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The prospective multicenter ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a diffuse optical spectroscopic imaging (DOSI)–derived imaging endpoint, the tissue optical index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine (Irvine, CA), and delivered to six institutions where 60 subjects with newly diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to four times during NAC treatment: baseline, 1-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor-to-normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from −82% to 321%, with a median of −36%. Using pCR as the reference standard and ROC curve methodology, %TOITN AUC was 0.60 (95% CI, 0.39–0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI, 0.63–1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. Cancer Res; 76(20); 5933–44. ©2016 AACR.

List of Chemotherapy regimens used in this study.

Tourniquet use creates a reduced blood surgical field during total knee arthroplasty (TKA), however, prolonged ischemia may cause postoperative tourniquet complications. To understand the effects of tourniquet-induced ischemia, we performed a prospective observational study using quantitative broadband diffuse optical spectroscopy (DOS) to measure tissue hemodynamics and water and lipid concentrations before, during, and after tourniquet placement in subjects undergoing TKA. Data wascollected for 6 months and, of the total subjects analyzed (n = 24), 22 were primary TKAs and 2 were revision TKA cases. We specifically investigated tourniquet-induced hemodynamics based upon subject-specific tissue composition and observed a significant relationship between the linear rate of deoxygenation after tourniquet inflation and water/lipid ratio (W/L, p

BACKGROUND AND OBJECTIVES Spatial frequency domain imaging (SFDI), an optical imaging technique capable of quantitatively measuring tissue hemodynamics over a large field-of-view, has captured the interest of scientists and clinicians due to its ability to image rapidly and noninvasively. The goal of this study was to apply SFDI in a preclinical murine model to assess its ability to measure hemodynamic changes due to hindlimb ischemia in vivo longitudinally. STUDY DESIGN/MATERIALS AND METHODS Complete unilateral femoral artery ligation was performed on a total of nine C57BL/6J mice to induce ischemia in the left hindlimb. Changes in vascular perfusion in each mouse were monitored through SFDI acquisition of both the ischemic and control limbs throughout the course of 4 weeks. High-frequency pulsed-wave Doppler ultrasound was also acquired to confirm occlusion of the left femoral artery post-ligation compared with the control limb, while histological analysis was used to quantify femoral artery lumen shape and size. RESULTS Tissue oxygen saturation in the ischemic limb normalized to the control limb decreased from a ratio of 0.96 ± 0.06 at baseline to 0.86 ± 0.10 at day 1, then 0.94 ± 0.06 at day 3, followed by 0.95 ± 0.14 at day 7, 0.91 ± 0.09 at day 14, 0.90 ± 0.09 at day 21, and 1.01 ± 0.09 at day 28. CONCLUSION The results of this study indicate the utility of SFDI to detect hemodynamic changes in a preclinical murine model, as well as how to effectively use this tool to extract information regarding ischemia-induced hindlimb changes. In our model, we observed a decline in tissue oxygen saturation within one day post-ischemic injury, followed by a return to baseline values over the 4-week study period. While reducing skin artifacts and modifying camera hardware could still improve this murine imaging approach, our multimodality study presented here suggests that SFDI can be used to reliably characterize ischemia-mediated changes in a clinically relevant mouse model of peripheral arterial disease. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Background Breast cancer patients with early-stage disease are increasingly administered neoadjuvant chemotherapy (NAC) to downstage their tumors prior to surgery. In this setting, approximately 31% of patients fail to respond to therapy. This demonstrates the need for techniques capable of providing personalized feedback about treatment response at the earliest stages of therapy to identify patients likely to benefit from changing treatment. Diffuse optical spectroscopic imaging (DOSI) has emerged as a promising functional imaging technique for NAC monitoring. DOSI uses non-ionizing near-infrared light to provide non-invasive measures of absolute concentrations of tissue chromophores such as oxyhemoglobin. In 2011, we reported a new DOSI prognostic marker, oxyhemoglobin flare: a transient increase in oxyhemoglobin capable of discriminating NAC responders within the first day of treatment. In this follow-up study, DOSI was used to confirm the presence of the flare as well as to investigate whether DOSI markers of NAC response are regimen dependent. Methods This dual-center study examined 54 breast tumors receiving NAC measured with DOSI before therapy and the first week following chemotherapy administration. Patients were treated with either a standard of care maximum tolerated dose (MTD) regimen or an investigational metronomic (MET) regimen. Changes in tumor chromophores were tracked throughout the first week and compared to pathologic response and treatment regimen at specific days utilizing generalized estimating equations (GEE). Results Within patients receiving MTD therapy, the oxyhemoglobin flare was confirmed as a prognostic DOSI marker for response appearing as soon as day 1 with post hoc GEE analysis demonstrating a difference of 48.77% between responders and non-responders (p p = 0.0010) between patients receiving MTD and MET regimens. Conclusions DOSI optical biomarkers are differentially sensitive to MTD and MET regimens at early timepoints suggesting the specific treatment regimen should be considered in future DOSI studies. Additionally, DOSI may help to identify regimen-specific responses in a more personalized manner, potentially providing critical feedback necessary to implement adaptive changes to the treatment strategy.

