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Significance: The integrity of the intestinal barrier is gaining recognition as a significant contributor to various pathophysiological conditions, including inflammatory bowel disease, celiac disease, environmental enteric dysfunction (EED), and malnutrition. EED, for example, manifests as complex structural and functional changes in the small intestine leading to increased intestinal permeability, inflammation, and reduced absorption of nutrients. Despite the importance of gut function, current techniques to assess intestinal permeability (such as endoscopic biopsies or dual sugar assays) are either highly invasive, unreliable, and/or difficult to perform in certain patient populations (e.g., infants). Aim: We present a portable, optical sensor based on transcutaneous fluorescence spectroscopy to assess gut function (in particular, intestinal permeability) in a fast and noninvasive manner. Approach: Participants receive an oral dose of a fluorescent contrast agent, and a wearable fiber-optic probe detects the permeation of the contrast agent from the gut into the blood stream by measuring the fluorescence intensity noninvasively at the fingertip. We characterized the performance of our compact optical sensor by comparing it against an existing benchtop spectroscopic system. In addition, we report results from a human study in healthy volunteers investigating the impact of skin tone and contrast agent dose on transcutaneous fluorescence signals. Results: The first study with eight healthy participants showed good correlation between our compact sensor and the existing benchtop spectroscopic system [correlation coefficient ðr Þ > 0.919, p < 0.001]. Further experiments in 14 healthy participants revealed an approximately linear relationship between the ingested contrast agent dose and the collected signal intensity. Finally, a parallel study on the impact of different skin tones showed no significant differences in signal levels between participants with different skin tones (p > 0.05). Conclusions: In this paper, we demonstrate the potential of our compact transcutaneous fluorescence sensor for noninvasive monitoring of intestinal health. [ABSTRACT FROM AUTHOR]

Significance: Cardiac troponin I (cTnI) is a primary biomarker for diagnosis of myocardial infarction (MI). In contrast to central laboratory tests for cTnI, point-of-care (POC) testing has the advantage of providing results when the patient is first encountered, which helps high-risk patients to be treated more rapidly and low-risk patients to be released in a timely fashion. A paper fluidic platform is good for POC testing because the paper is abundant, low cost, and disposable. However, current cTnI assays on paper platforms use antibodies as the recognition element, which has limitations due to the high cost of production and antibody stability issues at the POC. Aim: To develop an aptamer-based assay on a paper strip using surface-enhanced resonance Raman spectroscopy (SERRS) for detection of cTnI in the clinically relevant range at the POC. Approach: Gold nanoparticles (AuNPs) were functionalized with a Raman reporter molecule, malachite green isothiocyanate. The functionalized AuNPs were encapsulated in a silica shell and provided a SERRS signal using a handheld Raman system with a 638-nm excitation wavelength. A primary aptamer and a secondary aptamer of cTnI were used in a sandwich assay format to bind the cTnI on a test line of a paper fluidic platform. By measuring the SERRS signal from the test line, the concentration of cTnI was quantitatively determined. Results: The aptamer-based SERRS assay on a paper strip had a detection range of 0.016 to 0.1 ng / ml for cTnI, had good selectivity for cTnI compared to three other markers, had good stability over 10 days, and had good performance in the more complex serum sample matrix. Conclusions: The aptamer-based SERRS assay on a paper strip has the potential to provide a sensitive, selective, stable, repeatable, and cost-effective platform for the detection of cTnI toward eventual use in diagnosis of MI at the POC. [ABSTRACT FROM AUTHOR]

Researchers have found that decreased levels of circulating citrulline could be an indicator of intestinal failure. Typically, this amino acid, which is produced by the intestinal mucosa cells, circulates in the blood at a physiological level of ~40 µM. The current methodology for measuring this level involves the use of bulky equipment, such as mass spectroscopy and analysis at a central laboratory, which can delay diagnosis. Therefore, the current detection method is unsuited for routine monitoring at a doctor's office. Our research group proposes the development of a point-of-care (POC) device to overcome this issue. The proposed device utilizes surface-enhanced Raman spectroscopy (SERS) coupled with a specifically designed aptamer, capable of binding to citrulline, conjugated to colloidal gold nanoparticles. The assay is then embedded within a vertical flow paper-fluidic platform as a deliverable at the POC, and a handheld Raman spectrometer (638-nm excitation) was used to interrogate the sample. Results showed good dynamic range and specificity with an average 73% decrease in SERS signal intensity with increasing concentrations of citrulline (0 to 50 µM) in phosphate- buffered saline compared to its controls: glycine, glutamine, histidine, and valine, which showed less than 10% average decrease in the presence of 200 µM of each analyte. Further, the limit of detection (LOD) within a chip was determined to be 0.56 µM, whereas the LOD across chips was below 10 µM. [ABSTRACT FROM AUTHOR]

Liver cancer has one of the highest rates of human morbidity and mortality. However, in terms of pathology, liver cancer is traditionally clinically diagnosed based on observation of microscopic images of pathological liver sections. This paper investigates in vitro samples of rat models of bile duct carcinoma and presents a quantitative analysis method based on microscopic hyperspectral imaging technology to evaluate liver cancers at different stages. The example-based feature extraction method used in this paper mainly includes two algorithms: a morphological watershed algorithm is applied to find object and segment pathological components of pathological liver sections at different stages, and a support vector machine algorithm is implemented for liver tumor classification. Majority/minority analysis is utilized as the postclassification tool to eliminate small plaques from the preliminary classification results. Then, pseudocolor synthesis in RGB color space is used to produce the final results. The experimental results show that this method can effectively calculate the percent tumor areas in liver biopsies at different time points, that is, 3.338%, 11.952%, 15.125%, and 23.375% at 8, 12, 16, and 20 weeks, respectively. Notably, through tracking analysis, the processed results of 8-week images showed the possibility for early diagnosis of the liver tumor. [ABSTRACT FROM AUTHOR]

