Denervation results in reduced bone quality, largely attributed to reduced loading due to concurrent muscle atrophy. However, sensory and sympathetic nerves also directly innervate bone, suggesting additional potential inputs into bone remodeling. A quantitative baseline of bone morphological and functional changes after nerve injury is lacking. We investigated structural, biomechanical, and histological outcomes for time points up to three months following peripheral nerve injury. Our primary objective was to establish timelines over which bone and muscle structure and biomechanical function degraded after denervation. Additionally, we evaluated remodeling of bone innervation and vascularity and alterations in bone homeostatic markers after injury. Using a Lewis rat nerve injury model (n = 60 total rats), our findings showed rapid bone deterioration following transection of sciatic nerves of both male and female rats. Biomechanical properties of bone, including three-point bending yield force (P < 0.001), ultimate force (P < 0.001), and stiffness (P < 0.001), were significantly reduced as early as two weeks post-injury. At a slight delay compared to biomechanical changes, micro-CT and MRI revealed that bone mineral density (P < 0.0001) and cortical thickness (P < 0.001) also declined and porosity increased (P < 0.05) within three months. Immunohistochemical analysis revealed marked decreases in sensory (calcitonin gene-related protein; CGRP) and sympathetic (Neuropeptide-Y; NPY) neuropeptides, reduced osteoblast density in periosteal regions, and increased vascular (CD-31) area fraction, accompanied by increased vascular fragmentation. These findings support the possibility that both muscle and neuronal influences underlie denervation-related bone atrophy, setting the stage for evaluation of bone health after nerve repair and targeted rehabilitative or therapeutic interventions.

BACKGROUND:Advances in peripheral nerve surgery remain suboptimal, underscoring the need for novel therapies typically tested in small-animal models, where functional assessment, a critical translational endpoint, is inherently limited. Non-human primates (NHPs) bridge this gap but lack standardized quantitative functional assessments. Here, we aimed to design and validate a standardized, reproducible, and quantitative reaching-task system for measuring maximum active wrist extension in NHPs, and to demonstrate its applicability for the longitudinal assessment of motor recovery following radial nerve repair. New method A custom-built reaching-task system was developed to isolate wrist extension in NHPs while minimizing upper-limb compensation. A standardized dual-camera configuration enabled frame-by-frame kinematic analysis via motion-tracking software. Reliability was tested in two healthy NHPs across three repeated sessions, and a proof-of-concept experiment assessed recovery in an NHP following nerve repair. RESULTS:Maximum wrist extension angles showed high inter- and intra-subject reliability (ICC > 0.90), with a significant relationship between target height and extension angle (β = 3.92°, R² = 0.77). In the nerve repair model, maximum wrist extension improved from 20.1 ± 7.7° at 103 days post-repair to 39.5 ± 6.9° at 180 days (p < 0.001), consistent with electrophysiological evidence of reinnervation; kinematic profiles revealed gradual restoration of function. Comparison with existing methods This system standardizes limb positioning and target placement, enabling synchronized kinematics for consistent extraction of wrist angles. CONCLUSIONS:This reaching-task system provides a standardized, quantitative assessment of wrist extension after radial nerve repair, supporting its translational relevance as a platform for preclinical therapeutic evaluation.

When nerves are severed, such as during traumatic injury, an acute injury state is induced, characterized by biological and physical changes in the proximal and distal stumps. Beyond the initial injury phase, over a time frame of weeks to months, nerves that remain unrepaired progressively enter a chronic injury state, characterized by a change in the extracellular matrix structure of the distal stump, the down-regulation of neurotrophic factors and the loss of macrophages’ and Schwann cells’ ability to clear out degraded axons and myelin. There are also potential systemic impacts away from the site of injury, including in end organs such as muscle and bone. The literature suggests that several of these processes may be strongly influenced by innate and adaptive immune system responses, including a major role for complement pathways. This review details evidence in favor of such a possibility, as well as knowledge gaps and areas for future investigation.