This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions.

Noninvasive diffuse optical spectroscopy (DOS) is promising as an adjunct diagnostic imaging technique for distinguishing benign and malignant breast lesions. However, most DOS approaches require normalizing lesion optical biomarkers to healthy values in reference tissue since major tissue constituents exhibit large inter-patient variations. Our goal is to determine whether absolute measurements of minor optical absorbers such as collagen and methemoglobin (metHb) can successfully distinguish benign and malignant breast lesions. In this retrospective clinical study, 30 lesions with BIRADS score >= 3 (12 benign and 18 malignant lesions from 28 subjects) measured with broadband quantitative DOS were analyzed for their oxy-, deoxy- hemoglobin, water, lipids, collagen, and metHb concentrations as well as their optical scattering characteristics. Amongst all absolute DOS parameters (i.e., without normalization to healthy tissue) considered, only absolute metHb was observed to be significant for lesion discrimination (0.43±0.18 μM for benign vs 0.87±0.32 μM for malignant, p = 0.0002). Our findings demonstrate that lesion metHb concentration measured by quantitative DOS can improve noninvasive optical diagnosis of breast malignancies.

Diffuse optical spectroscopy (DOS), also known as near-infrared spectroscopy (NIRS), offers sub-micromolar sensitivity to tissue composition, perfusion, and oxygen metabolism; low patient risk since DOS requires neither ionizing radiation nor contrast agents; and relatively low-cost instrumentation. Consequently, DOS methods are applied in virtually all major areas of clinical research including neurologic disease, cancer, cardiovascular disease, metabolic disease, and trauma/critical care. Compared to other medical imaging technologies, DOS allows for ultracompact integration that can enable handheld, wearable, and even implanted DOS-based sensing strategies. In this presentation, we discuss our work to create a handheld frequency-domain quantitative tissue imager and a tumor-implantable DOS-based sensor roughly the size of a standard breast radiological clip.

Significance: Current imaging paradigms for differential diagnosis of suspicious breast lesions suffer from high false positive rates that force patients to undergo unnecessary biopsies. Diffuse optical spectroscopic imaging (DOSI) noninvasively probes functional hemodynamic and compositional parameters in deep tissue and has been shown to be sensitive to contrast between normal and malignant tissues. Aim: DOSI methods are under investigation as an adjunct to mammography and ultrasound that could reduce false positive rates and unnecessary biopsies, particularly in radiographically dense breasts. Methods: We performed a retrospective analysis of 212 subjects with suspicious breast lesions who underwent DOSI imaging. Physiological tissue parameters were z-score normalized to the patient’s contralateral breast tissue and input to univariate logistic regression models to discriminate between malignant tumors and the surrounding normal tissue. The models were then used to differentiate malignant lesions from benign lesions. Results: Models incorporating several individual hemodynamic parameters were able to accurately distinguish malignant tumors from both the surrounding background tissue and benign lesions with area under the curve (AUC) ≥0.85. Z-score normalization improved the discriminatory ability and calibration of these predictive models relative to unnormalized or ratio-normalized data. Conclusions: Findings from a large subject population study show how DOSI data normalization that accounts for normal tissue heterogeneity and quantitative statistical regression approaches can be combined to improve the ability of DOSI to diagnose malignant lesions. This improved diagnostic accuracy, combined with the modality’s inherent logistical advantages of portability, low cost, and nonionizing radiation, could position DOSI as an effective adjunct modality that could be used to reduce the number of unnecessary invasive biopsies.

