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OBJECTIVE: Diffuse correlation spectroscopy (DCS) is an optical technique that allows for the non-invasive measurement of blood flow. Recent work has shown that utilizing longer wavelengths beyond the traditional NIR range provides a significant improvement to signal-to-noise ratio (SNR). However, current detectors both sensitive to longer wavelengths and suitable for clinical applications (InGaAs/InP SPADs) suffer from suboptimal afterpulsing and dark noise characteristics. To overcome these barriers, we introduce a cross correlation method to more accurately recover blood flow information using InGaAs/InP SPADs. METHODS: Two InGaAs/InP SPAD detectors were used for during in vitro and in vivo DCS measurements. Cross correlation of the photon streams from each detector was performed to calculate the correlation function. Detector operating parameters were varied to determine parameters which maximized measurement SNR. State-space modeling was performed to determine the detector characteristics at each operating point. RESULTS: Evaluation of detector characteristics was performed across the range of operating conditions. Modeling the effects of the detector noise on the correlation function provided a method to correct the distortion of the correlation curve, yielding accurate recovery of flow information as confirmed by a reference detector. CONCLUSION: Through a combination of cross-correlation of the signals from two detectors, model-based characterization of detector response, and optimization of detector operating parameters, the method allows for the accurate estimation of the true blood flow index. Significance: This work presents a method by which DCS can be performed at longer NIR wavelengths with existing detector technology, taking advantage of the increased SNR.

Significance: The ability of diffuse correlation spectroscopy (DCS) to measure cerebral blood flow (CBF) in humans is hindered by the low signal-to-noise ratio (SNR) of the method. This limits the high acquisition rates needed to resolve dynamic flow changes and to optimally filter out large pulsatile oscillations and prevents the use of large source-detector separations (≥3 cm), which are needed to achieve adequate brain sensitivity in most adult subjects. Aim: To substantially improve SNR, we have built a DCS device that operates at 1064 nm and uses superconducting nanowire single-photon detectors (SNSPD). Approach: We compared the performances of the SNSPD-DCS in humans with respect to a typical DCS system operating at 850 nm and using silicon single-photon avalanche diode detectors. Results: At a 25-mm separation, we detected 13 ± 6 times more photons and achieved an SNR gain of 16 ± 8 on the forehead of 11 subjects using the SNSPD-DCS as compared to typical DCS. At this separation, the SNSPD-DCS is able to detect a clean pulsatile flow signal at 20 Hz in all subjects. With the SNSPD-DCS, we also performed measurements at 35 mm, showing a lower scalp sensitivity of 31 ± 6 % with respect to the 48 ± 8 % scalp sensitivity at 25 mm for both the 850 and 1064 nm systems. Furthermore, we demonstrated blood flow responses to breath holding and hyperventilation tasks. Conclusions: While current commercial SNSPDs are expensive, bulky, and loud, they may allow for more robust measures of non-invasive cerebral perfusion in an intensive care setting.

Recently, we developed a time-domain diffuse correlation spectroscopy (TD-DCS) method for neurovascular sensing with higher brain sensitivity. In this paper, laser pulse shaping was designed and demonstrated for TD-DCS at 1064 nm. A quantum superconducting nanowire single-photon detector (SNSPD) with high photon detection efficiency (PDE) and low jitter collects the back-scattered light from the brain. The presented approach is the first step towards scaling up a full fiber optic cap with 96 source channels and 192 custom-made single-photon detectors which will cover most of an adult head.

Diffuse correlation spectroscopy (DCS) is an established diffuse optical technique that uses the analysis of temporal speckle intensity fluctuations to measure blood flow in tissue. Recent advances in the field have seen the introduction of iDWS/iDCS, which have allowed for the use of conventional photodetectors to replace the single photon counting detectors required to measure the traditional, homodyne DCS signal. Here we detail a high framerate, highly parallel iDCS system at 1064 nm which allows for improved signal to noise ratio at extended source detector separations.

