In vivo two-dimensional quantitative imaging of skin and cutaneous microcirculation with perturbative spatial frequency domain imaging (p-SFDI).

We introduce perturbative spatial frequency domain imaging (p-SFDI) for fast two-dimensional (2D) mapping of the optical properties and physiological characteristics of skin and cutaneous microcirculation using spatially modulated visible light. Compared to the traditional methods for recovering 2D maps through a pixel-by-pixel inversion, p-SFDI significantly shortens parameter retrieval time, largely avoids the random fitting errors caused by measurement noise, and enhances the image reconstruction quality. The efficacy of p-SFDI is demonstrated by in vivo imaging forearm of one healthy subject, recovering the 2D spatial distribution of cutaneous hemoglobin concentration, oxygen saturation, scattering properties, the melanin content, and the epidermal thickness over a large field of view. Furthermore, the temporal and spatial variations in physiological parameters under the forearm reactive hyperemia protocol are revealed, showing its applications in monitoring temporal and spatial dynamics.

Handheld spatial frequency domain imager for noninvasive Sjögren's syndrome labial salivary gland biopsy.

A labial salivary gland biopsy (LSGB) plays an essential role in diagnosing Sjögren's syndrome (SS), but its clinical application is limited due to its invasiveness. Here, we present a handheld single snapshot multiple-frequency demodulation-spatial frequency domain imaging (SSMD-SFDI) device for a rapid optical biopsy of labial salivary glands noninvasively. The structural and physiological parameters of lower lip mucosa were obtained from the light reflectance of the layered oral mucosa. The recovered parameters were found to correlate strongly with the progression of SS. In our pilot study on 15 healthy subjects and 183 SS patients, a support vector machine (SVM) classifier using the measured parameters distinguished healthy subjects, LSGB I, II, III, and IV patients in sequence with AUCs of 0.979, 0.898, 0.906, and 0.978, respectively. Critical structural and physiological alterations in the mucosa due to SS were further identified and used to assess its risk using an explainable neural network. The handheld spatial frequency domain imager may serve as a valuable label-free and noninvasive tool for early diagnosing and surveying SS.

Single snapshot spatial frequency domain imaging for risk stratification of diabetes and diabetic foot.

Diabetic foot is one of the major complications of diabetes. In this work, a real-time Single Snapshot Multiple-frequency Demodulation (SSMD) - Spatial Frequency Domain Imaging (SFDI) system was used to image the forefoot of healthy volunteers, diabetes, and diabetic foot patients. A layered skin model was used to obtain the 2D maps of optical and physiological parameters, including cutaneous hemoglobin concentration, oxygen saturation, scattering properties, melanin content, and epidermal thickness, from every single snapshot. We observed a strong correlation between the measured optical and physiological parameters and the degree of diabetes. The cutaneous hemoglobin concentration, oxygen saturation, and epidermal thickness decrease, whereas the melanin content increases with the progress of diabetes. The melanin content further increases, and the reduced scattering coefficient and scattering power are lower for diabetic foot patients than those of both healthy and diabetic subjects. High accuracies (AUC) of 97.2% (distinguishing the diabetic foot patients among all subjects), 95.2% (separating healthy subjects from the diabetes patients), and 87.8% (classifying mild vs severe diabetes), respectively, are achieved in binary classifications in sequence using the SSMD-SFDI system, demonstrating its applicability to risk stratification of diabetes and diabetic foot. The prognostic value of the SSMD-SFDI system in the prediction of the occurrence of the diabetic foot and other applications in monitoring tissue microcirculation and peripheral vascular disease are also addressed.

Dynamic microcirculation PIPE model for functional neuroimaging, non-neuroimaging, and coherent hemodynamics spectroscopy: blood volume and flow velocity variations, and vascular autoregulation.