Hemozoin (Hz) is a crystal by-product of hemoglobin consumption by malaria parasites. There are currently no in vivo deep tissue sensing methods that can quantify Hz presence noninvasively, which would be advantageous for malaria research and treatment. In this work, we describe the broadband near-infrared optical characterization of synthetic Hz in static and dynamic tissue-simulating phantoms. Using hybrid frequency domain and continuous-wave near-infrared spectroscopy, we quantified the broadband optical absorption and scattering spectra of Hz and identified the presence of Hz at a minimum tissue-equivalent concentration of 0.014 µg/mL in static lipid emulsion phantoms simulating human adipose. We then constructed a whole blood-containing tissue-simulating phantom and demonstrated the detection of Hz at physiologically-relevant tissue oxygen saturations ranging from 70-90%. Our results suggest that quantitative diffuse optical spectroscopy may be useful for detecting deep tissue Hz in vivo.

Diffuse optical spectroscopy is a well-established methodology for noninvasive functional imaging of biological tissue. Intrinsic contrast is provided by optical absorbers including hemoglobin, water, and lipid, which provides physiologicallyrelevant information on tissue composition, metabolism, and structure. Frequency domain diffuse optical spectroscopy (FD-DOS), unlike continuous-wave DOS, provides measures of absolute absorption and scattering using phase-resolved intensity-modulated (>50 MHz) light and enables deeper and more accurate tissue characterization. However, the imaging depth and sensitivity of FD-DOS is almost always constrained by photodetector sensitivity. It has been recently demonstrated that by using highly sensitive silicon photomultiplier (SiPM) detectors, these limitations may be overcome. Though SiPMs are typically employed in photon-counting or pulsed time-domain measurement applications, they provide up to 30dB increase in signal to noise ratio and deeper tissue sensitivity, as compared to avalanche photodiodes in FDDOS. In this paper, we explore how fundamental SiPM characteristics affect the detection of FD-DOS signals. We develop simulations capable of evaluating and optimizing SiPM parameters (microcell size, microcell number, and recharge time constant) utilizing a Monte Carlo approach to SiPM response from modulated FD-DOS signals. The effects of these parameters are examined in relation to bandwidth and signal to noise ratio, thus providing a methodology for choosing the best SiPM for this unconventional application, and further improving FD-DOS performance.

We present work towards a fully embedded handheld frequency-domain diffuse optical spectroscopy (FD-DOS) imaging system capable of measuring tissue chromophores at a data display rate of 36.6 kHz, enabling real-time high spatial density diffuse optical imaging.

Objective To quantitatively measure tissue composition and hemodynamics during resuscitative endovascular balloon occlusion of the aorta (REBOA) in two tissue compartments using non-invasive two-channel broadband diffuse optical spectroscopy (DOS). Methods Tissue concentrations of oxy- and deoxyhemoglobin (HbO2 and HbR), water, and lipid were measured in a porcine model (n = 10) of massive hemorrhage (65% total blood volume over 1 h) and 30-min REBOA superior and inferior to the aortic balloon. Results After hemorrhage, hemoglobin oxygen saturation (StO2 = HbO2/[HbO2 + HbR]) at both sites decreased significantly (−29.9% and −42.3%, respectively). The DOS measurements correlated with mean arterial pressure (MAP) (R2 = 0.79, R2 = 0.88), stroke volume (SV) (R2 = 0.68, R2 = 0.88), and heart rate (HR) (R2 = 0.72, R2 = 0.88). During REBOA, inferior StO2 continued to decline while superior StO2 peaked 12 min after REBOA before decreasing again. Inferior DOS parameters did not associate with MAP, SV, or HR during REBOA. Conclusions Dual-channel regional tissue DOS measurements can be used to non-invasively track the formation of hemodynamically distinct tissue compartments during hemorrhage and REBOA. Conventional systemic measures MAP, HR, and SV are uncorrelated with tissue status in inferior (downstream) sites. Multi-compartment DOS may provide a more complete picture of the efficacy of REBOA and similar resuscitation procedures.

