Peripheral arterial disease (PAD) affects over 8.5 million people in the United States. Diagnostic tools to identify PAD continue to have low sensitivity for patients with diabetes and/or with poor vascular health in the small vessels of the lower extremities. A handheld device developed in our laboratory may address these limitations. The device combines dynamic vascular optical spectroscopy (DVOS) with pressure sensing to monitor the relationship between applied pressure and blood volume changes in tissues of interest, which is expected to differ between healthy and PAD subjects. Our probe is 20mm in diameter with the bottom face housing two infrared sources (wavelength λ = 780nm and 850nm) and one silicon photodetector located around 10mm from each source. The DVOS system continuously records the reflected light intensity from the local tissue at a frame rate of 10.24 frames per second. Simultaneously, the load applied by the probe to the tissue surface is measured continuously with a force sensor at the same frame rate. During data acquisition, the applied load is gradually increased, resulting in dynamic changes of the monitored DVOS signals. These recorded signals provide information on the response of the local tissue perfusion to changes in applied pressure. Here, we report on a preclinical study monitoring 3 vascular locations in the lower extremities of 3 healthy volunteers. Preliminary results suggest that on average there is a 0.03% change in total hemoglobin concentration per 10 mmHg change in applied pressure. We expect these changes to be significantly smaller in PAD patients.
Monitoring the carotid artery in patients who are at high-risk for stroke is crucial for early detection of abnormalities and may improve personalized, point-of-care diagnostics. We have developed a flexible 3-D printed patch for dynamic optical spectroscopy to evaluate the total blood oxygenation within the carotid artery. Each patch consists of a sensing module and detection module measuring 25 mm × 20 mm and 21 mm × 20 mm, respectively, placed a maximum distance of 32 mm apart. The sensing module contains four sources at wavelengths of 670 nm, 750 nm, 808 nm, and 850 nm placed in a square configuration, and the detection module contains two photodiodes in a parallel orientation. During data acquisition, two probes were applied proximally to both the left and right carotid arteries in the neck, and two probes were also placed proximally to the right and left radial arteries in the wrists. Six healthy participants were instructed to perform breathing exercises, such as a single deep breath, continuous deep breaths, and a timed breath hold, with intervals of routine breathing between each activity. Blood oxygenation was continuously measured during the data acquisition protocol. Our study demonstrated consistent blood oxygen content between the left and right carotid and radial arteries across all breathing exercises. Additionally, during a breath hold, we observed a 0.3% and a 0.1% decrease in oxygen saturation in the radial and carotid arteries, respectively. These findings underscore the system's potential to detect disease-related variations in individual carotid arteries, facilitating early detection.
We have developed an optical imaging system that allows monitoring arthritis in systemic lupus erythematosus (SLE) patients in multiple finger joints simultaneously. This system addresses the need for a low-cost accurate way to quickly assess SLE in a patient friendly manner. system comprises multiple flexible optical bands for each finger. Each band includes eight sets of three light-emitting-diodes (LEDs) (wavelength λ = 880 nm, 660 nm, and 530 nm) and a photodiode and can be wrapped around a proximal inter-phalangeal (PIP) joint allowing for the measurement of reflected and transmitted light from the LEDs by the photodetector. 24 LEDs and 8 detectors combine for a total of 192 measurements per finger per frame, which is acquired at a frame rate of 1 frame per second. We tested the performance of the system in a clinical pilot study comparing the results to an existing single-band system that makes measurements on one PIP joint at a time. During data acquisition, a partial venous inclusion is induced using a blood pressure cuff inflated to the subject’s diastolic blood pressure. Initial results show statistically significant differences between SLE patient and healthy volunteers, agreeing with our previous findings single-band technology.