Interstitial fiber-based spectroscopy is gaining interest for real-time in vivo optical biopsies, endoscopic interventions, and local monitoring of therapy. Different from other photonics approaches, time-domain diffuse optical spectroscopy (TD-DOS) can probe the tissue at a few cm distance from the fiber tip and disentangle absorption from the scattering properties. Nevertheless, the signal detected at a short distance from the source is strongly dominated by the photons arriving early at the detector, thus hampering the possibility of resolving late photons, which are rich in information about depth and absorption. To fully benefit from the null-distance approach, a detector with an extremely high dynamic range is required to effectively collect the late photons; the goal of our paper is to test its feasibility to perform TD-DOS measurements at null source–detector separations (NSDS). In particular, we demonstrate the use of a superconducting nanowire single photon detector (SNSPD) to perform TD-DOS at almost NSDS (≈ 150 μm) by exploiting the high dynamic range and temporal resolution of the SNSPD to extract late arriving, deep-traveling photons from the burst of early photons. This approach was demonstrated both on Monte Carlo simulations and on phantom measurements, achieving an accuracy in the retrieval of the water spectrum of better than 15%, spanning almost two decades of absorption change in the 700- to 1100-nm range. Additionally, we show that, for interstitial measurements at null source–detector distance, the scattering coefficient has a negligible effect on late photons, easing the retrieval of the absorption coefficient. Utilizing the SNSPD, broadband TD-DOS measurements were performed to successfully retrieve the absorption spectra of the liquid phantoms. Although the SNSPD has certain drawbacks for use in a clinical system, it is an emerging field with research progressing rapidly, and this makes the SNSPD a viable option and a good solution for future research in needle guided time-domain interstitial fiber spectroscopy. [ABSTRACT FROM AUTHOR]

The 5th International Conference on Biophotonics (ICOB) held April 30 to May 1, 2017, in Fremantle, Western Australia, brought together opinion leaders to discuss future directions for the field and opportunities to consider. The first session of the conference, "How to Set a Big Picture Biophotonics Agenda," was focused on setting the stage for developing a vision and strategies for translation and impact on society of biophotonic technologies. The invited speakers, panelists, and attendees engaged in discussions that focused on opportunities and promising applications for biophotonic techniques, challenges when working at the confluence of the physical and biological sciences, driving factors for advances of biophotonic technologies, and educational opportunities. We share a summary of the presentations and discussions. Three main themes from the conference are presented in this position paper that capture the current status, opportunities, challenges, and future directions of biophotonics research and key areas of applications: (1) biophotonics at the nano- to microscale level; (2) biophotonics at meso- to macroscale level; and (3) biophotonics and the clinical translation conundrum. [ABSTRACT FROM AUTHOR]

Gingival crevicular fluid (GCF) is a site-specific exudate in the gingival sulcus. GCF composition changes in response to diseases or mechanical stimuli, such as those occurring during orthodontic treatments. Raman microspectroscopy ( μ -RS) and surface-enhanced Raman spectroscopy (SERS) were adopted for a GCF analysis during different initial phases of orthodontic force application. GCF samples were pooled from informed patients using paper cones. SERS spectra were obtained from GCF extracted from these cones, whereas μ -RS spectra were directly acquired on paper cones without any manipulation. The spectral characteristics of the main functional groups and the changes in cytochrome, amide III, and amide I contributions were highlighted in the different phases of orthodontic treatment with both SERS and μ -RS analysis. μ -RS directly performed on the paper cones together with proper statistical methods can offer an effective approach for the development of a tool for monitoring the processes occurring during orthodontic treatments, which may help the clinician in the choice of type of treatment individually for each patient and accelerate and improve the orthodontic therapy. [ABSTRACT FROM AUTHOR]

Calibration, quantification, and standardization of the polarimetric instrumentation, as well as interpretation and understanding of the obtained data, require the development and use of well-calibrated phantoms and standards. We reviewed the status of tissue phantoms for a variety of applications in polarimetry; more than 500 papers are considered. We divided the phantoms into five groups according to their origin (biological/nonbiological) and fundamental polarimetric properties of retardation, depolarization, and diattenuation. We found that, while biological media are generally depolarizing, retarding, and diattenuating, only one of all the phantoms reviewed incorporated all these properties, and few considered at least combined retardation and depolarization. Samples derived from biological tissue, such as tendon and muscle, remain extremely popular to quickly ascertain a polarimetric system, but do not provide quantifiable results aside from relative direction of their principal optical axis. Microspheres suspensions are the most utilized phantoms for depolarization, and combined with theoretical models can offer true quantification of depolarization or degree of polarization. There is a real paucity of birefringent phantoms despite the retardance being one of the most interesting parameters measurable with polarization techniques. Therefore, future work should be directed at generating truly reliable and repeatable phantoms for this metric determination. Diattenuating phantoms are rare and application-specific. Given that diattenuation is considered to be low in most biological tissues, the lack of such phantoms is seen as less problematic. The heterogeneity of the phantoms reviewed points to a critical need for standardization in this field. Ultimately, all research groups involved in polarimetric studies and instruments development would benefit from sharing a limited set of standardized polarimetric phantoms, as is done earlier in the round robin investigations in ellipsometry. [ABSTRACT FROM AUTHOR]

Optical spectral images can be used to estimate the amount of bulk absorbers in tissues, specifically oxy- and deoxyhemoglobin, as well as scattering parameters. Most systems that capture spectral image data are large, heavy, and expensive. This paper presents a full end-to-end analysis of a low-cost reflectance-mode multispectral imaging system operating in the visible and near-infrared spectra. The system consists of 13 LEDs mounted on a printed circuit board, a monochrome machine vision camera, and a tablet computer to control the hardware. The bill of materials for the system is less than $1000. Hardware design and implementation are detailed. Calibration, image capture, and preprocessing are also discussed. In validation experiments, excellent agreement is observed in diffuse reflectance measurements between the spectral camera setup and a spectrometer. To demonstrate that such spectral image data can yield meaningful optical measurements in vivo, the forearms of eight volunteers are imaged in the system. Their data are then analyzed to estimate the tissue optical properties of different skin layers using a Monte Carlo lookup table. In three volunteers, spectral images are captured before and after inducing erythema using a warm wet towel. Across the three subjects, a clear increase in the blood content of the superficial plexus layer was observed as a result of the erythema. Collectively, these findings suggest that a low-cost system can capture accurate spectral data and that clinically meaningful information can be derived from it. [ABSTRACT FROM AUTHOR]