Frequency-domain near-infrared spectroscopy (FD-NIRS) provides quantitative noninvasive measurements of tissue optical absorption and scattering, as well as a safe and accurate method for characterizing tissue composition and metabolism. However, the poor scalability and high complexity of most FD-NIRS systems assembled to date have contributed to its limited clinical impact. To address these shortcomings, we present a scalable, digital-based FD-NIRS platform capable of measuring optical properties and tissue chromophore concentrations in real-time. The system provides single-channel FD-NIRS amplitude/phase, optical property, and chromophore data at a maximum display rate of 36.6 kHz, 17.9 kHz, and 10.2 kHz, respectively, and can be scaled to multiple channels as well as integrated into a handheld format. The entire system is enabled by several innovations including an ultra-high-speed k-nearest neighbor lookup table method (maximum of 250,000 inversions/s for a large 2500x700 table of absorption and reduced scattering coefficients), embedded FPGA and CPU high-speed co-processing, and high-speed data transfer (due to on-board processing). We show that our 6-wavelength, broad modulation bandwidth (1-400 MHz) system can be used to perform 2D high-density spatial mapping of optical properties and high speed quantification of hemodynamics.

Background We describe a novel strategy for power and sample size determination developed for studies utilizing investigational technologies with limited available preliminary data, specifically of imaging biomarkers. We evaluated diffuse optical spectroscopic imaging (DOSI), an experimental noninvasive imaging technique that may be capable of assessing changes in mammographic density. Because there is significant evidence that tamoxifen treatment is more effective at reducing breast cancer risk when accompanied by a reduction of breast density, we designed a study to assess the changes from baseline in DOSI imaging biomarkers that may reflect fluctuations in breast density in premenopausal women receiving tamoxifen. Method While preliminary data demonstrate that DOSI is sensitive to mammographic density in women about to receive neoadjuvant chemotherapy for breast cancer, there is no information on DOSI in tamoxifen treatment. Since the relationship between magnetic resonance imaging (MRI) and DOSI has been established in previous studies, we developed a statistical simulation approach utilizing information from an investigation of MRI assessment of breast density in 16 women before and after treatment with tamoxifen to estimate the changes in DOSI biomarkers due to tamoxifen. Results Three sets of 10,000 pairs of MRI breast density data with correlation coefficients of 0.5, 0.8 and 0.9 were simulated and generated and were used to simulate and generate a corresponding 5,000,000 pairs of DOSI values representing water, ctHHB, and lipid. Minimum sample sizes needed per group for specified clinically-relevant effect sizes were obtained. Conclusion The simulation techniques we describe can be applied in studies of other experimental technologies to obtain the important preliminary data to inform the power and sample size calculations. Electronic supplementary material The online version of this article (doi:10.1186/s12874-017-0329-1) contains supplementary material, which is available to authorized users.

Relatively few imaging and sensing technologies are employed to study human lactation physiology. In particular, human mammary development during pregnancy as well as mammary involution after lactation have been poorly described, despite their importance for breast cancer diagnosis and treatment during these phases. Our case study shows the potential of diffuse optical spectroscopic imaging (DOSI) to uniquely study the spatiotemporal changes in mammary tissue composition during the involution of the lactating breast toward its pre-pregnant state. At nine time intervals over a period of eight months after the cessation of breastfeeding, we reconstructed 2-D maps of mammary water content, lipid content, total hemoglobin (THb) concentration, oxygen saturation (StO2), and tissue optical scattering. Mammary lipid content in the nonareolar region showed a significant relative increase of 59%, whereas water content and THb concentration showed a significant relative decrease of 50% and 48%, respectively. Significant changes were also found in StO2 and tissue optical scattering. Our findings are consistent with the gradual replacement of fibroglandular tissue by adipose tissue and vascular regression during mammary involution. Moreover, our data provide unique insight into the dynamics of breast tissue composition and demonstrate the effectiveness of DOSI as a technique to study human lactation physiology.