Micro-computed tomography (micro-CT) is a commonly used tool for bone evaluation in animal model research. Micro-scale finite element analysis (µFEA) has been proposed to account for different loading scenarios, detailed three-dimensional (3D) bone structure, material properties, and distribution obtained from micro-CT to estimate bone mechanical properties and to predict its potential fracture. The in vivo application of µFEA has been limited to animal models due to the smaller bore size of micro-CT and the long scan time. This narrative review article describes studies that used micro-CT-based µFEA to predict bone mechanical competence, understand bone fracture and remodeling mechanisms, and to evaluate the impacts of the therapeutics, implants, and surgical interventions. Moreover, the concept, limitations, and future potentials of micro-CT-based FEA are discussed.

Background Evaluating peripheral nerve response after injury or repair remains a critical clinical challenge. Current medical imaging approaches provide limited insight into the degenerative or regenerative environment of affected nerves. Purpose To assess the efficacy of ultrashort echo time (UTE) quantitative MRI (qMRI) for evaluating peripheral nerve degeneration and regeneration in rat models of sciatic nerve injury and to assess correlations between UTE qMRI parameters and histologic findings. Materials and Methods In this animal study conducted from November 2022 to December 2023, four experimental groups were created in 6-8-week-old male Lewis rats: (a) sham injury (n = 16), where the sciatic nerve was exposed bilaterally at midthigh level but not transected; (b) injury/early autograft repair (n = 15), where a 10-mm nerve segment was excised, flipped, and resutured into the nerve gap; (c) injury/delayed isograft repair (n = 13), where nerves were transected, capped to prevent spontaneous regeneration, and repaired with a 10-mm isograft 2 months after injury; and (d) no repair, where nerves were capped after excising a 5-mm segment (n = 15). Rats underwent UTE qMRI with a 3-T scanner 1-3 months after surgery or repair. UTE magnetization transfer ratio (MTR), UTE T2*, and UTE T1 were compared using analysis of variance. Correlation analysis evaluated relationships between UTE qMRI-derived parameters and immunohistochemical outcomes. Results UTE MTR (P < .001), UTE T2* (P < .001), and UTE T1 (P < .001) showed lower values in early and delayed repair groups versus the sham group. UTE MTR showed excellent performance in distinguishing the sham group from early and delayed repair groups (mean area under the receiver operating characteristic curve, 0.93 ± 0.03). Histologic analysis demonstrated a moderate positive correlation between myelin area fraction and UTE MTR (r = 0.46; P = .007) and a weak negative correlation between collagen area fraction and UTE MTR (r = -0.38; P = .04). Conclusion UTE MRI-derived MTR effectively distinguished among rat models of peripheral nerve injury and repair and correlated with histologic findings. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Tan and Argentieri in this issue.

Increased bone fragility despite preserved or elevated BMD in type 2 diabetes mellitus (T2DM) is linked to nonenzymatic collagen crosslinking via advanced glycation end-products (AGEs). However, there is no noninvasive method clinically available to probe these collagen alterations in the bone. We examined the potential of ultrashort echo time quantitative magnetization transfer (UTE-qMT) MRI for detecting AGE-induced collagen crosslinking in bones. Rat tibial bones were subject to ribosylation ex vivo to induce AGE accumulation. UTE-qMT MRI was performed to quantify the magnetization exchange rate (kba) and macromolecular fraction (MMF), which were compared to mechanical properties from 3-point bending tests and AGE concentrations from fluorometric assays. Ribosylation significantly increased AGE crosslinking, confirmed by a 3-fold rise in AGE fluorescence intensity. UTE-qMT MRI revealed a significantly higher kba and MMF in ribosylated bones, whereas BMD did not show significant differences. A 3-point bending test showed that ribosylation reduced post-yield displacement, fracture displacement, and work-to-fracture from load–displacement curves, indicating reduced bone ductility and toughness. Importantly, kba and MMF correlated significantly with these mechanical properties, whereas BMD showed no significant correlations. These findings demonstrate that UTE-qMT MRI is a novel noninvasive tool sensitive to AGE-mediated collagen crosslinking and its critical role in predicting bone fragility.

