Widely wavelength tunable fast intensity-modulated light source for biophotonic applications.

High modulation depth, fast (megahertz to gigahertz), intensity-modulated light sources of various wavelengths within the 0.7-1.35 µm bio-penetration window are highly desirable for many biophotonic diagnosis systems. In this Letter, we present a novel scheme of a wavelength tunable, ultra-broadband light source which simply consists of a pump laser, a nonlinear fiber, and demodulation circuits. The working wavelength range of the light source is from 0.7 to 1.35 µm which covers a vast part of the bio-penetration window, and its modulation frequencies extends from tens of megahertz to gigahertz. The performances of the proposed light source in either working wavelength range or modulation frequency bandwidth are much superior to any typical laser diodes or solid state lasers currently employed in the frequency-domain or other biophotonic utilization. The wide applicability of this novel light source in diverse biophotonic applications can be observed from our carefully designed diffused optical spectroscopy phantom measurement.

Holographic polymer networks formed in liquid crystal phase modulators via a He-Ne laser to achieve ultra-fast optical response.

The holographic polymer network formed in liquid crystal (LC) phase modulators via a He-Ne laser in this study demonstrates ultra-fast optically response and low light scattering. These advantages are mainly caused by the small LC domains and uniform polymer network when processing LC cells via holographic exposure to a He-Ne laser. The use of this method to fabricate LC cells as phase modulators results in a decay time of 49 µs under 2π phase modulation at room temperature. The predicted fast optical response can be achieved when operating devices at high temperatures.

Continuous Wave Spectroscopy with Diffusion Theory for Quantification of Optical Properties: Comparison Between Multi-distance and Multi-wavelength Data Fitting Methods.

Typically, continuous wave spectroscopy (CWS) can be used to accurately quantify biological tissue optical properties (µ a and µ s ') by employing the diffuse reflectance information acquired at multiple source-detector separations (multi-distance). On the other hand, sample optical properties can also be obtained by fitting multi-wavelength light reflectance acquired at a single source detector separation to the diffusion theory equation. To date, multi-wavelength and multi-distance methods have not yet been rigorously compared for their accuracy in quantification of the sample optical properties. In this investigation, we compared the accuracy of the two above-mentioned quantifying methods in the optical properties recovery. The liquid phantoms had µ a between 0.004 and 0.011 mm(-1) and µ s ' between 0.55 and 1.07 mm(-1) whose optical properties mimic the human breast. Multi-distance data and multi-wavelength data were fitted to the same diffusion equation for consistency. The difference between benchmark µ a and µ s ' and the fitted results, ΔError (ΔE) was used to evaluate the accuracy of the two methods. The results showed that either method yielded ΔE within 15-30 % when values were within certain limits to standard values applicable to µ s ' and µ a for human adipose tissue. Both methods showed no significant differences in ΔE values. Our results suggest that both multi-distance and multi-wavelength methods can yield similar reasonable optical properties in biological tissue with a proper calibration.

Higher-order modulations of fs laser pulses for GHz frequency domain photon migration system.

Except the fundamental modulation frequency, by higher-order-harmonic modulations of mode-locked laser pulses and a simple frequency demodulation circuit, a novel approach to GHz frequency-domain-photon-migration (FDPM) system was reported. With this novel approach, a wide-band modulation frequency comb is available without any external modulation devices and the only electronics to extract the optical attenuation and phase properties at a selected modulation frequency in FDPM systems are good mixers and lock-in devices. This approach greatly expands the frequency range that could be achieved by conventional FDPM systems and suggests that our system could extract much more information from biological tissues than the conventional FDPM systems. Moreover, this demonstration will be beneficial for discerning the minute change of tissue properties.

Noninvasive hemoglobin quantification across different cohorts using a wearable diffuse reflectance spectroscopy system.

Quantifying hemoglobin is vital yet invasive through blood draws. We developed a wearable diffuse reflectance spectroscopy device comprising control and sensor boards with photodiodes and light-emitting diodes to noninvasively determine hemoglobin. Neural networks enabled recovery of optical parameters for chromophore fitting to calculate hemoglobin. Testing healthy and elderly subjects revealed strong correlation (r=0.9) between our system and invasive methods after data conversion. Bland-Altman analysis demonstrated tight 95% limits of agreement from -1.98 to 1.98 g/dL between the DRS and invasive hemoglobin concentrations. By spectroscopically isolating hemoglobin absorption, interference from melanin was overcome. Our device has the potential for future integration into wearable technology, enabling hemoglobin level tracking.

