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Significance: There is an essential need to develop wearable multimodality technologies that can continuously measure both blood flow and oxygenation in deep tissues to investigate and manage various vascular/cellular diseases. Aim: To develop a wearable dual-wavelength diffuse speckle contrast flow oximetry (DSCFO) for simultaneous measurements of blood flow and oxygenation variations in deep tissues. Approach: A wearable fiber-free DSCFO probe was fabricated using 3D printing to confine two small near-infrared laser diodes and a tiny CMOS camera in positions for DSCFO measurements. The spatial diffuse speckle contrast and light intensity measurements at the two different wavelengths enable quantification of tissue blood flow and oxygenation, respectively. The DSCFO was first calibrated using tissue phantoms and then tested in adult forearms during artery cuff occlusion. Results: Phantom tests determined the largest effective source–detector distance (15 mm) and optimal camera exposure time (10 ms) and verified the accuracy of DSCFO in measuring absorption coefficient variations. The DSCFO detected substantial changes in forearm blood flow and oxygenation resulting from the artery occlusion, which meet physiological expectations and are consistent with previous study results. Conclusions: The wearable DSCFO may be used for continuous and simultaneous monitoring of blood flow and oxygenation variations in freely behaving subjects.

This paper summarizes our recent progresses in developing and applying an innovative noncontact, multiscale, speckle contrast diffuse correlation tomography (scDCT) for rapid and high-density 3D imaging of tissue blood flow distributions in animals and humans.

Continuous and longitudinal monitoring of cerebral blood flow (CBF) in animal models provides information for studying the mechanisms and interventions of various cerebral diseases. Since anesthesia may affect brain hemodynamics, researchers have been seeking wearable devices for use in conscious animals. We present a wearable diffuse speckle contrast flowmeter (DSCF) probe for monitoring CBF variations in mice. The DSCF probe consists of a small low-power near-infrared laser diode as a point source and an ultrasmall low-power CMOS camera as a two-dimensional detector array, which can be affixed on a mouse head. The movement of red blood cells in brain cortex (i.e., CBF) produces spatial fluctuations of laser speckles, which are captured by the camera. The DSCF system was calibrated using tissue phantoms and validated in a human forearm and mouse brains for continuous monitoring of blood flow increases and decreases against the established technologies. Significant correlations were observed among these measurements ( $\text{R}^{2}\geq \,{\text{0.80}}$ , $\text{p} ). This small fiberless probe has the potential to be worn by a freely moving conscious mouse. Moreover, the flexible source–detector configuration allows for varied probing depths up to ${\sim\text{8 mm}}$ , which is sufficient for transcranially detecting CBF in the cortices of rodents and newborn infants.

Introduction: Tissue injuries are often associated with abnormal blood flow (BF). The ability to assess BF distributions in injured tissues enables objective evaluation of interventions and holds the potential to improve the acute management of these injuries on battlefield. Materials and Methods: We have developed a novel speckle contrast diffuse correlation tomography (scDCT) system for noncontact 3D imaging of tissue BF distributions. In scDCT, a galvo mirror was used to remotely project near-infrared point light to different source positions and an electron multiplying charge-coupled-device was used to detect boundary diffuse speckle contrasts. The normalized boundary data were then inserted into a modified Near-Infrared Fluorescence and Spectral Tomography program for 3D reconstructions of BF distributions. This article reports the first application of scDCT for noncontact 3D imaging of BF distributions in burn wounds. Results: Significant lower BF values were observed in the burned areas/volumes compared to surrounding normal tissues. Conclusions: The unique noncontact 3D imaging capability makes the scDCT applicable for intraoperative assessment of burns/wounds, without risk of infection and without interfering with sterility of the surgical field. The portable scDCT device holds the potential to be used by surgeons in combat surgical hospitals to improve the acute management of battlefield burn injuries.