Diffuse correlation spectroscopy (DCS) is an established diffuse optical technique that uses the analysis of temporal speckle intensity fluctuations to measure blood flow in tissue. DCS cerebral blood flow measurements in clinical applications have shown promise, but measurements contain contamination of the signal from changes in superficial blood flow. Recent studies have shown that moving to wavelengths beyond the water absorption peak at 970 nm when making DCS measurements improves SNR and reduced influence of superficial flow. Here, we present a DCS system operating at 1064 nm utilizing two InGaAs SPADs to calculate the cross correlation to address detector non-idealities.

Significance: Diffuse correlation spectroscopy (DCS) is an established optical modality that enables noninvasive measurements of blood flow in deep tissue by quantifying the temporal light intensity fluctuations generated by dynamic scattering of moving red blood cells. Compared with near-infrared spectroscopy, DCS is hampered by a limited signal-to-noise ratio (SNR) due to the need to use small detection apertures to preserve speckle contrast. However, DCS is a dynamic light scattering technique and does not rely on hemoglobin contrast; thus, there are significant SNR advantages to using longer wavelengths (>1000 nm) for the DCS measurement due to a variety of biophysical and regulatory factors. Aim: We offer a quantitative assessment of the benefits and challenges of operating DCS at 1064 nm versus the typical 765 to 850 nm wavelength through simulations and experimental demonstrations. Approach: We evaluate the photon budget, depth sensitivity, and SNR for detecting blood flow changes using numerical simulations. We discuss continuous wave (CW) and time-domain (TD) DCS hardware considerations for 1064 nm operation. We report proof-of-concept measurements in tissue-like phantoms and healthy adult volunteers. Results: DCS at 1064 nm offers higher intrinsic sensitivity to deep tissue compared with DCS measurements at the typically used wavelength range (765 to 850 nm) due to increased photon counts and a slower autocorrelation decay. These advantages are explored using simulations and are demonstrated using phantom and in vivo measurements. We show the first high-speed (cardiac pulsation-resolved), high-SNR measurements at large source–detector separation (3 cm) for CW-DCS and late temporal gates (1 ns) for TD-DCS. Conclusions: DCS at 1064 nm offers a leap forward in the ability to monitor deep tissue blood flow and could be especially useful in increasing the reliability of cerebral blood flow monitoring in adults.

Significance: The use of diffuse correlation spectroscopy (DCS) has shown efficacy in research studies as a technique capable of noninvasively monitoring blood flow in tissue with applications in neuromonitoring, exercise science, and breast cancer management. The ability of DCS to resolve blood flow in these tissues is related to the optical sensitivity and signal-to-noise ratio (SNR) of the measurements, which in some cases, particularly adult cerebral blood flow measurements, is inadequate in a significant portion of the population. Improvements to DCS sensitivity and SNR could allow for greater clinical translation of this technique. Aim: Interferometric diffuse correlation spectroscopy (iDCS) was characterized and compared to traditional homodyne DCS to determine possible benefits of utilizing heterodyne detection. Approach: An iDCS system was constructed by modifying a homodyne DCS system with fused fiber couplers to create a Mach–Zehnder interferometer. Comparisons between homodyne and heterodyne detection were performed using an intralipid phantom characterized at two extended source–detector separations (2.4, 3.6 cm), different photon count rates, and a range of reference arm power levels. Characterization of the iDCS signal mixing was compared to theory. Precision of the estimation of the diffusion coefficient and SNR of the autocorrelation curve were compared between different measurement conditions that mimicked what would be seen in vivo. Results: The mixture of signals present in the heterodyne autocorrelation function was found to agree with the derived theory and resulted in accurate measurement of the diffusion coefficient of the phantom. Improvement of the SNR of the autocorrelation curve up to ∼2× and up to 80% reduction in the variability of the diffusion coefficient fit were observed for all measurement cases as a function of increased reference arm power. Conclusions: iDCS has the potential to improve characterization of blood flow in tissue at extended source–detector separations, enhancing depth sensitivity and SNR.