Objective: To compare the effectiveness of positive pressure (PP) and negative pressure (NP) for reducing gas inclusions in biological tissues in preparation for acoustic imaging. Methods: Eighteen pieces of porcine liver in degassed saline were included in this study. For the PP group (n = 9 samples), a wristwatch waterproof tester was used to pressurize samples to 0.41 MPa (59 psi) for 10 min. For the NP group (n = 9 samples), a desiccator at -0.08 MPa (-12 psi) was used for 30 min. Backscatter coefficients (BSCs) were calculated over the central frequency range of the backscattered spectra and paired-samples t-tests were performed. Results: Utilization of PP resulted in a decrease in BSC for all samples, indicating less gas post-PP (pre-PP -13.0 +/- 4.3 dB [mean +/- SD], post-PP -18.9 +/- 5.0 dB, p = .001). Utilization of NP resulted in an increase in BSC for the majority of samples (pre-NP -14.6 +/- 6.0 dB, post-NP -13.1 +/- 5.3 dB, p = .177). Conclusion: Utilization of a simple PP chamber consistently resulted in a decrease in tissue gas, at lower pressures than previously reported. The vacuum method is ineffective, may result in a paradoxical increase in tissue gas, and may not be recommended for tissue degassing.

To prospectively evaluate ultrasound backscatter coefficients (BSCs) of the supraspinatus and infraspinatus muscles and compare with Goutallier classification on magnetic resonance imaging (MRI). Fifty-six participants had shoulder MRI exams and ultrasound exams of the supraspinatus and infraspinatus muscles. Goutallier MRI grades were determined and BSCs were measured. Group means were compared and the strength of relationships between the measures were determined. Using binarized Goutallier groups (0–2 versus 3–4), areas under the receiver operating characteristic curves (AUROCs) were calculated. The nearest integer cutoff value was determined using Youden’s index. BSC values were significantly different among most Goutallier grades for the supraspinatus and infraspinatus muscles (both p < 0.001). Strong correlations were found between the BSC values and Goutallier grades for the supraspinatus (τb = 0.72, p < 0.001) and infraspinatus (τb = 0.79, p < 0.001) muscles. BSC showed excellent performance for classification of the binarized groups (0–2 versus 3–4) for both supraspinatus (AUROC = 0.98, p < 0.0001) and infraspinatus (AUROC = 0.98, p < 0.0001) muscles. Using a cutoff BSC value of −17 dB, sensitivity, specificity, and accuracy for severe fatty infiltration were 87.0

Abstract Traumatic Brain Injury (TBI) is a serious injury that affects millions of people worldwide and has significant effects on neural pathways in the brain, making it a risk factor for neurodegenerative diseases. Most research that examines the link between TBI and neurodegeneration uses rodent models, however they do not fully recapitulate disease pathology and cannot capture human specific features including the effect of genetic variations. Human induced pluripotent stem cells (hiPSC)-derived cortical organoids have become the gold standard to model neurological disorders. They recapitulate certain aspects of physiological and neural pathways of the human brain and are easily reproducible, making them a better model. To understand the effects of TBI-induced neurodegeneration and explore potential treatment therapies, we model TBI in cortical hiPSC organoids through inducing mechanical injury. We assess AD-related morphological, biochemical, and functional downstream effects with a battery of assays. Among them, we measure the impact on neuronal activity using fluorescent Ca2+ indicators to measure Ca flux at a single-cell level post injury. Together, these assays will help us establish a human-based system to model in vitro TBI-induced neurodegeneration. We hope it can help contribute to evaluate specific therapies and diagnostic tools to stop progression of neurodegeneration after mechanical injury.

High-resolution magnetic resonance imaging (HR-MRI) has been increasingly used to assess the trabecular bone structure. High susceptibility at the marrow/bone interface may significantly reduce the marrow's apparent transverse relaxation time (T2*), overestimating trabecular bone thickness. Ultrashort echo time MRI (UTE-MRI) can minimize the signal loss caused by susceptibility-induced T2* shortening. However, UTE-MRI is sensitive to chemical shift artifacts, which manifest as spatial blurring and ringing artifacts partially due to non-Cartesian sampling. In this study, we proposed UTE-MRI at the resonance frequency of fat to minimize marrow-related chemical shift artifacts and the overestimation of trabecular thickness. Cubes of trabecular bone from six donors (75 ± 4 years old) were scanned using a 3 T clinical scanner at the resonance frequencies of fat and water, respectively, using 3D UTE sequences with five TEs (0.032, 1.1, 2.2, 3.3, and 4.4 ms) and a clinical 3D gradient echo (GRE) sequence at 0.2 × 0.2 × 0.4 mm3 voxel size. Trabecular bone thickness was measured in 30 regions of interest (ROIs) per sample. MRI results were compared with thicknesses obtained from micro-computed tomography (μCT) at 50 μm3 voxel size. Linear regression models were used to calculate the coefficient of determination between MRI- and μCT-based trabecular thickness. All MRI-based trabecular thicknesses showed significant correlations with μCT measurements. The correlations were higher (examined with paired Student's t-test, P < 0.01) for 3D UTE images performed at the fat frequency (R2 = 0.59-0.74, P < 0.01) than those at the water frequency (R2 = 0.18-0.52, P < 0.01) and clinical GRE images (R2 = 0.39-0.47, P < 0.01). Significantly reduced correlations were observed with longer TEs. This study highlighted the feasibility of UTE-MRI at the fat frequency for a more accurate assessment of trabecular bone thickness.