Selective retina therapy (SRT) targets the retinal pigment epithelium (RPE) with pulsed laser irradiation by inducing microbubble formation (MBF) at the intracellular melanin granula, which leads to selective cell disruption. The following wound healing process rejuvenates the chorio-retinal junction. Pulse energy thresholds for selective RPE effects vary intra- and interindividually. We present the evaluation of an algorithm that processes backscattered treatment light to detect MBF as an indicator of RPE cell damage since these RPE lesions are invisible during treatment. Eleven patients with central serous chorioretinopathy and four with diabetic macula edema were treated with a SRT system, which uses a wavelength of 527 nm, a repetition rate of 100 Hz, and a pulse duration of 1.7 μs. Fifteen laser pulses with stepwise increasing pulse energy were applied per treatment spot. Overall, 4626 pulses were used for algorithm parameter optimization and testing. Sensitivity and specificity were the metrics maximized through an automatic optimization process. Data were verified by fluorescein angiography. A sensitivity of 1 and a specificity of 0.93 were achieved. The method introduced in this paper can be used for guidance or automatization of microbubble-related treatments like SRT or selective laser trabeculoplasty. [ABSTRACT FROM AUTHOR]

This paper presents a silicon neural probe with a high-selectivity optical readout function and light emitting diodes for neurons photostimulation and fluorophore excitation. A high-selectivity Fabry-Perot optical filter on the top of a CMOS silicon photodiodes array can read the emitted fluorescence, which indicates the neurons physiological state. The design, fabrication, and characterization of the optical filter are presented. The SiO2/TiO2 based optical filter thin films were deposited by RF sputtering. The performance of the optical filter deposited on the top of the silicon photodiodes array, implemented in the neural probe, was tested through in-vitro fluorescence measurements. The transmittance peak of the fabricated optical filter is 81.8% at 561 nm, with a full width at half maximum of 28 nm. The peak responsivity of the CMOS silicon photodiode with the optical filter deposited on its top is 273.6 mA/W at 578 nm. The in-vitro fluorescence measurements results show a CMOS photodiode current proportional to the fluorophore concentration with a good linearity (R² = 0.9361). The results validate the use of the neural probe with the high-selectivity optical readout function to determine the presence of different fluorophore concentrations. The development of the device in a conventional CMOS process allows on-chip electronics readout. [ABSTRACT FROM AUTHOR]

Paper-based analytics allows building portable and disposable devices for point-of-care (POC) diagnosis. Conventional methods for quantifying proteins exhibit substantial disadvantages related to costs and difficulty of the technique when used in settings where fast and cost-effective assays are needed. We report the successful application of a simple, rapid, easy to use, and label-free aptasensor strategy based on the selective fluorescence of the NMM IX dye. For the probe design, the three-dimensional (3-D) structures of the DNA components were carefully analyzed using software for the 3-D visualization of crystallographic structures. The chimeric aptafluorescence molecule consists of two modules, a detection aptamer and a transduction sequence that induces the specific fluorescence of NMM IX. In the presence of thrombin, a fluorescent spot visible to the naked eye can be observed. The fluorescent response is directly proportional to protein concentration and can be easily quantified colorimetrically using a low-cost microscopy system. The recognition probe design might be adaptable to other relevant biological analytes by changing the sequence of the aptamer. This proof of principle represents a contribution to the development of useful, cheap, reliable, and simple protein quantification assays for POC testing. [ABSTRACT FROM AUTHOR]

To approach wide-field optical properties quantification in real heterogeneous biological tissue, we developed a Dual-Step setup that couples a punctual diffuse reflectance spectroscopy (DRS) technique with multispectral imaging (MSI). The setup achieves wide-field optical properties assessment through an initial estimation of scattering with DRS, which is used to estimate absorption with MSI. The absolute quantification of optical properties is based on the ACA-Pro algorithm that has been adapted both for DRS and for MSI. This paper validates the Dual-Step system not only on homogeneous Intralipid phantoms but also on a heterogeneous gelatine phantom with different scattering and absorbing properties. [ABSTRACT FROM AUTHOR]

Nowadays, dynamically developing optical (photonic) technologies play an ever-increasing role in medicine. Their adequate and effective implementation in diagnostics, surgery, and therapy needs reliable data on optical properties of human tissues, including skin. This paper presents an overview of recent results on the measurements and control of tissue optical properties. The issues reported comprise a brief review of optical properties of biological tissues and efficacy of optical clearing (OC) method in application to monitoring of diabetic complications and visualization of blood vessels and microcirculation using a number of optical imaging technologies, including spectroscopic, optical coherence tomography, and polarization- and speckle-based ones. Molecular modeling of immersion OC of skin and specific technique of OC of adipose tissue by its heating and photodynamic treatment are also discussed. [ABSTRACT FROM AUTHOR]

The issues involved with recording vital functions in the magnetic resonance imaging (MRI) environment using fiber-optic sensors are considered in this paper. Basic physiological parameters, such as respiration and heart rate, are fundamental for predicting the risk of anxiety, panic, and claustrophobic episodes in patients undergoing MRI examinations. Electronic transducers are generally hazardous to the patient and are prone to erroneous operation in heavily electromagnetically penetrated MRI environments; however, nonmetallic fiber-optic sensors are inherently immune to electromagnetic effects and will be crucial for acquiring the above-mentioned physiological parameters. Forty-seven MRI-tested or potentially MRI-compatible sensors have appeared in the literature over the last 20 years. The author classifies these sensors into several categories and subcategories, depending on the sensing element placement, method of application, and measurand type. The author includes five in-house-designed fiber Bragg grating based sensors and shares experience in acquiring physiological measurements during MRI scans. This paper aims to systematize the knowledge of fiber-optic techniques for recording life functions and to indicate the current directions of development in this area. [ABSTRACT FROM AUTHOR]

A light-based processing method to create an amorphous trehalose matrix for the stabilization of proteins is discussed. This method has potential applications in the stabilization of protein-based therapeutics and diagnostics. During light-assisted drying (LAD), proteins suspended in a trehalose solution are dehydrated using near-infrared (NIR) laser light. The goal of this study was to determine processing parameters that resulted in fast processing times and low end moisture contents (EMC), while maintaining the functionality of embedded proteins. We compared the effect of changing processing wavelength, power and resulting sample temperature, and substrate material on the EMC for two NIR laser sources (1064 and 1850 nm). The 1850-nm laser resulted in the lowest EMC (0.03 ± 0.01 gH2O/gDryWeight) after 20 min of processing on glass microfiber paper. This suggests a storage temperature of 68.3°C. We also tested the functionality of a model protein, lysozyme, after LAD processing using a standard assay. LAD showed no significant effect on the functionality of lysozyme when processed at a maximum temperature of ~44°C to an EMC of 0.17 ± 0.06 gH2O/gDryWeight. LAD is a promising technique for forming amorphous trehalose solids that could stabilize proteins at ambient temperatures. [ABSTRACT FROM AUTHOR]

