Evaluation of Hemodynamics in a Murine Hindlimb Ischemia Model Using Spatial Frequency Domain Imaging.

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.

Next-generation frequency domain diffuse optical imaging systems using silicon photomultipliers.

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.

Frequency domain diffuse optical spectroscopy with a near-infrared tunable vertical cavity surface emitting laser.

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.

Sample size and power determination when limited preliminary information is available.

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.

Miniature wireless LED-device for photodynamic-induced cell pyroptosis.

The inability of visible light to penetrate far through biological tissue limits its use for phototherapy and photodiagnosis of deep-tissue sites of disease. This is unfortunate because many visible dyes are excellent photosensitizers and photocatalysts that can induce a wide range of photochemical processes, including photogeneration of reactive oxygen species. One potential solution is to bring the light source closer to the site of disease by using a miniature implantable LED. With this goal in mind, we fabricated a wireless LED-based device (volume of 23 mm3) that is powered by RF energy and emits light with a wavelength of 573 nm. It has the capacity to excite the green absorbing dye Rose Bengal, which is an efficient type II photosensitizer. The wireless transfer of RF power is effective even when the device is buried in chicken breast and located 6 cm from the transmitting antenna. The combination of a wireless device as light source and Rose Bengal as photosensitizer was found to induce cell death of cultured HT-29 human colorectal adenocarcinoma cells. Time-dependent generation of protruding bubbles was observed in the photoactivated cells suggesting cell death by light-induced pyroptosis and supporting evidence was gained by cell staining with the fluorescence probes Annexin-V FITC and Propidium Iodide. The results reveal a future path towards a wireless implanted LED-based device that can trigger photodynamic immunogenic cell death in deep-seated cancerous tissue.

Optical imaging correlates with magnetic resonance imaging breast density and reveals composition changes during neoadjuvant chemotherapy.

INTRODUCTION: In addition to being a risk factor for breast cancer, breast density has been hypothesized to be a surrogate biomarker for predicting response to endocrine-based chemotherapies. The purpose of this study was to evaluate whether a noninvasive bedside scanner based on diffuse optical spectroscopic imaging (DOSI) provides quantitative metrics to measure and track changes in breast tissue composition and density. To access a broad range of densities in a limited patient population, we performed optical measurements on the contralateral normal breast of patients before and during neoadjuvant chemotherapy (NAC). In this work, DOSI parameters, including tissue hemoglobin, water, and lipid concentrations, were obtained and correlated with magnetic resonance imaging (MRI)-measured fibroglandular tissue density. We evaluated how DOSI could be used to assess breast density while gaining new insight into the impact of chemotherapy on breast tissue. METHODS: This was a retrospective study of 28 volunteers undergoing NAC treatment for breast cancer. Both 3.0-T MRI and broadband DOSI (650 to 1,000 nm) were obtained from the contralateral normal breast before and during NAC. Longitudinal DOSI measurements were used to calculate breast tissue concentrations of oxygenated and deoxygenated hemoglobin, water, and lipid. These values were compared with MRI-measured fibroglandular density before and during therapy. RESULTS: Water (r = 0.843; P < 0.001), deoxyhemoglobin (r = 0.785; P = 0.003), and lipid (r = -0.707; P = 0.010) concentration measured with DOSI correlated strongly with MRI-measured density before therapy. Mean DOSI parameters differed significantly between pre- and postmenopausal subjects at baseline (water, P < 0.001; deoxyhemoglobin, P = 0.024; lipid, P = 0.006). During NAC treatment measured at about 90 days, significant reductions were observed in oxyhemoglobin for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) and postmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentration for premenopausal subjects (-11.9%; 95% CI, -17.1 to -6.7) compared with baseline. Lipid increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5), and water increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6). Percentage change in water at the end of therapy compared with baseline correlated strongly with percentage change in MRI-measured density (r = 0.864; P = 0.012). CONCLUSIONS: DOSI functional measurements correlate with MRI fibroglandular density, both before therapy and during NAC. Although from a limited patient dataset, these results suggest that DOSI may provide new functional indices of density based on hemoglobin and water that could be used at the bedside to assess response to therapy and evaluate disease risk.

Characterizing tourniquet induced hemodynamics during total knee arthroplasty using diffuse optical spectroscopy.

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 was collected 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 < 0.0001) and baseline somatic tissue oxygen saturation, StO2 (p = 0.05). Subjects with a low W/L ratio exhibited a lower tissue metabolic rate of oxygen consumption, (tMRO2 ) (p = 0.008). Changes in deoxyhemoglobin [HbR] (p = 0.009) and lipid fraction (p = 0.001) were significantly different between high and low W/L subject groups during deoxygenation. No significant differences were observed for hemodynamics during reperfusion and total tourniquet time was neither significantly related to the hemodynamic hyperemic response (p = 0.73) nor the time to max StO2 after tourniquet release (p = 0.57). In conclusion, we demonstrate that DOS is capable of real-time monitoring of tissue hemodynamics distal to the tourniquet during TKA, and that tissue composition should be considered. DOS may help surgeons stratify hemodynamics based upon tissue composition and eventually aid the preoperative risk assessment of vascular occlusions from tourniquet use during TKA.

System Derived Spatial-Temporal CNN for High-Density fNIRS BCI.