Diffuse correlation spectroscopy (DCS) is an established diffuse optical technique that uses the analysis of temporal speckle intensity fluctuations to measure blood flow in tissue. As a non-invasive technique, DCS has been used to monitor patient cerebral blood flow at the bedside. Though an effective measurement tool, extra-cerebral contamination of the DCS signal limits the sensitivity to changes in brain blood flow. In order to overcome this depth sensitivity challenge, we present a method, overlapping volumes, acousto-optic modulated DCS (AOM-DCS), to improve sensitivity to deeper tissue structures.

Time-domain near-infrared spectroscopy (TD-NIRs) and Time-Domain Diffuse Correlation Spectroscopy (TD-DCS) are emerging imaging techniques that use a near-infrared, long coherence, pulsed laser to characterize oxygenation levels and blood flow. TD-DCS is a promising tool for bedside monitoring of brain activity due to its high time-resolution and portability. One potential new application area for TD-DCS is for detecting non-compressible torso hemorrhages (NCTH). NCTH is a serious traumatic injury that requires surgical intervention and is a leading cause of death in the military due to the lack of a rapid and portable imaging system sensitive enough to detect injury. Applying long wavelengths (1064 nm and 1120 nm) and time gating, TD-DCS can penetrate the superficial tissue layers and potentially detect bleeding deep within an organ. One limitation of current time-gating system is its reliance on full knowledge of the target tissue layers and properties in order to apply gating effectively. An automatic gating scheme that can adjust the time gate to quickly recalibrate itself to different imaging conditions, such as a different body area, can eliminate this limitation. Here, we use modeling and Monte Carlo simulations to search for characteristics in return signal profiles, specifically the time-of-flight and intensity profiles, as first step toward an automatic time-gating algorithm. We detail the simulation setups, parameter sweeps, and preliminary results in this report. These results show promise for TD-DCS as a tool for rapid and continuous monitoring of injuries in the field.

Diffuse correlation spectroscopy (DCS) is an established diffuse optical technique that uses the analysis of temporal speckle intensity fluctuations to measure blood flow in tissue. DCS has been shown to be an effective monitor of cerebral blood flow in many neuro-monitoring applications, though still suffers from depth sensitivity issues. Recent studies have shown that moving to 1064 nm when making DCS measurements improves SNR and sensitivity to depth, but detector challenges have slowed the change to that wavelength. Here, we present on a multipixel, interferometric DCS (iDCS) system that improves measurement capabilities at this wavelength.

Our team has recently shown the SNR and depth-sensitivity advantages of using 1064 nm light for diffuse correlation spectroscopy as well as the challenges of commercially available single-photon detectors at this wavelength. We will review two strategies for custom readout integrated circuit designs that simultaneously target lower pixel dead times and lower afterpulsing probabilities. Both designs use macropixels comprising many detectors, each having a programmable hold-off time. We will compare simulated autocorrelations for our detector models and compare predicted performance against commercial InGaAs/InP detectors.

Intra and post-operative blood flow monitoring of tissue has been shown to be effective in the improvement of patient outcomes. Diffuse correlation spectroscopy (DCS) has been shown to be effective in measuring blood flow at the bedside, and is a useful technique in measuring cerebral blood flow (CBF) in many clinical settings. However, DCS suffers from reduced sensitivity to blood flow changes at larger tissue depths, making measurements of CBF in adults difficult. This issue can be addressed with acousto-optic modulated diffuse correlation spectroscopy (AOM-DCS), which is a hybrid technique that combines the sensitivity of DCS to blood flow with ultrasound resolution to allow for improved spatial resolution of the optical signal based on knowledge of the area which is insonified by ultrasound. We present a quantitative model for perfusion estimation based on AOM-DCS in the presence of continuous wave ultrasound, supported by theoretical derivations, Monte Carlo simulations, and phantom and human subject experiments. Quantification of the influence of individual mechanisms that contribute to the temporal fluctuations of the optical intensity due to ultrasound is shown to agree with previously derived results. By using this model, the recovery of blood-flow induced scatterer dynamics based on ultrasound-modulated light is shown to deviate by less than one percent from the standard DCS measurement of scatterer dynamics over a range of optical scattering values and scatterer motion conditions. This work provides an important step towards future implementation of AOM-DCS setups with more complex spatio-temporal distributions of ultrasound pressure, which are needed to enhance the DCS spatial resolution.