This study evaluated the repeatability and reproducibility of using high-frequency quantitative ultrasound (QUS) measurement of backscatter coefficient (BSC), grayscale analysis, and gray-level co-occurrence matrix (GLCM) textural analysis, to characterize human rotator cuff muscles. The effects of varying scanner settings across two different operators and two US systems were investigated in a healthy volunteer with normal rotator cuff muscles and a patient with chronic massive rotator cuff injury and substantial muscle degeneration. The results suggest that BSC is a promising method for assessing rotator cuff muscles in both control and pathological subjects, even when operators were free to adjust system settings (depth, level of focus, and time-gain compensation). Measurements were repeatable and reproducible across the different operators and ultrasound imaging platforms. In contrast, grayscale and GLCM analyses were found to be less reliable in this setting, with significant measurement variability. Overall, the repeatability and reproducibility measurements of BSC indicate its potential as a diagnostic tool for rotator cuff muscle evaluation.

OBJECTIVE:Peripheral nerves remain a challenging target for medical imaging, given their size, anatomical complexity, and structural heterogeneity. Quantitative ultrasound (QUS) applies a set of techniques to estimate tissue acoustic parameters independent of the imaging platform. Many useful medical and laboratory applications for QUS have been reported, but challenges remain for deployment in vivo, especially for heterogeneous tissues. Several phenomena introduce variability in attenuation estimates, which may influence the estimation of other QUS parameters. For example, estimating the backscatter coefficient (BSC) requires compensation for the attenuation of overlying tissues between the transducer and the underlying tissue of interest. The purpose of this study is to extend prior studies by investigating the efficacy of several analytical methods of estimating attenuation compensation on QUS outcomes in the human median nerve. METHODS:Median nerves were imaged at the volar wrist in vivo and beam-formed radiofrequency (RF) data were acquired. Six analytical approaches for attenuation compensation were compared: 1-2) attenuation estimated by applying spectral difference method (SDM) and spectral log difference method (SLDM) independently to regions of interest (ROIs) overlying the nerve and to the nerve ROI itself; 3-4) attenuation estimation by applying SDM and SLDM to ROIs overlying the nerve, and transferring these properties to the nerve ROI; and 5-6) methods that apply previously published values of tissue attenuation to the measured thickness of each overlying tissue. Mean between-subject estimates of BSC-related outcomes as well as within-subject variability of these outcomes were compared among the 6 methods. RESULTS:Compensating for attenuation using SLDM and values from the literature reduced variability in BSC-based outcomes, compared to SDM. Variability in attenuation coefficients contributes substantially to variability in backscatter measurements. CONCLUSION:This work has implications for the application of QUS to in vivo diagnostic assessments in peripheral nerves and possibly other heterogeneous tissues.

