Objective: DOCI is a novel imaging modality with the ability to detect variations in endogenous fluorophore lifetimes by illuminating tissue with pulsed ultraviolet (UV) light. We have previously shown that DOCI is capable of delineating tumor margins. Tissue macro-/micro-environments, however, vary with organ site and histology. We therefore sought to better characterize DOCI signal analysis within the varying subsites of the oral cavity in this ex-vivo animal model.
Design: Fresh ex-vivo oral cavity specimens (n=66) from three New Zealand white rabbits were harvested for pulsed UV illumination utilizing a 6-diode in-series DOCI system. Photons produced were detected and fluorophore lifetimes calculated over a specified, homogenous, region of interest. Specimen site, size, histology, and relative average DOCI values analyzed.
Results: 66 specimens produced over 2 million data points for fluorophore lifetime analysis. The oral tongue muscle, dentition, and mucosa from the dorsal tongue, floor of mouth, and hard palate all produced unique DOCI relative average values. Each subsite was found to be uniquely different from one another and produced statistically significant differences in DOCI value (p<0.05).
Conclusions: DOCI has the ability to distinguish subtle differences in oral cavity subsites following fresh ex vivo harvest. The fluorophore lifetime relative average values of each tissue is uniquely different posing a novel strategy for intra operative oncologic imaging, surveillance, and possibly aid in the workup of pre-cancerous lesions. Growing a repository of normal tissue subsites is crucial for integrating an automated real-time deep learning algorithm for rapid tissue analysis.
We present measurements of sub-bandgap photoconductivity and photoconductive switches using GaAs doped heavily with Er such that nanoparticles of ErAs are formed. In addition to strong resonant absorption centered around 1550 nm, the material provides strong sub-bandgap photoconductivity and >> μW average power levels when fabricated into an efficient (square spiral) THz antenna and driven by a 1550- nm ultrafast fiber laser. Photo-Hall measurements prove that the predominant photocarrier is the electron and the linearity of the 1550-nm photocurrent (with laser power) suggests that the photoconductivity is “extrinsic”, not other possible mechanisms, such as two-photon absorption. These results have immediate relevance to the use of GaAs:Er switches as the transmitter in 1550-nm-driven THz imaging systems such as the “impulse imager” that we have successfully used for biomedical imaging applications.
This paper explores the utility of reflective THz imaging to assess the viability of surgical flaps. Flap surgery is a technique where tissue is harvested from a donor site and moved to a recipient while keeping the blood supply intact. This technique is common in head and neck tumor resection surgery where the reconstruction of complex and sensitive anatomic structures is routine following the resection of large and/or invasive tumors. Successful flap surgery results in tissue that is sufficiently perfused with both blood and extracellular water. If insufficient fluid levels are maintained, the flap tissue becomes necrotic and must be excised immediately to prevent infection developing and spreading to the surrounding areas.
The goal of this work is to investigate the hydration of surgical flaps and correlate image features to successful graft outcomes. Advancement flaps were created on the abdomens of rat models. One rat model was labeled control and care was taken to ensure a successful flap outcome. The flap on the second rat was compromised with restricted blood flow and allowed to fail. The flaps of both rats were imaged once a day over the course of a week at which point the compromised flap had begun to show signs of necrosis. Significant differences in tissue water content were observed between rats over the experimental period. The results suggest that THz imaging may enable early assessment of flap viability.
The THz electromagnetic properties of rough surface are explored and their effect on the observed contrast in THz images is quantified. Rough surface scatter is a major source of clutter in THz imaging as the rough features of skin and other tissues result in non-trivial reflection signal modulation. Traditional approaches to data collection utilize dielectric windows to flatten surfaces for THz imaging. However, there is substantial interest surrounding window free imaging as contact measurements are not ideal for a range of candidate diseases and injuries.
In this work we investigate the variation in reflected signal in the specular direction from rough surfaces targets with known roughness parameters. Signal to clutter ratios are computed and compared with that predicted by Rayleigh Rough surface scattering theory. It is shown that Rayleigh rough surface scattering theory, developed for rough features larger than the interacting wavelength, holds acceptable at THz frequencies with rough features much smaller than the wavelength. Additionally, we present some biological tissue imaging examples to illustrate the impact of rough surface scattering in image quality.
