a variety of possible applications in biomedical imaging and pharmaceutical science. TPI, a non-invasive imaging technique, has been used to image epithelial cancer ex vivo and recently in vivo. The diseased tissue showed a change in absorption compared to normal tissue, which was confirmed by histology. To understand the origins of the differences seen between diseased and normal tissue we have developed a TPS system. TPS has also been used to study solids of interest in the pharmaceutical industry. One particularly interesting example is ranitidine hydrochloride, which is used in treatment of stomach ulcers. Crystalline ranitidine has two polymorphic forms known as form 1 and form 2. These polymorphs have the same chemical formula but different crystalline structure that give rise to different physiochemical properties of the material. Using TPS it is possible to rapidly distinguish between the two polymorphic forms.

Terahertz imaging and spectroscopy of human skin in vivo

We demonstrate the application of terahertz pulse imaging for the in-vivo study of human tissue, in this case the upper layers of human skin. The terahertz pulses comprise frequencies from below 100 GHz to over 2 THz and are generated using optical pulse excited semiconductor devices with a conversion efficiency of better than 10-3. The terahertz pulses are used to obtain tomographic information on the skin surface tissue. From the data the stratum corneum thickness and hydration may be mapped or cross-sectional images displayed.

Terahertz pulse imaging of in-vitro basal cell carcinoma samples

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.

Terahertz pulse imaging in reflection geometry of skin tissue using time-domain analysis techniques

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.

Biomedical applications of terahertz pulse imaging

Over the last decade advances in laser and semiconductor technology has allowed us to investigate the terahertz region of the electromagnetic spectrum as a potential tool for medical imaging. The terahertz frequency range covers the far infrared wavelengths and is sensitive to librational and vibrational modes of molecules. Terahertz radiation is nonionizing and is not highly scattered like visible and near infrared light. Terahertz pulse imaging has already demonstrated it effectiveness in vivo and by differentiating between tissue types in particular, benign and malignant tissue in vitro.

Biomedical applications of terahertz technology

We present results which demonstrate the ability of Terahertz Pulse Imaging (TPI) to distinguish between carcinoma and normal tissue. This technique is the first to be used to identify basal cell carcinoma macroscopically in the terahertz frequency regime. The increase in absorption observed in the diseased tissue is attributed to an increase in the amount or a change in the binding of water within the basal cell carcinoma. This makes water an important molecular marker for TPI. Our results represent a new application for the use of terahertz radiation in distinguishing carcinoma from normal tissue.

Tissue classification using terahertz pulsed imaging

We demonstrate the application of terahertz pulsed imaging (TPI) in reflection geometry as a diagnostic aid for epithelial cancer, specifically basal cell carcinoma. Epithelial cancer, which includes skin, breast and colon cancer, accounts for about 85% of all cancers. The terahertz (THz) region is typically defined in the frequency range of 0.1-10 THz. The sensitivity of terahertz radiation to water makes TPI an ideal technique for the study of skin, particularly as cancerous tissue has been shown to contain more water than normal tissue. Twenty-one ex vivo skin samples from a previous study, which successfully identified all 17 samples exhibiting basal cell carcinoma, were analysed in detail using time-domain algorithms to determine the role of TPI as a diagnostic aid. Eight parameters were assessed, four of which were identified as uncorrelated. The samples were classified into two groups: diseased tissue, and tissue without disease. A sensitivity and specificity greater than 80 % for six of the parameters was attained. These results demonstrate the potential of TPI as a diagnostic aid.

An analytical model of skin: comparison with experimental results in vivo

Terahertz pulsed imaging is a non-invasive, non-ionizing imaging technique, using electromagnetic radiation defined in the frequency range 0.1 THz to 10 THz. Using reflection imaging systems with a frequency range 0.1 THz to 4 THz a far field diffraction limited lateral resolution of 3 mm to 110 microns is attainable. A three layer analytical model has been developed to simulate the hydration properties of skin in reflection. Earlier in vivo hydration measurements of the volar forearm and palm of the hand (thenar) are compared to this model. The time-domain analysis technique “time post pulse” (TPP) used to differentiate between diseased and normal tissue in a study of basal cell carcinoma was applied to the data. An increase in the value of TPP is observed with occlusion in the viable epidermis. This is attributed to an increase in the flux of water across the epidermis or dermis with increased stratum corneum hydration. This is verified by the literature. The change is observed in less than six minutes occlusion, making terahertz technology one of the most sensitive techniques for monitoring skin hydration levels. The contrast observed at the stratum corneum-viable epidermis interface is similar to that seen between diseased and normal tissue. Although water provides a good marker for studying diseased tissue, comparing results from DNA and protein analysis, it is not yet possible to conclude whether the contrast observed in basal cell carcinoma is due to increased water within the diseased tissue, a change in the vibrational modes of water with other functional groups, or a change in the vibrational modes of the functional groups alone. Further studies are required to determine whether terahertz technology is capable of differentiating between different histological subtypes in a collective system such as skin at a macroscopic level. The three layer analytical model provides a useful adjunct for identifying the source of contrast observed in the top surface of skin.