THz and mm-Wave Sensing of Corneal Tissue Water Content: Electromagnetic Modeling and Analysis.

Terahertz (THz) spectral properties of human cornea are explored as a function of central corneal thickness (CCT) and corneal water content, and the clinical utility of THz-based corneal water content sensing is discussed. Three candidate corneal tissue water content (CTWC) perturbations, based on corneal physiology, are investigated that affect the axial water distribution and total thickness. The THz frequency reflectivity properties of the three CTWC perturbations were simulated and explored with varying system center frequency and bandwidths (Q-factors). The modeling showed that at effective optical path lengths on the order of a wavelength the cornea presents a lossy etalon bordered by air at the anterior and the aqueous humor at the posterior. The simulated standing wave peak-to-valley ratio is pronounced at lower frequencies and its effect on acquired data can be modulated by adjusting the bandwidth of the sensing system. These observations are supported with experimental spectroscopic data. The results suggest that a priori knowledge of corneal thickness can be utilized for accurate assessments of corneal tissue water content. The physiologic variation of corneal thickness with respect to the wavelengths spanned by the THz band is extremely limited compared to all other structures in the body making CTWC sensing unique amongst all proposed applications of THz medical imaging

Terahertz Imaging and Remote Sensing Design for Applications in Medical Imaging

THz region (1 mm - 0.1 mm, or 300 GHz and 3 THz) of the electromagnetic spectrum attracts applications in medical imaging, with its high dielectric constant of water, low non-ionizing photon energy (0.4-40 meV), and robustness against scattering from rough surface interface. This study investigates THz optical imaging system design and engineering, and explores implementation of THz imaging method for application in remote sensing of physiological tissue. Specifically, the focus of this manuscript is to explore two important topics in remote sensing design, with analysis of quasi-optical systems design and effect of rough surface scattering in THz wavelength. An overview of THz imaging field and application to medical imaging are presented. A survey of current methods THz imaging and remote sensing scheme is made to provide context for system design consideration. As an example, the direct-detection THz imaging system is characterized, and used in experiments for the following sections. In the second section, a detailed analysis of commonly used quasi-optical component (off-axis parabolic mirrors) is performed to investigate its focusing properties at THz wavelength. Additional attention is directed to polarization aberration effect in the propagation of coherent, linearly polarized THz beam through series of mirrors. The third section applies Kirchhoff random rough surface scattering theory at THz region, and provides analysis of signal strength and variance in the signal-to-noise ratio (SNR) in imaging.Lastly, a beam-scanning imaging system is constructed and demonstrated as an effort toward practical clinical application. The system employs a spinning polygon mirror and Michelson interferometer based design to allow source, detector, and target to remain fixed and perform imaging at a dramatically faster speed. The system achieves a focused THz beam diameter of 1.66mm and a large depth of field of >25 mm, and acquisition speed of minimum 100 pixels/s. Images of characterization targets and ex vivo tissue samples are presented

Terahertz imaging and sensing for ophthalmic evaluation of corneal diseases

In the span of electromagnetic wave band from microwave to X-rays, Interactions of biological tissue and light at the terahertz (THz) wavelength band (λ ~ 30m - 3mm) are particularly unique for two reasons. First, the THz band retains a large dielectric constant for water from the microwave region while its shorter wavelength enables imaging applications with < 1mm resolution. Second, the effect of scattering from typical soft tissue structures (i.e. cells, collagen matrix, etc.) is less in the THz band compared to that in higher-frequency bands (IR band and up). Using this balance of properties, our study applies non-invasive THz sensing to study diseases and conditions that compromise our body’s ability to balance water in tissues.This study focuses on developing a novel medical imaging technology using THz frequency waves to accurately assess and image the tissue water content of the cornea, which is a critical refractive and protective component of the eye. In ophthalmology, most corneal disorders such as Fuchs endothelial dystrophy (failure of stromal hydration regulation), Keratoconus (corneal ectasia), pseudophakic bullous keratopathy (unintentionally damaged endothelial layer), and corneal graft rejection result in corneal edema. Corneal edema is a contributing factor leading to corneal opacity, and if left untreated, can lead to chronic vision impairment. Accurate corneal tissue water content (CTWC) measurement, therefore can help with early diagnosis and intervention for corneal diseases and further our understanding of the formation and progression of corneal disorders. This work details the development of a THz remote-sensing technique based on rigorous electromagnetic model of cornea-THz interaction, and an imaging system that can be practically implemented in the clinical setting. A novel ophthalmic THz imaging system is designed and implemented to perform completely non-contact, all normal-incidence imaging of the corneal surface. The imaging system uses a wavelength independent quasioptical design that achieves a <1.4 mm spatial resolution at 650 GHz. The corneal hydration sensing capability of this imager is demonstrated in in vivo corneas. For the first time, THz images of a living cornea showed the onset of acute corneal edema from endothelial damage. The THz imaging system is currently being used in the first phase of the clinical study to evaluate healthy and diseased corneas of patients with corneal graft and corneal dystrophies

Extended Squaraine Dyes With Large Two-Photon Absorption Cross-Sections

Extended bis(donor)-substituted squaraine chromophores exhibit very high two-photon cross-sections (as high as 33000 GM) in the near-IR; these can be attributed to the combination of large transition dipoles with small detuning energies. The modulus of the third-order nonlinear optical susceptibility at 1.3 μm has been found to be 7.0 × 10-11 esu for one of these chromophores. Copyright © 2006 American Chemical Society