In this presentation, a review and quasioptical imaging system and design considerations for an off-axis parabolic mirror based THz imaging systems are presented. It is shown that off-axis parabolic mirrors introduce off-axis intensity and polarization distortion. When a train of OAPs are used to relay THz beam, each distortions rapidly stacks to produce quite ugly beam and polarization profile. We show that the distortion of field distribution and polarization as a function of mirror curvature and focusing parameters. A brief review of design rules are shown to eliminate these distortions by a symmetric configurations of off-axis parabolic mirror train. The detrimental distortion effects were cancelled out by orienting the final two mirrors in a way to that recovers the original source profile. Comparisons of field profiles between compensated and uncompensated design are shown and imaging performance on characterization targets presented. In addition to benefits in field and polarization distribution the improved design facilitates 1D scanning with minimal change to overall optical path length.
Well-regulated corneal water content is critical for ocular health and function and can be adversely affected by a number of diseases and injuries. Current clinical practice limits detection of unhealthy corneal water content levels to central corneal thickness measurements performed by ultrasound or optical coherence tomography. Trends revealing increasing or decreasing corneal thickness are fair indicators of corneal water content by individual measurements are highly inaccurate due to the poorly understood relationship between corneal thickness and natural physiologic variation.
Recently the utility of THz imaging to accuarately measure corneal water content has been explored on with rabbit models. Preliminary experiments revealed that contact with dielectric windows confounded imaging data and made it nearly impossible to deconvolve thickness variations due to contact from thickness variations due to water content variation. A follow up study with a new optical design allowed the acquisition of rabbit data and the results suggest that the observed, time varying contrast was due entirely to the water dynamics of the cornea.
This paper presents the first ever in vivo images of human cornea. Five volunteers with healthy cornea were recruited and their eyes were imaged three times over the course of a few minutes with our novel imaging system. Noticeable changes in corneal reflectivity were observed and attributed to the drying of the tear film. The results suggest that clinically compatible, non-contact corneal imaging is feasible and indicate that signal acquired from non-contact imaging of the cornea is a complicated coupling of stromal water content and tear film.
This paper explores vasodynamics in response to histamine injection using reflective THz imaging. Histamine is a major contributor to allergic disease. Elevations in tissue histamine levels have been observed during anaphylaxis and experimental allergic responses of the skin, nose, and airways. In the skin specifically, vasodilation, vascular permeability, and pruritus is controlled by the release and resorption of histamine. These properties are leveraged in skin prick testing for allergies where histamine dihydrochloride is injected as a positive control to confirm allergen susceptibility prior to the administration of candidate allergens.
Subjective parameters such as skin coloration, irritation, and bulging as a consequence of histamine injection and histamine release are well characterized. However limited quantitative metrics on the body’s edematous response are available due to the lack of imaging diagnostics that can map surface tissue water content (TWC).
THz imaging was used to explore the utility of reflective THz imaging to quantify edematous responses to histamine. Rat models were injected with varying concentrations of histamine dihydrochloride and the resultant edematous response arising from perturbed vasodymanics was mapped. Significant build up and dissipation of surface tissue water content was observed and THz frequency contrast was seen to correlate with visual appearance in some cases and in others reveal tissue water content variations not discernable with the naked eye. The results suggest that THz imaging may be a valuable tool in quantifying the degree of allergic responses and assist in detecting hypersensitivity.
This paper describes the basic design, implementation, and testing of a polarization difference imaging system for use on aqueous targets. The ultimate performance limitation of THz imaging in many active areas of research is clutter from surface geometry. While the signal to nose ratio (SNR) of standard THz imaging systems is quite large, the signal to clutter ratio (SCR) often faced in an imaging application is orders of magnitude lower and, in many cases, lower than the contrast to noise (CNR) resulting in imagery where the contrast mechanism of interest does not significantly contribute to the overall observed contrast. To overcome these limitations we develop a system that uses a circularly polarized source and linearly polarized detectors to acquire images of transverse electric (TE) and transverse magnetic (TM) reflectivities of the target over the same field of view. Geletin based tissue mimicking phantoms are fabricated with spatially varying water content and modified with a range of surface topologies and surface roughness. TE and TM images are combined to yield self-calibrated clutter-suppressed images. The resulting image indicates that the imaging field clutter affected both polarization channels nearly equally allowing the system to resolve differences in phantom water content. This design is a step toward windowless THz imaging capability critical for clinical translation where patient imaging is dominated by clutter.