OBJECTIVE Blood flow is one such available observable promoting a wealth of physiological insight both individually and in combination with other metrics. APPROACH Near-infrared diffuse correlation spectroscopy (DCS) and, to a lesser extent, diffuse correlation tomography (DCT), have increasingly received interest over the past decade as noninvasive methods for tissue blood flow measurements and imaging. DCS/DCT offers several attractive features for tissue blood flow measurements/imaging such as noninvasiveness, portability, high temporal resolution, and relatively large penetration depth (up to several centimeters). MAIN RESULTS This review first introduces the basic principle and instrumentation of DCS/DCT, followed by presenting clinical application examples of DCS/DCT for the diagnosis and therapeutic monitoring of diseases in a variety of organs/tissues including brain, skeletal muscle, and tumor. SIGNIFICANCE Clinical study results demonstrate technical versatility of DCS/DCT in providing important information for disease diagnosis and intervention monitoring.

We modified and adapted a novel noncontact speckle contrast diffuse correlation tomography (scDCT) system, developed in our laboratory, for noninvasive 3D imaging of blood flow distributions in small animals and large human tissue volumes. The new system has the flexibility of selecting small and large regions of interest (ROIs) with different imaging depths for the use in both the small mouse head and large human mastectomy skin flaps. The capability of the upgraded scDCT system was demonstrated by continuous imaging of cerebral blood flow (CBF) changes in a small mouse head during sequential common carotid artery ligations and blood flow distributions in human mastectomy skin flaps during surgery. As expected, arterial occlusions resulted in substantial CBF decreases in deep brain tissues of the mouse. Spatial heterogeneity existed, and lower blood flow values were observed around the incision area of mastectomy skin flaps. The noncontact scDCT system with flexible ROIs and imaging depths has the potential to be used in many preclinical and clinical settings for noninvasive assessment of tissue hemodynamics and viability.

The objective of this study was to adapt a novel near-infrared diffuse correlation spectroscopy (DCS) flow-oximeter for simultaneous and continuous monitoring of relative changes in cerebral blood flow (rCBF) and cerebral oxygenation (i.e. oxygenated/deoxygenated/total hemoglobin concentration: Δ[HbO2]/Δ[Hb]/ΔTHC) during overnight nocturnal polysomnography (NPSG) diagnostic test for obstructive sleep apnea-hypopnea (OSAH). A fiber-optic probe was fixed on subject's frontal head and connected to the DCS flow-oximeter through a custom-designed fiber-optic connector, which allowed us to easily connect/detach the optical probe from the device when the subject went to bathroom. To minimize the disturbance to the subject, the DCS flow-oximeter was remotely operated by a desktop located in the control room. The results showed that apneic events caused significant variations in rCBF and ΔTHC. Moreover, the degrees of variations in all measured cerebral variables were significantly correlated with the severity of OSAH as determined by the apnea-hypopnea index (AHI), demonstrating the OSAH influence on both CBF and cerebral oxygenation. Large variations in arterial blood oxygen saturation (SaO2) were also found during OSAH. Since frequent variations/disturbances in cerebral hemodynamics may adversely impact brain function, future study will investigate the correlations between these cerebral variations and functional impairments for better understanding of OSAH pathophysiology.

Radiation therapy is a principal modality for head and neck cancers and its efficacy depends on tumor hemodynamics. Our laboratory developed a hybrid diffuse optical instrument allowing for simultaneous measurements of tumor blood flow and oxygenation. In this study, the clinically involved cervical lymph node was monitored by the hybrid instrument once a week over the treatment period of seven weeks. Based on treatment outcomes within one year, patients were classified into a complete response group (CR) and an incomplete response group (IR) with remote metastasis and/or local recurrence. A linear mixed models was used to compare tumor hemodynamic responses to the treatment between the two groups. Interestingly, we found that human papilloma virus (HPV-16) status largely affected tumor hemodynamic responses. For HPV-16 negative tumors, significant differences in blood flow index (BFI, p = 0.007) and reduced scattering coefficient (μs’, p = 0.0005) were observed between the two groups; IR tumors exhibited higher μs’ values and a continuous increase in BFI over the treatment period. For HPV-16 positive tumors, oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) were significant different (p = 0.003 and 0.01, respectively); IR group showed lower [HbO2] and StO2. Our results imply HPV-16 negative tumors with higher density of vasculature (μs’) and higher blood flow show poor responses to radiotherapy and HPV-16 positive tumors with lower tissue oxygenation level (lower StO2 and [HbO2]) exhibit poor treatment outcomes. Our diffuse optical measurements show the great potential for early prediction of radiotherapy in head and neck cancers.

