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While osteoporosis is reliably diagnosed using dual energy X-ray absorptiometry (DXA), screening rates are alarmingly low, contributing to preventable fractures. Raman spectroscopy (RS) can detect biochemical changes that occur in bones transcutaneously and can arguably be more accessible than DXA as a fracture risk assessment. A reasonable approach to translate RS is to interrogate phalangeal bones of human hands, where the soft tissues covering the bone are less likely to hamper transcutaneous measurements. To that end, we set out to first determine whether Raman spectra obtained from phalangeal bones correlate with distal radius fracture strength, which can predict subsequent osteoporotic fractures at the spine and hip. We performed RS upon diaphyseal and epiphyseal regions of exposed proximal phalanges from 12 cadaver forearms classified as healthy (n = 3), osteopenic (n = 4), or osteoporotic (n = 5) based on wrist T-scores measured by DXA. We observed a significant decrease in phosphate to matrix ratio and a significant increase in carbonate substitution in the osteoporotic phalanges relative to healthy and osteopenic phalanges. Multivariate regression models produced wrist T-score estimates with significant correlation to the DXA-measured values (r = 0.79). Furthermore, by accounting for phalangeal RS parameters, body mass index, and age, a multivariate regression significantly predicted distal radius strength measured in a simulated-fall biomechanical test (r = 0.81). These findings demonstrate the feasibility of interrogating the phalanges using RS for bone quality assessment of distant clinical sites of fragility fractures, such as the wrist. Future work will address transcutaneous measurement challenges as another requirement for scale-up and translation.

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The mitochondrial permeability transition pore (MPTP) and its positive regulator, cyclophilin D (CypD), play important pathophysiological roles in aging. In bone tissue, higher CypD expression and pore activity are found in aging; however, a causal relationship between CypD/MPTP and bone degeneration needs to be established. We previously reported that CypD expression and MPTP activity are downregulated during osteoblast (OB) differentiation and that manipulations in CypD expression affect OB differentiation and function. Using a newly developed OB-specific CypD/MPTP gain-of-function (GOF) mouse model, we here present evidence that overexpression of a constitutively active K166Q mutant of CypD (caCypD) impairs OB energy metabolism and function, and bone morphological and biomechanical parameters. Specifically, in a spatial-dependent and sex-dependent manner, OB-specific CypD GOF led to a decrease in oxidative phosphorylation (OxPhos) levels, higher oxidative stress, and general metabolic adaptations coincident with the decreased bone organic matrix content in long bones. Interestingly, accelerated bone degeneration was present in vertebral bones regardless of sex. Overall, our work confirms CypD/MPTP overactivation as an important pathophysiological mechanism leading to bone degeneration and fragility in aging. © 2023 American Society for Bone and Mineral Research (ASBMR).

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Back-illuminated charged-coupled device (BI-CCD) arrays increase quantum efficiency but also amplify etaloning, a multiplicative, wavelength-dependent fixed-pattern effect. When spectral data from hundreds of BI-CCD rows are combined, the averaged spectrum will generally appear etalon-free. This can mask substantial etaloning at the row level, even if the BI-CCD has been treated to suppress the effect. This paper compares two methods of etalon correction, one with simple averaging and one with row-by-row calibration using a fluorescence standard. Two BI-CCD arrays, both roughened by the supplier to reduce etaloning, were used to acquire Raman spectra of murine bone specimens. For one array, etaloning was the dominant source of noise under the exposure conditions chosen, even for the averaged spectrum across all rows; near-infrared-excited Raman peaks were noticeably affected. In this case, row-by-row calibration improved the spectral quality of the average spectrum. The other CCD's performance was shot-noise limited and therefore received no benefit from the extra calibration. The different results highlight the importance of checking for and correcting row-level fixed pattern when measuring weak Raman signals in the presence of a large fluorescence background.