KEYWORDS: Terahertz radiation, Tissues, Reflectivity, Quartz, In vivo imaging, Injuries, Electromagnetism, Dielectrics, Medical imaging, Animal model studies
The high contrast resolution afforded by terahertz (1 THz = 1012 Hz) imaging of physiologic tissue continues to drive explorations into the utility of THz technology for burn wound detection. Although we have previously reported the use of a novel, reflective THz imaging technology to sense spatiotemporal differences in reflectivity between partial and full thickness burn wounds, no evidence exists of a one-to-one correlation between structural damage observed in histological assessments of burn severity and THz signal. For example, varying burn induction methods may all result in a common burn wound severity, however, burn features observed in parallel THz imagery may not be identical. Successful clinical translation of THz technology as a comprehensive burn guidance tool, therefore, necessitates an understanding of THz signal and its relation to wound pathophysiology. In this work, longitudinal THz imagery was acquired with a quartz (n = 2.1, 500 μm) window of cutaneous wounds induced with the same brand geometry and contact pressure but varying contact times (5, 7, and 10 seconds) in in vivo, pre-clinical rat models (n=3) over a period of 3 days. Though all burn wounds were evaluated to be deep partial thickness with histology, THz contrasts observed for each burn contact time were intrinsically unique. This is the first preliminary in vivo evidence of a many-to-one relationship between changes in THz contrast and burn severity as ascertained by histology. Future large-scale studies are required to assess whether these observed changes in THz contrast may be interpreted as physiological changes occurring over time, morphometric changes related to anatomical change, or electromagnetic changes between dielectric substrate windows and the underlying tissue.
This paper presents a novel THz optical design that allows the acquisition of THz reflectivity maps of in vivo cornea
without the need for a field flattening window and preliminary imaging results of in vivo rabbit cornea. The
system’s intended use is to sense small changes in corneal tissue water content (CTWC) that can be precursors for a
host of diseases and pathologies. Unique beam optics allows the scanning of a curved surface at normal incidence
while keeping the source detector and target stationary. Basic system design principles are discussed and image sets
of spherical calibration targets and corneal phantom models are presented. The presented design will enable, for the
first time, non-contact THz imaging of animal and human cornea.
Terahertz (THz) imaging is a relatively new non-destructive analytical technique that is transitioning from established application research areas such as defense and biomedicine to studies of cultural heritage artifacts. Our research adopts a THz medical imaging system, originally designed for in vivo tissue hydration sensing, to acquire high contrast imagery of painted plaster samples in order to assess the ability of the system to image the Byzantine wall paintings at the Enkleistra of St. Neophytos in Paphos, Cyprus. The original 12th century paintings show evidence of later painting phases overlapping earlier iconography. A thin layer of lead white (2PbCO3·Pb(OH)2) underlies, in parts, later wall paintings, concealing the original painting scheme beneath. Traditional imaging modalities have been unable to image the underlying iconography due to a combination of absorption and scattering. We aim to use THz imaging and novel optical design to probe beyond the visible surface and perform in situ analysis of iconography beneath the lead white layer. Imaging results of painted plaster mock-ups covered with a thin layer of lead white and/or chalk, as well as of a painted wooden panel with obscured writing, are presented, and from these images sufficient contrast for feature identification is demonstrated. Preliminary results from the analysis of these mock-ups confirmed the utility of this technique and its potential to image concealed original paintings in the Enkleistra of St. Neophytos. The results encourage analysis of THz scattering within paint and plaster materials to further improve spatial resolution and penetration depth in THz imaging systems.