This study explored using a novel diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively monitor blood flow and oxygenation changes in head and neck tumors during radiation delivery. A fiber-optic probe connected to the DCS flow-oximeter was placed on the surface of the radiologically/clinically involved cervical lymph node. The DCS flow-oximeter in the treatment room was remotely operated by a computer in the control room. From the early measurements, abnormal signals were observed when the optical device was placed in close proximity to the radiation beams. Through phantom tests, the artifacts were shown to be caused by scattered x rays and consequentially avoided by moving the optical device away from the x-ray beams. Eleven patients with head and neck tumors were continually measured once a week over a treatment period of seven weeks, although there were some missing data due to the patient related events. Large inter-patient variations in tumor hemodynamic responses were observed during radiation delivery. A significant increase in tumor blood flow was observed at the first week of treatment, which may be a physiologic response to hypoxia created by radiation oxygen consumption. Only small and insignificant changes were found in tumor blood oxygenation, suggesting that oxygen utilizations in tumors during the short period of fractional radiation deliveries were either minimal or balanced by other effects such as blood flow regulation. Further investigations in a large patient population are needed to correlate the individual hemodynamic responses with the clinical outcomes for determining the prognostic value of optical measurements.

Noncontact diffuse correlation tomography (ncDCT) is an emerging technology for 3D imaging of deep tissue blood flow distribution without distorting hemodynamic properties. To adapt the ncDCT for imaging in vivo breast tumors, we designed a motorized ncDCT probe to scan over the breast surface. A computer-aided design (CAD)-based approach was proposed to create solid volume mesh from arbitrary breast surface obtained by a commercial 3D camera. The sources and detectors of ncDCT were aligned on the breast surface through ray tracing to mimic the ncDCT scanning with CAD software. The generated breast volume mesh along with the boundary data of ncDCT at the aligned source and detector pairs were used for finite-element-method-based flow image reconstruction. We evaluated the accuracy of source alignments on mannequin and human breasts; largest alignment errors were less than 10% in both tangential and radial directions of scanning. The impact of alignment errors (assigned 10%) on the tumor reconstruction was estimated using computer simulations. The deviations of simulated tumor location and blood flow contrast resulted from the alignment errors were 0.77 mm (less than the node distance of 1 mm) and 1%, respectively, which result in minor impact on flow image reconstruction. Finally, a case study on a human breast tumor was conducted and a tumor-to-normal flow contrast was reconstructed, demonstrating the feasibility of ncDCT in clinical application.

Our first step to adapt our recently developed noncontact diffuse correlation tomography (ncDCT) system for three-dimensional (3-D) imaging of blood flow distribution in human breast tumors is reported. A commercial 3-D camera was used to obtain breast surface geometry, which was then converted to a solid volume mesh. An ncDCT probe scanned over a region of interest on the mesh surface and the measured boundary data were combined with a finite element framework for 3-D image reconstruction of blood flow distribution. This technique was tested in computer simulations and in vivo human breasts with low-grade carcinoma. Results from computer simulations suggest that relatively high accuracy can be achieved when the entire tumor is within the sensitive region of diffuse light. Image reconstruction with a priori knowledge of the tumor volume and location can significantly improve the accuracy in recovery of tumor blood flow contrasts. In vivo imaging results from two breast carcinomas show higher average blood flow contrasts (5.9- and 10.9-fold) in the tumor regions compared to the surrounding tissues, which are comparable with previous findings using diffuse correlation spectroscopy. The ncDCT system has the potential to image blood flow distributions in soft and vulnerable tissues without distorting tissue hemodynamics.