In laserosteotomy, it is vital to avoid thermal damage of the surrounding tissue, such as carbonization, since carbonization does not only deteriorate the ablation efficiency but also prolongs the healing process. The state-of-the-art method to avoid carbonization is irrigation systems; however, it is difficult to determine the desired flow rate of the air and cooling water based on previous experiments without online monitoring of the bone surface. Lack of such feedback during the ablation process can cause carbonization in case of a possible error in the irrigation system or slow down the cutting process when irrigating with too much cooling water. The aim of this paper is to examine laser-induced breakdown spectroscopy as a potential tool for autocarbonization detection in laserosteotomy. By monitoring the laser-driven plasma generated during nanosecond pulse ablation of porcine bone samples, carbonization is hypothesized to be detectable. For this, the collected spectra were analyzed based on variation of a specific pair of emission line ratios in both groups of samples: normal and carbonized bone. The results confirmed a high accuracy of over 95% in classifying normal and carbonized bone. [ABSTRACT FROM AUTHOR]

This paper reports the development and system analysis of a laparoscopic system based on structured illumination technique capable of three-dimensional (3-D) reconstruction of porcine intestine during surgical anastomosis (connection of tubular structures). A calibration target is used to validate the system performance and results show a depth of field of 20 mm with an accuracy of 0.008 mm and precision of 0.25 mm. The imaging system is used to reconstruct a quantitative 3-D depth measurement of ex vivo porcine bowel tissues to mimic an end-to-end bowel anastomosis scenario. We demonstrate that the system can detect a suture in the tissue and map homogeneous surfaces of the intestine with different tissue pigments, affirming the feasibility for depth quantization for guiding and assisting medical diagnostic decisions in anastomosis surgery. [ABSTRACT FROM AUTHOR]

Immigration and epidemiological studies provide evidence indicating the correlation of high ultraviolet exposure during childhood and increased risks of melanoma in later life. While the explanation of this phenomenon has not been found in the skin, a class of hair has been hypothesized to be involved in this process by transmitting sufficient ultraviolet rays along the hair shaft to possibly cause damage to the stem cells in the hair follicle, ultimately resulting in melanoma in later life. First, the anatomy of hair and its possible contribution to melanoma development, and the tissue optical properties are briefly introduced to provide the necessary background. This paper emphasizes on the review of the experimental studies of the optical properties of human hair, which include the sample preparation, measurement techniques, results, and statistical analysis. The Monte Carlo photon simulation of human hair is next outlined. Finally, current knowledge of the optical studies of hair is discussed in the light of their possible contribution to melanoma development; the necessary future work needed to support this hypothesis is suggested. [ABSTRACT FROM AUTHOR]

This paper investigates terahertz (THz) imaging and classification of freshly excised murine xenograft breast cancer tumors. These tumors are grown via injection of E0771 breast adenocarcinoma cells into the flank of mice maintained on high-fat diet. Within 1 h of excision, the tumor and adjacent tissues are imaged using a pulsed THz system in the reflection mode. The THz images are classified using a statistical Bayesian mixture model with unsupervised and supervised approaches. Correlation with digitized pathology images is conducted using classification images assigned by a modal class decision rule. The corresponding receiver operating characteristic curves are obtained based on the classification results. A total of 13 tumor samples obtained from 9 tumors are investigated. The results show good correlation of THz images with pathology results in all samples of cancer and fat tissues. For tumor samples of cancer, fat, and muscle tissues, THz images show reasonable correlation with pathology where the primary challenge lies in the overlapping dielectric properties of cancer and muscle tissues. The use of a supervised regression approach shows improvement in the classification images although not consistently in all tissue regions. Advancing THz imaging of breast tumors from mice and the development of accurate statistical models will ultimately progress the technique for the assessment of human breast tumor margins. [ABSTRACT FROM AUTHOR]

Miniature lenses can transform commercial imaging systems, e.g., smartphones and webcams, into powerful, low-cost, handheld microscopes. To date, the reproducible fabrication of polymer lenses is still a challenge as they require controlled dispensing of viscous liquid. This paper reports a reproducible lens fabrication technique using liquid mold with programmable curvature and off-the-shelf materials. The lens curvature is controlled during fabrication by tuning the curvature of an interface of two immiscible liquids [polydimethylsiloxane (PDMS) and glycerol]. The curvature control is implemented using a visual feedback system, which includes a software-based guiding system to produce lenses of desired curvature. The technique allows PDMS lens fabrication of a wide range of sizes and focal lengths, within 20 min. The fabrication of two lens diameters: 1 and 5 mm with focal lengths ranging between 1.2 and 11 mm are demonstrated. The lens surface and bulk quality check performed using X-ray microtomography and atomic force microscopy reveal that the lenses are suitable for optical imaging. Furthermore, a smartphone microscope with ~1.4-µm resolution is developed using a self-assembly of a single high power fabricated lens and microaperture. The lenses have various potential applications, e.g., optofluidics, diagnostics, forensics, and surveillance. [ABSTRACT FROM AUTHOR]

The process of medical device innovation involves an iterative method that focuses on designing innovative, device-oriented solutions that address unmet clinical needs. This process has been applied to the field of biophotonics with many notable successes. Device innovation begins with identifying an unmet clinical need and evaluating this need through a variety of lenses, including currently existing solutions for the need, stakeholders who are interested in the need, and the market that will support an innovative solution. Only once the clinical need is understood in detail can the invention process begin. The ideation phase often involves multiple levels of brainstorming and prototyping with the aim of addressing technical and clinical questions early and in a cost-efficient manner. Once potential solutions are found, they are tested against a number of known translational factors, including intellectual property, regulatory, and reimbursement landscapes. Only when the solution matches the clinical need, the next phase of building a "to market" strategy should begin. Most aspects of the innovation process can be conducted relatively quickly and without significant capital expense. This white paper focuses on key points of the medical device innovation method and how the field of biophotonics has been applied within this framework to generate clinical and commercial success. [ABSTRACT FROM AUTHOR]

