Significance: The COVID-19 pandemic is changing the landscape of healthcare delivery in many countries, with a new shift toward remote patient monitoring (RPM).
Aim: The goal of this perspective is ...to highlight the existing and future role of wearable and RPM optical technologies in an increasingly at-home healthcare and research environment.
Approach: First, the specific changes occurring during the COVID-19 pandemic in healthcare delivery, regulations, and technological innovations related to RPM technologies are reviewed. Then, a review of the current state and potential future impact of optical physiological monitoring in portable and wearable formats is outlined.
Results: New efforts from academia, industry, and regulatory agencies are advancing and encouraging at-home, portable, and wearable physiological monitors as a growing part of healthcare delivery. It is hoped that these shifts will assist with disease diagnosis, treatment, management, recovery, and rehabilitation with minimal in-person contact. Some of these trends are likely to persist for years to come. Optical technologies already account for a large portion of RPM platforms, with a good potential for future growth.
Conclusions: The biomedical optics community has a potentially large role to play in developing, testing, and commercializing new wearable and RPM technologies to meet the changing healthcare and research landscape in the COVID-19 era and beyond.
Water and lipids are key participants in many biological processes, but there are few non-invasive methods that provide quantification of these components in vivo, and none that can isolate and ...quantify lipids in the blood. Here we develop a new imaging modality termed shortwave infrared meso-patterned imaging (SWIR-MPI) to provide label-free, non-contact, spatial mapping of water and lipid concentrations in tissue. The method utilizes patterned hyperspectral illumination to target chromophore absorption bands in the 900-1,300 nm wavelength range. We use SWIR-MPI to monitor clinically important physiological processes including edema, inflammation, and tumor lipid heterogeneity in preclinical models. We also show that SWIR-MPI can spatially map blood-lipids in humans, representing an example of non-invasive and contact-free measurements of in vivo blood lipids. Together, these results highlight the potential of SWIR-MPI to enable new capabilities in fundamental studies and clinical monitoring of major conditions including obesity, cancer, and cardiovascular disease.
Significance: Frequency domain diffuse optical spectroscopy (FD-DOS) uses intensity modulated light to measure the absorption and reduced scattering coefficients of turbid media such as biological ...tissue. Some FD-DOS instruments utilize a single modulation frequency, whereas others use hundreds of frequencies. The effect of modulation frequency choice and measurement bandwidth on optical property (OP) extraction accuracy has not yet been fully characterized.
Aim: We aim to assess the effect of modulation frequency selection on OP extraction error and develop a high-speed look-up table (LUT) approach for OP estimation.
Approach: We first used noise-free simulations of light transport in homogeneous media to determine optimized iterative inversion model parameters and developed a new multi-frequency LUT method to increase the speed of inversion. We then used experimentally derived noise models for two FD-DOS instruments to generate realistic simulated data for a broad range of OPs and modulation frequencies to test OP extraction accuracy.
Results: We found that repeated measurements at a single low-frequency (110 MHz) yielded essentially identical OP errors as a broadband frequency sweep (35 evenly spaced frequencies between 50 and 253 MHz) for these noise models. The inclusion of modulation frequencies >300 MHz diminished overall performance for one of the instruments. Additionally, we developed a LUT inversion algorithm capable of increasing inversion speeds by up to 6 × , with 1000 inversions / s and ∼1 % error when a single modulation frequency was used.
Conclusion: These results suggest that simpler single-frequency systems are likely sufficient for many applications and pave the way for a new generation of simpler digital FD-DOS systems capable of rapid, large-volume measurements with real-time feedback.
Blood lipid levels (i.e., triglycerides (TGs) and cholesterol) are a strong predictor of cardiovascular disease (CVD) risk. Current methods for measuring blood lipids require invasive blood draws and ...traditional lab testing, limiting their practicality for frequent monitoring. Optical measurements of lipoproteins, which carry TG and cholesterol in blood, may lead to simpler invasive or non-invasive methods for more frequent and rapid blood lipid measurements.
To investigate the effect of lipoproteins on optical properties of blood before and after a high-fat meal (i.e., the pre- and post-prandial state).
Simulations were performed using Mie theory to estimate lipoprotein scattering properties. A literature review was conducted to identify key simulation parameters including lipoprotein size distributions and number density. Experimental validation of
blood samples was conducted using spatial frequency domain imaging.
Our results indicated that lipoproteins in blood, particularly very low-density lipoproteins and chylomicrons, are highly scattering in the visible and near-infrared wavelength region. Estimates of the increase in the reduced scattering coefficient (
) of blood at 730 nm after a high-fat meal ranged from 4% for a healthy individual, to 15% for those with type 2 diabetes, to up to 64% for those suffering from hypertriglyceridemia. A reduction in blood scattering anisotropy (
) also occurred as a function of TG concentration increase.
These findings lay the foundation for future research in the development of optical methods for invasive and non-invasive optical measure of blood lipoproteins, which could improve early detection and management of CVD risk.
Spatial Frequency Domain Imaging (SFDI) can provide longitudinal, label-free, and widefield hemodynamic and scattering measurements of murine tumors in vivo. Our previous work has shown that the ...reduced scattering coefficient (μ'
) at 800 nm, as well as the wavelength dependence of scattering, both have prognostic value in tracking apoptosis and proliferation during treatment with anti-cancer therapies. However, there is limited work in validating these optical biomarkers in clinically relevant tumor models that manifest specific treatment resistance mechanisms that mimic the clinical setting. It was recently demonstrated that metronomic dosing of cyclophosphamide induces a strong anti-tumor immune response and tumor volume reduction in the E0771 murine breast cancer model. This immune activation mechanism can be blocked with an IFNAR-1 antibody, leading to treatment resistance. Here we present a longitudinal study utilizing SFDI to monitor this paired responsive-resistant model for up to 30 days of drug treatment. Mice receiving the immune modulatory metronomic cyclophosphamide schedule had a significant increase in tumor optical scattering compared to mice receiving cyclophosphamide in combination with the IFNAR-1 antibody (9% increase vs 10% decrease on day 5 of treatment, p < 0.001). The magnitude of these differences increased throughout the duration of treatment. Additionally, scattering changes on day 4 of treatment could discriminate responsive versus resistant tumors with an accuracy of 78%, while tumor volume had an accuracy of only 52%. These results validate optical scattering as a promising prognostic biomarker that can discriminate between treatment responsive and resistant tumor models.