We present a dynamic microcirculation PIPE model for functional neuroimaging, non-neuroimaging, and coherent hemodynamics spectroscopy. The temporal evolution of the concentration and oxygen saturation of hemoglobin in tissue, comprised of the contributions from the arterioles, capillaries, and venules of microvasculature, is determined by time-resolved hemodynamic and metabolic variations in blood volume, flow velocity, and oxygen consumption with a fluid mechanics treatment. Key parameters regarding microcirculation can be assessed, including the effective blood transit times through the capillaries and the venules, and the rate constant of oxygen release from hemoglobin to tissue. The vascular autoregulation can further be quantified from the relationship between the resolved blood volume and flow velocity variations. The PIPE model shows excellent agreement with the experimental cerebral and cutaneous coherent hemodynamics spectroscopy (CHS) and fMRI-BOLD data. It further identifies the impaired cerebral autoregulation distinctively in hemodialysis patients compared to healthy subjects measured by CHS. This new dynamic microcirculation PIPE model provides a valuable tool for brain and other functional studies with hemodynamic-based techniques. It is instrumental in recovering physiological parameters from analyzing and interpreting the signals measured by hemodynamic-based neuroimaging and non-neuroimaging techniques such as functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI) in response to brain activation, physiological challenges, or physical maneuvers.

Robust quantitative single-exposure laser speckle imaging with true flow speckle contrast in the temporal and spatial domains.

A systematic and robust laser speckle contrast imaging (LSCI) method and procedure is presented covering the LSCI system calibration, static scattering removal, and measurement noise estimation and correction to obtain a true flow speckle contrast K f 2 and the flow speed from single-exposure LSCI measurements. We advocate the use of K 2 as the speckle contrast instead of the conventional contrast K, as the former relates simply to the flow velocity and is with additive noise alone. We demonstrate the efficacy of the proposed true flow speckle contrast by imaging phantom flow at varying speeds, showing that (1) the proposed recipe greatly enhances the linear sensitivity of the flow index (inverse decorrelation time) and the linearity covers the full span of flow speeds from 0 to 40 mm/s; and (2) the true flow speed can be recovered regardless of the overlying static scattering layers and the type of speckle statistics (temporal or spatial). The fundamental difference between the apparent temporal and spatial speckle contrasts is further revealed. The flow index recovered in the spatial domain is much more susceptible to static scattering and exhibit a shorter linearity range than that obtained in the temporal domain. The proposed LSCI analysis framework paves the way to estimate the true flow speed in the wide array of laser speckle contrast imaging applications.

Lung cancer diagnosis with quantitative DIC microscopy and a deep convolutional neural network.

We present a study on lung squamous cell carcinoma diagnosis using quantitative TI-DIC microscopy and a deep convolutional neural network (DCNN). The 2-D phase map of unstained tissue sections is first retrieved from through-focus differential interference contrast (DIC) images based on the transport of intensity equation (TIE). The spatially resolved optical properties are then computed from the 2-D phase map via the scattering-phase theorem. The scattering coefficient ( µ S ) and the reduced scattering coefficient ( µ S ' ) are found to increase whereas the anisotropy factor (g) is found to decrease with cancer. A DCNN classifier is developed afterwards to classify the tissue using either the DIC images or 2-D optical property maps of µ S , µ S ' and g. The DCNN classifier with the optical property maps exhibits high accuracy, significantly outperforming the same DCNN classifier on the DIC images. The label-free quantitative phase microscopy together with deep learning may emerge as a promising approach for in situ rapid cancer diagnosis.

Transmission matrix-based Electric field Monte Carlo study and experimental validation of the propagation characteristics of Bessel beams in turbid media.

A novel Transmission matrix-based Electric field Monte Carlo (TEMC) method is introduced to study the propagation characteristics of Bessel beams with different orbital angular momentum (OAM) in turbid media. As an extension to the Electric field Monte Carlo (EMC) approach, electric field transmission modes were simulated to properly evaluate light interference. Beam transmission patterns, intensity attenuation, and the degree of polarization (DOP) through turbid media of varying thickness were analyzed. It was found that the OAM plays a subtle role in transmission through turbid media, showing only a weak correlation with total transmission, the preservation of DOP, and the penetration depth. The TEMC simulation results were in excellent agreement with experiments, validating the proposed method for the study of coherence phenomenon in turbid media.