Occlusion calibrations and gating techniques have been recently applied by our laboratory for continuous and absolute diffuse optical measurements of forearm muscle hemodynamics during handgrip exercises. The translation of these techniques from the forearm to the lower limb is the goal of this study as various diseases preferentially affect muscles in the lower extremity. This study adapted a hybrid near-infrared spectroscopy and diffuse correlation spectroscopy system with a gating algorithm to continuously quantify hemodynamic responses of medial gastrocnemius during plantar flexion exercises in 10 healthy subjects. The outcomes from optical measurement include oxy-, deoxy-, and total hemoglobin concentrations, blood oxygen saturation, and relative changes in blood flow (rBF) and oxygen consumption rate (rV˙O2). We calibrated rBF and rV˙O2 profiles with absolute baseline values of BF and V˙O2 obtained by venous and arterial occlusions, respectively. Results from this investigation were comparable to values from similar studies. Additionally, significant correlation was observed between resting local muscle BF measured by the optical technique and whole limb BF measured concurrently by a strain gauge venous plethysmography. The extensive hemodynamic and metabolic profiles during exercise will allow for future comparison studies to investigate the diagnostic value of hybrid technologies in muscles affected by disease.

We report a novel noncontact diffuse correlation spectroscopy flow-oximeter for simultaneous quantification of relative changes in tissue blood flow (rBF) and oxygenation (Δ[oxygenation]). The noncontact probe was compared against a contact probe in tissue-like phantoms and forearm muscles (n = 10), and the dynamic trends in both rBF and Δ[oxygenation] were found to be highly correlated. However, the magnitudes of Δ[oxygenation] measured by the two probes were significantly different. Monte Carlo simulations and phantom experiments revealed that the arm curvature resulted in a significant underestimation (~−20%) for the noncontact measurements in Δ[oxygenation], but not in rBF. Other factors that may cause the residual discrepancies between the contact and noncontact measurements were discussed, and further comparisons with other established technologies are needed to identify/quantify these factors. Our research paves the way for noncontact and simultaneous monitoring of blood flow and oxygenation in soft and vulnerable tissues without distorting tissue hemodynamics.

This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs′) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.

We report a low-cost compact diffuse speckle contrast flowmeter (DSCF) consisting of a small laser diode and a bare charge-coupled-device (CCD) chip, which can be used for contact measurements of blood flow variations in relatively deep tissues (up to ∼ 8 mm). Measurements of large flow variations by the contact DSCF probe are compared to a noncontact CCD-based diffuse speckle contrast spectroscopy and a standard contact diffuse correlation spectroscopy in tissue phantoms and a human forearm. Bland–Altman analysis shows no significant bias with good limits of agreement among these measurements: 96.5%±2.2% (94.4% to 100.0%) in phantom experiments and 92.8% in the forearm test. The relatively lower limit of agreement observed in the in vivo measurements (92.8%) is likely due to heterogeneous reactive responses of blood flow in different regions/volumes of the forearm tissues measured by different probes. The low-cost compact DSCF device holds great potential to be broadly used for continuous and longitudinal monitoring of blood flow alterations in ischemic/hypoxic tissues, which are usually associated with various vascular diseases.

Near-infrared (NIR) diffuse correlation spectroscopy (DCS) flowmeter is an emerging technique for measurement of deep tissue blood flow (up to centimeters). NIR spectroscopy (NIRS) can be used for quantification of tissue oxygenation. The combination of DCS tissue-flowmeter and NIRS tissue-oximeter allows for simultaneously quantifying tissue blood flow and oxygenation in deep tissues. A portable DCS flow-oximeter has also been developed for the measurement of relative changes of tissue blood flow and oxygenation. The novel DCS flow-oximeter employs a new design with significantly less cost (1/2), smaller size (1/5), simpler construction and easier operation compared to the hybrid instruments. Application examples in surgical rooms have shown that DCS-based techniques have high sensitivity to detect tissue hemodynamic changes in clinics. It is expected that with more clinical applications, DCS technologies will emerge rapidly as the technique of choice for clinical investigation of diseases and treatment responses.