Peripheral arterial disease (PAD) affects an estimated 8.5 million people in the United States. PAD is caused by atherosclerosis, which is a narrowing of the arteries due to plaque build-up. Patients with a severe presentation of the disease often require a surgical intervention to reopen the arteries and restore blood flow to the affected areas. During the intervention, physicians often monitor the progress of the intervention using contrast angiography. The process requires a contrast agent and high radiation doses. Our lab has proposed the use of dynamic vascular optical spectroscopy (DVOS) as a non-invasive, non-iodizing method to track changes in the arteries during an intervention. In this preliminary study, we found that the DVOS signal changes in response to intervention techniques such as balloon inflations and deflations. For our trial subject, we saw on average a 19.5% change in total hemoglobin concentration (HbT) due to injection of a contrast agent prior to balloon inflation and on average a 26.6% change in HbT due to injection of a contrast agent after a sequence of balloon inflations and deflations. The data suggest that DVOS can monitor vascular health and blood perfusion in arteries in real-time during a surgical intervention.
KEYWORDS: Wound healing, Arteries, Data acquisition, Diseases and disorders, Vascular diseases, Lab on a chip, Blood, Optical spectroscopy, Animal model studies, Optical sensing
SignificanceDue to the persistence of chronic wounds, a second surgical intervention is often necessary for patients with peripheral arterial disease (PAD) within a year of the first intervention. The dynamic vascular optical spectroscopy system (DVOS) may assist physicians in determining patient prognosis only a month after the first surgical intervention.AimWe aim to assess the DVOS utility in characterizing wound healing in PAD patients after endovascular intervention.ApproachThe DVOS used near-infrared light (670 < λ < 850 nm) to record hemodynamic response to a cuff inflation in 14 PAD patients with lower limb ulcers immediately before, immediately after, and at a first follow-up 3 to 4 weeks after intervention. Ankle-brachial index (ABI) and arterial duplex ultrasound (A-DUS) measurements were obtained when possible.ResultsThe total hemoglobin plateau time differed significantly between patients with ulcers that reduced in size (N = 9) and patients with ulcers that did not (N = 5) 3 to 4 weeks after intervention (p value < 0.001). Data correlated strongly (89% sensitivity, 100% specificity, and AUC = 0.96) with long-term wound healing. ABI and A-DUS measurements were not statistically associated with wound healing.ConclusionsThis pilot study demonstrates the potential of the DVOS to aid physicians in giving accurate long-term wound healing prognoses 1 month after intervention.
In this retrospective study, we evaluated imaging data from 65 breast cancer patients that were obtained one to three days before the initiation of neoadjuvant chemotherapy (NAC). Imaging was performed with a dynamic optical tomography breast imaging system (DOTBIS) over the course of a breath hold. From this imaging data, we extracted time-dependent signal traces of the total hemoglobin in the whole volume of the tumor-bearing breast. The inflection point and the slope at the steepest part of the curve were calculated for both the ascending (patient holds her breath) and descending slopes (patient releases her breath and starts breathing normally again). Our results show statistically significant differences in vascular changes between patients with a pathologic complete response (pCR) and non-pCR patients. This suggests that differences in the tumor-bearing breasts of these two patient groups exist even before treatment is started.
This work evaluates changes in features of 3D breast images generated by a so-called dynamic optical tomographic imaging system (DOTBIS) during neoadjuvant chemotherapy (NAC). Images from 23 breast cancer patients were analyzes and correlated with respect to treatment outcome and status of hormone receptors and human epidermal growth factor receptors. Our data shows that the ratio of the mean value of deoxy-hemoglobin (ctHHbN) at two weeks after the first treatment compared to baseline was statistically significantly lower in patients that achieve a pathologic complete response (pCR) (0.77 ± 0.22) as compared to patients with a non-pCR (1.14 ± 0.24, P < .005). These observations indicate that early changes in DOTBIS images can potentially be used to predict breast cancer response to NAC and may allow a better way to customize therapy to HR+/HER2- patients in order to optimize treatment.