Significance: The shortwave infrared (SWIR) optical window (∼900 to 2000 nm) has attracted interest for deep tissue imaging due to the lower scattering of light. SWIR spatial frequency domain imaging ...(SWIR SFDI) provides wide-field tissue optical property measurements in this wavelength band. Key design and performance characteristics, such as portability, wavelength selection, measurement resolution, and the effect of skin have not yet been addressed for SWIR SFDI.
Aim: To fabricate and characterize a SWIR SFDI system for clinical use.
Approach: The optimal choice of wavelengths was identified based on optical property uncertainty estimates and imaging depth. A compact light-emitting diode-based dual wavelength SWIR SFDI system was fabricated. A two-layer inverse model was developed to account for the layered structure of skin. Performance was validated using tissue-simulating phantoms and in-vivo measurements from three healthy subjects.
Results: The SWIR SFDI system had a μs′ resolution of at least 0.03 mm − 1 at 880 nm and 0.02 mm − 1 at 1100 nm. The two-layer inverse model reduced the error in deeper layer μs′ extractions by at least 24% in the phantom study. The two-layer model also increased the contrast between superficial vessels and the surrounding tissue for in-vivo measurements.
Conclusion: The clinic-ready SWIR SFDI device is sensitive to small optical property alterations in diffuse media, provides enhanced accuracy in quantifying optical properties in the deeper layers in phantoms, and provided enhanced contrast of subcutaneous blood vessels.
We present a Monte Carlo (MC) method to determine depth-dependent probability distributions of photon visitation and detection for optical reflectance measurements performed in the spatial frequency ...domain (SFD). These distributions are formed using an MC simulation for radiative transport that utilizes a photon packet weighting procedure consistent with the two-dimensional spatial Fourier transform of the radiative transport equation. This method enables the development of quantitative metrics for SFD optical sampling depth in layered tissue and its dependence on both tissue optical properties and spatial frequency. We validate the computed depth-dependent probability distributions using SFD measurements in a layered phantom system with a highly scattering top layer of variable thickness supported by a highly absorbing base layer. We utilize our method to establish the spatial frequency-dependent optical sampling depth for a number of tissue types and also provide a general tool to determine such depths for tissues of arbitrary optical properties.
Fluorescence quantum yield (QY) indicates the efficiency of the fluorescence process. The QY of many fluorophores is sensitive to local tissue environments, highlighting the possibility of using QY ...as an indicator of important parameters such as pH or temperature. QY is commonly measured by comparison to a well-known standard in nonscattering media. We propose a new imaging method, called quantum yield imaging (QYI), to spatially map the QY of a fluorophore within an optically diffusive media. QYI utilizes the wide-field diffuse optical technique spatial frequency domain imaging (SFDI) as well as planar fluorescence imaging. SFDI is used to measure the optical properties of the background media and the absorption contributed by the fluorophore. The unknown QY is then calculated by combining information from both modalities. A fluorescent sample with known QY is used to account for instrument response. To demonstrate QYI, rhodamine B and SNARF-5 were imaged in liquid phantoms with different background optical properties. The methanol:water ratio and pH were changed for rhodamine B and SNARF-5 solvents, respectively, altering the QY of each through a wide range. QY was determined with an agreement of 0.021 and 0.012 for rhodamine B and SNARF-5, respectively.
Cancer cells are mechanically sensitive to physical properties of the microenvironment, which can affect downstream signaling to promote malignancy, in part through the modulation of metabolic ...pathways. Fluorescence Lifetime Imaging Microscopy (FLIM) can be used to measure the fluorescence lifetime of endogenous fluorophores, such as the metabolic co-factors NAD(P)H and FAD, in live samples. We used multiphoton FLIM to investigate the changes in cellular metabolism of 3D breast spheroids derived from MCF-10A and MD-MB-231 cell lines embedded in collagen with varying densities (1 vs. 4 mg/ml) over time (Day 0 vs. Day 3). MCF-10A spheroids demonstrated spatial gradients, with the cells closest to the spheroid edge exhibiting FLIM changes consistent with a shift towards oxidative phosphorylation (OXPHOS) while the spheroid core had changes consistent with a shift towards glycolysis. The MDA-MB-231 spheroids had a large shift consistent with increased OXPHOS with a more pronounced change at the higher collagen concentration. The MDA-MB-231 spheroids invaded into the collagen gel over time and cells that traveled the farthest had the largest changes consistent with a shift towards OXPHOS. Overall, these results suggest that the cells in contact with the extracellular matrix (ECM) and those that migrated the farthest had changes consistent with a metabolic shift towards OXPHOS. More generally, these results demonstrate the ability of multiphoton FLIM to characterize how spheroids metabolism and spatial metabolic gradients are modified by physical properties of the 3D ECM.
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.
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).
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 < 0.0001). Flare was not observed in patients receiving MET therapy. Within all responding patients, the specific treatment was a significant predictor of day 1 changes in oxyhemoglobin, showing a difference of 39.45% (p = 0.0010) between patients receiving MTD and MET regimens.
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.
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