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Osteoarthritis (OA) is a debilitating degenerative disease affecting multiple joint tissues, including cartilage, bone, synovium, and adipose tissues. OA presents diverse clinical phenotypes and distinct molecular endotypes, including inflammatory, metabolic, mechanical, genetic, and synovial variants. Consequently, innovative technologies are needed to support the development of effective diagnostic and precision therapeutic approaches. Traditional analysis of bulk OA tissue extracts has limitations due to technical constraints, causing challenges in the differentiation between various physiological and pathological phenotypes in joint tissues. This issue has led to standardization difficulties and hindered the success of clinical trials. Gaining insights into the spatial variations of the cellular and molecular structures in OA tissues, encompassing DNA, RNA, metabolites, and proteins, as well as their chemical properties, elemental composition, and mechanical attributes, can contribute to a more comprehensive understanding of the disease subtypes. Spatially resolved biology enables biologists to investigate cells within the context of their tissue microenvironment, providing a more holistic view of cellular function. Recent advances in innovative spatial biology techniques now allow intact tissue sections to be examined using various -omics lenses, such as genomics, transcriptomics, proteomics, and metabolomics, with spatial data. This fusion of approaches provides researchers with critical insights into the molecular composition and functions of the cells and tissues at precise spatial coordinates. Furthermore, advanced imaging techniques, including high-resolution microscopy, hyperspectral imaging, and mass spectrometry imaging, enable the visualization and analysis of the spatial distribution of biomolecules, cells, and tissues. Linking these molecular imaging outputs to conventional tissue histology can facilitate a more comprehensive characterization of disease phenotypes. This review summarizes the recent advancements in the molecular imaging modalities and methodologies for in-depth spatial analysis. It explores their applications, challenges, and potential opportunities in the field of OA. Additionally, this review provides a perspective on the potential research directions for these contemporary approaches that can meet the requirements of clinical diagnoses and the establishment of therapeutic targets for OA.

Knee ligaments and tendons play an important role in stabilizing and controlling the motions of the knee. Injuries to the ligaments can lead to abnormal mechanical loading of the other supporting tissues (e.g., cartilage and meniscus) and even osteoarthritis. While the condition of knee ligaments can be examined during arthroscopic repair procedures, the arthroscopic evaluation suffers from subjectivity and poor repeatability. Near infrared spectroscopy (NIRS) is capable of non-destructively quantifying the composition and structure of collagen-rich connective tissues, such as articular cartilage and meniscus. Despite the similarities, NIRS-based evaluation of ligament composition has not been previously attempted. In this study, ligaments and patellar tendon of ten bovine stifle joints were measured with NIRS, followed by chemical and histological reference analysis. The relationship between the reference properties of the tissue and NIR spectra was investigated using partial least squares regression. NIRS was found to be sensitive towards the water ( R 2 CV = .65) and collagen ( R 2 CV = .57) contents, while elastin, proteoglycans, and the internal crimp structure remained undetectable. As collagen largely determines the mechanical response of ligaments, we conclude that NIRS demonstrates potential for quantitative evaluation of knee ligaments.

Nanomaterials are currently the state-of-the-art in the development of advanced biomedical devices and applications where classical approaches have failed. To date, majority of the literature on nanomaterial interaction with cells have largely focused on the biological responses of cells obtained via assays, with little interest on their biophysical responses. However, recent studies have shown that the biophysical responses of cells, such as stiffness and adhesive properties, play a significant role in their physiological function. In this paper, we investigate cell biophysical responses after uptake of nanoparticles. Atomic force microscopy was used to study changes in cell stiffness and adhesion upon boron nitride (BN) and hydroxyapatite (HAP) nanoparticle uptake. Results show increase in cell stiffness with varying nanoparticle (BN and HAP) concentration, while a decrease in cell adhesion trigger by uptake of HAP. In addition, changes in the biochemical response of the cell membrane were observed via Raman spectroscopy of nanoparticle treated cells. These findings have significant implications in biomedical applications of nanoparticles, e.g. in drug delivery, advanced prosthesis and surgical implants.