Approximately 12 million people in the United States are affected by peripheral artery disease (PAD), characterized by an accumulation of plaque in the arteries of the lower extremities. In advanced stages, treating physicians often recommend a surgical intervention to improve blood flow to the feet. However, about 50% of patients require a second intervention within 12 months. Here we report on the potential of dynamic optical imaging (DOI) to predict the long-term outcome of such surgery. Our DOI system consists of four detection patches, each configured with two SI-detectors and four laser diodes at different wavelengths (678 nm, 780 nm, 808 nm and 850 nm). These patches are placed on four different angiosomes of the foot to record the dynamical responses to inflations and deflations of a thigh cuff. Inflating a cuff causes blood to accumulate in the foot, while deflating the cuff reduces the amount of blood. DOI measurements can be characterized by a response time to cuff inflation (rise time), and a plateau time between cuff inflation and deflation. For this study 16 patients with no previous history of interventions were enrolled, and DOI data was collected before and after the intervention. 4 of the 16 patients needed a second intervention within 6 months. We found a strong correlation between the changes in pre-and post-intervention rise time and the 6 months treatment outcome. A ROC analysis showed that it was possible to categorize outcomes correctly with an AUC (Area Under the Curve) of about 83%, and corresponding specificity of 100% and sensitivity of 75%.
Ulcers are a common occurrence in diabetic patients with peripheral arterial disease (PAD). Early prognosis of ulcer healing can help patients avoid prolonged pain and future amputation by alerting physicians to intervention efficacy. However, monitoring of ulcers and predicting intervention success remains a challenge. We have developed a so-called vascular optical tomography imaging system (VOTIS) to address this problem. The system consists of patches with infrared sources and silicon photodiodes. The patches are placed on areas of interest in the lower extremities and light attenuation data is obtained at multiple frames per second. During data acquisition, a thigh cuff is inflated and deflated to affect blood flow to the lower extremities, resulting in dynamic changes of the recorded signals. Features such as maximum change in total absorption, response time to cuff inflation, and plateau time (PT) between cuff inflation and deflation can be extracted. Here we report on a pilot study of 10 PAD patients (70% diabetic) with ulcers, who had a surgical intervention to improve blood flow. VOTIS measurements were obtained immediately after the intervention, and again three weeks later. Prognosis was determined from EHR and classified as improvement (N=7) - when an ulcer reduces in size - or no improvement (N=3). In an ROC analysis, the VOTIS-derived biomarker PT demonstrated high classification potential (Sn=86%, Sp=100%, AUC=0.95).
In patients with peripheral artery disease (PAD), plaque is accumulating in arteries which leads to a reduction in blood supply to the extremities. In advanced stages, surgical intervention is required to reopen the arteries and restore limb perfusion. During this procedure, it is important to correctly identify which areas of the foot lack perfusion. The standard procedure to obtain this information is X-ray angiography, which is performed repeatedly during the intervention. The disadvantage of this procedure is the relatively high radiation dose and extensive use of contrast agents. To reduce this problem, we evaluate in this pilot study (involving 4 patients) the ability of vascular optical spectroscopy (VOS) to detect the X-ray contrast agent permeating the angiosomes in the foot. We show that the contrast agent can be detected by optical measurements as it temporarily replaces the blood in the different angiosomes, which leads to a 1% to 5% change in the signal amplitude. In addition, measurements of the blood pooling in the foot were performed before the intervention. We observed a strong correlation between the angiosomes that showed a worsen state in the measurement done before the intervention and the absence of angiographic contrast agent signals during the intervention itself. Among the 4 patients monitored, 2 showed a response to the contrast agent in their angiosomes and they corresponded to the patients with a relatively better perfusion in the pre-intervention measurements.