The biannual International Conference on Biophotonics was recently held on April 30 to May 1, 2017, in Fremantle, Western Australia. This continuing conference series brought together key opinion leaders in biophotonics to present their latest results and, importantly, to participate in discussions on the future of the field and what opportunities exist when we collectively work together for using biophotonics for biological discovery and medical applications. One session in this conference, entitled "Tumor Margin Identification: Critiquing Technologies," challenged invited speakers and attendees to review and critique representative label-free optical imaging technologies and their application for intraoperative assessment and guidance in surgical oncology. We are pleased to share a summary in this outlook paper, with the intent to motivate more research inquiry and investigations, to challenge these and other optical imaging modalities to evaluate and improve performance, to spur translation and adoption, and ultimately, to improve the care and outcomes of patients. [ABSTRACT FROM AUTHOR]

This paper proposes an in vivo laparoscopic lighting system design to address the illumination issues, namely poor lighting uniformity and low optical efficiency, existing in the state-of-the-art in vivo laparoscopic cameras. The transformable design of the laparoscopic lighting system is capable of carrying purposefully designed freeform optical lenses for achieving lighting performance with high illuminance uniformity and high optical efficiency in a desired target region. To design freeform optical lenses for extended light sources such as LEDs with Lambertian light intensity distributions, we present an effective and complete freeform optical design method. The procedures include (1) ray map computation by numerically solving a standard Monge– Ampere equation; (2) initial freeform optical surface construction by using Snell’s law and a lens volume restriction; (3) correction of surface normal vectors due to accumulated errors from the initially constructed surfaces; and (4) feedback modification of the solution to deal with degraded illuminance uniformity caused by the extended sizes of the LEDs. We employed an optical design software package to evaluate the performance of our laparoscopic lighting system design. The simulation results show that our design achieves greater than 95% illuminance uniformity and greater than 89% optical efficiency (considering Fresnel losses) for illuminating the target surgical region. [ABSTRACT FROM AUTHOR]

Modern gynecologic practice requires noninvasive diagnostics techniques capable of detecting morphological and functional alterations in tissues of female reproductive organs. Optical coherence tomography (OCT) is a promising tool for providing imaging of biotissues with high resolution at depths up to 2 mm. Design of the customized probes provides wide opportunities for OCT use in gynecology. This paper contains a retrospective insight into the history of OCT employment in gynecology, an overview of the existing gynecologic OCT probes, including those for combination with other diagnostic modalities, and state-of-the-art application of OCT for diagnostics of tumor and nontumor pathologies of female genitalia. Perspectives of OCT both in diagnostics and treatment planning and monitoring in gynecology are overviewed. [ABSTRACT FROM AUTHOR]

The application of optical coherence tomography (OCT) in the field of oncology has been prospering over the past decade. OCT imaging has been used to image a broad spectrum of malignancies, including those arising in the breast, brain, bladder, the gastrointestinal, respiratory, and reproductive tracts, the skin, and oral cavity, among others. OCT imaging has initially been applied for guiding biopsies, for intraoperatively evaluating tumor margins and lymph nodes, and for the early detection of small lesions that would often not be visible on gross examination, tasks that align well with the clinical emphasis on early detection and intervention. Recently, OCT imaging has been explored for imaging tumor cells and their dynamics, and for the monitoring of tumor responses to treatments. This paper reviews the evolution of OCT technologies for the clinical application of OCT in surgical and noninvasive interventional oncology procedures and concludes with a discussion of the future directions for OCT technologies, with particular emphasis on their applications in oncology [ABSTRACT FROM AUTHOR]

Adolf Friedrich Fercher, an outstanding pioneer of biomedical optics, passed away earlier this year. He was a brilliant and visionary researcher who pioneered various fields of biomedical optics, such as laser speckle flowgraphy, tissue interferometry, and optical coherence tomography (OCT). On the occasion of the 25th anniversary of OCT, this paper reviews and commemorates Fercher’s pioneering work. [ABSTRACT FROM AUTHOR]

As multiwavelength photoacoustic imaging becomes increasingly widely used to obtain quantitative estimates, the need for validation studies conducted on well-characterized experimental phantoms becomes ever more pressing. One challenge that such studies face is the design of stable, well-characterized phantoms and absorbers with properties in a physiologically realistic range. This paper performs a full experimental characterization of aqueous solutions of copper and nickel sulfate, whose properties make them close to ideal as chromophores in multiwavelength photoacoustic imaging phantoms. Their absorption varies linearly with concentration, and they mix linearly. The concentrations needed to yield absorption values within the physiological range are below the saturation limit. The shape of their absorption spectra makes them useful analogs for oxy- and deoxyhemoglobin. They display long-term photostability (no indication of bleaching) as well as resistance to transient effects (no saturable absorption phenomena), and are therefore suitable for exposure to typical pulsed photoacoustic light sources, even when exposed to the high number of pulses required in scanning photoacoustic imaging systems. In addition, solutions with tissue-realistic, predictable, and stable scattering can be prepared by mixing sulfates and Intralipid, as long as an appropriate emulsifier is used. Finally, the Grüneisen parameter of the sulfates was found to be larger than that of water and increased linearly with concentration. [ABSTRACT FROM AUTHOR]

This research extends the work of Hoffman et al. to provide both sectioning and super-resolution using random patterns within thick specimens. Two methods of processing structured illumination in reflectance have been developed without the need for a priori knowledge of either the optical system or the modulation patterns. We explore the use of two deconvolution algorithms that assume either Gaussian or sparse priors. This paper will show that while both methods accomplish their intended objective, the sparse priors method provides superior resolution and contrast against all tested targets, providing anywhere from ∼1.6× to ∼2× resolution enhancement. The methods developed here can reasonably be implemented to work without a priori knowledge about the patterns or point spread function. Further, all experiments are run using an incoherent light source, unknown random modulation patterns, and without the use of fluorescent tagging. These additional modifications are challenging, but the generalization of these methods makes them prime candidates for clinical application, providing super-resolved noninvasive sectioning in vivo. [ABSTRACT FROM AUTHOR]