Intraoperative monitoring of cerebral hemodynamics during carotid endarterectomy (CEA) provides essential information for detecting cerebral hypoperfusion induced by temporary internal carotid artery (ICA) clamping and post-CEA hyperperfusion syndrome. This study tests the feasibility and sensitivity of a novel dual-wavelength near-infrared diffuse correlation spectroscopy technique in detecting cerebral blood flow (CBF) and cerebral oxygenation in patients undergoing CEA. Two fiber-optic probes were taped on both sides of the forehead for cerebral hemodynamic measurements, and the instantaneous decreases in CBF and electroencephalogram (EEG) alpha-band power during ICA clamping were compared to test the measurement sensitivities of the two techniques. The ICA clamps resulted in significant CBF decreases (-24.7 ± 7.3%) accompanied with cerebral deoxygenation at the surgical sides (n = 12). The post-CEA CBF were significantly higher (+43.2 ± 16.9%) than the pre-CEA CBF. The CBF responses to ICA clamping were significantly faster, larger and more sensitive than EEG responses. Simultaneous monitoring of CBF, cerebral oxygenation and EEG power provides a comprehensive evaluation of cerebral physiological status, thus showing potential for the adoption of acute interventions (e.g., shunting, medications) during CEA to reduce the risks of severe cerebral ischemia and cerebral hyperperfusion syndrome.

Increase in tissue blood flow is one of the most acknowledged potential effects of massage; however, actual research studies examining this phenomenon are inconsistent and inconclusive. One possible reason for continued uncertainty regarding this topic is methodology, specifically how tissue blood flow is measured because limitations exist in previously utilized technologies. Near-infrared spectroscopy (NIRS) affords massage researchers a versatile and non-invasive measurement option by providing dynamic information on oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, and blood oxygen saturation in deep tissue. Near-infrared diffuse correlation spectroscopy (DCS) is an innovative technique for continuous non-invasive measurement of blood flow in deep tissue. The combination of these two technologies has resulted in a novel hybrid diffuse optical instrument for simultaneous measurement of limb muscle blood flow and oxygenation. The purposes of this short report are to review previous blood flow measurement techniques and limitations in massage therapy research, introduce a novel hybrid near-infrared diffuse optical instrument that addresses previous limitations in the assessment of hemodynamic properties, outline a proposed massage therapy pilot study utilizing the novel measurement technology, and present sample data from a pilot participant using the introduced novel technology.

A portable diffuse optical tissue flow-oximeter has been developed for evaluation of revascularization effects on ischemic muscle blood flow and oxygenation. The revascularization repairs of macro-circulation result in acute blood flow improvements in muscle microvasculature.

Four very low birth weight, very premature infants were monitored during a 12 degrees postural elevation using diffuse correlation spectroscopy (DCS) to measure microvascular cerebral blood flow (CBF) and transcranial Doppler ultrasound (TCD) to measure macrovascular blood flow velocity in the middle cerebral artery. DCS data correlated significantly with peak systolic, end diastolic, and mean velocities measured by TCD (p(A) =0.036, 0.036, 0.047). Moreover, population averaged TCD and DCS data yielded no significant hemodynamic response to this postural change (p0.05). We thus demonstrate feasibility of DCS in this population, we show correlation between absolute measures of blood flow from DCS and blood flow velocity from TCD, and we do not detect significant changes in CBF associated with a small postural change (12 degrees ) in these patients.