Optical imaging techniques have emerged as a possible alternative to predict pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). Our team developed a so-called diffuse optical tomographic breast imaging system (DOTBIS) which does not require the use of contrast agents or compression and enables imaging of the whole breast volume using low intensity near infrared light capable to measure tissue concentration of total hemoglobin (ctTHb). In this retrospective study, we evaluated 55 stage II-III BC patients in the neoadjuvant setting who received weekly paclitaxel x 12, followed by dose-dense adriamycin/cyclophosphamide every 2 weeks x 4. DOTBIS images were acquired from the patient whole breast volume at 6 different time points: at baseline (TP0); two weeks after the first taxane infusion (TP1); after four infusions of taxane (TP2); at the end of the taxane regimen and before starting AC cycle (TP3); after two AC infusions (TP4); and at the end of NAC and before surgery (TP5). In order to evaluate whether pCR status influences the change of ctTHb over time, we designed a multilevel mixed-effect model. pCR was defined as no invasive tumor cells from the breast and axillary tissue at surgery (ypT0 ypN0). Changes in ctTHb levels compared to baseline (TP0) values were statistically significant different between pCR (n = 20) and non-pCR (n=35) at all time points except at TP1 and at the end of the taxane cycle (TP3).
It is estimated that in the USA 1.5 million people suffer from systemic lupus erythematosus (SLE). This autoimmune disease often involves joints, and more than 90% of those affected will experience joint pain, stiffness and swelling at some time during the course of their illness. It is currently difficult to both diagnose and estimate the severity of lupus, because signs and symptoms vary considerably from person to person and there is no single diagnostic test for it. We explored the clinical utility of frequency-domain optical tomography (FDOT) to distinguish finger joints affected by SLE from healthy ones of volunteers. The proximal interphalangeal joints (PIP) of the 2nd to the 5th digit from both hands of 10 SLE patients and 4 healthy volunteers were examined. This resulted in a total of 80 joints affected by SLE and 32 healthy joints. The FDOT system was operated at a frequency of 600MHz. The laser diode employed produced a 1-mm beam at 670nm light, which was guided to 11 positions on the top of the PIP joints. At every location, using an exposure time of 80 ms for 16 phase steps, transmission images were acquired using an ICCD camera. First results of the analysis of the amplitude and phase shift of the images acquired show a sensitivity of 100% and a specificity of 80% to distinguish between joints of healthy volunteers and SLE patients.
Peripheral artery disease (PAD) affects approximately 12 million people in the US. The disease is caused by an accumulation of plaque in arteries, which leads to stenosis and reduction in blood flow. In advanced cases, surgery or endovascular interventions are required to re-establish blood flow to the extremities. In over 40% of these cases a second intervention is required within 12 months. Therefore, accurate monitoring the blood flow in the feet of these patients is crucial. In this study, dynamic vascular optical spectroscopy was used to assess perfusion in 4 different angiosomes of 25 patients who underwent a surgical intervention. Imaging was performed just before the intervention, 4 hours later and 1 month later. Each optical spectroscopy session consisted in inflating a thigh pressure cuff to 60 mmHg, maintaining the pressure for 60 seconds and releasing it, then repeating the procedure while inflating the cuff to 100 mmHg. Totalhemoglobin [THb] time traces for each angiosome were calculated. We found a strong correlation between the dynamic shapes of the THb-signals obtained before the intervention, 3 hours after the intervention and 1 month later and the longterm outcome of the procedure.
KEYWORDS: Luminescence, Principal component analysis, Tomography, Tumors, Data modeling, Animal model studies, Absorption, 3D modeling, Tissues, Bioluminescence
We present here a new dynamic fluorescence tomographic model that makes use of spatial-temporal constraints in order to reconstruction both fluorescent biomarkers and anatomical structure simultaneously within reasonable accuracy. A discrete cosine transformation (DCT) is used to compress images in the spatial and temporal domains. The appropriate set of dominant DCT components is found from analyzing mouse internal structure and measurements of dynamic time traces of fluorescent signals. These sought characteristic functions are used later as spatial-temporal constraints in the reconstruction, which can aid to bring internal structure of major organs as well as fluorescent biomarkers into the reconstruction image. We use radiative transfer equation (RTE) as a light propagation model that provides more accurate predictions of light distribution in small geometries and high absorbing media. In addition, the reconstructed tomographic images are processed with principal components analysis (PCA) in order to differential between various regions with different functional kinetic behaviors. The performance of this new method is tested using a dynamic data of fluorescent signals resulting from changes in tumor vasculature in response to anti-angiogenesis, and the preliminary results have been presented to show the potential of the proposed dynamic fluorescence tomographic model.