Single cell microscopy in a three-dimensional (3-D) environment is reported. Cells are grown in an agarose culture gel, located within microcapillaries and observed from different sides after adaptation of an innovative device for sample rotation. Thus, z-stacks can be recorded by confocal microscopy in different directions and used for illustration in 3-D. This gives additional information, since cells or organelles that appear superimposed in one direction, may be well resolved in another one. The method is tested and validated with single cells expressing a membrane or a mitochondrially associated green fluorescent protein, or cells accumulating fluorescent quantum dots. In addition, axial tomography supports measurements of cellular uptake and distribution of the anticancer drug doxorubicin in the nucleus (2 to 6 h after incubation) or the cytoplasm (24 h). This paper discusses that upon cell rotation an enhanced optical resolution in lateral direction compared to axial direction can be utilized to obtain an improved effective 3-D resolution, which represents an important step toward super-resolution microscopy of living cells. [ABSTRACT FROM AUTHOR]

This paper presents a fiber Bragg grating (FBG)-instrumented prosthetic silicone liner that provides cushioning for the residual limb and can successfully measure interface pressures inside prosthetic sockets of lower-limb amputees in a simple and practical means of sensing. The liner is made of two silicone layers between which 12 FBG sensors were embedded at locations of clinical interest. The sensors were then calibrated using a custom calibration platform that mimics a real-life situation. Afterward, a custom gait simulating machine was built to test the liner performance during an amputee's simulated gait. To validate the findings, the results were compared to those obtained by the commonly used F-socket mats. As the statistical findings reveal, both pressure mapping methods measured the interface pressure in a consistent way, with no significant difference (P-values ≥ 0.05). This pressure mapping technique in the form of a prosthetic liner will allow prosthetics professionals to quickly and accurately create an overall picture of the interface pressure distribution inside sockets in research and clinical settings, thereby improving the socket fit and amputee's satisfaction. [ABSTRACT FROM AUTHOR]

Laser ablation offers a procedure for precise, fast, and minimally invasive removal of superficial and early nodular basal cell carcinomas (BCCs). However, the lack of histopathological confirmation has been a limitation toward widespread use in the clinic. A reflectance confocal microscopy (RCM) imaging-guided approach offers cellular-level histopathology-like feedback directly on the patient, which may then guide and help improve the efficacy of the ablation procedure. Following an ex vivo benchtop study (reported in our earlier papers), we performed an initial study on 44 BCCs on 21 patients in vivo, using a pulsed erbium:ytterbium aluminum garnet laser and a contrast agent (aluminum chloride). In 10 lesions on six patients, the RCM imagingguided detection of either presence of residual tumor or complete clearance was immediately confirmed with histopathology. Additionally,34 BCCs on 15 patients were treated with RCM imaging-guided laser ablation, with immediate confirmation for clearance of tumor (no histopathology), followed by longer-term monitoring, currently in progress, with follow-up imaging (again, no histopathology) at 3, 6, and 18 months. Thus far, the imaging resolution appears to be sufficient and consistent for monitoring efficacy of ablation in the wound, both immediately postablation and subsequently during recovery.The efficacy results appear to be promising, with observed clearance in 19 cases of 22 cases with follow-ups ranging from 6 to 21 months. An additional 12 cases with 1 to 3 months of follow-ups has shown clearance of tumor but a longer follow-up time is required to establish conclusive results. Further instrumentation development will be necessary to cover larger areas with a more automatically controlled instrument for more uniform, faster, and deeper imaging of margins. [ABSTRACT FROM AUTHOR]

Leukocytes are mainly composed of neutrophils, basophils, eosinophils, monocytes, and lymphocytes. The number and proportion of different types of leukocytes correspond to different diseases, so an accurate segmentation of each type of leukocyte is important for the diagnosis of disease. However, the acquisition of blood cell images can be affected by external environmental factors, which can lead to variable light and darkness, complex backgrounds, and poorly characterized leukocytes. To address the problem of complex blood cell images collected under different environments and the lack of obvious leukocyte features, a leukocyte segmentation method based on improved U-net is proposed. First, adaptive histogram equalization-retinex correction was introduced for data enhancement to make the leukocyte features in the blood cell images clearer. Then, to address the problem of similarity between different types of leukocytes, convolutional block attention module is added to the four skip connections of U-net to focus the features from spatial and channel aspects, so that the network can quickly locate the high-value information of features in different channels and spaces. It avoids the problem of large amount of repeated computation of low-value information, prevents overfitting, and improves the training efficiency and generalization ability of the network. Finally, to solve the problem of class imbalance in blood cell images and to better segment the cytoplasm of leukocytes, a loss function combining focal loss and Dice loss is proposed. We use the BCISC public dataset to verify the effectiveness of the proposed method. The segmentation of multiple leukocytes using the method of this paper can achieve 99.53% accuracy and 91.89% mIoU. The experimental results show that the method achieves good segmentation results for lymphocytes, basophils, neutrophils, eosinophils, and monocytes. [ABSTRACT FROM AUTHOR]

Spectral imaging, which includes hyperspectral and multispectral imaging, can provide images in numerous wavelength bands within and beyond the visible light spectrum. Emerging technologies that enable compact, portable spectral imaging cameras can facilitate new applications in biomedical imaging. With this review paper, researchers will (1) understand the technological trends of upcoming spectral cameras, (2) understand new specific applications that portable spectral imaging unlocked, and (3) evaluate proper spectral imaging systems for their specific applications. We performed a comprehensive literature review in three databases (Scopus, PubMed, and Web of Science). We included only fully realized systems with definable dimensions. To best accommodate many different definitions of "compact," we included a table of dimensions and weights for systems that met our definition. There is a wide variety of contributions from industry, academic, and hobbyist spaces. A variety of new engineering approaches, such as Fabry–Perot interferometers, spectrally resolved detector array (mosaic array), microelectro-mechanical systems, 3D printing, light-emitting diodes, and smartphones, were used in the construction of compact spectral imaging cameras. In bioimaging applications, these compact devices were used for in vivo and ex vivo diagnosis and surgical settings. Compact and ultracompact spectral imagers are the future of spectral imaging systems. Researchers in the bioimaging fields are building systems that are low-cost, fast in acquisition time, and mobile enough to be handheld. [ABSTRACT FROM AUTHOR]

Researchers use ultrasound (US) to modulate diffusive light in a highly scattering medium like tissue. This paper analyzes the US--optical interaction in the scattering medium and derives an expression for the US-modulated optical radiance. The diffusion approximation to the radiative transport equation is employed to develop a Green's function for US-modulated light. The predicted modulated fluence and flux are verified using finite-difference time-domain simulations. The Green's function is then utilized to illustrate the modulated reflectance as the US--optical interaction increases in depth. The intent of this paper is to focus on high US frequencies necessary for high-resolution imaging because they are of interest for applications such as phase conjugation. [ABSTRACT FROM AUTHOR]