Several studies have demonstrated that hormone-blocking therapies are more effective at reducing breast cancer risk in women who exhibit >10% reduction in breast density compared to women who had little or no density change, suggesting that breast density is a predictor of tamoxifen effectiveness. The goal of this prospective study was to assess whether diffuse optical spectroscopic imaging (DOSI) can measure the changes in breast composition under adjuvant tamoxifen treatment for breast cancer. The primary aim was to determine whether the change in the DOSI measurement of water correlates with the change in the MRI-derived quantitative measurement of breast density after 18 months of treatment in the contralateral normal breast of subjects receiving tamoxifen. Pre-menopausal subjects receiving tamoxifen (N=11 total, N=9 analyzable) and controls (N=18 total, N=15 analyzable) were enrolled and measured with co-registered DOSI and non-contrast MRI before, and 6, 12 and 18 months after beginning tamoxifen. Across all subjects, baseline MRI fibroglandular density correlated strongly with DOSI water (r=0.86, p

Reflectance-based, handheld diffuse optical tomography (DOT) uses multi-spectral frequency-domain (FD) and/or continuous-wave (CW) discrete wavelength sources. During DOT reconstruction, spectral constraints are commonly applied assuming a limited number of chromophores in the tissue in order to more accurately recover chromophore concentrations and scattering parameters. However, there are cases where spectral recovery cannot be applied, such as for the quantification of unknown tissue absorbers, where the chromophore extinction spectra are not known a priori. Therefore, we have worked toward a hyperspectral, hybrid FD and CW-DOT approach that can accurately recover tissue absorption and scattering spectra without needing a spectral constraint. Our approach increases the number of recoverable chromophores continuously across a 650 - 1050 nm spectrum. We have implemented and evaluated this technique in a prototype handheld probe for reflectance-mode breast imaging. Currently, no handheld portable DOT probe has this broadband hyperspectral capability. We simulated the accuracy of optical property recovery, showing that hybrid DOT successfully recovers the absorption spectra with average of 10% error across 650 − 1000 nm spectrum. We have also validated this technique by successfully imaging an inhomogeneous physical phantom with optical properties mimicking breast tissue. The methodology for the probe design along with the results of simulations and phantom studies are presented.

In this paper, we show that interfering multiple photon density waves created by intensity-modulated sources in frequency domain diffuse optical spectroscopy (fd-DOS) can be used to recover the optical properties of homogenous and heterogeneous tissues. While fd-DOS can recover the optical properties of homogenous tissue using a single source-detector pair, heterogeneous or layered tissues such as breast, brain, and skin require additional source-detector pairs with multiple separations. Through modelling, we show that the varying illumination patterns created by the interference of two intensity modulated sources can be used to recover the optical properties of two-layer tissue using only a single detector and two phased sources. Two-dimensional fd-DOS models of the conventional multi-distance and proposed multi-phase approaches were compared for homogenous and two-layered tissues. In a homogenous tissue with absorption and reduced scattering coefficients representative of human breast, the simulation results showed that both multi-distance and multi-phase approaches are capable of recovering the absorption and reduced scattering coefficients of the tissue. However, the multi-phase approach has less precision than the conventional multidistance approach. In the two-layer model, the multi-phase approach was capable of recovering the optical properties of both layers, while the multi-distance approach could not.

Frequency domain diffuse optical spectroscopy (fd-DOS) uses modulated laser light to image tissue and extract quantitative chromophore information. Currently no fd-DOS systems are completely handheld and only one is capable of displaying chromophore data in real time, which could allow for real-time studies of tissue hemodynamics, spatial chromophore (e.g. water, lipid, and hemoglobin) concentrations, greater ease of use by clinicians, and more generally, a simple platform for quantitative tissue spectroscopy. We present progress towards a handheld, real time fd-DOS system based upon an all-digital FPGA coupled hardware approach that includes data collection and processing and can attain imaging speeds of >30Hz. Quantitative optical scattering and absorption measurements are found to be within 10% agreement as compared to a reference system. We conclude that high speed quantitative tissue chromophore assessments are possible with this system-on-a-chip fd-DOS approach, which will enable real time handheld monitoring of rapid physiological changes.

Diffuse optical imaging and tomography based upon frequency-domain near-infrared spectroscopy (fdNIRS) is used to noninvasively measure tissue structure and function through quantitative absolute measurements of tissue optical absorption and scattering. Here we describe how utilizing a silicon photomultiplier (SiPM) detector for fdNIRS improves performance. We discuss the operation of SiPMs, how they differ from other fdNIRS photodetectors, and show theoretically that SiPMs offer similar sensitivity to photomultiplier tube (PMT) detectors while having a higher dynamic range and lower cost, size, and operating voltage. With respect to avalanche photodiode (APD) detectors, theoretical and experimental data shows drastically increased signal to noise ratio performance, up to 25dB on human breast, head, and muscle tissue. Finally, we extend the dynamic range (∼10dB) of the SiPM through a nonlinear calibration technique which reduced absorption error by a mean 16 percentage points.