Breast cancer detection of large size to DCIS by hypoxia and angiogenesis using NIRS.

This investigation aimed to test all tumor-bearing patients who undergo biopsy to see if angiogenesis and hypoxia can detect cancer. We used continuous-wave near-infrared spectroscopy (NIRS) to measure blood hemoglobin concentration to obtain blood volume or total hemoglobin [Hbtot] and oxygen saturation for the angiogenesis and hypoxic biomarkers. The contralateral breast was used as a reference to derive the difference from breast tumor as a difference in total hemoglobin Δ[HBtot] and a difference in deoxygenation Δ([Hb]-[HbO2]). A total of 91 invasive cancers, 26 DCIS, 45 fibroblastomas, 96 benign tumors excluding cysts, and 67 normal breasts were examined from four hospitals. In larger-size tumors, there is significantly higher deoxygenation in invasive and ductal carcinoma in situ (DCIS) than in that of benign tumors, but no significant difference was seen in smaller tumors of ≤ 1 cm. With the two parameters of high total hemoglobin and hypoxia score, the sensitivity and specificity of cancer detection were 60.3 % and 85.3 %, respectively. In summary, smaller-size tumors are difficult to detect with NIRS, whereas DCIS can be detected by the same total hemoglobin and hypoxic score in our study.

Non-invasive assessment of skin hydration and sensation with diffuse reflectance spectroscopy.

The skin is a vital organ in the human body, providing essential functions such as protection, sensation, and metabolism. Skin hydration is one of the crucial factors in maintaining normal skin function. Insufficient skin hydration can lead to dryness, shedding of the stratum corneum, a decrease in skin barrier function, and may cause skin inflammation. Therefore, maintaining or improving skin hydration is critical in promoting healthy skin. Currently, the commonly used method for measuring skin hydration is bioelectrical capacitance analysis, which is often affected by environmental humidity and can only provide limited information. To overcome these limitations, this study used diffuse reflectance spectroscopy (DRS) in the wavelength range of 400-1000 nm to quantify skin absorption and scattering modulation caused by changes in skin hydration states. The advantages of this technique include rapid measurements, non-invasiveness, a straightforward optical setup, and suitability for prolonged skin monitoring. We found that DRS-derived skin absorption coefficients had a correlation coefficient of 0.93 with the skin capacitance at various skin hydration states. In addition, our findings reveal that absorption and scattering coefficients may be useful in discerning skin hydration enhancement induced by applying soaked cotton pads or cosmeceutical facial masks, as well as evaluating skin sensation. This study verifies that the DRS method could be a convenient and effective tool for evaluating skin hydration related information.

Noninvasive transcutaneous bilirubin measurement in adults using skin diffuse reflectance.

Accurate measurement of bilirubin concentration in adults is crucial for the diagnosis and management of liver and biliary tract diseases. Traditional methods relying on central laboratory testing pose challenges such as invasiveness, patient discomfort, and time consumption. Non-invasive alternatives have been explored, but their applicability to adult populations remains uncertain. This study aimed to develop and validate a portable non-invasive optical system based on spatially resolved diffuse reflectance spectroscopy (DRS) specifically tailored for adult transcutaneous bilirubin measurement. Forty-two adult patients with various underlying conditions were included in the study. Comparisons between transcutaneous bilirubin values measured by the DRS system and total serum bilirubin concentrations obtained through blood tests revealed strong correlations, particularly at the neck (r = 0.872) and the medial side of the right upper arm (r = 0.940). Bland-Altman analyses demonstrated substantial agreement between the transcutaneous bilirubin values and total serum bilirubin concentrations. The results highlight the potential of the non-invasive DRS system as a convenient and reliable tool for monitoring bilirubin values in adults.

Handheld diffuse reflectance spectroscopy system for noninvasive quantification of neonatal bilirubin and hemoglobin concentrations: a pilot study.