Cystoid macular edema (CME) and macular hole (MH) are the leading causes for visual loss in retinal diseases. The volume of the CMEs can be an accurate predictor for visual prognosis. This paper presents an automatic method to segment the CMEs from the abnormal retina with coexistence of MH in three-dimensionaloptical coherence tomography images. The proposed framework consists of preprocessing and CMEs segmentation. The preprocessing part includes denoising, intraretinal layers segmentation and flattening, and MH and vessel silhouettes exclusion. In the CMEs segmentation, a three-step strategy is applied. First, an AdaBoost classifier trained with 57 features is employed to generate the initialization results. Second, an automated shape-constrained graph cut algorithm is applied to obtain the refined results. Finally, cyst area information is used to remove false positives (FPs). The method was evaluated on 19 eyes with coexistence of CMEs and MH from 18 subjects. The true positive volume fraction, FP volume fraction, dice similarity coefficient, and accuracy rate for CMEs segmentation were 81.0% ± 7.8%, 0.80% ± 0.63%, 80.9% ± 5.7%, and 99.7% ± 0.1%, respectively. [ABSTRACT FROM AUTHOR]

This article addresses theoretical and numerical investigation of image formation in photoacoustic (PA) imaging with complex-shaped concave sensor arrays. The spatial resolution and the size of sensitivity region of PA and laser ultrasonic (LU) imaging systems are assessed using sensitivity maps and spatial resolution maps in the image plane. This paper also discusses the relationship between the size of high-sensitivity regions and the spatial resolution of real-time imaging systems utilizing toroidal arrays. It is shown that the use of arrays with toroidal geometry significantly improves the diagnostic capabilities of PA and LU imaging to investigate biological objects, rocks, and composite materials. [ABSTRACT FROM AUTHOR]

This paper presents the composite biostructures created by laser structuring of the single-walled carbon nanotubes (SWCNTs) in an albumin matrix. Under the exposure of femtosecond laser radiation, the heating of the albumin aqueous solution causes liquid water to evaporate. As a result, we obtained a solid-state composite in the bulk or film form. Using the molecular dynamic method, we showed the formation of a framework from SWCNTs by the example of splicing of the open end of one nanotube with the defect region of another nanotube under the action of the laser heating. Laser heating of SWCNTs up to a temperature of 80°C to 100°C causes the C--C bond formation. Raman spectra measured for the composite biostructures allowed us to describe the binding of oxygen atoms of amino acid residues of the albumin with the carbon atoms of the SWCNTs. It is found that the interaction energy of the nanotube atoms and albumin atoms amounts up to 580 kJ/mol. We used atomic force microscopy to investigate the surface of the composite biostructures. The pore size is in the range of 30 to 120 nm. It is proved that the proliferation of the fibroblasts occurred on the surface of the composite biostructures during 72 h of incubation. [ABSTRACT FROM AUTHOR]

Testing the human body's reaction to hypoxia (including the one generated by high altitude) is important in aeronautic medicine. This paper presents a method of monitoring blood oxygenation during experimental hypoxia using hyperspectral imaging (HSI) and a spectral unmixing model based on a modified Beer--Lambert law. A total of 20 healthy volunteers (males) aged 25 to 60 years were included in this study. A line-scan HSI system was used to acquire images of the faces of the subjects. The method generated oxyhemoglobin and deoxyhemoglobin distribution maps from the foreheads of the subjects at 5 and 10 min of hypoxia and after recovery in a high oxygen breathing mixture. The method also generated oxygen saturation maps that were validated using pulse oximetry. An interesting pattern of desaturation on the forehead was discovered during the study, showing one of the advantages of using HSI for skin oxygenation monitoring in hypoxic conditions. This could bring new insight into the physiological response to high altitude and may become a step forward in air crew testing. [ABSTRACT FROM AUTHOR]

This paper relates to the improvement of conventional surgical stereo microscopy via the application of digital recording devices and adaptive optics. The research is aimed at improving the working conditions of the surgeon during the operation, such that free head movement is possible. The depth clues known from conventional stereo microscopy in interaction with the human eye's functionality, such as convergence, disparity, angular elevation, parallax, and accommodation, are implemented in a digital recording system via adaptive optomechanical components. Two laterally moving pupil apertures have been used mimicking the digital implementation of the eye's vergence and head motion. The natural eye's accommodation is mimicked via the application of a tunable lens. Additionally, another system has been built, which enables tracking the surgeon's eye pupil through a digital displaying stereoscopic microscope to supply the necessary information for steering the recording system. The optomechanical design and experimental results for both systems, digital recording stereoscopic microscope and pupil tracking system, are shown. [ABSTRACT FROM AUTHOR]

This paper investigates the topical anti-inflammatory effect of a fish oil preparation (FOP) in a croton oil (CO) model of skin inflammation. The photoacoustic spectroscopy (PAS) was applied to estimate the percutaneous penetration of the FOP and as a model to evaluate the topical inflammatory response. After applying CO, the groups of mice received a topical application of a FOP on the left ear. The right ear received the vehicle that was used to dilute the CO. After 6 h, ear tissue was collected to determine the percent inhibition of edema, myeloperoxidase (MPO) activity, and cytokine levels and to perform PAS measurements. Treatment with FOP reduced edema and MPO activity, which was at least partially attributed to a decrease in the levels of tumor necrosis factor, interleukin-1β, interleukin-6, keratinocyte-derived chemokine, and monocyte chemoattractant protein-1. The topically applied FOP penetrated into the tissue and decreased the area of the bands that characterize inflamed tissue. The present results demonstrated the topical anti-inflammatory effect of the FOP. PAS suggests that FOP anti-inflammatory activity is linked with its ability to penetrate through the skin. [ABSTRACT FROM AUTHOR]

This paper proposes a method for improving the localization and the quantification of the optical parameters in photoacoustic (PA) tomography of biological tissues that are intrinsically heterogeneous in both optical and acoustic properties. It is based on the exploitation of both the PA signal, generated by the heterogeneous optical structures, and the secondary acoustic echoes due to the interaction between a primary PA wave generated near the tissue surface and the heterogeneous acoustic structures. These secondary echoes can also be collected through proper measurements of the PA signals. The experimental procedure is presented along with the method to filter the signal and the reconstruction algorithm that includes the account of the acoustic information. [ABSTRACT FROM AUTHOR]