Time-domain diffuse correlation spectroscopy (TD-DCS) aims to increase cerebral blood flow (CBF) sensitivity by discriminating photon time of flight. We report on the optimization of the laser pulse shape to maximize TD-DCS performance.

In-vivo, optical measurements of cerebral blood flow are confounded by superficial blood flow. Here, we present acousto-optic modulated diffuse correlation spectroscopy (AOM-DCS) for blood flow monitoring, showing good agreement between theoretical predictions and experimental results.

Diffuse correlation spectroscopy (DCS) is an emerging technique that allows for estimation of the motion of particles. By monitoring the time course of the speckle intensity fluctuations, the motion of the scattering particles, usually red blood cells in the microvasculature of biological tissues, can be quantified. Though these measurements are traditionally taken at near infrared wavelengths, where the attenuation of light by tissue chromophores, primarily hemoglobin, is reduced, the multiply scattered field is still heavily attenuated and expensive photon counting detectors are required to measure the signal intensity. By decreasing the cost of these systems, they may be more applicable in measuring patient hemodynamics at the bedside. Other groups have explored the use of heterodyne techniques [1,2] to amplify the intensity of the scattered field for detection with less expensive detectors, showing the potential for lowering the cost of DCS systems. Here we detail the performance characteristics of a single mode fiber (SMF) interferometer as well as follow through to investigate the theoretical relationship between the measured correlation function and the underlying dynamics. DCS measurements in the traditional homodyne configuration made with photon counting detectors are compared with those made with the interferometer with the photon counting detectors to explore experimental parameters that optimize the SNR of the blood flow index. The feasibility of utilizing fast photodiodes in the detection of the amplified field is also explored. Through the use of amplified optical signals, the detection of the DCS signal using less expensive detectors is shown to be possible. References: 1. Nakaji, H. US Application. No. 15/424581 (2017). 2. Zhou, W., Kholiqov, O., Chong, S. P. & Srinivasan, V. J. Highly parallel, interferometric diffusing wave spectroscopy for monitoring cerebral blood flow dynamics. Optica 5, 518 (2018).

Diffuse correlation spectroscopy (DCS) is an emerging technology that allows for the quantitative estimation of blood flow in tissue. By monitoring the autocorrelation of the time course of light speckle intensity, information about the motion of scattering particles, mostly red blood cells in the microvasculature of biological tissues, can be determined. The speckle fluctuations are due to motion of scatters along the entire path length of the photon from the source to the detector, which makes the determination of the location of the motion a difficult task. Multi-distance and tomographic methods have been employed to measure decorrelation times at different source detector separations, which helps to separate superficial blood flow from blood flow deeper in the tissue. DCS in the time-domain (TD-DCS) is being evaluated as a method to increase depth sensitivity by considering only the late arriving photons. Depth resolved quantification of blood flow is especially important when blood flow measurements of the brain are desired, as the superficial blood flow of the scalp is a known contaminant to the cortical signal. Recent demonstrations by other groups have shown the utility of ultrasound tagging of light to be an effective method to discriminate flow at different depths.1 Here we utilize ultrasound pulses to modulate the motion of particles at specific depths, which is dependent upon the time-of-flight of the ultrasound pulse. By analyzing the autocorrelation of the speckle intensity at different delay periods after the pulse, quantitative, depth specific information about the flow can be determined. References: 1. Tsalach, A. et al. Depth selective acousto-optic flow measurement. Biomed. Opt. Express 6, 4871–86 (2015).

Diffuse correlation spectroscopy (DCS) is a technique that has traditionally required low noise, single photo counting detectors. By utilizing an interferometric approach, we show that these hardware conditions can be relaxed.

Monte Carlo modeling of photon propagation has been used in the examination of particular areas of the body to further enhance the understanding of light propagation through tissue. This work seeks to improve upon the established simulation methods through more accurate representations of the simulated tissues in the wrist as well as the characteristics of the light source. The Monte Carlo simulation program was developed using Matlab. Generation of different tissue domains, such as muscle, vasculature, and bone, was performed in Solidworks, where each domain was saved as a separate .stl file that was read into the program. The light source was altered to give considerations to both viewing angle of the simulated LED as well as the nominal diameter of the source. It is believed that the use of these more accurate models generates results that more closely match those seen in-vivo, and can be used to better guide the design of optical wrist-worn measurement devices.