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Bone fragility and fracture risk are assessed by measuring the areal bone mineral density (aBMD) using dual-energy X-ray absorptiometry (DXA). While aBMD correlates with bone strength, it is a poor predictor of fragility fracture risk. Alternatively, fracture toughness assesses the bone's resistance to crack propagation and fracture, making it a suitable bone quality metric. Here, we explored how femoral midshaft measurements from DXA, micro-computed tomography (µCT), and Raman spectroscopy could predict fracture toughness. We hypothesized that ovariectomy (OVX) decreases aBMD and fracture toughness compared to controls and we can optimize a multivariate assessment of bone quality by combining results from X-ray and Raman spectroscopy. Female mice underwent an OVX (n = 5) or sham (n = 5) surgery at 3 months of age. Femurs were excised 3 months after ovariectomy and assessed with Raman spectroscopy, µCT, and DXA. Subsequently, a notch was created on the anterior side of the mid-diaphysis of the femurs. Three-point bending induced a controlled fracture that initiated at the notch. The OVX mice had a significantly lower aBMD, cortical thickness, and fracture toughness when compared to controls (p < 0.05). A leave one out cross-validated (LOOCV) partial least squares regression (PLSR) model based only on the combination of aBMD and cortical thickness showed no significant predictive correlations with fracture toughness, whereas a PLSR model based on principal components derived from the full Raman spectra yielded significant prediction (r2 = 0.71, p < 0.05). Further, the PLSR model was improved by incorporating aBMD, cortical thickness, and principal components from Raman spectra (r2 = 0.92, p < 0.001). This exploratory study demonstrates combining X-ray with Raman spectroscopy leads to a more accurate assessment of bone fracture toughness and could be a useful diagnostic tool for the assessment of fragility fracture risk.

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Spatially offset Raman spectroscopy (SORS) is able to detect bone signal transcutaneously and could assist in predicting bone fracture risk. Criteria for optimal source-detector offsets for transcutaneous human measurements, however, are not well-established. Although larger offsets yield a higher percentage of bone signal, the absolute amount of bone signal decreases. Spectral unmixing into bone, adipose, and non-adipose components was employed to quantify changes in bone signal to noise ratio across a range of offsets, and optimal offsets for phalanx and metacarpal measurements were determined. The bone signal to noise ratio was maximized at offsets ranging from 4-6 mm.

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Transcutaneous determination of a bone's Raman spectrum is challenging because the type I collagen in the overlying soft tissue is spectroscopically identical to that in bone. In a previous transcutaneous study of murine tibiae, we developed a library-based model called SOLD to unmix spatially offset Raman measurements into three spectra: a bone estimate, a soft tissue estimate, and a residual. Here, we demonstrate the value of combining the bone estimate and the residual to produce a "top layer subtracted" (tls) spectrum. We report superior prediction of two standard bone metrics (volumetric bone mineralization density and maximum torque) using partial least squares regression models based upon tls spectra rather than SOLD bone estimates, implying that the spectral residuals contain useful information. Simulations reinforce experimental in vivo findings. This chemometric approach, which we denote as SOLD/TLS, could have broad applicability in situations where comprehensive spectral libraries are difficult to acquire.

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Infrared spectroscopic tissue imaging is a potentially powerful adjunct tool to current histopathology techniques. By coupling the biochemical signature obtained through infrared spectroscopy to the spatial information offered by microscopy, this technique can selectively analyze the chemical composition of different features of unlabeled, unstained tissue sections. In the past, the tissue features that have received the most interest were parenchymal and epithelial cells, chiefly due to their involvement in dysplasia and progression to carcinoma; however, the field has recently turned its focus toward stroma and areas of fibrotic change. These components of tissue present an untapped source of biochemical information that can shed light on many diverse disease processes, and potentially hold useful predictive markers for these same pathologies. Here we review the recent applications of infrared spectroscopic imaging to stromal and fibrotic regions of diseased tissue, and explore the potential of this technique to advance current capabilities for tissue analysis.

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Improvements in human-machine interaction may help overcome the unstable and uncertain environments that cause problems in everyday living. Here we experimentally evaluated intent feedback (IF), which estimates and displays the human operator's underlying intended trajectory in real-time. IF is a filter that combines a model of the arm with position and force data to determine the intended position. Subjects performed targeted reaching motions while seeing either their actual hand position or their estimated intent as a cursor while they experienced white noise forces rendered by a robotic handle. We found significantly better reaching performance during force exposure using the estimated intent. Additionally, in a second set of subjects with a reduced modeled stiffness, IF reduced estimated arm stiffness to about half that without IF, indicating a more relaxed state of operation. While visual distortions typically degrade performance and require an adaptation period to overcome, this particular distortion immediately enhanced performance. In the future, this method could provide novel insights into the nature of control. IF might also be applied in driving and piloting applications to best follow a person's desire in unpredictable or turbulent conditions.