Background We investigated the relationship of two commonly used quantitative ultrasound (QUS) parameters, speed of sound (SoS) and attenuation coefficient ( α ), with water and macromolecular contents of bovine cortical bone strips as measured with ultrashort echo time (UTE) magnetic resonance imaging (MRI). Methods SoS and α were measured in 36 bovine cortical bone strips utilizing a single-element transducer with nominal 5 MHz center frequency based on the time of flight principles after accommodating for reflection losses. Specimens were then scanned using UTE MRI to measure total, bound, and pore water proton density (TWPD, BWPD, and PWPD) as well as macromolecular proton fraction and macromolecular transverse relaxation time (T2-MM). Specimens were also scanned using microcomputed tomography (μCT) at 9-μm isometric voxel size to measure bone mineral density (BMD), porosity, and pore size. The elastic modulus (E) of each specimen was measured using a 4-point bending test. Results α demonstrated significant positive Spearman correlations with E ( R = 0.69) and BMD ( R = 0.44) while showing significant negative correlations with porosity ( R = -0.41), T2-MM ( R = -0.47), TWPD ( R = -0.68), BWPD ( R = -0.67), and PWPD ( R = -0.45). Conclusions The negative correlation between α and T2-MM is likely indicating the relationship between QUS and collagen matrix organization. The higher correlations of α with BWPD than with PWPD may indicate that water organized in finer structure (bound to matrix) provides lower acoustic impedance than water in larger pores, which is yet to be investigated thoroughly. Relevance statement This study highlights the importance of future investigations exploring the relationship between QUS measures and all major components of the bone, including the collagenous matrix and water. Investigating the full potential of QUS and its validation facilitates a more affordable and accessible tool for bone health monitoring in clinics. Key points • Ultrasound attenuation demonstrated significant positive correlations with bone mechanics and mineral density. • Ultrasound attenuation demonstrated significant negative correlations with porosity and bone water contents. • This study highlights the importance of future investigations exploring the relationship between QUS measures and all major components of the bone. Graphical Abstract

Ultrasound (US) is an increasingly prevalent and effective diagnostic modality for neuromuscular imaging. Gray-scale B-mode imaging has been the dominant US approach to evaluating nerves qualitatively or making morphometric measurements of nerves, providing important insights into pathological changes for conditions such as carpal tunnel syndrome. Among more recent ultrasound strategies, high-frequency ultrasound (often defined as >15 MHz for clinical applications), quantitative ultrasound and image textural analysis offer promising enhancements for improved and more objective approaches to nerve imaging. In this study, we evaluated the repeatability and reproducibility of backscatter coefficient (BSC) and imaging texture features extracted by gray-level co-occurrence matrices (GLCMs) in homogeneous tissue-mimicking reference phantoms and in median nerves in the wrists of healthy participants. We also investigated several practical sources of variability in the assessment of quantitative parameters, including influences of operators, and participant-to-participant variability. Overall, BSC- and GLCM-based outcomes are highly repeatable and reproducible after operator training, based on measurement of descriptive statistics, repeatability coefficient (RC) and reproducibility coefficient recommended by Quantitative Imaging Biomarker Alliance (QIBA RDC). GLCM parameters appear more reproducible and repeatable than BSC-based parameters in healthy participants in vivo. However, such variability noted here must be compared with the value ranges and variability of the results in pathological nerves, including median nerves afflicted by trauma, overuse syndromes such as carpal tunnel syndrome and after surgical repair.

Aim: This review article describes quantitative ultrasound (QUS) techniques and summarizes their strengths and limitations when applied to peripheral nerves. Methods: A systematic review was conducted on publications after 1990 in Google Scholar, Scopus, and PubMed databases. The search terms "peripheral nerve", "quantitative ultrasound", and "elastography ultrasound" were used to identify studies related to this investigation. Results: Based on this literature review, QUS investigations performed on peripheral nerves can be categorized into three main groups: (1) B-mode echogenicity measurements, which are affected by a variety of post-processing algorithms applied during image formation and in subsequent B-mode images; (2) ultrasound (US) elastography, which examines tissue stiffness or elasticity through modalities such as strain ultrasonography or shear wave elastography (SWE). With strain ultrasonography, induced tissue strain, caused by internal or external compression stimuli that distort the tissue, is measured by tracking detectable speckles in the B-mode images. In SWE, the propagation speed of shear waves, generated by externally applied mechanical vibrations or internal US "push pulse" stimuli, is measured to estimate tissue elasticity; (3) the characterization of raw backscattered ultrasound radiofrequency (RF) signals, which provide fundamental ultrasonic tissue parameters, such as the acoustic attenuation and backscattered coefficients, that reflect tissue composition and microstructural properties. Conclusions: QUS techniques allow the objective evaluation of peripheral nerves and reduce operator- or system-associated biases that can influence qualitative B-mode imaging. The application of QUS techniques to peripheral nerves, including their strengths and limitations, were described and discussed in this review to enhance clinical translation.