Diffuse optical methods were used to monitor two different therapies in K1735 malignant mouse melanoma tumor models: anti-vascular therapy and radiation therapy. Anti-vascular therapy induced acute variation in hemodynamic parameters within an hour, and radiation therapy induced longitudinal changes within 2 weeks. During anti-vascular therapy, the drug Combretastatin A-4 3-O-Phosphate (CA4P, 2.5 mg/200 mul PBS/mouse) significantly decreased tissue blood flow (65%) and blood oxygenation (38%) one hour after injection. In the longitudinal study, single-fraction ionizing radiation (12 Gy x 1) induced significant reduction of tissue blood flow (36%) and blood oxygenation (24%) 14 days after radiation. The results correlated well with contrast enhanced ultrasound, tumor histology, and a nitroimidazole hypoxia marker (EF5). The research provides further evidence that noninvasive diffuse optical spectroscopies can be useful tools for monitoring cancer therapy in vivo.

We combine diffuse optical spectroscopy DOS and dif- fuse correlation spectroscopy DCS to noninvasively monitor early hemodynamic response to neoadjuvant chemotherapy in a breast cancer patient. The potential for early treatment monitoring is dem- onstrated. Within the first week of treatment day 7 DOS revealed significant changes in tumor/normal contrast compared to pretreat- ment day 0 tissue concentrations of deoxyhemoglobin rctHHbT/N =69±21%, oxyhemoglobin rctO2HbT/N=73±25%, total hemo- globin rctTHbT/N=72±17%, and lipid concentration rctLipidT/N =116±13%. Similarly, DCS found significant changes in tumor/ normal blood flow contrast rBFT/N=75±7%on day 7 with respect to day 0. Our observations suggest the combination of DCS and DOS enhances treatment monitoring compared to either technique alone. The hybrid approach also enables construction of indices reflecting tissue metabolic rate of oxygen, which may provide new insights about therapy mechanisms. © 2007 Society of Photo-Optical Instrumentation Engi

A multi-modal diffuse optical instrument has been developed for real-time monitoring of tumor blood flow and oxygenation during prostate photodynamic therapy. Ultimate goal is to correlate those hemodynamic responses with patient outcomes.

We have employed near-infrared optical methods to mea- sure noninvasively the dynamics of muscle blood flow and oxygen saturation (StO2) during cuff occlusion and plantar flexion exercise. Relative muscle oxygen consumption (rVO2) was also computed from these data. Diffuse correlation spectroscopy provides information about blood flow, and diffuse reflectance spectroscopy provides infor- mation about blood oxygenation. Ten healthy subjects and one pa- tient with peripheral arterial disease (PAD) were studied during 3-min arterial cuff occlusion of arm and leg, and during 1-min plantar flex- ion exercise. Signals from different layers (cutaneous tissues and muscles) during cuff occlusion were differentiated, revealing strong hemodynamic responses from muscle layers. During exercise in healthy legs, the observed ;4.7 fold increase in relative blood flow (rBF) was significantly lower than the corresponding increase in rVO2 (;7 fold). The magnitudes of rBF and rVO2 during exercise in the PAD patient were ;1/2 of the healthy controls, and the StO2 recovery time was twice that of the controls. The hybrid instrument improves upon current technologies for measuring muscle responses by simul- taneously measuring rBF and StO2 . The instrument thus provides a method for evaluation of microcirculation and muscle metabolism in patients with vascular diseases. © 2005 Society of Photo-Optical Instrumentation

Purpose: To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy. Experimental Design: Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2). Results: DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average ± SE: 168.1 ± 39.5%) and subsequent decrease (59.2 ± 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute−1) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2 = 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2 = 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P ≤ 0.015) of treatment durability. Conclusion: These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.

Laser-speckle flowmetry was used to characterize activation flow coupling after electrical somatosensory stimulation of forepaw and hindpaw in the rat. Quantification of functional activation was made with high transverse spatial (μm) and temporal (msec) resolution. Different activation levels and duration of stimulation were quantitatively investigated, and were in good agreement with previous laser-Doppler measurements. Interestingly, the magnitude but not the overall shape of the response was found to scale with stimulus amplitude and the distance from the activation centroid. The results provide new insights about the spatial characteristics of cerebral blood flow response to functional activation, and the method should lead to improved understanding of the coupling of neuronal activity and hemodynamics under normal and pathologic conditions.