The prevalence rate of neonatal jaundice can reach 80%, of which 5% may develop dangerous hemolytic jaundice. The blood test for obtaining bilirubin and hemoglobin concentration is the gold standard for diagnosing hemolytic jaundice; however, frequently drawing blood from jaundice neonates for the screening purpose is not practical. We have developed a handheld diffuse reflectance spectroscopy system to noninvasively determine the bilirubin and hemoglobin levels in neonates. Our study showed that the correlation coefficients were 0.95 and 0.80 for bilirubin and hemoglobin between the results from the blood tests and our handheld system, respectively. This handheld system could be an effective tool for screening hemolytic jaundice.

Investigating the clinical implication of corneometer and mexameter readings towards objective, efficient evaluation of psoriasis vulgaris severity.

In clinical settings, although Psoriasis Area and Severity Index (PASI) scoring system can provide a quick visual assessment of the severity of psoriasis vulgaris, there is still a strong demand for higher efficiency and accuracy in quantifying the inflammation status of psoriatic lesions. Currently, there are already commercial systems, such as the Courage + Khazaka Corneometer and Mexameter that measure skin capacitance and optical reflectance, for conveniently quantifying the status of skin barrier function and erythema of skin. Despite numerous comparisons of the Courage + Khazaka system with the PASI scoring system, they are rarely compared on parity with diffuse reflectance spectroscopy (DRS) based systems. In this study, we employed a custom-built DRS system shown to be able to determine the skin water-protein binding status and the hemoglobin concentration, and we performed cross-validation of the DRS measurement results with the readings derived from the Corneometer and Mexameter as well as a portion of the PASI scores. Our results revealed that the erythema readings from the Mexameter were a good representation of skin oxygenated hemoglobin but not the deoxygenated hemoglobin. On the other hand, the dermatologists recruited in this study were inclined to rate higher scores on the "erythema" category as skin's deoxygenated hemoglobin level was higher. Thus, the Mexameter derived erythema readings may not be coherent with the PASI erythema scores. Further, the Corneometer derived skin capacitance readings were well correlated to the PASI "desquamation" and "thickness" scores, while the PASI "desquamation" evaluation was a dominating factor contributing to the DRS deduced water-protein binding status. We conclude that the DRS method could be a valuable addition to existing skin capacitance/reflectance measurement systems and the PASI scoring system toward achieving a more efficient and objective clinical psoriasis vulgaris severity evaluation.

Monitoring adaptation of skin tissue oxygenation during cycling ergometer exercise by frequency-domain diffuse optical spectroscopy.

In addition to supplying oxygen molecule O2 for metabolic functions during the adaptation to exercise, blood also plays a critical role in heat dissipation for core temperature stabilization. This study investigates the status of hemodynamic oxygenation in the forearm's skin tissue of three participants during a complete ergometer exercise from the resting to exercising, and to recovering conditions using a three-wavelength frequency-domain diffuse reflectance spectroscopy (FD DRS) alongside the monitoring of heartbeat rate and skin temperature. The FD DRS system was synchronized with radiofrequency (RF)-modulated input photon sources and the respective output to extract time-course absorption and scattering coefficients of the skin tissue, which, through the fitting of lambert's law of absorbance, can be used to determine the concentration of oxygenated/deoxygenated hemoglobin molecules, and consequentially, the oxygen saturation of skin tissue and total hemoglobin (THb) concentration. Expressly, a sudden jump in heartbeat rate at the beginning of the exercise, a temporal lag of the rising edge of skin temperature behind that of the THb concentration in the procession of step-wise incremental working intensity, and the uprising of THb in the exhaustion zone in responses to the physiological adaptation to exercise were identified. Finally, conclusive remarks were drawn that the FD DRS system is useful in extracting the hemodynamic properties of forearm skin which is often being neglected in previous exercise physiology studies by DRS-related techniques. The detailed variation of hemodynamic and optical scattering parameters of forearm skin elucidated in the studies can be applied for the analysis of athletes' physiological status, and may be a potential reference for the design of future wearable devices.

Investigation of water bonding status of normal and psoriatic skin in vivo using diffuse reflectance spectroscopy.