Despite numerous advances, malaria continues to kill nearly half a million people globally every year. New analytical methods and diagnostics are critical to understanding how treatments under development affect the lifecycle of malaria parasites. A biomarker that has been gaining interest is the "malaria pigment" hemozoin. This byproduct of hemoglobin digestion by the parasite has a unique spectral signature but is difficult to differentiate from hemoglobin and other tissue chromophores. Hemozoin can be detected in blood samples, but only utilizing approaches that require specialized training and facilities. Diffuse optical spectroscopy (DOS) is a noninvasive sensing technique that is sensitive to near-infrared absorption and scattering and capable of probing centimeter-deep volumes of tissue in vivo. DOS is relatively low-cost, does not require specialized training and thus potentially suitable for use in low-resource settings. In this work, we assess the potential of DOS to detect and quantify the presence of hemozoin noninvasively and at physiologically relevant levels. We suspended synthetic hemozoin in Intralipid-based tissue-simulating phantoms in order to mimic malaria infection in multiply-scattering tissue. Using a fiber probe that combines frequency-domain and continuous-wave broadband DOS (650-1000 nm), we detected hemozoin concentrations below 250 ng/ml, which corresponds to parasitemia sensitivities comparable to modern rapid diagnostic tests. We used the experimental variability to simulate and estimate the sensitivity of DOS to hemozoin in tissue that includes hemoglobin, water, and lipid under various tissue oxygen saturation levels. The results indicate that with increased precision, it may be possible to detect Hz noninvasively with DOS.

We present a near-infrared tunable vertical cavity surface emitting laser (VCSEL) based upon a unique electrothermally tunable microelectromechanical systems (MEMS) topside mirror designed for tissue imaging and sensing. At room temperature, the laser is tunable from 769-782nm with single mode CW output and a peak output power of 1.3mW. We show that the tunable VCSEL is suitable for use in frequency domain diffuse optical spectroscopy by measuring the optical properties of a tissue-simulating phantom over the tunable range. These results indicate that tunable VCSELs may be an attractive choice to enable high spectral resolution optical sensing in a wearable format.

A quantitative and dynamic analysis of skeletal muscle structure and function can guide training protocols and optimize interventions for rehabilitation and disease. While technologies exist to measure body composition, techniques are still needed for quantitative, long-term functional imaging of muscle at the bedside. We evaluate whether diffuse optical spectroscopic imaging (DOSI) can be used for long-term assessment of resistance training (RT). DOSI measures of tissue composition were obtained from 12 adults before and after 5 weeks of training and compared to lean mass fraction (LMF) from dual-energy X-ray absorptiometry (DXA). Significant correlations were detected between DXA LMF and DOSI-measured oxy-hemo/myoglobin, deoxy-hemo/myoglobin, total-hemo/myoglobin, water, and lipid. RT-induced increases of ∼6% in oxy-hemo/myoglobin (3.4±1.0 μM, p=0.00314) and total-hemo/myoglobin (4.9±1.1 μM, p=0.00024) from the medial gastrocnemius were detected with DOSI and accompanied by ∼2% increases in lean soft tissue mass (36.4±12.4 g, p=0.01641) and ∼60% increases in 1 rep-max strength (41.5±6.2 kg, p=1.9E-05). DOSI measures of vascular and/or muscle changes combined with correlations between DOSI and DXA suggest that quantitative diffuse optical methods can be used to evaluate body composition, provide feedback on long-term interventions, and generate new insight into training-induced muscle adaptations.