Two near-infrared diffuse spectroscopies were used to simultaneously measure the blood flow and oxygenation in human skeletal muscles. The hemodynamics of nine healthy-volunteers and one PVD-patient during arterial cuff-occlusion and plantar-flexion exercise were characterized.

Measurement of concentration, oxygenation, and flow characteristics of blood cells can reveal information about tissue metabolism and functional heterogeneity. An improved multifunctional hybrid system has been built on the basis of our previous hybrid instrument that combines two near-infrared diffuse optical techniques to simultaneously monitor the changes of blood flow, total hemoglobin concentration (THC) and blood oxygen saturation (StO2). Diffuse correlation spectroscopy (DCS) monitors blood flow (BF) by measuring the optical phase shifts caused by moving blood cells, while diffuse photon density wave spectroscopy (DPDW) measures tissue absorption and scattering. Higher spatial resolution, higher data acquisition rate and higher dynamic range of the improved system allow us to monitor rapid hemodynamic changes in rat brain and human muscles. We have designed two probes with different source-detector pairs and different separations for the two types of experiments. A unique non-contact probe mounted on the back of a camera, which allows continuous measurements without altering the blood flow, was employed to in vivo monitor the metabolic responses in rat brain during KCl induced cortical spreading depression (CSD). A contact probe was used to measure changes of blood flow and oxygenation in human muscle during and after cuff occlusion or exercise, where the non-contact probe is not appropriate for monitoring the moving target. The experimental results indicate that our multifunctional hybrid system is capable of in vivo and non-invasive monitoring of the hemodynamic changes in different tissues (smaller tissues in rat brain, larger tissues in human muscle) under different conditions (static versus moving). The time series images of flow during CSD obtained by our technique revealed spatial and temporal hemodynamic changes in rat brain. Two to three fold longer recovery times of flow and oxygenation after cuff occlusion or exercise from calf flexors in a patient with peripheral vascular disease (PVD) were found.

Changes in blood flow and oxygenation during and after PDT provide information about tumor vessel and cellular damage. The characterization of these changes may improve our understanding of PDT mechanisms and help predict treatment efficacy. We have designed a hybrid system that can non-invasively measure in vivo hemodynamic changes and provide independent information about tumor oxygenation and blood flow. Diffuse correlation spectroscopy (DCS) monitors blood flow by measuring the optical phase shifts caused by moving blood cells, while diffuse photon density wave (DPDW) spectroscopy measures tissue absorption and scattering. When mounted on a camera, our unique probe allows non-contact measurements that avoid compressing the tumor and altering blood flow. An optical filter mounted in front of the camera lens cut off light below 650nm, which allowed monitoring of blood flow during PDT. The utility of the hybrid system was demonstrated by monitoring the hemodynamic changes during and after PDT in mice bearing the experimental radiation-induced fibrosarcoma (RIF). For the first time, we non-invasively and continually monitored the in vivo flow changes during PDT. Relative oxygen consumption was calculated using flow values measured by DCS and oxygenation measured by a broadband absorption spectrometer. During PDT an initial rapid increase in blood flow was found, followed by a decrease and slow recovery. After PDT, substantial and continued reductions in blood saturation, blood flow and oxygen consumption were found after 3 hours, suggesting that permanent damage to tumor cells and blood vessels had occurred. The comparison of flow values after PDT as measured by DCS and by Power Doppler ultrasound (CWFA) demonstrated that both techniques non-invasively detected similar global changes in tumor blood flow or perfusion after PDT.