Blood, saliva, mucus, sweat, sputum, and other biological fluids are often hindered in their ability to be used in point-of-care (POC) diagnostics because their assays require some form of off-site sample pre-preparation to effectively separate biomarkers from larger components such as cells. The rapid isolation, identification, and quantification of proteins and other small molecules circulating in the blood plasma from larger interfering molecules are therefore particularly important factors for optical blood diagnostic tests, in particular, when using optical approaches that incur spectroscopic interference from hemoglobin-rich red blood cells (RBCs). In this work, a sequential spiral polydimethylsiloxane (PDMS) microfluidic device for rapid (∼1 min) on-chip blood cell separation is presented. The chip utilizes Dean-force induced migration via two 5-loop Archimedean spirals in series. The chip was characterized in its ability to filter solutions containing fluorescent beads and silver nanoparticles and further using blood solutions doped with a fluorescent protein. Through these experiments, both cellular and small molecule behaviors in the chip were assessed. The results exhibit an average RBC separation efficiency of ∼99% at a rate of 5.2 × 106 cells per second while retaining 95% of plasma components. This chip is uniquely suited for integration within a larger point-of-care diagnostic system for the testing of blood plasma, and the use of multiple filtering spirals allows for the tuning of filtering steps, making this device and the underlying technique applicable for a wide range of separation applications.

From the miniaturization of large sample processing machines to the creation of handheld point-of-care devices, microfluidics has the potential to be a powerful tool in the advancement of diagnostic technologies. Here, we compare different prototyping modalities towards the generation of an inertial microfluidic blood filter: i.e. a 'centrifuge-on-a-chip'. While photolithography is currently the method of choice for soft lithography mold fabrication, offering high design fidelity, we believe simpler methods, such as milling or 3D printing, will soon become equally viable options in the field of microfluidic device fabrication. Three modalities for optofluidic PDMS chip fabrication were compared: micromachining, 3D printing, and SU8 photolithography. The filtration efficiency of the chips were tested with whole blood and compared spectroscopically by monitoring the outlet absorbance at the 540 nm peak intrinsic to oxyhemoglobin at the outlet of each filter chip.

Traumatic injury resulting in hemorrhage is a prevalent cause of death worldwide. The current standard of care for trauma patients is to restore hemostasis by controlling bleeding and administering intravenous volume resuscitation. Adequate resuscitation to restore tissue blood flow and oxygenation is critical within the first hours following admission to assess severity and avoid complications. However, current clinical methods for guiding resuscitation are not sensitive or specific enough to adequately understand the patient condition. To better address the shortcomings of the current methods, an approach to monitor intestinal perfusion and oxygenation using a multiwavelength (470, 560, and 630 nm) optical sensor has been developed based on photoplethysmography and reflectance spectroscopy. Specifically, two sensors were developed using three wavelengths to measure relative changes in the small intestine. Using vessel occlusion, systemic changes in oxygenation input, and induction of hemorrhagic shock, the capabilities and sensitivity of the sensor were explored in vivo. Pulsatile and nonpulsatile components of the red, blue, and green wavelength signals were analyzed for all three protocols (occlusion, systemic oxygenation changes, and shock) and were shown to differentiate perfusion and oxygenation changes in the jejunum. The blue and green signals produced better correlation to perfusion changes during occlusion and shock, while the red and blue signals, using a new correlation algorithm, produced better data for assessing changes in oxygenation induced both systemically and locally during shock. The conventional modulation ratio method was found to be an ineffective measure of oxygenation in the intestine due to noise and an algorithm was developed based on the Pearson correlation coefficient. The method utilized the difference in phase between two different wavelength signals to assess oxygen content. A combination of measures from the three wavelengths provided verification of oxygenation and perfusion states, and showed promise for the development of a clinical monitor.