Most techniques that are used for diagnosis and therapy of diseases are invasive. Reliable noninvasive methods are always needed for the comfort of patients. Owing to its noninvasiveness, ease of use, and easy repeatability, exhaled breath analysis is a very good candidate for this purpose. Breath analysis can be performed using different techniques, such as gas chromatography mass spectrometry (MS), proton transfer reaction- MS, and selected ion flow tube-MS. However, these devices are bulky and require complicated procedures for sample collection and preconcentration. Therefore, these are not practical for routine applications in hospitals. Laser-based techniques with small size, robustness, low cost, low response time, accuracy, precision, high sensitivity, selectivity, low detection limit, real-time, and point-of-care detection have a great potential for routine use in hospitals. In this review paper, the recent advances in the fields of external cavity lasers and breath analysis for detection of diseases are presented. [ABSTRACT FROM AUTHOR]

This paper presents a method that uses fiber Bragg grating (FBG) sensors to distinguish the temporal gait patterns in gait cycles. Unlike most conventional methods that focus on electronic sensors to collect those physical quantities (i.e., strains, forces, pressure, displacements, velocity, and accelerations), the proposed method utilizes the backreflected peak wavelength from FBG sensors to describe the motion characteristics in human walking. Specifically, the FBG sensors are sensitive to external strain with the result that their back-reflected peak wavelength will be shifted according to the extent of the influence of external strain. Therefore, when subjects walk in different gait patterns, the strains on FBG sensors will be different such that the magnitude of the backreflected peak wavelength varies. To test the reliability of the FBG sensor platform for gait pattern detection, the gold standard method using force-sensitive resistors (FSRs) for defining gait patterns is introduced as a reference platform. The reliability of the FBG sensor platform is determined by comparing the detection results between the FBG sensors and FSRs platforms. The experimental results show that the FBG sensor platform is reliable in gait pattern detection and gains high reliability when compared with the reference platform. [ABSTRACT FROM AUTHOR]

This paper presents a newly developed dermatological laser (with a central wavelength 975 nm) for application in therapies requiring deep penetration of tissue, e.g., cutaneous (dermal) neurofibroma (von Recklinghausen disease) and hemangiomas. This laser can work either in pulses or continues wave mode. Laser radiation is transmitted toward the application region by optical fiber with a diameter of 0.6 mm. The compact design of the laser facilitates its transport and increases the comfort of use. [ABSTRACT FROM AUTHOR]

Choroid thickness and volume estimated from optical coherence tomography (OCT) images have emerged as important metrics in disease management. This paper presents an automated three-dimensional (3-D) method for segmenting the choroid from 1-μm wide-view swept source OCT image volumes, including the Bruch's membrane (BM) and the choroidal-scleral interface (CSI) segmentation. Two auxiliary boundaries are first detected by modified Canny operators and then the optical nerve head is detected and removed. The BM and the initial CSI segmentation are achieved by 3-D multiresolution graph search with gradient-based cost. The CSI is further refined by adding a regional cost, calculated from the wavelet-based gradual intensity distance. The segmentation accuracy is quantitatively evaluated on 32 normal eyes by comparing with manual segmentation and by reproducibility test. The mean choroid thickness difference from the manual segmentation is 19.16 ± 4.32 μm, the mean Dice similarity coefficient is 93.17 ± 1.30%, and the correlation coefficients between fovea-centered volumes obtained on repeated scans are larger than 0.97. [ABSTRACT FROM AUTHOR]

This paper explores the potential of optical coherence microscopy (OCM) for the in situ monitoring of biofilm growth. The quantitative imaging of the early developmental biology of a representative biofilm, Klebsiella pneumonia (KP-1), was performed using a swept source-based Fourier domain OCM system. The growth dynamics of the KP-1 biofilms and their transient response under perturbation was investigated using the enface visualization of microcolonies and their spatial localization. Furthermore, the optical density (OD) and planar density of the biofilms are calculated using an OCM technique and compared with OD and colony forming units measured using standard procedures via the sampling of the flow-cell effluent. [ABSTRACT FROM AUTHOR]

An adequate water balance (hydration extent) is one of the basic factors of normal eye function, including its external shells: the cornea and the sclera. Adequate control of corneal and scleral hydration is very important for early diagnosis of a variety of eye diseases, stating indications for and contraindications against keratorefractive surgeries and the choice of contact lens correction solutions. THz systems of creating images in reflected beams are likely to become ideal instruments of noninvasive control of corneal and scleral hydration degrees. This paper reports on the results of a study involving transmittance and reflectance spectra for the cornea and the sclera of rabbit and human eyes, as well as those of the rabbit eye, in the frequency range of 0.13 to 0.32 THz. The dependence of the reflectance coefficient of these tissues on water mass percentage content was determined. The experiments were performed on three corneas, three rabbit scleras, two rabbit eyes, and three human scleras. The preliminary results demonstrate that the proposed technique, based on the use of a continuous THz radiation, may be utilized to create a device for noninvasive control of corneal and scleral hydration, which has clear potential of broad practical application. [ABSTRACT FROM AUTHOR]

A microfluidic chip with microchannels ranging from 8 to 96 μmwas used to mimic blood vessels down to the capillary level. Blood flow within the microfluidic channels was analyzed with split-spectrum amplitudedecorrelation angiography (SSADA)-based optical coherence tomography (OCT) angiography. It was found that the SSADA decorrelation value was related to both blood flow speed and channel width. SSADA could differentiate nonflowing blood inside the microfluidic channels from static paper. The SSADA decorrelation value was approximately linear with blood flow velocity up to a threshold Vsat of 5.83 ± 1.33 mm/s (mean ± standard deviation over the range of channel widths). Beyond this threshold, it approached a saturation value Dsat. Dsat was higher for wider channels, and approached a maximum value Dsm as the channel width became much larger than the beam focal spot diameter. These results indicate that decorrelation values (flow signal) in capillary networks would be proportional to both flow velocity and vessel caliber but would be capped at a saturation value in larger blood vessels. These findings are useful for interpretation and quantification of clinical OCT angiography results. [ABSTRACT FROM AUTHOR]