Psoriasis affects more than 125 million people worldwide, and the diagnosis and treatment efficacy evaluation of the disease mainly rely on clinical assessments that could be subjective. Our previous study showed that the skin erythema level could be quantified using diffuse reflectance spectroscopy (DRS), and the hemoglobin concentration of most psoriatic lesion was higher than that of its adjacent uninvolved skin. While the compromised epidermal barrier function has been taken as the major cause of clinical manifestation of skin dryness and inflammation of psoriasis, very few methods can be used to effectively evaluate this function. In this study, we investigate the near infrared spectroscopic features of psoriatic (n = 21) and normal (n = 21) skin that could link to the epidermal barrier function. From the DRS measurements, it was found that the water bonding status and light scattering properties of psoriasis are significantly different from those of uninvolved or normal skin. The connection between these parameters to the epidermal barrier function and morphology will be discussed. Our results suggest that objective evaluation of epidermal barrier function of psoriasis could be achieved using a simple DRS system.

Analysis of a diffusion-model-based approach for efficient quantification of superficial tissue properties.

Previously, we reported using a diffusing probe in conjunction with a two-layer diffusion model for accurately recovering the optical properties of superficial volumes. However, the two-layer diffusion equation is computationally less efficient than a standard diffusion equation (SDE) by 3 orders of magnitude. In this Letter, we present a new approach extended from the diffusing probe geometry that enables the use of a diffusion model that has efficiency comparable to an SDE. Our Monte Carlo simulation results indicate that this new approach is not only very accurate but also sensitive to the presence of 0.5 mm(3) inhomogeneities and could be used for monitoring the early progression of skin melanoma.

Chromophore concentrations, absorption and scattering properties of human skin in-vivo.

Absorption and reduced scattering coefficients of in-vivo human skin provide critical information on non-invasive skin diagnoses for aesthetic and clinical purposes. To date, very few in-vivo skin optical properties have been reported. Previously, we reported absorption and scattering properties of in-vivo skin in the wavelength range from 650 to 1000 nm using the diffusing probe in the "modified two-layer geometry". In this study, we determine the spectra of skin optical properties continuously in the range from 500 to 1000 nm. It was found that the concentration of chromophores, such as oxy-hemoglobin, deoxy-hemoglobin, and melanin, calculated based on the absorption spectra of eighteen subjects at wavelengths above and below 600 nm were distinct because of the inherent difference in the interrogation region. The scattering power, which is related to the average scatterer's size, demonstrates a clear contrast between skin phototypes, skin sites, and wavelengths. We also applied venous occlusion on forearms and found that the concentrations of oxy- and deoxy-hemoglobin as assessed at wavelengths above and below 600 nm were different. Our results suggest that diffuse reflectance techniques with the visible and near infrared light sources can be employed to investigate the hemodynamics and optical properties of upper dermis and lower dermis.

Noninvasive transcutaneous bilirubin assessment of neonates with hyperbilirubinemia using a photon diffusion theory-based method.

Transcutaneous bilirubinometers are widely used to screen neonatal jaundice. However, it was reported that their accuracy is compromised at low and high bilirubin levels. We used a photon diffusion theory-based method valid in the 450-600 nm wavelength region to overcome this obstacle. Our clinical study results showed that our system could properly determine the transcutaneous bilirubin concentrations at total serum bilirubin levels higher than 14 mg/dL, where a commercial bilirubinometer failed to provide proper results in several cases. These findings suggested that photon diffusion theory could be employed to improve the core algorithm of modern bilirubinometers and enhance their applicability.

In vivo determination of skin near-infrared optical properties using diffuse optical spectroscopy.

We develop a superficial diffusing probe with a 3 mm source-detector separation that can be used in combination with diffuse optical spectroscopic (DOS) methods to noninvasively determine full-spectrum optical properties of superficial in vivo skin in the wavelength range from 650 to 1000 nm. This new probe uses a highly scattering layer to diffuse photons emitted from a collimated light source and relies on a two-layer diffusion model to determine tissue absorption coefficient mu a and reduced scattering coefficient mu's. By employing the probe to measure two-layer phantoms that mimic the optical properties of skin, we demonstrate that the probe has an interrogation depth of 1 to 2 mm. We carry out SSFDPM (steady state frequency-domain photon migration) measurements using this new probe on the volar forearm and palm of 15 subjects, including five subjects of African descent, five Asians, and five Caucasians. The optical properties of in vivo skin determined using the superficial diffusing probe show considerable similarity to published optical properties of carefully prepared ex vivo epidermis+dermis.