KEYWORDS: Terahertz radiation, Tissues, Magnetic resonance imaging, Reflectivity, Skin, In vivo imaging, Imaging systems, Abdomen, Medical imaging, Water
Terahertz (THz) detection has been proposed and applied to a variety of medical imaging applications in view of its
unrivaled hydration profiling capabilities. Variations in tissue dielectric function have been demonstrated at THz
frequencies to generate high contrast imagery of tissue, however, the source of image contrast remains to be verified
using a modality with a comparable sensing scheme. To investigate the primary contrast mechanism, a pilot
comparison study was performed in a burn wound rat model, widely known to create detectable gradients in tissue
hydration through both injured and surrounding tissue. Parallel T2 weighted multi slice multi echo (T2w MSME)
7T Magnetic Resonance (MR) scans and THz surface reflectance maps were acquired of a full thickness skin burn in
a rat model over a 5 hour time period. A comparison of uninjured and injured regions in the full thickness burn
demonstrates a 3-fold increase in average T2 relaxation times and a 15% increase in average THz reflectivity,
respectively. These results support the sensitivity and specificity of MRI for measuring in vivo burn tissue water
content and the use of this modality to verify and understand the hydration sensing capabilities of THz imaging for
acute assessments of the onset and evolution of diseases that affect the skin. A starting point for more sophisticated
in vivo studies, this preliminary analysis may be used in the future to explore how and to what extent the release of
unbound water affects imaging contrast in THz burn sensing.
THz imaging system design will play an important role making possible imaging of targets with arbitrary properties
and geometries. This study discusses design consideration and imaging performance optimization techniques in THz
quasioptical imaging system optics. Analysis of field and polarization distortion by off-axis parabolic (OAP) mirrors
in THz imaging optics shows how distortions are carried in a series of mirrors while guiding the THz beam. While
distortions of the beam profile by individual mirrors are not significant, these effects are compounded by a series of
mirrors in antisymmetric orientation. It is shown that symmetric orientation of the OAP mirror effectively cancels this
distortion to recover the original beam profile. Additionally, symmetric orientation can correct for some geometrical
off-focusing due to misalignment. We also demonstrate an alternative method to test for overall system optics
alignment by investigating the imaging performance of the tilted target plane. Asymmetric signal profile as a function
of the target plane’s tilt angle indicates when one or more imaging components are misaligned, giving a preferred tilt
direction. Such analysis can offer additional insight into often elusive source device misalignment at an integrated
system. Imaging plane tilting characteristics are representative of a 3-D modulation transfer function of the imaging
system. A symmetric tilted plane is preferred to optimize imaging performance.
This paper presents novel a first pass on the thorough analysis of THz optical designs intended for image acquisition of
burn wounds in animal models. Current THz medical imaging research typically employs and fixed source detector
architecture coupled by a train of off-axis parabolic mirrors. When used individually, parabolic mirrors have near
diffraction limited focusing properties, extremely low loss, and are dispersion free. However, when a combination or train
of multiple parabolic mirrors are utilized geometric errors can be generated early in the train and exacerbated as the beam
propagates to the detector. These errors manifest as significant increases in spot size, asymmetries about the optical axis
in beam irradiance and polarization, and the generation of cross polarization components. This work presents a novel
configuration of off-axis parabolic mirrors designed to maximize the practicality of beam alignment and image acquisition.
Quasi-physical optics simulations of the optical performance are described and significant perturbations in polarization
symmetry were observed. The configuration can be described as in between two canonical parabolic mirror configurations.
The performance of three different pairs of off-axis parabolic mirror pairs coupled to the novel configuration are presented
herein.
The THz impulse radar is an “RF-inspired” sensor system that has performed remarkably well since its initial development nearly six years ago. It was developed for ex vivo skin-burn imaging, and has since shown great promise in the sensitive detection of hydration levels in soft tissues of several types, such as in vivo corneal and burn samples. An intriguing aspect of the impulse radar is its hybrid architecture which combines the high-peak-power of photoconductive switches with the high-responsivity and -bandwidth (RF and video) of Schottky-diode rectifiers. The result is a very sensitive sensor system in which the post-detection signal-to-noise ratio depends super-linearly on average signal power up to a point where the diode is “turned on” in the forward direction, and then behaves quasi-linearly beyond that point. This paper reports the first nonlinear systems analysis done on the impulse radar using MATLAB.