Quantitative diagnosis of tissue microstructure with wide-field high spatial frequency domain imaging.

Non-contact and minimally invasive endoscopic optical imaging is an invaluable diagnostic tool for tissue examination and cancer screening. The point sampling techniques with high sensitivity to the tissue microenvironment are time consuming and often not affordable in clinics. There is a major clinical need for a large field-of-view (FOV) rapid screening method to highlight subtle tissue microstructural alterations. To address this unmet need, we have developed High Spatial Frequency Domain Imaging (HSFDI)-a non-contact imaging modality that spatially maps the tissue microscopic scattering structures over a large field of view (>1cm2). Based on an analytical reflectance model of sub-diffusive light from forward-peaked highly scattering media, HSFDI quantifies the spatially-resolved parameters of the light scattering phase function (i.e., the backscattering probability and the light spreading length) from the reflectance of structured light modulated at high spatial frequencies. Enhanced signal to noise ratio (SNR) is achieved at even ultra-high modulation frequencies with single snapshot multiple frequency demodulation (SSMD). The variations in tissue microstructures, including the strength of the background (pudding) refractive index fluctuation and the prominent scattering structure (plum) morphology, can then be inferred. After validation with optical phantoms, measurements of fresh ex vivo tissue samples revealed significant contrast and differentiation of the phase function parameters between different types and disease states (normal, inflammatory, and cancerous) of tissue whereas tissue absorption and reduced scattering coefficients only show modest changes. HSFDI may provide wide-field images of microscopic structural biomarkers unobtainable with either diffuse light imaging or point-based optical sampling. Potential clinical applications include the rapid screening of excised tissue and the noninvasive examination of suspicious lesions during operation.

DeCoST: A New Approach in Drug Repurposing From Control System Theory.

In this paper, we propose DeCoST (Drug Repurposing from Control System Theory) framework to apply control system paradigm for drug repurposing purpose. Drug repurposing has become one of the most active areas in pharmacology since the last decade. Compared to traditional drug development, drug repurposing may provide more systematic and significantly less expensive approaches in discovering new treatments for complex diseases. Although drug repurposing techniques rapidly evolve from "one: disease-gene-drug" to "multi: gene, dru" and from "lazy guilt-by-association" to "systematic model-based pattern matching," mathematical system and control paradigm has not been widely applied to model the system biology connectivity among drugs, genes, and diseases. In this paradigm, our DeCoST framework, which is among the earliest approaches in drug repurposing with control theory paradigm, applies biological and pharmaceutical knowledge to quantify rich connective data sources among drugs, genes, and diseases to construct disease-specific mathematical model. We use linear-quadratic regulator control technique to assess the therapeutic effect of a drug in disease-specific treatment. DeCoST framework could classify between FDA-approved drugs and rejected/withdrawn drug, which is the foundation to apply DeCoST in recommending potentially new treatment. Applying DeCoST in Breast Cancer and Bladder Cancer, we reprofiled 8 promising candidate drugs for Breast Cancer ER+ (Erbitux, Flutamide, etc.), 2 drugs for Breast Cancer ER- (Daunorubicin and Donepezil) and 10 drugs for Bladder Cancer repurposing (Zafirlukast, Tenofovir, etc.).

In vivo real-time imaging of cutaneous hemoglobin concentration, oxygen saturation, scattering properties, melanin content, and epidermal thickness with visible spatially modulated light.