Determination of optical properties of superficial volumes of layered tissue phantoms.

Previously, we reported the design of a new diffusing probe that employs a standard two-layer diffusion model to recover the optical properties of turbid samples. This particular probe had a source-detector separation of 2.5 mm and performance was validated with Monte Carlo simulations and homogeneous phantom experiments. The goal of the current study is to characterize the performance of this new method in the context of two-layer phantoms that mimic the optical properties of human skin. We analyze the accuracy of the recovered top layer optical properties and their dependences on the thickness of the top layer of two-layer phantoms. Our results demonstrate that the optical properties of the top layer can be accurately determined with a 1.6 mm source-detector separation diffusing probe when this layer thickness is as thin as 1 mm. Monte Carlo simulations illustrate that the interrogation depth can be further decreased by shortening the source-detector separation.

Artificial neural networks for retrieving absorption and reduced scattering spectra from frequency-domain diffuse reflectance spectroscopy at short source-detector separation.

Diffuse reflectance spectroscopy (DRS) based on the frequency-domain (FD) technique has been employed to investigate the optical properties of deep tissues such as breast and brain using source to detector separation up to 40 mm. Due to the modeling and system limitations, efficient and precise determination of turbid sample optical properties from the FD diffuse reflectance acquired at a source-detector separation (SDS) of around 1 mm has not been demonstrated. In this study, we revealed that at SDS of 1 mm, acquiring FD diffuse reflectance at multiple frequencies is necessary for alleviating the influence of inevitable measurement uncertainty on the optical property recovery accuracy. Furthermore, we developed artificial neural networks (ANNs) trained by Monte Carlo simulation generated databases that were capable of efficiently determining FD reflectance at multiple frequencies. The ANNs could work in conjunction with a least-square optimization algorithm to rapidly (within 1 second), accurately (within 10%) quantify the sample optical properties from FD reflectance measured at SDS of 1 mm. In addition, we demonstrated that incorporating the steady-state apparatus into the FD DRS system with 1 mm SDS would enable obtaining broadband absorption and reduced scattering spectra of turbid samples in the wavelength range from 650 to 1000 nm.

Light distribution modulated diffuse reflectance spectroscopy.

Typically, a diffuse reflectance spectroscopy (DRS) system employing a continuous wave light source would need to acquire diffuse reflectances measured at multiple source-detector separations for determining the absorption and reduced scattering coefficients of turbid samples. This results in a multi-fiber probe structure and an indefinite probing depth. Here we present a novel DRS method that can utilize a few diffuse reflectances measured at one source-detector separation for recovering the optical properties of samples. The core of innovation is a liquid crystal (LC) cell whose scattering property can be modulated by the bias voltage. By placing the LC cell between the light source and the sample, the spatial distribution of light in the sample can be varied as the scattering property of the LC cell modulated by the bias voltage, and this would induce intensity variation of the collected diffuse reflectance. From a series of Monte Carlo simulations and phantom measurements, we found that this new light distribution modulated DRS (LDM DRS) system was capable of accurately recover the absorption and scattering coefficients of turbid samples and its probing depth only varied by less than 3% over the full bias voltage variation range. Our results suggest that this LDM DRS platform could be developed to various low-cost, efficient, and compact systems for in-vivo superficial tissue investigation.

Fabrication of a Dipole-assisted Solid Phase Extraction Microchip for Trace Metal Analysis in Water Samples.

This paper describes a fabrication protocol for a dipole-assisted solid phase extraction (SPE) microchip available for trace metal analysis in water samples. A brief overview of the evolution of chip-based SPE techniques is provided. This is followed by an introduction to specific polymeric materials and their role in SPE. To develop an innovative dipole-assisted SPE technique, a chlorine (Cl)-containing SPE functionality was implanted into a poly(methyl methacrylate) (PMMA) microchip. Herein, diverse analytical techniques including contact angle analysis, Raman spectroscopic analysis, and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) analysis were employed to validate the utility of the implantation protocol of the C-Cl moieties on the PMMA. The analytical results of the X-ray absorption near-edge structure (XANES) analysis also demonstrated the feasibility of the Cl-containing PMMA used as an extraction medium by virtue of the dipole-ion interactions between the highly electronegative C-Cl moieties and the positively charged metal ions.