We present a framework for characterizing the performance of an experimental imaging technology, diffuse optical spectroscopic imaging (DOSI), in a 2-year multicenter American College of Radiology Imaging Network (ACRIN) breast cancer study (ACRIN-6691). DOSI instruments combine broadband frequency-domain photon migration with time-independent near-infrared (650 to 1000 nm) spectroscopy to measure tissue absorption and reduced scattering spectra and tissue hemoglobin, water, and lipid composition. The goal of ACRIN-6691 was to test the effectiveness of optically derived imaging endpoints in predicting the final pathologic response of neoadjuvant chemotherapy (NAC). Sixty patients were enrolled over a 2-year period at participating sites and received multiple DOSI scans prior to and during 3- to 6-month NAC. The impact of three sources of error on accuracy and precision, including different operators, instruments, and calibration standards, was evaluated using a broadband reflectance standard and two different solid tissue-simulating optical phantoms. Instruments showed

Frequency-domain photon migration (FDPM) uses modulated laser light to measure the bulk optical properties of turbid media and is increasingly applied for noninvasive functional medical imaging in the near-infrared. Although semiconductor edge-emitting laser diodes have been traditionally used as miniature light sources for this application, we show that vertical-cavity surface-emitting lasers (VCSELs) exhibit output power and modulation performance characteristics suitable for FDPM measurements of tissue optical properties at modulation frequencies exceeding 1GHz. We also show that an array of multiple VCSEL devices can be coherently modulated at frequencies suitable for FDPM and can improve optical power. In addition, their small size and simple packaging make them an attractive choice as components in wearable sensors and clinical FDPM-based optical spectroscopy systems. We demonstrate the benefits of VCSEL technology by fabricating and testing a unique, compact VCSEL-based optical probe with an integrated avalanche photodiode. We demonstrate sensitivity of the VCSEL-based probe to subcutaneous tissue hemodynamics that was induced during an arterial cuff occlusion of the upper arm in a human subject.

Diffuse optical spectroscopic imaging (DOSI) and diffuse correlation spectroscopy (DCS) are modelbased near-infrared (NIR) methods that measure tissue optical properties (broadband absorption, mu(a), and reduced scattering, mu(s)) and blood flow (blood flow index, BFI), respectively. DOSI-derived mu(a) values are used to determine composition by calculating the tissue concentration of oxy- and deoxyhemoglobin(HbO2,HbR), water, and lipid. We developed and evaluated a combined, coregistered DOSI/ DCS handheld probe for mapping and imaging these parameters. We show that uncertainties of 0.3 mm(-1) (37%) in mu(s) and 0.003 mm(-1) (33%) in mu(a) lead to similar to 53% and 9% errors in BFI, respectively. DOSI/ DCS imaging of a solid tissue-simulating flow phantom and a breast cancer patient reveals well-defined spatial distributions of BFI and composition that clearly delineates both the flow channel and the tumor. BFI reconstructed with DOSI-corrected mu(a) and mu(s) values had a tumor/ normal contrast of 2.7, 50% higher than the contrast using commonly assumed fixed optical properties. In conclusion, spatially coregistered imaging of DOSI and DCS enhances intrinsic tumor contrast and information content. This is particularly important for imaging diseased tissues where there are significant spatial variations in mu(a) and mu(s) as well as potential uncoupling between flow and metabolism. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, Funding Agencies|National Institute of Biomedical Imaging and Bioengineering [P41EB015890]; National Cancer Institute [R01CA142989, U54CA136400]; Chao Family Comprehensive Cancer Center [P30CA62203]; Arnold and Mabel Beckman Foundation; Fulbright Visiting Scholar grant; Swedish Governmental Agency for Innovation Systems (VINNOVA) [2015-0153]; NIH [P41-EB015893, 1R01NS060653]

Diffuse optical imaging of biological tissue is a well-established methodology used to measure functional information from intrinsic contrast due to hemoglobin, water, and lipid. This information is exploited in frequency domain diffuse optical spectroscopy (FD-DOS) systems, which have been used to investigate chemotherapy response, optical mammography, and brain imaging. FD-DOS depth sensitivity and dynamic range are typically constrained by photodetector sensitivity. Here we present FD-DOS utilizing a silicon photomultiplier (SiPM) detector that has a higher signal-to-noise ratio (SNR) compared to an avalanche photodiode (APD), and thus enables extended source-detector (S/D) separations and increased depth penetration. We find the SiPM to have 10-30 dB greater SNR than a comparably sized APD while detecting 1.5-2 orders of magnitude lower light levels, down to ∼4 pW at 50 MHz modulation. The SiPM and APD recover optical property values of tissue-simulating phantoms within 13% agreement and are stable with 1% coefficient of variation over one hour. Finally, the SiPM is used to accurately recover optical properties in a reflectance geometry at S/D separations up to 48 mm in phantoms mimicking human breast tissue.