An intuitive and generalisable approach to spatial-temporal feature extraction for high-density (HD) functional Near-Infrared Spectroscopy (fNIRS) brain-computer interface (BCI) is proposed, demonstrated here using Frequency-Domain (FD) fNIRS for motor-task classification. Enabled by the HD probe design, layered topographical maps of Oxy/deOxy Haemoglobin changes are used to train a 3D convolutional neural network (CNN), enabling simultaneous extraction of spatial and temporal features. The proposed spatial-temporal CNN is shown to effectively exploit the spatial relationships in HD fNIRS measurements to improve the classification of the functional haemodynamic response, achieving an average F1 score of 0.69 across seven subjects in a mixed subjects training scheme, and improving subject-independent classification as compared to a standard temporal CNN.

Optical imaging and spectroscopy for the study of the human brain: status report.

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.

Multi-modality optical neural imaging using coherence control of VCSELs.

Neural optical imaging can evaluate cortical hemodynamic fluctuations which reflect neural activity and disease state. We evaluate the use of vertical-cavity surface-emitting lasers (VCSELs) as illumination source for simultaneous imaging of blood flow and tissue oxygenation dynamics ex vivo and in vivo and demonstrate optical imaging of blood flow changes and oxygenation changes in response to induced ischemia. Using VCSELs we show a rapid switching from a single-mode to a special multi-mode rapid current sweep operation and noise values reduced to within a factor of 40% compared to non-coherent LED illumination. These VCSELs are promising for long-term portable continuous monitoring of brain dynamics in freely moving animals.

Broadband diffuse optical spectroscopy of absolute methemoglobin concentration can distinguish benign and malignant breast lesions.

SIGNIFICANCE: Noninvasive diffuse optical spectroscopy (DOS) is a promising adjunct diagnostic imaging technique for distinguishing benign and malignant breast lesions. Most DOS approaches require normalizing lesion biomarkers to healthy tissue since major tissue constituents exhibit large interpatient variations. However, absolute optical biomarkers are desirable as it avoids reference measurements which may be difficult or impractical to acquire. AIM: Our goal is to determine whether absolute measurements of minor absorbers such as collagen and methemoglobin (metHb) can successfully distinguish lesions. We hypothesize that metHb would exhibit less interpatient variability and be more suitable as an absolute metric for malignancy. However, we would expect collagen to exhibit more variability, because unlike metHb, collagen is also present in the healthy tissue. APPROACH: In this retrospective clinical study, 30 lesions with breast imaging reporting and database system score ( BIRADS ) > = 3 (12 benign and 18 malignant) measured with broadband quantitative DOS were analyzed for their oxyhemoglobin (HbO), deoxyhemoglobin (HHb), water, lipids, collagen, metHb concentrations, and optical scattering characteristics. Wilcoxon rank sum test was used to compare benign and malignant lesions for all variables in both normalized and absolute forms. RESULTS: Among all absolute DOS parameters considered, only absolute metHb was observed to be significant for lesion discrimination (0.43 ± 0.18 µM for benign versus 0.87 ± 0.32 µM for malignant, p = 0.0002). Absolute metHb concentration was also determined to be the best predictor of malignancy with an area under the curve of 0.89. CONCLUSIONS: Our findings demonstrate that lesion metHb concentration measured by DOS can improve noninvasive optical diagnosis of breast malignancies. Since metHb concentration found in normal breast tissue is extremely low, metHb may be a more direct indicator of malignancy that does not depend on other biomarkers found in healthy tissue with significant variability. Furthermore, absolute parameters require reduced measurement time and can be utilized in cases where healthy reference tissue is not available.

A scalable, multi-wavelength, broad bandwidth frequency-domain near-infrared spectroscopy platform for real-time quantitative tissue optical imaging.

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.

Breast cancer differential diagnosis using diffuse optical spectroscopic imaging and regression with z-score normalized data.

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.

Quantitative diffuse optical spectroscopy for noninvasive measurements of the malaria pigment hemozoin.

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.

Optimizing sensitivity and dynamic range of silicon photomultipliers for frequency-domain near infrared spectroscopy.

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.

Diffuse optical spectroscopic imaging for the investigation of human lactation physiology: a case study on mammary involution.

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.

Non-invasive Dual-Channel Broadband Diffuse Optical Spectroscopy of Massive Hemorrhage and Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in Swine.

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.

Tissue oxygen saturation predicts response to breast cancer neoadjuvant chemotherapy within 10 days of treatment.

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 z-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on z-score normalization using only tissue oxygen saturation (StO2) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR (AUC = 0.92; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue StO2 to surrounding tissue StO2 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.

Vertical-cavity surface-emitting laser sources for gigahertz-bandwidth, multiwavelength frequency-domain photon migration.

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 1 GHz. 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.

Performance assessment of diffuse optical spectroscopic imaging instruments in a 2-year multicenter breast cancer trial

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 <0.0010 mm−1 (10.3%) and 0.06 mm−1 (4.7%) deviation in broadband absorption and reduced scattering, respectively, over the 2-year duration of ACRIN-6691. These variations establish a useful performance criterion for assessing instrument stability. The proposed procedures and tests are not limited to DOSI; rather, they are intended to provide methods to characterize performance of any instrument used in translational optical imaging.