Ultrasound (US) is an important imaging tool for skeletal muscle analysis. The advantages of US include point-of-care access, real-time imaging, cost-effectiveness, and absence of ionizing radiation. However, US can be highly dependent on the operator and/or US system, and a portion of the potentially useful information carried by raw sonographic data is discarded in image formation for routine qualitative US. Quantitative ultrasound (QUS) methods provide analysis of the raw or post-processed data, revealing additional information about normal tissue structure and disease status. There are four QUS categories that can be used on muscle and are important to review. First, quantitative data derived from B-mode images can help determine the macrostructural anatomy and microstructural morphology of muscle tissues. Second, US elastography can provide information about muscle elasticity or stiffness through strain elastography or shear wave elastography (SWE). Strain elastography measures the induced tissue strain caused either by internal or external compression by tracking tissue displacement with detectable speckle in B-mode images of the examined tissue. SWE measures the speed of induced shear waves traveling through the tissue to estimate the tissue elasticity. These shear waves may be produced using external mechanical vibrations or internal “push pulse” ultrasound stimuli. Third, raw radiofrequency signal analyses provide estimates of fundamental tissue parameters, such as the speed of sound, attenuation coefficient, and backscatter coefficient, which correspond to information about muscle tissue microstructure and composition. Lastly, envelope statistical analyses apply various probability distributions to estimate the number density of scatterers and quantify coherent to incoherent signals, thus providing information about microstructural properties of muscle tissue. This review will examine these QUS techniques, published results on QUS evaluation of skeletal muscles, and the strengths and limitations of QUS in skeletal muscle analysis.

Rising healthcare costs have been linked to overtreatment and overuse of available resources. Identifying and eliminating low-value services is vital for reducing such costs. At many institutions, including ours, all ileostomy and colostomy specimens are sent for pathological evaluation. It is estimated that approximately 120,000 ileostomy/colostomy procedures are done every year, and at least 1 million patients have stomas at any given time in North America. Hence, we decided to analyze the pathological findings and cost-benefit of undertaking the pathological evaluation of these colostomy and ileostomy specimens. The pathology database of our department was searched for all ileostomy and colostomy specimens received between 2000 and 2020, resulting in a total of 2762 cases (1944 ileostomy and 818 colostomy). We performed a cost-benefit analysis and pathologic review of these cases. The results of our study show that 99.38% of these specimens did not show any significant pathological abnormality, and non-neoplastic pathologic findings accounted for 99.63% of cases. Less than 1% of our cases showed any clinically significant pathological findings. All 10 cases that showed a neoplastic or malignant diagnosis showed some abnormal finding that was appreciated at the time of gross examination. We conclude that microscopic evaluation of ileostomy and colostomy specimens incurs significant costs and provides no clear value or relevant information for patient care. The results of our study provide support for ileostomy and colostomy specimens to be triaged by gross-only pathological examination in the first instance for the vast majority of cases.

Introduction: Numerous synthetic, hybrid, and biological grafts and conduits have been deployed to facilitate axonal regeneration across peripheral nerve gaps. Though some strategies have showed promise, larger gaps continue to be an unsolved clinical challenge. Recent evidence suggests that tension-based strategies offer a promising alternative approach to nerve repair. However, whether and to what degree severed peripheral nerves tolerate and accommodate tension, especially in the critical early stages of intervention, is less clear.Methods: In this study, we evaluated a number of immuno-histochemical outcomes to test the hypothesis that injured rat sciatic nerves accommodate strains of up to 20%, a deformation magnitude that exceeds oft-quoted thresholds for nerve damage. We also assessed the possibility of integrating tension with conduit-based approaches for nerve repair.Results and Discussion: There were no deficits in axonal, basal laminar, or extracellular matrix morphology with tension, though proximal and distal stumps of nerves in all experimental groups displayed abnormal morphology in proximity to the site of injury. Axons of stretched nerves successfully grew through guidance conduits into the distal stump within 6 weeks of repair, thus demonstrating the feasibility of combining tension- and conduit-based regenerative strategies.