Background Changes in subcutaneous adipose tissue (AT) structure and metabolism have been shown to correlate with the development of obesity and related metabolic disorders. Measurements of AT physiology could provide new insight into metabolic disease progression and response to therapy. An emerging functional imaging technology, Diffuse Optical Spectroscopic Imaging (DOSI), was used to obtain quantitative measures of near infrared (NIR) AT optical and physiological properties. Methods 10 overweight or obese adults were assessed during three-months on calorie-restricted diets. DOSI-derived tissue concentrations of hemoglobin, water, and lipid and the wavelength-dependent scattering amplitude (A) and slope (b) obtained from 30 abdominal locations and three time points (T0, T6, T12) were calculated and analyzed using linear mixed effects models, and were also used to form 3D surface images. Results Subjects lost a mean of 11.7 ± 3.4% of starting weight, while significant changes in A (+0.23 ± 0.04 mm−1, adj. p < 0.001), b (−0.17 ± 0.04, adj. p < 0.001), tissue water fraction (+7.2 ± 1.1%, adj. p < 0.001) and deoxyhemoglobin [HbR] (1.1 ± 0.3 µM, adj. p < 0.001) were observed using mixed effect model analysis. Discussion Optical scattering signals reveal alterations in tissue structure which possibly correlate with reductions in adipose cell volume, while water and hemoglobin dynamics suggest improved AT perfusion and oxygen extraction. These results suggest that DOSI measurements of NIR optical and physiological properties could be used to enhance understanding of the role of AT in metabolic disorders and provide new strategies for diagnostic monitoring of obesity and weight loss.

Young patients with dense breasts have a relatively low-positive biopsy rate for breast cancer (∼1 in 7). South Korean women have higher breast density than Westerners. We investigated the benefit of using a functional and metabolic imaging technique, diffuse optical spectroscopic imaging (DOSI), to help the standard of care imaging tools to distinguish benign from malignant lesions in premenopausal Korean women. DOSI uses near-infrared light to measure breast tissue composition by quantifying tissue concentrations of water (ctH2O), bulk lipid (ctLipid), deoxygenated (ctHHb), and oxygenated (ctHbO2) hemoglobin. DOSI spectral signatures specific to abnormal tissue and absent in healthy tissue were also used to form a malignancy index. This study included 19 premenopausal subjects (average age 41±9), corresponding to 11 benign and 10 malignant lesions. Elevated lesion to normal ratio of ctH2O, ctHHb, ctHbO2, total hemoglobin (THb=ctHHb+ctHbO2), and tissue optical index (ctHHb×ctH2O/ctLipid) were observed in the malignant lesions compared to the benign lesions (p90% sensitivity and specificity. Malignant lesions showed significantly higher metabolism and perfusion than benign lesions. DOSI spectral features showed high discriminatory power for distinguishing malignant and benign lesions in dense breasts of the Korean population.

Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing [Formula: see text]-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on [Formula: see text]-score normalization using only tissue oxygen saturation ([Formula: see text]) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR ([Formula: see text]; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue [Formula: see text] to surrounding tissue [Formula: see text] are more likely to achieve pCR. This early predictor of pCR occurs prior to reductions in tumor size and could enable dynamic feedback for optimization of chemotherapy strategies in breast cancer.

We present an approach for performing frequency domain diffuse optical spectroscopy (fd-DOS) utilizing a near-infrared tunable vertical cavity surface emitting laser (VCSEL) that enables high spectral resolution optical sensing in a miniature format. The tunable VCSEL, designed specifically for deep tissue imaging and sensing, utilizes an electrothermally tunable microelectromechanical systems topside mirror to tune the laser cavity resonance. At room temperature, the laser is tunable across 14nm from 769 to 782nm with single mode CW output and a peak output power of 1.3mW. We show that the tunable VCSEL is suitable for use in fd-DOS by measuring the optical properties of a tissue-simulating phantom over the tunable range. Optical properties were recovered within 0.0006mm(−1) (absorption) and 0.09mm(−1) (reduced scattering) compared to a broadband fd-DOS reference system. Our results indicate that tunable VCSELs may be an attractive choice to enable high spectral resolution optical sensing in a wearable format.