Terahertz (THz) hydration sensing continues to gain traction in the medical imaging community due to its unparalleled
sensitivity to tissue water content. Rapid and accurate detection of fluid shifts following induction of thermal skin burns
as well as remote corneal hydration sensing have been previously demonstrated in vivo using reflective, pulsed THz
imaging. The hydration contrast sensing capabilities of this technology were recently confirmed in a parallel 7 Tesla
Magnetic Resonance (MR) imaging study, in which burn areas are associated with increases in local mobile water
content. Successful clinical translation of THz sensing, however, still requires quantitative assessments of system
performance measurements, specifically hydration concentration sensitivity, with tissue substitutes. This research aims
to calibrate the sensitivity of a novel, reflective THz system to tissue water content through the use of hydration
phantoms for quantitative comparisons of THz hydration imagery.Gelatin phantoms were identified as an appropriate
tissue-mimicking model for reflective THz applications, and gel composition, comprising mixtures of water and protein,
was varied between 83% to 95% hydration, a physiologically relevant range. A comparison of four series of gelatin
phantom studies demonstrated a positive linear relationship between THz reflectivity and water concentration, with
statistically significant hydration sensitivities (p < .01) ranging between 0.0209 - 0.038% (reflectivity: %hydration). The
THz-phantom interaction is simulated with a three-layer model using the Transfer Matrix Method with agreement in
hydration trends. Having demonstrated the ability to accurately and noninvasively measure water content in tissue
equivalent targets with high sensitivity, reflective THz imaging is explored as a potential tool for early detection and
intervention of corneal pathologies.
Research in THz imaging is generally focused on three primary application areas: medical, security, and nondestructive
evaluation (NDE). While work in THz security imaging and personnel screening is populated by a number of different
active and passive system architectures, research in medical imaging in is generally performed with THz time-domain
systems. These systems typically employ photoconductive or electro-optic source/detector pairs and can acquire depth
resolved data or spectrally resolved pixels by synchronously sampling the electric field of the transmitted/reflected
waveform. While time-domain is a very powerful scientific technique, results reported in the literature suggest that
desired THz contrast in medical imaging may not require the volume of data accessible from time-resolved
measurements and that a simpler direct detection, active technique may be sufficient for specific applications. In this
talk we discuss an active direct detection reflectometer system architecture operating at a center frequency of ~ 525 GHz
that uses a photoconductive source and schottky diode detector. This design takes advantage or radar-like pulse
rectification and novel reflective optical design to achieve high target imaging contrast with significant potential for high
speed acquisition time. Results in spatially resolved hydration mapping of burn wounds are presented and future
outlooks discussed.
Terahertz (THz) sensing has shown potential as a novel imaging modality in medical applications due to
its high water sensitivity. The design of medical THz sensing systems and their successful application to
in vivo settings has attracted recent interest to the field, and highlighted the need for improved
understanding of the interaction of THz waves with biological tissues. This paper explores the modeling
of composite materials which combine strongly-interacting water with weakly-interacting species such as
those that are common to biological tissues. The Bruggeman, Maxwell-Garnett, and power law effective
media models are introduced and discussed. A reflection-mode 100 GHz Gunn diode sensing system was
used to measure the reflectivity of solutions of water and dioxane as a function of relative concentration,
and the results were compared with the predictions of the Maxwell-Garnett, power law, and Bruggeman
mixing theories. The Maxwell-Garnett model fit poorly to experimental data on near-equal mixtures of
water and dioxane and improved when the concentration of water exceeded ~55% or was below ~15%.
The first-order power law model fit poorly to experimental data across the entire range except at nearpure
solutions. Power law models employing 1/2 and 1/3 terms improved goodness of fit, but did not
match the accuracy of the Bruggeman model. The Bruggeman provided the best fit to experimental data
model as compared to Maxwell-Garnett and the power models and accurately predicted the solution
reflectivity through the whole range of concentrations. This analysis suggests that the Bruggeman model
may offer improved accuracy over more conventional dielectric mixing models when developing
simulation tools for THz reflectometry of hydrated biological tissues.
Applications for terahertz (THz) medical imaging have proliferated over the past few years due to advancements in
source/detector technology and vigorous application development. While considerable effort has been applied to
improving source output power and detector sensitivity, significantly less work has been devoted to improving image
acquisition method and time. The majority of THz medical imaging systems in the literature typically acquire pixels by
translating the target of interest beneath a fixed illumination beam. While this single-pixel whiskbroom methodology is
appropriate for in vitro models, it is unsuitable for in vivo large animal and patient imaging due to practical constraints.