Resolution and material assessment capability of a vibroacoustographic imaging system

There has been significant growth in non-invasive screening techniques for evaluating abnormal tissue. Vibroacoustography (VA), an imaging modality based on ultrasound-stimulated acoustic emission and non-linear scattering characteristics of the target, has previously been used to generate relative real-time, pathology-specific image contrast between abnormal tissue and normal surrounding tissue; however, an in-depth tissue assessment has yet to be completed. VA utilizes two non-destructive low MHz ultrasound tones to produce an acoustic beat frequency in the low kHz range. The acoustic radiation force perturbs the target as a function of its mechanical and acoustic properties and the emissive acoustic waves are detected by a nearby hydrophone to form an image based on the viscoelastic characteristics of the target. We have previously reported that our VA imaging system can distinguish suspect tissue from normal tissue in tissue-mimicking phantoms (TMPs) and ex vivo models with high image contrast; however, the goal of this work is to assess the measurement performance and resolution capabilities of this system in pre-clinical models, specifically TMPs in tissue assessment. Lateral and axial resolution, as well as material characterization, studies were performed on isotropic two-layered and multiple-layered TMP targets. The resolution studies resulted in ∼1 mm lateral and ∼12 mm axial, which were confirmed and validated for a confocal transducer geometry. The system showed sufficient measurement performance to detect regions with elastic moduli difference of at least 10 kPa and lateral width of at least 4 mm. This result, coupled with high imaging contrast, supports the utilization of VA for potential applications in in vivo medical imaging and tissue assessment for intraoperative applications

Methods for Registering and Calibrating in Vivo Terahertz Images of Cutaneous Burn Wounds

A method to register THz and visible images of cutaneous burn wounds and to calibrate THz image data is presented. Images of partial and full thickness burn wounds in 9 rats were collected over 435 mins. = 7.25 hours following burn induction. A two-step process was developed to reference the unknown structure of THz imaging contrast to the known structure and the features present in visible images of the injury. This process enabled the demarcation of a wound center for each THz image, independent of THz contrast. Threshold based segmentation enabled the automated identification of air (0% reflectivity), brass (100% reflectivity), and abdomen regions within the registered THz images. Pixel populations, defined by the segmentations, informed unsupervised image calibration and contrast warping for display. The registered images revealed that the largest variation in THz tissue reflectivity occurred superior to the contact region at ~0.13%/min. Conversely the contact region showed demonstrated an ~6.5-fold decrease at ~0.02%/min. Exploration of occlusion effects suggests that window contact may affect the measured edematous response

Non-invasive terahertz imaging of tissue water content for flap viability assessment.

Accurate and early prediction of tissue viability is the most significant determinant of tissue flap survival in reconstructive surgery. Perturbation in tissue water content (TWC) is a generic component of the tissue response to such surgeries, and, therefore, may be an important diagnostic target for assessing the extent of flap viability in vivo. We have previously shown that reflective terahertz (THz) imaging, a non-ionizing technique, can generate spatially resolved maps of TWC in superficial soft tissues, such as cornea and wounds, on the order of minutes. Herein, we report the first in vivo pilot study to investigate the utility of reflective THz TWC imaging for early assessment of skin flap viability. We obtained longitudinal visible and reflective THz imagery comparing 3 bipedicled flaps (i.e. survival model) and 3 fully excised flaps (i.e. failure model) in the dorsal skin of rats over a postoperative period of 7 days. While visual differences between both models manifested 48 hr after surgery, statistically significant (p < 0.05, independent t-test) local differences in TWC contrast were evident in THz flap image sets as early as 24 hr. Excised flaps, histologically confirmed as necrotic, demonstrated a significant, yet localized, reduction in TWC in the flap region compared to non-traumatized skin. In contrast, bipedicled flaps, histologically verified as viable, displayed mostly uniform, unperturbed TWC across the flap tissue. These results indicate the practical potential of THz TWC sensing to accurately predict flap failure 24 hours earlier than clinical examination

Terahertz Imaging of Cutaneous Edema: Correlation With Magnetic Resonance Imaging in Burn Wounds.

ObjectiveIn vivo visualization and quantification of edema, or 'tissue swelling' following injury, remains a clinical challenge. Herein, we investigate the ability of reflective terahertz (THz) imaging to track changes in tissue water content (TWC)-the direct indicator of edema-by comparison to depth-resolved magnetic resonance imaging (MRI) in a burn-induced model of edema.MethodsA partial thickness and full thickness burns were induced in an in vivo rat model to elicit unique TWC perturbations corresponding to burn severity. Concomitant THz surface maps and MRI images of both burn models were acquired with a previously reported THz imaging system and T2-weighted MRI, respectively, over 270 min. Reflectivity was analyzed for the burn contact area in THz images, while proton density (i.e., mobile TWC) was analyzed for the same region at incrementally increasing tissue depths in companion, transverse MRI images. A normalized cross correlation of THz and depth-dependent MRI measurements was performed as a function of time in histologically verified burn wounds.ResultsFor both burn types, strong positive correlations were evident between THz reflectivity and MRI data analyzed at greater tissue depths (>258 μm). MRI and THz results also revealed biphasic trends consistent with burn edema pathogenesis.ConclusionThis paper offers the first in vivo correlative assessment of mobile TWC-based contrast and the sensing depth of THz imaging.SignificanceThe ability to implement THz imaging immediately following injury, combined with TWC sensing capabilities that compare to MRI, further support THz sensing as an emerging tool to track fluid in tissue