Peripheral artery disease (PAD) is a common condition with high morbidity. While measurement of tissue oxygen saturation (S(t)O(2)) has been demonstrated, this is the first study to assess both S(t)O(2) and relative blood flow (rBF) in the extremities of PAD patients. Diffuse optics is employed to measure hemodynamic response to treadmill and pedal exercises in 31 healthy controls and 26 patients. For S(t)O(2), mild and moderate/severe PAD groups show pronounced differences compared with controls. Pre-exercise mean S(t)O(2) is lower in PAD groups by 9.3% to 10.6% compared with means of 63.5% to 66.2% in controls. For pedal, relative rate of return of S(t)O(2) to baseline is more rapid in controls (p0.05). Patterns of rBF also differ among groups. After both exercises, rBF tend to occur at depressed levels among severe PAD patients compared with healthy (p0.05); post-treadmill, rBF tend to occur at elevated levels among healthy compared with severe PAD patients (p0.05). Additionally, relative rate of return to baseline S(t)O(2) is more rapid among subjects with reduced levels of depression in rBF (p = 0.041), even after adjustment for ankle brachial index. This suggests a physiologic connection between rBF and oxygenation that can be measured using diffuse optics, and potentially employed as an evaluative tool in further studies.

A noncontact diffuse correlation spectroscopy (DCS) probe has been developed using two separated optical paths for the source and detector. This unique design avoids the interference between the source and detector and allows large source-detector separations for deep tissue blood flow measurements. The noncontact probe has been calibrated against a contact probe in a tissue-like phantom solution and human muscle tissues; flow changes concurrently measured by the two probes are highly correlated in both phantom (R(2)=0.89, p10(-5)) and real-tissue (R(2)=0.77, p10(-5), n=9) tests. The noncontact DCS holds promise for measuring blood flow in vulnerable (e.g., pressure ulcer) and soft (e.g., breast) tissues without distorting tissue hemodynamic properties.

Arterial revascularization in patients with peripheral arterial disease (PAD) reestablishes large arterial blood supply to the ischemic muscles in lower extremities via bypass grafts or percutaneous transluminal angioplasty (PTA). Currently no gold standard is available for assessment of revascularization effects in lower extremity muscles. This study tests a novel near-infrared diffuse correlation spectroscopy flow-oximeter for monitoring of blood flow and oxygenation changes in medial gastrocnemius (calf) muscles during arterial revascularization. Twelve limbs with PAD undergoing revascularization were measured using a sterilized fiber-optic probe taped on top of the calf muscle. The optical measurement demonstrated sensitivity to dynamic physiological events, such as arterial clamping/releasing during bypass graft and balloon inflation/deflation during PTA. Significant elevations in calf muscle blood flow were observed after revascularization in patients with bypass graft (+48.1 ± 17.5%) and patients with PTA (+43.2 ± 11.0%), whereas acute post-revascularization effects in muscle oxygenation were not evident. The decoupling of flow and oxygenation after revascularization emphasizes the need for simultaneous measurement of both parameters. The acute elevations/improvements in calf muscle blood flow were associated with significant improvements in symptoms and functions. In total, the investigation corroborates potential of the optical methods for objectively assessing the success of arterial revascularization.

We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.

Photodynamic therapy (PDT) requires oxygen to cause cellular and vascular tumor damage. Tissue oxygen concentration, in turn, is influenced by blood flow and blood oxygenation. Real-time clinical measurement of these hemodynamic quantities, however, is rare. This paper reports the development and application of a probe, combining diffuse reflectance spectroscopy (DRS) for measurement of tumor blood oxygenation and diffuse correlation spectroscopy (DCS) for measurement of tumor blood flow. The instrument was adapted for clinical use during interstitial prostate PDT. Three patients with locally recurrent prostate cancer received 2 mg/ kg motexafin lutetium (MLu) 3 h before illumination and a total light dose of 100 J/cm(2) at 150 mW/cm. Prostrate blood oxygen saturation (StO2) decreased only slightly (approximately 3%) after treatment. On the other hand, prostate blood flow and total hemoglobin concentration over the course of PDT decreased by 50% and 15%, respectively, suggesting MLu-mediated PDT has an anti-vascular effect. While it is certainly impossible to draw definite conclusions from measurements of only three patients, the observed differences in tumor blood flow and blood oxygenation responses during PDT can, in principle, be used to choose among tissue oxygen consumption models and therefore emphasize the potential clinical value for simultaneous monitoring of both parameters.