Abstract Study Objectives Accurate identification of sleep stages is essential in the diagnosis of sleep disorders (e.g. obstructive sleep apnea [OSA]) but relies on labor-intensive electroencephalogram (EEG)-based manual scoring. Furthermore, long-term assessment of sleep relies on actigraphy differentiating only between wake and sleep periods without identifying specific sleep stages and having low reliability in identifying wake periods after sleep onset. To address these issues, we aimed to develop an automatic method for identifying the sleep stages from the photoplethysmogram (PPG) signal obtained with a simple finger pulse oximeter. Methods PPG signals from the diagnostic polysomnographies of susptected OSA patients (n = 894) were utilized to develop a combined convolutional and recurrent neural network. The deep learning model was trained individually for three-stage (wake/NREM/REM), four-stage (wake/N1+N2/N3/REM), and five-stage (wake/N1/N2/N3/REM) classification of sleep. Results The three-stage model achieved an epoch-by-epoch accuracy of 80.1% with Cohen’s κ of 0.65. The four- and five-stage models achieved 68.5% (κ = 0.54), and 64.1% (κ = 0.51) accuracies, respectively. With the five-stage model, the total sleep time was underestimated with a mean bias error (SD) of of 7.5 (55.2) minutes. Conclusion The PPG-based deep learning model enabled accurate estimation of sleep time and differentiation between sleep stages with a moderate agreement to manual EEG-based scoring. As PPG is already included in ambulatory polygraphic recordings, applying the PPG-based sleep staging could improve their diagnostic value by enabling simple, low-cost, and reliable monitoring of sleep and help assess otherwise overlooked conditions such as REM-related OSA.

Degenerative joint conditions are often characterized by changes in articular cartilage and subchondral bone properties. These changes are often associated with subchondral plate thickness and trabecular bone morphology. Thus, evaluating subchondral bone integrity could provide essential insights for diagnosis of joint pathologies. This study investigates the potential of optical spectroscopy for characterizing human subchondral bone properties. Osteochondral samples (n = 50) were extracted from human cadaver knees (n = 13) at four anatomical locations and subjected to NIR spectroscopy. The samples were then imaged using micro-computed tomography to determine subchondral bone morphometric properties, including: plate thickness (Sb.Th), trabecular thickness (Tb.Th), volume fraction (BV/TV), and structure model index (SMI). The relationship between the subchondral bone properties and spectral data in the 1 st (650–950 nm), 2 nd (1100–1350 nm) and 3 rd (1600–1870 nm) optical windows were investigated using partial least squares (PLS) regression multivariate technique. Significant correlations (p < 0.0001) and relatively low prediction errors were obtained between spectral data in the 1 st optical window and Sb.Th (R 2  = 92.3%, error = 7.1%), Tb.Th (R 2  = 88.4%, error = 6.7%), BV/TV (R 2  = 83%, error = 9.8%) and SMI (R 2  = 79.7%, error = 10.8%). Thus, NIR spectroscopy in the 1 st tissue optical window is capable of characterizing and estimating subchondral bone properties, and can potentially be adapted during arthroscopy.

Near-infrared (NIR) spectroscopy is a powerful analytical method for rapid, non-destructive and label-free assessment of biological materials. Compared to mid-infrared spectroscopy, NIR spectroscopy excels in penetration depth, allowing intact biological tissue assessment, albeit at the cost of reduced molecular specificity. Furthermore, it is relatively safe compared to Raman spectroscopy, with no risk of laser-induced photothermal damage. A typical NIR spectroscopy workflow for biological tissue characterization involves sample preparation, spectral acquisition, pre-processing and analysis. The resulting spectrum embeds intrinsic information on the tissue’s biomolecular, structural and functional properties. Here we demonstrate the analytical power of NIR spectroscopy for exploratory and diagnostic applications by providing instructions for acquiring NIR spectra, maps and images in biological tissues. By adapting and extending this protocol from the demonstrated application in connective tissues to other biological tissues, we expect that a typical NIR spectroscopic study can be performed by a non-specialist user to characterize biological tissues in basic research or clinical settings. We also describe how to use this protocol for exploratory study on connective tissues, including differentiating among ligament types, non-destructively monitoring changes in matrix formation during engineered cartilage development, mapping articular cartilage proteoglycan content across bovine patella and spectral imaging across the depth-wise zones of articular cartilage and subchondral bone. Depending on acquisition mode and experiment objectives, a typical exploratory study can be completed within 6 h, including sample preparation and data analysis. This protocol describes how to perform near-infrared spectroscopy and imaging of connective tissues. Detailed guidelines are provided for sample preparation, spectral acquisition and data pre-processing and analysis, with example applications.

The severity of obstructive sleep apnea (OSA) is classified using apnea-hypopnea index (AHI). Accurate determination of AHI currently requires manual analysis and complicated registration setup making it expensive and labor intensive. Partially for these reasons, OSA is a heavily underdiagnosed disease as only 7% of women and 18% of men suffering from OSA have diagnosis. To resolve these issues, we introduce an artificial neural network (ANN) that estimates AHI and oxygen desaturation index (ODI) using only the blood oxygen saturation signal (SpO2), recorded during ambulatory polygraphy, as an input. Therefore, hypopneas associated only with an arousal were not considered in this study. SpO2 signals from 1692 patients were used for training and 99 for validation. Two test sets were used consisting of 198 and 1959 patients. In the primary test set, the median absolute errors of ANN estimated AHI and ODI were 0.78 events/hour and 0.68 events/hour respectively. Based on the ANN estimated AHI and ODI, 90.9% and 94.4% of the test patients were classified into the correct OSA severity category. In conclusion, AHI and ODI can be reliably determined using neural network analysis of SpO2 signal. The developed method may enable a more affordable screening of OSA.