The aim of this study was to investigate the optical chemotherapy changes induced by neoadjuvant chemotherapy (NAC) in PgR-positive and PgR-negative breast cancer subtypes using a diffuse optical tomographic breast imaging system (DOTBIS). ctTHb reduction in the tumor volume was greater for patients with PgR-negative, a statistically significant difference of 48.91μM, p = .022, which suggest that PgR-negative tumors are generally less resistant to NAC. These observations indicate that PgR negativity may be combined to optically derived biomarkers for predicting pCR during neoadjuvant chemotherapy.
We have developed a system of flexible optical imaging bands that can be used to assess the effects of systemic lupus erythematosus (SLE) on finger joints. Each imaging band consists of four pairs of light sources and a photodetector. The light sources contain three different light emitting diodes with wavelengths of 530 nm, 655 nm and 940 nm. Two of these imaging bands are wrapped around the proximal interphalangeal (PIP) joints of the index-, middle-, and ringfingers. The imaging bands gather transmitted and reflected light intensities from the tissues for ~ 4 minutes including two venous occlusions. This results in hemodynamic time traces for all source-detector pairs. From theses traces a rise, plateau, and fall time are calculated. We found that, on average, signals obtained from SLE patients displayed a shorter rise time and longer plateau time as compared to signals from healthy controls. Performing a two-dimensional linear discriminant analysis on the rise and plateau times, we obtained the best specificity of 89% and the best sensitivity of 76 %. Area under the receiver operating characteristic (ROC) curve is 0.86.
Peripheral Arterial Disease (PAD) is caused by a reduction of the internal diameters of the arteries in the upper or lower extremities mainly due to atherosclerosis. If not treated, its worsening may led to a complete occlusion, causing the death of the cells lacking proper blood supply, followed by gangrene that may require chirurgical amputation. We have recently performed a clinical study in which good sensitivities and specificities were achieved with dynamic diffuse optical tomography. To gain a better understanding of the physiological foundations of many of the observed effects, we started to develop a mathematical model for PAD. The model presented in this work is based on a multi-compartment Windkessel model, where the vasculature in the leg and foot is represented by resistors and capacitors, the blood pressure with a voltage drop, and the blood flow with a current. Unlike existing models, the dynamics induced by a thigh-pressure-cuff inflation and deflation during the measurements are taken into consideration. This is achieved by dynamically varying the resistances of the large veins and arteries. By including the effects of the thigh-pressure cuff, we were able to explain many of the effects observed during our dynamic DOT measurements, including the hemodynamics of oxy- and deoxy-hemoglobin concentration changes. The model was implemented in MATLAB and the simulations were normalized and compared with the blood perfusion obtained from healthy, PAD and diabetic patients. Our preliminary results show that in unhealthy patients the total system resistance is sensibly higher than in healthy patients.
Dynamic optical tomographic imaging has shown promise in diagnosing and monitoring peripheral arterial disease
(PAD), which affects 8 to 12 million in the United States. PAD is the narrowing of the arteries that supply blood to the
lower extremities. Prolonged reduced blood flow to the foot leads to ulcers and gangrene, which makes placement of
optical fibers for contact-based optical tomography systems difficult and cumbersome. Since many diabetic PAD
patients have foot wounds, a non-contact interface is highly desirable. We present a novel non-contact dynamic
continuous-wave optical tomographic imaging system that images the vasculature in the foot for evaluating PAD. The
system images at up to 1Hz by delivering 2 wavelengths of light to the top of the foot at up to 20 source positions
through collimated source fibers. Transmitted light is collected with an electron multiplying charge couple device
(EMCCD) camera. We demonstrate that the system can resolve absorbers at various locations in a phantom study and
show the system’s first clinical 3D images of total hemoglobin changes in the foot during venous occlusion at the thigh.
Our initial results indicate that this system is effective in capturing the vascular dynamics within the foot and can be used
to diagnose and monitor treatment of PAD in diabetic patients.
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