This paper presents a scanned beam imaging system based on prior work that enables for reduced image acquisition time
while allowing the source, target and detector to remain stationary. The system employs a spinning polygonal mirror and
a set of high-density polyethylene (HDPE) objective lenses, and operates at a center illumination frequency of 525GHz
with ~125GHz of 3dB bandwidth. The system achieves a focused beam diameter of 1.66mm and a large depth of field of
<25 mm. Images of characterization targets and ex vivo tissue samples are presented and compared to results obtained
with conventional fixed beam scanning systems.
KEYWORDS: Terahertz radiation, Magnetic resonance imaging, Tissues, Skin, In vivo imaging, Reflectivity, Visualization, Injuries, Medical imaging, Natural surfaces
Terahertz (THz) imaging is an expanding area of research in the field of medical imaging due to its high sensitivity to
changes in tissue water content. Previously reported in vivo rat studies demonstrate that spatially resolved hydration
mapping with THz illumination can be used to rapidly and accurately detect fluid shifts following induction of burns
and provide highly resolved spatial and temporal characterization of edematous tissue. THz imagery of partial and
full thickness burn wounds acquired by our group correlate well with burn severity and suggest that hydration
gradients are responsible for the observed contrast. This research aims to confirm the dominant contrast mechanism
of THz burn imaging using a clinically accepted diagnostic method that relies on tissue water content for contrast
generation to support the translation of this technology to clinical application. The hydration contrast sensing
capabilities of magnetic resonance imaging (MRI), specifically T2 relaxation times and proton density values N(H),
are well established and provide measures of mobile water content, lending MRI as a suitable method to validate
hydration states of skin burns. This paper presents correlational studies performed with MR imaging of ex vivo
porcine skin that confirm tissue hydration as the principal sensing mechanism in THz burn imaging. Insights from
this preliminary research will be used to lay the groundwork for future, parallel MRI and THz imaging of in vivo rat
models to further substantiate the clinical efficacy of reflective THz imaging in burn wound care.
Terahertz (THz) hydration sensing and image has been a topic of increased interest recently due largely to improvements
in source and detector technology and the identification of applications where current hydration sensing techniques are
insufficient. THz medical imaging is an expanding field of research and tissue hydration plays a key role in the contrast
observed in THz tissue reflectance and absorbance maps. This paper outlines the most recent results in burn and corneal
imaging where hydration maps were used to assess tissue status. A 3 day study was carried out in rat models where a
THz imaging system was used to assess the severity and extent of burn throughout the first day of injury and at the 24,
48, and 72 hour time points. Marked difference in tissue reflectance were observed between the partial and full
thickness burns and image features were identified that may be used as diagnostic markers for burn severity. Companion
histological analysis performed on tissue excised on Day 3 confirms hypothesized burn severity. The results of these
preliminary animal trials suggest that THz imaging may be useful in burn wound assessment where current clinical
modalities have resolution and/or sensitivity insufficient for accurate diagnostics.
THz and millimeter wave technology have shown the potential to become a valuable
medical imaging tool because of its sensitivity to water and safe, non-ionizing photon
energy. Using the high dielectric constant of water in these frequency bands, reflectionmode
THz sensing systems can be employed to measure water content in a target with
high sensitivity. This phenomenology may lead to the development of clinical systems to
measure the hydration state of biological targets. Such measurements may be useful in
fast and convenient diagnosis of conditions whose symptoms can be characterized by
changes in water concentration such as skin burns, dehydration, or chemical exposure. To
explore millimeter wave sensitivity to hydration, a reflectometry system is constructed to
make water concentration measurements at 100 GHz, and the minimum detectable water
concentration difference is measured. This system employs a 100 GHz Gunn diode
source and Golay cell detector to perform point reflectivity measurements of a wetted
polypropylene towel as it dries on a mass balance. A noise limited, minimum detectable
concentration difference of less than 0.5% by mass can be detected in water
concentrations ranging from 70% to 80%. This sensitivity is sufficient to detect hydration
changes caused by many diseases and pathologies and may be useful in the future as a
diagnostic tool for the assessment of burns and other surface pathologies.
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