Introduction Visual assessment and imaging of the donor liver are inaccurate in predicting fibrosis and remain surrogates for histopathology. We demonstrate that 3‐s scans using a handheld near‐infrared‐spectroscopy (NIRS) instrument can identify and quantify fibrosis in fresh human liver samples. Methods We undertook NIRS scans on 107 samples from 27 patients, 88 from 23 patients with liver disease, and 19 from four organ donors. Results Liver disease patients had a median immature fibrosis of 40% (interquartile range [IQR] 20–60) and mature fibrosis of 30% (10%–50%) on histopathology. The organ donor livers had a median fibrosis (both mature and immature) of 10% (IQR 5%–15%). Using machine learning, this study detected presence of cirrhosis and METAVIR grade of fibrosis with a classification accuracy of 96.3% and 97.2%, precision of 96.3% and 97.0%, recall of 96.3% and 97.2%, specificity of 95.4% and 98.0% and area under receiver operator curve of 0.977 and 0.999, respectively. Using partial‐least square regression machine learning, this study predicted the percentage of both immature (R2 = 0.842) and mature (R2 = 0.837) with a low margin of error (root mean square of error of 9.76% and 7.96%, respectively). Conclusion This study demonstrates that a point‐of‐care NIRS instrument can accurately detect, quantify and classify liver fibrosis using machine learning.

We demonstrate in this study the potential of near infrared (NIR) spectroscopy as a tool for monitoring progression of cartilage degeneration in an animal model. Osteoarthritic degeneration was artificially induced in one joint in laboratory rats, and the animals were sacrificed at four time points: 1, 2, 4, and 6 weeks (3 animals/week). NIR spectra were acquired from both (injured and intact) knees. Subsequently, the joint samples were subjected to histological evaluation and glycosaminoglycan (GAG) content analysis, to assess disease severity based on the Mankin scoring system and to determine proteoglycan loss, respectively. Multivariate spectral techniques were then employed for classification (principal component analysis and support vector machines) and prediction (partial least squares regression) of the samples’ Mankin scores and GAG content from their NIR spectra. Our results demonstrate that NIR spectroscopy is sensitive to degenerative changes in articular cartilage, and is capable of distinguishing between mild (weeks 1 Mankin <=2) and advanced (weeks 4 Mankin =>3) cartilage degeneration. In addition, the spectral data contains information that enables estimation of the tissue’s Mankin score (error = 12.6%, R 2  = 86.2%) and GAG content (error = 7.6%, R 2  = 95%). We conclude that NIR spectroscopy is a viable tool for assessing cartilage degeneration post-injury, such as, post-traumatic osteoarthritis.

Articular cartilage exhibits a zonal architecture, comprising three distinct zones: superficial, middle, and deep. Collagen fibers, being the main solid constituent of articular cartilage, exhibit unique angular and size distribution in articular cartilage zones. There is a gap in knowledge on how the unique properties of collagen fibers across articular cartilage zones affect the scattering properties of the tissue. This study hypothesizes that the structural properties of articular cartilage zones affect its scattering parameters. We provide scattering coefficient and scattering anisotropy factor of articular cartilage zones in the spectral band of 400 to 1400 nm. We enumerate the differences and similarities of the scattering properties of articular cartilage zones and provide reasoning for these observations. We utilized collimated transmittance and integrating sphere measurements to estimate the scattering coefficients of bovine articular cartilage zones and bulk tissue. We used the relationship between the scattering coefficients to estimate the scattering anisotropy factor. Polarized light microscopy was applied to estimate the depth-wise angular distribution of collagen fibers in bovine articular cartilage. We report that the Rayleigh scatterers contribution to the scattering coefficients, the intensity of the light scattered by the Rayleigh and Mie scatterers, and the angular distribution of collagen fibers across tissue depth are the key parameters that affect the scattering properties of articular cartilage zones and bulk tissue. Our results indicate that in the short visible region, the superficial and middle zones of articular cartilage affect the scattering properties of the tissue, whereas in the far visible and near-infrared regions, the articular cartilage deep zone determines articular cartilage scattering properties. This study provides scattering properties of articular cartilage zones. Such findings support future research to utilize optical simulation to estimate the penetration depth, depth-origin, and pathlength of light in articular cartilage for optical diagnosis of the tissue.