We present the real-time single snapshot multiple frequency demodulation - spatial frequency domain imaging (SSMD-SFDI) platform implemented with a visible digital mirror device that is capable of imaging and monitoring dynamic turbid medium and processes over a large field of view. One challenge in quantitative imaging of biological tissue such as the skin is the complex structure rendering techniques based on homogeneous medium models to fail. To address this difficulty we have also developed a novel method that maps the layered structure to a homogeneous medium for spatial frequency domain imaging. The varying penetration depth of spatially modulated light on its wavelength and modulation frequency is used to resolve the layered structure. The efficacy of the real-time SSMD-SFDI platform and this two-layer model is demonstrated by imaging forearms of 6 healthy subjects under the reactive hyperemia protocol. The results show that our approach not only successfully decouples light absorption by melanin from that by hemoglobin and yields accurate determination of cutaneous hemoglobin concentration and oxygen saturation, but also provides reliable estimation of the scattering properties, the melanin content and the epidermal thickness in real time. Potential applications of our system in imaging skin physiological and functional states, cancer screening, and microcirculation monitoring are discussed at the end.

Trapping two types of particles by modified circular Airy beams.

The radiation force of modified circular Airy beams (MCAB) exerted on both a high-refractive-index particle and a low-refractive-index particle are analyzed in this paper. Our results show that the two kinds of particles can be simultaneously stably trapped by MCAB at different positions. Compared with the common circular Airy beams (CAB) with the same parameters, trapping forces on the two kinds of particles are greatly increased because of the enhanced abruptly autofocusing property and the appearance of hollow region in MCAB. The trapping forces can be modulated by varying parameters of MCAB, and it is important to choose appropriate parameters to trap particles in practice.

[Design and Implementation of a Portable Forced Oscillation Respiration Resistance Detector].

This paper proposes a forced oscillation respiration resistance detector which has the characteristics of portable and friendly interface,with remote transmission function.STM32 is used to produce single frequency or complex frequency oscillation signal.In the experiments,the signal was magnified by the power amplifier to drive speaker to generate oscillates airflow into the subject's oral cavity.The analog to digital coverter of STM32 was used to measure the signals obtained by the pressure sensor and the flow sensor,and then the operation parameters were to be displayed on the TFT-LCD touch screen,and could also be transferred to the master computer.Simulated lung and volunteerism were used to verify the reliability of the detector.The test results showed that the system was reliable,and it achieved the significance in respiratory impedance detecting.

[Design of Oxygen Saturation, Heart Rate, Respiration Rate Detection System Based on Smartphone of Android Operating System].

In this paper, we designed an oxygen saturation, heart rate, respiration rate monitoring system based on smartphone of android operating system, physiological signal acquired by MSP430 microcontroller and transmitted by Bluetooth module.

[Assessment Method of Remnant α-1, 3-galactosyle Epitopes in Animal Tissue-derived Biomaterials].

The aim of this study was to establish an assessment method for determining α-Gal (α-1, 3-galactosyle) epitopes contained in animal tissue or animal tissue-derived biological materials with ELISA inhibition assay. Firstly, a 96 well plate was coated with Gal α-1, 3-Gal/bovine serum albumin (BSA) as a solid phase antigen and meanwhile, the anti-α-Gal M86 was used to react with α-Gal antigens which contained in the test materials. Then, the residual antibodies (M86) in the supernatant of M86-Gal reaction mixture were measured using ELISA inhibition assay by the α-Gal coating plate. The inhibition curve of the ELISA inhibition assay, the R2 = 0.999, was well established. Checking using both α-Gal positive materials (rat liver tissues) and α-Gal negative materials (human placenta tissues) showed a good sensitivity and specificity. Based on the presently established method, the α-Gal expression profile of rat tissues, decellular animal tissue-derived biological materials and porcine dermal before and after decellular treatment were determined. The M86 ELISA inhibition assay method, which can quantitatively determine the α-Gal antigens contained in animal tissues or animal tissue-derived biomaterials, was refined. This M86 specific antibody based-ELISA inhibition assay established in the present study has good sensitivity and specificity, and could be a useful method for determining remnant α-1, 3Gal antigens in animal tissue-derived biomaterials.